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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.


Humphries R.M.,University of California at Los Angeles | Pollett S.,University of Sydney | Sakoulas G.,University of California at San Diego
Clinical Microbiology Reviews | Year: 2013

Daptomycin is a lipopeptide antimicrobial with in vitro bactericidal activity against Gram-positive bacteria that was first approved for clinical use in 2004 in the United States. Since this time, significant data have emerged regarding the use of daptomycin for the treatment of serious infections, such as bacteremia and endocarditis, caused by Gram-positive pathogens. However, there are also increasing reports of daptomycin nonsusceptibility, in Staphylococcus aureus and, in particular, Enterococcus faecium and Enterococcus faecalis. Such nonsusceptibility is largely in the context of prolonged treatment courses and infections with high bacterial burdens, but it may occur in the absence of prior daptomycin exposure. Nonsusceptibility in both S. aureus and Enterococcus is mediated by adaptations to cell wall homeostasis and membrane phospholipid metabolism. This review summarizes the data on daptomycin, including daptomycin's unique mode of action and spectrum of activity and mechanisms for nonsusceptibility in key pathogens, including S. aureus, E. faecium, and E. faecalis. The challenges faced by the clinical laboratory in obtaining accurate susceptibility results and reporting daptomycin MICs are also discussed. © 2013, American Society for Microbiology. All Rights Reserved.


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.


Glassock R.J.,University of California at Los Angeles
Current Hypertension Reports | Year: 2010

Levels of urinary albumin excretion that are below the usual limit of detection by qualitative testing, but are above normal levels (microalbuminuria; MA), can be readily identified by simple measures, such as the urinary albumin to creatinine ratio in untimed urine samples. Such measurements, particularly when combined with assessment of estimated glomerular filtration rate (eGFR), have utility as biomarkers for enhanced risk of all-cause mortality, cardiovascular events, progressive chronic kidney disease, and end-stage renal disease in diabetic and nondiabetic subjects. However, it is controversial whether "isolated" MA (MA in the absence of a clear reduction in eGFR, urine sediment abnormalities, or structural renal disease) should be regarded as kidney disease. Such MA could also be regarded as a manifestation of a diffuse endothelial (microvascular) injury and thereby collateral kidney damage. This article reviews the current evidence concerning MA as a marker of kidney disease or kidney damage. © 2010 The Author(s).


de Chadarevian S.,University of California at Los Angeles
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2016

Historians working on recent science work close to where the archives are created or become accessible. Based on this experience, the essay presents a reflection on the archives of contemporary life sciences. It addresses three questions: firstly, what is special about the archival situation of contemporary sciences? Secondly, which sources do contemporary historians use and what opportunities and challenges do they offer? And finally, what potential changes to the archives of contemporary sciences are we witnessing? The essay draws a distinction between, on the one side, the history of science when the actors are still alive-a situation that presents a particular set of issues in respect to the available sources-and, on the other side, questions relating specifically to the life sciences at the turn of the millennium-a period which will eventually not be considered as 'contemporary' any more. It reviews changes in scientific practice, historiographical trends and archival practices and considers the place of paper records, digital sources, material artefacts and oral sources in the archives of contemporary sciences. It argues that the commercialisation and privatisation of science may prove a bigger problem for the future historian than the shift to the digital medium. It concludes by welcoming the closer interactions between scientists, historians, curators and archivists prompted by recent developments. © 2015 Elsevier Ltd.


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.


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.


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.


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).


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.


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.


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.


Maish M.S.,University of California at Los Angeles
Surgical Clinics of North America | Year: 2010

This article discusses the diaphragm from a surgical perspective. Although it is a relatively simple organ compared with other structures, the diaphragm serves important anatomic and functional roles necessary for proper respiratory function. It is an organ of little irregularity or disease, and easily manipulated in the operating room by those who have a basic understanding of its anatomic details. © 2010 Elsevier Inc.


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.


Turner J.A.,University of California at Los Angeles
International Journal of Women's Health | Year: 2010

Pre-eclampsia is a significant, multifactorial, multiorgan disease affecting 5%-8% of all pregnancies in the US where it is the third leading cause of maternal mortality. Despite improvements in the diagnosis and management of pre-eclampsia, severe complications can occur in both the mother and the fetus, and there is no effective method of prevention. Early detection and identification of pregnant women most at risk of developing the disease have proven challenging, but recent efforts combining biochemical and biophysical markers are promising. Efforts at prevention of pre-eclampsia with aspirin and calcium have had limited success, but research on modifiable risk factors, such as obesity surgery, are encouraging. Obstetric management of severe pre-eclampsia focuses on medical management of blood pressure and prevention of seizures using magnesium sulfate, but the ultimate cure remains delivery of the fetus and placenta. Timing of delivery depends on several factors, including gestational age, fetal lung maturity, and most importantly, disease severity. Anesthetic management includes regional anesthesia with careful evaluation of the patient's airway, volume status, and coagulation status to reduce morbidity and mortality. The potential complications of general anesthesia, including intracranial hemorrhage, in these patients make regional anesthesia the preferred choice in many cases. Nevertheless, it is important to be aware of the contraindications to neuraxial anesthesia and to prepare always for the possibility of encountering a difficult airway. © 2010 Turner, publisher and licensee Dove Medical Press Ltd.


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.


Heng M.C.Y.,University of California at Los Angeles
International Journal of Dermatology | Year: 2011

Wound healing in adult skin, a complex process involving many cell types and processes such as epidermal, fibroblastic, and endothelial cell proliferation, cell migration, matrix synthesis, and wound contraction, almost invariably results in scar tissue formation and wound induration. Unlike in adult skin, wound healing in embryos involves repair processes that result in the essentially perfect regeneration of damaged tissue. This paper discusses key mechanisms that lead to scar tissue formation in adult human skin and treatment modalities, including curcumin gel, that may result in essentially perfect skin regeneration following surgical procedures. © 2011 The International Society of Dermatology.


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.


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.


van der Bliek A.M.,University of California at Los Angeles
EMBO Journal | Year: 2016

A fascinating story is unfolding at the interface between mitochondria and the ER. Two new papers, one in this issue of The EMBO Journal (Wu et al, ) and one in the journal Autophagy (Chen et al, ), further clarify the role of mitochondrial outer membrane protein FUNDC1 in autophagy and connect it to mitochondrial fission occurring at the interface between mitochondria and the ER. © 2016 EMBO.


Wesseling-Perry K.,University of California at Los Angeles
Pediatric Nephrology | Year: 2010

Recent studies have demonstrated that levels of fibroblast growth factor 23 (FGF-23), a key regulator of phosphorus and vitamin D metabolism, rise dramatically as renal function declines and may play a key initiating role in disordered mineral and bone metabolism in patients with chronic kidney disease (CKD). The physiologic importance of FGF-23 in mineral metabolism was first identified in human genetic and acquired rachitic diseases and further characterized in animal models. FGF-23 and its regulators, including phosphate regulating endopeptidase homolog, dentin matrix 1 (DMP1), and matrix extracellular phosphoglycoprotein, are made primarily in bone, specifically in osteocytes. Dysregulation of these proteins results in osteomalacia, implicating the osteocyte in the regulation of skeletal mineralization. Studies in pediatric patients with CKD, the majority of whom have altered skeletal mineralization in early stages of CKD, have demonstrated that skeletal expression of both FGF-23 and its regulator, DMP1, are increased in early stages of CKD and that expression of these proteins is associated with alterations in skeletal mineralization. Thus, dysregulation of osteocytic proteins occur very early in the course of CKD and appear to be central to altered bone and mineral metabolism in this patient population. © 2009 IPNA.


Lake J.A.,University of California at Los Angeles
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

The origin of the eukaryotes is a fundamental scientific question that for over 30 years has generated a spirited debate between the competing Archaea (or three domains) tree and the eocyte tree. As eukaryotes ourselves, humans have a personal interest in our origins. Eukaryotes contain their defining organelle, the nucleus, after which they are named. They have a complex evolutionary history, over time acquiring multiple organelles, including mitochondria, chloroplasts, smooth and rough endoplasmic reticula, and other organelles all of which may hint at their origins. It is the evolutionary history of the nucleus and their other organelles that have intrigued molecular evolutionists, myself included, for the past 30 years and which continues to hold our interest as increasingly compelling evidence favours the eocyte tree. As with any orthodoxy, it takes time to embrace new concepts and techniques. © 2015 The Authors.


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.


Kurdistani S.K.,University of California at Los Angeles
Progress in Drug Research | Year: 2011

Cancer is a disease of genome sequence alterations as well as epigenetic changes. Epigenetics refers in part to the mechanisms by which histones affect various DNA-based processes, such as gene regulation. Histones are proteins around which the DNA wraps itself to form chromatin - the physiologically relevant form of the human genome. Histones are modified extensively by posttranslational modifications that alter chromatin structure and serve to recruit to or exclude protein complexes from DNA. Aberrations in histone modifications occur frequently in cancer including changes in their levels and distribution at gene promoters, gene coding regions, repetitive DNA sequences, and other genomic elements. Locus-specific alterations in histone modifications may have adverse effects on expression of nearby genes but so far have not been shown to have clinical utility. Cancer cells also exhibit alterations in global levels of specific histone modifications, generating an additional layer of epigenetic heterogeneity at the cellular level in tumor tissues. Unlike locus-specific changes, the cellular epigenetic heterogeneity can be used to define previously unrecognized subsets of cancer patients with distinct clinical outcomes. In general, increased prevalence of cells with lower global levels of histone modifications is prognostic of poorer clinical outcome such as increased risk of tumor recurrence and/or decreased survival probability. Prognostic utility of histone modifications has been demonstrated independently for multiple cancers including those of prostate, lung, kidney, breast, ovary, and pancreas, suggesting a fundamental association between global histone modification levels and tumor aggressiveness, regardless of cancer tissue of origin. Cellular levels of histone modifications may also predict response to certain chemotherapeutic agents, serving as predictive biomarkers that could inform clinical decisions on choice and course of therapy. The challenge before us is to understand how global levels of histone modifications are established and maintained and what their mechanistic links are to the cancer clinical behavior. © 2011 Springer Basel AG.


Naylor D.E.,University of California at Los Angeles
Epilepsia | Year: 2010

Seizures rapidly become self-sustaining and pharmacoresistant to benzodiazepines during status epilepticus (SE). A decrease in the number of postsynaptic γ-aminobutyric acid (GABA)A receptors with SE causes a loss of synaptic inhibition, whereas increases in postsynaptic glutamatergic receptors further upset the balance between excitation and inhibition. Although extracellular GABA levels may increase during SE and contribute to postsynaptic GABAA receptor desensitization, other pathways involving glutamatergic activation ultimately may be responsible for the persistent down-regulation of postsynaptic GABAA receptors and erosion of synaptic inhibition. © 2010 International League Against Epilepsy.


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).


Laine L.,Yale University | Jensen D.M.,University of California at Los Angeles | Jensen D.M.,Digestive Diseases Research Center
American Journal of Gastroenterology | Year: 2012

This guideline presents recommendations for the step-wise management of patients with overt upper gastrointestinal bleeding. Hemodynamic status is first assessed, and resuscitation initiated as needed. Patients are risk-stratified based on features such as hemodynamic status, comorbidities, age, and laboratory tests. Pre-endoscopic erythromycin is considered to increase diagnostic yield at first endoscopy. Pre-endoscopic proton pump inhibitor (PPI) may be considered to decrease the need for endoscopic therapy but does not improve clinical outcomes. Upper endoscopy is generally performed within 24h. The endoscopic features of ulcers direct further management. Patients with active bleeding or non-bleeding visible vessels receive endoscopic therapy (e.g., bipolar electrocoagulation, heater probe, sclerosant, clips) and those with an adherent clot may receive endoscopic therapy; these patients then receive intravenous PPI with a bolus followed by continuous infusion. Patients with flat spots or clean-based ulcers do not require endoscopic therapy or intensive PPI therapy. Recurrent bleeding after endoscopic therapy is treated with a second endoscopic treatment; if bleeding persists or recurs, treatment with surgery or interventional radiology is undertaken. Prevention of recurrent bleeding is based on the etiology of the bleeding ulcer. H. pylori is eradicated and after cure is documented anti-ulcer therapy is generally not given. Nonsteroidal anti-inflammatory drugs (NSAIDs) are stopped; if they must be resumed low-dose COX-2-selective NSAID plus PPI is used. Patients with established cardiovascular disease who require aspirin should start PPI and generally re-institute aspirin soon after bleeding ceases (within 7 days and ideally 1-3 days). Patients with idiopathic ulcers receive long-term anti-ulcer therapy. © 2012 by the American College of Gastroenterology.


Kalantar-Zadeh K.,University of California at Los Angeles
Kidney international. Supplement | Year: 2010

Recent evidence suggests that the traditional syndromes known as renal osteodystrophy, secondary hyperparathyroidism, and vitamin D deficiency are related to mortality in persons with moderate to advanced chronic kidney disease (CKD). The so-called 'kidney bone disease', also known as 'mineral and bone disorders', is defined to include bone disorders, mineral disarrays, and vascular calcification. We have identified 14 common and clinically relevant conditions of contemporary nature that are related to the kidney bone disease, including calcitriol (active vitamin D) deficiency, 25(OH)-vitamin D deficiency, biochemical hyperparathyroidism, relatively low parathyroid hormone (PTH) level, increased serum alkaline phosphatase (hyperphosphatasemia), elevated fibroblast growth factor (FGF)-23, high turnover bone disease, adynamic bone disease, uremic osteoporosis, vascular calcification, hyper- and hypophosphatemia, and hyper- and hypocalcemia. We present a critical review of these 14 conditions with emphasis on patient survival and other pertinent clinical outcomes. We also review unresolved controversies surrounding the management of these conditions by administration of nutritional vitamin D (ergocalciferol and cholecalciferol), vitamin D receptor activators (calcitriol, alphacalcidiol, doxercalciferol), D-mimetics (paricalcitol, maxacalcitol), calcimimetics (cinacalcet), recombinant PTH (teriparatide), and receptor activator of nuclear factor-kappaB ligand modulators (denosumab); compare mortality predictability of PTH and alkaline phosphatase; and examine potential risks of bone disorders and mineral disarrays in CKD patients.


Collier J.H.,University of Chicago | Segura T.,University of California at Los Angeles
Biomaterials | Year: 2011

This manuscript is part of a debate on the statement that " the use of short synthetic adhesion peptides, like RGD, is the best approach in the design of biomaterials that guide cell behavior for regenerative medicine and tissue engineering" We take the position that although there are some acknowledged disadvantages of using short peptide ligands within biomaterials, it is not necessary to discard the notion of using peptides within biomaterials entirely, but rather to reinvent and evolve their use. Peptides possess advantageous chemical definition, access to non-native chemistries, amenability to de novo design, and applicability within parallel approaches. Biomaterials development programs that require such aspects may benefit from a peptide-based strategy. © 2011 Elsevier Ltd.


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).


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.


Colicelli J.,University of California at Los Angeles
Current Biology | Year: 2010

RAS proteins conduct signaling from surface receptors to cytoplasmic effectors, and RAS gain-of-function mutations are pervasive in cancer. A new mechanism for RAS signal attenuation with implications for receptor trafficking has been uncovered. © 2010 Elsevier Ltd All rights reserved.


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.


Lee T.,Seoul National University | Chen Y.,University of California at Los Angeles
MRS Bulletin | Year: 2012

Resistive memory devices based on organic materials that can be configured to two or more stable resistance states have been extensively explored as information storage media due to their advantages, which include simple device structures, low fabrication costs, and flexibility. Various organic-based materials such as small molecules, polymers, and composite materials have been observed to show bistability. This review provides a general summary about the materials, structures, characteristics, and mechanisms of organic resistive memory devices. Several critical strategies for device fabrication, performance enhancement, and integrated circuit architectures are also discussed. © 2012 Materials Research Society.


Helled R.,University of California at Los Angeles
Astrophysical Journal Letters | Year: 2011

Knowledge of Saturn's axial moment of inertia can provide valuable information on its internal structure. We suggest that Saturn's angular momentum may be determined by the Solstice Mission (Cassini XXM) by measuring Saturn's pole precession rate and the Lense-Thirring acceleration on the spacecraft, and therefore put constraints on Saturn's moment of inertia. It is shown that Saturn's moment of inertia can change up to ∼2% due to different core properties. However, a determination of Saturn's rotation rate is required to constrain its axial moment of inertia. A change of about seven minutes in rotation period leads to a similar uncertainty in the moment of inertia value as different core properties (mass, radius). A determination of Saturn's angular momentum and rotation period by the Solstice Mission could reveal important information on Saturn's internal structure, in particular, its core properties. © 2011. The American Astronomical Society. 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.


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.


Cservenka A.,University of California at Los Angeles
Drug and Alcohol Dependence | Year: 2016

Background: Individuals with a family history of alcoholism are at much greater risk for developing an alcohol use disorder (AUD) than youth or adults without such history. A large body of research suggests that there are premorbid differences in brain structure and function in family history positive (FHP) individuals relative to their family history negative (FHN) peers. Methods: This review summarizes the existing literature on neurobiological phenotypes present in FHP youth and adults by describing findings across neurophysiological and neuroimaging studies. Results: Neuroimaging studies have shown FHP individuals differ from their FHN peers in amygdalar, hippocampal, basal ganglia, and cerebellar volume. Both increased and decreased white matter integrity has been reported in FHP individuals compared with FHN controls. Functional magnetic resonance imaging studies have found altered inhibitory control and working memory-related brain response in FHP youth and adults, suggesting neural markers of executive functioning may be related to increased vulnerability for developing AUDs in this population. Additionally, brain activity differences in regions involved in bottom-up reward and emotional processing, such as the nucleus accumbens and amygdala, have been shown in FHP individuals relative to their FHN peers. Conclusions: It is critical to understand premorbid neural characteristics that could be associated with cognitive, reward-related, or emotional risk factors that increase risk for AUDs in FHP individuals. This information may lead to the development of neurobiologically informed prevention and intervention studies focused on reducing the incidence of AUDs in high-risk youth and adults. © 2015 Elsevier Ireland Ltd.


