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San Diego, CA, United States

The University of California, San Diego , is a public research university located in the La Jolla area of San Diego, California, in the United States. The university occupies 2,141 acres near the coast of the Pacific Ocean with the main campus resting on approximately 1,152 acres . Established in 1960 near the pre-existing Scripps Institution of Oceanography, UC San Diego is the seventh oldest of the 10 University of California campuses and offers over 200 undergraduate and graduate degree programs, enrolling about 22,700 undergraduate and 6,300 graduate students. UC San Diego is one of America's Public Ivy universities, which recognizes top public research universities in the United States. UC San Diego was ranked 8th among public universities and 37th among all universities in the United States, and rated the 18th Top World University by U.S. News & World Report 's 2015 rankings.UC San Diego is organized into six undergraduate residential colleges , three graduate schools ), and two professional medical schools UC San Diego is also home to Scripps Institution of Oceanography, one of the first centers dedicated to ocean, earth and atmospheric science research and education.The university operates 19 organized research units , including the Qualcomm Institute , San Diego Supercomputer Center and the Kavli Institute for Brain and Mind, as well as eight School of Medicine research units, six research centers at Scripps Institution of Oceanography and two multi-campus initiatives, including the Institute on Global Conflict and Cooperation.The UC San Diego Health System, the region’s only academic health system, provides patient care, conducts medical research and educates future health care professionals. It comprises UC San Diego Medical Center in Hillcrest, UC San Diego Thornton Hospital, Moores Cancer Center, Shiley Eye Center, Sulpizio Cardiovascular Center and Jacobs Medical Center as well as other primary and specialty practices of UC San Diego Medical Group. UC San Diego is also affiliated with several regional research centers, such as the Salk Institute, the Sanford-Burnham Medical Research Institute, the Sanford Consortium for Regenerative Medicine, and the Scripps Research Institute.UC San Diego faculty, researchers, and alumni have won twenty Nobel Prizes, eight National Medals of Science, eight MacArthur Fellowships, two Pulitzer Prizes, and two Fields Medals. Additionally, of the current faculty, 29 have been elected to the National Academy of Engineering, 95 to the National Academy of science, 45 to the Institute of Medicine and 106 to the American Academy of Arts and science. Wikipedia.


Lubarda V.A.,University of California at San Diego | Lubarda V.A.,Montenegrin Academy of science and Arts
International Journal of Plasticity | Year: 2011

Among all directions available for dislocation emission from the surface of a cylindrical circular void, the direction of the most likely emission is determined. It is shown that this direction is different from the direction of the maximum shear stress at the surface of the void due to the applied loading. The critical stress and the direction of the dislocation emission are determined for circular nanovoids under remote uniaxial, pure shear, and arbitrary biaxial loading. The analysis includes effects of the loading orientation relative to the discrete slip plane orientation. It is shown that dislocations are emitted more readily from larger nanovoids and that wider dislocations are emitted under lower applied stress than narrow dislocations. Different mechanisms, under much lower stress, operate for growth of the micron-size voids. © 2010 Elsevier Ltd. All rights reserved. Source


Constable C.G.,University of California at San Diego
Physics of the Earth and Planetary Interiors | Year: 2011

This review examines results from time-varying geomagnetic field models that span several thousand years, and from variations in dipole moment strength up to million year time scales. For the past 400 years, twin magnetic flux lobes bordering the inner core tangent cylinder in both northern and southern hemispheres dominate the geomagnetic field and appear more or less fixed in location. In contrast, the millennial scale view shows that such features are quite mobile and subject to morphological changes on time scales of a few centuries to a thousand years, possibly reflecting large scale reorganization of core flow. The lobes rarely venture into the Pacific hemisphere, and average fields over various time scales generally reveal two or three sets of lobes, of diminished amplitude. Thus millennial scale models are suggestive of thermal core-mantle coupling generating a weak bias in the average field rather than a strong inhibition of large scale field changes. The recovery of variations in dipole moment on million year time scales allows frequency domain analyses to search for characteristic time scales for core dynamics that might be associated with excursion and reversal rate, time taken for reversals, or any signs of control by Earth's orbital parameters. The spectrum is characteristically red for the time interval 0-160. Ma, suggesting non-stationarity associated with average reversal rate changes, probably reflecting the impact of superchrons and a continually evolving core. Distinct regimes of power law decay with frequency may reflect different physical processes contributing to the secular variation. Evidence for non-stationarity at shorter time-scales is also present in dipole moment variations over 0-2. Ma with average growth rate faster than the decay process. Rates of change of dipole moment and rapid local field variations found in the paleomagnetic record are evaluated in the context of the 400 year historical record and the spectrum of geomagnetic variations for 0-160. Ma. © 2011 Elsevier B.V. Source


