Los Angeles, CA, United States
Los Angeles, CA, United States

The University of California, Los Angeles , is a public research university located in the Westwood neighborhood of Los Angeles, California, United States. Founded in 1919, it became the University of California Southern Branch in 1927, making it the second-oldest undergraduate campus of the ten-campus system after the original University of California campus at Berkeley . It offers 337 undergraduate and graduate degree programs in a wide range of disciplines. With an approximate enrollment of 30,000 undergraduate and 12,000 graduate students, UCLA is the university with the largest enrollment in the state of California and the most applied to university in the United States with over 112,000 applications for Fall 2015.The university is organized into five undergraduate colleges, seven professional schools, and four professional health science schools. The undergraduate colleges are the College of Letters and Science; Henry Samueli School of Engineering and Applied Science ; School of the Arts and Architecture; School of Theater, Film, and Television; and School of Nursing. Fifteen Nobel laureates, one Fields Medalist, and three Turing Award winners have been faculty, researchers, or alumni. Among the current faculty members, 52 have been elected to the National Academy of science, 28 to the National Academy of Engineering, 39 to the Institute of Medicine, and 124 to the American Academy of Arts and science. The university was elected to the Association of American Universities in 1974.UCLA student-athletes compete as the Bruins in the Pacific-12 Conference. The Bruins have won 125 national championships, including 112 NCAA team championships. UCLA student-athletes have won 250 Olympic medals: 125 gold, 65 silver and 60 bronze. The Bruins have competed in every Olympics since 1920 with one exception , and have won a gold medal in every Olympics that the United States has participated in since 1932. Wikipedia.


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Patent
University of Notre Dame and University of California at Los Angeles | Date: 2016-09-14

Systems and methods are provided for identifying markers for inflammation in a tissue image. The tissue image is captured as an image of a histology slide. Subcellular structures in the tissue image are segmented via a first automated process to identify at least one variety of immune cells within the image. Glands and vilii are identified within the tissue image via a second automated process. Neutrophils are identified within the tissue image via a third automated process. An output representing the identified glands, villi, neutrophils, and other immune cells is provided to a human operator.


Koehler C.M.,University of California at Los Angeles
Trends in Biochemical Sciences | Year: 2012

Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer that is important for a diverse range of mitochondrial activities beyond the process of ATP production. Thus not surprisingly, derangements in cardiolipin metabolism are now appreciated to contribute to an assortment of pathological conditions. A comprehensive inventory of enzymes involved in cardiolipin biosynthesis and remodeling was just recently obtained. Post-biosynthesis, the acyl chain composition of cardiolipin is modified by up to three distinct remodeling enzymes that produce either a homogeneous tissue-specific mature form of cardiolipin or alternatively 'bad' cardiolipin that has been linked to mitochondrial dysfunction. In this review, we initially focus on the newly identified players in cardiolipin metabolism and then shift our attention to how changes in cardiolipin metabolism contribute to human disease. © 2011 Elsevier Ltd.


Chow E.K.-H.,National University of Singapore | Ho D.,University of California at Los Angeles
Science Translational Medicine | Year: 2013

Nanotechnology-based chemotherapeutics and imaging agents represent a new era of "cancer nanomedicine" working to deliver versatile payloads with favorable pharmacokinetics and capitalize on molecular and cellular targeting for enhanced specificity, efficacy, and safety. Despite the versatility of many nanomedicine-based platforms, translating new drug or imaging agents to the clinic is costly and often hampered by regulatory hurdles. Therefore, translating cancer nanomedicine may largely be application-defined, where materials are adapted only toward specific indications where their properties confer unique advantages. This strategy may also realize therapies that can optimize clinical impact through combinatorial nanomedicine. In this review, we discuss how particular materials lend themselves to specific applications, the progress to date in clinical translation of nanomedicine, and promising approaches that may catalyze clinical acceptance of nano.


Krenske E.H.,University of Melbourne | Houk K.N.,University of California at Los Angeles
Accounts of Chemical Research | Year: 2013

This Account describes how attractive interactions of aromatic rings with other groups can influence and control the stereoselectivity of many reactions. Recent developments in theory have improved the accuracy in the modeling of aromatic interactions. Quantum mechanical modeling can now provide insights into the roles of these interactions at a level of detail not previously accessible, both for ground-state species and for transition states of chemical reactions. In this Account, we show how transition-state modeling led to the discovery of the influence of aryl groups on the stereoselectivities of several types of organic reactions, including asymmetric dihydroxylations, transfer hydrogenations, hetero-Diels-Alder reactions, acyl transfers, and Claisen rearrangements.Our recent studies have also led to a novel mechanistic picture for two classes of (4 + 3) cycloadditions, both of which involve reactions of furans with oxyallyl intermediates. The first class of cycloadditions, developed by Hsung, features neutral oxyallyl intermediates that contain a chiral oxazolidinone auxiliary. Originally, it was thought that these cycloadditions relied on differential steric crowding of the two faces of a planar intermediate. Computations reveal a different picture and show that cycloaddition with furan takes place preferentially through the more crowded transition state: the furan adds on the same side as the Ph substituent of the oxazolidinone. The crowded transition state is stabilized by a CH-π interaction between furan and Ph worth approximately 2 kcal/mol.Attractive interactions with aromatic rings also control the stereoselectivity in a second class of (4+3) cycloadditions involving chiral alkoxy siloxyallyl cations. Alkoxy groups derived from chiral α-methylbenzyl alcohols favor crowded transition states, where a stabilizing CH-π interaction is present between the furan and the Ar group. The cationic cycloadditions are stepwise, while the Hsung cycloadditions are concerted. Our results suggest that this form of CH- π-directed stereocontrol is quite general and likely controls the stereoselectivities of other addition reactions in which one face of a planar intermediate bears a pendant aromatic substituent. © 2012 American Chemical Society.


Ganz T.,University of California at Los Angeles
Nature Reviews Immunology | Year: 2015

Iron is an essential trace element for multicellular organisms and nearly all microorganisms. Although iron is abundant in the environment, common forms of iron are minimally soluble and therefore poorly accessible to biological organisms. Microorganisms entering a mammalian host face multiple mechanisms that further restrict their ability to obtain iron and thereby limit their pathogenicity. Iron levels also modulate host defence, as iron content in macrophages regulates their cytokine production. Here, we review recent advances that highlight the role of systemic and cellular iron-regulating mechanisms in protecting hosts from infection, emphasizing aspects that are applicable to human health and disease. © 2015 Macmillan Publishers Limited. All rights reserved.


Plath K.,University of California at Los Angeles | Lowry W.E.,University of California at Los Angeles
Nature Reviews Genetics | Year: 2011

Induction of pluripotency by transcription factors has become a commonplace method to produce pluripotent stem cells. Great strides have been made in our understanding of the mechanism by which this occurs - particularly in terms of transcriptional and chromatin-based events - yet only a small part of the complete picture has been revealed. Understanding the mechanism of reprogramming to pluripotency will have important implications for improving the efficiency and quality of reprogramming and advancing therapeutic application of induced pluripotent stem cells. It will also help to reveal the machinery that stabilizes cell identity and to instruct the design of directed differentiation or lineage switching strategies. To inform the next phase in understanding reprogramming, we review the latest findings, highlight ongoing debates and outline future challenges. © 2011 Macmillan Publishers Limited. All rights reserved.


Patent
National University of Singapore and University of California at Los Angeles | Date: 2015-02-24

A reagent comprising a nanodiamond particle linked to a paramagnetic ion for use as a contrast agent in magnetic resonance (MR) imaging in which T2-weighted magnetic images are obtained, and in particular in which both T1- and T2-weighted magnetic images are obtained, are described and claimed. Also claimed are novel reagents of this type, methods for their preparation and their use in diagnostics.


Patent
Finelite INC., University of California at Los Angeles and The Regents Of The University Of California | Date: 2014-04-30

A modular lighting system for lighting a work area is disclosed. The system includes a power supply with power outlets for powering LED fixtures. The power supply preferably operates at or below a fixed power output level, such as to illuminate the work area using less than 0.2 Watts per square foot of energy. The lighting system also includes an occupancy sensor and/or a light level sensor for controlling lighting levels in the work area in response to detection of a person, ambient light levels and/or a combination thereof. The lighting system can also include computer unit with a micro-processor and a memory unit for running software or firmware the executes lighting programs, stores light usage histories and/or provides system reports to a remote computer by a wireless means and/or over a computer network.


Smale S.T.,University of California at Los Angeles | Tarakhovsky A.,Rockefeller University | Natoli G.,Italian National Cancer Institute
Annual Review of Immunology | Year: 2014

A fundamental property of cells of the innate immune system is their ability to elicit a transcriptional response to a microbial stimulus or danger signal with a high degree of cell type and stimulus specificity. The selective response activates effector pathways to control the insult and plays a central role in regulating adaptive immunity through the differential regulation of cytokine genes. Selectivity is dictated by signaling pathways and their transcription factor targets. However, a growing body of evidence supports models in which different subsets of genes exhibit distinct chromatin features that play active roles in shaping the response. Chromatin also participates in innate memory mechanisms that can promote tolerance to a stimulus or prime cells for a more robust response. These findings have generated interest in the capacity to modulate chromatin regulators with small-molecule compounds for the treatment of diseases associated with innate or adaptive immunity. © 2014 by Annual Reviews. All rights reserved.


Estrin D.,University of California at Los Angeles | Sim I.,University of California at San Francisco
Science | Year: 2010

Standardized interfaces and shared components are critical for realizing the potential of mobile-device-enabled health care delivery and research.


Grant
Agency: National Aeronautics and Space Administration | Branch: | Program: STTR | Phase: Phase I | Award Amount: 123.47K | Year: 2016

Tyvak, in collaboration with UCLA, proposes a novel approach to the challenge of creating a large reflector for Ka-band high data rate links. We propose to attach the primary reflector surface permanently to the surface of a 6U spacecraft and illuminate the reflector using a Cassegrain style subreflector with an illuminating antenna that is permanently mounted to the transmitter / receiver inside the satellite. While other approaches focus on deploying the reflector surface itself, including Tyvak?s own deployable dish project, this proposed innovation uses minimal moving parts to achieve a high gain design.


Patent
Singapore University of Technology, Design, Hong Kong University of Science, Technology and University of California at Los Angeles | Date: 2013-11-12

The invention provides a clothing matching system and a method for generating at least an outfit suggestion comprising the steps of determining a colour classification of a user, providing a plurality of articles of clothing, selecting a dress code based on the user preference and generating at least one outfit suggestion based on the colour classification of the user, the plurality of clothing items and the selected dress code.


White A.C.,University of California at Los Angeles | Lowry W.E.,University of California at Los Angeles
Trends in Cell Biology | Year: 2015

Significant progress has been made to identify the cells at the foundation of tumorigenesis, the cancer cell of origin (CCO). The majority of data points towards resident adult stem cells (ASCs) or primitive progenitors as the CCO for those cancers studied, highlighting the importance of stem cells not only as propagators but also as initiators of cancer. Recent data suggest tumor initiation at the CCOs can be regulated through both intrinsic and extrinsic signals and that the identity of the CCOs and their propensity to initiate tumorigenesis is context dependent. In this review, we summarize some of the recent findings regarding CCOs and solid tumor initiation and highlight its relation with bona fide human cancer. © 2014 Elsevier Ltd.


Roberts P.H.,University of California at Los Angeles | King E.M.,University of California at Berkeley
Reports on Progress in Physics | Year: 2013

Few areas of geophysics are today progressing as rapidly as basic geomagnetism, which seeks to understand the origin of the Earth's magnetism. Data about the present geomagnetic field pours in from orbiting satellites, and supplements the ever growing body of information about the field in the remote past, derived from the magnetism of rocks. The first of the three parts of this review summarizes the available geomagnetic data and makes significant inferences about the large scale structure of the geomagnetic field at the surface of the Earth's electrically conducting fluid core, within which the field originates. In it, we recognize the first major obstacle to progress: because of the Earth's mantle, only the broad, slowly varying features of the magnetic field within the core can be directly observed. The second (and main) part of the review commences with the geodynamo hypothesis: the geomagnetic field is induced by core flow as a self-excited dynamo. Its electrodynamics define 'kinematic dynamo theory'. Key processes involving the motion of magnetic field lines, their diffusion through the conducting fluid, and their reconnection are described in detail. Four kinematic models are presented that are basic to a later section on successful dynamo experiments. The fluid dynamics of the core is considered next, the fluid being driven into motion by buoyancy created by the cooling of the Earth from its primordial state. The resulting flow is strongly affected by the rotation of the Earth and by the Lorentz force, which alters fluid motion by the interaction of the electric current and magnetic field. A section on 'magnetohydrodynamic (MHD) dynamo theory' is devoted to this rotating magnetoconvection. Theoretical treatment of the MHD responsible for geomagnetism culminates with numerical solutions of its governing equations. These simulations help overcome the first major obstacle to progress, but quickly meet the second: the dynamics of Earth's core are too complex, and operate across time and length scales too broad to be captured by any single laboratory experiment, or resolved on present-day computers. The geophysical relevance of the experiments and simulations is therefore called into question. Speculation about what may happen when computational power is eventually able to resolve core dynamics is given considerable attention. The final part of the review is a postscript to the earlier sections. It reflects on the problems that geodynamo theory will have to solve in the future, particularly those that core turbulence presents. © 2013 IOP Publishing Ltd.


Ganz T.,University of California at Los Angeles
Blood | Year: 2011

Under evolutionary pressure to counter the toxicity of iron and to maintain adequate iron supply for hemoglobin synthesis and essential metabolic functions, humans and other vertebrates have effective mechanisms to conserve iron and to regulate its concentration, storage, and distribution in tissues. The iron-regulatory hormone hepcidin, first described 10 years ago, and its receptor and iron channel ferroportin control the dietary absorption, storage, and tissue distribution of iron. Hepcidin causes ferroportin internalization and degradation, thereby decreasing iron transfer into blood plasma from the duodenum, from macrophages involved in recycling senescent erythrocytes, and from iron-storing hepatocytes. Hepcidin is feedback regulated by iron concentrations in plasma and the liver and by erythropoietic demand for iron. Genetic malfunctions affecting the hepcidinferroportin axis are a main cause of iron overload disorders but can also cause iron-restricted anemias. Modulation of hepcidin and ferroportin expression during infection and inflammation couples iron metabolism to host defense and decreases iron availability to invading pathogens. This response also restricts the iron supply to erythropoietic precursors and may cause or contribute to the anemia associated with infections and inflammatory disorders. © 2011 by The American Society of Hematology.


Kagan Y.Y.,University of California at Los Angeles
Geophysical Journal International | Year: 2010

We discuss various statistical distributions of earthquake numbers. Previously, we derived several discrete distributions to describe earthquake numbers for the branching model of earthquake occurrence: these distributions are the Poisson, geometric, logarithmic and the negative binomial (NBD). The theoretical model is the 'birth and immigration' population process. The first three distributions above can be considered special cases of the NBD. In particular, a point branching process along the magnitude (or log seismic moment) axis with independent events (immigrants) explains the magnitude/moment-frequency relation and the NBD of earthquake counts in large time/space windows, as well as the dependence of the NBD parameters on the magnitude threshold (magnitude of an earthquake catalogue completeness). We discuss applying these distributions, especially the NBD, to approximate event numbers in earthquake catalogues. There are many different representations of the NBD. Most can be traced either to the Pascal distribution or to the mixture of the Poisson distribution with the gamma law. We discuss advantages and drawbacks of both representations for statistical analysis of earthquake catalogues. We also consider applying the NBD to earthquake forecasts and describe the limits of the application for the given equations. In contrast to the one-parameter Poisson distribution so widely used to describe earthquake occurrence, the NBD has two parameters. The second parameter can be used to characterize clustering or overdispersion of a process. We determine the parameter values and their uncertainties for several local and global catalogues, and their subdivisions in various time intervals, magnitude thresholds, spatial windows, and tectonic categories. The theoretical model of how the clustering parameter depends on the corner (maximum) magnitude can be used to predict future earthquake number distribution in regions where very large earthquakes have not yet occurred. © 2010 The Author Journal compilation © 2010 RAS.


Devries T.,University of California at Los Angeles
Global Biogeochemical Cycles | Year: 2014

This study presents a new estimate of the oceanic anthropogenic CO 2(Cant) sink over the industrial era (1780 to present), from assimilation of potential temperature, salinity, radiocarbon, and CFC-11 observations in a global steady state ocean circulation inverse model (OCIM). This study differs from previous data-based estimates of the oceanic C ant sink in that dynamical constraints on ocean circulation are accounted for, and the ocean circulation is explicitly modeled, allowing the calculation of oceanic Cant storage, air-sea fluxes, and transports in a consistent manner. The resulting uncertainty of the OCIM-estimated C ant uptake, transport, and storage is significantly smaller than the comparable uncertainty from purely data-based or model-based estimates. The OCIM-estimated oceanic Cant storage is 160-166 PgC in 2012, and the oceanic Cant uptake rate averaged over the period 2000-2010 is 2.6 PgC yr-1 or about 30% of current anthropogenic CO2 emissions. This result implies a residual (primarily terrestrial) C ant sink of about 1.6 PgC yr-1 for the same period. The Southern Ocean is the primary conduit for Cant entering the ocean, taking up about 1.1 PgC yr-1 in 2012, which represents about 40% of the contemporary oceanic Cant uptake. It is suggested that the most significant source of remaining uncertainty in the oceanic Cant sink is due to potential variability in the ocean circulation over the industrial era. Key Points The oceanic anthropogenic C sink is estimated in a data assimilation model Combining tracer and dynamical constraints reduces uncertainty of estimates The global ocean storage of anthropogenic carbon in 2012 is 160-166 Pg C ©2014. American Geophysical Union. All Rights Reserved.


Eisenberger N.I.,University of California at Los Angeles
Psychosomatic Medicine | Year: 2012

Experiences of social rejection or loss have been described as some of the most "painful" experiences that we, as humans, face and perhaps for good reason. Because of our prolonged period of immaturity, the social attachment system may have co-opted the pain system, borrowing the pain signal to prevent the detrimental consequences of social separation. This review summarizes a program of research that has explored the idea that experiences of physical pain and social pain rely on shared neural substrates. First, evidence showing that social pain activates pain-related neural regions is reviewed. Then, studies exploring some of the expected consequences of such a physical pain-social pain overlap are summarized. These studies demonstrate that a) individuals who are more sensitive to one kind of pain are also more sensitive to the other and b) factors that increase or decrease one kind of pain alter the other in a similar manner. Finally, what these shared neural substrates mean for our understanding of socially painful experience is discussed. © 2012 by the American Psychosomatic Society.


Tobinick E.,University of California at Los Angeles
Current Alzheimer Research | Year: 2012

Excess tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Alzheimer's disease(AD). Clinical improvement following perispinal administration of etanercept in patients with Alzheimer's disease and other forms of dementia and brain dysfunction is characteristically evident within minutes. The rapidity and constellation of the clinical effects across multiple domains (cognition, mood, memory, motor function, and attention) suggest they are mediated by non-synaptic signaling mechanisms previously unrecognized for etanercept. These mechanisms likely extend beyond the known roles of TNF as a gliotransmitter that modulates synaptic strength, synaptic scaling, and AMPA receptor trafficking. Preliminary basic science and clinical investigation suggests that perispinal administration of etanercept may lead to its rapid penetration into the cerebrospinal fluid (CSF) within the cerebral ventricles. Diffusion of large molecules into the periventricular brain parenchyma is known to occur, but this process may not be sufficient to explain the rapidity of the clinical effects. There exist populations of cells, including CSF-contacting neurons and modified ependymal cells called tanycytes, that have receptive surfaces in direct contact with the CSF. It is hypothesized that the rapid clinical effects of perispinal etanercept involve non-synaptic signal transduction across the ependymal barrier and into neuronal networks via these CSF-contacting cells. This hypothesis challenges the dogma that penetration of a therapeutic into the cerebral parenchyma through the endothelium of the cerebral vasculature (the so-called blood- brain barrier) is necessary to produce rapid clinical effects in AD. CSF-contacting cells may constitute a therapeutic target for a diverse group of brain, psychiatric and spinal disorders. © 2012 Bentham Science Publishers.


Hewison M.,University of California at Los Angeles
Rheumatic Disease Clinics of North America | Year: 2012

Interaction with the immune system is one of the most well-established nonclassic effects of vitamin D. For many years this was considered to be a manifestation of granulomatous diseases such sarcoidosis, in which synthesis of active 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) is known to be dysregulated. However, recent reports have supported a role for 1,25(OH) 2D 3 in mediating normal function of the innate and adaptive immune systems. Crucially, these effects seem to be mediated via localized autocrine or paracrine synthesis of 1,25(OH) 2D 3 from precursor 25-hydroxyvitamin D 3, the main circulating metabolite of vitamin D. The ability of vitamin D to influence normal human immunity is highly dependent on the vitamin D status of individuals, and may lead to aberrant response to infection or autoimmunity in those who are lacking vitamin D. The potential health significance of this has been underlined by increasing awareness of impaired vitamin D status in populations across the globe. This article describes some of the recent developments with respect to vitamin D and the immune system, and possible clinical implications. © 2012 Elsevier Inc.


Zuckerman B.,University of California at Los Angeles
Astrophysical Journal Letters | Year: 2014

The occurrence of planets in binary star systems has been investigated via a variety of techniques that sample a wide range of semi-major axes, but with a preponderance of such results applicable to planets with semi-major axes less than a few astronomical units. We utilize a new method - the presence or absence of heavy elements in the atmospheres of white dwarf stars - to elucidate the frequency in main sequence binary star systems of planets with semi-major axes greater than a few astronomical units. We consider only binaries where a putative planetary system orbits one member (no circumbinary planets). For main sequence binaries where the primary star is of spectral type A or F, data in the published literature suggests that the existence of a secondary star with a semi-major axis less than about 1000 AU suppresses the formation and/or long-term stability of an extended planetary system around the primary. For these spectral types and initial semi-major axis ≥1000 AU, extended planetary systems appear to be as common around stars in binary systems as they are around single stars. © 2014. The American Astronomical Society. All rights reserved.


Chen W.,University of California at Los Angeles
Cell death & disease | Year: 2012

We recently identified Grainyhead-like 2 (GRHL2), a mammalian homolog of Grainyhead in Drosophila, to be a novel transcription factor that regulates hTERT gene expression and enhances proliferation of normal human epidermal keratinocytes (NHEK). In the current study, we show that GRHL2 impairs keratinocyte differentiation through transcriptional inhibition of the genes clustered at the epidermal differentiation complex (EDC), located at chromosome 1q21. Gene expression profiling and subsequent in vitro assays revealed consistent downregulation of EDC genes, for example, IVL, KRT1, FLG, LCEs, and SPRRs, in NHEK expressing exogenous GRHL2. In vivo binding assay by chromatin immunoprecipitation revealed GRHL2 association at the promoter regions of its target genes, many of which belong to EDC. Exogenous GRHL2 expression also inhibited recruitment of histone demethylase Jmjd3 to the EDC gene promoters and enhanced the level of histone 3 Lys 27 trimethylation enrichment at these promoters. Survey of GRHL2 expression in human skin tissues demonstrated enhanced protein and mRNA levels in chronic skin lesions with impaired keratinocyte differentiation, for example, atopic dermatitis and psoriasis, compared with normal epidermis. These data indicate that GRHL2 impairs epidermal differentiation by inhibiting EDC gene expression through epigenetic mechanisms and support its role in the hyperproliferative skin diseases.


Zhang L.,Jiangsu University | Tu K.N.,University of California at Los Angeles
Materials Science and Engineering R: Reports | Year: 2014

Composite lead-free solders, containing micro and nano particles, have been widely studied. Due to grain boundary drag or Zener drag, these particles can refrain the solder microstructure from coarsening in services, especially for Cu6Sn5, Ag3Sn intermetallic compounds and the β-Sn phases. Due to dispersion hardening or dislocation drag, the mechanical properties of the composite solder alloys were enhanced significantly. Moreover, these particles can influence the rate of interfacial reactions, and some particles can transform into a layer of intermetallic compound. Wettability, creep resistance, and hardness properties were affected by these particles. A systematic review of the development of these lead-free composite solders is given here, which hopefully may find applications in microbumps to be used in the future 3D IC technology.


Vlashi E.,University of California at Los Angeles | Pajonk F.,University of California at Los Angeles
Seminars in Cancer Biology | Year: 2015

Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms. © 2014 Elsevier Ltd.


Kendall G.C.,University of California at Los Angeles
Science translational medicine | Year: 2012

Duchenne muscular dystrophy (DMD) causes profound and progressive muscle weakness and loss, resulting in early death. DMD is usually caused by frameshifting deletions in the gene DMD, which leads to absence of dystrophin protein. Dystrophin binds to F-actin and components of the dystrophin-associated glycoprotein complex and protects the sarcolemma from contraction-induced injury. Antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach aimed at restoring the DMD reading frame and allowing expression of an intact dystrophin glycoprotein complex. To date, low levels of dystrophin protein have been produced in humans by this method. We performed a small-molecule screen to identify existing drugs that enhance antisense-directed exon skipping. We found that dantrolene, currently used to treat malignant hyperthermia, potentiates antisense oligomer-guided exon skipping to increase exon skipping to restore the mRNA reading frame, the sarcolemmal dystrophin protein, and the dystrophin glycoprotein complex in skeletal muscles of mdx mice when delivered intramuscularly or intravenously. Further, dantrolene synergized with multiple weekly injections of antisense to increase muscle strength and reduce serum creatine kinase in mdx mice. Dantrolene similarly promoted antisense-mediated exon skipping in reprogrammed myotubes from DMD patients. Ryanodine and Rycal S107, which, like dantrolene, targets the ryanodine receptor, also promoted antisense-driven exon skipping, implicating the ryanodine receptor as the critical molecular target.


Hahn B.H.,University of California at Los Angeles
New England Journal of Medicine | Year: 2013

A 20-year-old woman was evaluated by her rheumatologist because she was disabled by flares of systemic lupus erythematosus (SLE). A diagnosis of SLE had been made 2 years earlier, on the basis of a photosensitive malar rash, oral ulcers, polyarthritis, pericarditis, and positive assays for antinuclear antibodies (ANA) and anti-double-stranded DNA (dsDNA) antibodies. Treatment with analgesics and hydroxychloroquine for 6 months was not beneficial; prednisone at a dose of 40 mg daily resulted in some improvement, but the patient gained 6.8 kg (15 lb) and required two hospitalizations for infections. SLE flares occurred when the prednisone dose was less than 30 mg daily. Trials of methotrexate, mycophenolate mofetil, and azathioprine either had unacceptable side effects or failed to control flares or permit prednisone tapering. On examination, she had cushingoid features with 20 swollen, tender joints and 3 oral ulcers. The ANA titer was positive, at 1:320. An assay for anti-dsDNA antibodies was negative, and the serum complement level was normal. The rheumatologist recommended a trial of belimumab. Copyright © 2013 Massachusetts Medical Society.


Barrett H.C.,University of California at Los Angeles
Proceedings. Biological sciences / The Royal Society | Year: 2013

The psychological capacity to recognize that others may hold and act on false beliefs has been proposed to reflect an evolved, species-typical adaptation for social reasoning in humans; however, controversy surrounds the developmental timing and universality of this trait. Cross-cultural studies using elicited-response tasks indicate that the age at which children begin to understand false beliefs ranges from 4 to 7 years across societies, whereas studies using spontaneous-response tasks with Western children indicate that false-belief understanding emerges much earlier, consistent with the hypothesis that false-belief understanding is a psychological adaptation that is universally present in early childhood. To evaluate this hypothesis, we used three spontaneous-response tasks that have revealed early false-belief understanding in the West to test young children in three traditional, non-Western societies: Salar (China), Shuar/Colono (Ecuador) and Yasawan (Fiji). Results were comparable with those from the West, supporting the hypothesis that false-belief understanding reflects an adaptation that is universally present early in development.


Blumstein D.T.,University of California at Los Angeles
Proceedings. Biological sciences / The Royal Society | Year: 2013

Play has been defined as apparently functionless behaviour, yet since play is costly, models of adaptive evolution predict that it should have some beneficial function (or functions) that outweigh its costs. We provide strong evidence for a long-standing, but poorly supported hypothesis: that early social play is practice for later dominance relationships. We calculated the relative dominance rank by observing the directional outcome of playful interactions in juvenile and yearling yellow-bellied marmots (Marmota flaviventris) and found that these rank relationships were correlated with later dominance ranks calculated from agonistic interactions, however, the strength of this relationship attenuated over time. While play may have multiple functions, one of them may be to establish later dominance relationships in a minimally costly way.


Teplow D.B.,University of California at Los Angeles
Alzheimer's Research and Therapy | Year: 2013

According to Thomas Kuhn, the success of 'normal science,' the science we all practice on a daily basis, depends on the adherence to, and practice of, a paradigm accepted by the scientific community. When great scientific upheavals occur, they involve the rejection of the current paradigm in favor of a new paradigm that better integrates the facts available and better predicts the behavior of a particular scientific system. In the field of Alzheimer's disease, a recent example of such a paradigm shift has been the apparent rejection of the 'amyloid cascade hypothesis,' promulgated by Hardy and Higgins in 1992 to explain the etiology of Alzheimer's disease, in favor of what has been referred to as the 'oligomer cascade hypothesis'. This paradigm shift has been breathtaking in its rapidity, its pervasiveness in the Alzheimer's disease field, and its adoption in an increasing number of other fields, including those of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prionoses. However, these facts do not mean, a priori, that the experiments extant, and any re-interpretation of them, should be accepted by rote as support for the new paradigm. In the discussion that follows, I consider the foundational studies leading to the oligomer cascade hypothesis and evaluate the current state of the paradigm. I argue here that, more often than not, insufficient rigor has been applied in studies upon which this new paradigm has been based. Confusion, rather than clarity, has resulted. If the field is to make progress forward using as its paradigmatic basis amyloid β-protein oligomerization, then an epistemological re-evaluation of the amyloid β-protein oligomer system is required. © 2013 BioMed Central Ltd.


Lake J.E.,University of California at Los Angeles | Currier J.S.,University of California at Los Angeles
The Lancet Infectious Diseases | Year: 2013

The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin-glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs. © 2013 Elsevier Ltd.


Mitsuyasu R.,University of California at Los Angeles
Current Opinion in HIV and AIDS | Year: 2013

PURPOSE OF REVIEW: Interest in finding a potential 'cure' for HIV has taken on greater interest and urgency since the report of an individual who underwent allogeneic stem cell transplant from a CCR5 delta 32 homozygote donor after high-dose chemotherapy for acute myeloid leukemia. The potential role of cancer chemotherapy and other cancer-directed treatment approaches is discussed in the context of their potential role in helping to eliminate HIV from the infected host. RECENT FINDINGS: Cancer chemotherapy and other cancer-targeted agents have been used successfully in treating a variety of malignancies in both HIV-infected and HIV-uninfected individuals. Lessons learned from these strategies may be of importance in helping to define more effective ways of controlling and eliminating HIV as well. Application of these anticancer strategies to patients with HIV are beginning to be explored and may help determine their potential usefulness in this disease as well. SUMMARY: Although cytotoxic chemotherapy is a crude and not particularly effective way of removing HIV latently infected cells and tissue reservoirs, several new approaches to targeting and controlling cancer proliferation may be of value in HIV cure research and may one day help to end this disease. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Xiao H.,University of California at Los Angeles
Molecular & cellular proteomics : MCP | Year: 2012

Lung cancer is often asymptomatic or causes only nonspecific symptoms in its early stages. Early detection represents one of the most promising approaches to reduce the growing lung cancer burden. Human saliva is an attractive diagnostic fluid because its collection is less invasive than that of tissue or blood. Profiling of proteins in saliva over the course of disease progression could reveal potential biomarkers indicative of oral or systematic diseases, which may be used extensively in future medical diagnostics. There were 72 subjects enrolled in this study for saliva sample collection according to the approved protocol. Two-dimensional difference gel electrophoresis combined with MS was the platform for salivary proteome separation, quantification, and identification from two pooled samples. Candidate proteomic biomarkers were verified and prevalidated by using immunoassay methods. There were 16 candidate protein biomarkers discovered by two-dimensional difference gel electrophoresis and MS. Three proteins were further verified in the discovery sample set, prevalidation sample set, and lung cancer cell lines. The discriminatory power of these candidate biomarkers in lung cancer patients and healthy control subjects can reach 88.5% sensitivity and 92.3% specificity with AUC = 0.90. This preliminary data report demonstrates that proteomic biomarkers are present in human saliva when people develop lung cancer. The discriminatory power of these candidate biomarkers indicate that a simple saliva test might be established for lung cancer clinical screening and detection.


Ganz T.,University of California at Los Angeles
Journal of Innate Immunity | Year: 2012

As a principal aspect of their scavenging function, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recover iron, mainly for the production of hemoglobin in new erythrocytes but also for other carriers and enzymes requiring iron. Splenic red pulp macrophages are specialized for iron recycling with increased expression of proteins for the uptake of hemoglobin, breakdown of heme and the export of iron. In humans, recycling macrophages contribute the majority of the iron flux into extracellular fluid, exceeding the contribution of dietary iron absorption and release of stored iron from hepatocytes. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. In addition to their homeostatic role, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. This review discusses the iron-scavenging function of macrophages in the context of iron homeostasis and host defense. © 2012 S. Karger AG, Basel.


Payer D.E.,University of California at Los Angeles
Emotion (Washington, D.C.) | Year: 2012

Emotion regulation can be achieved in various ways, but few studies have evaluated the extent to which the neurocognitive substrates of these distinct operations overlap. In the study reported here, functional magnetic resonance imaging (fMRI) was used to measure activity in the amygdala and prefrontal cortex of 10 participants who completed two independent tasks of emotion regulation-reappraisal, measuring intentional emotion regulation, and affect labeling, measuring incidental emotion regulation-with the objective of identifying potential overlap in the neural substrates underlying each task. Analyses focused on a priori regions of interest in the amygdala and inferior frontal gyrus (IFG). For both tasks, fMRI showed decreased amygdala activation during emotion regulation compared with emotion conditions. During reappraisal, this decrease in amygdala activation was accompanied by a proportional decrease in emotional intensity ratings; during affect labeling, the decrease in amygdala activation correlated with self-reported aggression. Importantly, across participants, the magnitude of decrease in amygdala activation during reappraisal correlated with the magnitude of decrease during affect labeling, even though the tasks were administered on separate days, and values indexing amygdala activation during each task were extracted independently of one another. In addition, IFG-amygdala connectivity, assessed via psychophysiological interaction analysis, overlapped between tasks in two regions within the right IFG. The results suggest that the two tasks recruit overlapping regions of prefrontal cortex, resulting in similar reductions in amygdala activation, regardless of the strategy employed. Intentional and incidental forms of emotion regulation, despite their phenomenological differences, may therefore converge on a common neurocognitive pathway. (PsycINFO Database Record (c) 2012 APA, all rights reserved).