Silverman S.L.,University of California at Los Angeles
Annals of the New York Academy of Sciences | Year: 2011

Bisphosphonates are the gold standard of treatment of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis. They have potential use in multiple musculoskeletal conditions other than osteoporosis and have also been shown to treat Paget's disease of the bone and osteogenesis imperfecta. Bisphophonates may have potential use in periprosthetic bone loss, osteonecrosis of the hip, fibrous dysplasia, and calcinosis in juvenile dermatomyositis. © 2010 New York Academy of Sciences.


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.


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.


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.


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.


Tashkin D.P.,University of California at Los Angeles | Ferguson G.T.,Pulmonary Research Institute of Southeast Michigan
Respiratory Research | Year: 2013

Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β2-agonists (LABAs), such as formoterol and salmeterol. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease. © 2013 Tashkin and Ferguson; licensee BioMed Central Ltd.


Gheorghiade M.,Northwestern University | Vaduganathan M.,Harvard University | Fonarow G.C.,University of California at Los Angeles | Bonow R.O.,Northwestern University
Journal of the American College of Cardiology | Year: 2013

With a prevalence of 5.8 million in the United States alone, heart failure (HF) is associated with high morbidity, mortality, and healthcare expenditures. Close to 1 million hospitalizations for heart failure (HHF) occur annually, accounting for over 6.5 million hospital days and a substantial portion of the estimated $37.2 billion that is spent each year on HF in the United States. Although some progress has been made in reducing mortality in patients hospitalized with HF, rates of rehospitalization continue to rise, and approach 30% within 60 to 90 days of discharge. Approximately half of HHF patients have preserved or relatively preserved ejection fraction (EF). Their post-discharge event rate is similar to those with reduced EF. HF readmission is increasingly being used as a quality metric, a basis for hospital reimbursement, and an outcome measure in HF clinical trials. In order to effectively prevent HF readmissions and improve overall outcomes, it is important to have a complete and longitudinal characterization of HHF patients. This paper highlights management strategies that when properly implemented may help reduce HF rehospitalizations and include adopting a mechanistic approach to cardiac abnormalities, treating noncardiac comorbidities, increasing utilization of evidence-based therapies, and improving care transitions, monitoring, and disease management. © 2013 American College of Cardiology Foundation.


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.


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.


Hinman J.D.,University of California at Los Angeles
Current Opinion in Neurology | Year: 2014

Purpose of review The axon plays a central role in both the injury and repair phases after stroke. This review highlights emerging principles in the study of axonal injury in stroke and the role of the axon in neural repair after stroke. Recent findings Ischemic stroke produces a rapid and significant loss of axons in the acute phase. This early loss of axons results from a primary ischemic injury that triggers a wave of calcium signaling, activating proteolytic mechanisms and downstream signaling cascades. A second progressive phase of axonal injury occurs during the subacute period and damages axons that survive the initial ischemic insult but go on to experience a delayed axonal degeneration driven in part by changes in axoglial contact and axonal energy metabolism. Recovery from stroke is dependent on axonal sprouting and reconnection that occurs during a third degenerative/regenerative phase. Despite this central role played by the axon, comparatively little is understood about the molecular pathways that contribute to early and subacute axonal degeneration after stroke. Recent advances in axonal neurobiology and signaling suggest new targets that hold promise as potential molecular therapeutics including axonal calcium signaling, axoglial energy metabolism and cell adhesion as well as retrograde axonal mitogen-activated protein kinase pathways. These novel pathways must be modeled appropriately as the type and severity of axonal injury vary by stroke subtype. Summary Stroke-induced injury to axons occurs in three distinct phases each with a unique molecular underpinning. A wealth of new data about the molecular organization and molecular signaling within axons is available but not yet robustly applied to the study of axonal injury after stroke. Identifying the spatiotemporal patterning of molecular pathways within the axon that contribute to injury and repair may offer new therapeutic strategies for the treatment of stroke. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


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.


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.


Nielsen M.D.,Ohio State University | Ozolins V.,University of California at Los Angeles | Heremans J.P.,Ohio State University
Energy and Environmental Science | Year: 2013

As over 93% of the world's energy comes from thermal processes, new materials that maximize heat transfer or minimize heat waste are crucial to improving efficiency. Here we focus on fully dense electrical insulators at the low end of the spectrum of lattice thermal conductivity κL. We present an experimentally validated predictive tool that shows how the high deformability of lone-pair electron charge density can limit κL in crystalline materials. Using first-principles density-functional theory (DFT) calculations, we predict that several ABX2 (groups I-V-VI 2) compounds based on the rocksalt structure develop soft phonon modes due to the strong hybridization and repulsion between the lone-pair electrons of the group V cations and the valence p orbitals of group VI anions. In many cases, this creates lattice instabilities and the compounds either do not exist or crystallize in a different structure. Marginally stable ABX 2 compounds have anharmonic bonds that result in strong phonon-phonon interactions. We show experimentally how these can reduce κL to the amorphous limit. This journal is © The Royal Society of Chemistry 2013.


Olsen R.W.,University of California at Los Angeles
Neurochemical Research | Year: 2014

The GABAA receptors (GABAARs) play an important role in inhibitory transmission in the brain. The GABAARs could be identified using a medicinal chemistry approach to characterize with a series of chemical structural analogues, some identified in nature, some synthesized, to control the structural conformational rigidity/flexibility so as to define the ‘receptor-specific’ GABA agonist ligand structure. In addition to the isosteric site ligands, these ligand-gated chloride ion channel proteins exhibited modulation by several chemotypes of allosteric ligands, that help define structure and function. The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABAARs. This ligand site is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Also in the trans-membrane domain are allosteric modulatory ligand sites, mostly positive, for diverse chemotypes with general anesthetic efficacy, namely, the volatile and intravenous agents: barbiturates, etomidate, propofol, long-chain alcohols, and neurosteroids. The last are apparent endogenous positive allosteric modulators of GABAARs. These binding sites depend on the GABAAR heteropentameric subunit composition, i.e., subtypes. Two classes of pharmacologically very important allosteric modulatory ligand binding site reside in the extracellular domain at modified agonist sites at other subunit interfaces: the benzodiazepine site, and the low-dose ethanol site. The benzodiazepine site is specific for certain subunit combination subtypes, mainly synaptically localized. In contrast, the low-dose (high affinity) ethanol site(s) is found at a modified benzodiazepine site on different, extrasynaptic, subtypes. © 2014, Springer Science+Business Media New York.


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.


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.


Mullen B.R.,University of California at Los Angeles
ASN neuro | Year: 2013

Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders, including ASDs (autism spectrum disorders). In this study, we examined the combinatorial effect of two factors thought to be involved in autism--reduction in the expression of the extracellular matrix protein reelin and prenatal exposure to an organophosphate pesticide, CPO (chlorpyrifos oxon). Mice with reduced reelin expression or prenatal exposure to CPO exhibited subtle changes in ultrasound vocalization, open field behaviour, social interaction and repetitive behaviour. Paradoxically, mice exposed to both variables often exhibited a mitigation of abnormal behaviours, rather than increased behavioural abnormalities as expected. We identified specific differences in males and females in response to both of these variables. In addition to behavioural abnormalities, we identified anatomical alterations in the olfactory bulb, piriform cortex, hippocampus and cerebellum. As with our behavioural studies, anatomical alterations appeared to be ameliorated in the presence of both variables. While these observations support an interaction between loss of reelin expression and CPO exposure, our results suggest a complexity to this interaction beyond an additive effect of individual phenotypes.


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.


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.


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.


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.


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.


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.


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.


Li J.,University of California at Los Angeles
Astrophysical Journal | Year: 2011

We use time-series ultraviolet full sun images to construct limb-synoptic maps of the Sun. On these maps, large-scale, long-lived coronal streamers appear as repetitive sinusoid-like arcs projected over the polar regions. They are caused by high altitude plasma produced from sunspot-rich regions at latitudes generally far from the poles. The non-uniform longitudinal distribution of these streamers reveals four longitudinal zones at the surface of the Sun from which sunspots erupt preferentially over the 5 year observing interval (2006 January to 2011 April). Spots in these zones (or clusters) have individual lifetimes short compared to the lifetimes of the coronal features which they sustain, and they erupt at different times. The four sunspot clusters contain >75% of all numbered sunspots in this period. They occupy two distinct longitudinal zones separated by 180° and each spanning 100° in longitude. The rotation rates of the spot clusters are 5% faster than the rates at both the surface and the bottom of the convection zone. While no convincing theoretical framework exists to interpret the sunspot clusters in the longitude-time space, their persistent and nonuniform distribution indicates long-lived, azimuthal structures beneath the surface, and are compatible with the existence of previously reported active longitudes on the Sun. © 2011. The American Astronomical Society. All rights reserved.


Huang Y.-T.,University of California at Los Angeles | Lee S.,Seoul National University
Physical Review Letters | Year: 2012

We propose a new integral formula for all tree-level scattering amplitudes of N=6 supersymmetric Chern-Simons theory. It resembles the Roiban-Spradlin- Volovich-Witten formula for N=4 supersymmetric Yang-Mills theory based on a twistor string theory formulation. Our formula implies that the (2k)-point tree-level amplitude is closely related to degree (k-1) curves in CPk -1. © 2012 American Physical Society.


Alter G.J.,University of California at Los Angeles
Plastic and Reconstructive Surgery | Year: 2011

Background: Labia minora reduction (labioplasty, labiaplasty) is the most common female genital aesthetic procedure. The majority of labia reductions are performed by trimming the labial edges. Many of these women present with (1) asymmetry; (2) scalloping of the labial edges with wide, occasionally painful scars; and (3) abrupt termination and distortion of the clitoral hood at its normal junctions with the clitoral frenula and the upper labium. Reconstruction can usually be performed with wedge excisions, labial YV advancement, and touch-up trimming. Reconstruction of a labial amputation, however, required the development of a new clitoral hood flap. Methods: Twenty-four clitoral hood flaps were performed on 17 patients from June of 2006 through May of 2010. An island clitoral hood flap randomly based on the dartos fascia of the lower clitoral hood and medial labium majus is transposed to the ipsilateral labial defect to reconstruct a labium. Of the 10 patients with unilateral flaps, nine of the patients had previous bilateral labial reductions. Reconstruction of the opposite side in these nine women was performed using one or a combination of the following: wedge excisions, YV advancement flaps, or controlled touch-up trimming. Results: All 24 flaps survived, with four minor complications. Five patients underwent revision of a total of seven flaps, but only two were for complications. As experience increased, revisions for aesthetic improvement became less common. Conclusion: Reconstruction of labia minora defects secondary to trimming labia reductions is very successful using a combination of clitoral hood flaps, wedge excisions, and YV advancements. Copyright © 2011 by the American Society of Plastic Surgeons.


Swanson E.B.,University of California at Los Angeles
Journal of Strategic Information Systems | Year: 2010

When firms innovate with information technology (IT), they frequently retain consultants, who presumably bring certain capabilities to the process. But what capabilities are these and why do they seem to be so needed? In this essay, I consider several different consultancy specializations - business strategy, technology assessment, business process improvement, systems integration, business support services - and how they facilitate an IT innovation process both within and across firms. For each specialization, I examine the consultancy's capabilities and contributions both to the client (within an engagement) and to the broader support of the innovation (across and beyond engagements). The analysis suggests a number of conjectures as to the influence of consultancies on an IT innovation's adoption, diffusion and eventual institutionalization. © 2010 Elsevier B.V. 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.


Voskuhl R.R.,University of California at Los Angeles | Gold S.M.,University of Hamburg
Nature Reviews Neurology | Year: 2012

The pathogenesis of multiple sclerosis (MS) involves complex interactions between genetic susceptibility and environmental triggers. Clinical observations suggest that the study of sex differences might provide important insight into mechanisms of pathogenesis and progression of the disease in patients. MS occurs more frequently in women than in men, indicating that sex-related factors have an effect on an individual's susceptibility to developing the condition. These factors include hormonal, genetic and environmental influences, as well as gene-environment interactions and epigenetic mechanisms. Interestingly, women do not have a poorer prognosis than men with MS despite a higher incidence of the disease and more-robust immune responses, which suggests a mechanism of resilience. Furthermore, the state of pregnancy has a substantial effect on disease activity, characterized by a reduction in relapse rates during the third trimester but an increased relapse rate in the postpartum period. However, pregnancy has little effect on long-term disability in women with MS. The unravelling of the mechanisms underlying these clinical observations in the laboratory and application of the results to the clinical setting is a unique and potentially fruitful strategy to develop novel therapeutic approaches for MS © 2012 Macmillan Publishers Limited. All rights reserved.


Tobinick E.,University of California at Los Angeles
Expert Review of Neurotherapeutics | Year: 2010

Etanercept is a potent antagonist of TNF, a pleotropic immune signaling molecule that is also a pivotal regulator of synaptic function. Excess TNF is centrally involved in the pathogenesis of a variety of inflammatory neurological disorders, including Alzheimers disease, sciatica, traumatic brain injury and spinal cord injury. Perispinal etanercept produces rapid improvement in both Alzheimers disease and sciatica and in other forms of disc-related pain. Basic research and the observed clinical effects suggest that etanercept has the surprising ability to penetrate into the cerebrospinal fluid after perispinal administration. Perispinal administration is a novel method of delivery designed to introduce this anti-TNF molecule into the bidirectional cerebrospinal venous system and the cerebrospinal fluid to facilitate its selective delivery to either spinal structures or the brain. The scientific rationale, physiologic mechanisms, clinical effects and potential clinical indications of this therapeutic approach are the subject of this article. © 2010 Expert Reviews Ltd.


Ringach D.L.,University of California at Los Angeles
Vision Research | Year: 2010

A common computation in visual cortex is the divisive normalization of responses by a pooled signal of the activity of cells within its neighborhood. From a geometrical point of view, normalization constraints the population response to high-contrast stimuli to lie on the surface of a high-dimensional sphere. Here we study the implications this constraint imposes on the representation of a circular variable, such as the orientation of a visual stimulus. New results are derived for the infinite dimensional case of a homogeneous populations of neurons with identical tuning curves but different orientation preferences. An important finding is that the ability of the population to discriminate between any two orientations depends exclusively on the Fourier amplitude spectrum of the orientation tuning curve. We also study the problem of encoding by a finite set of neurons. A central result is that, under normalization, optimal encoding can be achieved by a finite number of neurons with heterogeneous tuning curves. In other words, increasing the number of neurons in the population does not always allow for an improved population code. These results are used to estimate the number of neurons involved in the coding of orientation at one position in the visual field. If the cortex were to code orientation optimally, we find that a small number (∼4) of neurons should suffice. © 2010 Elsevier Ltd.


Bonavida B.,University of California at Los Angeles
Critical Reviews in Oncogenesis | Year: 2014

Natural killer (NK) cells were discovered four decades ago, independently, by the Kiessling and Herberman groups. Since then, significant advances have accrued regarding the functional and molecular properties of NK cells as well as their clinical relevance. The important feature of NK cells is their inability to kill normal cells, while they are highly cytotoxic for infected or transformed cells. This discrimination has been largely resolved by the discovery of both activating and inhibitory receptors on NK cells and corresponding ligands on target cells. This review focuses briefly on several issues related to NK cells: (1) the phenotypic properties of NK cells, (2) the heterogeneity of NK cell activities, (3) the determination of three major NK subsets (Free, Binder, and Killer), (4) the maturation and activation of NK subsets, (5) the response of NK cells to various cytokines, (6) the target-induced inactivation and cell death of NK cells, (7) the multiple mechanisms of cell-mediated cytotoxicity, (8) the characterization of NK cytotoxic factors (NKCF), and (9) the role of membrane fluidity in cytotoxicity. These subjects are described chronologically beginning shortly after the discovery of NK cells as a result of Ron Herberman's leadership, and I am gratefully indebted to him. © 2014 by Begell House, Inc.


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.


The micro-array profiling of micro-RNA has been performed in rat skeletal muscle tissues, isolated from male adult offspring of intrauterine plus postnatal growth restricted model (IPGR). Apparently, the GLUT4 mRNA expression in male sk. muscle was found to be unaltered in contrast to females. The over-expression of miR-29a and miR-23a in the experimental group of SMSP (Starved Mother Starved Pups) have been found to regulate the glucose transport activity with respect to their control counterparts CMCP (Control Mother Control Pups) as confirmed in rat L6 myoblast-myocyte cell culture system. The ex-vivo experimentation demonstrates an aberration in insulin signaling pathway in male sk. muscle that leads to the localization of the membrane-bound Glut4 protein. We have identified through a series of experiments one important protein factor SMAD4, a co-SMAD critical to the TGF-beta signaling pathway. This factor is targeted by miR-29a, as identified in an in vitro reporter-assay system in cell-culture experiment. The other micro-RNA, miR-23a, targets SMAD4 indirectly that seems to be critical in regulating insulin-dependent glucose transport activity. MicroRNA mimics, inhibitors and siRNA studies indicate the role of SMAD4 as inhibitory for glucose transport activities in normal physiological condition. The data demonstrate for the first time a critical function of microRNAs in fine-tuning the regulation of glucose transport in skeletal muscle. Chronic starved conditions (IPGR) in sk. muscle up-regulates microRNA changing the target protein expression patterns, such as SMAD4, to alter the glucose transport pathways for the survival. The innovative outcome of this paper identifies a critical pathway (TGF-beta) that may act negatively for the mammalian glucose transport machinery. © 2012 Santanu Raychaudhuri.


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.


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.


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.