Stegenga J.,University of California at San Diego
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2011

An astonishing volume and diversity of evidence is available for many hypotheses in the biomedical and social sciences. Some of this evidence-usually from randomized controlled trials (RCTs)-is amalgamated by meta-analysis. Despite the ongoing debate regarding whether or not RCTs are the 'gold-standard' of evidence, it is usually meta-analysis which is considered the best source of evidence: meta-analysis is thought by many to be the platinum standard of evidence. However, I argue that meta-analysis falls far short of that standard. Different meta-analyses of the same evidence can reach contradictory conclusions. Meta-analysis fails to provide objective grounds for intersubjective assessments of hypotheses because numerous decisions must be made when performing a meta-analysis which allow wide latitude for subjective idiosyncrasies to influence its outcome. I end by suggesting that an older tradition of evidence in medicine-the plurality of reasoning strategies appealed to by the epidemiologist Sir Bradford Hill-is a superior strategy for assessing a large volume and diversity of evidence. © 2011 Elsevier Ltd. Source


Xiong J.,University of California at San Diego
Current Gene Therapy | Year: 2014

The spalt (sal) family is a class of evolutionarily conserved genes originally identified in Drosophila as homeotic genes required for embryonic development. In vertebrates, the expression of sal-like 4 (SALL4) is specifically enriched in both embryonic and adult stem/stem-like cells. SALL4 is a master regulator that contributes to cell stemness in biological development and tumor growth. Thus, Sall4 has emerged as a target for gene therapy. In addition, numerous mutations affecting the Sall4 gene have been discovered and clinically linked to a series of congenital abnormalities, such as Duane/Duane-related syndromes, ventricular septal defect and premature ovarian failure. This review delineates the underlying mechanisms of key functions of SALL4 and its use as a target for gene therapy. Finally, I summarize and discuss advances made on the application of Sall4 and its functions in diagnostics and treatments for human diseases. © 2014 Bentham Science Publishers. Source


Vincent L.G.,University of California at San Diego | Engler A.J.,Sanford Consortium for Regenerative Medicine
Nature Materials | Year: 2013

Jason Burdick and colleagues have demonstrated that the differentiation of mesenchymal stem cells (MSCs) encapsulated in degradable, covalently crosslinked hyaluronic hydrogels is mediated by degradation-specific traction stresses. To make their gels degradable, the researchers first incorporated both methacrylate and maleimide functional groups onto the hyaluronic backbone, and used the reactions of the maleimide groups with the thiols on degradable peptides to form a primary gel. The gel could then be covalently crosslinked by radical polymerization of the methacrylate groups in the presence of both a photoinitiator and ultraviolet light. When using the degradable hydrogel, Burdick and co-authors found that local degradability was needed for entrapped cells to be able to rearrange their cytoskeletal structure and undergo osteogenesis. The findings from Burdick and colleagues support the notion that, unlike in two dimensions, in three dimensions matrix-driven cell tension drives cell fate irrespective of cell morphology and spread area. Source


Subramani S.,University of California at San Diego
Nature Cell Biology | Year: 2015

Protein ubiquitylation in mammals is known to trigger selective autophagy of peroxisomes through a process termed pexophagy. The physiological peroxisomal target for pexophagy-related ubiquitylation has been controversial, but two studies have now identified the protein PEX5 as the real candidate. © 2015 Macmillan Publishers Limited. Source


Etzold S.,University of California at San Diego | Juge N.,UK Institute of Food Research
Current Opinion in Structural Biology | Year: 2014