Said J.W.,University of California at Los Angeles
Modern Pathology | Year: 2013

Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. The aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma and its blastoid variant, and B lymphoblastic lymphoma. Differences in histology, cytogenetic and molecular abnormalities, as well as the relationship with the tumor microenvironment, help define characteristic signatures for these neoplasms, and in turn dictate potential therapeutic targets. Rather than survey the entire spectrum of aggressive B-cell lymphomas, this report aims to identify and characterize important clinically aggressive subtypes of DLBCL, and explore the relationship of DLBCL to BL and the gray zone between them (B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL). © 2013 USCAP, Inc. All rights reserved.


Glassock R.J.,University of California at Los Angeles
Kidney International | Year: 2013

Multiple-relapsing minimal-change disease (MCD) often requires exposure to potentially toxic agents in an attempt to achieve a lasting remission of nephrotic syndrome. Munyentwali and co-workers describe an experience using rituximab in adults with multiple-relapsing MCD that supports both efficacy and safety of this agent. However, the optimal dosing regimen and mechanism of action remain unclear. Thus, randomized controlled trials are warranted in both adults and children to better define the role of rituximab in multiple-relapsing MCD. © 2012 International Society of Nephrology.


Stivers T.,University of California at Los Angeles
Patient Education and Counseling | Year: 2012

Objective: The objective of the study is to examine predictors of children answering questions during primary care pediatric visits. Methods: Relying on a sample of 322 video-taped community practice encounters, this study identifies predictors of when children answer physicians' questions. Multi-level multivariate regressions were used to model the relationships among communication and socio-demographic variables and whether or not children answered questions pediatricians asked them. Results: Whereas race and education predict whether physicians select children to answer questions, these factors are not associated with whether children answer physicians' questions. Instead, a child's performance is associated with communication practices specific to physician-child interaction such as the grammatical type of question and doctor gaze. Conclusion: Children are less responsive to physicians' questions than their parents but their failure to answer is predictable and thus can be improved. By increasing their participation in the visit, physicians may (a) secure more information about children's health and (b) socialize children to be more pro-active patients. Practice implications: Physicians can improve the likelihood that children will answer their questions by (a) asking them social questions early in the visit, (b) phrasing their questions as yes-no questions, and (c) and directing their gaze at the children during each question. © 2011 Elsevier Ireland Ltd.


Pearl J.,University of California at Los Angeles
Epidemiology | Year: 2010

In 2 recent communications, Cole and Frangakis (Epidemiology. 2009;20:3-5) and VanderWeele (Epidemiology. 2009;20:880-883) conclude that the consistency rule used in causal inference is an assumption that precludes any side-effects of treatment/exposure on the outcomes of interest. They further develop auxiliary notation to make this assumption formal and explicit. I argue that the consistency rule is a theorem in the logic of counterfactuals and need not be altered. Instead, warnings of potential side-effects should be embodied in standard modeling practices that make causal assumptions explicit and transparent. © 2010 by Lippincott Williams & Wilkins.


Jura M.,University of California at Los Angeles | Young E.D.,University of California at Los Angeles
Annual Review of Earth and Planetary Sciences | Year: 2014

Evidence is now compelling that elements heavier than helium in many white dwarf atmospheres have accumulated by accretion from orbiting rocky bodies, often larger than 100 km in diameter, such as asteroids. Consequently, we now possess a powerful tool to measure the elemental constituents of extrasolar minor planets. To zeroth order, the accreted extrasolar parent bodies resemble bulk Earth: They are at least 85% by mass composed of oxygen, magnesium, silicon, and iron; carbon and ice are only trace constituents. Assembled data for white dwarf pollutions suggest that differentiation of extrasolar planetesimals, leading to iron-rich cores and aluminum-rich crusts, is common. Except for instances of unexpectedly high calcium abundances, the compositions of extrasolar planetesimals can be understood as resulting from processes similar to those controlling the formation and evolution of objects in the inner Solar System. © 2014 by Annual Reviews. All rights reserved.


Weber T.S.,University of California at Los Angeles | Deutsch C.,University of California at Los Angeles
Nature | Year: 2010

The major nutrients nitrate and phosphate have one of the strongest correlations in the sea, with a slope similar to the average nitrogen (N) to phosphorus (P) content of plankton biomass (N/P = 16:1). The processes through which this global relationship emerges despite the wide range of N/P ratios at the organism level are not known. Here we use an ocean circulation model and observed nutrient distributions to show that the N/P ratio of biological nutrient removal varies across latitude in Southern Ocean surface waters, from 12:1 in the polar ocean to 20:1 in the sub-Antarctic zone. These variations are governed by regional differences in the species composition of the plankton community. The covariation of dissolved nitrate and phosphate is maintained by ocean circulation, which mixes the shallow subsurface nutrients between distinct biogeographic provinces. Climate-driven shifts in these marine biomes may alter the mean N/P ratio and the associated carbon export by Southern Ocean ecosystems. © 2010 Macmillan Publishers Limited. All rights reserved.


Carmichael S.T.,University of California at Los Angeles
Stroke | Year: 2010

Studies of neural repair after stroke have developed from a relatively small number of laboratories doing highly creative discovery science to a field in which reproducible evidence supports distinct pathways, processes, and molecules that promote recovery. This review focuses on some emerging targets for neural repair or recovery in stroke and on their limitations. © 2010 American Heart Association, Inc.


Carey M.,University of California at Los Angeles
Nature Structural and Molecular Biology | Year: 2012

The recent mapping and modeling of protein-protein interfaces between general transcription factors TFIIE, TFIIH and Pol II have provided new insights into TFIIH-mediated melting of the transcription start site to form an open Pol II preinitiation complex and the stabilization of the complex by TFIIE, leading to a new mechanistic model for open-complex formation. © 2012 Nature America, Inc. All rights reserved.


Glaspy J.,University of California at Los Angeles
Seminars in Thrombosis and Hemostasis | Year: 2014

Anemia is frequently observed in cancer patients and can cause symptoms and result in red cell transfusions. The erythropoiesis stimulating agents (ESAs) have been shown to increase hemoglobin levels and reduce transfusion requirements in anemic subjects with cancer who are receiving chemotherapy. Initially, these benefits motivated broad use of the ESAs in oncology. Over the past 10 years, recognition of the adverse events that can be associated with ESA use in these patients, particularly venous thrombosis, has resulted in a rethinking of the issue of who are the correct candidates for treatment. Different health care systems have come to different conclusions based upon the available data and additional data are still being generated. This article will review the data concerning the safety of ESAs in cancer patients, including the results of additional trials published in the past 2 years. This will include a discussion of the potential of ESAs to impact tumor progression or survival. Thrombosis remains the most important and best documented adverse event associated with ESA therapy in oncology. The mechanism(s) through which ESAs alter thrombosis risk are still very poorly understood. © 2014 by Thieme Medical Publishers, Inc.


Sofroniew M.V.,University of California at Los Angeles
Neuroscientist | Year: 2014

Astrocytes are increasingly recognized as exerting complex functions essential for normal neural activity in the healthy central nervous system (CNS). Because astrocytes also respond to all forms of CNS injury or disease, there is growing interest in how reactive astrogliosis might alter astrocyte functions and thereby affect neural functions. Reactive astrogliosis is heterogeneous and regulated in a context specific manner by different molecular signals. Prominent among astrocyte signaling mechanisms is the ability to respond to, as well as to produce, many different cytokines and inflammatory mediators. These signaling mechanisms enable astrocytes to interact with diverse cell types in ways that may contribute to crosstalk between immune/inflammatory and neural systems. Consistent with this notion is the increasing evidence that cytokines and inflammatory mediators modulate astrocyte signaling not only to influence immune and inflammatory activities in the CNS, but also to influence synaptic and neural functions in ways that may affect complex behaviors such as sickness behavior, pain, appetite, sleep, and mood. © 2013 The Author(s).


Brookmeyer R.,University of California at Los Angeles
Journal of Acquired Immune Deficiency Syndromes | Year: 2010

Objective: To evaluate the statistical accuracy of estimates of current HIV incidence rates from cross-sectional surveys, and to identify characteristics of assays that improve accuracy. Methods: Performed mathematical and statistical analysis of the cross-sectional estimator of HIV incidence to evaluate bias and variance. Developed probability models to evaluate impact of long tails of the window period distribution on accuracy. Results: The standard cross-sectional estimate of HIV incidence rate is estimating a time-lagged incidence where the lag time, called the shadow, depends on the mean and the coefficient of variation of window periods. Equations show how the shadow increases with the mean and the coefficient of variation. We find with an assay such as BED capture enzyme immunoassay, if only 0.5% are elite controllers who remain in the window until death, then the shadow is over 2.3 years, implying that estimates reflect HIV incidence more than 2 years in the past rather than current levels. If even 5% of AIDS cases are unrecognized and not excluded from the numbers in the window, then the shadow is more than 2.2 years. Conclusions: Small perturbations to the tail of the window period distribution can have large effects on the accuracy of current HIV incidence estimates. The shadow and mean window period are useful for comparing the accuracy of assays. The results help explain differences reported between cohort and cross-sectional HIV incidence estimates. Screening out elite or viremic controllers by RNA polymerase chain reaction testing, and persons with advanced HIV disease (with AIDS or on antiretrovirals) may considerably improve the accuracy of HIV incidence estimates based on BED or similar assays. © 2010 by Lippincott Williams & Wilkins.


Ribas A.,University of California at Los Angeles
Seminars in Oncology | Year: 2010

Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. These tumor responses are mediated by the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) as demonstrated in patient-derived tumor biopsies. Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy. © 2010 Elsevier Inc. All rights reserved.


Lusis A.J.,University of California at Los Angeles | Weiss J.N.,University of California at Los Angeles
Circulation | Year: 2010

New technology is making it possible to see both the "forest" and the "trees" in biological systems. Systems biology might be best defined as the attempt to integrate new discoverydriven technologies that allow us to track biological networks holistically with classic hypothesis-driven approaches. Mathematical biology, in the form of bioinformatics to elucidate the structure of biological networks, as well as conceptual and detailed modeling to illuminate how network structure relates to function, will play an increasingly critical role in this effort. In this truly exciting era of cardiovascular biology, we can glimpse how the mysteries of human cardiovascular diseases might ultimately be solved. © 2010 American Heart Association. All rights reserved.


Prager J.P.,University of California at Los Angeles
Pain Medicine (United States) | Year: 2010

Spinal cord stimulation (SCS) can have dramatic effects on painful, vascular, and motor symptoms of complex regional pain syndrome (CRPS), but its precise mechanism of action is unclear. Better understanding of the physiologic effects of SCS may improve understanding not only of this treatment modality but also of CRPS pathophysiology. Effects of SCS on pain perception are likely to occur through activation of inhibitory GABA-ergic and cholinergic spinal interneurons. Increased release of both neurotransmitters has been demonstrated following SCS in animal models of neuropathic pain, with accompanying reductions in pain behaviors. Effects of SCS on vascular symptoms of CRPS are thought to occur through two main mechanisms: antidromic activation of spinal afferent neurons and inhibition of sympathetic efferents. Cutaneous vasodilation following SCS in animal models has been shown to involve antidromic release of calcitonin gene-related peptide and possibly nitric oxide, from small-diameter sensory neurons expressing the transient receptor potential V1 (TRPV1) receptor. The involvement of sympathetic efferents in the effects of SCS has not been studied in animal models of neuropathic pain, but has been demonstrated in models of angina pectoris. In conclusion, SCS is of clinical benefit in CRPS, and although its mechanism of action merits further elucidation, what little we do know is informative and can partially explain some of the pathophysiology of CRPS.


Ranganath V.K.,University of California at Los Angeles
Rheumatology (Oxford, England) | Year: 2013

To evaluate the impact of comorbidities on achieving remission by examining changes in the clinical disease activity index (CDAI) in RA patients in the community-based Consortium of Rheumatology Researchers of North America (CORRONA) registry. A subcohort of 1548 RA subjects with varying disease duration met the following inclusion criteria: started a DMARD/biologic agent, continued therapy ≥ 3 months, CDAI ≥ 2.8 at study entry and followed longitudinally from baseline to follow-up (mean time 7.46 months). Patients reported comorbidities according to a standardized list of 33 conditions. Entry characteristics were compared across age categories using one-way analysis of variance. Linear and logistic regression models were constructed to assess characteristics [e.g. age, disease duration, number of previous DMARDs/biologics, baseline modified health assessment questionnaire (MHAQ), baseline CDAI and number of comorbidities] associated with primary outcomes: change in CDAI (baseline to follow-up) and CDAI remission (yes/no). Although disease activity measures at entry were similar across age categories, older patients had more comorbidities, less improvement in CDAI/MHAQ and were less likely to attain remission at follow-up. However, after adjusting covariates an increasing number of patient-reported comorbidities and higher baseline CDAI (but not age) were consistently and independently associated with a lower likelihood of clinical improvement or remission (P < 0.001). In this observational cohort of community RA patients an increasing number of patients reported comorbidities, independently correlated with less CDAI improvement over time. These results reaffirm that comorbidities may be an important factor in consideration of treat-to-target recommendations and aid in understanding achievable RA therapeutic goals.


Sherstov A.A.,University of California at Los Angeles
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2012

A basic question in any computational model is how to reliably compute a given function when the inputs or intermediate computations are subject to noise at a constant rate. Ideally, one would like to use at most a constant factor more resources compared to the noise-free case. This question has been studied for decision trees, circuits, automata, data structures, broadcast networks, communication protocols, and other models. Buhrman et al. (2003) posed the noisy computation problem for real polynomials. We give a complete solution to this problem. For any polynomial p: {0, 1} n → [-1, 1], we construct a polynomial P robust: ℝ n → ℝ of degree O(deg p + log 1/ε) that ε-approximates p and is robust to noise in the inputs: |p(x) - P robust(x + δ)| < ε for all x ε {0, 1} n and all δ ε [-1/3; 1/3} n. This result is optimal with respect to all parameters. We construct P robust explicitly for each p. Previously, it was open to give such a construction even for p = x 1 ⊕ x 2 ⊕ ⋯ x n (Buhrman et al., 2003). The proof contributes a technique of independent interest, which allows one to force partial cancellation of error terms in a polynomial. © 2012 ACM.


Chen J.,University of California at Los Angeles | Sayed A.H.,University of California at Los Angeles
IEEE Transactions on Signal Processing | Year: 2012

We propose an adaptive diffusion mechanism to optimize global cost functions in a distributed manner over a network of nodes. The cost function is assumed to consist of a collection of individual components. Diffusion adaptation allows the nodes to cooperate and diffuse information in real-time; it also helps alleviate the effects of stochastic gradient noise and measurement noise through a continuous learning process. We analyze the mean-square-error performance of the algorithm in some detail, including its transient and steady-state behavior. We also apply the diffusion algorithm to two problems: distributed estimation with sparse parameters and distributed localization. Compared to well-studied incremental methods, diffusion methods do not require the use of a cyclic path over the nodes and are robust to node and link failure. Diffusion methods also endow networks with adaptation abilities that enable the individual nodes to continue learning even when the cost function changes with time. Examples involving such dynamic cost functions with moving targets are common in the context of biological networks. © 2012 IEEE.


Monti M.M.,University of California at Los Angeles
Annual Review of Clinical Psychology | Year: 2012

Awake but not aware: This puzzling dissociation of the two central elements of consciousness defines the vegetative state. Traditionally, this condition has been believed to imply a brain with preserved hypothalamic and brainstem autonomic functions but with no capacity for cortical cognitive processes. As is discussed in this review, over a 20-year span neuroimaging techniques have clearly demonstrated that this characterization of patients in a vegetative state is incorrect. Contrary to the initial belief, the "vegetative" brain can retain several high-level aspects of cognitive functions, across sensory modalities, including language processing and learning dynamics. Nonetheless, the residual cognitive functions observed in vegetative patients might reflect intact but functionally disconnected cortical modules that do not give rise to the subjective feeling of phenomenological awareness. © Copyright ©2012 by Annual Reviews. All rights reserved.


Charles A.,University of California at Los Angeles
Current Opinion in Neurology | Year: 2013

Purpose of Review: Migraine has traditionally been categorized as a pain disorder, focusing on headache as its central feature. This narrow view does not account for the complex array of premonitory and postrdromal symptoms that occur in the hours before and after headache. This review outlines evidence that supports a broader view of migraine as a pathological brain state. Recent Findings: Studies of the clinical features of a migraine attack, in combination with imaging and electrophysiological studies, provide evidence that migraine involves widespread changes in brain function and connectivity. These changes parallel those seen in other brain states such as sleep. Neurochemical mediators, including adenosine, and nonsynaptic signalling mechanisms involving astrocytes may play a role in the migraine state. Summary: Consideration of a migraine attack as a brain state provides an expanded framework for understanding all of its symptoms, and the underlying alterations in the activity of multiple brain networks. Mechanisms driving the transition to the migraine state may represent novel targets for acute and preventive therapies. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Zaidel D.W.,University of California at Los Angeles
Frontiers in Human Neuroscience | Year: 2014

Creativity is commonly thought of as a positive advance for society that transcends the status quo knowledge. Humans display an inordinate capacity for it in a broad range of activities, with art being only one. Most work on creativity's neural substrates measures general creativity, and that is done with laboratory tasks, whereas specific creativity in art is gleaned from acquired brain damage, largely in observing established visual artists, and some in visual de novo artists (became artists after the damage). The verb 'to create' has been erroneously equated with creativity; creativity, in the classic sense, does not appear to be enhanced following brain damage, regardless of etiology. The turning to communication through art in lieu of language deficits reflects a biological survival strategy. Creativity in art, and in other domains, is most likely dependent on intact and healthy knowledge and semantic conceptual systems, which are represented in several pathways in the cortex. It is adversely affected when these systems are dysfunctional, for congenital reasons (savant autism) or because of acquired brain damage (stroke, dementia, Parkinson's), whereas inherent artistic talent and skill appear less affected. Clues to the neural substrates of general creativity and specific art creativity can be gleaned from considering that art is produced spontaneously mainly by humans, that there are unique neuroanatomical and neurofunctional organizations in the human brain, and that there are biological antecedents of innovation in animals. © 2014 Zaidel.


Braslow J.T.,Semel Institute for Neuroscience and Human Behavior | Braslow J.T.,University of California at Los Angeles
Annual Review of Clinical Psychology | Year: 2013

Recovery (also known as the "recovery orientation," "recovery vision," or "recovery philosophy") has been the dominant paradigm shaping current mental health policy for the past decade. It is claimed to be a revolutionary departure from the past and a guide to policy that will transform outcomes of severe mental illness. This review looks critically at the history of recovery and examines the ways in which this history has shaped the values, beliefs, and practices of current recovery-based policies. Recovery is a treatment philosophy that emerged from the ruins of deinstitutionalization and the psychopharmaceutical revolution. Yet paradoxically, recovery reflects many of the same ideas that made deinstitutionalization and the era of psychopharmacology possible. Further, history reveals how the recovery movement is deeply indebted to and embedded within the sociocultural values of neoliberalism that have shaped public policy since the presidential election of Ronald Reagan in 1980. Copyright © 2013 by Annual Reviews.


Conklin J.L.,University of California at Los Angeles
Journal of Neurogastroenterology and Motility | Year: 2013

For several decades esophageal manometry has been the test of choice to evaluate disorders of esophageal motor function. The recent introduction of high-resolution manometry for the study of esophageal motor function simplified performance of esophageal manometry, and revealed previously unidentified patterns of normal and abnormal esophageal motor function. Presentation of pressure data as color contour plots or esophageal pressure topography led to the development of new tools for analyzing and classifying esophageal motor patterns. The current standard and still developing approach to do this is the Chicago classification. While this methodical approach is improving our diagnosis of esophageal motor disorders, it currently does not address all motor abnormalities. We will explore the Chicago classification and disorders that it does not address.© 2013 The Korean Society of Neurogastroenterology and Motility.


Dobkin B.H.,University of California at Los Angeles
Current Opinion in Neurology | Year: 2013

Given the progressively falling cost of miniaturized wearable gyroscopes, accelerometers, and other physiologic sensors, as well as inexpensive data transmission, sensing systems may become as ubiquitous as cell phones for healthcare. Neurorehabilitation can develop these mobile health platforms for daily care and clinical trials to improve exercise and fitness, skills learning, and physical functioning. © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Glynn S.M.,University of California at Los Angeles
Clinical Child and Family Psychology Review | Year: 2013

The papers in this section focus on public health responses and implementation considerations in addressing the challenges military families confront when parents go to war. While many military families show resilience, the challenges resulting from a decade of war with multiple deployments are detailed, as are innovative military and civilian programs designed to help service members and their families reintegrate successfully into the community. As more and more service members leave active duty, the burden of meeting military families' psychological needs will transition from the Department of Defense (DoD) and into the Veterans Administration (VA) and civilian arenas. While many strategies to support successful readjustment are offered, in this time of dwindling mental health resources and competing needs, it is unclear what priority the broader society places on meeting the needs of returning service members and their families. A growing emphasis on family-centered care in the Veterans Administration may help meet this gap. © 2013 Springer Science+Business Media New York (Outside the USA).


Bui A.L.,University of California at Los Angeles | Fonarow G.C.,University of California at Los Angeles
Journal of the American College of Cardiology | Year: 2012

With a prevalence of 5.8 million in the United States alone, heart failure (HF) is a common syndrome associated with substantial morbidity, mortality, and healthcare expenditures. Close to 1 million HF hospitalizations occur annually in the United States, with the majority of these resulting from worsening congestion in patients previously diagnosed with HF. An estimated $37.2 billion is spent each year on HF in the United States. These statistics emphasize the need to develop and implement more effective strategies to assess, monitor, and treat HF. It has also become increasingly apparent that interventions geared toward identifying and monitoring subclinical congestion would be of value in the home management of chronic HF. Earlier identification and treatment of congestion together with improved care coordination, management of comorbid conditions, and enhanced patient self-management may help to prevent hospitalizations in patients with chronic HF. Such home monitoring extends from the promotion of self-care and home visitations to telemedicine and remote monitoring of external or implantable devices. This paper discusses the challenges in monitoring patients with HF, reviews clinical trials testing different monitoring strategies in HF, and highlights ongoing investigations into the optimal approaches to home monitoring for HF. © 2012 by the American College of Cardiology Foundation.


Cole S.W.,University of California at Los Angeles
American Journal of Public Health | Year: 2013

Recent analyses have discovered broad alterations in the expression of human genes across different social environments. The emerging field of social genomics has begun to identify the types of genes sensitive to social regulation, the biological signaling pathways mediating these effects, and the genetic polymorphisms that modify their individual impact. The human genome appears to have evolved specific "social programs" to adapt molecular physiology to the changing patterns of threat and opportunity ancestrally associated with changing social conditions. In the context of the immune system, this programming now fosters many of the diseases that dominate public health. The embedding of individual genomes within a broader metagenomic network provides a framework for integrating molecular, physiologic, and social perspectives on human health.


Zimmerman F.J.,University of California at Los Angeles
Annual Review of Public Health | Year: 2011

The large increase in obesity in the past 30 years has often been explained in rational choice terms; for example, a decline in food prices has engendered greater food consumption. On closer examination, this kind of explanation does not fit the facts of the current obesity epidemic. Instead, an unprecedented expansion in the scope, power, and ubiquity of food marketing has coincided with an unprecedented expansion in food consumption in predictable ways. Ongoing protestations that the causes of the recent increase in obesity are unknown may overstate the case. Ample evidence indicates that the obesity epidemic is, at least to a large degree, the result of increased marketing power over the American diet. Only by reigning in or countering marketing power can rationality be restored to the dietary choices of Americans. © 2011 by Annual Reviews. rights reserved.


Zhou Z.H.,University of California at Los Angeles
Advances in Protein Chemistry and Structural Biology | Year: 2011

Single-particle cryo electron microscopy (cryoEM) is a technique for determining three-dimensional (3D) structures from projection images of molecular complexes preserved in their "native," noncrystalline state. Recently, atomic or near-atomic resolution structures of several viruses and protein assemblies have been determined by single-particle cryoEM, allowing ab initio atomic model building by following the amino acid side chains or nucleic acid bases identifiable in their cryoEM density maps. In particular, these cryoEM structures have revealed extended arms contributing to molecular interactions that are otherwise not resolved by the conventional structural method of X-ray crystallography at similar resolutions. High-resolution cryoEM requires careful consideration of a number of factors, including proper sample preparation to ensure structural homogeneity, optimal configuration of electron imaging conditions to record high-resolution cryoEM images, accurate determination of image parameters to correct image distortions, efficient refinement and computation to reconstruct a 3D density map, and finally appropriate choice of modeling tools to construct atomic models for functional interpretation. This progress illustrates the power of cryoEM and ushers it into the arsenal of structural biology, alongside conventional techniques of X-ray crystallography and NMR, as a major tool (and sometimes the preferred one) for the studies of molecular interactions in supramolecular assemblies or machines. © 2011 Elsevier Inc. All rights reserved.


Pearl J.,University of California at Los Angeles
International Journal of Biostatistics | Year: 2011

Principal stratification has recently become a popular tool to address certain causal inference questions, particularly in dealing with post-randomization factors in randomized trials. Here, we analyze the conceptual basis for this framework and invite response to clarify the value of principal stratification in estimating causal effects of interest. © 2011 Berkeley Electronic Press. All rights reserved.


Engel Jr. J.,University of California at Los Angeles
Epilepsy Currents | Year: 2013

Surgical treatment for epilepsy has made tremendous strides in the past few decades as a result of advances in neurodiagnostics-particularly structural and functional neuroimaging-and improved surgical techniques. This has not only resulted in better outcomes with respect to epileptic seizures and quality of life, and reduced surgical morbidity and mortality, but it has also increased the population of patients now considered as surgical candidates, particularly in the pediatric age range, and enhanced cost-effectiveness sufficient to make surgical treatment available to countries with limited resources. Yet surgical treatment for epilepsy remains arguably the most underutilized of all accepted medical interventions. In the United States, less than 1% of patients with pharmacoresistant epilepsy are referred to epilepsy centers.Although the number of epilepsy surgery centers has increased appreciably over the past two decades, the number of therapeutic surgical procedures performed for epilepsy has not increased at all. For patients who are referred, the average delay from onset of epilepsy to surgery is more than 20 years-too late for many to avoid a lifetime of disability or premature death. Not only has there been no consistent message to convince neurologists and primary care physicians to refer patients for surgery, but the increase in epilepsy surgery centers in the United States has appeared to result in a divergence of approaches to surgical treatment. Efforts are still needed to further improve the safety and efficacy of surgical treatment, including the identification of biomarkers that can reliably determine the extent of the epileptogenic region; however, the greatest benefits would derive from increasing access for potential surgical candidates to epilepsy surgery facilities. Information is needed to determine why appropriate surgical referrals are not being made. Consensus conferences are necessary to resolve controversies that still exist regarding presurgical evaluation and surgical approaches. Standards should be established for certifying epilepsy centers as recommended by the Institute of Medicine's report on epilepsy. Finally, the epilepsy community should not be promoting epilepsy surgery per se but instead emphasize that epilepsy centers do more than epilepsy surgery, promoting the message: All patients with disabling pharmacoresistant seizures deserve evaluation by specialists at epilepsy centers who can provide a variety of advanced diagnostic and therapeutic services. © American Epilepsy Society.


Amarasekare P.,University of California at Los Angeles
Journal of Animal Ecology | Year: 2010

Random dispersal leads to spatial coexistence via two mechanisms (emigration-mediated and source-sink), both of which involve the movement of organisms from areas of higher to lower fitness. What is not known is whether such coexistence would occur if organisms dispersed non-randomly, using cues such as density and habitat quality to gauge fitness differences between habitats. Here, I conduct a comparative analysis of random and non-random dispersal strategies in a foodweb with a basal resource, top predator, and two intermediate consumers that exhibit a trade-off between competitive ability and predator susceptibility. I find a striking contrast between density- and habitat-dependent dispersal in their effects on spatial coexistence. Dispersal in response to competitor and predator density facilitates coexistence while dispersal in response to habitat quality (resource productivity and predator pressure) inhibits it. Moreover, density-dependent dispersal changes species' distribution patterns from interspecific segregation to interspecific aggregation, while habitat-dependent dispersal preserves the interspecific segregation observed in the absence of dispersal. Under density-dependent dispersal, widespread spatial coexistence results in an overall decline in the abundance of the inferior competitor that is less susceptible to predation and an overall increase in the abundance of the superior competitor that is more susceptible to predation. Under habitat-dependent dispersal, restricted spatial coexistence results in species' abundances being essentially unchanged from those observed in the absence of dispersal. A key outcome is that when the superior competitor moves in the direction of increasing fitness but the inferior competitor does not, spatial coexistence is possible in both resource-poor and resource-rich habitats. However, when the inferior competitor moves in the direction of increasing fitness but the superior competitor does not, spatial coexistence is precluded in resource-poor habitats and greatly reduced in resource-rich habitats. This suggests that species-specific differences may play an important role in driving spatial coexistence patterns. The comparative framework yields predictions that can be tested with experiments that manipulate the relative mobilities of interacting species, or observational data on relative abundances and distribution patterns. © 2009 British Ecological Society.


Pearl J.,University of California at Los Angeles
Psychological Methods | Year: 2014

This comment clarifies how structural causal models unify the graphical and potential outcome approaches to mediation, and why the resulting mediation formulas are identical in both frameworks. It further explains under what conditions ignorability-based assumptions are over-restrictive and why such assumptions require graphical interpretations before they can be judged for plausibility. Finally, the comment explains the key difference between traditional and modern methods of causal mediation, and demonstrates why the notion of mediation requires counterfactual rather than Bayes conditionals to be properly defined. © 2014 American Psychological Association.


Heber D.,University of California at Los Angeles
American Journal of Clinical Nutrition | Year: 2010

Obesity is the result of the accumulation of excess body fat and not simply excess weight that can be muscle or fat. Adipocytes function in the adaptation to starvation, in exercise energetics, and in the immune defense against pathogens. Sustained positive energy balance results in excessive accumulation of adipocytes, which, in the abdomen, leads to chronic inflammation. Although informative studies have been performed with cultured adipocytes, an integrative approach to the regulation of abdominal adipose tissue involves feedback from autocrine and paracrine effectors secreted by adipocytes, the immune system, and blood flow through adipose tissue. Numerous adipokines, chemokines, and cytokines feed back to other bodily systems to regulate both energy balance and immune function. Studies of the interactions of the gastrointestinal tract and the central nervous system, as well as psychophysiological considerations of reward circuitry in the central nervous system, have shown a general adaptation to starvation that is opposed to those strategies being proposed for the prevention and treatment of obesity, ie, food restriction and increased physical activity. The obesogenic environment of highly palatable foods with hidden fats and sugars can promote metabolic syndrome and obesity, whereas fruit and vegetables with antiinflammatory phytochemicals can counteract metabolic syndrome. Therefore, a plant-based diet and the seamless integration of increased physical activity and social support to alter modern diets and lifestyles hold out the greatest hope for the solution of the obesity epidemic. Both public health and medical nutrition approaches can benefit from this integrative view of obesity. © 2010 American Society for Nutrition.


Hurvitz S.A.,University of California at Los Angeles
Cancer Treatment Reviews | Year: 2011

Because of its direct clinical relevance, overall survival is the gold standard endpoint for measuring clinical efficacy. However, achieving improvements in overall survival can be confounded by factors such as crossover to active treatment arms and subsequent treatment with non-experimental active therapies. Powering studies to detect significant overall survival increases requires prohibitively large patient numbers and long follow-up and may not always be practical. Trials incorporating progression free survival (PFS) or time to progression (TTP) as primary outcome measures are likely to be shorter, require fewer patients and are usually more affordable, which may ultimately translate into a more rapid evaluation of potentially effective experimental therapies. In heavily pretreated metastatic breast cancer, significant improvements in progression-free survival may indicate a clinically meaningful benefit for patients with otherwise limited salvage therapy options available. Approval for several newer agents in the advanced resistant or refractory metastatic breast cancer setting has been based on prolonged progression-free survival or time to progression as primary trial endpoints. In this paper, clinical trial data relating to OS, PFS and TTP endpoints are reviewed and the use of surrogate markers of survival for the evaluation of new drugs is considered. © 2011 Elsevier Ltd.


Rhodes E.J.,University of California at Los Angeles
Annual Review of Earth and Planetary Sciences | Year: 2011

Optical dating of sediment using optically stimulated luminescence has become important for studying Earth surface processes, and this technique continues to develop rapidly. A group of closely linked luminescence methods can be used to estimate the time since grains of quartz and feldspar were last exposed to daylight by detecting their subsequent response to environmental ionizing radiation exposure. The technique is well suited to the dating of deposits as young as one year to several hundred thousand years. Recent technical developments have established a dating protocol with improved precision, a high degree of reliability, and an in-built means to detect incomplete signal removal during deposition. This approach has been extended to age estimation for single grains, opening up a wider range of potential environments and new possibilities for understanding postdepositional grain movement. Ongoing research offers the possibility of significant age range extension and novel applications including low-temperature thermochronology. Copyright © 2011 by Annual Reviews. All rights reserved.


Schmitt A.K.,University of California at Los Angeles
Annual Review of Earth and Planetary Sciences | Year: 2011

Complex and protracted crystallization histories over geologic timescales are recorded in accessory minerals (e.g., zircon, allanite). Although magmatic crystallization was traditionally assumed to occur essentially instantaneously for the purposes of interpreting mineral geochronometers with low absolute time resolution for ancient samples, it emerged relatively recently that magmatic crystallization can occur over extended durations. This discovery arose from applying high-spatial-resolution accessory mineral dating techniques for uranium series isotopes to young volcanic and cognate plutonic rocks. The emerging pattern from these studies is that individual crystals and crystal populations record crystallization episodes lasting from <1,000 to many hundreds of thousands of years. Accessory mineral dating of volcanic rocks and cognate plutonic xenoliths opens new research avenues for crystal age fingerprinting that correlates pyroclastic deposits, lavas, and plutonic rocks by using characteristic age distributions. It also provides direct observations on magmatic accumulation and residence times, and the preeruptive configuration of subterraneous magma bodies and intrusive complexes with implications for the forecasting of volcanic eruptions. Awareness of potentially protracted crystallization in igneous rocks should guide the interpretation of accessory mineral ages. Copyright © 2011 by Annual Reviews. All rights reserved.


Daboussi L.,University of California at Los Angeles | Costaguta G.,University of California at Los Angeles | Payne G.S.,University of California at Los Angeles
Nature Cell Biology | Year: 2012

Clathrin-coated vesicles mediate endocytosis and transport between the trans-Golgi network (TGN) and endosomes in eukaryotic cells. Clathrin adaptors play central roles in coat assembly, interacting with clathrin, cargo and membranes. Two main types of clathrin adaptor act in TGN-endosome traffic: GGA proteins and the AP-1 complex. Here we characterize the relationship between GGA proteins, AP-1 and other TGN clathrin adaptors using live-cell and super-resolution microscopy in yeast. We present evidence that GGA proteins and AP-1 are recruited sequentially in two waves of coat assembly at the TGN. Mutations that decrease phosphatidylinositol 4-phosphate (PtdIns(4)P) levels at the TGN slow or uncouple AP-1 coat assembly from GGA coat assembly. Conversely, enhanced PtdIns(4)P synthesis shortens the time between adaptor waves. Gga2p binds directly to the TGN PtdIns(4)-kinase Pik1p and contributes to Pik1p recruitment. These results identify a PtdIns(4)P-based mechanism for regulating progressive assembly of adaptor-specific clathrin coats at the TGN. © 2012 Macmillan Publishers Limited. All rights reserved.