Wexler H.M.,University of California at Los Angeles
Anaerobe | Year: 2012

Bacteroides fragilis is a gram-negative anaerobic commensal that can be a virulent pathogen when it escapes its normal niche in the human gut. Recent increases in reports of multi-drug resistance strains of this organism have lent urgency to understanding its mechanisms of antimicrobial resistance. We have identified and characterized RND-type multi-drug efflux pumps in . B. fragilis which can pump out a variety of substrates and whose transcription levels can be elevated by a wide variety of antimicrobials, antiseptic agents, bile and other stressors. Our research is directed toward understanding how the efflux pump genes are controlled and how we may exploit that understanding to develop more effective, targeted therapy that will cure the infection without disrupting the entire gut microbiome that is so important in many aspects of human health. © 2012 .


Iruela-Arispe M.L.,University of California at Los Angeles
Cardiovascular Research | Year: 2010

Inflammation and angiogenesis are frequently coupled in pathological situations such as atherosclerosis, diabetes, and arthritis. The inflammatory response increases capillary permeability and induces endothelial activation, which, when persistent, results in capillary sprouting. This inflammation-induced angiogenesis and the subsequent remodelling steps are in large part mediated by extracellular matrix (ECM) proteins and proteases. The focal increase in capillary permeability is an early consequence of inflammation, and results in the deposition of a provisional fibrin matrix. Subsequently, ECM turnover by proteases permits an invasive program by specialized endothelial cells whose phenotype can be regulated by inflammatory stimuli. ECM activity also provides specific mechanical forces, exposes cryptic adhesion sites, and releases biologically active fragments (matrikines) and matrix-sequestered growth factors, all of which are critical for vascular morphogenesis. Further matrix remodelling and vascular regression contribute to the resolution of the inflammatory response and facilitate tissue repair. © The Author 2009. For permissions please.


Kwong L.M.,University of California at Los Angeles
The American journal of managed care | Year: 2011

Venous thromboembolism (VTE) following joint replacement surgery represents an economic as well as a clinical burden; however, the risk of thromboembolic events is greatly reduced by appropriate anticoagulation. Rivaroxaban, a Factor Xa inhibitor currently in phase III development, was compared with the low molecular weight heparin enoxaparin in 4 clinical trials, collectively called the RECORD program (REgulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism). In a pooled analysis of data from the RECORD trials, rivaroxaban was superior to enoxaparin regimens in reducing the composite end point of symptomatic venous thromboembolism and all-cause mortality in patients following elective primary total hip or total knee arthroplasty (THA or TKA), with a comparable incidence of major bleeding events. In cost-effectiveness analyses, compared with enoxaparin, rivaroxaban showed the potential to reduce costs associated with the prophylaxis and treatment of thromboembolic events in a post-orthopedic surgery/arthroplasty population.


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.


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.


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.


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.


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.


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.


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.


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.


Orkoulas G.,University of California at Los Angeles
Journal of Chemical Physics | Year: 2010

Precise simulation of phase transitions is crucial for colloid/protein crystallization for which fluid-fluid demixing may be metastable against solidification. In the Gibbs-Duhem integration method, the two coexisting phases are simulated separately, usually at constant-pressure, and the phase boundary is established iteratively via numerical integration of the Clapeyron equation. In this work, it is shown that the phase boundary can also be reproduced in a way that avoids integration of Clapeyron equations. The two phases are simulated independently via tempering techniques and the simulation data are analyzed according to histogram reweighting. The main output of this analysis is the density of states which is used to calculate the free energies of both phases and to determine phase coexistence. This procedure is used to obtain the phase diagram of a square-well model with interaction range 1.15σ, where σ is the particle diameter. The phase boundaries can be estimated with the minimum number of simulations. In particular, very few simulations are required for the solid phase since its properties vary little with temperature. © 2010 American Institute of Physics.


Hewison M.,University of California at Los Angeles
Scandinavian Journal of Clinical and Laboratory Investigation | Year: 2012

Prominent amongst the non-classical effects of vitamin D is its interaction with the immune system. Although this has been recognized for many years, it is only through recent studies that we have been able to fully understand the impact of vitamin D on normal innate and adaptive immune function. In particular these studies have illustrated how impaired vitamin D status has important ramifications for dysregulated immune responses to infection and aberrant inflammatory responses associated with autoimmune disease. Indeed it seems likely that the effects of vitamin D will extend beyond these established immune diseases to include additional novel effects, such as interaction with the enteric gut microbiota. Central to this new perspective on vitamin D and immunity has been the elucidation of pivotal mechanisms that underpin the interface between vitamin D and target immune cells. In particular, it is now clear that effects of vitamin D on monocytes, macrophages, dendritic cells, and lymphocytes are not constrained by the metabolic pathways associated with classical endocrine actions of vitamin D. Instead, it is now important to also consider intracrine and paracrine pathways that are subject to a distinct set of modulatory signals, and which may also be influenced by disease-specific dysregulation. The current review will discuss this by comparing the intracrine, paracrine and endocrine metabolic systems that influence the interaction between vitamin D and the immune system. © 2012 Informa Healthcare.


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.


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.


Cutler D.M.,Harvard University | Lleras-Muney A.,University of California at Los Angeles
Journal of Health Economics | Year: 2010

Using a variety of data sets from two countries, we examine possible explanations for the relationship between education and health behaviors, known as the education gradient. We show that income, health insurance, and family background can account for about 30 percent of the gradient. Knowledge and measures of cognitive ability explain an additional 30 percent. Social networks account for another 10 percent. Our proxies for discounting, risk aversion, or the value of future do not account for any of the education gradient, and neither do personality factors such as a sense of control of oneself or over one's life. © 2009 Elsevier B.V.


Riedl M.A.,University of California at Los Angeles
Allergy and Asthma Proceedings | Year: 2011

Hereditary angioedema (HAE) is a genetic autosomal dominant condition caused by C1-esterase inhibitor protein (C1INH) deficiency that results in episodic tissue angioedema. Recently, new therapies have been developed to more effectively manage this rare but serious condition. This review will provide a concise summary of HAE acute treatment options for the practicing allergist/immunologist. Clinical study data for emerging HAE therapies were reviewed and summarized. Based on efficacy and safety data from completed clinical studies, three new HAE treatments have recently been approved by the Food and Drug Administration: nanofiltered plasma-derived C1INH for prophylactic therapy, pasteurized plasma-derived C1INH for acute therapy, and ecallantide for acute therapy. Two other promising therapies, recombinant C1INH and icatibant, are in various stages of the U.S. regulatory process. The medical management of HAE is entering a new era with the availability of safe, effective condition-specific treatments. Clinicians should consider a number of patient- and medication-specific factors when designing individualized treatment plans for HAE patients. Copyright © 2011, OceanSide Publications, Inc.


Coito A.J.,University of California at Los Angeles
Current Opinion in Organ Transplantation | Year: 2011

Purpose of Review: Hepatic ischemia reperfusion injury (IRI) linked to leukocyte recruitment and subsequent release of cytokines and free radicals remains a significant complication in organ transplantation. The aim of this review is to bring attention to advances made in our understanding of the mechanisms of leukocyte recruitment to sites of inflammatory stimulation in liver IRI. Recent Findings: Leukocyte transmigration across endothelial and extracellular matrix barriers is dependent on adhesive events, as well as on focal matrix degradation mechanisms. Whereas adhesion molecules are critical for the successful promotion of leukocyte transmigration by providing leukocyte attachment to the vascular endothelium, matrix metalloproteinases (MMPs) are important for facilitating leukocyte movement across vascular barriers. Among different MMPs, MMP-9, an inducible gelatinase expressed by leukocytes during hepatic IRI, is emerging as an important mediator of leukocyte traffic to inflamed liver. Summary: It is generally accepted that the understanding of the molecular mechanisms involved in leukocyte recruitment will lead to the development of novel targeted therapeutic approaches for hepatic IRI and liver transplantation. Here, we review mechanisms of leukocyte traffic in liver IRI and the role of some of the proteins that are thought to be important for this process. © 2011 Wolters Kluwer Health - Lippincott Williams & Wilkins.


Schonmann R.H.,University of California at Los Angeles
PloS one | Year: 2013

The ways in which natural selection can allow the proliferation of cooperative behavior have long been seen as a central problem in evolutionary biology. Most of the literature has focused on interactions between pairs of individuals and on linear public goods games. This emphasis has led to the conclusion that even modest levels of migration would pose a serious problem to the spread of altruism through population viscosity in group structured populations. Here we challenge this conclusion, by analyzing evolution in a framework which allows for complex group interactions and random migration among groups. We conclude that contingent forms of strong altruism that benefits equally all group members, regardless of kinship and without greenbeard effects, can spread when rare under realistic group sizes and levels of migration, due to the assortment of genes resulting only from population viscosity. Our analysis combines group-centric and gene-centric perspectives, allows for arbitrary strength of selection, and leads to extensions of Hamilton's rule for the spread of altruistic alleles, applicable under broad conditions.


Tao T.,University of California at Los Angeles
Combinatorics Probability and Computing | Year: 2010

Let G = (G, +) be an additive group. The sumset theory of Plnnecke and Ruzsa gives several relations between the size of sumsets A + B of finite sets A, B, and related objects such as iterated sumsets kA and difference sets A B, while the inverse sumset theory of Freiman, Ruzsa, and others characterizes those finite sets A for which A + A is small. In this paper we establish analogous results in which the finite set A ⊂ G is replaced by a discrete random variable X taking values in G, and the cardinality |A| is replaced by the Shannon entropy H(X). In particular, we classify those random variables X which have small doubling in the sense that H(X1 + X2) = H(X) + O(1) when X1, X2 are independent copies of X, by showing that they factorize as X = U + Z, where U is uniformly distributed on a coset progression of bounded rank, and H(Z) = O(1). When G is torsion-free, we also establish the sharp lower bound H (X + Y) ≥. H(X) + 1/2 log 2 - o (1), where o(1) goes to zero as H(X) → ∞. Copyright © 2010 Cambridge University Press.


Knowledge of a sex partner's HIV serostatus can influence sexual behavior and inform harm-reduction strategies. We sought to determine how often Peruvian men who have sex with men (MSM) and transgender women (TW) knew the HIV serostatus of their sex partners, if this knowledge was associated with any predictive factors or unprotected anal intercourse (UAI), and if UAI was associated with partner serostatus. We analyzed data from the 2008 Peruvian MSM Sentinel Surveillance Survey. Data were collected by CASI about each participant's three most recent male sex partners. Primary outcome was knowledge of a partner's HIV test result. Multivariate analysis assessed the effect of age, education, sexual identity, number of male partners, alcohol use during intercourse, type of partnership and length of partnership using logistic regression. 735 participants provided data on 1,643 of their most recent sex partners from the last 3 months. 179/735 (24.4%) of all participants knew HIV test results for at least one of their 3 most recent partners, corresponding to 230/1643 (14.0%) of all sexual partnerships in the last 3 months. In multivariate analysis, casual (OR: 0.27, 95% CI: 0.17-0.42) and exchange sex (OR: 0.31, 95% CI: 0.11-0.88) partners, compared to stable partners, were negatively associated with knowledge of partner serostatus, whereas relationships lasting longer than one night (<3 months OR: 2.20, 95% CI: 1.39-3.51; 3 months to 1 year OR: 3.00, 95% CI: 1.80-5.01; ≥ 1 year OR: 4.13, 95% CI: 2.40-7.10) were positively associated with knowledge of partner serostatus. Knowledge of partner serostatus was not associated with unprotected anal intercourse with that partner. Few MSM and TW in Peru know their partners' HIV serostatus. Our findings suggest that the type and length of partnership influence the likelihood of knowing a partner's serostatus. Further research should explore the contexts and practices of partner communication, their effect on sexual behavior, and interventions to promote discussion of HIV testing and serostatus as an HIV prevention strategy in this population.


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.


Gatti R.A.,University of California at Los Angeles
Annals of the New York Academy of Sciences | Year: 2012

Within less than 10 years after the realization of the double helix of DNA, the ability of aminoglycosides to influence the misreading or readthrough of premature termination codons was discovered. It took another three decades to clone and sequence disease genes and appreciate the similarity of mutation spectra for most inborn errors. Nonsense mutations once again have become the target of readthrough compounds. In this brief review, we trace the development in our laboratory of the next generation of readthrough agents, small molecule readthrough (SMRT) drug-like chemicals, and assays for comparing their in vitro activity. Possible mechanisms of action and potential clinical applications are considered. © 2012 New York Academy of Sciences.


Slutsky D.J.,University of California at Los Angeles
Hand Clinics | Year: 2014

Scaphoid fractures can be treated with minimal soft tissue dissection using percutaneous methods. Arthroscopy is a helpful tool when using these percutaneous scaphoid screw insertion techniques. Arthroscopy aids in optimal guidewire positioning, it is invaluable in assessing the quality of fracture reduction, and it allows one to evaluate the vascularity of the fracture fragments as well as the stability of fixation. Arthroscopy also allows assessment of screw length ensuring no radiocarpal penetration with retrograde (volar) insertion as well as checking for well-buried screw threads in the proximal pole with dorsal (antegrade) insertion. © 2014 Elsevier Inc.


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.


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.


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.


DeGiorgio C.M.,University of California at Los Angeles
Epilepsy and Behavior | Year: 2010

Lacosamide (LCM) is a novel antiepileptic drug that exerts a strong antiepileptic effect via slow inactivation of voltage-gated sodium channels. LCM has been approved by the Food and Drug Administration for treatment of partial seizures at doses up to 400. mg/day. Clinical trials have employed doses up to 600. mg/day. LCM has been associated with atrial fibrillation at high doses (600. mg/day) in patients with diabetes who had risk factors for heart disease. To our knowledge, atrial flutter or atrial fibrillation has not been reported in people with epilepsy. We report atrial flutter/atrial fibrillation at high doses of LCM (600. mg/day) in a patient with epilepsy who had no significant risk factors for heart disease, which resolved following discontinuation of LCM. The literature regarding LCM-related cardiac death and arrhythmia is discussed. Physicians should be aware of the potential cardiac effects of this novel antiepileptic drug. © 2010 Elsevier Inc.


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.


Dore R.K.,University of California at Los Angeles
Rheumatic Disease Clinics of North America | Year: 2011

Denosumab (Prolia) is a fully human monoclonal antibody directed against receptor activator of nuclear factor-κB ligand (RANKL), which interferes with the formation, activation, and survival of osteoclasts. It was approved by the Food and Drug Administration in June 2010 as a new treatment for postmenopausal osteoporosis in women who are at high risk for fracture. Given its mechanism of action, it is an antiresorptive therapy that is administered as a 60-mg subcutaneous injection every 6 months. It is the first biologic antiresorptive therapy for osteoporosis, and the first osteoporosis therapy to show efficacy and safety in patients with renal impairment. © 2011.


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.


Kerner B.,University of California at Los Angeles
Frontiers in Psychiatry | Year: 2015

Bipolar disorder is a common, complex psychiatric disorder characterized by mania and depression. The disease aggregates in families, but despite much effort, it has been difficult to delineate the basic genetic model or identify specific genetic risk factors. Not only single gene Mendelian transmission and common variant hypotheses but also multivariate threshold models and oligogenic quasi-Mendelian modes of inheritance have dominated the discussion at times. Almost complete sequence information of the human genome and falling sequencing costs now offer the opportunity to test these models in families in which the disorder is transmitted over several generations. Exome-wide sequencing studies have revealed an astonishing number of rare and potentially damaging mutations in brain-expressed genes that could have contributed to the disease manifestation. However, the statistical analysis of these data has been challenging, because genetic risk factors displayed a high degree of dissimilarity across families. This scenario is not unique to bipolar disorder, but similar results have also been found in schizophrenia, a potentially related psychiatric disorder. Recently, our group has published data which supported an oligogenic genetic model of transmission in a family with bipolar disorder. In this family, three affected siblings shared rare, damaging mutations in multiple genes, which were linked to stress response pathways. These pathways are also the target for drugs frequently used to treat bipolar disorder. This article discusses these findings in the context of previously proclaimed disease models and suggests future research directions, including biological confirmation and phenotype stratification as an approach to disease heterogeneity. © 2015 Kerner.


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.


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.


Arab L.,University of California at Los Angeles
Nutrition and Cancer | Year: 2010

Coffee consumption is a major and frequent dietary exposure in diverse cultures around the globe whose safety has been questioned. A substantial body of epidemiologic evidence, consisting of over 500 papers relating the consumption of coffee to cancer of various sites, has accumulated to date. Numerous individual, site-specific meta analyses have been undertaken at various times. However, there is no comprehensive, up-to-date overview of the entirety of the knowledge base. To address this need, this review summarized the findings of the meta analyses and recent papers on site-specific human cancers among coffee consumers. For hepatocellular and endometrial cancers, there appears to be a strong and consistent protective association; for colorectal cancer, the direction of association is borderline protective. There appears to be no association with breast, pancreatic, kidney, ovarian, prostate, or gastric cancer. Risk of bladder cancer appears to be associated with heavy coffee consumption in some populations and among men. The associations with childhood leukemia and mother's consumption of coffee were ambiguous-with some suggestion of risk at high levels of daily consumption. Copyright © 2010, Taylor & Francis Group, LLC.


Rajagopal D.,University of California at Los Angeles
Environmental Research Letters | Year: 2013

The absence of a globally-consistent and binding commitment to reducing greenhouse emissions provides a rationale for partial policies, such as renewable energy mandates, product emission standards, etc to target lifecycle emissions of the regulated products or services. While appealing in principle, regulation of lifecycle emissions presents several practical challenges. Using biofuels as an illustrative example, we highlight some outstanding issues in the design and implementation of life cycle-based policies and discuss potential remedies. We review the literature on emissions due to price effects in fuel markets, which are akin to emissions due to indirect land use change, but are, unlike the latter, ignored under all current life cycle emissions-based regulations. We distinguish the current approaches to regulating indirect emissions into hard and soft approaches and discuss their implications. © 2013 IOP Publishing Ltd.


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.