Penagarikano O.,University of California at Los Angeles | Geschwind D.H.,University of California at Los Angeles
Trends in Molecular Medicine | Year: 2012

Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous condition characterized by the presence of repetitive/restrictive behaviors and variable deficits in language and social behavior. Many genes predisposing an individual to ASD have been identified, and understanding the causal disease mechanism(s) is critical to be able to develop treatments. Neurobiological, genetic, and imaging data provide strong evidence for the CNTNAP2 gene as a risk factor for ASD and related neurodevelopmental disorders. This review discusses the clinical genetics and current understanding of the biology of CNTNAP2 as related to ASD and illustrates how the integration of multiple research approaches, from human studies to animal models, converge to inform functional biology focused on novel treatment development. © 2012 Elsevier Ltd.


Thomason M.E.,Wayne State University | Thompson P.M.,University of California at Los Angeles
Annual Review of Clinical Psychology | Year: 2011

The functional significance of the brain's white matter was not fully appreciated until new imaging methods were developed to visualize fiber pathways and connections in the living brain. Rapid advances in diffusion tensor imaging (DTI) have led to substantial insights into human brain development and disease processes and have thrust white matter into the focus of researchers and clinicians alike. The full clinical potential of this relatively new technique remains to be determined, but early indicators suggest that DTI will be a significant new technology in mapping mechanisms of human health and disease. Here we review brain changes that have been studied with DTI over the human lifespan and findings in a variety of neuropsychiatric disorders. We also suggest future areas where DTI is likely to have significant impact. Copyright © 2011 by Annual Reviews. All rights reserved.


Shapley A.E.,University of California at Los Angeles
Annual Review of Astronomy and Astrophysics | Year: 2011

The epoch of galaxy assembly from 2≤â(c)1/2z≤â(c)1/24 marks a critical stage during the evolution of today's galaxy population. During this period, the star-formation activity in the Universe was at its peak level, and the structural patterns observed among galaxies in the local Universe were not yet in place. A variety of novel techniques have been employed over the past decade to assemble multiwavelength observations of galaxies during this important epoch. In this primarily observational review, I present a census of the methods used to find distant galaxies and the empirical constraints on their multiwavelength luminosities and colors. I then discuss what is known about the stellar content and past histories of star formation in high-redshift galaxies; their interstellar contents including dust, gas, and heavy elements; and their structural and dynamical properties. I conclude by considering some of the most pressing and open questions regarding the physics of high-redshift galaxies, which are to be addressed with future facilities. © 2011 by Annual Reviews. All rights reserved.


Tserkovnyak Y.,University of California at Los Angeles | Loss D.,University of Basel
Physical Review Letters | Year: 2012

We theoretically study the magnetization dynamics of a thin ferromagnetic film exchange coupled with a surface of a strong three-dimensional topological insulator. We focus on the role of electronic zero modes imprinted by domain walls (DWs) or other topological textures in the magnetic film. Thermodynamically reciprocal hydrodynamic equations of motion are derived for the DW responding to electronic spin torques, on the one hand, and fictitious electromotive forces in the electronic chiral mode fomented by the DW, on the other. An experimental realization illustrating this physics is proposed based on a ferromagnetic strip, which cuts the topological insulator surface into two gapless regions. In the presence of a ferromagnetic DW, a chiral mode transverse to the magnetic strip acts as a dissipative interconnect, which is itself a dynamic object that controls (and, inversely, responds to) the magnetization dynamics. © 2012 American Physical Society.


Sack L.,University of California at Los Angeles
Nature communications | Year: 2012

Leaf size and venation show remarkable diversity across dicotyledons, and are key determinants of plant adaptation in ecosystems past and present. Here we present global scaling relationships of venation traits with leaf size. Across a new database for 485 globally distributed species, larger leaves had major veins of larger diameter, but lower length per leaf area, whereas minor vein traits were independent of leaf size. These scaling relationships allow estimation of intact leaf size from fragments, to improve hindcasting of past climate and biodiversity from fossil remains. The vein scaling relationships can be explained by a uniquely synthetic model for leaf anatomy and development derived from published data for numerous species. Vein scaling relationships can explain the global biogeographical trend for smaller leaves in drier areas, the greater construction cost of larger leaves and the ability of angiosperms to develop larger and more densely vascularised lamina to outcompete earlier-evolved plant lineages.


Liebeskind D.S.,University of California at Los Angeles
Current Opinion in Neurology | Year: 2010

PURPOSE OF REVIEW: Reperfusion of the ischemic territory forms the basis of most acute stroke treatments. This overview of the literature relating to reperfusion in acute ischemic stroke published within the last year provides a snapshot of a rapidly evolving aspect of cerebrovascular disease. RECENT FINDINGS: Arterial revascularization from systemic thrombolysis to combination endovascular procedures to achieve recanalization has proliferated. Stroke imaging continues to discern features of critical pathophysiology that may influence tissue fate and clinical outcome. Balancing the risk of hemorrhagic transformation against the therapeutic aim to salvage the ischemic penumbra remains a formidable challenge. Collateral therapeutics that enhance perfusion outside the ischemic core present novel dimension to acute stroke therapy, focused on ischemia and not just the clot or plaque. SUMMARY: These timely findings illustrate the essential role of reperfusion in acute stroke, delineating aspects of arterial revascularization and collateral therapeutics to be refined in coming years. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Chang H.R.,University of California at Los Angeles
Cancer | Year: 2010

Overexpression, or gene amplification, of the human epidermal growth factor receptor 2 (HER2) is evident in 20% to 25% of breast cancers. The biologic agent trastuzumab is an HER2-targeted monoclonal antibody that inhibits the proliferation of tumor cells and induces tumor cell death through multiple mechanisms of action. Currently, trastuzumab is approved for use in the adjuvant and metastatic settings. Trials combining trastuzumab with neoadjuvant chemotherapy suggest that patients with HER2-positive breast cancer also may benefit from preoperative trastuzumab. For this article, the author reviewed efficacy and safety data from key studies of patients who received neoadjuvant trastuzumab-based therapy. Studies were identified from literature searches of publication and congress databases. The results of 3 large phase 3 trials (the M. D. Anderson Cancer Center neoadjuvant trastuzumab trial, the Neoadjuvant Herceptin [NOAH] trial, and the German Breast Group/Gynecologic Oncology Study Group "GeparQuattro" trial) demonstrated that, compared with chemotherapy alone, neoadjuvant trastuzumab plus chemotherapy significantly increased pathologic complete response rates to as high as 65%. Improvements in disease-free, overall, and event-free survival also were reported in the NOAH trial. In addition to demonstrated efficacy, a low incidence of cardiac dysfunction suggests that neoadjuvant trastuzumab is both effective and well tolerated. Similar results have been reported in a range of phase 2 studies using different trastuzumab-based regimens. These encouraging data led the National Comprehensive Cancer Network to recommend treating patients who have operable, locally advanced, HER2-positive breast cancer with neoadjuvant paclitaxel plus trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide plus trastuzumab. © 2010 American Cancer Society.


Smith T.J.,University of California at Los Angeles | Smith T.J.,University of Michigan
Pharmacological Reviews | Year: 2010

This topically limited review explores the relationship between the immune system and insulin-like growth factors (IGF-I and IGF-II) and the proteins through which they act, including IGF-I receptor (IGF-IR) and the IGF-I binding proteins. The IGF/IGF-IR pathway plays important and diverse roles in tissue development and function. It regulates cell cycle progression, apoptosis, and the translation of proteins. Many of the consequences ascribed to IGF-IR activation result from its association with several accessory proteins that are either identical or closely related to those involved in insulin receptor signaling. Relatively recent awareness that IGF-I and IGF-IR regulate immune function has cast this pathway in an unexpected light; it may represent an important switch governing the quality and amplitude of immune responses. IGF-I/IGF-IR signaling may also participate in the pathogenesis of autoimmune diseases, although its relationship with these processes seems complex and relatively unexplored. On the one hand, IGF-I seems to protect experimental animals from developing insulin-deficient diabetes mellitus. In contrast, activating antibodies directed at IGF-IR have been detected in patients with Graves' disease, where the receptor is overexpressed by multiple cell types. The frequency of IGF-IR+ B and T cells is substantially increased in patients with that disease. Potential involvement of IGF-I and IGF-IR in the pathogenesis of autoimmune diseases suggests that this pathway might constitute an attractive therapeutic target. IGF-IR has been targeted in efforts directed toward drug development for cancer, employing both small-molecule and monoclonal antibody approaches. These have been generally well-tolerated. Recognizing the broader role of IGF-IR in regulating both normal and pathological immune responses may offer important opportunities for therapeutic intervention in several allied diseases that have proven particularly difficult to treat. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


Goda K.,University of Tokyo | Goda K.,University of California at Los Angeles | Jalali B.,University of California at Los Angeles
Nature Photonics | Year: 2013

Dispersive Fourier transformation is an emerging measurement technique that overcomes the speed limitations of traditional optical instruments and enables fast continuous single-shot measurements in optical sensing, spectroscopy and imaging. Using chromatic dispersion, dispersive Fourier transformation maps the spectrum of an optical pulse to a temporal waveform whose intensity mimics the spectrum, thus allowing a single-pixel photodetector to capture the spectrum at a scan rate significantly beyond what is possible with conventional space-domain spectrometers. Over the past decade, this method has brought us a new class of real-time instruments that permit the capture of rare events such as optical rogue waves and rare cancer cells in blood, which would otherwise be missed using conventional instruments. In this Review, we discuss the principle of dispersive Fourier transformation and its implementation across a wide range of diverse applications. © 2013 Macmillan Publishers Limited. All rights reserved.


Riedl M.A.,University of California at Los Angeles
Journal of Allergy and Clinical Immunology: In Practice | Year: 2013

Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH), also known as HAE type III, is a familial condition only clinically recognized within the past three decades. Similar to HAE from C1-INH deficiency (HAE types I and II), affected individuals experience unpredictable angioedema episodes of the skin, gastrointestinal tract, and airway. Unique clinical features of HAE with normal C1-INH include the predominance of affected women, frequent exacerbation by estrogen, and a prominence of angioedema that involves the face and oropharynx. The underlying pathophysiology of HAE with normal C1-INH is poorly understood, but indirect evidence points to contact pathway dysregulation with bradykinin-mediated angioedema. Currently, evaluation is complicated by a lack of confirmatory laboratory testing such that clinical criteria must often be used to make the diagnosis of HAE with normal C1-INH. Factor XII mutations have been identified in only a minority of persons affected by HAE with normal C1-INH, limiting the utility of such analysis. To date, no controlled clinical studies have examined the efficacy of therapeutic agents for HAE with normal C1-INH, although published evidence supports frequent clinical benefit with medications shown effective in HAE due to C1-INH deficiency. © 2013 American Academy of Allergy, Asthma&Immunology.


Modlin R.L.,University of California at Los Angeles
Journal of Investigative Dermatology | Year: 2012

The innate immune system must recognize and rapidly respond to microbial pathogens, providing a first line of host defense. This is accomplished through an array of pattern recognition receptors (PRRs) that reside in specific subcellular compartments and can bind pathogen-associated molecular patterns. PRRs also recognize self-molecules that are released after cell damage or death, known as danger-associated molecular patterns, which can be actively transported across cell membranes. The activation of PRRs leads to host defense pathways in infectious diseases, but can also contribute to tissue injury in autoimmune diseases. The identification of these pathways has provided new insight into mechanisms of vaccination and holds promise for developing better vaccines. Finally, the identification of PRRs, their ligands, and signaling pathways provides an opportunity for developing new immunotherapeutic approaches to skin conditions in which activation of the innate immune response contributes to disease pathogenesis. © 2012 The Society for Investigative Dermatology.


Cecka J.M.,University of California at Los Angeles
American Journal of Transplantation | Year: 2010

The ways we measure whether a patient is sensitized to HLA antigens and to what extent sensitization affects access to transplantation have changed remarkably during the past decade. What we mean by sensitized and broadly sensitized today is heavily dependent upon the sensitivity of the test that is used to measure antibodies. Because we provide additional allocation points for broadly sensitized patients in the United States kidney allocation system in an effort to compensate for their biological disadvantage, some consistency and accountability are required. The calculated panel-reactive antibody, which provides an estimate of the percentage of deceased organ donors that will be crossmatch incompatible for a candidate provides both consistency and accountability. © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons.


Demer J.L.,University of California at Los Angeles
Eye (Basingstoke) | Year: 2015

Ocular motor diversity exceeds capabilities of only six extraocular muscles (EOMs), but this deficiency is overcome by the plethora of fibers within individual EOMs surpassing requirements of homogeneous actuators. This paper reviews emerging evidence that regions of individual EOMs can be differentially innervated to exert independent oculorotary torques, broadening the oculomotor repertoire, and potentially explaining diverse strabismus pathophysiology. Parallel structure characterizes EOM and tendon fibers, with little transverse coupling of experimentally imposed or actively generated tension. This arrangement enables arbitrary groupings of tendon and muscle fibers to act relatively independently. Coordinated force generation among EOM fibers occurs only upon potentially mutable coordination of innervational commands, whose central basis is suggested by preliminary findings of apparent compartmental segregation of abducens motor neuron pools. Humans, monkeys, and other mammals demonstrate separate, nonoverlapping intramuscular nerve arborizations in the superior vs inferior compartments of the medial rectus (MR) and lateral rectus (LR) EOMs that could apply force at the superior vs inferior portions of scleral insertions, and in the medial vs lateral compartments of the superior oblique that act at the equatorial vs posterior scleral insertions that might preferentially implement incycloduction vs infraduction. Magnetic resonance imaging of the MR during several physiological ocular motor behaviors indicates differential compartmental function. Differential compartmental pathology can influence clinical strabismus. Partial abducens palsy commonly affects the superior LR compartment more than the inferior, inducing vertical strabismus that might erroneously be attributed to cyclovertical EOM pathology. Surgery may selectively manipulate EOM compartments. © 2015 Macmillan Publishers Limited. All rights reserved.


Soderstrom N.C.,University of California at Los Angeles | Bjork R.A.,University of California at Los Angeles
Perspectives on Psychological Science | Year: 2015

The primary goal of instruction should be to facilitate long-term learning—that is, to create relatively permanent changes in comprehension, understanding, and skills of the types that will support long-term retention and transfer. During the instruction or training process, however, what we can observe and measure is performance, which is often an unreliable index of whether the relatively long-term changes that constitute learning have taken place. The time-honored distinction between learning and performance dates back decades, spurred by early animal and motor-skills research that revealed that learning can occur even when no discernible changes in performance are observed. More recently, the converse has also been shown—specifically, that improvements in performance can fail to yield significant learning—and, in fact, that certain manipulations can have opposite effects on learning and performance. We review the extant literature in the motor- and verbal-learning domains that necessitates the distinction between learning and performance. In addition, we examine research in metacognition that suggests that people often mistakenly interpret their performance during acquisition as a reliable guide to long-term learning. These and other considerations suggest that the learning–performance distinction is critical and has vast practical and theoretical implications. © The Author(s) 2015


Jewitt D.,University of California at Los Angeles
Astronomical Journal | Year: 2012

Some asteroids eject dust, unexpectedly producing transient, comet-like comae and tails. First ascribed to the sublimation of near-surface water ice, mass-losing asteroids (also called "main-belt comets") can in fact be driven by a surprising diversity of mechanisms. In this paper, we consider 11 dynamical asteroids losing mass, in nine of which the ejected material is spatially resolved. We address mechanisms for producing mass loss including rotational instability, impact ejection, electrostatic repulsion, radiation pressure sweeping, dehydration stresses, and thermal fracture, in addition to the sublimation of ice. In two objects (133P and 238P) the repetitive nature of the observed activity leaves ice sublimation as the only reasonable explanation, while in a third ((596) Scheila), a recent impact is the cause. Another impact may account for activity in P/2010 A2, but this tiny object can also be explained as having shed mass after reaching rotational instability. Mass loss from (3200) Phaethon is probably due to cracking or dehydration at extreme (1000K) perihelion temperatures, perhaps aided by radiation pressure sweeping. For the other bodies, the mass-loss mechanisms remain unidentified, pending the acquisition of more and better data. While the active asteroid sample size remains small, the evidence for an astonishing diversity of mass-loss processes in these bodies is clear. © 2012. The American Astronomical Society. All rights reserved..


Tashkin D.P.,University of California at Los Angeles
Current Opinion in Pulmonary Medicine | Year: 2013

PURPOSE OF REVIEW: This article reviews findings from longitudinal observational studies in both general and chronic obstructive pulmonary disease (COPD) populations, as well as from intervention trials in COPD, in which the annual rate of decline in forced expired volume in 1 s (FEV1) has been measured. The purpose of the review is to describe the individual variability in rates of decline in FEV1 within these populations, explore the factors contributing to this variability and discuss its implications. RECENT FINDINGS: Individual rates of decline in FEV1 have been found to vary considerably across participants with COPD in both observational cohorts and intervention trials from decreases as rapid as 150- 200 ml per year to increases of up to approximately 150 ml per year, with mean rates of decline ranging from 33 to 69 ml per year. Aside from technical and biologic (e.g., time of day, season, weather, fatigue) sources of variation, other influential factors have included smoking status (most notably current versus former smoking), baseline smoking intensity, baseline lung function, airway hyperresponsiveness, exacerbation frequency, and, variably, age and sex. The presence of emphysema may also be a determinant, as well as certain biomarkers and gene variants. SUMMARY: The wide distribution of individual rates of decline in FEV1 includes especially rapid and slow declines. Future research is needed to identify biomarkers that both are predictive of a rapid decline within individuals who might then be targeted for special intervention and might also serve as surrogate endpoints in interventional trials. Copyright © Lippincott Williams & Wilkins.


Glassock R.J.,University of California at Los Angeles
Clinical Journal of the American Society of Nephrology | Year: 2012

Nephrotic syndrome in older adult patients is a common clinical conundrum. Membranous nephropathy (MN) is a lesion frequently found to underlie the nephrotic state in such patients. Determining with reasonable certainty whether the nephrotic syndrome andMNis primary (idiopathic) or due to an underlying disease such as neoplasia can be a daunting clinical challenge. By way of a presentation of an illustrative case and a focused review of the relevant literature, the approach to evaluation of such patients, with an emphasis on the putative causative role of neoplasia in MN, is analyzed and a potential contemporary pathway for acquiring the correct diagnosis is offered. © 2012 by the American Society of Nephrology.


Vican L.,University of California at Los Angeles
Astronomical Journal | Year: 2012

DEBRIS is a flux-limited survey of nearby stars (spectral types A-M) for evidence of debris disks with the Herschel Space Observatory. One goal of the survey is to determine disk incidence as a function of various stellar parameters. Understanding debris disk evolution depends on knowledge of the precise age of stars around which these debris disks are found. However, finding ages for field stars is notoriously difficult. Furthermore, in an unbiased sample like DEBRIS, one is working with stars across many spectral types. This requires a multi-method approach to age determination. In this paper, we outline several methods of age determination broken down by spectral type, including some strengths and limitations of each method. In total, we were able to calculate ages for 263 of 274 F-, G-, and K-type stars, and all 83 A-type stars in the DEBRIS sample. © 2012. The American Astronomical Society. All rights reserved.


Pearl J.,University of California at Los Angeles
American Journal of Epidemiology | Year: 2011

In choosing covariates for adjustment or inclusion in propensity score analysis, researchers must weigh the benefit of reducing confounding bias carried by those covariates against the risk of amplifying residual bias carried by unmeasured confounders. The latter is characteristic of covariates that act like instrumental variables-that is, variables that are more strongly associated with the exposure than with the outcome. In this issue of the Journal (Am J Epidemiol. 2011;174(11):1213-1222), Myers et al. compare the bias amplification of a near-instrumental variable with its bias-reducing potential and suggest that, in practice, the latter outweighs the former. The author of this commentary sheds broader light on this comparison by considering the cumulative effects of conditioning on multiple covariates and showing that bias amplification may build up at a faster rate than bias reduction. The author further derives a partial order on sets of covariates which reveals preference for conditioning on outcome-related, rather than exposure-related, confounders. © The Author 2011.


Sharma S.,University of California at Los Angeles
Nanoscale | Year: 2013

Actin remodeling is an area of interest in biology in which correlative microscopy can bring a new way to analyze protein complexes at the nanoscale. Advances in EM, X-ray diffraction, fluorescence, and single molecule techniques have provided a wealth of information about the modulation of the F-actin structure and its regulation by actin binding proteins (ABPs). Yet, there are technological limitations of these approaches to achieving quantitative molecular level information on the structural and biophysical changes resulting from ABPs interaction with F-actin. Fundamental questions about the actin structure and dynamics and how these determine the function of ABPs remain unanswered. Specifically, how local and long-range structural and conformational changes result in ABPs induced remodeling of F-actin needs to be addressed at the single filament level. Advanced, sensitive and accurate experimental tools for detailed understanding of ABP-actin interactions are much needed. This article discusses the current understanding of nanoscale structural and mechanical modulation of F-actin by ABPs at the single filament level using several correlative microscopic techniques, focusing mainly on results obtained by Atomic Force Microscopy (AFM) analysis of ABP-actin complexes.


Flint J.,Oxford Genetics | Eskin E.,University of California at Los Angeles
Nature Reviews Genetics | Year: 2012

Genome-wide association studies (GWASs) have transformed the field of human genetics and have led to the discovery of hundreds of genes that are implicated in human disease. The technological advances that drove this revolution are now poised to transform genetic studies in model organisms, including mice. However, the design of GWASs in mouse strains is fundamentally different from the design of human GWASs, creating new challenges and opportunities. This Review gives an overview of the novel study designs for mouse GWASs, which dramatically improve both the statistical power and resolution compared to classical gene-mapping approaches. © 2012 Macmillan Publishers Limited. All rights reserved.


Rome L.H.,University of California at Los Angeles | Kickhoefer V.A.,University of California at Los Angeles
ACS Nano | Year: 2013

Vaults are naturally occurring nanoparticles found widely in eukaryotes. The particles can be produced in large quantities and are assembled in situ from multiple copies of the single structural protein following expression. Using molecular engineering, recombinant vaults can be functionally modified and targeted, and their contents can be controlled by packaging. Here, we review the development of engineered vaults as a platform for a wide variety of therapeutic applications and we examine future directions for this unique nanoparticle system. © 2012 American Chemical Society.


Furst D.E.,University of California at Los Angeles
Rheumatology (Oxford, England) | Year: 2013

To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS. Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (≥ 15 and <60 ng/ml) and anaemia of inflammation (≥ 60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores. At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001). Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.


Lukacs R.U.,University of California at Los Angeles
Nature protocols | Year: 2010

The successful isolation and cultivation of prostate stem cells will allow us to study their unique biological properties and their application in therapeutic approaches. Here we describe step-by-step procedures on the basis of previous work in our laboratory for the harvesting of primary prostate cells from adolescent male mice by a modified enzymatic procedure; the isolation of an enriched population of prostate stem cells through cell sorting; and the cultivation of prostate stem cells in vitro and characterization of these cells and their stem-like activity, including in vivo tubule regeneration. Normally, it will take approximately 8 h to harvest prostate cells, isolate the stem cell-enriched population and set up the in vitro sphere assay. It will take up to 8 weeks to analyze the unique properties of the stem cells, including their regenerative capacity in vivo.


Sahai A.,University of California at Los Angeles | Watersy B.,University of Texas at Austin
Proceedings of the Annual ACM Symposium on Theory of Computing | Year: 2014

We introduce a new technique, that we call punctured programs, to apply indistinguishability obfuscation towards cryptographic problems. We use this technique to carry out a systematic study of the applicability of indistinguishability obfuscation to a variety of cryptographic goals. Along the way, we resolve the 16-year-old open question of Deniable Encryption, posed by Canetti, Dwork, Naor, and Ostrovsky in 1997: In deniable encryption, a sender who is forced to reveal to an adversary both her message and the randomness she used for encrypting it should be able to convincingly provide "fake" randomness that can explain any alternative message that she would like to pretend that she sent. We resolve this question by giving the first construction of deniable encryption that does not require any pre-planning by the party that must later issue a denial. In addition, we show the generality of our punctured programs technique by also constructing a variety of core cryptographic objects from indistinguishability obfuscation and one-way functions (or close variants). In particular we obtain: public key encryption, short "hash-and-sign" selectively secure signatures, chosen-ciphertext secure public key encryption, non-interactive zero knowledge proofs (NIZKs), injective trapdoor functions, and oblivious transfer. These results suggest the possibility of indistinguishability obfuscation becoming a "central hub" for cryptography. © 2014 ACM.


Tottenham N.,University of California at Los Angeles
Developmental Psychobiology | Year: 2012

In altricial species, like the human, caregiver presence is necessary for typical emotional development. Children who have been raised in institutional care early in life experience caregiver deprivation and are at significantly elevated risk for emotional difficulties. The current manuscript examines the non-human and human literatures on amygdala development following caregiver deprivation and presents an argument that in the absence of the species-expected caregiver presence, human amygdala development exhibits rapid development and perhaps premature engagement that results in some of the emotional phenotypes observed following early institutional care. © 2012 Wiley Periodicals, Inc.


Ribas A.,University of California at Los Angeles | Tumeh P.C.,University of California at Los Angeles
Clinical Cancer Research | Year: 2014

It is conceivable that, in the near future, an assay that defines the likelihood of a patient with advanced cancer to respond to immunotherapy based on PD1/L1 blockade will be the initial decision point to select the treatment of patients with any cancer type. ©2014 AACR.


Geschwind D.H.,University of California at Los Angeles | Flint J.,University of Oxford
Science | Year: 2015

Large-scale genomic investigations have just begun to illuminate the molecular genetic contributions to major psychiatric illnesses, ranging from small-effect-size common variants to larger-effect-size rare mutations. The findings provide causal anchors from which to understand their neurobiological basis. Although these studies represent enormous success, they highlight major challenges reflected in the heterogeneity and polygenicity of all of these conditions and the difficulty of connecting multiple levels of molecular, cellular, and circuit functions to complex human behavior. Nevertheless, these advances place us on the threshold of a new frontier in the pathophysiological understanding, diagnosis, and treatment of psychiatric disease. © 2015, American Association for the Advancement of Science. All rights reserved.


Han B.,University of California at Los Angeles | Eskin E.,University of California at Los Angeles
American Journal of Human Genetics | Year: 2011

Meta-analysis is an increasingly popular tool for combining multiple different genome-wide association studies (GWASs) in a single aggregate analysis in order to identify associations with very small effect sizes. Because the data of a meta-analysis can be heterogeneous, referring to the differences in effect sizes between the collected studies, what is often done in the literature is to apply both the fixed-effects model (FE) under an assumption of the same effect size between studies and the random-effects model (RE) under an assumption of varying effect size between studies. However, surprisingly, RE gives less significant p values than FE at variants that actually show varying effect sizes between studies. This is ironic because RE is designed specifically for the case in which there is heterogeneity. As a result, usually, RE does not discover any associations that FE did not discover. In this paper, we show that the underlying reason for this phenomenon is that RE implicitly assumes a markedly conservative null-hypothesis model, and we present a new random-effects model that relaxes the conservative assumption. Unlike the traditional RE, the new method is shown to achieve higher statistical power than FE when there is heterogeneity, indicating that the new method has practical utility for discovering associations in the meta-analysis of GWASs. © 2011 The American Society of Human Genetics.


Mitchell J.L.,University of California at Los Angeles
Astrophysical Journal Letters | Year: 2012

The mechanisms behind the occurrence of large cloud outbursts and precipitation on Titan have been disputed. A global- and annual-mean estimate of surface fluxes indicated only 1% of the insolation, or 0.04Wm-2, is exchanged as sensible and/or latent fluxes. Since these fluxes are responsible for driving atmospheric convection, it has been argued that moist convection should be quite rare and precipitation even rarer, even if evaporation globally dominates the surface-atmosphere energy exchange. In contrast, climate simulations indicate substantial cloud formation and/or precipitation. We argue that the top-of-atmosphere (TOA) radiative imbalance is diagnostic of horizontal heat transport by Titan's atmosphere, and thus constrains the strength of the methane cycle. Simple calculations show the TOA radiative imbalance is ∼0.5-1Wm-2 in Titan's equatorial region, which implies 2-3MW of latitudinal heat transport by the atmosphere. Our simulation of Titan's climate suggests this transport may occur primarily as latent heat, with net evaporation at the equator and net accumulation at higher latitudes. Thus, the methane cycle could be 10-20times previous estimates. Opposing seasonal transport at solstices, compensation by sensible heat transport, and focusing of precipitation by large-scale dynamics could further enhance the local, instantaneous strength of Titan's methane cycle by a factor of several. A limited supply of surface liquids in regions of large surface radiative imbalance may throttle the methane cycle, and if so, we predict more frequent large storms over the lakes district during Titan's northern summer. © 2012 The American Astronomical Society. All rights reserved.


Nemeth E.,University of California at Los Angeles
Blood | Year: 2013

In this issue of Blood, Cooke et al demonstrate the potential of a fully human anti-hepcidin antibody as a novel therapeutic for iron-restricted anemias such as anemia of inflammation, cancer, or chronic kidney disease (formerly known as "anemia of chronic diseases"). © 2013 by The American Society of Hematology.


Gomez-Pinilla F.,University of California at Los Angeles
Preventive Medicine | Year: 2011

Objective: Exercise and select diets have important influences on health and plasticity of the nervous system, and the molecular mechanisms involved with these actions are starting to be elucidated. New evidence indicates that exercise, in combination with dietary factors, exerts its effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Methods: Published studies in animals and humans describing the effects of exercise and diets in brain plasticity and cognitive abilities are discussed. Results: New evidence indicates that exercise and select diets exert their effects by affecting molecular events related to the management of energy metabolism and synaptic plasticity. An important instigator in the molecular machinery stimulated by exercise is brain-derived neurotrophic factor (BDNF), which acts at the interface of metabolism and plasticity. Conclusions: Recent studies show that selected dietary factors share similar mechanisms with exercise, and in some cases they can complement the action of exercise. Therefore, exercise and dietary management appear as a non-invasive and effective strategy to counteract neurological and cognitive disorders. © 2011 Elsevier Inc.


Finn R.S.,University of California at Los Angeles
Clinical Cancer Research | Year: 2010

Hepatocellular carcinoma (HCC), once considered an orphan disease in the West, has become a global health concern. It is the third leading cause of cancer death worldwide, and its incidence continues to increase. Historically, the development of new systemic agents for advanced HCC has been lacking despite no clear benefit with traditional cytotoxic therapies. Although two randomized studies with sorafenib for the treatment of HCC patients have recently been completed, survival benefits have been modest and highlight the unmet medical need among patients with HCC. Given the clear need, clinical development of novel systemic agents in HCC has begun in earnest. These clinical studies are founded on a growing body of basic and translational science that has identified several potential molecular targets in HCC. The successful development of such targeted agents in the future will be linked to our ability to appropriately select patients for treatment based on their clinical stage (including extent of liver disease and extent of tumor) and on potential predictive markers of response. Here, we review these data in the context of rational drug development in HCC in the front-line setting and in previously treated patients. ©2010 AACR.


Dev A.,University of California at Los Angeles
Current topics in microbiology and immunology | Year: 2011

Members of the NF-κB transcription factor family play a critical role in the development of innate immunity. Upon recognition of pathogen infections or tissue damage, the NF-κB pathway is strongly activated by cellular pattern recognition receptors, including Toll-like receptors and multiple cytosolic receptors such as RIG-I-like helicases and NOD family proteins. NF-κB is required not only for the expression, but also for subsequent signal transduction of numerous downstream cytokines. NF-κB-responsive genes affect a diverse array of cellular processes including apoptosis and cell survival, and often directly control the course of a pathogen infection. In this review, we will examine signaling pathways leading to NF-κB activation during the innate immune response and mechanisms of pathogen-modulation of these pathways; the specifics of NF-κB-dependent gene programs, and the physiological consequences for the immune system caused by the absence of individual NF-κB subunits.


Wilson E.B.,University of California at Los Angeles
Current topics in microbiology and immunology | Year: 2011

The immune system has evolved multipronged responses that are critical to effectively defend the body from invading pathogens and to clear infection. However, the same weapons employed to eradicate infection can have caustic effects on normal bystander cells. Therefore, tight regulation is vital and the host must balance engendering correct and sufficient immune responses to pathogens while limiting errant and excessive immunopathology. To accomplish this task, a complex network of positive and negative immune signals are delivered, which in most instances successfully eliminate the pathogen. However, in response to some viral infections, immune function is rapidly suppressed leading to viral persistence. Immune suppression is a critical obstacle to the control of many persistent viral infections such as HIV, hepatitis C, and hepatitis B virus, which together affect more than 500 million individuals worldwide. Thus, the ability to therapeutically enhance immunity is a potentially powerful approach to resolve persistent infections. The host-derived cytokine IL-10 is a key player in the establishment and perpetuation of viral persistence. This chapter discusses the role of IL-10 in viral persistence and explores the exciting prospect of therapeutically blocking IL-10 to increase antiviral immunity and vaccine efficacy.


Slamon D.,University of California at Los Angeles
The New England journal of medicine | Year: 2011

Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).


Han P.,University of California at Los Angeles | Weiss P.S.,University of California at Los Angeles
Surface Science Reports | Year: 2012

We review electronic substrate-mediated interactions (SMIs), which stem from adsorption-induced perturbations of substrate surface electronic states. We examine the experimental progress that exploits electronic SMIs as a means to control the order and structures of surface self-assemblies, with emphasis on scanning tunneling microscopy (STM), a technique that is sensitive to both the spatial and the energetic distributions of surface electronic states. Furthermore, we examine the opportunities and challenges associated with the use of electronic SMIs to control the bulk properties of low-dimensional materials. © 2011 Elsevier B.V. All rights reserved.


Glassock R.J.,University of California at Los Angeles
Current Opinion in Nephrology and Hypertension | Year: 2011

Purpose of review: This review will analyze contemporary information concerning the possible pathogenetic mechanisms involved in IgA nephropathy, emphasizing studies in humans rather than experimental animals. Recent findings: Deposition of IgA in the glomeruli, the hallmark of IgA nephropathy, may be a quite common phenomenon. Aberrant O-linked galactosylation of IgA subclass (IgA1) appears to play a central role and 'auto-immunity' to a conformational epitope related to glycans at the hinge region of IgA1 is apparently required. Both a circulating immune complex and an in-situ immune complex mechanism have been advanced. Mediator systems, such as complement activation and engagement of innate immune system, also play prominent roles in determining the clinical onset and severity of disease. Genetic influences are evident but the fine details of genetic predisposition and its impact on outcomes still need to be further elucidated. Summary: Progress in understanding the details of the pathogenesis of IgA nephropathy will lead to a better means of diagnosis (including noninvasive tests for diagnosis), more accurate individualized prognosis and personalized treatment regimens for this globally distributed and very common primary glomerular disease. © 2011 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Wang Z.,Changzhou University | Xu X.,Changzhou University | Kwon O.,University of California at Los Angeles
Chemical Society Reviews | Year: 2014

Nucleophilic phosphine catalysis of allenes with electrophiles is one of the most powerful and straightforward synthetic strategies for the generation of highly functionalized carbocycle or heterocycle structural motifs, which are present in a wide range of bioactive natural products and medicinally important substances. The reaction topologies can be controlled through a judicious choice of the phosphine catalyst and the structural variations of starting materials. This Tutorial Review presents selected examples of nucleophilic phosphine catalysis using allenes and electrophiles. This journal is © the Partner Organisations 2014.