Wasson J.T.,University of California at Los Angeles
Geochimica et Cosmochimica Acta | Year: 2011

During the past three decades many iron meteorites have been collected from the deserts of North Africa. Almost all are now characterized, and the distribution among classes is found to be very different from those that were in museums prior to the collection of meteorites from hot and cold (Antarctica) deserts. Similar to the iron meteorites from Antarctica, the irons from Northwest Africa include a high fraction of ungrouped irons and of minor subgroups of group IAB. The different distribution is attributed to the small median size of the desert meteorites (∼1.3. kg in North African irons, ∼30. kg in non-desert irons). It appears that a sizable fraction of these small (several centimeter) masses constitute melt pockets produced by impacts in chondritic regoliths; they were never part of a large (meter-to-kilometer) magma bodies. As a result, a meter-size fragment ejected from the regolith of the asteroid may contain several of these small metallic masses. It may be that such stochastic sampling effects enhanced the fraction of IAB-sHL irons among the irons from Northwest Africa. The variety observed in small meteoroids is also enhanced because (relative to large) small fragments are more efficiently ejected from asteroids and because the orbital parameters of small meteoroids are more strongly affected by collisions and drag effects, they evolve to have Earth-crossing perihelia more rapidly than large meteoroids; as a result, the set of small meteoroids tends to sample a larger number of parent asteroids than does the set of larger meteoroids. © 2010 Elsevier Ltd.


Schauble E.A.,University of California at Los Angeles
Geochimica et Cosmochimica Acta | Year: 2011

Equilibrium mass-dependent magnesium isotope fractionation factors are estimated for a range of crystalline compounds including oxides, silicates, carbonates, and salts containing the Mg(H2O)62+ solvation complex. Fractionation factors for the gas-phase species Mg and MgO are also presented. Fractionation factors are calculated with density functional perturbation theory (DFPT), using norm-conserving pseudopotentials. The results suggest that there will be substantial inter-mineral fractionation, particularly between tetrahedrally coordinated Mg2+ in spinel (MgAl2O4) and the more common octahedrally coordinated Mg2+-sites in silicate and carbonate minerals. Isotope fractionations calculated for Mg2+ in hexaaquamagnesium(2+) salts are in good agreement with previous fractionation models of Mgaq2+ based on large molecular clusters (Black et al., 2007), but show possibly more significant disagreement with a more recent study (Rustad et al., 2010). These models further suggest that solvated Mgaq2+, in the form of Mg(H2O)62+, will have higher 26Mg/24Mg than coexisting magnesite and dolomite. Calculated fractionations are consistent with Mg-isotope fractionations observed in peridotite mineral separates and inorganic carbonate precipitates. Predicted large, temperature-sensitive spinel-silicate fractionations, in particular, may find use in determining equilibration temperatures of peridotites and other high-temperature rock types. © 2010 Elsevier Ltd.


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.


Cloughesy T.,University of California at Los Angeles
Seminars in Oncology | Year: 2011

Glioblastoma is an aggressive form of brain cancer with a poor long-term prognosis. Treatment regimens for newly diagnosed disease range from surgical resection alone to surgery followed by radiotherapy with concurrent and adjuvant chemotherapy. Ongoing investigations are focused on optimization of chemotherapy by improving dosing and duration schedules and utilization of biomarkers for patient selection. Our understanding of glioblastoma tumor biology, the role of molecular signaling pathways, cellular repair mechanisms, and angiogenesis has increased greatly over the past few years, leading to the investigation of a variety of targeted therapies. In addition, advances in radiographic assessment have significantly impacted not only improvement in diagnosis, but interpretation of response to therapy. In order to effectively evaluate the clinical utility of new agents, as well as incorporate advances in radiographic assessment, changes to current clinical trial design need to be considered. This article reviews the care for newly diagnosed glioblastoma, as well as how recent findings might be incorporated into patient care. © 2011 Elsevier Inc. All rights reserved.


Warren P.H.,University of California at Los Angeles
Earth and Planetary Science Letters | Year: 2011

Plots such as ε 54Cr vs. ε 50Ti and ε 54Cr vs. δ 17O reveal a fundamental dichotomy among planetary materials. The "carbonaceous" chondrites, by virtue of high ε 50Ti and high ε 62Ni, as well as, especially for any given δ 17O, high ε 54Cr, are separated by a wide margin from all other materials. The significance of the bimodality is further manifested by several types of meteorites with petrological-geochemical characteristics that suggest membership in the opposite category from the true pedigree as revealed by the stable isotopes. Ureilites, for example, despite having diversely low δ 17O and about the same average carbon content as the most C-rich carbonaceous chondrite, have clear stable-isotopic signatures of noncarbonaceous pedigree. The striking bimodality on the ε 54Cr vs. ε 50Ti and ε 54Cr vs. δ 17O diagrams suggests that the highest taxonomic division in meteorite/planetary classification should be between carbonaceous and noncarbonaceous materials. The bimodality may be an extreme manifestation of the effects of episodic accretion of early solids in the protoplanetary nebula. However, an alternative, admittedly speculative, explanation is that the bimodality corresponds to a division between materials that originally accreted in the outer solar system (carbonaceous) and materials that accreted in the inner solar system (noncarbonaceous). In any event, both the Earth and Mars plot squarely within the noncarbonaceous composition-space. Applying the lever rule to putative mixing lines on the ε 50Ti vs. ε 54Cr and δ 17O vs. ε 54Cr diagrams, the carbonaceous/(carbonaceous+noncarbonaceous) mixing ratio C/(C+NC) is most likely close to (very roughly) 24% for Earth and 9% for Mars. Estimated upper limits for C/(C+NC) are 32% for Earth and 18% for Mars. However, the uncertainties are such that isotopic data do not require or even significantly suggest that Earth has higher C/(C+NC) than Mars. Among known chondrite groups, EH yields a relatively close fit to the stable-isotopic composition of Earth. © 2011 Elsevier B.V.


Benner A.D.,University of Texas at Austin | Graham S.,University of California at Los Angeles
Child Development | Year: 2011

Changes in perceptions of discrimination were examined with 668 Latino students (62% Mexican American; 56% female; Mage=14.6years). Adolescents' reports of discrimination increased across the first 2years of high school. Perceptions of discrimination were higher for boys and for primary language brokers, as well as for adolescents in schools with more ethnically diverse student bodies but a less diverse teaching staff. Path analysis revealed that higher levels of discrimination and increases in discrimination across time influenced Latino adolescents' academic outcomes (i.e., grades, absences) indirectly via their influences on perceptions of school climate. Findings highlight previously understudied individual and school contextual factors that shape experiences of discrimination and the mechanisms by which discrimination indirectly influences Latino adolescents' outcomes. © 2011 The Authors. Child Development © 2011 Society for Research in Child Development, Inc..


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.


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.


Rivaroxaban (Bayer AG, Leverkusen, Germany) is a highly selective direct inhibitor of factor Xa. It has completed Phase III clinical trials evaluating its efficacy and safety against enoxaparin in the prophylaxis against venous thromboembolism (VTE) in orthopedic patients following primary total hip and total knee arthroplasty. Rivaroxaban has been extensively studied worldwide in 12,729 patients in the Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of DVT and PE (RECORD) program. Pivotal clinical trials have demonstrated the superior efficacy in reducing total VTE in comparison with both the North American and European regimens of enoxaparin. Safety of the drug was found to be excellent, with no demonstrable cardiovascular or hepatic effects and no statistically significant increase in major bleeding. A pooled analysis of data collected on the patients from the four RECORD trials revealed rivaroxaban to be the first antithrombotic agent to demonstrate superiority over another antithrombotic (enoxaparin) in reducing symptomatic VTE and all-cause mortality. While there was a significant difference in the composite safety endpoint of major and clinically relevant nonmajor bleeding in the pooled analysis with the use of rivaroxaban compared with enoxaparin, there was no significant difference in major bleeding or in any other bleeding. © 2011 Kwong, publisher and licensee Dove Medical Press Ltd.


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.


Jones D.,University of California at Los Angeles
Clinics in Plastic Surgery | Year: 2011

This article discusses the role of injectable soft-tissue fillers in the aging face, and their clinical and chemical behavior. Temporary and permanent fillers are discussed, namely hyaluronic acids, calcium hydroxylapatite, poly-l-lactic acid, liquid silicone, and polymethylmethacrylate. Techniques and outcomes are presented. © 2011 Elsevier Inc.


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.).


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.


Schlichting I.,Max Planck Institute For Medizinische Forschung | Schlichting I.,German Electron Synchrotron | Miao J.,University of California at Los Angeles
Current Opinion in Structural Biology | Year: 2012

X-ray free-electron lasers (X-FELs) produce X-ray pulses with extremely brilliant peak intensity and ultrashort pulse duration. It has been proposed that radiation damage can be 'outrun' by using an ultra intense and short X-FEL pulse that passes a biological sample before the onset of significant radiation damage. The concept of 'diffraction-before-destruction' has been demonstrated recently at the Linac Coherent Light Source, the first operational hard X-ray FEL, for protein nanocrystals and giant virus particles. The continuous diffraction patterns from single particles allow solving the classical 'phase problem' by the oversampling method with iterative algorithms. If enough data are collected from many identical copies of a (biological) particle, its three-dimensional structure can be reconstructed. We review the current status and future prospects of serial femtosecond crystallography (SFX) and single-particle coherent diffraction imaging (CDI) with X-FELs. © 2012 Elsevier Ltd.


Bianchi S.M.,University of California at Los Angeles
Future of Children | Year: 2011

American families and workplaces have both changed dramatically over the past half-century. Paid work by women has increased sharply, as has family instability. Education-related inequality in work hours and income has grown. These changes, says Suzanne Bianchi, pose differing work-life issues for parents at different points along the income distribution. Between 1975 and 2009, the labor force rate of mothers with children under age eighteen increased from 47.4 percent to 71.6 percent. Mothers today also return to work much sooner after the birth of a child than did mothers half a century ago. High divorce rates and a sharp rise in the share of births to unmarried mothers mean that more children are being raised by a single parent, usually their mother. Workplaces too have changed, observes Bianchi. Today's employees increasingly work nonstandard hours. The well-being of highly skilled workers and less-skilled workers has been diverging. For the former, work hours may be long, but income has soared. For lower-skill workers, the lack of "good jobs" disconnects fathers from family obligations. Men who cannot find work or have low earnings potential are much less likely to marry. For low-income women, many of whom are single parents, the work-family dilemma is how to care adequately for children and work enough hours to support them financially. Jobs for working-class and lower middle-class workers are relatively stable, except in economic downturns, but pay is low, and both parents must work full time to make ends meet. Family income is too high to qualify for government subsidized child care, but too low to afford highquality care in the private market. These families struggle to have a reasonable family life and provide for their family's economic well-being. Bianchi concludes that the "work and family" problem has no one solution because it is not one problem. Some workers need more work and more money. Some need to take time off around the birth of a child without permanently derailing a fulfilling career. Others need short-term support to attend to a family health crisis. How best to meet this multiplicity of needs is the challenge of the coming decade.


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.


Di Lorenzo P.,University of Rome La Sapienza | Sayed A.H.,University of California at Los Angeles
IEEE Transactions on Signal Processing | Year: 2013

This article proposes diffusion LMS strategies for distributed estimation over adaptive networks that are able to exploit sparsity in the underlying system model. The approach relies on convex regularization, common in compressive sensing, to enhance the detection of sparsity via a diffusive process over the network. The resulting algorithms endow networks with learning abilities and allow them to learn the sparse structure from the incoming data in real-time, and also to track variations in the sparsity of the model. We provide convergence and mean-square performance analysis of the proposed method and show under what conditions it outperforms the unregularized diffusion version. We also show how to adaptively select the regularization parameter. Simulation results illustrate the advantage of the proposed filters for sparse data recovery. © 1991-2012 IEEE.


Kim J.,University of California at Los Angeles
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2011

Turbulence physics responsible for high skin-friction drag in turbulent boundary layers is first reviewed. A self-sustaining process of near-wall turbulence structures is then discussed from the perspective of controlling this process for the purpose of skin-friction drag reduction. After recognizing that key parts of this self-sustaining process are linear, a linear systems approach to boundary-layer control is discussed. It is shown that singular-value decomposition analysis of the linear system allows us to examine different approaches to boundary-layer control without carrying out the expensive nonlinear simulations. Results from the linear analysis are consistent with those observed in full nonlinear simulations, thus demonstrating the validity of the linear analysis. Finally, fundamental performance limit expected of optimal control input is discussed. © 2011 The Royal Society.


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.


Wong G.C.L.,University of California at Los Angeles
MRS Bulletin | Year: 2011

Bacterial biofilms are integrated, multi-species communities of cells that adhere to almost any surface and are fundamental to the ecology and biology of bacteria. Not only do biofilms contribute to human health and disease, they also play important roles in the context of energy and the environment. The formation of biofilms requires interactions between bacteria and the surfaces they colonize, and both microbe and surface can impact the structure, function, and composition of these communities. Bacteria in biofilms exhibit surprisingly sophisticated social behavior, both cooperative and competitive, made possible by their cell biology. However, they are also hierarchically organized systems governed by complex physical and chemical interactions. Because of this, the study of bacterial biofilms has recently attracted the attention of materials scientists, physicists, chemists, and nanotechnology experts who import not only new tools, but also new concepts and perspectives. This issue reviews recent progress in multidisciplinary studies of biofilms. © 2011 Materials Research Society.


Scelza B.A.,University of California at Los Angeles
Evolution and Human Behavior | Year: 2014

Evolutionary scientists have predicted a universal sex difference in response to different forms of infidelity, with men expected to be more upset than women by a sexual infidelity when both a sexual transgression and an emotional transgression occur. Although this finding has proven to be robust, the vast majority of studies have occurred in industrialized countries and student populations. Here I present the first test of the jealousy hypothesis among a small-scale, natural fertility population, the Himba of Namibia. In this population, the majority of both men and women report greater distress over a sexual infidelity, with men reaching an almost unanimous consensus (96%). Despite the skew for both men and women, there is a significant sex difference in the direction predicted by the evolutionary hypothesis, providing further support for this view. The increased risks of both pregnancy and paternity loss that occur in this natural fertility population may help to explain why these results differ from previously studied populations. More broadly, these data suggest that both the type and the intensity of jealousy expressed may be facultative responses and that further investigation of correlates related to life history trade-offs, forms of investment, and the sexual division of labor can help us to understand the inter-cultural variation in jealous response. © 2014 Elsevier Inc.


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.


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.


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.


Kim S.H.,Yonsei University | Saver J.L.,University of California at Los Angeles
Stroke | Year: 2015

Results-Among 595 patients (297 placebo and 298 tPA treated) with documented initial BT, 77.1% had initial BT <37.0°C and 22.9% 37.0°C. Patients with higher initial BT had lower baseline stroke severity in both tPA-treated patients (the National Institute of Health Stroke Scale median, 11 versus 15; P=0.05) and placebo-treated patients (median, 13 versus 16; P<0.01). Patients with higher initial BT also had lower infarction volume on computed tomography at 3 months in both tPA-treated patients (median, 9.6 versus 16.7 cm; P=0.08) and placebo-treated patients (median, 13.1 versus 28.1 cm; P=0.02), but no clinical outcome differences. Analysis of lytic treatment effect found no heterogeneity in the degree of tPA benefit in both higher and lower BT groups (37.0°C: odds ratio for the modified Rankin Scale 0-1 outcome, 2.55; 95% confidence interval, 1.05-6.21 and <37.0°C: odds ratio, 2.30; 95% confidence interval, 1.38-3.84; heterogeneity P=0.83).Conclusions-In patients with hyperacute stroke, higher presenting temperatures are associated with less severe neurological deficits and reduced final infarct volumes. Presenting temperature does not modify the benefit of tPA on 3-month favorable outcome.Background and Purpose-Body temperature (BT) is an important physiological factor in acute ischemic stroke. However, the relationship of initial BT to stroke severity and degree of benefit from thrombolytic therapy has been delineated incompletely.Methods-We analyzed the public data set of the 2 National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator (tPA) stroke trials, comparing patients with lower (<37.0°C) and higher (37.0°C) presenting BT. © 2014 American Heart Association, Inc.


Bonavida B.,University of California at Los Angeles
Critical Reviews in Oncogenesis | Year: 2014

Cancer remains one of the most dreadful diseases. Whereas most treatment regimens for various cancers have resulted in improved clinical responses and sometimes cures, unfortunately, subsets of cancer patients are either pretreatment resistant or develop resistance following therapy. These subsets of patients develop cross-resistance to unrelated therapeutics and usually succumb to death. Thus, delineating the underlying molecular mechanisms of resistance of various cancers and identifying molecular targets for intervention are the current main focus of research investigations. One approach to investigate cancer resistance has been to identify pathways that regulate resistance and develop means to disrupt these pathways in order to override resistance and sensitize the resistant cells to cell death. Hence, we have identified one pathway that is dysregulated in cancer, namely, the NF-κB/Snail/YY1/RKIP loop, that has been shown to regulate, in large part, tumor cell resistance to apoptosis by chemotherapeutic and immunotherapeutic cytotoxic drugs. The dysregulated resistant loop is manifested by the overexpression of NF-κB, Snail, and YY1 activities and the underexpression of RKIP. The induction of RKIP expression results in the downregulation of NF-κB, Snail, and YY1 and the sensitization of resistant cells to drug-induced apoptosis. These findings identified RKIP, in addition to its anti-proliferative and metastatic suppressor functions, as an anti-resistance factor. This brief review describes the role of RKIP in the regulation of drug sensitivity via disruption of the NF-κB/Snail/ YY1/RKIP loop that regulates resistance in cancer cells. © 2014 by Begell House, 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.


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.