Smale S.T.,University of California at Los Angeles
Current Opinion in Genetics and Development | Year: 2010

Most studies of tissue-specific and developmental stage-specific transcription have focused on the DNA motifs, transcription factors, or chromatin events required for the active transcription of a gene in cells in which the gene is expressed, or for its active or heritable silencing in nonexpressing cells. However, accumulating evidence suggests that, in multicellular eukaryotes, enhancers or promoters for tissue-specific genes interact with pioneer transcription factors in embryonic stem cells and at other early stages of development, long before the genes are transcribed. These early interactions, which can lead to the presence of unmethylated CpG dinucleotides, histone modification signatures, and/or chromatin remodeling, may carry out different functions at different classes of genes. © 2010 Elsevier Ltd.


Law J.A.,University of California at Los Angeles | Jacobsen S.E.,University of California at Los Angeles | Jacobsen S.E.,Howard Hughes Medical Institute
Nature Reviews Genetics | Year: 2010

Cytosine DNA methylation is a stable epigenetic mark that is crucial for diverse biological processes, including gene and transposon silencing, imprinting and X chromosome inactivation. Recent findings in plants and animals have greatly increased our understanding of the pathways used to accurately target, maintain and modify patterns of DNA methylation and have revealed unanticipated mechanistic similarities between these organisms. Key roles have emerged for small RNAs, proteins with domains that bind methylated DNA and DNA glycosylases in these processes. Drawing on insights from both plants and animals should deepen our understanding of the regulation and biological significance of DNA methylation. © 2010 Macmillan Publishers Limited. All rights reserved.


Stanton A.L.,University of California at Los Angeles
Journal of consulting and clinical psychology | Year: 2013

The diagnosis and treatment of cancer are highly stressful experiences that can profoundly affect emotional and physical well-being. Hundreds of longitudinal investigations that identify risk and protective factors for psychological and physical adjustment in adults living with cancer and numerous randomized controlled psychosocial intervention trials constitute the relevant knowledge base on factors that promote quality of life and health in this group. A critical step for the development of maximally effective interventions is to attend to the mechanisms by which interventions achieve their effects. Our goals in this article are to provide a rationale for theoretical and empirical consideration of mediating processes in intervention research, review existing randomized psychosocial intervention trials for adults diagnosed with cancer that include evaluation of mediators, and offer recommendations for research. We draw from the existing conceptual and empirical literature regarding examination of mediating processes and review 16 randomized controlled trials that include evaluations of mediators. The current conceptual and empirical literature on evaluating mediators of interventions provides robust rationales and procedures for testing mediators of psychosocial interventions for adults diagnosed with cancer. Promising classes of mediators include alterations in cognitions (i.e., expectancies, illness representations), self-efficacy for using coping strategies and other skills targeted by the intervention, psychological and physical symptoms related to cancer (e.g., mood disturbance, pain), and psychosocial resources (e.g., self-esteem). Focused attention to mechanisms underlying the efficacy of interventions can help integrate theory, research, and practice to promote the well-being and health of individuals with cancer.


Hamidi H.,University of California at Los Angeles
British Journal of Cancer | Year: 2014

Background:To study the molecular mechanism regulating sensitivity to MEK inhibition in pancreatic cancer cell lines.Methods:A growth inhibition assay determined sensitivity to MEK162 in a panel of 29 pancreatic cancer cell lines. For the same panel, KRAS mutational status and copy-number variation (CNV) was determine using PCR, array CGH and FISH. Two sensitive and two resistant cell lines were further interrogated for difference in baseline and MEK162-induced gene expression, as well as signal transduction using microarray and western blotting. Cell cycle and apoptosis analysis was measured by flow cytometry.Results:We report a strong correlation between both specific KRAS mutational subtype and CNV, and sensitivity to MEK inhibition. Cell lines with a KRAS (V12) mutation and KRAS gains or loss (n=7) are ∼10 times more resistant than those having neither a KRAS (V12) mutation nor KRAS CNV (n=14). Significant differences in baseline and MEK162-induced gene expression exist between the sensitive and resistant lines, especially in genes involved in RAS, EGF receptor and PI3K pathways. This was further supported by difference in signal transduction. MEK 162 blocked ERK1/2, as well as inhibited PI3K and S6 and increased p27KIP1 levels in the sensitive lines.Conclusions:Given the potency of MEK162, it may be a promising new therapy for patients with pancreatic cancer and KRAS mutational subtypes, and CNV may serve as important biomarkers for selecting patients that benefit from MEK-targeting based on these preclinical data.British Journal of Cancer advance online publication 28 August 2014; doi:10.1038/bjc.2014.475 www.bjcancer.com.


Hu W.,University of California at Los Angeles
Proceedings of the IEEE Computer Society Conference on Computer Vision and Pattern Recognition | Year: 2012

This paper presents a method for learning 3D object templates from view labeled object images. The 3D template is defined in a joint appearance and geometry space composed of deformable planar part templates placed at different 3D positions and orientations. Appearance of each part template is represented by Gabor filters, which are hierarchically grouped into line segments and geometric shapes. AND-OR trees are further used to quantize the possible geometry and appearance of part templates, so that learning can be done on a subsampled discrete space. Using information gain as a criterion, the best 3D template can be searched through the AND-OR trees using one bottom-up pass and one top-down pass. Experiments on a new car dataset with diverse views show that the proposed method can learn meaningful 3D car templates, and give satisfactory detection and view estimation performance. Experiments are also performed on a public car dataset, which show comparable performance with recent methods. © 2012 IEEE.


Adams J.S.,University of California at Los Angeles | Hewison M.,University of California at Los Angeles
Journal of Clinical Endocrinology and Metabolism | Year: 2010

The past decade, particularly the last 18 months, witnessed a vigorous increase in interest in vitamin D from both the lay and biomedical worlds. Much of the growing interest in vitamin D is powered by new data being extracted from the National Health and Nutrition Examination Survey (NHANES). The newest statistics demonstrate that more than 90% of the pigmented populace of the United States (Blacks, Hispanics, and Asians) now suffer from vitamin D insufficiency (25-hydroxyvitamin D<30 ng/ml), with nearly three fourths of the white population in this country also being vitamin D insufficient. This represents a near doubling of the prevalence of vitamin D insufficiency seen just 10 yr ago in the same population. This review attempts to provide some explanation for: 1) the rapid decline in vitamin D status in the United States; 2) the adverse impact of vitamin D insufficiency on skeletal, infectious/inflammatory, and metabolic health in humans; and 3) the therapeutic rationale and reliable means for vigorous supplementation of our diets with vitamin D. Copyright © 2010 by The Endocrine Society.


Ruiz A.,University of California at Los Angeles
Investigative ophthalmology & visual science | Year: 2012

We report generation of a mouse model in which the STRA6 gene has been disrupted functionally to facilitate the study of visual responses, changes in ocular morphology, and retinoid processing under STRA6 protein deficiency. A null mouse line, stra6 -/-, was generated. Western Blot and immunocytochemistry were used to determine expression of STRA6 protein. Visual responses and morphological studies were performed on 6-week, 5-month and 10-month-old mice. The retinoid content of eye tissues was evaluated in dark-adapted mice by high performance liquid chromatography. STRA6 protein was not detectable in stra6 -/- null mice, which had a consistent reduction, but not total ablation of their visual responses. The mice also showed significant depletion of their retinoid content in retinal pigment epithelium (RPE) and neurosensory retina, including a 95% reduction in retinyl esters. At the morphological level, a reduction in thickness of the neurosensory retina due to shortening of the rod outer and inner segments was observed when compared to control litter mates with a commensurate reduction in rod a- and b-wave amplitudes. In addition, there was a reduction in cone photoreceptor cell number and cone b-wave amplitude. A typical hallmark in stra6 -/- null eyes was the presence of a persistent primary hypertrophic vitreous, an optically dense vascularized structure located in the vitreous humor between the posterior surface of the lens and neurosensory retina. Our studies of stra6 -/- null mice established the importance of the STRA6 protein for the uptake, intracellular transport, and processing of retinol by the RPE. In its absence, rod photoreceptor outer and inner segment length was reduced, and cone cell numbers were reduced, as were scotopic and photopic responses. STRA6 also was required for dissolution of the primary vitreous. However, it was clear from these studies that STRA6 is not the only pathway for retinol uptake by the RPE.


DeVore G.R.,University of California at Los Angeles
American Journal of Obstetrics and Gynecology | Year: 2015

The cerebroplacental ratio (CPR) is emerging as an important predictor of adverse pregnancy outcome, and this has implications for the assessment of fetal well-being in fetuses diagnosed as small for gestational age (SGA) and those appropriate for gestational age close to term. Interest in this assessment tool has been rekindled because of recent reports associating an abnormal ratio with adverse perinatal events and associated postnatal neurological outcome. Fetuses with an abnormal CPR that are appropriate for gestational age or have late-onset SGA (>34 weeks of gestation) have a higher incidence of fetal distress in labor requiring emergency cesarean delivery, a lower cord pH, and an increased admission rate to the newborn intensive care unit when compared with fetuses with a normal CPR. Fetuses with early-onset SGA (<34 weeks of gestation) with an abnormal CPR have a higher incidence of the following when compared with fetuses with a normal CPR: (1) lower gestational age at birth, (2) lower mean birthweight, (3) lower birthweight centile, (4) birthweight less than the 10th centile, (5) higher rate of cesarean delivery for fetal distress in labor, (6) higher rate of Apgar scores less than 7 at 5 minutes, (7) an increased rate of neonatal acidosis, (8) an increased rate of newborn intensive care unit admissions, (9) higher rate of adverse neonatal outcome, and (10) a greater incidence of perinatal death. The CPR is also an earlier predictor of adverse outcome than the biophysical profile, umbilical artery, or middle cerebral artery. In conclusion, the CPR should be considered as an assessment tool in fetuses undergoing third-trimester ultrasound examination, irrespective of the findings of the individual umbilical artery and middle cerebral artery measurements. © 2015 Elsevier Inc.


Tu S.-Y.,University of California at Los Angeles | Sayed A.H.,University of California at Los Angeles
IEEE Transactions on Signal Processing | Year: 2012

Adaptive networks consist of a collection of nodes with adaptation and learning abilities. The nodes interact with each other on a local level and diffuse information across the network to solve estimation and inference tasks in a distributed manner. In this work, we compare the mean-square performance of two main strategies for distributed estimation over networks: consensus strategies and diffusion strategies. The analysis in the paper confirms that under constant step-sizes, diffusion strategies allow information to diffuse more thoroughly through the network and this property has a favorable effect on the evolution of the network: diffusion networks are shown to converge faster and reach lower mean-square deviation than consensus networks, and their mean-square stability is insensitive to the choice of the combination weights. In contrast, and surprisingly, it is shown that consensus networks can become unstable even if all the individual nodes are stable and able to solve the estimation task on their own. When this occurs, cooperation over the network leads to a catastrophic failure of the estimation task. This phenomenon does not occur for diffusion networks: we show that stability of the individual nodes always ensures stability of the diffusion network irrespective of the combination topology. Simulation results support the theoretical findings. © 2012 IEEE.


Shaw K.L.,University of California at Los Angeles
Science translational medicine | Year: 2011

Hematopoietic stem cell (HSC) transplantation may be curative for severe combined immunodeficiency (SCID). However, for a majority of infants with SCID a suitable donor is not available, and even with a matched donor, allogeneic HSC transplantation itself carries potential complications such as graft-versus-host disease as well as side effects from myelosuppressive chemotherapy. In the past decade, substantial advances have been made in the transplantation of gene-modified autologous HSCs, especially for two forms of SCID: X-linked SCID (SCID-X1) and adenosine deaminase (ADA)-deficient SCID. Two new reports in this issue of Science Translational Medicine add to the accumulating findings from gene therapy trials in Italy, France, and the United States that show clinical benefits of this alternative treatment.


Papp B.,University of California at Los Angeles | Plath K.,University of California at Los Angeles
Cell Research | Year: 2011

In 2006, the wall came down that limited the experimental conversion of differentiated cells into the pluripotent state. In a landmark report, Shinya Yamanaka's group described that a handful of transcription factors (Oct4, Sox2, Klf4 and c-Myc) can convert a differentiated cell back to pluripotency over the course of a few weeks, thus reprograming them into induced pluripotent stem (iPS) cells. The birth of iPS cells started off a rush among researchers to increase the efficiency of the reprogramming process, to reveal the underlying mechanistic events, and allowed the generation of patient- and disease-specific human iPS cells, which have the potential to be converted into relevant specialized cell types for replacement therapies and disease modeling. This review addresses the steps involved in resetting the epigenetic landscape during reprogramming. Apparently, defined events occur during the course of the reprogramming process. Immediately, upon expression of the reprogramming factors, some cells start to divide faster and quickly begin to lose their differentiated cell characteristics with robust downregulation of somatic genes. Only a subset of cells continue to upregulate the embryonic expression program, and finally, pluripotency genes are upregulated establishing an embryonic stem cell-like transcriptome and epigenome with pluripotent capabilities. Understanding reprogramming to pluripotency will inform mechanistic studies of lineage switching, in which differentiated cells from one lineage can be directly reprogrammed into another without going through a pluripotent intermediate. © 2011 IBCB, SIBS, CAS All rights reserved.


Brookmeyer R.,University of California at Los Angeles
Epidemiologic Reviews | Year: 2010

In this article, the author reviews current approaches and methods for measuring the scope of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic and their strengths and weaknesses. In recent years, various public health agencies have revised statistical estimates of the scope of the HIV/AIDS pandemic. The author considers the reasons underlying these revisions. New sources of data for estimating HIV prevalence have become available, such as nationally representative probability-based surveys. New technologies such as biomarkers that indicate when persons became infected are now used to determine HIV incidence rates. The author summarizes the main sources of errors and problems with these and other approaches and discusses opportunities for improving their reliability. Changing methods and data sources present new challenges, because incidence and prevalence estimates produced at different points in time are not directly comparable with each other, which complicates assessment of time trends. The methodological changes help explain the changes in global statistics. As methods and data sources continue to improve, the development of statistical tools for better assessing the extent to which changes in HIV/AIDS statistics can be attributed to changes in methodology versus real changes in the underlying epidemic is an important challenge. © 2010 The Author.


Sorvillo F.,University of California at Los Angeles
Emerging infectious diseases | Year: 2011

Cysticercosis has emerged as a cause of severe neurologic disease in the United States that primarily affects immigrants from Latin America. Moreover, the relevance of cysticercosis as a public health problem has been highlighted by local transmission. We searched the biomedical literature for reports documenting cases of cysticercosis acquired in the United States. A total of 78 cases, principally neurocysticercosis, were reported from 12 states during 1954-2005. A confirmed or presumptive source of infection was identified among household members or close personal contacts of 16 (21%) case-patients. Several factors, including the severe, potentially fatal, nature of cysticercosis; its fecal-oral route of transmission; the considerable economic effect; the availability of a sensitive and specific serologic test for infection by adult Taenia solium tapeworms; and the demonstrated ability to find a probable source of infection among contacts, all provide a compelling rationale for implementation of public health control efforts.


Humphries R.M.,University of California at Los Angeles | Linscott A.J.,Ochsner Health System
Clinical Microbiology Reviews | Year: 2015

Bacterial gastroenteritis is a disease that is pervasive in both the developing and developed worlds. While for the most part bacterial gastroenteritis is self-limiting, identification of an etiological agent by bacterial stool culture is required for the management of patients with severe or prolonged diarrhea, symptoms consistent with invasive disease, or a history that may predict a complicated course of disease. Importantly, characterization of bacterial enteropathogens from stool cultures in clinical laboratories is one of the primary means by which public health officials identify and track outbreaks of bacterial gastroenteritis. This article provides guidance for clinical microbiology laboratories that perform stool cultures. The general characteristics, epidemiology, and clinical manifestations of key bacterial enteropathogens are summarized. Information regarding optimal specimen collection, transport, and processing and current diagnostic tests and testing algorithms is provided. This article is an update of Cumitech 12A (P. H. Gilligan, J. M. Janda, M. A. Karmali, and J. M. Miller, Cumitech 12A, Laboratory diagnosis of bacterial diarrhea, 1992). © 2015, American Society for Microbiology. All Rights Reserved.


Ganz T.,University of California at Los Angeles | Nemeth E.,University of California at Los Angeles
Annual Review of Medicine | Year: 2011

The hepatic peptide hormone hepcidin is the principal regulator of iron absorption and its tissue distribution. Pathologically increased hepcidin concentrations cause or contribute to iron-restrictive anemias including anemias associated with inflammation, chronic kidney disease and some cancers. Hepcidin deficiency results in iron overload in hereditary hemochromatosis and ineffective erythropoiesis. The hepcidin-ferroportin axis is the principal regulator of extracellular iron homeostasis in health and disease, and is a promising target for the diagnosis and treatment of iron disorders and anemias. © 2011 by Annual Reviews. All rights reserved.


Papp B.,University of California at Los Angeles | Plath K.,University of California at Los Angeles
Cell | Year: 2013

Reprogramming to induced pluripotent stem cells (iPSCs) proceeds in a stepwise manner with reprogramming factor binding, transcription, and chromatin states changing during transitions. Evidence is emerging that epigenetic priming events early in the process may be critical for pluripotency induction later. Chromatin and its regulators are important controllers of reprogramming, and reprogramming factor levels, stoichiometry, and extracellular conditions influence the outcome. The rapid progress in characterizing reprogramming is benefiting applications of iPSCs and is already enabling the rational design of novel reprogramming factor cocktails. However, recent studies have also uncovered an epigenetic instability of the X chromosome in human iPSCs that warrants careful consideration. © 2013 Elsevier Inc.


Hartenstein V.,University of California at Los Angeles
Wiley interdisciplinary reviews. Developmental biology | Year: 2013

Early neurogenesis comprises the phase of nervous system development during which neural progenitor cells are born. In early development, the embryonic ectoderm is subdivided by a conserved signaling mechanism into two main domains, the epidermal ectoderm and the neurectoderm. Subsequently, cells of the neurectoderm are internalized and form a cell layer of proliferating neural progenitors. In vertebrates, the entire neurectoderm folds into the embryo to give rise to the neural tube. In Drosophila and many other invertebrates, a subset of neurectodermal cells, called neuroblasts (NBs), delaminates and forms the neural primordium inside the embryo where they divide in an asymmetric, stem cell-like mode. The remainder of the neurectodermal cells that stay behind at the surface loose their neurogenic potential and later give rise to the ventral part of the epidermis. The genetic and molecular analysis of the mechanisms controlling specification and proliferation of NBs in the Drosophila embryo, which played a significant part in pioneering the field of modern developmental neurobiology, represents the topic of this review. Copyright © 2013 Wiley Periodicals, Inc.


Wang A.,University of California at Los Angeles
Stem cells and development | Year: 2011

It has been debated whether human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) express distinctive transcriptomes. By using the method of weighted gene co-expression network analysis, we showed here that iPSCs exhibit altered functional modules compared with ESCs. Notably, iPSCs and ESCs differentially express 17 modules that primarily function in transcription, metabolism, development, and immune response. These module activations (up- and downregulation) are highly conserved in a variety of iPSCs, and genes in each module are coherently co-expressed. Furthermore, the activation levels of these modular genes can be used as quantitative variables to discriminate iPSCs and ESCs with high accuracy (96%). Thus, differential activations of these functional modules are the conserved features distinguishing iPSCs from ESCs. Strikingly, the overall activation level of these modules is inversely correlated with the DNA methylation level, suggesting that DNA methylation may be one mechanism regulating the module differences. Overall, we conclude that human iPSCs and ESCs exhibit distinct gene expression networks, which are likely associated with different epigenetic reprogramming events during the derivation of iPSCs and ESCs.


Schweitzer S.O.,University of California at Los Angeles
American Journal of Public Health | Year: 2013

Drug shortages are threatening care quality and costcontainment efforts. I describe the pharmaceutical marketplace changes that have caused the problem, and propose new policies to solve it, through changing incentives for producers and purchasers. I propose a grading scheme for the Food and Drug Administration when it inspects manufacturing facilities in the United States and abroad. The inspections' focus would change from closing unsafe plants to improving production process quality, reducing the likelihood that plants will be closed-the most frequent cause of drug shortages.


Pearl J.,University of California at Los Angeles
International Journal of Biostatistics | Year: 2010

This paper summarizes recent advances in causal inference and underscores the paradigmatic shifts that must be undertaken in moving from traditional statistical analysis to causal analysis of multivariate data. Special emphasis is placed on the assumptions that underlie all causal inferences, the languages used in formulating those assumptions, the conditional nature of all causal and counterfactual claims, and the methods that have been developed for the assessment of such claims. These advances are illustrated using a general theory of causation based on the Structural Causal Model (SCM) described in Pearl (2000a), which subsumes and unifies other approaches to causation, and provides a coherent mathematical foundation for the analysis of causes and counterfactuals. In particular, the paper surveys the development of mathematical tools for inferring (from a combination of data and assumptions) answers to three types of causal queries: those about (1) the effects of potential interventions, (2) probabilities of counterfactuals, and (3) direct and indirect effects (also known as "mediation"). Finally, the paper defines the formal and conceptual relationships between the structural and potential-outcome frameworks and presents tools for a symbiotic analysis that uses the strong features of both. The tools are demonstrated in the analyses of mediation, causes of effects, and probabilities of causation. Copyright © 2010 The Berkeley Electronic Press. All rights reserved.


Baxter R.M.,University of California at Los Angeles | Vilain E.,University of California at Los Angeles
Annual Review of Genomics and Human Genetics | Year: 2013

Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs. Copyright © 2013 by Annual Reviews. All rights reserved.


Hewison M.,University of California at Los Angeles
Clinical Endocrinology | Year: 2012

In the last 5 years, there has been a remarkable change in our understanding of the health benefits of vitamin D. The classical actions of vitamin D as a determinant of mineral metabolism and rachitic bone disease have been expanded to include a broader role in skeletal homoeostasis and prevalent bone disorders such as osteoporosis. However, it is the nonskeletal function of vitamin D that has attracted most attention. Although pluripotent responses to vitamin D have been recognized for many years, our new perspective on nonclassical vitamin D function stems from two more recent concepts. The first is that impaired, vitamin D status is common to many populations across the globe. This has prompted studies to explore the health impact of suboptimal circulating levels of vitamin D, with association studies linking vitamin D 'insufficiency' to several chronic health problems including autoimmune and cardiovascular disease, hypertension and common cancers. In support of a broader role for vitamin D in human health, studies in vitro and using animal models have highlighted immunomodulatory and anticancer effects of vitamin D that appear to depend on localized activation of vitamin D. The conclusion from these reports is that many nonclassical actions of vitamin D are independent of conventional vitamin D endocrinology and are therefore more sensitive to variations in vitamin D status. The current review summarizes these developments, with specific reference to the newly identified effects of vitamin D on the immune system, but also highlights the challenges in translating these observations to clinical practice. © 2012 Blackwell Publishing Ltd.


Park M.,University of California at Los Angeles
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

When pathogens encounter a novel environment, such as a new host species or treatment with an antimicrobial drug, their fitness may be reduced so that adaptation is necessary to avoid extinction. Evolutionary emergence is the process by which new pathogen strains arise in response to such selective pressures. Theoretical studies over the last decade have clarified some determinants of emergence risk, but have neglected the influence of fitness on evolutionary rates and have not accounted for the multiple scales at which pathogens must compete successfully. We present a cross-scale theory for evolutionary emergence, which embeds a mechanistic model of within-host selection into a stochastic model for emergence at the population scale. We explore how fitness landscapes at within-host and between-host scales can interact to influence the probability that a pathogen lineage will emerge successfully. Results show that positive correlations between fitnesses across scales can greatly facilitate emergence, while cross-scale conflicts in selection can lead to evolutionary dead ends. The local genotype space of the initial strain of a pathogen can have disproportionate influence on emergence probability. Our cross-scale model represents a step towards integrating laboratory experiments with field surveillance data to create a rational framework to assess emergence risk.


Nipah virus targets human endothelial cells via NiV-F and NiV-G envelope glycoproteins, resulting in endothelial syncytia formation and vascular compromise. Endothelial cells respond to viral infection by releasing innate immune effectors, including galectins, which are secreted proteins that bind to specific glycan ligands on cell surface glycoproteins. We demonstrate that galectin-1 reduces NiV-F mediated fusion of endothelial cells, and that endogenous galectin-1 in endothelial cells is sufficient to inhibit syncytia formation. Galectin-1 regulates NiV-F mediated cell fusion at three distinct points, including retarding maturation of nascent NiV-F, reducing NiV-F lateral mobility on the plasma membrane, and directly inhibiting the conformational change in NiV-F required for triggering fusion. Characterization of the NiV-F N-glycome showed that the critical site for galectin-1 inhibition is rich in glycan structures known to bind galectin-1. These studies identify a unique set of mechanisms for regulating pathophysiology of NiV infection at the level of the target cell.


Ozcan A.,University of California at Los Angeles
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2014

In this article, I discuss some of the emerging applications and the future opportunities and challenges created by the use of mobile phones and their embedded components for the development of next-generation imaging, sensing, diagnostics and measurement tools. The massive volume of mobile phone users, which has now reached ~7 billion, drives the rapid improvements of the hardware, software and high-end imaging and sensing technologies embedded in our phones, transforming the mobile phone into a cost-effective and yet extremely powerful platform to run, e.g., biomedical tests, and perform scientific measurements that would normally require advanced laboratory instruments. This rapidly evolving and continuing trend will help us transform how medicine, engineering and sciences are practiced and taught globally. © 2014 the Partner Organisations.


Cusack D.F.,University of California at Los Angeles
Soil Biology and Biochemistry | Year: 2013

Urban areas in tropical regions are expanding rapidly, with significant potential to affect local ecosystem dynamics. In particular, nitrogen (N) availability may increase in urban-proximate forests because of atmospheric N deposition. Unlike temperate forests, many tropical forests on highly weathered soils have high background N availability, so plant growth is unlikely to respond to increased N inputs. However, microbial activity and decomposition of carbon-rich plant tissue can respond positively to added N in these forests, as has been observed in a growing number of fertilization studies. The relevance of these controlled studies to landscape-scale dynamics in urban-proximate moist tropical forests requires further investigation. I used ten forest stands in three watersheds along an urban-remote gradient in Puerto Rico to test the hypotheses that urban activity has a positive effect on soil N availability, and that decomposition enzyme activities vary with soil N. I found that mineral N, total dissolved N (TDN), and ammonium:nitrate (NH4 +:NO3 -) ratios varied by nearly one order of magnitude across the urban-remote gradient, and variability among urban sites was high. On average, urban forests had higher soil NO3 -, lower NH4 +, and lower C:N values than remote forests, suggesting high nitrification rates and/or external inputs of NO3 - to the urban forests, and enrichment in N relative to C. Total mineral N and total dissolved N were positively correlated with the activities of enzymes that acquire carbon (C) and phosphorus (P) from organic matter. Across this gradient soil N levels were stronger predictors of enzyme activities than soil C or pH, which drive enzyme activities globally. The ratio of NH4 +:NO3 - was the strongest predictor of oxidative enzyme activities. Compared to global averages, ratios of C:N:P enzyme activities across these tropical forests indicated lower relative N-acquisition and higher relative P-acquisition, with N-acquisition lowest in the urban watershed, and P-acquisition highest in the upper-elevation remote watershed. These results suggest a strong urban effect on forest soil N levels, and show a link between changes in N availability and microbial processing of soil organic matter. © 2012 Elsevier Ltd.


Saab S.,University of California at Los Angeles
American Journal of Gastroenterology | Year: 2014

The care of hepatitis C virus (HCV) in African Americans represents an opportunity to address a major health disparity in medicine. In all facets of HCV infection, African Americans are inexplicably affected, including in the prevalence of the virus, which is higher among them compared with most of the racial and ethnic groups. Ironically, although fibrosis rates may be slow, hepatocellular carcinoma and mortality rates appear to be higher among African Americans. Sustained viral response (SVR) rates have historically significantly trailed behind Caucasians. The reasons for this gap in SVR are related to both viral and host factors. Moreover, low enrollment rates in clinical trials hamper the study of the efficacy of anti-viral therapy. Nevertheless, the gap in SVR between African Americans and Caucasians may be narrowing with the use of direct-acting agents. Gastroenterologists, hepatologists, primary care physicians, and other health-care providers need to address modifiable risk factors that affect the natural history, as well as treatment outcomes, for HCV among African Americans. Efforts need to be made to improve awareness among health-care providers to address the differences in screening and referral patterns for African Americans.Am J Gastroenterol advance online publication, 2 September 2014; doi:10.1038/ajg.2014.243.


Rana A.,University of California at Los Angeles | Rera M.,University of California at Los Angeles | Walker D.W.,University of California at Los Angeles
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Longlived Parkin-overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusionpromoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced DrosophilaMitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration.


Mecklenburg M.,University of California at Los Angeles | Regan B.C.,University of California at Los Angeles
Physical Review Letters | Year: 2011

A model of electrons hopping from atom to atom in graphene's honeycomb lattice gives low-energy electronic excitations that obey a relation formally identical to a 2+1 dimensional Dirac equation. Graphene's spin equivalent, "pseudospin," arises from the degeneracy introduced by the honeycomb lattice's two inequivalent atomic sites per unit cell. Previously it has been thought that the usual electron spin and the pseudospin indexing the graphene sublattice state are merely analogues. Here we show that the pseudospin is also a real angular momentum. This identification explains the suppression of electron backscattering in carbon nanotubes and the angular dependence of light absorption by graphene. Furthermore, it demonstrates that half-integer spin like that carried by the quarks and leptons can derive from hidden substructure, not of the particles themselves, but rather of the space in which these particles live. © 2011 American Physical Society.


Hansen B.M.S.,University of California at Los Angeles | Murray N.,Canadian Institute for Theoretical Astrophysics
Astrophysical Journal | Year: 2012

We demonstrate that the observed distribution of "hot Neptune"/"super-Earth" systems is well reproduced by a model in which planet assembly occurs in situ, with no significant migration post-assembly. This is achieved only if the amount of mass in rocky material is 50-100 M ⊕ interior to 1AU. Such a reservoir of material implies that significant radial migration of solid material takes place, and that it occurs before the stage of final planet assembly. The model not only reproduces the general distribution of mass versus period but also the detailed statistics of multiple planet systems in the sample. We furthermore demonstrate that cores of this size are also likely to meet the criterion to gravitationally capture gas from the nebula, although accretion is rapidly limited by the opening of gaps in the gas disk. If the mass growth is limited by this tidal truncation, then the scenario sketched here naturally produces Neptune-mass objects with substantial components of both rock and gas, as is observed. The quantitative expectations of this scenario are that most planets in the "hot Neptune/super-Earth" class inhabit multiple-planet systems, with characteristic orbital spacings. The model also provides a natural division into gas-rich (hot Neptune) and gas-poor (super-Earth) classes at fixed period. The dividing mass ranges from 3 M ⊕ at 10day orbital periods to 10 M ⊕ at 100day orbital periods. For orbital periods <10days, the division is less clear because a gas atmosphere may be significantly eroded by stellar radiation. © 2012. The American Astronomical Society. All rights reserved..


Tomboulis E.T.,University of California at Los Angeles
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We consider lattice gauge theories at strong coupling with gauge group U(NC), or SU(NC) restricted to the meson sector, and coupled to NF flavors of fundamental representation staggered fermions. We study the formation of a chiral condensate by means of resummation of a hopping expansion. Different classes of graphs become dominant as the parameter (NF/NC) is varied. By performing graph resummation we obtain an equation for determining the condensate as a function of (NF/NC) and mass m. For values of (NF/N C) below a critical value, one reproduces the well-known result of the existence of a nonvanishing condensate solution in the m=0 limit. Above the critical (NF/NC) value, however, no such solution exists, its abrupt disappearance indicating a first-order transition to a chirally symmetric phase with composite (colorless) excitation spectrum. © 2013 American Physical Society.


Gilles J.,University of California at Los Angeles
IEEE Transactions on Signal Processing | Year: 2013

Some recent methods, like the empirical mode decomposition (EMD), propose to decompose a signal accordingly to its contained information. Even though its adaptability seems useful for many applications, the main issue with this approach is its lack of theory. This paper presents a new approach to build adaptive wavelets. The main idea is to extract the different modes of a signal by designing an appropriate wavelet filter bank. This construction leads us to a new wavelet transform, called the empirical wavelet transform. Many experiments are presented showing the usefulness of this method compared to the classic EMD. © 2013 IEEE.


Zhou Q.,University of California at Los Angeles
Physical Review Letters | Year: 2011

An efficient algorithm is developed to construct disconnectivity graphs by a random walk over basins of attraction. This algorithm can detect a large number of local minima, find energy barriers between them, and estimate local thermal averages over each basin of attraction. It is applied to the Sherrington-Kirkpatrick (SK) spin glass Hamiltonian where existing methods have difficulties even for a moderate number of spins. Finite-size results are used to make predictions in the thermodynamic limit that match theoretical approximations and recent findings on the free energy landscapes of SK spin glasses. © 2011 American Physical Society.


Furst D.E.,University of California at Los Angeles
Seminars in Arthritis and Rheumatism | Year: 2010

Objectives: To assess the risk of serious and nonserious bacterial and viral infections associated with the use of biologic therapy (abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab) in patients with rheumatoid arthritis (RA). Methods: Information was derived from PubMed, EMBASE, and the Cochrane clinical trials register and database of systematic reviews and relevant congress abstracts up to and including February 2008. Results: Compared with the general population, patients with RA have a heightened risk of infection, including tuberculosis. Long-term clinical trials and postmarketing studies indicate that anakinra and the tumor necrosis factor (TNF) inhibitors are associated with an increased risk of infections versus conventional disease-modifying antirheumatic drugs (DMARDs), especially early in the course of treatment. The most common sites of infection are the respiratory tract (including pneumonia), skin and soft tissue, and the urinary tract. The risk of tuberculosis also appears higher with TNF inhibitors (in particular, infliximab) versus DMARDs, although this can be reduced by screening and prophylaxis. TNF inhibitors do not appear to significantly increase the risk of reactivating chronic viral infections. Influenza and pneumococcal vaccinations are generally effective in the face of TNF inhibitors or abatacept. Available data suggest that the risk of infections and serious infections with abatacept and rituximab may be similar to that of the TNF inhibitors. To date, there have been no reports from clinical trials of increased tuberculosis or opportunistic infections with abatacept or rituximab. Conclusions: All marketed TNF inhibitors for compared to control RA appear to increase the risk of serious and nonserious infections compared with DMARDs. Although suggestive, data for abatacept and rituximab are less definitive and longer periods of patient exposure to these agents are needed before an assessment of their risks can be made. © 2010 Elsevier Inc.


Kagawa Singer M.,University of California at Los Angeles
Preventive Medicine | Year: 2012

Culture is often cited as an underlying cause of the undue burden of disease borne by communities of color along the entire life cycle. However, culture is rarely defined or appropriately measured. Scientifically, culture is a complex, integrated, and dynamic conceptual framework that is incongruent with the way it is operationalized in health behavior theories: as a unidimensional, static, and immutable character element of a homogeneous population group. This paper lays out this contradiction and proposes a more scientifically grounded approach to the use of culture. The premise is that if the concept of culture were better operationalized, results from studies of diverse population groups would produce findings that are more scientifically valid and relevant to the community. Practitioners could then use these findings to develop more effective strategies to reduce health disparities and improve the health of all population groups. Six steps are proposed to increase our ability to achieve greater clarity on what culture is and to identify how it impacts health behavior and ultimately health outcomes, enabling researchers to build a stronger science of cultural diversity. © 2012.


Malik R.,Massachusetts Institute of Technology | Zhou F.,University of California at Los Angeles | Ceder G.,University of California at Los Angeles
Nature Materials | Year: 2011

Lithium-ion batteries are a key technology for multiple clean energy applications. Their energy and power density is largely determined by the cathode materials, which store Li by incorporation into their crystal structure. Most commercialized cathode materials, such as LiCoO2 (ref. ), LiMn2 O4 (ref. ), Li(Ni,Co,Al)O2 or Li(Ni,Co,Mn)O2 (ref. ), form solid solutions over a large concentration range, with occasional weak first-order transitions as a result of ordering of Li or electronic effects. An exception is LiFePO4, which stores Li through a two-phase transformation between FePO4 and LiFePO4 (ref1-4). Notwithstanding having to overcome extra kinetic barriers, such as nucleation of the second phase and growth through interface motion, the observed rate capability of LiFePO4 has become remarkably high. In particular, once transport limitations at the electrode level are removed through carbon addition and particle size reduction, the innate rate capability of LiFePO4 is revealed to be very high. We demonstrate that the reason LiFePO4 functions as a cathode at reasonable rate is the availability of a single-phase transformation path at very low overpotential, allowing the system to bypass nucleation and growth of a second phase. The Li x FePO4 system is an example where the kinetic transformation path between LiFePO4 and FePO4 is fundamentally different from the path deduced from its equilibrium phase diagram. © 2011 Macmillan Publishers Limited. All rights reserved.


Tarling E.,University of California at Los Angeles
Current Opinion in Lipidology | Year: 2013

PURPOSE OF REVIEW: To offer a comprehensive review on the role of ABCG1 in cellular sterol homeostasis. RECENT FINDINGS: Early studies with Abcg1 mice indicated that ABCG1 was crucial for tissue lipid homeostasis, especially in the lung. More recent studies have demonstrated that loss of ABCG1 has wide-ranging consequences and impacts lymphocyte and stem cell proliferation, endothelial cell function, macrophage foam cell formation, as well as insulin secretion from pancreatic β cells. Recent studies have also demonstrated that ABCG1 functions as an intracellular lipid transporter, localizes to intracellular vesicles/endosomes, and that the transmembrane domains are sufficient for localization and transport function. SUMMARY: ABCG1 plays a crucial role in maintaining intracellular sterol and lipid homeostasis. Loss of this transporter has significant, cell-type-specific consequences ranging from effects on cellular proliferation, to surfactant production and/or insulin secretion. Elucidation of the mechanisms by which ABCG1 affects intracellular sterol flux/movement should provide important information that may link ABCG1 to diseases of dysregulated tissue lipid homeostasis. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Wang H.,University of California at Los Angeles | Houk K.N.,University of California at Los Angeles
Chemical Science | Year: 2014

Torsional effects control the π-facial stereoselectivities of a variety of synthetically important organic reactions. This review surveys theoretical calculations that have led to the understanding of the influence of the torsional effects on several types of stereoselective organic reactions, especially electrophilic additions and cycloadditions to alkenes. © 2014 The Royal Society of Chemistry.


Clarke S.G.,University of California at Los Angeles
Trends in Biochemical Sciences | Year: 2013

Methylated lysine and arginine residues in histones represent a crucial part of the histone code, and recognition of these methylated residues by protein interaction domains modulates transcription. Although some methylating enzymes appear to be histone specific, many can modify histone and non-histone substrates and an increasing number are specific for non-histone substrates. Some of the non-histone substrates can also be involved in transcription, but a distinct subset of protein methylation reactions occurs at residues buried deeply in ribosomal proteins that may function in protein-RNA interactions rather than protein-protein interactions. Additionally, recent work has identified enzymes that catalyze protein methylation reactions at new sites in ribosomal and other proteins. These reactions include modifications of histidine and cysteine residues as well as the N terminus. © 2013 Elsevier Ltd.


Feldman J.L.,University of California at Los Angeles | Del Negro C.A.,College of William and Mary | Gray P.A.,University of Washington
Annual Review of Physiology | Year: 2013

Breathing is an essential behavior that presents a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to both rapidly and slowly changing conditions, and how particular dysfunctions result in disease. We focus on recent advancements related to two essential sites for respiratory rhythmogenesis: (a) the preBötzinger Complex (preBötC) as the site for the generation of inspiratory rhythm and (b) the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) as the site for the generation of active expiration. Copyright © 2013 by Annual Reviews. All rights reserved.


Hansen B.M.S.,University of California at Los Angeles
Astrophysical Journal | Year: 2012

We present a new empirical calibration of equilibrium tidal theory for extrasolar planet systems, extending a prior study by incorporating detailed physical models for the internal structure of planets and host stars. The resulting strength of the stellar tide produces a coupling that is strong enough to reorient the spins of some host stars without causing catastrophic orbital evolution, thereby potentially explaining the observed trend in alignment between stellar spin and planetary orbital angular momentum. By isolating the sample whose spins should not have been altered in this model, we also show evidence for two different processes that contribute to the population of planets with short orbital periods. We apply our results to estimate the remaining lifetimes for short-period planets, examine the survival of planets around evolving stars, and determine the limits for circularization of planets with highly eccentric orbits. Our analysis suggests that the survival of circularized planets is strongly affected by the amount of heat dissipated, which is often large enough to lead to runaway orbital inflation and Roche lobe overflow. © 2012. The American Astronomical Society. All rights reserved.


Fan Y.C.,University of California at Los Angeles | Kwon O.,University of California at Los Angeles
Chemical Communications | Year: 2013

In nucleophilic phosphine catalysis, tertiary phosphines undergo conjugate additions to activated carbon-carbon multiple bonds to form β-phosphonium enolates, β-phosphonium dienolates, β-phosphonium enoates, and vinyl phosphonium ylides as intermediates. When these reactive zwitterionic species react with nucleophiles and electrophiles, they may generate carbo- and heterocycles with multifarious molecular architectures. This article describes the reactivities of these phosphonium zwitterions, the applications of phosphine catalysis in the syntheses of biologically active compounds and natural products, and recent developments in the enantioselective phosphine catalysis. © 2013 The Royal Society of Chemistry.


Lee C.,University of California at Los Angeles | Kim C.-J.,University of California at Los Angeles
Physical Review Letters | Year: 2011

Superhydrophobic (SHPo) surfaces have shown promise for passive drag reduction because their surface structures can hold a lubricating gas film between the solid surface and the liquid in contact with it. However, the types of SHPo surfaces that would produce any meaningful amount of reduction get wet under liquid pressure or at surface defects, both of which are unavoidable in the real world. In this Letter, we solve the above problem by (1) discovering surface structures that allow the restoration of a gas blanket from a wetted state while fully immersed underwater and (2) devising a self-controlled gas-generation mechanism that maintains the SHPo condition under high liquid pressures (tested up to 7 atm) as well as in the presence of surface defects, thus removing a fundamental barrier against the implementation of SHPo surfaces for drag reduction. © 2011 The American Physical Society.


Nonacs P.,University of California at Los Angeles
BMC Evolutionary Biology | Year: 2011

Background: Phylogenetic analyses strongly associate nonsocial ancestors of cooperatively-breeding or eusocial species with monogamy. Because monogamy creates high-relatedness family groups, kin selection has been concluded to drive the evolution of cooperative breeding (i.e., the monogamy hypothesis). Although kin selection is criticized as inappropriate for modeling and predicting the evolution of cooperation, there are no examples where specific inclusive fitness-based predictions are intrinsically wrong. The monogamy hypothesis may be the first case of such a flawed calculation. Results: A simulation model mutated helping alleles into non-cooperative populations where females mated either once or multiply. Although multiple mating produces sibling broods of lower relatedness, it also increases the likelihood that one offspring will adopt a helper role. Examining this tradeoff showed that under a wide range of conditions polygamy, rather than monogamy, allowed helping to spread more rapidly through populations. Further simulations with mating strategies as heritable traits confirmed that multiple-mating is selectively advantageous. Although cooperation evolves similarly regardless of whether dependent young are close or more distant kin, it does not evolve if they are unrelated. Conclusions: The solitary ancestral species to cooperative breeders may have been predominantly monogamous, but it cannot be concluded that monogamy is a predisposing state for the evolution of helping behavior. Monogamy may simply be coincidental to other more important life history characteristics such as nest defense or sequential provisioning of offspring. The differing predictive outcome from a gene-based model also supports arguments that inclusive fitness formulations poorly model some evolutionary questions. Nevertheless, cooperation only evolves when benefits are provided for kin: helping alleles did not increase in frequency in the absence of potential gains in indirect fitness. The key question, therefore, is not whether kin selection occurs, but how best to elucidate the differing evolutionary advantages of genetic relatedness versus genetic diversity. © 2011 Nonacs; licensee BioMed Central Ltd.


Ferando I.,University of California at Los Angeles
Epilepsia | Year: 2012

Epilepsies consist of a spectrum of neurologic disorders typically characterized by unpredictable and dysfunctional network behaviors in the central nervous system (CNS), which lead to discrete episodes of large bouts of uncontrolled neuronal synchrony that interfere with the normal functioning of the brain. Temporal lobe epilepsy (TLE) is accompanied by changes in interneuronal innervation and modifications in different γ-aminobutyric acid (GABA)(A) receptor subunits. Hormones play an important role in modulating the overall excitability of neurons, and at the same time hormonal pathways are frequently modified during epilepsy. This review focuses on TLE-correlated modifications of GABAergic transmission, and in particular on the implications of some of our own findings related to GABA(A) Rs containing the δ subunits (δ-GABA(A) Rs). These are extra- or perisynaptic GABA(A) Rs that mediate tonic inhibition, a major component of the inhibitory mechanism in the brain. The most potent endogenous modulators of δ-GABA(A) Rs are neurosteroids, which act as positive allosteric modulators. Plasticity of δ-GABA(A) Rs during TLE consists of down-regulation of the subunit in the dentate gyrus granule cells (DGGCs), while being up-regulated in interneurons. Surprisingly, the level of tonic inhibition in DGGCs remains unchanged, consistent with the idea that it becomes mediated by GABA(A) Rs containing other subunits. In parallel, tonic inhibition in a TLE model ceases to be sensitive to neurosteroid potentiation. In contrast, as predicted by the anatomic plasticity, interneuronal tonic current is increased, and remains sensitive to neurosteroids. These findings have important pharmacologic implications. Where neurosteroids normally have sedative and anticonvulsant effects, bimodal and cell-type specific modulations in their natural targets might weaken the inhibitory control on the dentate gate, under circumstances of altered neurosteroids levels (stress, ovarian cycle, or the postpartum period). Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.


Takei S.,University of California at Los Angeles | Tserkovnyak Y.,University of California at Los Angeles
Physical Review Letters | Year: 2014

Superfluid spin transport - dissipationless transport of spin - is theoretically studied in a ferromagnetic insulator with easy-plane anisotropy. We consider an open geometry where the spin current is injected into the ferromagnet from one side by a metallic reservoir with a nonequilibrium spin accumulation and ejected into another metallic reservoir located downstream. Spin transport is studied using a combination of magnetoelectric circuit theory, Landau-Lifshitz-Gilbert phenomenology, and microscopic linear-response theory. We discuss how spin superfluidity can be probed in a magnetically mediated negative electron-drag experiment. © 2014 American Physical Society.


Ritz B.,University of California at Los Angeles
PloS one | Year: 2012

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson's Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57-10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96-2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.


Park J.W.,University of California at Los Angeles | Razavi B.,University of California at Los Angeles
Digest of Technical Papers - IEEE International Solid-State Circuits Conference | Year: 2014

Recent work on RF receivers has exploited N-path filters to address two critical issues, namely, blocker tolerance and high RF selectivity [1,2]. However, these designs face three drawbacks: (1) the low-noise amplifier (LNA) incorporates a Gm stage that, even with a virtual ground at its output nodes, must still withstand strong blockers at its input; (2) the low-order filter transfer function does not provide sufficient selectivity in narrow-band applications such as GSM or WCDMA; (3) they consume roughly 60mW around 2GHz. © 2014 IEEE.


Schlacher K.,Sloan Kettering Cancer Center | Schlacher K.,University of California at Los Angeles | Wu H.,University of California at Los Angeles | Jasin M.,Sloan Kettering Cancer Center
Cancer Cell | Year: 2012

Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis. © 2012 Elsevier Inc..


Sherstov A.A.,University of California at Los Angeles
SIAM Journal on Computing | Year: 2012

A strong direct product theorem (SDPT) states that solving n instances of a problem requires Ω(n) times the resources for a single instance, even to achieve success probability 2 -en for a small enough constant ε > 0. We prove that quantum communication complexity obeys an SDPT whenever the communication lower bound for a single instance is proved by the generalized discrepancy method, the strongest technique in that model. We prove that quantum query complexity obeys an SDPT whenever the query lower bound for a single instance is proved by the polynomial method, one of the two main techniques in that model. In both models, we prove the corresponding XOR lemmas and threshold direct product theorems. © 2012 Society for Industrial and Applied Mathematics.


Kawamoto H.K.,University of California at Los Angeles
Plastic and Reconstructive Surgery | Year: 2011

Given the multiple permutations in craniofacial malformations, classification of median craniofacial dysplasia or midline Tessier no. 0 to 14 clefts has been difficult and disjointed. In this review, the authors present a summary of normal embryology, prior terminology, and their proposed new classification system. Median craniofacial dysplasia has tissue agenesis and holoprosencephaly at one end (the hypoplasias), frontonasal hyperplasia and excessive tissue (the hyperplasias) at the other end, and abnormal splitting or clefting and normal tissue volume (dysraphia) occupying the middle portion of the spectrum. These three distinct subclassifications have different forms of anomalies within their groups. Copyright © 2011 by the American Society of Plastic Surgeons.


Deutsch C.,University of California at Los Angeles | Weber T.,University of California at Los Angeles
Annual Review of Marine Science | Year: 2012

Microbial life in the ocean contains immense taxonomic and physiological diversity, yet its collective activity yields global cycles of the major biolimiting elements N and P that are tightly linked. Moreover, the availability of N and P in seawater is closely matched to the metabolic demands of "average" plankton, as if plankton composition and the oceanic nutrient reservoirs were mutually influenced. These simple observations have broad implications for the function of nutrient cycles within the Earth system, which can operate either as a biological homeostat that buffers ocean fertility against large changes or as an amplifier of climate perturbations, by alleviating or exacerbating the nutrient limitation of biological productivity and ocean C storage. A mechanistic understanding of these observations and dynamics must draw upon diverse fields, from physiology and evolution to physical oceanography and paleoceanography, and must account for processes spanning a wide range of spatial and temporal scales. Here we summarize this understanding from the perspective of the nutrient distributions themselves and their changes over time. We offer a synthesis view in which ocean circulation communicates the resource constraints of stoichiometrically distinct planktonic biomes across large spatial scales, allowing geochemical constancy to emerge from rich biological diversity. Copyright © 2012 by Annual Reviews. All rights reserved.


Motivala S.J.,University of California at Los Angeles
Annals of Behavioral Medicine | Year: 2011

Background: Poor sleep is prospectively linked to all-cause and cardiovascular mortality. Inflammatory processes may be an important biological mechanism linking poor sleep to cardiovascular disease. Such processes involve active participation of signaling molecules called cytokines in development of atherosclerotic plaques. Purpose: I review evidence from experimental sleep deprivation and clinical observational studies suggesting a bidirectional relationship between sleep and inflammatory cytokines. Results: Findings from sleep deprivation studies indicate that sleep loss is associated with increases in these cytokines. Similarly, studies in clinical populations with sleep problems, such as primary insomnia patients and those diagnosed with major depression, also show elevations in these same cytokines. Conclusions: Bidirectional communication between the brain and the immune system is carried out through a complex network of autonomic nerves, endocrine hormones, and cytokines. Disturbed sleep appears to perturb the functioning of this network and therefore contribute to elevations in inflammatory mediators linked to cardiovascular disease. © 2011 The Society of Behavioral Medicine.


Rubin A.E.,University of California at Los Angeles
Geochimica et Cosmochimica Acta | Year: 2010

Chondrite groups (CV, CK, CR) with large average chondrule sizes have low proportions of RP plus C chondrules, high proportions of enveloping compound chondrules, high proportions of chondrules with (thick) igneous rims, and relatively low proportions of type-I chondrules containing sulfide. In contrast, chondrite groups (CM, CO, OC, R, EH, EL) with smaller average chondrule sizes have the opposite properties. Equilibrated CK chondrites have plagioclase with relatively low Na; equilibrated OC, R, EH and EL chondrites have more sodic plagioclase. Enveloping compound chondrules and chondrules with igneous rims formed during a remelting event after the primary chondrule was incorporated into a dustball. Repeated episodes of remelting after chondrules were surrounded by dust would tend to produce large chondrules. RP and C chondrules formed by complete melting of their precursor assemblages; remelting of RP and C chondrules surrounded by dust would tend to produce porphyritic chondrules as small dust particles mixed with the melt, providing nuclei for crystallizing phenocrysts. This process would tend to diminish the numbers of RP and C chondrules. Correlations among these chondrule physical properties suggest that chondrite groups with large chondrules were typically surrounded by thick dust-rich mantles that formed in locally dusty nebular environments. Chondrules that were surrounded by thick dust mantles tended to cool more slowly because heat could not quickly radiate away. Slow cooling led to enhanced migration of sulfide to chondrule surfaces and more extensive sulfide evaporation. These chondrules also lost Na; the plagioclase that formed from equilibrated CK chondrites was thus depleted in Na. © 2010 Elsevier Ltd.


Shim J.,University of California at Los Angeles | Mukherjee T.,University of California at Los Angeles | Banerjee U.,University of California at Los Angeles
Nature Cell Biology | Year: 2012

The Drosophila lymph gland is a haematopoietic organ in which progenitor cells, which are most akin to the common myeloid progenitor in mammals, proliferate and differentiate into three types of mature cell-plasmatocytes, crystal cells and lamellocytes-the functions of which are reminiscent of mammalian myeloid cells. During the first and early second instars of larval development, the lymph gland contains only progenitors, whereas in the third instar, a medial region of the primary lobe of the lymph gland called the medullary zone contains these progenitors, and maturing blood cells are found juxtaposed in a peripheral region designated the cortical zone. A third group of cells referred to as the posterior signalling centre functions as a haematopoietic niche. Similarly to mammalian myeloid cells, Drosophila blood cells respond to multiple stresses including hypoxia, infection and oxidative stress. However, how systemic signals are sensed by myeloid progenitors to regulate cell-fate determination has not been well described. Here, we show that the haematopoietic progenitors of Drosophila are direct targets of systemic (insulin) and nutritional (essential amino acid) signals, and that these systemic signals maintain the progenitors by promoting Wingless (WNT in mammals) signalling. We expect that this study will promote investigation of such possible direct signal sensing mechanisms by mammalian myeloid progenitors. © 2012 Macmillan Publishers Limited. All rights reserved.


Voskuhl R.,University of California at Los Angeles
Biology of Sex Differences | Year: 2011

Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways. © 2011 Voskuhl; licensee BioMed Central Ltd.


Thorne R.M.,University of California at Los Angeles
Geophysical Research Letters | Year: 2010

The flux of energetic electrons in the Earth's outer radiation belt can vary by several orders of magnitude over time scales less than a day, in response to changes in properties of the solar wind instigated by solar activity. Variability in the radiation belts is due to an imbalance between the dominant source and loss processes, caused by a violation of one or more of the adiabatic invariants. For radiation belt electrons, non-adiabatic behavior is primarily associated with energy and momentum transfer during interactions with various magnetospheric waves. A review is presented here of recent advances in both our understanding and global modeling of such wave-particle interactions, which have led to a paradigm shift in our understanding of electron acceleration in the radiation belts; internal local acceleration, rather than radial diffusion now appears to be the dominant acceleration process during the recovery phase of magnetic storms. Copyright 2010 by the American Geophysical Union.


Horwich T.B.,University of California at Los Angeles | Fonarow G.C.,University of California at Los Angeles
Journal of the American College of Cardiology | Year: 2010

Heart failure (HF) is common, results in poor clinical outcomes, and is associated with large health care costs. The incidence of HF continues to rise, with approximately 670,000 new cases per year and a 20% lifetime risk of HF for persons 40 years and older in the U.S. Risk factors for HF have been identified, and thus preventative strategies should have a positive effect on disease burden, morbidity, and mortality. Although coronary artery disease and hypertension have traditionally been considered among the most important modifiable risk factors for the development of HF, recent studies have highlighted the importance of increasingly prevalent metabolic risk factors: glucose, diabetes, obesity, and the metabolic syndrome. This report will present evidence for the link between glucose, diabetes, obesity, metabolic syndrome, and incident HF. Furthermore, we will discuss how risk factor modification and other preventive therapies may help curb the rising incidence of HF. © 2010 American College of Cardiology Foundation.


Domigan C.K.,University of California at Los Angeles | Iruela-Arispe M.L.,University of California at Los Angeles
Cell | Year: 2014

The distribution and patterning of blood vessels is controlled by vascular endothelial growth factor (VEGF), which is precisely regulated throughout its life cycle. Okabe et al. show that VEGF is titrated away from the endothelium by adjacent neurons via endocytosis, regulating density and trajectory of blood vessels. © 2014 Elsevier Inc.


Bai J.,University of California at Los Angeles | Huang Y.,University of California at Los Angeles
Materials Science and Engineering R: Reports | Year: 2010

Graphene is a semimetal with a zero band gap, and therefore cannot be used for effective field-effect transistors (FETs) at room temperature. Theoretical study predicted an appreciable band gap opening with the formation of nanometer graphene nanoribbons (GNRs), providing opportunities for graphene based transistor application. In this paper, we review recent developments in fabrication and electrical property studies of GNRs. We first study the theoretic prediction of electrical structures in ideal graphene nanoribbons which is closely related to the edge configurations. Different experimental efforts to fabricate GNRs are introduced and the electrical transport behaviors of fabricated GNR device are described. We then investigate the effect of edge disorder and charge impurities on real device performance, in which Anderson localization and Coulomb blockade effect are discussed to explain the observed transport behaviors. Other approaches such as symmetry broken to induce band gap on bulk graphene are also described. © 2010 Elsevier B.V. All rights reserved.


Liao L.,University of California at Los Angeles | Duan X.,University of California at Los Angeles
Materials Science and Engineering R: Reports | Year: 2010

Graphene is emerging as an interesting electronic material for future electronics due to its exceptionally high carrier mobility and single-atomic thickness. Graphene-dielectric integration is of critical importance for the development of graphene transistors and a new generation of graphene based electronics. Deposition of dielectric materials onto graphene is of significant challenge due to the intrinsic material incompatibility between pristine graphene and dielectric oxide materials. Here we review various strategies being researched for graphene-dielectric integration. Physical vapor deposition (PVD) can be used to directly deposit dielectric materials on graphene, but often introduces significant defects into the monolayer of carbon lattice; atomic layer deposition (ALD) process has also been explored to deposit high-κ dielectrics on graphene, which however requires functionalization of graphene surface with reactive groups, inevitably leading to a significant degradation in carrier mobilities. Using naturally oxidized thin aluminum or polymer as buffer layer for dielectric deposition can mitigate the damages to graphene lattice and improve the carrier mobility of the resulted top-gated transistors. Lastly, a physical assembly approach has recently been explored to integrate dielectric nanostructures with graphene without introducing any appreciable defects, and enabled top-gated graphene transistors with the highest carrier mobility reported to date. We will conclude with a brief summary and perspective on future opportunities. © 2010 Elsevier B.V. All rights reserved.


Torday J.S.,University of California at Los Angeles
Medical Hypotheses | Year: 2015

The history of physiologic cellular-molecular interrelationships can be traced all the way back to the unicellular state by following the pathway formed by lipids ubiquitously accommodating calcium homeostasis, and its consequent adaptive effects on oxygen uptake by cells, tissues and organs. As a result, a cohesive, mechanistically integrated view of physiology can be formulated by recognizing the continuum comprising conception, development, physiologic homeostasis and death mediated by soluble growth factor signaling. Seeing such seemingly disparate processes as embryogenesis, chronic disease and dying as the gain and subsequent loss of cell-cell signaling provides a novel perspective for physiology and medicine. It is emblematic of the self-organizing, self-referential nature of life, starting from its origins. Such organizing principles obviate the pitfalls of teleologic evolution, conversely providing a way of resolving such seeming dichotomies as holism and reductionism, genotype and phenotype, emergence and contingence, proximate and ultimate causation in evolution, cells and organisms. The proposed approach is scale-free and predictive, offering a Central Theory of Biology. © 2015 Elsevier Ltd.


Filler S.G.,University of California at Los Angeles
Trends in Microbiology | Year: 2013

The invasion and stimulation of normally non-phagocytic host cells, such as epithelial and endothelial cells, is a key step in the pathogenesis of many fungal infections. In most cases, host cell invasion and/or stimulation of a proinflammatory response is induced when proteins or carbohydrates on the fungal cell surface bind to receptors on the host cell. Although many of these fungal-host cell interactions have only been investigated in vitro, the therapeutic efficacy of blocking the host cell receptors for Candida albicans and Rhizopus oryzae has been demonstrated in experimental animal models of infection. We summarize recent studies of the fungal receptors on normally non-phagocytic host cells and the therapeutic implications of blocking these receptors. © 2013 Elsevier Ltd.


Pearl J.,University of California at Los Angeles
Prevention Science | Year: 2012

Recent advances in causal inference have given rise to a general and easy-to-use formula for assessing the extent to which the effect of one variable on another is mediated by a third. This Mediation Formula is applicable to nonlinear models with both discrete and continuous variables, and permits the evaluation of path-specific effects with minimal assumptions regarding the data-generating process. We demonstrate the use of the Mediation Formula in simple examples and illustrate why parametric methods of analysis yield distorted results, even when parameters are known precisely. We stress the importance of distinguishing between the necessary and sufficient interpretations of "mediated-effect" and show how to estimate the two components in nonlinear systems with continuous and categorical variables. © 2012 Society for Prevention Research.


King N.P.,University of Washington | Lai Y.-T.,University of California at Los Angeles
Current Opinion in Structural Biology | Year: 2013

Molecular self-assembly offers a means by which sophisticated materials can be constructed with unparalleled precision. Designing self-assembling protein structures is of particular interest as a result of the unique functional capabilities of proteins. Custom-designed protein materials could lead to new possibilities in therapeutics, bioenergy, and materials science. Although the field was long hampered by the challenges involved in designing such complex molecules, novel approaches and computational tools have recently led to remarkable progress. Here we review recent design studies in the context of three fundamental aspects of self-assembling materials: subunit organization, subunit interactions, and regulation of assembly. © 2013 Elsevier Ltd.


De Aguiar Vallim T.Q.,University of California at Los Angeles | Tarling E.J.,University of California at Los Angeles | Edwards P.A.,University of California at Los Angeles
Cell Metabolism | Year: 2013

Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases. © 2013 Elsevier Inc.


King C.R.,University of California at Los Angeles
Seminars in Radiation Oncology | Year: 2013

Radiotherapy (RT) after prostatectomy may potentially eradicate any residual localized microscopic disease in the prostate bed. The current dilemma is whether to deliver adjuvant RT solely on the basis of high-risk pathology (pT3 or positive margins), but in the absence of measurable prostate-specific antigen, or whether early salvage radiotherapy (SRT) would yield equivalent outcomes. Although the results of current randomized trials answering this very question remain years away, the best evidence to date supports early SRT as the better strategy. In terms of SRT, the pooled evidence reveals that one should initiate RT at the lowest prostate-specific antigen possible to maximize results. Similarly, the pooled data suggest that there is a dose-response favoring doses >70 Gy to the prostate bed. The evidence regarding the role of androgen deprivation therapy and the use of elective pelvic nodal RT is weak, and ongoing randomized trials are underway. Several clinical scenarios are presented for discussion. © 2013.


Bowman K.W.,University of California at Los Angeles
Atmospheric Environment | Year: 2013

Dramatic changes in the global distribution of energy production and consumption have led to critical air quality challenges for developing and developed countries. The role of air quality constituents such as ozone in climate forcing require mitigation strategies that encompass more than short-term exposure. Advances are highlighted in the three essential elements of modern ozone air quality monitoring: observations, models, and assimilation. To meet the challenges of air quality and climate, a case is made that a next generation ozone air quality monitoring system can be built around a new generation of low-earth orbiting and geostationary satellites with the potential to estimate near surface ozone. A set of recommendations needed for this system to address global air quality and climate are made. The policy implications of such an international ozone AQ monitoring are considered in light of recent international initiatives. © 2013 Elsevier Ltd.


Chlebowski R.T.,University of California at Los Angeles
Breast | Year: 2013

Introduction and aims: To provide a current perspective on nutrition and physical activity influence on breast cancer. Methods and results: A comprehensive literature review was conducted and selective presentation of findings follows. While some observational studies have associated higher dietary fat intake with higher breast cancer incidence, two full-scale randomized, clinical trials of dietary fat intake reduction programs were negative. However, a lifestyle intervention targeting fat intake reduction in the Women's Intervention Nutrition Study (WINS), resulted in weight loss and also reduced breast cancer recurrences in women with early stage disease. Observational studies evaluating specific nutrient intakes and dietary supplements have provided mixed results. Several observational studies find women with early stage breast cancer with lower 25-hydroxyvitamin D levels at higher recurrence risk, a finding requiring cautious interpretation. The lifestyle factor most strongly and consistently associated with both breast cancer incidence and breast cancer recurrence risk is physical activity. A meta-analyses of observational studies supports the concept that moderate recreational physical activity (about 3-4hwalking per week) may reduce breast cancer incidence and that women with early stage breast cancer who increased or maintain their physical activity may have lower recurrence risk as well. Feasibility of achieving increased physical activity and weight loss in women with early-stage breast cancer has been established. Two full-scale randomized clinical trials are evaluating weight loss/maintenance and increased physical activity in relation to recurrence risk in women with early-stage, resected breast cancer. Discussion/conclusions: Dietary intake may influence breast cancer but influence is difficult to separate from influence of body weight. A consistent body of observational study evidence suggests higher physical activity has favorable influence on breast cancer incidence and outcome. While awaiting definitive evidence from ongoing randomized trials, breast cancer patients can reasonably be counseled to avoid weight gain and reduce body weight if overweight or obese and increase or maintain a moderate level of physical activity. © 2013.


Hansen B.M.S.,University of California at Los Angeles | Murray N.,University of Toronto
Astrophysical Journal | Year: 2013

We present a Monte Carlo model for the structure of low-mass (total mass <25 M ⊕) planetary systems that form by the in situ gravitational assembly of planetary embryos into final planets. Our model includes distributions of mass, eccentricity, inclination, and period spacing that are based on the simulation of a disk of 20 M ⊕, forming planets around a solar-mass star, and assuming a power-law surface density distribution that drops with distance a as a -1.5. The output of the Monte Carlo model is then subjected to the selection effects that mimic the observations of a transiting planet search such as that performed by the Kepler satellite. The resulting comparison of the output to the properties of the observed sample yields an encouraging agreement in terms of the relative frequencies of multiple-planet systems and the distribution of the mutual inclinations when moderate tidal circularization is taken into account. The broad features of the period distribution and radius distribution can also be matched within this framework, although the model underpredicts the distribution of small period ratios. This likely indicates that some dissipation is still required in the formation process. The most striking deviation between the model and observations is in the ratio of single to multiple systems in that there are roughly 50% more single-planet candidates observed than are produced in any model population. This suggests that some systems must suffer additional attrition to reduce the number of planets or increase the range of inclinations. © 2013. The American Astronomical Society. All rights reserved.


Sofroniew M.V.,University of California at Los Angeles
Nature Reviews Neuroscience | Year: 2015

Astrocytes form borders (glia limitans) that separate neural from non-neural tissue along perivascular spaces, meninges and tissue lesions in the CNS. Transgenic loss-of-function studies reveal that astrocyte borders and scars serve as functional barriers that restrict the entry of inflammatory cells into CNS parenchyma in health and disease. Astrocytes also have powerful pro-inflammatory potential. Thus, astrocytes are emerging as pivotal regulators of CNS inflammatory responses. This Review discusses evidence that astrocytes have crucial roles in attracting and restricting CNS inflammation, with important implications for diverse CNS disorders. © 2015 Macmillan Publishers Limited. All rights reserved.


Fink M.P.,University of California at Los Angeles | Shaw Warren H.,Massachusetts General Hospital
Nature Reviews Drug Discovery | Year: 2014

Sepsis, a common and potentially fatal systemic illness, is triggered by microbial infection and often leads to impaired function of the lungs, kidneys or other vital organs. Since the early 1980s, a large number of therapeutic agents for the treatment of sepsis have been evaluated in randomized controlled clinical trials. With few exceptions, the results from these trials have been disappointing, and no specific therapeutic agent is currently approved for the treatment of sepsis. To improve upon this dismal record, investigators will need to identify more suitable therapeutic targets, improve their approaches for selecting candidate compounds for clinical development and adopt better designs for clinical trials.


Corren J.,University of California at Los Angeles
Discovery Medicine | Year: 2013

Asthma is a common chronic disease characterized by intermittent chest symptoms, variable airways obstruction, and bronchial hyperresponsiveness. Research performed over the past one to two decades has sought to better understand the heterogeneous clinical nature of asthma. Whereas older attempts at phenotyping asthma emphasized the duality of allergic vs. non-allergic asthma, more recent non-biased analyses have attempted to cluster patients by a multitude of possible features, including age of onset, atopy, severity of airways obstruction, and requirement for medication. Examples of these phenotypes include early-onset mild allergic asthma, later-onset asthma associated with obesity, and severe non-atopic asthma with frequent exacerbations. The elucidation of asthma phenotypes has been further refined by including information regarding pathophysiologic mechanisms present in different groups. These groups, called endotypes, include examples such as aspirin-exacerbated respiratory disease and allergic bronchopulmonary mycosis. A growing understanding of these mechanistically distinct groups, along with the identification of relevant cellular or molecular biomarkers, is already showing promise as a way of predicting clinical response to various asthma therapies. As the number of targeted treatments for asthma continues to grow, physicians will have the opportunity to practice an individualized approach to diagnosis and treatment, which will hopefully improve asthma outcomes and quality of life for these patients. © Discovery Medicine.