Whitelegge J.,University of California at Los Angeles
Expert Review of Proteomics | Year: 2013

American Society for Mass Spectrometry Sanibel meeting on top-down mass spectrometry St Pete Beach, FL, USA, 24-27 January 2013 Top-down mass spectrometry involves analysis of intact proteins, typically using electrospray ionization, as multiple charging enhances dissociation and thus identification by comparison of precursor and product ion masses with protein sequence databases. Traditionally a low-throughput, precision technology performed on high-resolution Fourier-transform ion cyclotron resonance mass analyzers, top-down proteomics aims to increase throughput for whole proteome analysis while preserving the inherent value of an intact protein mass measurement. This years' American Society for Mass Spectrometry Sanibel meeting brought together established scientists who have demonstrated the viability of the top-down approach and its applicability to virtually all segments of the proteome, mixing them with researchers from diverse areas and with the common interest of advancing top-down into the high-throughput proteomics mainstream. Advances in instrumentation including the orbitrap analyzer, ionization mechanisms, dissociation strategies and informatics, as well as a wide variety of applications, were discussed in depth, leading to the inescapable conclusion that the future for top-down is bright. © 2013 Expert Reviews Ltd.


Warren P.H.,University of California at Los Angeles
Geochimica et Cosmochimica Acta | Year: 2011

The abundant, diverse ureilite meteorites are peridotitic asteroidal mantle restites that have remarkably high bulk carbon contents (average 3wt%) and have long been linked to the so-called carbonaceous chondrites (although this term is potentially misleading, because the high petrologic type "carbonaceous" chondrites are, if anything, C-poor compared to ordinary chondrites). Ureilite oxygen isotopic compositions, i.e., diversely negative (CCAM-like) Δ17O, viewed in isolation, have long been viewed as confirming the carbonaceous-chondritic derivation hypothesis. However, a very different picture emerges through analysis of a compilation of recently published high-precision isotopic data for chromium, titanium and nickel for ureilites and various other planetary materials. Ureilites have lower ε62Ni and far lower ε50Ti and ε54Cr than any known variety of carbonaceous chondrite. On a plot of ε50Ti vs. ε54Cr, and similarly Δ17O vs. ε54Cr, ureilite compositions cluster far from and in a direction approximately orthogonal to a trend internal to the carbonaceous chondrites, and the carbonaceous chondrites are separated by a wide margin from all other planetary materials. I conclude that notwithstanding the impressive resemblance to carbonaceous chondrites in terms of diversely negative Δ17O, the ureilite precursors accreted from preponderantly noncarbonaceous (sensu stricto) materials. Despite total depletion of basaltic matter, the ureilites retain moderate pyroxene/olivine ratios; which is an expected outcome from simple partial melting of moderate-SiO2/(FeO+MgO) noncarbonaceous chondritic material, but would imply an additional process of major reduction of FeO if the precursor material were carbonaceous-chondritic. The striking bimodality of planetary materials on the ε50Ti vs. ε54Cr and Δ17O vs. ε54Cr diagrams may be an extreme manifestation of the effects of episodic accretion of early solids in the protoplanetary nebula. However, an alternative, admittedly speculative, explanation is that the bimodality corresponds to a division between materials that originally accreted in the outer solar system (carbonaceous) and materials that accreted in the inner solar system (noncarbonaceous, including the ureilites). © 2011 Elsevier Ltd.


Loo S.K.,University of California at Los Angeles | Makeig S.,University of California at San Diego
Neurotherapeutics | Year: 2012

Summary: Psychiatric research applications of electroencephalography (EEG), the earliest approach to imaging human cortical brain activity, are attracting increasing scientific and clinical interest. For more than 40 years, EEG research has attempted to characterize and quantify the neurophysiology of attention-deficit/hyperactivity disorder (ADHD), most consistently associating it with increased frontocentral theta band activity and increased theta to beta (θ/β) power ratio during rest compared to non-ADHD controls. Recent reports suggest that while these EEG measures demonstrate strong discriminant validity for ADHD, significant EEG heterogeneity also exists across ADHD-diagnosed individuals. In particular, additional studies validating the use of the θ/β power ratio measure appear to be needed before it can be used for clinical diagnosis. In recent years, the number and the scientific quality of research reports on EEG-based neurofeedback (NF) for ADHD have grown considerably, although the studies reviewed here do not yet support NF training as a first-line, stand-alone treatment modality. In particular, more research is needed comparing NF to placebo control and other effective treatments for ADHD. Currently, after a long period of relative stasis, the neurophysiological specificity of measures used in EEG research is rapidly increasing. It is likely, therefore, that new EEG studies of ADHD using higher density recordings and new measures drawn from viewing EEG as a 3-dimensional functional imaging modality, as well as intensive re-analyses of existing EEG study data, can better characterize the neurophysiological differences between and within ADHD and non-ADHD subjects, and lead to more precise diagnostic measures and effective NF approaches. © 2012 The American Society for Experimental NeuroTherapeutics, Inc.


MacDonald G.M.,University of California at Los Angeles
Journal of Quaternary Science | Year: 2010

The IPCC 4th Assessment Report (FAR) is considered in light of Holocene palaeo-records of Arctic and Subarctic land temperatures and the response of the boreal forest-tundra boundary to past and present warming. The palaeo-records appear to support and amplify some of the conclusions in FAR and raise questions about others. Comparison of the FAR estimates for late 21st-century warming with Arctic and Subarctic palaeoclimatic records suggests that anticipated future warming will be unprecedented compared to earlier Holocene warming including the Holocene Thermal Maximum (HTM) and subsequent Medieval Warm Period (MWP). Annual warming and winter warming will likely be greater than during earlier periods in the Holocene, but summer temperatures projected by FAR may approximate or not far exceed the summer warming of the HTM. The geographically synchronous pattern of 21st-century warming projected by FAR will differ from the observed geographic variability in the timing of the HTM, particularly in the western Arctic. Further palaeo-record syntheses are required to fully delineate the similarities and differences between the HTM and the projected conditions of the 21st century. In addition, palaeo-records suggest that the Arctic and Subarctic climate may be sensitive to relatively small changes in solar irradiance and understanding the potential effects of natural variations in irradiance on the future climate of the Arctic and Subarctic remains a question deserving further research. FAR mapped estimates of a significant northward displacement of boreal forest and woodland due to warming imply that boreal forest or woodland will displace tundra as far north as the Arctic coastline by AD 2100. In Eurasia the estimated AD 2100 location of the tree line appears to approximate the HTM location. In North America an advance of forest to the coastline on the north slope of Alaska, central Canada and northern Quebec would far outdistance the relatively limited northward advances of boreal forest during the HTM. However, rates of tree species advance and subsequent forest development based on palaeo-records and currently observed tree line advances raise questions about the likelihood that northward migration and subsequent increases in the population sizes of boreal tree species could occur rapidly enough to establish continuous forest and woodland as far north as the Arctic coastlines of Eurasia and NorthAmerica by AD 2100. Determining potential rates of northward advance of the northern forests requires further ecological and palaeoecological investigations. © 2009 John Wiley & Sons, Ltd.


Rajagopal D.,University of California at Los Angeles
Journal of Industrial Ecology | Year: 2014

The application of life cycle assessment (LCA) in a policy context highlights the need for a "consequential" LCA (CLCA), which differs from an "attributional" LCA (ALCA). Although CLCA offers some advantages over ALCA, such as a capacity to account for emissions resulting from both substitution and price effects, it entails additional assumptions and cost and may yield estimates that are more uncertain (e.g., estimates of impact of biofuel policies on greenhouse gas [GHG] emissions). We illustrate how a CLCA that relies on simple partial equilibrium models could provide important insights on the direction and magnitude of price effects while limiting the complexity of CLCA. We describe how such a CLCA, when applied early in the policy life cycle, could help identify policy formulations that reduce the magnitude of adverse price effects relative to the beneficial substitution effect on emissions because-as the experience with biofuel regulations indicates-regulating price effects is costly and controversial. We conclude that the salient contribution of CLCA in the policy process might lie in warning policy makers about the vulnerabilities in a policy with regard to environmental impact and to help modify potentially counterproductive formulations rather than in deriving the precise estimates for uncertain variables, such as the life cycle GHG intensity of product or average indirect emissions. © 2013 by Yale University.


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.


Amin S.T.,University of California at Los Angeles
Journal of the American Heart Association | Year: 2013

Although there are multiple methods of risk stratification for ST-elevation myocardial infarction (STEMI), this study presents a prospectively validated method for reclassification of patients based on in-hospital events. A dynamic risk score provides an initial risk stratification and reassessment at discharge. The dynamic TIMI risk score for STEMI was derived in ExTRACT-TIMI 25 and validated in TRITON-TIMI 38. Baseline variables were from the original TIMI risk score for STEMI. New variables were major clinical events occurring during the index hospitalization. Each variable was tested individually in a univariate Cox proportional hazards regression. Variables with P<0.05 were incorporated into a full multivariable Cox model to assess the risk of death at 1 year. Each variable was assigned an integer value based on the odds ratio, and the final score was the sum of these values. The dynamic score included the development of in-hospital MI, arrhythmia, major bleed, stroke, congestive heart failure, recurrent ischemia, and renal failure. The C-statistic produced by the dynamic score in the derivation database was 0.76, with a net reclassification improvement (NRI) of 0.33 (P<0.0001) from the inclusion of dynamic events to the original TIMI risk score. In the validation database, the C-statistic was 0.81, with a NRI of 0.35 (P=0.01). This score is a prospectively derived, validated means of estimating 1-year mortality of STEMI at hospital discharge and can serve as a clinically useful tool. By incorporating events during the index hospitalization, it can better define risk and help to guide treatment decisions.


Murphy N.P.,University of California at Los Angeles
ACS Chemical Neuroscience | Year: 2015

Opioid peptides are the endogenous ligands of opioid receptors, which are also the molecular target of naturally occurring and synthetic opiates, such as morphine and heroin. Since their discovery in the 1970s, opioid peptides, which are found widely throughout the central nervous system and the periphery, have been intensely studied because of their involvement in pain and pleasure. Over the years, our understanding of opioid peptides has widened to cover a multitude of functions, including learning and memory, affective state, gastrointestinal transit, feeding, immune function, and metabolism. Unsurprisingly, aberrant opioid activity is implicated in numerous pathologies, including drug addiction, overeating, pain, depression, and obesity. To date, virtually all preclinical and clinical studies aimed at understanding the function of endogenous opioids have relied upon manipulating endogenous opioid fluxes using opioid receptor ligands or genetic manipulations of opioid receptors and endogenous opioids. Difficulties in directly monitoring endogenous opioid fluxes, particularly in the central nervous system, have presented a major obstacle to fully understanding endogenous opioid function. This review summarizes these challenges and offers suggestions for future goals while focusing on the neurobiology of reward, specifically drawing attention to studies that have succeeded in dynamically measuring opioid peptides. © 2015 American Chemical Society.


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.


Kagan Y.Y.,University of California at Los Angeles
Tectonophysics | Year: 2010

We propose that the widely observed and universal Gutenberg-Richter relation is a mathematical consequence of the critical branching nature of earthquake process in a brittle fracture environment. These arguments, though preliminary, are confirmed by recent investigations of the seismic moment distribution in global earthquake catalogs and by the results on the distribution in crystals of dislocation avalanche sizes. We consider possible systematic and random errors in determining earthquake size, especially its seismic moment. These effects increase the estimate of the parameter β of the power-law distribution of earthquake sizes. In particular, we find that estimated β-values may be inflated by 1-3% because relative moment uncertainties decrease with increasing earthquake size. Moreover, earthquake clustering greatly influences the β-parameter. If clusters (aftershock sequences) are taken as the entity to be studied, then the exponent value for their size distribution would decrease by 5-10%. The complexity of any earthquake source also inflates the estimated β-value by at least 3-7%. The centroid depth distribution also should influence the β-value, and an approximate calculation suggests that the exponent value may be increased by 2-6%. Taking all these effects into account, we propose that the recently obtained β-value of 0.63 could be reduced to about 0.52-0.56: near the universal constant value (1/2) predicted by theoretical arguments. We also consider possible consequences of the universal β-value and its relevance for theoretical and practical understanding of earthquake occurrence in various tectonic and Earth structure environments. Using comparative crystal deformation results may help us understand the generation of seismic tremors and slow earthquakes and illuminate the transition from brittle fracture to plastic flow. © 2010 Elsevier B.V.


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.


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.


Scott A.J.,University of California at Los Angeles
Papers in Regional Science | Year: 2010

The paper analyses factors influencing the destinations chosen by 13 different categories of migrant engineers in the USA between 1994 to 1999. Migration patterns are analysed with the aid of fractional-response regression models. The objective is to assess the relative weight of employment opportunities and selected amenities in guiding the migratory shifts of these workers. Engineers are divided into two categories representing individuals of working age and those who are either retired or are close to retirement. The results indicate that local employment opportunities have a dominant impact on the destinations chosen by the former group and that amenities play virtually no role in this regard. However, warmer winters have some modest positive effect on destinations chosen by the latter group. Resumen: El artículo analiza los factores que influyen en el destino elegido por 13 categorías diferentes de ingenieros emigrantes en los EE.UU. entre 1994 y 1999. Se analizan los patrones migratorios con la ayuda de modelos de regresión de respuesta fraccional. El objetivo es evaluar el peso relativo de las oportunidades de empleo y ciertos servicios en influir en los desplazamientos migratorios de estos trabajadores. Los ingenieros se dividen en dos categorías que representan a individuos en edad laboral y a aquellos que o están retirados o cerca de hacerlo. Los resultados indican que las oportunidades de empleo local tienen un impacto dominante en los destinos elegidos por el primer grupo y que los servicios apenas influyen en este aspecto. Sin embargo, los inviernos cálidos tienen un efecto positivo modesto en los destinos elegidos por el último grupo. © 2009 the author(s). Journal compilation © 2009 RSAI.


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.


Roberts P.H.,University of California at Los Angeles
Reports on progress in physics. Physical Society (Great Britain) | 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.


Jalali B.,University of California at Los Angeles
Nature Photonics | Year: 2016

Mode-locked lasers have enabled some of the most precise measurements ever performed, from attosecond time-domain spectroscopy to metrology with frequency combs. However, such extreme precision belies the complexity of the underlying mode-locking dynamics. This complexity is particularly evident in the emergence of the mode-locked state, an intrinsically singular, non-repetitive transition. Many details of mode-locking are well understood, yet conventional spectroscopy cannot resolve the nascent dynamics in passive mode-locking on their natural nanosecond timescale, the single pulse period. Here, we capture the pulse-resolved spectral evolution of a femtosecond pulse train from the initial fluctuations, recording ∼900,000 consecutive periods. We directly observe critical phenomena on timescales from tens to thousands of roundtrips, including the birth of the broadband spectrum, accompanying wavelength shifts and transient interference dynamics described as auxiliary-pulse mode-locking. Enabled by the time-stretch transform, the results may impact laser design, ultrafast diagnostics and nonlinear optics. © 2016 Nature Publishing Group


Mehta M.R.,University of California at Los Angeles
Cell | Year: 2011

The brain's grid and place cells, which contribute to spatial representations of the external environment, are thought to be modulated by the hyperpolarization-activated cation current (I h). Giocomo et al. and Hussaini et al. now provide new insights into these cells' unique activity patterns by studying transgenic mice lacking I h. © 2011 Elsevier Inc.


Scelza B.A.,University of California at Los Angeles
Biology Letters | Year: 2011

Seeking out extra-pair paternity (EPP) is a viable reproductive strategy for females in many pairbonded species. Across human societies, women commonly engage in extra-marital affairs, suggesting this strategy may also be an important part of women's reproductive decision-making. Here, I show that among the Himba 17 per cent of all recorded marital births are attributed by women to EPP, and EPP is associated with significant increases in women's reproductive success. In contrast, there are no cases of EPP among children born into 'love match' marriages. This rate of EPP is higher than has been recorded in any other small-scale society. These results illustrate the importance of seeking EPP as a mechanism of female choice in humans, while simultaneously showing it to be highly variable and context-dependent. © 2011 The Royal Society.


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.


Bisley J.W.,University of California at Los Angeles
Journal of Physiology | Year: 2011

Visual attention is the mechanism the nervous system uses to highlight specific locations, objects or features within the visual field. This can be accomplished by making an eye movement to bring the object onto the fovea (overt attention) or by increased processing of visual information in neurons representing more peripheral regions of the visual field (covert attention). This review will examine two aspects of visual attention: the changes in neural responses within visual cortices due to the allocation of covert attention; and the neural activity in higher cortical areas involved in guiding the allocation of attention. The first section will highlight processes that occur during visual spatial attention and feature-based attention in cortical visual areas and several related models that have recently been proposed to explain this activity. The second section will focus on the parietofrontal network thought to be involved in targeting eye movements and allocating covert attention. It will describe evidence that the lateral intraparietal area, frontal eye field and superior colliculus are involved in the guidance of visual attention, and describe the priority map model, which is thought to operate in at least several of these areas. © 2010 The Author. Journal compilation © 2010 The Physiological Society.


White B.D.,University of Washington | Chien A.J.,University of Washington | Dawson D.W.,University of California at Los Angeles
Gastroenterology | Year: 2012

Aberrant Wnt/β-catenin signaling is widely implicated in numerous malignancies, including cancers of the gastrointestinal tract. Dysregulation of signaling is traditionally attributed to mutations in Axin, adenomatous polyposis coli, and β-catenin that lead to constitutive hyperactivation of the pathway. However, Wnt/β-catenin signaling is also modulated through various other mechanisms in cancer, including cross talk with other altered signaling pathways. A more complex view of Wnt/β-catenin signaling and its role in gastrointestinal cancers is now emerging as divergent phenotypic outcomes are found to be dictated by temporospatial context and relative levels of pathway activation. This review summarizes the dysregulation of Wnt/β-catenin signaling in colorectal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, with particular emphasis on the latter two. We conclude by addressing some of the major challenges faced in attempting to target the pathway in the clinic. © 2012 AGA Institute.


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.