Doppler shifts of the Fe I spectral line at 5250Å from the full solar disk obtained over the period 1986 to 2009 are analyzed to determine the circulation velocity of the solar surface along meridional planes. Simultaneous measurements of the Zeeman splitting of this line are used to obtainmeasurements of the solarmagnetic field that are used to select low field points and impose corrections for the magnetically induced Doppler shift. The data utilized is from a new reduction that preserves the full spatial resolution of the original observations so that the circulation flow can be followed to latitudes of 80° N/S. The deduced meridional flowis shownto differ from the circulation velocities derived frommagnetic pattern movements.Areversed circulation pattern is seen in polar regions for three successive solar minima. A surge in circulation velocity at low latitudes is seen during the rising phases of cycles 22 and 23. © 2010 The American Astronomical Society.


Hansen B.M.S.,University of California at Los Angeles
Astrophysical Journal | Year: 2010

We provide an "effective theory" of tidal dissipation in extrasolar planet systems by empirically calibrating a model for the equilibrium tide. The model is valid to high order in eccentricity and parameterized by two constants of bulk dissipation-one for dissipation in the planet and one for dissipation in the host star. We are able to consistently describe the distribution of extrasolar planetary systems in terms of period, eccentricity, and mass (with a lower limit of a Saturn mass) with this simple model. Our model is consistent with the survival of short-period exoplanet systems, but not with the circularization period of equal mass stellar binaries, suggesting that the latter systems experience a higher level of dissipation than exoplanet host stars. Our model is also not consistent with the explanation of inflated planetary radii as resulting from tidal dissipation. The paucity of short-period planets around evolved A stars is explained as the result of enhanced tidal inspiral resulting from the increase in stellar radius with evolution. © 2010. The American Astronomical Society.


Tomboulis E.T.,University of California at Los Angeles
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

We investigate nonlocal field theories, a subject that has attracted some renewed interest in connection with nonlocal gravity models. We study, in particular, scalar theories of interacting delocalized fields, the delocalization being specified by nonlocal integral kernels. We distinguish between strictly nonlocal and quasilocal (compact support) kernels and impose conditions on them to insure UV finiteness and unitarity of amplitudes. We study the classical initial value problem for the partial integro-differential equations of motion in detail. We give rigorous proofs of the existence but accompanying loss of uniqueness of solutions due to the presence of future, as well as past, "delays," a manifestation of acausality. In the quantum theory we derive a generalization of the Bogoliubov causality condition equation for amplitudes, which explicitly exhibits the corrections due to nonlocality. One finds that, remarkably, for quasilocal kernels all acausal effects are confined within the compact support regions. We briefly discuss the extension to other types of fields and prospects of such theories. © 2015 American Physical Society.


Perry S.,University of California at Los Angeles
Advances in the Study of Behavior | Year: 2012

Cebus capucinus has converged with Old World monkeys by having strong, long-term social bonds among related females that are characterized by linear dominance hierarchies, frequent grooming, and coalition formation, biased toward maternal kin. Males also maintain long-term relationships with kin, by comigrating with close male relatives. Males need male allies to take over groups with mature females. The alpha male sires virtually all offspring born to females who are not his direct descendants. Thus, the males who assist the alpha male in gaining and preserving access to breeding females typically must delay breeding until the alpha male's daughters have matured. Infanticide by alpha males is the primary cause of infant death. Females support the current alpha male, thereby preventing disruptive takeovers that could result in infanticide. Some alpha males maintain their position for up to 18. years. Under such conditions, survival rates and the average degree of relatedness within a group are high. High male reproductive skew, frequent coalitionary lethal aggression, and infanticide put selective pressures on both males and females to engage in coalition formation. The rich repertoire of stereotyped recruitment signals suggests a long evolutionary history of coalition formation. The unusual diversity of traditional dyadic social conventions in this species may also be a consequence of selection for ability to test the quality of social bonds. © 2012 Elsevier Inc.


Allen M.J.,University of California at Los Angeles | Tung V.C.,University of California at Los Angeles | Kaner R.B.,University of California at Los Angeles
Chemical Reviews | Year: 2010

Graphene is the name given to a two-dimensional sheet of sp 2-hybridized carbon. Its extended honeycomb network is the basic building block of other important allotropes; it can be stacked to form 3D graphite, rolled to form 1D nanotubes, and wrapped to form 0D fullerenes. Substrate-based growth of single layers by chemical vapor deposition (CVD) or the reduction of silicon carbide relies on the ability to walk a narrow thermodynamic tightrope. Graphite has a rich chemistry in which it can participate in reactions as either a reducing agent (electron donor) or an oxidizer (electron acceptor). Solution processing of chemically derived graphene and the depositions achieved soon led researchers to consider using the material in transparent conductors. The graphite oxide has produced the first chemically derived micrometer-scale graphene, synthetic techniques for smaller planar, benzene-based macromolecules.


Bier E.,University of California at San Diego | De Robertis E.M.,Howard Hughes Medical Institute | De Robertis E.M.,University of California at Los Angeles
Science | Year: 2015

Bone morphogenetic proteins (BMPs) act in dose-dependent fashion to regulate cell fate choices in a myriad of developmental contexts. In early vertebrate and invertebrate embryos, BMPs and their antagonists establish epidermal versus central nervous system domains. In this highly conserved system, BMP antagonists mediate the neural-inductive activities proposed by Hans Spemann and Hilde Mangold nearly a century ago. BMPs distributed in gradients subsequently function as morphogens to subdivide the three germ layers into distinct territories and act to organize body axes, regulate growth, maintain stem cell niches, or signal inductively across germ layers. In this Review, we summarize the variety of mechanisms that contribute to generating reliable developmental responses to BMP gradients and other morphogen systems. © 2015, American Association for the Advancement of Science. All rights reserved.


Overman J.J.,University of California at Los Angeles | Carmichael S.T.,University of California at Los Angeles
Neuroscientist | Year: 2014

Changes in brain circuits occur within specific paradigms of action in the adult brain. These paradigms include changes in behavioral activity patterns, alterations in environmental experience, and direct brain injury. Each of these paradigms can produce axonal sprouting, dendritic morphology changes, and alterations in synaptic connectivity. Activity-, experience-, and injury-dependent plasticity alter neuronal network function and behavioral output, and in the case of brain injury, may produce neurological recovery. The molecular substrate for adult neuronal plasticity overlaps in these three paradigms in key signaling pathways. These common pathways for adult plasticity suggest common mechanisms for activity-, experience-, and injury-dependent plasticity. These common pathways may also interact to enhance or impede each other during adult recovery of function after injury. This review focuses on common molecular changes evoked during the process of adult neuronal plasticity, with a focus on neural repair in stroke. © The Author(s) 2013.


Danovitch G.M.,University of California at Los Angeles
Kidney International | Year: 2014

The Declaration of Istanbul defines organ transplant commercialism as '...a policy or practice in which an organ is treated as a commodity, including by being bought or sold or used for material gain.' It is this treatment of the organ that inevitably leads to its financial value being placed before the welfare of either its donor or its recipient or others in need of organ transplantation. International experience over the past two decades has proven this point and outcomes of commercial donation for both organ donors and their recipients have been poor. Commercial organ donation also comes at the expense of, not in addition to, unpaid, 'altruistic' donation. Other consequences of commercial donation are discussed in addition to a review of measures taken by the international community to put an end to the exploitation of vulnerable organ donors and the provision of ethically acceptable options for those in need of organ transplantation. © 2013 International Society of Nephrology.


Goel A.,University of California at Los Angeles
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

The discrimination and production of temporal patterns on the scale of hundreds of milliseconds are critical to sensory and motor processing. Indeed, most complex behaviours, such as speech comprehension and production, would be impossible in the absence of sophisticated timing mechanisms. Despite the importance of timing to human learning and cognition, little is known about the underlying mechanisms, in particular whether timing relies on specialized dedicated circuits and mechanisms or on general and intrinsic properties of neurons and neural circuits. Here, we review experimental data describing timing and interval-selective neurons in vivo and in vitro. We also review theoretical models of timing, focusing primarily on the state-dependent network model, which proposes that timing in the subsecond range relies on the inherent time-dependent properties of neurons and the active neural dynamics within recurrent circuits. Within this framework, time is naturally encoded in populations of neurons whose pattern of activity is dynamically changing in time. Together, we argue that current experimental and theoretical studies provide sufficient evidence to conclude that at least some forms of temporal processing reflect intrinsic computations based on local neural network dynamics.


Asensio O.I.,University of California at Los Angeles | Delmas M.A.,University of California at Los Angeles
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

In the electricity sector, energy conservation through technological and behavioral change is estimated to have a savings potential of123 million metric tons of carbon per year, which represents 20% of US household direct emissions in the United States. In this article, we investigate the effectiveness of nonprice information strategies to motivate conservation behavior. We introduce environment and health-based messaging as a behavioral strategy to reduce energy use in the home and promote energy conservation. In a randomized controlled trial with real-time appliancelevel energy metering, we find that environment and health-based information strategies, which communicate the environmental and public health externalities of electricity production, such as pounds of pollutants, childhood asthma, and cancer, outperform monetary savings information to drive behavioral change in the home. Environment and health-based information treatments motivated 8% energy savings versus control and were particularly effective on families with children, who achieved up to 19% energy savings. Our results are based on a panel of 3.4 million hourly appliance-level kilowatt-hour observations for 118 residences over 8 mo. We discuss the relative impacts of both cost-savings information and environmental health messaging strategies with residential consumers.


Yeaman M.R.,University of California at Los Angeles
Nature Reviews Microbiology | Year: 2014

Platelets have traditionally been viewed as fragmentary mediators of coagulation. However, recent molecular and cellular evidence suggests that they have multiple roles in host defence against infection. From first-responders that detect pathogens and rapidly deploy host-defence peptides, to beacons that recruit and enhance leukocyte functions in the context of infection, to liaisons that facilitate the T cell-B cell crosstalk that is required in adaptive immunity, platelets represent a nexus at the intersection of haemostasis and antimicrobial host defence. In this Review, I consider recent insights into the antimicrobial roles of platelets, which are mediated both directly and indirectly to integrate innate and adaptive immune responses to pathogens. © 2014 Macmillan Publishers Limited. All rights reserved.


Antibody-mediated immunotherapy has gained significant momentum since 1997 when the US Food and Drug Administration approved the first monoclonal antibody (mAb) for the treatment of B-cell non-Hodgkin lymphoma (B-NHL), namely, rituximab (chimeric anti-CD20 mAb). Subsequently, more than 20 approved mAbs have been in use clinically for the treatment of various cancers and several non-cancer-related diseases. Further, the combination treatment of mAbs with chemotherapy, immunotherapy, proteaosome inhibitors, and other inhibitors has resulted in synergistic anti-tumor activity with significant objective clinical responses. Despite their successful clinical use, the underlying mechanisms of rituximab's in vivo activities remain elusive. Further, it is not clear why a subset of patients is initially unresponsive and many responding patients become refractory and resistant to further treatments; hence, the underlying mechanisms of resistance are not known, Attempts have been made to develop model systems to investigate resistance to mAb therapy with the hope to apply the findings in both the generation of new therapeutics and in their use as new prognostic biomarkers. This review focuses on the development of resistance to rituximab treatments and discusses possible underlying mechanisms of action, postulated mechanisms of resistance in model systems, and suggested means to overcome resistance. Several prior reviews on the subject of rituximab resistance have been published and the present review both complements as well as adds new topics of relevance. © 2014 Elsevier Inc. All rights reserved.


Cho H.J.,University of California at Los Angeles
Psychological medicine | Year: 2013

Although basic research on neuroimmune interactions suggests that inflammatory processes may play a role in the development of fatigue, population-based evidence on this association is limited. This study examined whether plasma C-reactive protein (CRP) and interleukin-6 (IL-6), biomarkers of systemic inflammation, predict fatigue onset. The Whitehall II study is a large-scale cohort study conducted in 20 civil service departments in London. Plasma CRP and IL-6 were measured in 4847 non-fatigued participants at phase 3 (1991-1993, aged 39-63 years). Fatigue was assessed using the Vitality subscale of the 36-item Short Form Health Survey (SF-36) at phase 3 and phase 4 (1995-1996). During a mean follow-up of 3.1 years, 957 new fatigue cases (19.7%) were identified using the pre-established cut-off score of ≤ 50 on the Vitality subscale. CRP values were dichotomized as low (<1.0 mg/l ) or high (≥ 1.0 mg/l) using the Centers for Disease Control/American Heart Association recommendations. Similarly, IL-6 values were also dichotomized as low (<1.5 pg/ml) or high (≥ 1.5 pg/ml). After full adjustment for sociodemographic and biobehavioral covariates, the odds ratios for new-onset fatigue were 1.28 [95% confidence interval (CI) 1.09-1.49, p = 0.003] for high CRP and 1.24 (95% CI 1.06-1.45, p = 0.008) for high IL-6. Similar results were found when CRP and IL-6 were treated as continuous variables. Plasma CRP and IL-6 were prospectively associated with new-onset fatigue, supporting the hypothesis that low-grade inflammation has a role in the development of fatigue.


Timmermans S.,University of California at Los Angeles
Journal of health and social behavior | Year: 2010

A pressing concern in contemporary health policy is whether the medical profession's mandate to take care of clients has been undermined by the influx of money into health care. We examine the medical profession's transformation over the past decades. First, we review how sociologists have viewed the medical profession over the past half-century as one stakeholder among other stakeholders vying for market share and power in the health care field. We then examine three recent challenges to the profession that exemplify the tension between self-interest and collective altruism to act in the best interest of patients: (1) the rise of patient consumerism, (2) the advent of evidence-based medicine, and (3) the increasing power of the pharmaceutical industry. We show the resilience of the medical profession as it adapts and transforms in response to these challenges. We conclude with implications to help inform policy makers' assessments of how the medical profession will react to policy initiatives.


Glaspy J.,University of California at Los Angeles
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2012

Patients with cancer frequently develop a multifactorial anemia. The past decade has seen a dramatic improvement in understanding of the biology of the anemia of chronic disease, which has increased interest in studies of parenteral iron or antihepcidin strategies in these patients. Randomized trials have shown that therapy with erythropoiesis-stimulating agents (ESAs) is associated with a reduction in transfusion rates in patients with cancer undergoing chemotherapy. More recently, some studies have suggested that ESA therapy may increase the risk of tumor progression or reduce survival in patients with cancer. This topic was extensively reviewed previously. This update supplements prior reviews with data generated over the past 4 years. During this interval, interest in thrombosis and its role in cancer biology has increased, and concerns about the thrombotic risks of ESAs has moved to the forefront. Until additional safety data are forthcoming, ESAs should be used only to treat chemotherapy-induced anemia, with the goal of preventing transfusions. Patients and physicians should be aware of the safety data for these products. © JNCCN-Journal of the National Comprehensive Cancer Network.


Wong D.T.,University of California at Los Angeles
Journal of the American Dental Association (1939) | Year: 2012

The ability to monitor health and wellness, as well as detect oral and systemic illnesses early through noninvasive means, are highly desirable goals in health care promotion and delivery. Saliva is an emerging medium to be explored for health and disease surveillance, as well as for personalized medicine. A major mandate is to demonstrate clinicians' ability to use saliva to detect and monitor systemic diseases. To realize the translational and clinical vision of salivary diagnostics, two prerequisites are essential. The first is the need to develop and optimize diagnostic tools tailored to saliva. The second is the need to substantiate the scientific underpinnings of salivary biomarkers reflecting systemic diseases. The author describes five diagnostic alphabets (proteome, transcriptome, microRNA, metabolome and microbiome) and point-of-care technology platforms that are in place to advance the translational and clinical path. For mechanistic studies (that is, basic science studies), animal models are in place to elucidate the scientific mechanisms of systemic diseases reflected in saliva. Significant advancements have been made in the development of salivary diagnostic tools. The translation of the scientific mechanisms of systemic diseases reflected in saliva is in progress. On the scientific credentialing of salivary biomarkers for the detection of systemic diseases, salivary diagnostics will have an effect on access to care, health disparities and global health. Dentistry can advance into the realm of primary health care with integration of chairside screening for medical conditions.


Handel N.,University of California at Los Angeles
Plastic and Reconstructive Surgery | Year: 2013

BACKGROUND: The double-bubble deformity is a widely recognized complication of breast augmentation, but there have been very few articles in the peer-reviewed literature devoted exclusively to this topic. METHODS: Prior publications addressing the anatomy of the inframammary fold and its relationship to the double-bubble deformity are systematically reviewed. Disagreements among authorities regarding the precise anatomical structure of the inframammary fold are addressed. The cause and surgical correction of the double-bubble deformity are discussed in detail as they relate to the anatomy of the fold. RESULTS: The key to understanding the causes and correction of the double bubble lies in an appreciation of the anatomy of the inframammary fold. Correction of the deformity varies depending on whether or not patients had preexisting anatomical features predisposing them to development of a double bubble. CONCLUSION: A variety of surgical strategies, including use of a dual-plane pocket, form-stable shaped implants, capsulorrhaphy, pocket plane conversion, and use of acellular dermal matrices can play a role in prevention and treatment of the double-bubble deformity. Copyright © 2013 by the American Society of Plastic Surgeons.


Hu L.,University of California at Los Angeles | Hecht D.S.,University of California at Los Angeles | Gruner G.,University of California at Los Angeles
Chemical Reviews | Year: 2010

A study was conducted to demonstrate the fabrication, properties, and applications of carbon nanotube (CNT) thin films. Chemical vapor deposition (CVD) growth and solution-based coating methods were demonstrated as nanotube thin film fabrication methods. The electronic, optoelectronic, transport, and mechanical properties of nanotube thin films were also investigated. These thin films had significant device applications, including thin film transistors, transparent electrodes, and as nanoporous electrodes for energy storage. It was demonstrated that CNTs were produced by three major methods, such as arc-discharge and laser ablation, and chemical vapor deposition (CVD). CVD was the most common method for direct growth of CNT thin films where catalyst nanoparticles on substrates were used as seeds for CNT growth. The key parameters that control the growth kinetics were the hydrocarbon carrier gas, the growth time and temperature, and the catalyst composition.


Willis K.S.,University of California at Los Angeles
Biological Conservation | Year: 2015

Remote sensing allows for cost- and time-efficient monitoring of landscapes vital to the conservation of natural resources, ecosystems, and biodiversity. This review synthesizes and recommends best practice change detection methods for land management groups to monitor chief ecological change indicators currently monitored in United States protected areas. The indicators frequently monitored via change detection and reviewed here include: land use/land cover, disturbance, and phenology. Landsat data products are recommended for monitoring land use/land cover and disturbance, due to their continuous data accessibility free of cost since 1972. Data from the Moderate Resolution Imaging Spectrometer (MODIS) are recommended for monitoring changes in phenology due to its 1-2. day return interval at any given location. Best-practice remote sensing methods are stressed, such as careful validation of results, either by combination of remotely sensed datasets with high resolution imagery or in situ data, in order to increase accuracy and to better align the remotely sensed data to the scale of the on-the-ground processes. Reported results should always be presented with utmost clarity in a manner that is both applicable to managers and understood by the general public. Increased collaborations between ecologists, land managers, conservation groups, and scientists are compulsory for successful integration of remote sensing-based monitoring, which is vital for effective conservation in protected areas. Remote sensing change detection quantifies the effects of humans on a landscape scale without creating further disturbances to ecologically sensitive areas; the results of which can be used for efficient conservation management into the future. © 2014 Elsevier Ltd.


Akimov A.V.,University of California at Los Angeles | Prezhdo O.V.,University of California at Los Angeles
Chemical Reviews | Year: 2015

Progress in computational chemistry has been motivated by research and development in technological or biomedical applications, as work in these areas can lead to solutions for practical problems that have a direct impact on society. The growing capabilities of computational techniques create interesting opportunities for studying a greater range of smaller-scale systems, which can be investigated extensively through the use of large-scale computational facilities and resources. The possibility of performing such types of simulations is also motivated by steady progress in computer technologies, covering new techniques for mathematical operations in processors and the use of parallel and high-throughput computing architectures.


Ganz T.,University of California at Los Angeles
Physiological Reviews | Year: 2013

The iron hormone hepcidin and its receptor and cellular iron exporter ferroportin control the major fluxes of iron into blood plasma: intestinal iron absorption, the delivery of recycled iron from macrophages, and the release of stored iron from hepatocytes. Because iron losses are comparatively very small, iron absorption and its regulation by hepcidin and ferroportin determine total body iron content. Hepcidin is in turn feedback-regulated by plasma iron concentration and iron stores, and negatively regulated by the activity of erythrocyte precursors, the dominant consumers of iron. Hepcidin and ferroportin also play a role in host defense and inflammation, and hepcidin synthesis is induced by inflammatory signals including interleukin-6 and activin B. This review summarizes and discusses recent progress in molecular characterization of systemic iron homeostasis and its disorders, and identifies areas for further investigation. © 2013.


Griffin D.R.,University of California at Los Angeles | Kasko A.M.,University of California at Los Angeles
Journal of the American Chemical Society | Year: 2012

Hydrogel scaffolds are commonly used as 3D carriers for cells because their properties can be tailored to match natural extracellular matrix. Hydrogels may be used in tissue engineering and regenerative medicine to deliver therapeutic cells to injured or diseased tissue through controlled degradation. Hydrolysis and enzymolysis are the two most common mechanisms employed for hydrogel degradation, but neither allows sequential or staged release of cells. In contrast, photodegradation allows external real-time spatial and temporal control over hydrogel degradation, and allows for staged and sequential release of cells. We synthesized and characterized a series of macromers incorporating photodegradbale ortho-nitrobenzyl (o-NB) groups in the macromer backbone. We formed hydrogels from these macromers via redox polymerization and quantified the apparent rate constants of degradation (kapp) of each via photorheology at 370 nm, 10 mW/cm2. Decreasing the number of aryl ethers on the o-NB group increases kapp, and changing the functionality from primary to seconday at the benzylic site dramatically increases kapp. Human mesenchymal stem cells (hMSCs) survive encapsulation in the hydrogels (90% viability postencapsulation). By exploiting the differences in reactivity of two different o-NB linkers, we quantitatively demonstrate the biased release of one stem cell population (green-fluoroescent protein expressing hMSCs) over another (red-fluorescent protein expressing hMSCs). © 2012 American Chemical Society.


Seeman T.E.,University of California at Los Angeles
The journals of gerontology. Series B, Psychological sciences and social sciences | Year: 2011

To evaluate whether social contacts, support, and social strain/conflict are related to executive function and memory abilities in middle-age and older adults. Longitudinal data on social contacts, support, and strain/conflict were examined in relation to executive function and memory at ages 35-85 years using data from the national Midlife in the U.S. (MIDUS) study. Age-related differences in patterns of association were also examined. Regression analyses, controlling for age, sex, race, education, chronic health conditions, and health behaviors, revealed significant positive associations between histories of greater social contacts and support and both executive function and episodic memory, whereas declines in social contacts were negatively associated with both outcomes. Greater average reported frequency of social exchanges characterized by strain or conflict was negatively associated with executive function but not episodic memory. Patterns were generally consistent across different age groups; where differences were seen, associations were stronger in younger age group. Positive and negative aspects of social relationships are related to cognition throughout adulthood, consistent with the hypothesis that social factors have life-long influences on cognition. Positive and negative aspects of social engagement may thus be important factors to consider in relation to efforts to promote optimal cognitive development and cognitive aging.


Glassock R.J.,University of California at Los Angeles
American Journal of Kidney Diseases | Year: 2010

Ever since its first delineation as a distinct clinicopathologic entity in 1957, idiopathic membranous nephropathy (MN) has been the subject of intense laboratory and clinical investigation. The availability of laboratory models (particularly active and passive Heymann nephritis) of this disorder has been a boon to investigators. Concepts regarding the fundamental mechanisms of immune deposit formation, a sine qua non of idiopathic MN, have evolved and now are firmly established. Circulating autoantibodies (immunoglobulin G4 and immunoglobulin G1 subclasses) interacting with antigens native to or planted in the glomerular capillary wall at the podocyte cell membrane-basement membrane interface generally are regarded as the fundamental pathobiological mechanism. Thus, MN now is regarded as a podocytopathy. The immune deposits evoke an alteration in glomerular capillary permeability, probably through complement-mediated injury of the podocyte and its slit-pore membrane; however, cell-mediated immunity also may have a role, and the physical presence of immune deposits and basement membrane alterations also may participate. The exact nature of the autoantibody systems operative in human idiopathic MN is being uncovered rapidly. It is hoped that this 50-year odyssey will culminate in real progress in the diagnosis, prognosis, and therapy for the human disease. © 2010 National Kidney Foundation, Inc.


Kahru A.,Estonian National Institute of Chemical Physics and Biophysics | Ivask A.,Estonian National Institute of Chemical Physics and Biophysics | Ivask A.,University of California at Los Angeles
Accounts of Chemical Research | Year: 2013

Some researchers consider nanotechnology the next industrial revolution, and consumer products and a variety of industries increasingly use synthetic nanoparticles. In this Account, we review the initial accomplishments of nanoecotoxicology, a discipline that is just a decade old. This new subdiscipline of ecotoxicology faces two important and challenging problems: the analysis of the safety of nanotechnologies in the natural environment and the promotion of sustainable development while mitigating the potential pitfalls of innovative nanotechnologies. In this Account, we provide a snapshot of the publicly available scientific information regarding the ecotoxicity of engineered nanoparticles. We pay special attention to information relevant to aquatic freshwater species commonly used for risk assessment and regulation.Just as the development of ecotoxicology has lagged behind that of toxicology, nanoecotoxicological research has developed much more slowly than nanotoxicology. Although the first nanotoxicolology papers were published in 1990s, the first nanoecotoxicology papers came out in 2006. A meta-analysis of scientific publications covering different environmental impacts of nanomaterials showed that the importance of research into the environmental impact of nanotechnology has gradually increased since 2005. Now the most frequently cited papers in the environmental disciplines are often those that focus on synthetic nanoparticles.The first nanoecotoxicology studies focused on adverse effects of nanoparticles on fish, algae and daphnids, which are ecotoxicological model organisms for classification and labeling of chemicals (these model organisms are also used in the EU chemical safety policy adopted in 2007: Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH)). Based on our experience, we propose a multitrophic battery of nanoecotoxicological testing that includes particle-feeding and a priori particle-"proof" prokaryotic and eukaryotic organisms at different food-chain levels. Using this battery of selected test organisms, we demonstrated that TiO2 nanoparticles were toxic to algae and that ZnO and CuO nanoparticles were toxic to several aquatic invertebrate test species. Thus, one single biotest cannot predict the ecotoxicological effects of chemicals/nanoparticles, and researchers should use several tests instead. Moreover, produced nanoparticles usually vary in features such as size, shape, and coating; therefore, a single nanoparticle species may actually include many entities with different physicochemical properties. An ecotoxicity analysis of all these variants would require a huge number of laboratory tests. To address these issues, high throughput bioassays and computational (QSAR) models that serve as powerful alternatives to conventional (eco)toxicity testing must be implemented to handle both the diversity of nanomaterials and the complexity of ecosystems. © 2012 American Chemical Society.


Tomiyama A.J.,University of California at Los Angeles
Appetite | Year: 2014

Weight stigma is highly pervasive, but its consequences are understudied. This review draws from theory in social psychology, health psychology, and neuroendocrinology to construct an original, generative model called the cyclic obesity/weight-based stigma (COBWEBS) model. This model characterizes weight stigma as a "vicious cycle" - a positive feedback loop wherein weight stigma begets weight gain. This happens through increased eating behavior and increased cortisol secretion governed by behavioral, emotional, and physiological mechanisms, which are theorized to ultimately result in weight gain and difficulty of weight loss. The purpose of this review is to evaluate the existing literature for evidence supporting such a model, propose ways in which individuals enter, fight against, and exit the cycle, and conclude by outlining fruitful future directions in this nascent yet important area of research. © 2014 Elsevier Ltd.


Kramer J.R.,University of California at Los Angeles | Deming T.J.,University of California at Los Angeles
Journal of the American Chemical Society | Year: 2012

Conformation-switchable glycopolypeptides were prepared by the living polymerization of glycosylated l-cysteine-N-carboxyanhydride (glyco-C NCA) monomers. These new monomers were prepared in high yield by coupling of alkene-terminated C-linked glycosides of d-galactose or d-glucose to l-cysteine using thiol-ene "click" chemistry, followed by their conversion to the corresponding glyco-C NCAs. The resulting glycopolypeptides were found to be water-soluble and α-helical in solution. Aqueous oxidation of the side-chain thioether linkages in these polymers to sulfone groups resulted in disruption of the α-helical conformations without loss of water solubility. The ability to switch chain conformation and remain water-soluble is unprecedented in synthetic polymers, and allows new capabilities to control presentation of sugar functionality in subtly different contexts. © 2012 American Chemical Society.


Perlmutter E.,University of California at Los Angeles
Journal of High Energy Physics | Year: 2011

We investigate a class of near-extremal solutions of Einstein-Maxwell- scalar theory with electric charge and power law scaling, dual to charged IR phases of relativistic field theories at low temperature. These are exact solutions of theories with domain wall vacua; hence, we use nonconformal holography to relate the bulk and boundary theories. We numerically construct a global interpolating solution between the IR charged solutions and the UV domain wall vacua for arbitrary physical choices of Lagrangian parameters. By passing to a conformal frame in which the domain wall metric becomes that of AdS, we uncover a generalized scale invariance of the IR scaling solution, indicating a connection to the physics of Lifshitz fixed points. Finally, guided by effective field theoretic principles and the physics of nonconformal D-branes, we argue for the applicability of domain wall holography even in theories with AdS critical points, namely those theories for which a scalar potential is dominated by a single exponential term over a large range. © SISSA 2011.


Bower J.E.,University of California at Los Angeles
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Fatigue is a common adverse effect of cancer treatment and may persist for years after treatment completion. However, risk factors for post-treatment fatigue have not been determined. On the basis of studies suggesting an inflammatory basis for fatigue, this study tested the hypothesis that expression-regulating polymorphisms in proinflammatory cytokine genes would predict post-treatment fatigue in breast cancer survivors. Women diagnosed with early-stage breast cancer (n = 171) completed questionnaires to assess fatigue and other behavioral symptoms (ie, depressive symptoms, memory complaints, sleep disturbance) and provided blood for genotyping within 3 months after primary treatment. Genomic DNA was extracted from peripheral-blood leukocytes and assayed for single nucleotide polymorphisms (SNPs) in the promoter regions of three cytokine genes: ILB -511 C>T (rs16944), IL6 -174 G>C (rs1800795), and TNF -308 G>A (rs1800629). An additive genetic risk score was computed by summing the number of high-expression alleles (zero, one, or two) across all three polymorphisms. The genetic risk index was significantly associated with fatigue; as the number of high-expression alleles increased, so did self-reported fatigue severity (P = .002). Analyses of individual SNPs showed that TNF -308 and IL6 -174 were independently associated with fatigue (P = .032). The genetic risk index was also associated with depressive symptoms (P = .007) and memory complaints (P = .016). These findings further implicate inflammatory processes as contributors to cancer-related fatigue and suggest a new strategy for identifying and treating patients at risk for this symptom based on genetic variants in proinflammatory cytokine genes.


Xu J.,Harvard University | Smale S.T.,University of California at Los Angeles
Cell | Year: 2012

In this issue and in a recent issue of Cell, Vahedi et al. and Samstein et al. provide new insights into the strategies used to establish an enhancer landscape during development of cell lineages. They report that enhancer landscapes characterizing T cell lineages are pre-established and strongly influenced by environmental stimuli. © 2012 Elsevier Inc.


Kaback H.R.,University of California at Los Angeles
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Lactose permease (LacY), a paradigm for the largest family of membrane transport proteins, catalyzes the coupled translocation of a galactoside and an H+ across the Escherichia coli membrane (galactoside/H+ symport). Initial X-ray structures reveal N- and C-terminal domains, each with six largely irregular transmembrane helices surrounding an aqueous cavity open to the cytoplasm. Recently, a structure with a narrow periplasmic opening and an occluded galactoside was obtained, confirming many observations and indicating that sugar binding involves induced fit. LacY catalyzes symport by an alternating access mechanism. Experimental findings garnered over 45 y indicate the following: (i ) The limiting step for lactose/H+ symport in the absence of the H+ electrochemical gradient (ΔμH+) is deprotonation, whereas in the presence of ΔμH+, the limiting step is opening of apo LacY on the other side of the membrane; (ii ) LacY must be protonated to bind galactoside (the pK for binding is ∼10.5); (iii ) galactoside binding and dissociation, not ΔμH+ , are the driving forces for alternating access; (iv) galactoside binding involves induced fit, causing transition to an occluded intermediate that undergoes alternating access; (v) galactoside dissociates, releasing the energy of binding; and (vi ) Arg302 comes into proximity with protonated Glu325, causing deprotonation. Accumulation of galactoside against a concentration gradient does not involve a change in Kd for sugar on either side of the membrane, but the pKa (the affinity for H+) decreases markedly. Thus, transport is driven chemiosmotically but, contrary to expectation, ΔμH+ acts kinetically to control the rate of the process.


Singer A.J.,State University of New York at Stony Brook | Talan D.A.,View Medical | Talan D.A.,University of California at Los Angeles
New England Journal of Medicine | Year: 2014

Abscesses are a common form of skin and soft-tissue infection and are increasing in incidence. Although the diagnosis of an abscess can be straightforward, ultrasonography may be helpful in cases in which the abscess is deep, complex, or obscured by extensive cellulitis. A standard approach to incision and drainage remains the mainstay of abscess management, whereas routine packing may be unnecessary. The use of smaller incisions with loop drains and the use of primary closure may be considered in appropriate cases. Adjunctive antibiotic treatment and wound cultures should be limited to patients with severe cases, immunocompromised patients, and those in whom initial therapy is failing. Because of the relatively high failure rates even with optimal treatment, patient education and follow-up are recommended. Copyright © 2014 Massachusetts Medical Society.


Rice T.,University of California at Los Angeles
Annual Review of Public Health | Year: 2013

People often make decisions in health care that are not in their best interest, ranging from failing to enroll in health insurance to which they are entitled, to engaging in extremely harmful behaviors. Traditional economic theory provides a limited tool kit for improving behavior because it assumes that people make decisions in a rational way, have the mental capacity to deal with huge amounts of information and choice, and have tastes endemic to them and not open to manipulation. Melding economics with psychology, behavioral economics acknowledges that people often do not act rationally in the economic sense. It therefore offers a potentially richer set of tools than provided by traditional economic theory to understand and influence behaviors. Only recently, however, has it been applied to health care. This article provides an overview of behavioral economics, reviews some of its contributions, and shows how it can be used in health care to improve people's decisions and health. © 2013 by Annual Reviews. All rights reserved.