Deng J.C.,University of California at Los Angeles
Influenza and other Respiratory Viruses | Year: 2013

Viral and bacterial respiratory tract infections are a leading cause of morbidity and mortality worldwide, despite the development of vaccines and potent antibiotics. Frequently, viruses and bacteria can co-infect the same host, resulting in heightened pathology and severity of illness compared to single infections. Bacterial superinfections have been a significant cause of death during every influenza pandemic, including the 2009 H1N1 pandemic. This review will analyze the epidemiology and global impact of viral and bacterial co-infections of the respiratory tract, with an emphasis on bacterial infections following influenza. We will next examine the mechanisms by which viral infections enhance the acquisition and severity of bacterial infections. Finally, we will discuss current management strategies for diagnosing and treating patients with suspected or confirmed viral-bacterial infections of the respiratory tract. Further investigation into the interactions between viral and bacterial infections is necessary for developing new therapeutic approaches aimed at mitigating the severity of co-infections.© 2013 Blackwell Publishing Ltd.


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.


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.


The Alzheimer's Disease Neuroimaging Initiative (ADNI) is providing critical new information on biomarkers in cognitively normal elderly, persons with mild cognitive impairment (MCI), and patients with mild Alzheimer's disease (AD). The data provide insights into the progression of the pathology of AD over time, assist in understanding which biomarkers might be most useful in clinical trials, and facilitate development of disease-modifying treatments. ADNI results are intended to support new AD treatment development; this report considers how ADNI information can be integrated in AD drug development programs. Cerebrospinal fluid (CSF) amyloid beta protein (Aβ) measures can be used in Phase I studies to detect any short term effects on Aβ levels in the CSF. Phase II studies may benefit most from biomarker measures that can inform decisions about Phase III. CSF Aβ levels, CSF total tau and phospo-tau measures, fluorodexoyglucose positron emission tomography (FDG PET), Pittsburgh Compound B (PIB) amyloid imaging, or magnetic resonance imaging (MRI) may be employed to select patients in enriched trials or as outcomes for specific disease-modifying interventions. Use of biomarkers may allow Phase II trials to be conducted more efficiently with smaller populations of patients or shorted treatment times. New drug applications (NDAs) may include biomarker outcomes of phase III trials. ADNI patients are highly educated and are nearly all of Caucasian ethnicity limiting the generalizability of the results to other populations commonly included in global clinical trials. ADNI has inspired or collaborates with biomarker investigations worldwide and together these studies will provide biomarker information that can reduce development times and costs, improve drug safety, optimize drug efficacy, and bring new treatments to patients with or at risk for AD. © 2010 Elsevier Inc.


Chakravarty S.,University of California at Los Angeles
Physical Review B - Condensed Matter and Materials Physics | Year: 2014

I comment on two recent papers on the Kerr effect as evidence of gyrotropic order in cuprates, and I suggest that the arguments may not be sound. The difficulty is that, in practically all cases, the wave vector kz perpendicular to the copper-oxygen plane is not a good quantum number. This appears to be problematic for Orenstein and Moore [Phys. Rev. B 87, 165110 (2013)PRBMDO1098-012110.1103/PhysRevB.87.165110], whereas, in Hosur et al. [Phys. Rev. B 87, 115116 (2013)PRBMDO1098-012110.1103/PhysRevB.87.115116], the symmetry arguments may turn out to be robust, but the microscopic picture is wanting. Thus, the Kerr effect in cuprates remains a puzzle as there is little doubt that the arguments presented against time-reversal symmetry breaking appear to be rather strong on experimental grounds in both of these papers. © 2014 American Physical Society.


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.


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.


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.


Sofroniew M.V.,University of California at Los Angeles
Cold Spring Harbor Perspectives in Biology | Year: 2015

In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond to CNS damage and disease through a process called astrogliosis. For many decades, astrogliosis was sparsely studied and enigmatic. This article examines recent evidence supporting a definition of astrogliosis as a spectrum of heterogeneous potential changes in astrocytes that occur in a context-specific manner as determined by diverse signaling events that vary with the nature and severity of different CNS insults. Astrogliosis is associated with essential beneficial functions, but under specific circumstances can lead to harmful effects. Potential dysfunctions of astrocytes and astrogliosis are being identified that can contribute to, or be primary causes of, CNS disorders, leading to the notion of astrocytopathies. A conceptual framework is presented that allows consideration of normally occurring and dysfunctional astrogliosis and their different roles in CNS disorders. © 2015 Cold Spring Harbor Laboratory Press.


Ovbiagele B.,University of California at Los Angeles
Stroke | Year: 2010

Background and Purpose-: Recent data suggest declining overall deaths attributable to stroke. However, little is known about time trends in mortality during stroke hospitalization, which may reflect a stroke's direct effects, medical complications, or care quality. This study assessed nationwide patterns in hospital deaths after experiencing an acute stroke. Methods-: Data were obtained from all US states that contributed to the Nationwide Inpatient Sample. All patients admitted to hospitals between 1997 and 2006 with a discharge diagnosis of stroke (identified by the International Classification of Diseases, Ninth Revision procedure codes) were included. Time trends in the proportion of stroke hospitalizations that resulted in death were assessed. Independent predictors of in-hospital mortality after stroke were evaluated using multivariable logistic regression. Results-: Between 1997 and 2006, overall stroke hospitalizations lessened from 1 351 293 in 1997 to 1998 to 1 202 449 in 2005 to 2006, whereas percentage stroke hospitalizations that resulted in death decreased from 11.5% in 1997 to 1998 to 10.3% in 2005 to 2006 (P<0.0001). Odds of mortality decreased regardless of stroke type: ischemic stroke (OR 0.89, 95% CI=0.86 to 0.92), subarachnoid hemorrhage (OR 0.85, 95% CI=0.78 to 0.92), and intracerebral hemorrhage (OR 0.90, 95% CI=0.86 to 0.94). In multivariable analyses, older age, female sex, non-Medicare insurance, and multiple comorbidities were independently linked to higher odds of in-hospital mortality. Conclusions-: The percentage of stroke hospitalizations resulting in death decreased over the last decade likely reflecting advancements in acute stroke care. However, specific individual/hospital-level characteristics may be targets for facilitating further declines. © 2010 American Heart Association, Inc.


Alveolar septation marks the beginning of the transition from the saccular to alveolar stage of lung development. Inflammation can disrupt this process and permanently impair alveolar formation resulting in alveolar hypoplasia as seen in bronchopulmonary dysplasia in preterm newborns. NF-κB is a transcription factor central to multiple inflammatory and developmental pathways including dorsal-ventral patterning in fruit flies; limb, mammary and submandibular gland development in mice; and branching morphogenesis in chick lungs. We have previously shown that epithelial overexpression of NF-κB accelerates lung maturity using transgenic mice. The purpose of this study was to test our hypothesis that targeted deletion of NF-κB signaling in lung epithelium would impair alveolar formation. We generated double transgenic mice with lung epithelium-specific deletion of IKKβ, a known activating kinase upstream of NF-κB, using a cre-loxP transgenic recombination strategy. Lungs of resulting progeny were analyzed at embryonic and early postnatal stages to determine specific effects on lung histology, and mRNA and protein expression of relevant lung morphoreulatory genes. Lastly, results measuring expression of the angiogenic factor, VEGF, were confirmed in vitro using a siRNA-knockdown strategy in cultured mouse lung epithelial cells. Our results showed that IKKβ deletion in the lung epithelium transiently decreased alveolar type I and type II cells and myofibroblasts and delayed alveolar formation. These effects were mediated through increased alveolar type II cell apoptosis and decreased epithelial VEGF expression. These results suggest that epithelial NF-κB plays a critical role in early alveolar development possibly through regulation of VEGF.


Fonarow G.C.,University of California at Los Angeles
Circulation Journal | Year: 2011

Heart failure (HF) results in substantial morbidity, mortality, and costs, yet quality of care varies widely and is frequently inadequate. Performance improvement registries have been developed to improve the quality of care and outcomes for patients with HF in both the inpatient and outpatient settings. HF registries in the United States include ADHERE, OPTIMIZE-HF, GWTG-HF, and IMPROVE HF. These registries collect data on clinical characteristics, admission, hospital, discharge, and/or outpatient care, as well as outcomes. Web-based tools that provide real-time feedback of performance and other quality measures benchmarked to other sites and national data are frequently utilized. Process-of-care improvement tools, including evidence-based clinical decision support, customizable order sets, and patient education are also used. Participation in performance improvement registries has been associated with substantial improvements in the use of guideline-recommended therapies for HF in both the inpatient and outpatient settings. Conformity with HF quality measures has also been shown to improve and disparities in care have also been reduced or eliminated. There have also been improvements in clinical outcomes. This paper reviews the evidence that participation in HF performance improvement registries is associated with improved use of guideline-recommended HF therapies, better conformity with quality measures, and improved outcomes in patients with HF.


Deming T.J.,University of California at Los Angeles
Nature Materials | Year: 2010

Heating and cooling of peptide amphiphile suspensions converts disorganized nanofibers into liquid-crystalline nanofiber bundles that gel on addition of salts are discussed. The technique produces highly aligned nanofiber bundles that gel on addition of salts. A principal goal of regenerative medicine is the use of synthetic scaffolds to replace or repair damaged tissues. The addition of salts screens repulsions between like-charged nanofibers, allowing them to interact and also grow in length. The combination of benign cross linking and the formation of highly aligned gels in the presence of cells or molecules is a significant advance in the preparation of nanostructured scaffolds. Although there are many studies to be carried out before these gels are proved to be useful in humans, they offer many advantages for directed cell growth in vitro and for the formation of nanostructured filaments.


Borgman C.L.,University of California at Los Angeles
Journal of the American Society for Information Science and Technology | Year: 2012

We must all accept that science is data and that data are science, and thus provide for, and justify the need for the support of, much-improved data curation. (Hanson, Sugden, & Alberts,) Researchers are producing an unprecedented deluge of data by using new methods and instrumentation. Others may wish to mine these data for new discoveries and innovations. However, research data are not readily available as sharing is common in only a few fields such as astronomy and genomics. Data sharing practices in other fields vary widely. Moreover, research data take many forms, are handled in many ways, using many approaches, and often are difficult to interpret once removed from their initial context. Data sharing is thus a conundrum. Four rationales for sharing data are examined, drawing examples from the sciences, social sciences, and humanities: (1) to reproduce or to verify research, (2) to make results of publicly funded research available to the public, (3) to enable others to ask new questions of extant data, and (4) to advance the state of research and innovation. These rationales differ by the arguments for sharing, by beneficiaries, and by the motivations and incentives of the many stakeholders involved. The challenges are to understand which data might be shared, by whom, with whom, under what conditions, why, and to what effects. Answers will inform data policy and practice. © 2012 ASIS&T.


Cacioppo J.T.,University of Chicago | Cacioppo S.,University of Chicago | Capitanio J.P.,University of California at Davis | Cole S.W.,University of California at Los Angeles
Annual Review of Psychology | Year: 2015

Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter of a century. Although the focus of research has been on objective social roles and health behavior, the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others. Accordingly, population-based longitudinal research indicates that perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior. Human and animal investigations of neuroendocrine stress mechanisms that may be involved suggest that (a) chronic social isolation increases the activation of the hypothalamic pituitary adrenocortical axis, and (b) these effects are more dependent on the disruption of a social bond between a significant pair than objective isolation per se. The relational factors and neuroendocrine, neurobiological, and genetic mechanisms that may contribute to the association between perceived isolation and mortality are reviewed. © 2015 by Annual Reviews. All rights reserved.


Shi H.,University of California at Los Angeles
Nature Genetics | Year: 2016

Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ∼3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 new genes significantly associated with obesity-related traits (BMI, lipids and height). Many of these genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Mendez M.F.,University of California at Los Angeles
Archives of Medical Research | Year: 2012

Patients with Alzheimer's disease (AD), the most prevalent neurodegenerative dementia, are usually elderly; however, ∼4-5% develop early-onset AD (EOAD) with onset before age 65. Most EOAD is sporadic, but about 5% of patients with EOAD have an autosomal dominant mutation such as Presenilin 1, Presenilin 2, or alterations in the Amyloid Precursor Protein gene. Although most Alzheimer's research has concentrated on older, late-onset AD (LOAD), there is much recent interest and research in EOAD. These recent studies indicate that EOAD is a heterogeneous disorder with significant differences from LOAD. From 22-64% of EOAD patients have a predominant nonamnestic syndrome presenting with deficits in language, visuospatial abilities, praxis, or other non-memory cognition. These nonamnestic patients may differ in several ways from the usual memory or amnestic patients. Patients with nonamnestic EOAD compared to typical amnestic AD have a more aggressive course, lack the apolipoprotein E. e{open}4 (APOE e{open}4) susceptibility gene for AD, and have a focus and early involvement of non-hippocampal areas of brain, particularly parietal neocortex. These differences in the EOAD subtypes indicate differences in the underlying amyloid cascade, the prevailing pathophysiological theory for the development of AD. Together the results of recent studies suggest that nonamnestic subtypes of EOAD constitute a Type 2 AD distinct from the usual, typical disorder. In sum, the study of EOAD can reveal much about the clinical heterogeneity, predisposing factors, and neurobiology of this disease. © 2012 IMSS.


Fromer L.,University of California at Los Angeles
International Journal of COPD | Year: 2011

Current primary care patterns for chronic obstructive pulmonary disease (COPD) focus on reactive care for acute exacerbations, often neglecting ongoing COPD management to the detriment of patient experience and outcomes. Proactive diagnosis and ongoing multifactorial COPD management, comprising smoking cessation, influenza and pneumonia vaccinations, pulmonary rehabilitation, and symptomatic and maintenance pharmacotherapy according to severity, can significantly improve a patient's health-related quality of life, reduce exacerbations and their consequences, and alleviate the functional, utilization, and financial burden of COPD. Redesign of primary care according to principles of the chronic care model, which is implemented in the patient-centered medical home, can shift COPD management from acute rescue to proactive maintenance. The chronic care model and patient-centered medical home combine delivery system redesign, clinical information systems, decision support, and self-management support within a practice, linked with health care organization and community resources beyond the practice. COPD care programs implementing two or more chronic care model components effectively reduce emergency room and inpatient utilization. This review guides primary care practices in improving COPD care workflows, highlighting the contributions of multidisciplinary collaborative team care, care coordination, and patient engagement. Each primary care practice can devise a COPD care workflow addressing risk awareness, spirometric diagnosis, guideline-based treatment and rehabilitation, and self-management support, to improve patient outcomes in COPD. © 2011 Fromer, publisher and licensee Dove Medical Press Ltd.


MacDonald G.M.,University of California at Los Angeles
Journal of Experimental Biology | Year: 2010

The levels of CO2 in the atmosphere have already far exceeded values attained at any other time over at least the past 650,000 years. Temperature increases due to rising greenhouse gases will be amplified in Arctic and subarctic regions, and winter warming will be enhanced relative to summer warming. Climate in large areas of high latitudes may have no analogue in current climates or those of the recent geological past. Experimental field manipulations and laboratory studies indicate that plants will exhibit complex responses in photosynthesis, growth rates, phenology and reproductive functioning due to this combination of increasing temperatures, changing seasonality and increasing levels of CO2. The resulting changes in the abundance, distribution, growth rates and production of fruit and phenology of plant species will in turn impact animal populations. In predicting what the future biota of the 'New Arctic' will be like and developing appropriate conservation strategies, Grinnellian niche-based approaches are likely to be insufficient, and experimental ecological studies of organism response to specific anticipated changes in climate are crucial. © 2010, Published by The Company of Biologists Ltd.


LaCour M.J.,University of California at Los Angeles | Green D.P.,Columbia University
Science | Year: 2014

Can a single conversation change minds on divisive social issues, such as same-sex marriage? A randomized placebo-controlled trial assessed whether gay (n = 22) or straight (n = 19) messengers were effective at encouraging voters (n = 972) to support same-sex marriage and whether attitude change persisted and spread to others in voters' social networks. The results, measured by an unrelated panel survey, show that both gay and straight canvassers produced large effects initially, but only gay canvassers' effects persisted in 3-week, 6-week, and 9-month follow-ups.We also find strong evidence of within-household transmission of opinion change, but only in the wake of conversations with gay canvassers. Contact with gay canvassers further caused substantial change in the ratings of gay men and lesbians more generally. These large, persistent, and contagious effects were confirmed by a follow-up experiment. Contact with minorities coupled with discussion of issues pertinent to them is capable of producing a cascade of opinion change.


Regional Studies. Creativity is a concept whose time has come in economic and urban geography. It is also a concept that calls for enormous circumspection. An attempt is made to show that the interdependent processes of learning, creativity and innovation are situated within concrete fields of social relationships. Because much existing research on creative cities fails adequately to grasp this point, it tends to offer a flawed representation of urban dynamics and leads in many instances to essentially regressive policy advocacies. Cognitive-cultural capitalism is a more robust theoretical framework through which contemporary urbanization processes can be described. The framework of cognitive-cultural capitalism shapes the peculiar logic of learning, creativity and innovation that are observed in cities today but also has many wider and deeper impacts on urban outcomes. It has important policy implications so a critique of current policy stances derived from creative city ideas is also provided. © 2014 Regional Studies Association.


Smale S.T.,University of California at Los Angeles
Immunological Reviews | Year: 2012

A fundamental feature of the transcriptional response to an nuclear factor-κB (NF-κB)-inducing stimulus is that the response is highly selective and limited to the activation of only a subset of potential NF-κB target genes. One major contributor to selectivity of the response is likely to be the capacity of different NF-κB dimers to regulate different sets of target genes. The NF-κB family of transcription factors consists of five proteins, RelA, c-Rel, RelB, p50, and p52, which assemble into several homodimeric and heterodimeric species. Studies of mutant mouse strains have revealed that each family member, and perhaps each dimer, carries out unique functions in regulating transcription in cells of the immune system and in many other cell types. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins. Unique DNA-binding specificities and affinities make additional contributions to selectivity of the response, with growing evidence that some NF-κB dimers can adopt different conformations and thereby function differently when bound to different DNA sequences. Despite significant advances, our knowledge remains limited and many years of additional work will be needed to fully understand how the dimer-specific functions of NF-κB contribute to transcriptional selectivity. © 2012 John Wiley & Sons A/S.


Prins M.L.,University of California at Los Angeles
Epilepsy Research | Year: 2012

Cerebral metabolism of ketones is a normal part of the process of brain development. While the mature brain relies on glucose as a primary fuel source, metabolism of ketone bodies remains an alternative energy source under conditions of starvation. The neuroprotective properties of brain ketone metabolism make this alternative substrate a viable therapeutic option for various pathologies. Since the ability to revert to utilizing ketones as an alternative substrate is greatest in the younger post-weaned brain, this particular therapeutic approach remains an untapped resource particularly for pediatric pathological conditions. © 2011.


Ardell A.J.,University of California at Los Angeles
Acta Materialia | Year: 2013

Published data on the coarsening behavior of γ′ precipitates in three ternary Ni-Al-Cr alloys are examined in light of the theory of trans-interface-diffusion-controlled (TIDC) coarsening, in which the kinetics is controlled by diffusion through the coherent precipitate-matrix interface. The experimental data are independent of the equilibrium γ′ volume fraction, as expected for TIDC coarsening. Kinetics of the type 〈r〉n â̂'t for the growth of precipitates of average radius 〈r〉, and XAl and XCr â̂' t-1/n for the variations of the far-field matrix solute concentrations, XAl,Cr, with aging time, t, are characteristic of TIDC coarsening. The temporal exponent n ≈ 2.4 was obtained from the fitting of published particle size distributions. Based on correlation coefficients, the dependencies of 〈r〉n on t and X Al,Cr on t-1/n were comparable for n = 2.4 and n = 3 (the temporal exponent for matrix-diffusion-controlled coarsening). The dependencies of volume fraction, f, and number density, Nv, on t are also compared with theoretical predictions. Using a thermodynamic model of the Ni-Al-Cr phase diagram, the interfacial free energy, σ, was estimated from analysis of the data; σ varies from ∼14.5 to 19 mJ m-2 in the three alloys. Interfacial diffusion coefficients, also obtained from analysis of the data, are greater than those in the γ′ phase but smaller than those in the γ phase, which is consistent with the demands of the TIDC theory. Comparisons with the results from previously published work are noted and all discrepancies are discussed. © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.


Wright E.M.,University of California at Los Angeles
Molecular Aspects of Medicine | Year: 2013

There are three families of glucose transporters in the human genome, SLC2, SLC5 and SLC50. Here I review the structure and function of the SLC5 and SLC50 genes. The human sodium glucose cotransporter family (SLC5) has 12 human genes expressed in tissues ranging from epithelia to the central nervous system. The functions of all are known based on studies using heterologous expression systems: 10 are tightly coupled plasma membrane Na+/substrate cotransporters for solutes such as glucose, myoinositol, and anions; 1 is a Na+/Cl-/Choline cotransporter; and another is a glucose activated ion channel. The exon organization of most of the genes is similar in that they contain 14-15 exons. However, the choline transporter CHT is encoded in by the 8 exon SLC5A7 gene and the myoinositol SMIT transporter by the 1 exon SLC5A3 gene. Mutations in 3 SLC5 genes produce genetic phenotypes (glucose-galactose-malabsorption, renal glucosuria and hypothyroidism). Members of the SLC5 family are multifunctional membrane proteins in that they also behave as uniporters, urea and water channels, and urea and water cotransporters. The atomic structure of a closely related bacterial homolog has been solved and the structural core is common to six unrelated transporters, e.g. members of the SLC6 family of neurotransporters, and this leads to the conclusion that these work by a similar mechanism. The new SWEET class of glucose uniporters, SLC50, only has only one member in the human genome, SLC50A1. The SWEETs are found mostly in plants where they appear to be responsible for sugar efflux and are targeted by pathogens and symbionts for nutrition. © 2012 Elsevier Ltd. All rights reserved.


Kennedy R.D.,University of California at Los Angeles
Chemical Communications | Year: 2010

The reactions of triphenylphosphine with the azido-ortho-closo- dicarbadodecaboranes 1-N3-2-R-closo-1,2-C2B 10H10 [R = Me (1a), Ph (1b)] produce the stable and isolatable carboranyl phosphazides 1-(N3PPh3)-2-R-closo-1, 2-C2B10H10 [R = Me (2a), Ph (2b)] in good yields. Single crystal X-ray diffraction analysis revealed that, in the solid state, phosphazide 2a adopts an unusual s-cis conformation, whereas 2b adopts an s-trans conformation. © 2010 The Royal Society of Chemistry.


Grether G.F.,University of California at Los Angeles
Biological Journal of the Linnean Society | Year: 2014

Normal development depends on specific genetic and environmental inputs. When environments change, entire populations of organisms may simultaneously express maladaptive phenotypes. Selection in the new environment may gradually restore the ancestral phenotype by favouring alleles that counteract the environmental perturbation. This evolutionary process is called genetic compensation, and its effect on the fate of novel phenotypes is opposite to that of genetic assimilation. When genetic compensation occurs along a spatial environmental gradient, it results in the geographic pattern known as countergradient variation. Another place to look for genetic compensation is where human activities are causing environmental changes that affect how traits develop. For example, pollutants with endocrine-disrupting effects are altering the reproductive behaviour of natural populations of animals. If such pollutants persist long enough for genetic compensation to occur, the animals may come to depend on the presence of these chemicals for normal development. Taking genetic compensation into account could enhance our understanding of the role of behaviour in evolution in at least three ways: first, behavioural interactions are often the source of selection against environmentally induced phenotypes; second, behavioural traits themselves may often be targets of genetic compensation; and third, behavioural plasticity can delay or prevent genetic compensation. I present examples to illustrate each of these points, and further explore the ramifications of this understudied and underappreciated evolutionary process. © 2013 The Linnean Society of London.


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.


Charles-Schoeman C.,University of California at Los Angeles
Current Rheumatology Reports | Year: 2012

Patients with rheumatoid arthritis (RA) suffer significantly increased cardiovascular (CV) morbidity and mortality, when compared with the general population. Both traditional CV risk factors and high levels of systemic inflammation have been linked to the increased CV risk in RA patients, but significant uncertainty remains regarding the mechanisms through which these factors contribute to CV disease (CVD). In addition, ongoing questions remain regarding how best to identify RA patients at high risk for CVD and what primary and secondary prevention strategies are effective at influencing CVoutcome. The present review summarizes recent research in this field. © Springer Science+Business Media, LLC 2012.


Rice T.,University of California at Los Angeles
Health systems in transition | Year: 2013

This analysis of the United States health system reviews the developments in organization and governance, health financing, health-care provision, health reforms and health system performance. The US health system has both considerable strengths and notable weaknesses. It has a large and well-trained health workforce, a wide range of high-quality medical specialists as well as secondary and tertiary institutions, a robust health sector research program and, for selected services, among the best medical outcomes in the world. But it also suffers from incomplete coverage of its citizenry, health expenditure levels per person far exceeding all other countries, poor measures on many objective and subjective measures of quality and outcomes, an unequal distribution of resources and outcomes across the country and among different population groups, and lagging efforts to introduce health information technology. It is difficult to determine the extent to which deficiencies are health-system related, though it seems that at least some of the problems are a result of poor access to care. Because of the adoption of the Affordable Care Act in 2010, the United States is facing a period of enormous potential change. Improving coverage is a central aim, envisaged through subsidies for the uninsured to purchase private insurance, expanded eligibility for Medicaid (in some states) and greater protection for insured persons. Furthermore, primary care and public health receive increased funding, and quality and expenditures are addressed through a range of measures. Whether the ACA will indeed be effective in addressing the challenges identified above can only be determined over time. World Health Organization 2013 (acting as the host organization for, and secretariat of, the European Observatory on Health Systems and Policies).


Rosenthal T.,University of California at Los Angeles
Annual Review of Medicine | Year: 2012

Measurements of health care spending and outcomes in a geographic area and comparisons of one area to another have been used to make observations about health delivery systems and guide health care policy. Medicare claims files are a ready source of data about health care utilization and have served as the basis for a large number of studies in the United States. If ecologic studies are to accurately reflect local practices, potential variables must be accounted for. In the United States, differences in disease burden and socioeconomic factors are important variables affecting health care spending and outcomes. The assertion that regional variation in Medicare spending in the last two years of life is indicative of widespread waste in the U.S. health care system became a controversial part of the health care reform debate in 20092010. © 2012 by Annual Reviews. All rights reserved.


Smale S.T.,University of California at Los Angeles
Trends in Immunology | Year: 2014

Regulated changes in transcription play a central role in virtually all events that accompany the development of the immune system and its response to microbial and environmental cues. Over the past 30 years, a large number of proteins that regulate transcription in the immune system have been discovered and much has been learned about their mechanisms of action. However, the field remains in its infancy, with technical challenges and the complexity of gene regulation circuitry limiting our current knowledge and providing formidable barriers to further advancement. Despite these barriers, the development of new and increasingly sophisticated technologies is speeding progress towards an understanding of the gene-specific and global logic through which transcription is regulated in key immunological settings. © 2014 Elsevier Ltd.


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.


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.


Choi T.Y.,University of California at Los Angeles
Journal of cardiovascular computed tomography | Year: 2011

Medical radiation exposure is a major concern, and several methods have been proposed to reduce radiation doses in multidetector cardiac computed tomography (CT). The purpose of this study was to review radiation doses of clinical cardiac CT performed at our center and to evaluate the effect of radiation dose reduction strategies on the median dose delivered to patients over time. This study included 623 consecutive clinical patients (male, 58%) who were referred for imaging. The effective dose (mSv) was derived from the product of the dose-length-product (DLP) and a conversion coefficient for the chest (0.014). The median radiation dose of all patients was 3.0 mSv (interquartile range [IQR], 1.9-8.1 mSv). A significant difference was observed in radiation dose between the prospective (n = 384) and retrospective (n = 239) gating groups (2.0 vs 9.6 mSv; P < 0.0001). Compared with patients with coronary artery bypass grafting (CABG; n = 52), patients without CABG had significantly lower median radiation dose (prospective gating: 2.0 vs 3.4 mSv, P < 0.0001; retrospective gating: 9.3 vs 10.3 mSv, P < 0.0001). In patients with CABG, a significant difference was observed in radiation dose between prospective and retrospective gating (3.4 vs 10.3; P < 0.0001). The median radiation doses per month at our center decreased from 6.2 to 2.1 mSv over time with increasing use of prospective gating (≤91%). Radiation reduction techniques have led to progressive decreases in radiation exposure over time, primarily because of prospective gating. Copyright © 2011 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.


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.


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..


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.


Rigby D.L.,University of California at Los Angeles
Regional Studies | Year: 2013

Rigby D. L. Technological relatedness and knowledge space: entry and exit of US cities from patent classes, Regional Studies. US patent and citation data are used to measure technological relatedness between major patent classes in the United States Patent and Trademark Office (USPTO). The technological relatedness measures, constructed as the probability that a patent in class j will cite a patent in class i, form the links of a knowledge network. Changes in this knowledge network are examined from 1975 to 2005. Evolution of the patent knowledge base within US metropolitan areas is tracked by combining the knowledge network with annual patent data for each city. Entries and exits of cities from patent classes are linked to local and non-local measures of technological relatedness. © 2013 © 2013 Regional Studies Association.


Zuckerman B.,University of California at Los Angeles | Song I.,University of Georgia
Astrophysical Journal | Year: 2012

The gaseous molecular disk that orbits the main-sequence A-type star 49 Ceti has been known since 1995, but the stellar age and the origin of the observed carbon monoxide molecules have been unknown. We now identify 49 Ceti as a member of the 40Myr old Argus Association and present a colliding comet model to explain the high CO concentrations seen at 49 Ceti and the 30Myr old A-type star HD 21997. The model suggests that massive - 400 Earth mass - analogs of the Sun's Kuiper Belt are in orbit around some A-type stars, that these large masses are composed primarily of comet-like objects, and that these objects are rich in CO and perhaps also CO2. We identify additional early-type members of the Argus Association and the Tucana/Horologium and Columba Associations; some of these stars display excess mid-infrared emission as measured with the Widefield Infrared Survey Explorer. © 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.


Xu J.,University of California at Los Angeles | Nicholson B.J.,University of Texas Health Science Center at San Antonio
Biochimica et Biophysica Acta - Biomembranes | Year: 2013

Defects in several different connexins have been associated with several different diseases. The most common of these is deafness, where a few mutations in connexin (Cx) 26 have been found to contribute to over 50% of the incidence of non-syndromic deafness in different human populations. Other mutations in Cx26 or Cx30 have also been associated with various skin phenotypes linked to deafness (palmoplanta keratoderma, Bart-Pumphrey syndrome, Vohwinkel syndrome, keratitis-ichthyosis-deafness syndrome, etc.). The large array of disease mutants offers unique opportunities to gain insights into the underlying function of gap junction proteins and their channels in the normal and pathogenic physiologies of the cochlea and epidermis. This review focuses on those mutants where the impact on channel function has been assessed, and correlated with the disease phenotype, or organ function in knock-out mouse models. These approaches have provided evidence supporting a role of gap junctions and hemichannels in K+ removal and recycling in the ear, as well as possible roles for nutrient passage, in the cochlea. In contrast, increases in hemichannel opening leading to increased cell death, were associated with several keratitis-ichthyosis-deafness syndrome skin disease/hearing mutants. In addition to providing clues for therapeutic strategies, these findings allow us to better understand the specific functions of connexin channels that are important for normal tissue function. This article is part of a Special Issue entitled: The communicating junctions, roles and dysfunctions. © 2012 Elsevier B.V.


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.


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.


Goswami P.,Rice University | Chakravarty S.,University of California at Los Angeles
Physical Review Letters | Year: 2011

Four-component massive and massless Dirac fermions in the presence of long range Coulomb interaction and chemical potential disorder exhibit striking fermionic quantum criticality. For an odd number of flavors of Dirac fermions, the sign of the Dirac mass distinguishes the topological and the trivial band insulator phases, and the gapless semimetallic phase corresponds to the quantum critical point that separates the two. Up to a critical strength of disorder, the semimetallic phase remains stable, and the universality class of the direct phase transition between two insulating phases is unchanged. Beyond the critical strength of disorder the semimetallic phase undergoes a phase transition into a disorder controlled diffusive metallic phase, and there is no longer a direct phase transition between the two types of insulating phases. © 2011 American Physical Society.


Edelson R.,University of Maryland University College | Malkan M.,University of California at Los Angeles
Astrophysical Journal | Year: 2012

We have developed the ''S IX'' statistic to identify bright, highly likely active galactic nucleus (AGN) candidates solely on the basis of Wide-field Infrared Survey Explorer (WISE), Two Micron All-Sky Survey (2MASS), and ROSAT all-sky survey (RASS) data. This statistic was optimized with data from the preliminary WISE survey and the Sloan Digital Sky Survey, and tested with Lick 3 m Kast spectroscopy. We find that sources with S IX< 0 have a ≳95% likelihood of being an AGN (defined in this paper as a Seyfert 1, quasar, or blazar). This statistic was then applied to the full WISE/2MASS/RASS dataset, including the final WISE data release, to yield the ''W2R'' sample of 4316 sources with S IX< 0. Only 2209 of these sources are currently in the Veron-Cetty and Veron (VCV) catalog of spectroscopically confirmed AGNs, indicating that the W2R sample contains nearly 2000 new, relatively bright (J ≲ 16) AGNs. We utilize the W2R sample to quantify biases and incompleteness in the VCV catalog. We find that it is highly complete for bright (J< 14), northern AGNs, but the completeness drops below 50% for fainter, southern samples and for sources near the Galactic plane. This approach also led to the spectroscopic identification of 10 new AGNs in the Kepler field, more than doubling the number of AGNs being monitored by Kepler. The W2R sample contains better than 1 bright AGN every 10 deg2, permitting construction of AGN samples in any sufficiently large region of sky. © 2012. The American Astronomical Society. All rights reserved.


Martin G.M.,University of Washington | Martin G.M.,University of California at Los Angeles
FASEB Journal | Year: 2011

In this contribution to the series of reflective essays celebrating the 25th anniversary of The FASEB Journal, our task is to assess the growth of research on the biology of aging during this period and to suggest where we might be heading during the next 25 yr. A review of the literature suggests a healthy acceleration of progress during the past decade, perhaps largely due to progress on the genetics of longevity of model organisms. Progress on the genetics of health span in these model organisms has lagged, however. Research on the genetic basis of the remarkable interspecific variations in life span has only recently begun to be seriously addressed. The spectacular advances in genomics should greatly accelerate progress. Research on environmental effects on life span and health span needs to be accelerated. Stochastic variations in gene expression in aging have only recently been addressed. These can lead to random departures from homeostasis during aging. © FASEB.


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.


Yoshizawa J.M.,University of California at Los Angeles
Methods in molecular biology (Clifton, N.J.) | Year: 2013

MicroRNAs (miRNAs) in human saliva have recently become an emerging field in saliva research for -diagnostics applications and its potential role in biological implications. miRNAs are short noncoding RNA molecules that play important roles in regulating a variety of cellular processes. Dysregulation of miRNAs are known to be associated with many diseases. miRNAs were found present in the saliva of OSCC patients and could serve as potential biomarkers for oral cancer detection. Understanding the biological function of miRNAs in association with diseases is important towards utilizing miRNAs as diagnostic markers. There are currently a variety of profiling methods available for detecting miRNA expression levels. In this chapter, we overview the Applied Biosystem Stem-loop RT based Taqman MicroRNA Assay for salivary miRNA profiling. Using this highly sensitive and specific assay, miRNAs in saliva are profiled with only a few nanograms of starting RNA. This method is also applicable for studying biomarkers in other body fluids or clinical samples that contain small amounts of RNA.


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.