Rullo O.J.,University of California at Los Angeles | Tsao B.P.,University of California at Los Angeles
Annals of the Rheumatic Diseases | Year: 2013

Many identified genetic risk factors for systemic lupus erythematosus (SLE) contribute to the function of the immune system, which has expanded our understanding of disease pathogenesis. We outline the genetic variants in recently identified SLE-associated loci, the immunological pathways affected by these gene products and the disease manifestations linked to these loci. Pathways potentially influenced by SLE risk variants include: apoptosis, DNA degradation and clearance of cellular debris; antigen presentation; type I interferon, Toll-like receptor and nuclear factor kappa κB activation; defective clearance of immune complexes containing nuclear antigens; B and T-cell function and signalling; and monocyte and neutrophil function and signalling. These identified SLE susceptibility loci are predominantly common variants that have been confirmed among multiple ancestries, suggesting shared mechanisms in disease aetiology. Ongoing genetic studies continue the investigation of specific functional variants, and their potential consequences on immune dysregulation, enhancing our understanding of links between genotypes and specific disease manifestations. The next generation of sequencing explores the identification of causal rare variants that may contribute robust genetic effects to developing SLE. Novel insights coming from genetic studies of SLE provide the opportunity to elucidate pathogenic mechanisms as well as contribute to the development of innovative therapeutic targets for this complex disease.


Wang G.,University of California at Los Angeles
Nuclear Physics A | Year: 2013

We present measurements of pion elliptic flow (ν2) in Au + Au collisions at sNN=200,62.4,39,27and19.6GeV, as a function of event-by-event charge asymmetry (A ±), based on data from the STAR experiment at RHIC. We find that π -(π +) elliptic flow linearly increases (decreases) with charge asymmetry for most centrality bins and for all the beam energies under study. The slope parameter (r) from ν2(A ±) difference between π - and π + shows a centrality dependency similar to calculations of the Chiral Magnetic Wave. The measurements of charge separation with respect to the reaction plane in search of Local Parity Violation and the Chiral Magnetic Effect are also presented for Au+Au collisions at sNN=200,62.4,39,27,19.6,11.5and7.7GeV, and for U + U collisions at 193 GeV. © 2013 Elsevier B.V.


Gleason C.J.,University of California at Los Angeles | Smith L.C.,University of California at Los Angeles
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Rivers provide critical water supply for many human societies and ecosystems, yet global knowledge of their flow rates is poor. We show that useful estimates of absolute river discharge (in cubic meters per second)may be derived solely from satellite images,with no ground-based or a priori information whatsoever. The approach works owing to discovery of a characteristic scaling law uniquely fundamental to natural rivers, here termed a river's at-many-stations hydraulic geometry. A first demonstration using Landsat Thematic Mapper images over three rivers in the United States, Canada, and China yields absolute discharges agreeing to within 20-30% of traditional in situ gauging station measurements and good tracking of flow changes over time. Within such accuracies, the door appears open for quantifying river resources globally with repeat imaging, both retroactively and henceforth into the future, with strong implications for water resource management, food security, ecosystem studies, flood forecasting, and geopolitics.


Gorin M.B.,University of California at Los Angeles | Gorin M.B.,Jules Stein Eye Institute
Molecular Aspects of Medicine | Year: 2012

Age-related macular degeneration (AMD) is a common condition among the elderly population that leads to the progressive central vision loss and serious compromise of quality of life for its sufferers. It is also one of the few disorders for whom the investigation of its genetics has yielded rich insights into its diversity and causality and holds the promise of enabling clinicians to provide better risk assessments for individuals as well as to develop and selectively deploy new therapeutics to either prevent or slow the development of disease and lessen the threat of vision loss. The genetics of AMD began initially with the appreciation of familial aggregation and increase risk and expanded with the initial association of APOE variants with the disease. The first major breakthroughs came with family-based linkage studies of affected (and discordant) sibs, which identified a number of genetic loci and led to the targeted search of the 1q31 and 10q26 loci for associated variants. Three of the initial four reports for the CFH variant, Y402H, were based on regional candidate searches, as were the two initial reports of the ARMS2/HTRA1 locus variants. Case-control association studies initially also played a role in discovering the major genetic variants for AMD, and the success of those early studies have been used to fuel enthusiasm for the methodology for a number of diseases. Until 2010, all of the subsequent genetic variants associated with AMD came from candidate gene testing based on the complement factor pathway. In 2010, several large-scale genome-wide association studies (GWAS) identified genes that had not been previously identified. Much of this historical information is available in a number of recent reviews (Chen et al.; 2010b; Deangelis et al.; 2011; Fafowora and Gorin, 2012b; Francis and Klein, 2011; Kokotas et al.; 2011). Large meta analysis of AMD GWAS has added new loci and variants to this collection (Chen et al.; 2010a; Kopplin et al.; 2010; Yu et al.; 2011). This paper will focus on the ongoing controversies that are confronting AMD genetics at this time, rather than attempting to summarize this field, which has exploded in the past 5 years. © 2012 Elsevier Ltd. All rights reserved.


MacDonald G.M.,University of California at Los Angeles
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

The current Southwest drought is exceptional for its high temperatures and arguably the most severe in history. Coincidentally, there has been an increase in forest and woodland mortality due to fires and pathogenic outbreaks. Although the high temperatures and aridity are consistent with projected impacts of greenhouse warming, it is unclear whether the drought can be attributed to increased greenhouse gasses or is a product of natural climatic variability. Climate models indicate that the 21st century will be increasingly arid and droughts more severe and prolonged. Forest and woodland mortality due to fires and pathogens will increase. Demography and food security dictate that water demand in the Southwest will remain appreciable. If projected population growth is twinned with suburb-centered development, domestic demands will intensify. Meeting domestic demands through transference from agriculture presents concerns for rural sustainability and food security. Environmental concerns will limit additional transference from rivers. It is unlikely that traditional supply-side solutions such as more dams will securely meet demands at current per-capita levels. Significant savings in domestic usage can be realized through decreased applications of potable water to landscaping, but this is a small fraction of total regional water use, which is dominated by agriculture. Technical innovations, policy measures, and market-based solutions that increase supply and decrease water demand are all needed.Meeting 21st-century sustainability challenges in the Southwest will also require planning, cooperation, and integration that surpass 20th-century efforts in terms of geographic scope, jurisdictional breadth, multisectoral engagement, and the length of planning timelines.


Ribas A.,University of California at Los Angeles
Cancer Discovery | Year: 2015

Adaptive immune resistance is a process in which the cancer changes its phenotype in response to a cytotoxic or proinflammatory immune response, thereby evading it. This adaptive process is triggered by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T-cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1–blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies. Significance: Several new immunotherapy strategies to treat cancer are based on inhibiting processes through which cancer adapts and evades from an immune response. Recognizing the specific adaptive resistance mechanisms in each case is likely to allow the personalized development of immunothera pies tailored to block how a particular cancer protects itself from the immune system. © 2015 American Association for Cancer Research.


Sullivan P.P.,Sun System | McWilliams J.C.,University of California at Los Angeles
Annual Review of Fluid Mechanics | Year: 2010

We discuss the coupling processes between surface gravity waves and adjacent winds and currents in turbulent boundary layers. These processes mediate exchanges of momentum, heat, and gases between the atmosphere and ocean and thus are of global significance for climate. Surface waves grow primarily by pressure-form stress from airflow over the waveforms, and they dissipate in the open sea by wave breaking that injects and stirs momentum, energy, and bubbles into the ocean. Wave motions pump wind eddies that control fluxes across the lower atmosphere. Flow separation occurs behind steep wave crests, and at high winds the crests flatten into spume, which diminishes the drag coefficient. In the ocean the Lagrangian-mean wave velocity, Stokes drift, induces a vortex force and material transport. These generate Langmuir circulations penetrating throughout the boundary layer and enhancing entrainment at the stratified interior interface in combination with other turbulent eddies and inertial-shear instability. Copyright © 2010 by Annual Reviews. All rights reserved.


Squires T.M.,University of California at Santa Barbara | Mason T.G.,University of California at Los Angeles
Annual Review of Fluid Mechanics | Year: 2010

In microrheology, the local and bulk mechanical properties of a complex fluid are extracted from the motion of probe particles embedded within it. In passive microrheology, particles are forced by thermal fluctuations and probe linear viscoelasticity, whereas active microrheology involves forcing probes externally and can be extended out of equilibrium to the nonlinear regime. Here we review the development, present state, and future directions of this field. We organize our review around the generalized Stokes-Einstein relation (GSER), which plays a central role in the interpretation of microrheology. By discussing the Stokes and Einstein components of the GSER individually, we identify the key assumptions that underpin each, and the consequences that occur when they are violated. We conclude with a discussion of two techniques-multiple particle-tracking and nonlinear microrheology-that have arisen to handle systems in which the GSER breaks down. Copyright © 2010 by Annual Reviews. All rights reserved.


Shin D.S.,University of California at Los Angeles | Ribas A.,University of California at Los Angeles
Current Opinion in Immunology | Year: 2015

Unleashing the immune system to fight cancer has become one of the main treatment modalities since the anti-CTLA-4 antibody, ipilimumab was approved for patients with advanced melanoma in 2011. Pembrolizumab and nivolumab, two anti-PD-1 antibodies recently approved for the treatment of patients with metastatic melanoma, are being actively investigated for the treatment of multiple caners including lung, breast, bladder and renal cancers along with other anti-PD-1/L1 antibodies. Early results of combining of anti-CTLA-4 antibody and anti-PD-1 antibody treatment for advanced melanoma patients are showing impressive response rates with manageable toxicity profiles. There are several other checkpoint molecules that are likely potential inhibitory targets. The outcome of blocking some of these negative immune regulators, such as LAG-3 or TIM-3, is being pursued in the clinic or about to enter clinical development. Blockade of these molecules is demonstrating promising preclinical activity alone or when combined with anti-PD-1/L1. Future studies will define bio-markers of these therapies and how to target them alone or in combination with other immunotherapies, chemotherapy, radiotherapy and small molecule inhibitors. © 2015.


Silk J.B.,University of California at Los Angeles | House B.R.,University of California at Los Angeles
Proceedings of the National Academy of Sciences of the United States of America | Year: 2011

A growing body of evidence shows that humans are remarkably altruistic primates. Food sharing and division of labor play an important role in all human societies, and cooperation extends beyond the bounds of close kinship and networks of reciprocating partners. In humans, altruism is motivated at least in part by empathy and concern for the welfare of others. Although altruistic behavior is well-documented in other primates, the range of altruistic behaviors in other primate species, including the great apes, is much more limited than it is in humans. Moreover, when altruism does occur among other primates, it is typically limited to familiar group members - close kin, mates, and reciprocating partners. This suggests that there may be fundamental differences in the social preferences that motivate altruism across the primate order, and there is currently considerable interest in how we came to be such unusual apes. A body of experimental studies designed to examine the phylogenetic range of prosocial sentiments and behavior is beginning to shed some light on this issue. In experimental settings, chimpanzees and tamarins do not consistently take advantage of opportunities to deliver food rewards to others, although capuchins and marmosets do deliver food rewards to others in similar kinds of tasks. Although chimpanzees do not satisfy experimental criteria for prosociality in food delivery tasks, they help others complete tasks to obtain a goal. Differences in performance across species and differences in performance across tasks are not yet fully understood and raise new questions for further study.


Bilder R.M.,University of California at Los Angeles
Journal of the International Neuropsychological Society | Year: 2011

Neuropsychology is poised for transformations of its concepts and methods, leveraging advances in neuroimaging, the human genome project, psychometric theory, and information technologies. It is argued that a paradigm shift toward evidence-based science and practice can be enabled by innovations, including (1) formal definition of neuropsychological concepts and tasks in cognitive ontologies; (2) creation of collaborative neuropsychological knowledgebases; and (3) design of Web-based assessment methods that permit free development, large-sample implementation, and dynamic refinement of neuropsychological tests and the constructs these aim to assess. This article considers these opportunities, highlights selected obstacles, and offers suggestions for stepwise progress toward these goals. (JINS, 2011, 17, 7-13) © Copyright 2010. The International Neuropsychological Society 2010.


Previous studies of both clinically-derived and in vitro passage-derived daptomycin-resistant (DAP-R) Staphylococcus aureus strains demonstrated the coincident emergence of increased DAP MICs and resistance to host defense cationic peptides (HDP-R). In the present investigation, we studied a parental DAP-susceptible (DAP-S) methicillin-resistant Staphylococcus aureus (MRSA) strain and three isogenic variants with increased DAP MICs which were isolated from both DAP-treated and DAP-untreated rabbits with prosthetic joint infections. These strains were compared for: in vitro susceptibility to distinct HDPs differing in size, structure, and origin; i.e.; thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]; cell membrane (CM) phospholipid and fatty acid content; CM order; envelope surface charge; cell wall thickness; and mprF single nucleotide polymorphisms (SNPs) and expression profiles. In comparison with the parental strain, both DAP-exposed and DAP-naive strains exhibited: (i) significantly reduced susceptibility to each HDP (P<0.05); (ii) thicker cell walls (P<0.05); (iii) increased synthesis of CM lysyl-phosphatidylglycerol (L-PG); (iv) reduced content of CM phosphatidylglycerol (PG); and (v) SNPs within the mprF locus No significant differences were observed between parental or variant strains in outer CM content of L-PG, CM fluidity, CM fatty acid contents, surface charge, mprF expression profiles or MprF protein content. An isolate which underwent identical in vivo passage, but without evolving increased DAP MICs, retained parental phenotypes and genotype. THESE RESULTS SUGGEST: i) DAP MIC increases may occur in the absence of DAP exposures in vivo and may be triggered by organism exposure to endogenous HDPs: and ii) gain-in-function SNPs in mprF may contribute to such HDP-DAP cross-resistance phenotypes, although the mechanism of this relationship remains to be defined.


King C.R.,University of California at Los Angeles
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: Salvage radiotherapy (SRT) after radical prostatectomy can potentially eradicate residual microscopic disease. Defining the optimal patient and treatment factors is essential and is particularly relevant within the context of adjuvant vs early vs delayed postoperative radiotherapy (RT). Methods and Materials: A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships. Results: Prostate-specific antigen (PSA) level before SRT (P<.0001) and RT dose (P=.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI, ∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose-response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI, ∼0.9-3.2). The observed dose-response was less robust on sensitivity analysis. Conclusions: This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data. Progressively better tumor control rates with SRT after radical prostatectomy are achieved with a lower PSA at initiation and with a higher RT dose. Early salvage RT may be an equivalent strategy to adjuvant RT. © 2012 Elsevier Inc. All rights reserved.


Vinters H.V.,University of California at Los Angeles
Annual Review of Pathology: Mechanisms of Disease | Year: 2015

Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions. © 2015 by Annual Reviews.


Razani B.,University of California at Los Angeles
Science signaling | Year: 2010

Although NF-kappaB (nuclear factor kappaB) was discovered less than 25 years ago, it is one of the most well-studied transcription factors. It plays critical roles in various immune and cellular processes, and its dysregulation is a major driver of cancer and inflammatory pathology. A new book published by Cold Spring Harbor Laboratory Press, NF-kappaB: A Network Hub Controlling Immunity, Inflammation, and Cancer, provides a series of excellent reviews on the architecture, regulation, and pathophysiological roles of NF-kappaB signaling by some of the leading investigators in the field.


Ganz T.,University of California at Los Angeles | Nemeth E.,University of California at Los Angeles
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2012

Despite fluctuations in dietary iron intake and intermittent losses through bleeding, the plasma iron concentrations in humans remain stable at 10-30. μM. While most of the iron entering blood plasma comes from recycling, appropriate amount of iron is absorbed from the diet to compensate for losses and maintain nontoxic amounts in stores. Plasma iron concentration and iron distribution are similarly regulated in laboratory rodents. The hepatic peptide hepcidin was identified as the systemic iron-regulatory hormone. In the efferent arc, hepcidin regulates intestinal iron absorption, plasma iron concentrations, and tissue iron distribution by inducing degradation of its receptor, the cellular iron exporter ferroportin. Ferroportin exports iron into plasma from absorptive enterocytes, from macrophages that recycle the iron of senescent erythrocytes, and from hepatocytes that store iron. In the more complex and less well understood afferent arc, hepatic hepcidin synthesis is transcriptionally regulated by extracellular and intracellular iron concentrations through a molecular complex of bone morphogenetic protein receptors and their iron-specific ligands, modulators and iron sensors. Through as yet undefined pathways, hepcidin is also homeostatically regulated by the iron requirements of erythroid precursors for hemoglobin synthesis. In accordance with the role of hepcidin-mediated iron redistribution in host defense, hepcidin production is regulated by inflammation as well. Increased hepcidin concentrations in plasma are pathogenic in iron-restrictive anemias including anemias associated with inflammation, chronic kidney disease and some cancers. Hepcidin deficiency causes iron overload in hereditary hemochromatosis and ineffective erythropoiesis. Hepcidin, ferroportin and their regulators represent potential targets for the diagnosis and treatment of iron disorders and anemias. This article is part of a Special Issue entitled: Cell Biology of Metals. © 2012 Elsevier B.V.


Arnold A.P.,University of California at Los Angeles
Trends in Genetics | Year: 2012

The 20th-century theory of mammalian sex determination states that the embryo is sexually indifferent until the differentiation of gonads, after which sex differences in phenotype are caused by the differential effects of gonadal hormones. However, this theory is inadequate because some sex differences precede differentiation of the gonads and/or are determined by non-gonadal effects of the sexual inequality in the number and type of sex chromosomes. In this article, I propose a general theory of sex determination, which recognizes multiple parallel primary sex-determining pathways initiated by genes or factors encoded by the sex chromosomes. The separate sex-specific pathways interact to synergize with or antagonize each other, enhancing or reducing sex differences in phenotype. © 2011 Elsevier Ltd.


Chase M.H.,University of California at Los Angeles
Sleep Medicine Reviews | Year: 2013

Data accumulated during the last 40 years, since the discovery that there is a loss of muscle tone during REM sleep, have delineated many of the neurotransmitter systems, synaptic mechanisms and neuronal circuitries involved in the control of somatic motoneurons during sleep and waking states. Nevertheless, there are still a number of extant controversies as well as paradoxical and conflicting data. For example, the paradoxical modulation of motor activity that occurs in individuals with cataplexy during wakefulness compared to REM sleep is unresolved as are the mechanisms that are responsible for the control of hypoglossal motoneurons during normal states and those that are operative during sleep disorders such as obstructive sleep apnea. In addition, the circuitry whereby the hypocretinergic system promotes motor activation during wakefulness, and motor inhibition during REM sleep, has yet to be clarified. The use of new techniques, such those involving optogenetics and nanoparticles, will help to clarify the preceding issues and provide as a foundation for addressing a number of current critical unanswered questions such as those dealing with the differential control of motor activity in newborns and the aged. The resulting data will strengthen the foundation for the development of efficacious therapeutics to treat disorders of motor control that occur during sleep as well as wakefulness. © 2012 .


Modlin R.L.,University of California at Los Angeles | Bloom B.R.,Harvard University
Science Translational Medicine | Year: 2013

Tuberculosis (TB) remains a devastating infectious disease and, with the emergence of multidrug-resistant forms, represents a major global threat. Much of our understanding of pathogenic and immunologic mechanisms in TB has derived from studies in experimental animals. However, it is becoming increasingly clear in TB as well as in other inflammatory diseases that there are substantial differences in immunological responses of humans not found or predicted by animal studies. Thus, it is critically important to understand mechanisms of pathogenesis and immunological protection in humans. In this review, we will address the key immunological question: What are the necessary and sufficient immune responses required for protection against TB infection and disease in people - specifically protection against infection, protection against the establishment of latency or persistence, and protection against transitioning from latent infection to active disease.


Vervliet B.,Catholic University of Leuven | Craske M.G.,University of California at Los Angeles | Hermans D.,Catholic University of Leuven
Annual Review of Clinical Psychology | Year: 2013

Exposure-based treatments for clinical anxiety generally are very effective, but relapse is not uncommon. Likewise, laboratory studies have shown that conditioned fears are easy to extinguish, but they recover easily. This analogy is striking, and numerous fear extinction studies have been published that highlight the processes responsible for the extinction and return of acquired fears. This review examines and integrates the most important results from animal and human work. Overall, the results suggest that fear extinction is relatively easy to "learn" but difficult to "remember." It follows that treatments will benefit from an enhanced focus on the long-term retrieval of fear extinction. We review the available studies on the prevention of return of fear and the prospects of weakening fear memories forever. We show that the behavioral principles outlined in learning theory provide a continuous inspiration for preclinical (neurobiological) and clinical research on the extinction and return of fear. Copyright © 2013 by Annual Reviews.


Sankar R.,University of California at Los Angeles
CNS Drugs | Year: 2012

Clobazam was initially developed in the early 1970s as a nonsedative anxiolytic agent, and is currently available as adjunctive therapy for epilepsy and anxiety disorders in more than 100 countries. In October 2011, clobazam (Onfi TM; Lundbeck Inc., Deerfield, IL, USA) was approved by the US FDA for use as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is a long-acting 1,5-benzodiazepine whose structure distinguishes it from the classic 1,4-benzodiazepines, such as diazepam, lorazepam and clonazepam. Clobazam is well absorbed, with peak concentrations occurring linearly 1-4 hours after administration. Both clobazam and its active metabolite, N-desmethylclobazam, are metabolized in the liver via the cytochrome P450 pathway. The mean half-life of N-desmethylclobazam (67.5 hours) is nearly double the mean half-life of clobazam (37.5 hours). Clobazam was synthesized with the anticipation that its distinct chemical structure would provide greater efficacy with fewer benzodiazepine-associated adverse effects. Frequently reported adverse effects of clobazam therapy include dizziness, sedation, drowsiness and ataxia. Evidence gathered from approximately 50 epilepsy clinical trials in adults and children indicated that the sedative effects observed with clobazam treatment were less severe than those reported with 1,4-benzodiazepines. In several studies of healthy volunteers and patients with anxiety, clobazam appeared to enhance participants performance in cognitive tests, further distinguishing it from the 1,4-benzodiazepines.The anxiolytic and anticonvulsant effects of clobazam are associated with allosteric activation of the ligand-gated GABA A receptor. GABA A receptors are found extensively throughout the CNS, occurring synaptically and extrasynaptically. GABA A receptors are composed of five protein subunits, two copies of a single type of α subunit, two copies of one type of β subunit and a γ subunit. This arrangement results in a diverse assortment of receptor subtypes. As benzodiazepine pharmacology is influenced by differences in affinity for particular GABA A subtypes, characterizing the selectivity of different benzodiazepines is a promising avenue for establishing appropriate use of these agents in neurological disorders. Molecular techniques have significantly advanced since the inception of clobazam as a clinical agent, adding to the understanding of the GABA A receptor, its subunits and benzodiazepine pharmacology. Transgenic mouse models have been particularly useful in this regard. Comparative studies between transgenic and wild-type mice have further defined relationships between GABA A receptor composition and drug effects. From such studies, we have learned that sedating and amnesic effects are mediated by the GABA A α 1 subunit, α 2 receptors mediate anxiolytic effects, α subunits are involved with anticonvulsant activity, α 5 may be implicated in learning and memory, and β 3 subunit deficiency decreases GABA inhibition. Despite progress in determining the role of various subunits to specific benzodiazepine pharmacological actions, the precise mechanism of action of clobazam, and more importantly, how that mechanism of action translates into clinical consequences (i.e. efficacy, tolerability and safety) remain unknown. Testing clobazam and 1,4-benzodiazepines using a range of recombinant GABA A receptor subtypes would hopefully elucidate the subunits involved and strengthen our understanding of clobazam and its mechanism of action. © 2012 Adis Data Information BV. All rights reserved.


Rosove M.H.,University of California at Los Angeles
Seminars in Arthritis and Rheumatism | Year: 2014

Objective: To review the clinical features and pathophysiologic mechanisms of the thrombotic microangiopathies (TMAs) including acquired and congenital thrombotic thrombocytopenic purpura (TTP), Shiga toxin-induced and atypical (non-Shiga toxin-induced) hemolytic uremic syndrome (HUS), and the TMAs associated with pregnancy, drugs, and organ transplantation. Methods: PubMed Medline was used to identify articles published from 2000 to July 2013 using the following key words: thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, Shiga toxin, ADAMTS13, and eculizumab. Articles in languages other than English, papers available in abstract form only, and nearly all single case reports were excluded. Small series, reports from registries and study groups, reviews, guidelines, and articles concerning pathophysiology and therapy were preferentially considered. Results: Impaired post-secretion processing of unusually large von Willebrand multimers due to deficiency of ADAMTS13 (IgG antibodies or congenital), dysregulation of the alternative complement pathway (mutations and/or specific antibodies), and endothelial injury are pathophysiologic mechanisms involved in the TMAs. Acquired and congenital TTP are due primarily to severe ADAMTS13 deficiency, atypical HUS is commonly associated with complement dysregulation, and Shiga toxin, drugs, immune complexes, and others likely damage endothelium. However, there is considerable mechanistic overlap, and the TMAs often have multifactorial causation. Plasma procedures, complement pathway inhibition, immunosuppression, and general supportive care are the principal therapies. Conclusions: The TMAs are very important conditions because of their associated organ damage and mortality rates. Prompt recognition and categorization by both clinical presentation and pathophysiologic mechanisms should become routine as they are crucial to an optimal treatment plan. Treatment advances have substantially reduced the morbidity of these disorders. Investigational therapies are promising. © 2014 Elsevier Inc.


Irwin M.R.,University of California at Los Angeles
Current Psychiatry Reports | Year: 2013

Over two-thirds of the 11.4 million cancer survivors in the United States can expect long-term survival, with many others living with cancer as a chronic disease controlled by ongoing therapy. Behavioral comorbidities often arise during treatment and persist long term to complicate survival and reduce quality of life. This review focuses on depression and insomnia with an emphasis on understanding the role of cancer-specific factors and their contribution to the prevalence of these behavioral comorbidities in cancer patients following cancer diagnosis and treatment. The clinical significance of depression and insomnia for cancer patients is further stressed by epidemiological observations that link depression and insomnia to cancer morbidity and mortality risk. © 2013 Springer Science+Business Media New York.


Charles A.,University of California at Los Angeles
Headache | Year: 2013

A migraine attack is an extraordinarily complex brain event that takes place over hours to days. This review focuses on recent human studies that shed light on the evolution of a migraine attack. It begins with a constellation of premonitory symptoms that are associated with activation of the hypothalamus and may involve the neurotransmitter dopamine. Even in the premonitory phase, patients experience sensitivity to sensory stimuli, indicating that central sensitization is a primary phenomenon. The migraine attack progresses to a phase that in some patients includes aura, which involves changes in cortical function, blood flow, and neurovascular coupling. The aura phase overlaps with the headache phase, which is associated with further changes in blood flow and function of the brainstem, thalamus, hypothalamus, and cortex. Serotonin receptors, nitric oxide, calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide, and prostanoids are demonstrated specific chemical mediators of migraine based on therapeutic and triggered migraine studies. A number of migraine symptoms persist beyond resolution of headache into a postdromal phase, accompanied by persistent blood flow changes in several brain regions. Although these phases of migraine have substantial temporal, neurochemical, and anatomical overlap, each represents an important window onto the pathophysiology of migraine as well as a target for therapeutic intervention. A comprehensive approach to migraine requires an understanding of the entire range of mechanisms and resultant symptoms that occur throughout the evolution of an attack. © 2012 American Headache Society.


Reuben D.B.,University of California at Los Angeles
Neurology | Year: 2013

Motor function involves complex physiologic processes and requires the integration of multiple systems, including neuromuscular, musculoskeletal, and cardiopulmonary, and neural motor and sensory-perceptual systems. Motor-functional status is indicative of current physical health status, burden of disease, and long-term health outcomes, and is integrally related to daily functioning and quality of life. Given its importance to overall neurologic health and function, motor function was identified as a key domain for inclusion in the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox). We engaged in a 3-stage developmental process to: 1) identify key subdomains and candidate measures for inclusion in the NIH Toolbox, 2) pretest candidate measures for feasibility across the age span of people aged 3 to 85 years, and 3) validate candidate measures against criterion measures in a sample of healthy individuals aged 3 to 85 years (n = 340). Based on extensive literature review and input from content experts, the 5 subdomains of dexterity, strength, balance, locomotion, and endurance were recommended for inclusion in the NIH Toolbox motor battery. Based on our validation testing, valid and reliable measures that are simultaneously low-cost and portable have been recommended to assess each subdomain, including the 9-hole peg board for dexterity, grip dynamometry for upper-extremity strength, standing balance test, 4-m walk test for gait speed, and a 2-minute walk test for endurance.


Weinmaster G.,University of California at Los Angeles | Fischer J.,University of Texas at Austin
Developmental Cell | Year: 2011

In the first volume of Developmental Cell, it was reported that the classic Drosophila neurogenic gene neuralized encodes a ubiquitin ligase that monoubiquitylates the Notch ligand Delta, thus promoting Delta endocytosis. A requirement for ligand internalization by the signal-sending cell, although counterintuitive, remains to date a feature unique to Notch signaling. Ten years and many ubiquitin ligases later, we discuss sequels to these three papers with an eye toward reviewing the development of ideas for how ligand ubiquitylation and endocytosis propel Notch signaling. © 2011 Elsevier Inc.


Rozengurt E.,University of California at Los Angeles
Physiology | Year: 2011

Protein kinase D (PKD) is an evolutionarily conserved protein kinase family with structural, enzymological, and regulatory properties different from the PKC family members. Signaling through PKD is induced by a remarkable number of stimuli, including G-protein-coupled receptor agonists and polypeptide growth factors. PKD1, the most studied member of the family, is increasingly implicated in the regulation of a complex array of fundamental biological processes, including signal transduction, cell proliferation and differentiation, membrane trafficking, secretion, immune regulation, cardiac hypertrophy and contraction, angiogenesis, and cancer. PKD mediates such a diverse array of normal and abnormal biological functions via dynamic changes in its spatial and temporal localization, combined with its distinct substrate specificity. Studies on PKD thus far indicate a striking diversity of both its signal generation and distribution and its potential for complex regulatory interactions with multiple downstream pathways, often regulating the subcellular localization of its targets. © 2011 by the American Physiological Society.


Hewison M.,University of California at Los Angeles
Nature Reviews Endocrinology | Year: 2011

Interaction between vitamin D and the immune system has been recognized for many years, but its relevance to normal human physiology has only become evident in the past 5 years. Studies of innate immune responses to pathogens such as Mycobacterium tuberculosis have shown that pathogen-recognition receptor-mediated activation of localized vitamin D metabolism and signaling is a key event associated with infection. Vitamin D, acting in an intracrine fashion, is able to induce expression of antibacterial proteins and enhance the environment in which they function. The net effect of these actions is to support increased bacterial killing in a variety of cell types. The efficacy of such a response is highly dependent on vitamin D status; in other words, the availability of circulating 25-hydroxyvitamin D for intracrine conversion to active 1,25-dihydroxyvitamin D by the enzyme 25-hydroxyvitamin D-1α-hydroxylase. The potential importance of this mechanism as a determinant of human disease is underlined by increasing awareness of vitamin D insufficiency across the globe. This Review will explore the molecular and cellular systems associated with antibacterial responses to vitamin D in different tissues and possible consequences of such a response for the prevention and treatment of human immune disorders. © 2011 Macmillan Publishers Limited. All rights reserved.


Hill K.L.,University of California at Los Angeles
Current Opinion in Microbiology | Year: 2010

Motility of the sleeping sickness parasite, Trypanosoma brucei, impacts disease transmission and pathogenesis. Trypanosome motility is driven by a flagellum that harbors a canonical 9 + 2 axoneme, together with trypanosome-specific elaborations. Trypanosome flagellum biology and motility have been the object of intense research over the last two years. These studies have led to the discovery of a novel form of motility, termed social motility, and provided revision of long-standing models for cell propulsion. Recent work has also uncovered novel structural features and motor proteins associated with the flagellar apparatus and has identified candidate signaling molecules that are predicted to regulate flagellar motility. Together with earlier inventories of flagellar proteins from proteomic and genomic studies, the stage is now set to move forward with functional studies to elucidate molecular mechanisms and investigate parasite motility in the context of host-parasite interactions. © 2010 Elsevier Ltd.


Maddahi J.,University of California at Los Angeles
Journal of Nuclear Cardiology | Year: 2012

An ideal positron emission tomography (PET) tracer should be highly extractable by the myocardium and able to provide high-resolution images, should enable quantification of absolute myocardial blood flow (MBF), should be compatible with both pharmacologically induced and exercise-induced stress imaging, and should not require an on-site cyclotron. The PET radionuclides nitrogen-13 ammonia and oxygen-15 water require an on-site cyclotron. Rubidium-82 may be available locally due to the generator source, but greater utilization is limited because of its relatively low myocardial extraction fraction, long positron range, and generator cost. Flurpiridaz F 18, a novel PET tracer in development, has a high-extraction fraction, short positron range, and relatively long half-life (as compared to currently available tracers), and may be produced at regional cyclotrons. Results of early clinical trials suggest that both pharmacologically and exercise-induced stress PET imaging protocols can be completed more rapidly and with lower patient radiation exposure than with single-photon emission computerized tomography (SPECT) tracers. As compared to SPECT images in the same patients, flurpiridaz F 18 PET images showed better defect contrast. Flurpiridaz F 18 is a potentially promising tracer for assessment of myocardial perfusion, measurement of absolute MBF, calculation of coronary flow reserves, and assessment of cardiac function at the peak of the stress response Copyright © 2012 American Society of Nuclear Cardiology.


Montecino-Rodriguez E.,University of California at Los Angeles | Dorshkind K.,University of California at Los Angeles
Immunity | Year: 2012

Models of hematopoiesis often depict lymphocyte production as a uniform process in which a homogenous population of hematopoietic stem cells (HSCs) generates progenitors from which all types of lymphocytes are derived. However, it is increasingly evident that these schemes are too simplistic and that the lymphoid potential of HSCs and precursors arising in the embryo, fetus, neonate, and adult is remarkably distinct. We review recent findings regarding the development of B lymphocytes, and the B-1 B cell lineage in particular, as a case in point. These studies show that B-1 and B-2 B cells involved in innate and adaptive immune responses, respectively, arise in staggered waves of development from distinct progenitors. We discuss theimplications of this layered model of B cell development for understanding normal and dysregulated Blymphopoiesis. © 2012 Elsevier Inc.


Yang X.,University of California at Los Angeles
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

Recent genome-wide association studies have identified hundreds of genetic loci as being associated with vascular diseases or traits and their risk factors. Many of the loci uncovered represent novel discoveries with no obvious candidate genes and molecular mechanisms, testifying to the complexity of vascular diseases. To understand the functional consequences of genetic variations and help pinpoint the underlying genes and mechanisms of common complex diseases, functional genomics that integrate genetic variations and intermediate molecular traits such as gene expression has been extensively studied in the past few years. This review summarizes the key concepts of functional genomics, the current state of the field, and its application in vascular diseases. © 2012 American Heart Association, Inc.


Carmichael S.T.,University of California at Los Angeles
Archives of Neurology | Year: 2012

There is no current medical therapy for stroke recovery. Principles of physiological plasticity have been identified during recovery in both animal models and human stroke. Stroke produces a loss of physiological brain maps in adjacent peri-infarct cortex and then a remapping of motor and sensory functions in this region. This remapping of function in peri-infarct cortex correlates closely with recovery. Recent studies have shown that the stroke produces abnormal conditions of excitability in neuronal circuits adjacent to the infarct that may be the substrate for this process of brain remapping and recovery. Stroke causes a hypoexcitability in peri-infarct motor cortex that stems from increased tonic γ-aminobutyric acid activity onto neurons. Drugs that reverse this γ-aminobutyric acid signaling promote recovery after stroke. Stroke also increases the sensitivity of glutamate receptor signaling in peri-infarct cortex well after the stroke event, and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors in peri-infarct cortex promotes recovery after stroke. Both blocking tonic γ-aminobutyric acid currents and stimulating α-amino-3-hydroxyl-5- methyl-4-isoxazole-propionate receptors promote recovery after stroke when initiated at quite a delay, more than 3 to 5 days after the infarct. These changes in the excitability of neuronal circuits in peri-infarct cortex after stroke may underlie the process of remapping motor and sensory function after stroke and may identify new therapeutic targets to promote stroke recovery. © 2012 American Medical Association. All rights reserved.


Ponticelli C.,IRCCS Humanitas Hospital | Glassock R.J.,University of California at Los Angeles
Clinical Journal of the American Society of Nephrology | Year: 2014

Membranous nephropathy (MN) is an autoimmune disease usually associated with a nephrotic syndrome and it may progress to ESRD in the long term. Its etiology is often unknown (idiopathicMN), whereas other cases have a recognizable etiology (secondary MN). In idiopathic MN, the glomerular lesions are mainly caused by autoantibodies against a podocyte membrane protein, the M-type of phospholipase A2 receptor 1. The natural course of idiopathic MN is quite varied with spontaneous complete or partial remissions a relatively common occurrence. Patientswith asymptomatic non-nephrotic proteinuria seldomprogress and need only conservativemanagement. Those with persistent full-blown nephrotic syndrome and those with declining renal function are candidates for specific treatment with any of several regimens. Cyclical therapy with alternating monthly intravenous and oral glucocorticoids combined with a cytotoxic agent can induce remission and preserve renal function in the long term. Cyclosporine or tacrolimus can induce remission, but relapses are frequent after the drug withdrawal. Mycophenolate mofetil monotherapy seems to be ineffective, but may be beneficial when administered together with steroids. The experience with adrenocorticotropic hormone, natural or synthetic, is limited to a few studies with short-term follow-up, but high rates of remission can be seen after prolonged treatment. A high rate of remission and good tolerance have also been reported with rituximab. Patients with moderate renal insufficiency may also benefit fromtreatment, but at a price of frequent and serious side effects.With these limitations in mind, idiopathic MN may be considered a treatable disease in many patients. © 2014 by the American Society of Nephrology.


Jewitt D.,University of California at Los Angeles
Astronomical Journal | Year: 2013

Asteroids near the Sun can attain equilibrium temperatures sufficient to induce surface modification from thermal fracture, desiccation, and decomposition of hydrated silicates. We present optical observations of nine asteroids with perihelia <0.25 AU (sub-solar temperatures ≥800 K) taken to search for evidence of thermal modification. We find that the broadband colors of these objects are diverse but statistically indistinguishable from those of planet-crossing asteroids having perihelia near 1 AU. Furthermore, images of these bodies taken away from perihelion show no evidence for on-going mass-loss (model-dependent limits ≲1 kg s-1) that might result from thermal disintegration of the surface. We conclude that, while thermal modification may be an important process in the decay of near-Sun asteroids and in the production of debris, our new data provide no evidence for it. © 2013. The American Astronomical Society. All rights reserved.


Pardridge W.M.,University of California at Los Angeles
Expert Opinion on Therapeutic Targets | Year: 2015

The blood-brain barrier (BBB) limits the uptake of most drugs by brain, and the traditional approach to the BBB problem is the use of medicinal chemistry to increase drug lipid solubility, and increase lipid-mediated transport across the BBB. This review advocates a new model to CNS drug discovery of BBB-penetrating small molecules, whereby drug candidates are screened for carrier-mediated transport (CMT) across the BBB.Areas covered: CMT systems are expressed by genes within the Solute Carrier (SLC) Transporter Gene Family, which now totals > 400 transporter genes. Emphasis is placed on reconciliation of the substrate transporter profile (STP) of BBB transport in vivo with the STP of the cloned SLC transporter in vitro. This reconciliation is crucial to the identification, from sometimes a large number of candidates, of the respective SLC transporter that is responsible for BBB transport in vivo for a given class of nutrients.Expert opinion: Dual track screening of a small molecule library for drugs that have the dual properties of affinity for a neural cell drug receptor target, and affinity for a BBB CMT transporter target, can lead to a revolution in how small molecule drugs are identified in CNS drug discovery programs. © 2015 Informa UK, Ltd.


Qu Y.,University of California at Los Angeles | Qu Y.,Xi'an University of Science and Technology | Duan X.,University of California at Los Angeles
Chemical Society Reviews | Year: 2013

There is increasing interest in developing artificial systems that can mimic natural photosynthesis to directly harvest and convert solar energy into usable or storable energy resources. Photocatalysis, in which solar photons are used to drive redox reactions to produce chemical fuel, is the central process to achieve this goal. Despite significant efforts to date, a practically viable photocatalyst with sufficient efficiency, stability and low cost is yet to be demonstrated. It is often difficult to simultaneously achieve these different performance metrics with a single material component. The heterogeneous photocatalysts with multiple integrated functional components could combine the advantages of different components to overcome the drawbacks of single component photocatalysts. A wide range of heterostructures, including metal/semiconductor, semiconductor/semiconductor, molecule/semiconductor and multi-heteronanostructures, have been explored for improved photocatalysts by increasing the light absorption, promoting the charge separation and transportation, enhancing the redox catalytic activity and prolonging the functional life-time. The present review gives a concise overview of heterogeneous photocatalysts with a focus on the relationship between the structural architecture and the photocatalytic activity and stability. © 2013 The Royal Society of Chemistry.


Cepeda C.,University of California at Los Angeles
ASN neuro | Year: 2010

The discovery of the HD (Huntington's disease) gene in 1993 led to the creation of genetic mouse models of the disease and opened the doors for mechanistic studies. In particular, the early changes and progression of the disease could be followed and examined systematically. The present review focuses on the contribution of these genetic mouse models to the understanding of functional changes in neurons as the HD phenotype progresses, and concentrates on two brain areas: the striatum, the site of most conspicuous pathology in HD, and the cortex, a site that is becoming increasingly important in understanding the widespread behavioural abnormalities. Mounting evidence points to synaptic abnormalities in communication between the cortex and striatum and cell-cell interactions as major determinants of HD symptoms, even in the absence of severe neuronal degeneration and death.


Tashkin D.P.,University of California at Los Angeles
Expert Opinion on Pharmacotherapy | Year: 2014

Introduction: Chronic obstructive pulmonary disease (COPD) is a progressive disease, the clinical course of which is punctuated by acute exacerbations. While long-acting bronchodilators and inhaled corticosteroids can reduce exacerbations, some patients do not respond adequately to these agents. Roflumilast, a novel orally active, once-daily phophodiesterase-4-selective inhibitor with anti-inflammatory properties, has been shown to reduce exacerbations and has been approved for the treatment of the subset of COPD patients with symptoms of chronic cough and sputum who have a history of exacerbations. Areas covered: This article describes the pre-clinical and clinical pharmacology of roflumilast and analytically reviews the published data from the most relevant Phase-II and -III clinical trials evaluating its efficacy and safety. Expert opinion: Roflumilast is the first drug specifically targeted to a particular subset of the heterogeneous population of COPD patients, namely those with chronic bronchitis in addition to severe airflow obstruction and an exacerbation history. Its efficacy in reducing exacerbations in patients already receiving a LABA or anticholinergic bronchodilator underscores its potential utility as an add-on agent in patients who continue to experience exacerbations despite treatment with other agents. Adverse events include gastrointestinal side effects, most commonly, as well as unexplained weight loss. © 2014 Informa UK, Ltd.


Vaish A.,University of California at Los Angeles
Analytical chemistry | Year: 2011

We present a configuration for fluorescence spectroscopy that exploits the optical properties of semitransparent gold films and widely available instrumentation. This method enables monitoring of biomolecule interactions with small molecules tethered on substrates in multicomponent environments. The neurotransmitter serotonin (5-hydroxytryptamine) was covalently attached to self-assembled monolayers on thin gold films at low density to facilitate antibody recognition. Protein-binding studies were performed in a fluorescently labeled immunoassay format. We find that the use of this method enables evaluation of nonspecific binding and relative quantification of specific binding between competing binding partners. This fluorescence spectroscopy technique has the potential to assess biosensor or medical device responses in complex biological matrices.


Mikesell L.,University of California at Los Angeles
Medical Education | Year: 2013

Context Good social relationships are crucial to well-being and to health in particular. The perception of having supportive social relationships has effects on reducing morbidity and mortality comparable with those of a good diet, regular exercise and cessation of moderate smoking. This suggests that supportive, trusting relationships with doctors could have a substantial direct biomedical effect on patients' health. Methods A critical review of the patient-doctor relationship (PDR) literature is presented, along with a review of relevant interactional studies that examine doctor-patient interactions from the perspective of conversation analysis (CA). This literature shows how patients respond to doctors' verbal and non-verbal behaviours in systematic ways that affect how they disclose and how they relate to doctors. Results Findings from the CA literature suggest that clinicians might consider several important interactional features to improve the PDR and perhaps also patient health outcomes: (i) the use of open-ended questions (e.g. 'What brought you in today?') and positive polarity items (e.g. 'Is there something else you wanted to talk about today?') elicits patient concerns and addresses unmet concerns more effectively than the use of closed questions and negative polarity items, respectively; (ii) eye gaze suggests availability and an attending recipient, and patients indicate that doctor attentiveness at crucial parts of their problem presentation is important, and (iii) verbal dysfluencies are one practice speakers employ to gain the attention of a non-attending recipient. Doctors may want to pay attention to patients' dysfluencies to better understand when their attention is valued. Conclusions Constructing supportive relationships with patients often does not require a great investment of time, but it does require commitment to 'being there for patients'. This review suggests that when doctors attune to language and social practices during medical consultations, the relationships they develop with patients may substantially improve patients' health and be intrinsically rewarding for both doctors and patients. © Blackwell Publishing Ltd 2013.


Lohmueller K.E.,University of California at Los Angeles
PLoS Genetics | Year: 2014

Population genetic studies have found evidence for dramatic population growth in recent human history. It is unclear how this recent population growth, combined with the effects of negative natural selection, has affected patterns of deleterious variation, as well as the number, frequency, and effect sizes of mutations that contribute risk to complex traits. Because researchers are performing exome sequencing studies aimed at uncovering the role of low-frequency variants in the risk of complex traits, this topic is of critical importance. Here I use simulations under population genetic models where a proportion of the heritability of the trait is accounted for by mutations in a subset of the exome. I show that recent population growth increases the proportion of nonsynonymous variants segregating in the population, but does not affect the genetic load relative to a population that did not expand. Under a model where a mutation's effect on a trait is correlated with its effect on fitness, rare variants explain a greater portion of the additive genetic variance of the trait in a population that has recently expanded than in a population that did not recently expand. Further, when using a single-marker test, for a given false-positive rate and sample size, recent population growth decreases the expected number of significant associations with the trait relative to the number detected in a population that did not expand. However, in a model where there is no correlation between a mutation's effect on fitness and the effect on the trait, common variants account for much of the additive genetic variance, regardless of demography. Moreover, here demography does not affect the number of significant associations detected. These findings suggest recent population history may be an important factor influencing the power of association tests and in accounting for the missing heritability of certain complex traits. © 2014 Kirk E Lohmueller.


Albert F.W.,University of California at Los Angeles | Albert F.W.,Gonda Center 5309 | Kruglyak L.,University of California at Los Angeles | Kruglyak L.,Gonda Center 5309 | Kruglyak L.,Howard Hughes Medical Institute
Nature Reviews Genetics | Year: 2015

We are in a phase of unprecedented progress in identifying genetic loci that cause variation in traits ranging from growth and fitness in simple organisms to disease in humans. However, a mechanistic understanding of how these loci influence traits is lacking for the majority of loci. Studies of the genetics of gene expression have emerged as a key tool for linking DNA sequence variation to phenotypes. Here, we review recent insights into the molecular nature of regulatory variants and describe their influence on the transcriptome and the proteome. We discuss conceptual advances from studies in model organisms and present examples of complete chains of causality that link individual polymorphisms to changes in gene expression, which in turn result in physiological changes and, ultimately, disease risk. © 2015 Macmillan Publishers Limited.


Martinson H.G.,University of California at Los Angeles
Wiley Interdisciplinary Reviews: RNA | Year: 2011

When intron-defined splicing was replaced by exon-defined splicing in the evolution of higher eukaryotes, the splicing apparatus had to rely on the cleavage/polyadenylation (CP) apparatus for help in defining the 3′-terminal exon. The 3′-terminal exon-definition complex that resulted consists of splicing factors on the upstream 3′ splice site (ss) interacting with CP factors on the downstream poly(A) signal. A speculative model for assembly of this processing complex proposes several discrete steps. First, the splicing factor, U2AF65, interacts with the CP factor, CFI m. Then, CFI m is displaced from U2AF65 by the poly(A) polymerase during a remodeling step. Finally, the U2 snRNP interacts with CPSF in a step resembling spliceosomal A-complex formation. The result is mutual enhancement of both splicing and CP for the exon. In contrast, when the poly(A) signal is preceded by a 5′ rather than a 3′ ss, competition replaces cooperation. Thus, a poly(A) site in an intron must compete with the upstream 5′ ss for pairing with the 3′ ss further upstream, across the presumptive exon. If the poly(A) site wins the competition, a terminal exon is defined. But if the 5′ ss wins (by defining the upstream exon as internal, followed by pairing with a 3′ ss across the downstream intron), then the poly(A) site is suppressed. The U1 snRNP obviously participates in this competition through its role in splice site pairing. However, the U1 snRNP can also bind elsewhere in the transcript, apart from splice sites, to regulate CP by direct interaction with the CP factors. © 2010 John Wiley & Sons, Ltd.


Corren J.,University of California at Los Angeles
Discovery medicine | Year: 2012

Elevated numbers of blood and tissue eosinophils are present in allergic diseases and experimental evidence suggests that eosinophils play an important pathogenic role in these conditions. Regulation of eosinophil maturation, recruitment, and survival is under the control of a small group of factors, including interleukin-5 (IL-5). Given the probable importance of eosinophils to allergy and other associated disorders, IL-5 has been proposed as a potential molecular target in the treatment of these diseases. IL-5 antagonist therapies in current development include two monoclonal anti-IL-5 antibodies (mepolizumab, reslizumab), a monoclonal antibody directed at the IL-5 receptor (benralizumab), and anti-sense oligonucleotide therapy (TPI ASM8). Anti-IL5 antibody therapy has been the most extensively studied of these agents, and trials have been performed in patients with bronchial asthma, nasal polyposis, atopic dermatitis, eosinophilic esophagitis, hypereosinophilic syndrome, and Churg-Strauss syndrome. In studies of asthmatics, anti-IL-5 showed minimal efficacy in patients with moderate, controlled asthma. In patients with severe, refractory asthma associated with eosinophilia, however, clinical trials have demonstrated significant reductions in asthma exacerbations. Clinical studies in other disorders, particularly eosinophilic esophagitis and hypereosinophilic syndrome, have also shown significant improvements in blood and/or tissue eosinophilia and variable alterations in clinical disease activity. Strategies aimed at the inhibition of IL-5 may hold great promise in the treatment of eosinophilic diseases.


Luders E.,University of California at Los Angeles
Annals of the New York Academy of Sciences | Year: 2014

A growing body of research suggests that meditation practices are associated with substantial psychological as well as physiological benefits. In searching for the biological mechanisms underlying the beneficial impact of meditation, studies have revealed practice-induced alterations of neurotransmitters, brain activity, and cognitive abilities, just to name a few. These findings not only imply a close link between meditation and brain structure, but also suggest possible modulating effects of meditation on age-related brain atrophy. Given that normal aging is associated with significant loss of brain tissue, meditation-induced growth and/or preservation might manifest as a seemingly reduced brain age in meditators (i.e., cerebral measures characteristic of younger brains). Surprisingly, there are only three published studies that have addressed the question of whether meditation diminishes age-related brain degeneration. This paper reviews these three studies with respect to the brain attributes studied, the analytical strategies applied, and the findings revealed. The review concludes with an elaborate discussion on the significance of existing studies, implications and directions for future studies, as well as the overall relevance of this field of research. © 2013 New York Academy of Sciences.


Blanchette J.-F.,University of California at Los Angeles
Journal of the American Society for Information Science and Technology | Year: 2011

In both the popular press and scholarly research, digital information is persistently discussed in terms that imply its immateriality. In this characterization, the digital derives its power from its nature as a mere collection of 0s and 1s wholly independent from the particular media on which it is stored-hard drive, network wires, optical disk, etc.-and the particular signal carrier which encodes bits-variations of magnetic field, voltages, or pulses of light. This purported immateriality endows bits with considerable advantages: they are immune from the economics and logistics of analog media, and from the corruption, degradation, and decay that necessarily result from the handling of material carriers of information, resulting in a worldwide shift "from atom to bits" as captured by Negroponte. This is problematic: however immaterial it might appear, information cannot exist outside of given instantiations in material forms. But what might it mean to talk of bits as material objects? In this paper I argue that bits cannot escape the material constraints of the physical devices that manipulate, store, and exchange them. Such an analysis reveals a surprising picture of computing as a material process through and through. © 2011 ASIS&T.


Ringman J.M.,University of California at Los Angeles
Archives of neurology | Year: 2012

To study the effect of familial Alzheimer disease (FAD) mutations and APOE genotype on plasma signaling protein levels. Cross-sectional comparison of plasma levels of 77 proteins measured using multiplex immune assays. A tertiary referral dementia research center. Thirty-three persons from families harboring PSEN1 or APP mutations, aged 19 to 59 years. Protein levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs) and among APOE genotype groups, using multiple linear regression models. Twenty-one participants were FAD MCs and 12 were NCs. Six had the APOE ε2/3, 6 had the ε3/4, and 21 had the ε3/3 genotype. Levels of 17 proteins differed among APOE genotype groups, and there were significant interactions between age and APOE genotype for 12 proteins. Plasma levels of apolipoprotein E and superoxide dismutase 1 were highest in the ε2 carriers, lowest in ε4 carriers, and intermediate in the ε3 carriers. Levels of multiple interleukins showed the opposite pattern and, among the ε4 carriers, demonstrated significant negative correlations with age. Although there were no significant differences between FAD MCs and NCs, there were interactions between mutation status and APOE genotype for 13 proteins. We found different patterns of inflammatory markers in young and middle-aged persons among APOE genotype groups. The APOE ε4 carriers had the lowest levels of apolipoprotein E. Young ε4 carriers have increased inflammatory markers that diminish with age. We demonstrated altered inflammatory responses in young and middle adulthood in ε4 carriers that may relate to AD risk later in life.


Sturm R.,RAND Corporation | Hattori A.,University of California at Los Angeles
International Journal of Obesity | Year: 2013

Clinically severe or morbid obesity (body mass index (BMI) >40 or 50 kg m-2) entails far more serious health consequences than moderate obesity for patients, and creates additional challenges for providers. The paper provides time trends for extreme weight categories (BMI >40 and >50 kg m-2) until 2010, using data from the Behavioral Risk Factor Surveillance System. Between 2000 and 2010, the prevalence of a BMI >40 kg m-2 (type III obesity), calculated from self-reported height and weight, increased by 70%, whereas the prevalence of BMI >50 kg m-2 increased even faster. Although the BMI rates at every point in time are higher among Hispanics and Blacks, there were no significant differences in trends between them and non-Hispanic Whites. The growth rate appears to have slowed down since 2005. Adjusting for self-report biases, we estimate that in 2010 15.5 million adult Americans or 6.6% of the population had an actual BMI >40 kg m-2. The prevalence of clinically severe obesity continues to be increasing, although less rapidly in more recent years than prior to 2005. © 2013 Macmillan Publishers Limited.


Li G.,University of California at Los Angeles | Zhu R.,University of California at Los Angeles | Yang Y.,University of California at Los Angeles
Nature Photonics | Year: 2012

Recent progress in the development of polymer solar cells has improved power-conversion efficiencies from 3% to almost 9%. Based on semiconducting polymers, these solar cells are fabricated from solution-processing techniques and have unique prospects for achieving low-cost solar energy harvesting, owing to their material and manufacturing advantages. The potential applications of polymer solar cells are broad, ranging from flexible solar modules and semitransparent solar cells in windows, to building applications and even photon recycling in liquid-crystal displays. This Review covers the scientific origins and basic properties of polymer solar cell technology, material requirements and device operation mechanisms, while also providing a synopsis of major achievements in the field over the past few years. Potential future developments and the applications of this technology are also briefly discussed. © 2012 Macmillan Publishers Limited. All rights reserved.


Solis N.V.,University of California at Los Angeles | Filler S.G.,University of California at Los Angeles
Nature Protocols | Year: 2012

Oropharyngeal candidiasis is a frequent cause of morbidity in patients with defects in cell-mediated immunity or saliva production. Animal models of this infection are important for studying disease pathogenesis and evaluating vaccines and antifungal therapies. Here we describe a simple mouse model of oropharyngeal candidiasis. Mice are rendered susceptible to oral infection by injection with cortisone acetate and then inoculated by placing a swab saturated with Candida albicans sublingually. This process results in a reproducible level of infection, the histopathology of which mimics that of pseudomembranous oropharyngeal candidiasis in humans. By using this model, data are obtained after 5-9 d of work. © 2012 Nature America, Inc. All rights reserved.


Dobkin B.H.,University of California at Los Angeles
Current atherosclerosis reports | Year: 2013

Neurologic rehabilitation aims to reduce impairments and disabilities so that persons with serious stroke can return to participation in usual self-care and daily activities as independently as feasible. New strategies to enhance recovery draw from a growing understanding of how types of training, progressive task-related practice of skills, exercise for strengthening and fitness, neurostimulation, and drug and biological manipulations can induce adaptations at multiple levels of the nervous system. Recent clinical trials provide evidence for a range of new interventions to manage walking, reach and grasp, aphasia, visual field loss, and hemi-inattention.


Tashkin D.P.,University of California at Los Angeles
Annals of the American Thoracic Society | Year: 2013

Regular smoking of marijuana by itself causes visible and microscopic injury to the large airways that is consistently associated with an increased likelihood of symptoms of chronic bronchitis that subside after cessation of use. On the other hand, habitual use of marijuana alone does not appear to lead to significant abnormalities in lung function when assessed either cross-sectionally or longitudinally, except for possible increases in lung volumes and modest increases in airway resistance of unclear clinical significance. Therefore, no clear link to chronic obstructive pulmonary disease has been established. Although marijuana smoke contains a number of carcinogens and cocarcinogens, findings from a limited number of well-designed epidemiological studies do not suggest an increased risk for the development of either lung or upper airway cancer from light or moderate use, although evidence is mixed concerning possible carcinogenic risks of heavy, long-term use. Although regular marijuana smoking leads to bronchial epithelial ciliary loss and impairs the microbicidal function of alveolar macrophages, evidence is inconclusive regarding possible associated risks for lower respiratory tract infection. Several case reports have implicated marijuana smoking as an etiologic factor in pneumothorax/pneumomediastinum and bullous lung disease, although evidence of a possible causal link from epidemiologic studies is lacking. In summary, the accumulated weight of evidence implies far lower risks for pulmonary complications of even regular heavy use of marijuana compared with the grave pulmonary consequences of tobacco. Copyright © 2013 by the American Thoracic Society.


Lee S.S.,University of California at Los Angeles
Journal of Abnormal Child Psychology | Year: 2011

Although genetic and environmental factors are separately implicated in the development of antisocial behavior (ASB), interactive models have emerged relatively recently, particularly those incorporating molecular genetic data. Using a large sample of male Caucasian adolescents and young adults from the National Longitudinal Study of Adolescent Health (Add Health), the association of deviant peer affiliation, the 30-base pair variable number tandem repeat polymorphism in promoter region of the monoamine oxidase-A (MAOA) gene, and their interaction, with antisocial behavior (ASB) was investigated. Weighted analyses accounting for over-sampling and clustering within schools as well as controlling for age and wave suggested that deviant peer affiliation and MAOA genotype were each significantly associated with levels of overt ASB across a 6-year period. Only deviant peer affiliation was significantly related to covert ASB, however. Additionally, there was evidence suggestive of a gene-environment interaction (G × E) where the influence of deviant peer affiliation on overt ASB was significantly stronger among individuals with the high-activity MAOA genotype than the low-activity genotype. MAOA was not significantly associated with deviant peer affiliation, thus strengthening the inference of G × E rather than gene-environment correlation (rGE). Different forms of gene-environment interplay and implications for future research on ASB are discussed. © 2010 The Author(s).


Dobkin B.H.,University of California at Los Angeles | Duncan P.W.,Wake forest University
Neurorehabilitation and Neural Repair | Year: 2012

Body weight-supported treadmill training (BWSTT) and robotic-assisted step training (RAST) have not, so far, led to better outcomes than a comparable dose of progressive over-ground training (OGT) for disabled persons with stroke, spinal cord injury, multiple sclerosis, Parkinson's disease, or cerebral palsy. The conceptual bases for these promising rehabilitation interventions had once seemed quite plausible, but the results of well-designed, randomized clinical trials have been disappointing. The authors reassess the underpinning concepts for BWSTT and RAST, which were derived from mammalian studies of treadmill-induced hind-limb stepping associated with central pattern generation after low thoracic spinal cord transection, as well as human studies of the triple crown icons of task-oriented locomotor training, massed practice, and activity-induced neuroplasticity. The authors retrospectively consider where theory and practice may have fallen short in the pilot studies that aimed to produce thoroughbred interventions. Based on these shortcomings, the authors move forward with recommendations for the future development of workhorse interventions for walking. In the absence of evidence for physical therapists to employ these strategies, however, BWSTT and RAST should not be provided routinely to disabled, vulnerable persons in place of OGT outside of a scientifically conducted efficacy trial. © The Author(s) 2012.


Smale S.T.,University of California at Los Angeles
Current Opinion in Immunology | Year: 2012

In cells of the innate immune system, the transcriptional response to a microbial stimulus is tailored to both the stimulus and cell type, suggesting the existence of highly sophisticated regulatory mechanisms. Early studies suggested that specificity is dictated by sets of differentially induced transcription factors that synergistically activate target genes containing their binding sites. However, recent studies have revealed additional interrelated regulatory layers, which are the topic of this article. In particular, individual transcription factors may require different post-translational modifications and coregulatory interactions to regulate different target genes. Furthermore, competence for induction is programmed at an early stage of development by factors involved in lineage commitment, and the architecture and chromatin structure of each promoter play critical roles in transcriptional specificity. © 2011 Elsevier Ltd.


Lehrer R.I.,University of California at Los Angeles | Lu W.,University of Maryland Baltimore County
Immunological Reviews | Year: 2012

Defensins are small, multifunctional cationic peptides. They typically contain six conserved cysteines whose three intramolecular disulfides stabilize a largely β-sheet structure. This review of human α-defensins begins by describing their evolution, including their likely relationship to the Big Defensins of invertebrates, and their kinship to the β-defensin peptides of many if not all vertebrates, and the θ-defensins found in certain non-human primates. We provide a short history of the search for leukocyte-derived microbicidal molecules, emphasizing the roles played by luck (good), preconceived notions (mostly bad), and proper timing (essential). The antimicrobial, antiviral, antitoxic, and binding properties of human α-defensins are summarized. The structural features of α-defensins are described extensively and their functional contributions are assessed. The properties of HD6, an enigmatic Paneth cell α-defensin, are contrasted with those of the four myeloid α-defensins (HNP1-4) and of HD5, the other α-defensin of human Paneth cells. The review ends with a decalogue that may assist researchers or students interested in α-defensins and related aspects of neutrophil function. © 2011 John Wiley & Sons A/S.


Thiemann S.,University of California at Los Angeles | Baum L.G.,University of California at Los Angeles
Annual Review of Immunology | Year: 2016

Galectins are a family of mammalian carbohydrate-binding proteins expressed by many cell types. Galectins can function intracellularly and can also be secreted to bind to cell surface glycoconjugate counterreceptors. Some galectins are made by immune cells, whereas other galectins are secreted by different cell types, such as endothelial or epithelial cells, and bind to immune cells to regulate immune responses. Galectin binding to a single glycan ligand is a low-affinity interaction, but the multivalency of galectins and the glycan ligands presented on cell surface glycoproteins results in high-avidity binding that can reversibly scaffold or cluster these glycoproteins. Galectin binding to a specific glycoprotein counterreceptor is regulated in part by the repertoire of glycosyltransferase enzymes (which make the glycan ligands) expressed by that cell, and the effect of galectin binding results from clustering or retention of specific glycoprotein counterreceptors bearing these specific ligands. Copyright © 2016 by Annual Reviews. All rights reserved.


Tang C.S.,University of California at Los Angeles
International Journal of Production Economics | Year: 2010

Marketing and operations are two key functional areas that contribute to the success of a firm. By acquiring and analyzing information regarding customers and competitors, marketing can be viewed an external-focused functional area that determines "what" kind of products (or services) a company should provide through "which" channel at "what" price. By viewing this marketing plan as the "demand" from an internal customer, operations is by-and-large an internal-focused functional area that examines "how" to deliver this demand by using internal or external resources. Due to their inherent roles and responsibilities, coordination and collaborations between marketing and operations areas can be difficult in practice. As such, the conflict between marketing and operations arises when the operation's "supply" does not meet the marketing's "demand." Over the last two decades, researchers have developed different quantitative models to examine the issue of coordination/collaboration in the context of marketing operations interfaces. The intent of this paper is two-fold. We present a unified framework for classifying various marketing-operations interface models that may serve as a guide to navigate through the sea of research articles in this important area. Also, by examining some missing gaps, we discuss some topics for potential future research. © 2010 Elsevier B.V. All rights reserved.


Cooper E.L.,University of California at Los Angeles
Physics of Life Reviews | Year: 2010

This review will examine the evolution of immune mechanisms by emphasizing information from animal groups exclusive of all vertebrates. There will be a focus on concepts that propelled the immune system into prominent discourse in the life sciences. The self/not self hypothesis was crucial and so was the concern for immunologic memory or anamnesia, development of cancer, autoimmunity, and clonal selection. Now we may be able to deconstruct clonal selection since it is not applicable in the sense that it is not applicable to invertebrate mechanisms. Clonal selection seems to be purely as all evidence indicates a vertebrate strategy and therefore irrelevant to invertebrates. Some views may insist that anthropocentric mammalian immunologists utilized a tool to propel: the universal innate immune system of ubiquitous and plentiful invertebrates as an essential system for vertebrates. This was advantageous for all immunology; moreover innate immunity acquired an extended raison d'être. Innate immunity should help if there would be a failure of the adaptive immune system. Still to be answered are questions concerning immunologic surveillance that includes clonal selection. We can then ask does immunologic surveillance play a role in the survival of invertebrates that most universally seem to not develop cancer of vertebrates especially mammals; invertebrates only develop benign tumor. A recent proposal concerns an alternative explanation that is all embracing. Danger hypothesis operates in striking contrast to the self/not self hypothesis. This view holds that the immune system is adapted to intervene not because self is threatened but because of the system's sense of danger. This perception occurs by means of signals other than recognition of microbial pattern recognition molecules characteristic of invertebrates. Response to danger may be another way of analyzing innate immunity that does not trigger the production of clones and therefore does not rely entirely on the self/not self model. The review will end with certain perspectives on artificial immune systems new on the scene and the product of computational immunologists. The tentative view is to question if the immune systems of invertebrates might be amenable to such an analysis? This would offer more credence to the innate system, often pushed aside thus favoring the adaptive responses. © 2010 Elsevier B.V. All rights reserved.


Perlmutter E.,University of California at Los Angeles
Journal of High Energy Physics | Year: 2012

In recent applications of AdS/CFT to condensed matter physics, a metric that transforms covariantly under dilatation has been argued to signal hyperscaling violation in a dual quantum field theory. We contextualize and introduce large, in some cases infinite, families of supergravity solutions with this property, focusing on scale covariant generalizations of AdS and Schrödinger spacetimes. These embeddings rely on various aspects of dimensional reduction and flux compactification of eleven-dimensional supergravity. Our top-down approach can be viewed as a partial holographic classification of the landscape of strongly coupled, UV complete quantum field theories with hyperscaling violation. © 2012 SISSA.


Yeates T.O.,University of California at Los Angeles | Kent S.B.H.,University of Chicago
Annual Review of Biophysics | Year: 2012

Although natural proteins are chiral and are all of one "handedness," their mirror image forms can be prepared by chemical synthesis. This opens up new opportunities for protein crystallography. A racemic mixture of the enantiomeric forms of a protein molecule can crystallize in ways that natural proteins cannot. Recent experimental data support a theoretical prediction that this should make racemic protein mixtures highly amenable to crystallization. Crystals obtained from racemic mixtures also offer advantages in structure determination strategies. The relevance of these potential advantages is heightened by advances in synthetic methods, which are extending the size limit for proteins that can be prepared by chemical synthesis. Recent ideas and results in the area of racemic protein crystallography are reviewed. © 2012 by Annual Reviews. All rights reserved.


Glanzman D.L.,University of California at Los Angeles
Current Biology | Year: 2010

Until recently, the literature on learning-related synaptic plasticity in invertebrates has been dominated by models assuming plasticity is mediated by presynaptic changes, whereas the vertebrate literature has been dominated by models assuming it is mediated by postsynaptic changes. Here I will argue that this situation does not reflect a biological reality and that, in fact, invertebrate and vertebrate nervous systems share a common set of mechanisms of synaptic plasticity. © 2010 Elsevier Ltd. All rights reserved.


Ylvisaker D.,University of California at Los Angeles
Journal of Statistical Software | Year: 2016

Jan de Leeuw came to University of California, Los Angeles (UCLA) Statistics at a crucial time in its history. We set out some details of what he found when he arrived on UCLA’s north campus in 1987, what was there when he left it some 27 years later, and how he fashioned the changes that are now so widely recognized. © 2016, American Statistical Association. All rights reserved.


Sayed A.H.,University of California at Los Angeles
Proceedings of the IEEE | Year: 2014

This paper surveys recent advances related to adaptation, learning, and optimization over networks. Various distributed strategies are discussed that enable a collection of networked agents to interact locally in response to streaming data and to continually learn and adapt to track drifts in the data and models. Under reasonable technical conditions on the data, the adaptive networks are shown to be mean square stable in the slow adaptation regime, and their mean square error performance and convergence rate are characterized in terms of the network topology and data statistical moments. Classical results for single-agent adaptation and learning are recovered as special cases. The performance results presented in this work are useful in comparing network topologies against each other, and in comparing adaptive networks against centralized or batch implementations. The presentation is complemented with various examples linking together results from various domains. © 2014 IEEE.

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