Engel J.,University of California at Los Angeles
Biomarkers in Medicine | Year: 2011

Epilepsy is the most common serious primary disease of the brain, accounting for 1% of the global burden of disease. Diagnosis and treatment suffer from a lack of reliable biomarkers for either epileptogenicity, the presence and severity of an epilepsy condition, or epileptogenesis, the development and progression of an epilepsy condition. The identification of reliable biomarkers would greatly facilitate differential diagnosis, eliminate the current trial-and-error approach to pharmacotherapy, facilitate presurgical evaluation, and greatly improve the cost-effectiveness of drug discovery and clinical trials of agents designed to treat, prevent and cure epilepsy. Identification of reliable biomarkers of epileptogenicity and epileptogenesis for research and clinical applications is a high-priority goal for the epilepsy community. Recent advances in electrophysiology, neuroimaging, molecular biology and genetics promise to reveal clinically useful biomarkers for epilepsy in the near future. © 2011 Future Medicine Ltd.


Pandya-Jones A.,University of California at Los Angeles
Wiley Interdisciplinary Reviews: RNA | Year: 2011

Splicing of RNA polymerase II transcripts is a crucial step in gene expression and a key generator of mRNA diversity. Splicing and transcription have generally been studied in isolation, although in vivo pre-mRNA splicing occurs in concert with transcription. The two processes appear to be functionally connected because a number of variables that regulate transcription have been identified as also influencing splicing. However, the mechanisms that couple the two processes are largely unknown. This review highlights the observations that implicate splicing as occurring during transcription and describes the evidence supporting functional interactions between the two processes. I discuss postulated models of how splicing couples to transcription and consider the potential impact that such coupling might have on exon recognition. © 2011 John Wiley & Sons, Ltd.


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.


Cole S.W.,University of California at Los Angeles
Psychoneuroendocrinology | Year: 2010

Functional genomics strategies have been slow to penetrate research on human stress and coping, but recent conceptual advances have yielded a raft of new findings relating social and psychological conditions to broad alterations in human gene expression. This article reviews the field of human stress genomics, analyzes some of the conceptual and technical issues that initially hampered its progress, and outlines an abstractionist approach to genomic data analysis that has revealed a surprisingly consistent pattern of human transcriptional responses to diverse types of socio-environmental adversity. This field is now poised for another round of significant advances as research begins to incorporate the effects of DNA polymorphism, target a broader array of healthy and diseased tissues, and identify general teleologic and regulatory themes by pooling results over a growing body of studies analyzing the human transcriptional response to stress. © 2010 Elsevier Ltd.


Enzmann D.R.,University of California at Los Angeles
Radiology | Year: 2012

A diagnostic radiology value chain is constructed to define its main components, all of which are vulnerable to change, because digitization has caused disaggregation of the chain. Some components afford opportunities to improve productivity, some add value, while some face outsourcing to lower labor cost and to information technology substitutes, raising commoditization risks. Digital image information, because it can be competitive at smaller economies of scale, allows faster, differential rates of technological innovation of components, initiating a centralization-to-decentralization technology trend. Digitization, having triggered disaggregation of radiology's professional service model, may soon usher in an information business model. This means moving from a mind-set of "reading images" to an orientation of creating and organizing information for greater accuracy, faster speed, and lower cost in medical decision making. Information businesses view value chain investments differently than do small professional services. In the former model, producing a better business product will extend image interpretation beyond a radiologist's personal fund of knowledge to encompass expanding external imaging databases. A follow-on expansion with integration of image and molecular information into a report will offer new value in medical decision making. Improved interpretation plus new integration will enrich and diversify radiology's key service products, the report and consultation. A more robust, information-rich report derived from a "systems" and "computational" radiology approach will be facilitated by a transition from a professional service to an information business. Under health care reform, radiology will transition its emphasis from volume to greater value. Radiology's future brightens with the adoption of a philosophy of offering information rather than "reads" for decision making. Staunchly defending the status quo via turf wars is unlikely to constitute a forward-looking, competitive strategy. © RSNA, 2012.


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).


Greenland S.,University of California at Los Angeles
Annals of Epidemiology | Year: 2012

This article summarizes arguments against the use of power to analyze data, and illustrates a key pitfall: Lack of statistical significance (e.g., p > .05) combined with high power (e.g., 90%) can occur even if the data support the alternative more than the null. This problem arises via selective choice of parameters at which power is calculated, but can also arise if one computes power at a prespecified alternative. As noted by earlier authors, power computed using sample estimates (" observed power" ) replaces this problem with even more counterintuitive behavior, because observed power effectively double counts the data and increases as the P value declines. Use of power to analyze and interpret data thus needs more extensive discouragement. © 2012 Elsevier Inc.


Goh C.,University of California at Los Angeles
The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research | Year: 2013

Peg-interferon alpha-2a and 2b and ribavirin have become the mainstays of chronic hepatitis C treatment. Although various cutaneous side effects have been reported, alopecia areata in its various forms have rare reports and has not been well categorized. Here we present a case of alopecia universalis occurring shortly after treatment for chronic hepatitis C, and we discuss some of the implications this has in understanding the pathophysiology of alopecia areata.


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.


Pastor W.A.,San Diego Institute for Allergy and Immunology | Pastor W.A.,University of California at Los Angeles | Aravind L.,U.S. National Institutes of Health | Rao A.,San Diego Institute for Allergy and Immunology
Nature Reviews Molecular Cell Biology | Year: 2013

In many organisms, the methylation of cytosine in DNA has a key role in silencing 'parasitic' DNA elements, regulating transcription and establishing cellular identity. The recent discovery that ten-eleven translocation (TET) proteins are 5-methylcytosine oxidases has provided several chemically plausible pathways for the reversal of DNA methylation, thus triggering a paradigm shift in our understanding of how changes in DNA methylation are coupled to cell differentiation, embryonic development and cancer. © 2013 Macmillan Publishers Limited. All rights reserved.


Cornwall J.M.,University of California at Los Angeles
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2016

We reexamine the d=3 dynamical gluon mass problem in pure-glue non-Abelian SU(N) gauge theories, paying particular attention to the observed (in Landau gauge) violation of positivity for the spectral function of the gluon propagator. This is expressed as a large bulge in the propagator at small momentum, due to the d=3 avatar of asymptotic freedom. Mass is defined through m-2=Δ(p=0), where Δ(p) is the scalar function for the gluon propagator in some chosen gauge; it is not a pole mass and is generally gauge dependent, except in the gauge-invariant pinch technique (PT). We truncate the PT equations with a recently proposed method called the vertex paradigm that automatically satisfies the QED-like Ward identity relating the three-gluon PT vertex function with the PT propagator. The mass is determined by a homogeneous Bethe-Salpeter equation involving this vertex and propagator. This gap equation also encapsulates the Bethe-Salpeter equation for the massless scalar excitations, essentially Nambu-Goldstone fields, that necessarily accompany gauge-invariant gluon mass. The problem is to find a good approximate value for m and at the same time explain the bulge, which by itself leads, in the gap equation for the gluon mass, to excessively large values for the mass. Our point is not to give a high-accuracy determination of m but to clarify the way in which the propagator bulge and a fairly accurate estimate of m can coexist, and we use various approximations that illustrate the underlying mechanisms. The most critical point is to satisfy the Ward identity. In the PT we estimate a gauge-invariant dynamical gluon mass of m≈Ng2/(2.48π). We translate these results to the Landau gauge using a background-quantum identity involving a dynamical quantity κ such that m=κmL, where mL-2≡ΔL(p=0). Given our estimates for m, κ, the relation is fortuitously well satisfied for SU(2) lattice data. © 2016 American Physical Society.


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.


Kraut J.A.,Medical and Research Services | Kraut J.A.,University of California at Los Angeles | Madias N.E.,St Elizabeths Medical Center | Madias N.E.,Tufts University
New England Journal of Medicine | Year: 2014

Lactic acidosis results from the accumulation of lactate and protons in the body fluids and is often associated with poor clinical outcomes. The effect of lactic acidosis is governed by its severity and the clinical context. Mortality is increased by a factor of nearly three when lactic acidosis accompanies low-flow states or sepsis,1 and the higher the lactate level, the worse the outcome.2 Although hyperlactatemia is often attributed to tissue hypoxia, it can result from other mechanisms. Control of the triggering conditions is the only effective means of treatment. However, advances in understanding its pathophysiological features and the factors causing cellular dysfunction in the condition could lead to new therapies. This overview of lactic acidosis emphasizes its pathophysiological aspects, as well as diagnosis and management. We confine our discussion to disorders associated with accumulation of the l optical isomer of lactate, which represent the vast majority of cases of lactic acidosis encountered clinically. Copyright © 2014 Massachusetts Medical Society.


Ganz D.A.,University of California at Los Angeles
The American journal of managed care | Year: 2010

To determine whether nurse practitioner (NP) comanagement can improve the quality of care for 5 chronic conditions in an academic geriatrics practice. STUDY DESIGN and From September 2006 to September 2007, 18 primary care geriatricians were divided into an intervention group that could refer patients to an NP for comanagement of dementia, depression, falls, heart failure, and/or urinary incontinence, or a control group that indicated which patients would have been referred to the NP for these conditions. The NP used structured visit notes to guide care delivery for the 5 conditions concordant with Assessing Care of Vulnerable Elders-3 (ACOVE-3) quality indicators. We reviewed charts to determine adherence to recommended processes of care. A total of 200 patients (108 intervention, 92 control) were eligible for at least 1 process of care recommended by ACOVE-3 for the 5 conditions. Patients' mean (SD) age was 85 years (7 years), 67% were women, and patients were eligible for a mean (SD) of 6.9 (4.4) processes of care. Intervention patients were eligible for more care processes than controls (7.8 vs 5.9 processes per patient; P = .002). Quality of care was higher for patients in the intervention group compared with the control group (54% vs 34% of care processes completed; P <.001). The adjusted absolute difference between intervention and control groups in care processes completed was 20% (95% confidence interval = 13%, 27%). NP comanagement of 5 chronic conditions was associated with higher quality of care, even in a practice of geriatricians.


Glassock R.J.,University of California at Los Angeles
Current Opinion in Nephrology and Hypertension | Year: 2012

PURPOSE OF REVIEW: The morphological features of membranous nephropathy have been recognized for over five decades, but the pathogenetic mechanisms underlying this lesion in humans have only recently been elucidated. This review analyzes the recent developments in understanding the pathogenesis of the primary and secondary forms of membranous nephropathy. RECENT FINDINGS: Seminal studies have identified several autologous antigens that are targets of an autoantibody response in primary membranous nephropathy. The leading candidate autoantigen is M-type phospholipase A2 receptor (PLA2R) protein. Autoantibodies to PLA2R, usually of IgG4 subclass, are found in 70-80% of patients with primary membranous nephropathy, bind to conformational epitopes on PLA2R expressed in the glomerular podocyte, form immune complexes in situ and induce proteinuria, mostly likely via local activation of complement. The autoimmune response is governed by genes at the HLA-DQA1 locus. The level of autoantibody to PLA2R correlates with the severity of the clinical disease and predicts recurrences in renal allografts (at least in some patients). Most forms of secondary membranous nephropathy appear to be due to distinctly different pathogenetic mechanisms. SUMMARY: The identification of target antigens provides new tools for diagnosis, prognosis and monitoring of therapy in human membranous nephropathy. © 2012 Lippincott Williams & Wilkins, Inc.


Bendiksen O.O.,University of California at Los Angeles
Progress in Aerospace Sciences | Year: 2011

Unsteady transonic flow theory is reviewed and classical results from the nonlinear asymptotic theory are combined with new results from computational fluid dynamics. The emphasis is on applications to the field of aeroelasticity and on clarifying the limitations of linearized theories in problems involving mixed subsonicsupersonic flows. The inherent differences between nonlinear transonic aerodynamics and linear subsonic and supersonic aerodynamics are considered from a theoretical and computational standpoint, and the practical implications of these differences in formulating suitable aerodynamic models for aeroelastic stability calculations are discussed. Transonic similarity principles are reviewed and their relevance in understanding flutter, divergence, and control reversal phenomena of transonic aircraft is illustrated through practical examples. © 2010 Elsevier Ltd. All rights reserved.


Harmon G.S.,University of California at Los Angeles | Lam M.T.,University of California at San Diego | Glass C.K.,University of California at San Diego
Chemical Reviews | Year: 2011

The Peroxisome proliferator-activated receptors (PPAR) subtype structural similarities contribute to the partial overlapping function of PPARs across different tissues. Resolution of the crystal structure of ligand-free (apo) or ligand-bound (holo) nuclear receptor LBDs with the associated coactivator fragments has provided the molecular details of ligand-induced transcriptional activation by nuclear receptors. The first step of nuclear receptor activation is initiated by ligand binding. The specificity of the LBD-ligand complex is largely based on hydrophobic interactions, hydrogen-bonding networks, and the steric size and shape of the binding pocket. PPARs are activated by fatty acids and naturally occurring fatty acid-derived molecules including eicosanoid and prostaglandin derivatives. Some evidence suggests that a portion of the anti-inflammatory effects of PPAR ligands may be mediated through coactivator competition.


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.


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.


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.


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.


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.


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.


Ghiani C.A.,University of California at Los Angeles
ASN neuro | Year: 2011

Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide)/kg to timed-pregnant rats at GD15 (gestational day 15) and GD16. Increased thickness of the CP (cortical plate) and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter), and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.


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.


Koos B.J.,University of California at Los Angeles
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011

Reduced mitochondrial oxidative phosphorylation, via activation of adenylate kinase and the resulting exponential rise in the cellular AMP/ATP ratio, appears to be a critical factor underlying O2 sensing in many chemoreceptive tissues in mammals. The elevated AMP/ATP ratio, in turn, activates key enzymes that are involved in physiologic adjustments that tend to balance ATP supply and demand. An example is the conversion of AMP to adenosine via 5'-nucleotidase and the resulting activation of adenosine A2A receptors, which are involved in acute oxygen sensing by both carotid bodies and the brain. In fetal sheep, A2A receptors associated with carotid bodies trigger hypoxic cardiovascular chemoreflexes, while central A2A receptors mediate hypoxic inhibition of breathing and rapid eye movements. A2A receptors are also involved in hypoxic regulation of fetal endocrine systems, metabolism, and vascular tone. In developing lambs, A2A receptors play virtually no role in O2 sensing by the carotid bodies, but brain A2A receptors remain critically involved in the roll-off ventilatory response to hypoxia. In adult mammals, A2A receptors have been implicated in O2 sensing by carotid glomus cells, while central A2A receptors likely blunt hypoxic hyperventilation. In conclusion, A2A receptors are crucially involved in the transduction mechanisms of O2 sensing in fetal carotid bodies and brains. Postnatally, central A2A receptors remain key mediators of hypoxic respiratory depression, but they are less critical for O2 sensing in carotid chemoreceptors, particularly in developing lambs. © 2011 the American Physiological Society.


Miklowitz D.J.,University of California at Los Angeles
Current Psychiatry Reports | Year: 2011

The longitudinal course of bipolar disorder (BD) is highly impairing. This article reviews recent research on functional impairment in the course of BD, the roles of social and intrafamilial stress in relapse and recovery, and the role of adjunctive psychosocial interventions in reducing risk and enhancing functioning. Comparative findings in adult and childhood BD are highlighted. Life events and family-expressed emotion have emerged as significant predictors of the course of BD. Studies of social information processing suggest that impairments in the recognition of facial emotions may characterize both adult- and earlyonset bipolar patients. Newly developed psychosocial interventions, particularly those that focus on family and social relationships, are associated with more rapid recovery from episodes and better psychosocial functioning. Familybased psychoeducational approaches are promising as early interventions for children with BD or children at risk of developing the disorder. For adults, interpersonal therapy, mindfulness-based strategies, and cognitive remediation may offer promise in enhancing functioning. © Springer Science+Business Media, LLC 2011.


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.


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.


Oconnor M.-F.,University of California at Los Angeles
Dialogues in Clinical Neuroscience | Year: 2012

Complicated grief (CG) is a disorder marked by intense and persistent yearning for the deceased, in addition to other criteria. The present article reviews what is known about the immunologic and neuroimaging biomarkers of both acute grief and CG. Attachment theory and cognitive stress theory are reviewed as they pertain to bereavement, as is the biopsychosocial model of CG. Reduced immune cell function has been replicated in a variety of bereaved populations. The regional brain activation to grief cues frequently includes the dorsal anterior cingulate cortex and insula, and also the posterior cingulate cortex. Using theory to point to future research directions, we may eventually learn which biomarkers are helpful in predicting CG, and its treatment. © 2012, LLS SAS.


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.


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.


Frohlich J.,University of California at Los Angeles | Van Horn J.D.,University of Southern California
Journal of Psychopharmacology | Year: 2014

The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia. © 2013 The Author(s).


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.


Bostean G.,University of California at Los Angeles
Journal of Immigrant and Minority Health | Year: 2013

Latino immigrants, particularly Mexican, have some health advantages over U.S.-born Mexicans and Whites. Because of their lower socioeconomic status, this phenomenon has been called the epidemiologic "Hispanic Paradox." While cultural theories have dominated explanations for the Paradox, the role of selective migration has been inadequately addressed. This study is among the few to combine Mexican and U.S. data to examine health selectivity in activity limitation, self-rated health, and chronic conditions among Mexican immigrants, ages 18 and over. Drawing on theories of selective migration, this study tested the "healthy migrant" and "salmon-bias" hypotheses by comparing the health of Mexican immigrants in the U.S. to non-migrants in Mexico, and to return migrants in Mexico. Results suggest that there are both healthy migrant and salmon-bias effects in activity limitation, but not other health aspects. In fact, consistent with prior research, immigrants are negatively selected on self-rated health. Future research should consider the complexities of migrants' health profiles and examine selection mechanisms alongside other factors such as acculturation. © 2012 Springer Science+Business Media, LLC.


Glynn S.M.,University of California at Los Angeles