The mucosal layer covering our gut epithelium represents the first line of host defenses against the luminal content, while enabling contacts between the resident microbiota and the host. Mucus is mainly composed of mucins, large glycoproteins containing a protein core and a high number of O-linked oligosaccharides. Mucin glycans act as binding sites or carbon sources for the intestinal microbes, thereby functioning as a host-specific determinant affecting the microbiota composition and human health. Reflecting the structural diversity of mucin glycans and their prime location, commensal and pathogenic microbes have evolved a range of adhesins allowing their interaction with the host. However, despite the recognised importance of mucin glycans in modulating intestinal homeostasis, information on carbohydrate-binding proteins from gut bacteria is disparate. This review is focussed on recent structural insights into host-microbe interactions mediated by mucins. © 2014. Source


Nieh J.C.,University of California at San Diego
Current Biology | Year: 2010

Decision making in superorganisms such as honey bee colonies often uses self-organizing behaviors, feedback loops that allow the colony to gather information from multiple individuals and achieve reliable and agile solutions. Honey bees use positive feedback from the waggle dance to allocate colony foraging effort. However, the use of negative feedback signals by superorganisms is poorly understood. I show that conspecific attacks at a food source lead to the production of stop signals, communication that was known to reduce waggle dancing and recruitment but lacked a clear natural trigger. Signalers preferentially targeted nestmates visiting the same food source, on the basis of its odor. During aggressive food competition, attack victims increased signal production by 43 fold. Foragers that attacked competitors or experienced no aggression did not alter signal production. Biting ambush predators also attack foragers at flowers. Simulated biting of foragers or exposure to bee alarm pheromone also elicited signaling (88-fold and 14-fold increases, respectively). This provides the first clear evidence of a negative feedback signal elicited by foraging peril to counteract the positive feedback of the waggle dance. As in intra- and intercellular communication, negative feedback may play an important, though currently underappreciated, role in self-organizing behaviors within superorganisms. © 2010 Elsevier Ltd. All rights reserved. Source


Naviaux R.K.,University of California at San Diego
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed "oxidative shielding" response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics. Source


Wyles D.L.,University of California at San Diego
Journal of Infectious Diseases | Year: 2013

The addition of hepatitis C virus (HCV) protease inhibitors (PIs) to interferon and ribavirin therapy has significantly improved the efficacy of treatment for HCV infection. However, for patients who do not respond to therapy, the selection of HCV variants with resistance to PIs is likely. Resistant variants, such as R155K and A156T/V, result in extensive cross-resistance to other HCV PIs. Despite the rapid and frequent appearance of PI-resistant HCV variants, the long-term clinical implications are unknown. In particular, progress in the development of other HCV antivirals, such as NS5A inhibitors, next-generation NS3 protease inhibitors, and NS5B nucleoside and nonnucleoside inhibitors, has provided a broad selection of potent antivirals such that interferon-free therapy is a reality. Promising results from early stages of interferon-free trials will be reviewed. © 2013 The Author. Source


Ghosh P.,University of California at San Diego
Cell Cycle | Year: 2015

Environmental cues are transmitted to the interior of the cell via a complex network of signaling hubs. Receptor tyrosine kinases (RTKs) and trimeric G proteins are 2 such major signaling hubs in eukaryotes. Canonical signal transduction via trimeric G proteins is spatially and temporally restricted, i.e., triggered exclusively at the plasma membrane (PM) by agonist activation of G-protein-coupled receptors (GPCRs) via a process that completes within a few hundred milliseconds. Recently, a rapidly emerging paradigm has revealed a non-canonical pathway for activation of trimeric G proteins by the non-receptor GEF, GIV/Girdin, that has distinctive temporal and spatial features. Such activation can be triggered by multiple growth factor RTKs, can occur at the PM and on internal membranes discontinuous with the PM, and can continue for prolonged periods of time. The molecular mechanisms that govern such non-canonical G protein activation and the relevance of this new paradigm in health and disease is discussed. © 2015 Taylor & Francis Group, LLC. Source


Ovbiagele B.,University of California at San Diego
Journal of Stroke and Cerebrovascular Diseases | Year: 2013

A recent observational study of >20,000 patients with recent ischemic stroke suggested that systolic blood pressure (SBP) maintained in a low-normal range may be associated with increased risk of recurrent stroke, especially within the first 6 months after the first stroke. Using a distinct cohort, the current study aimed to independently evaluate the relationship between low-normal SBP levels and risk of recurrent stroke through analysis of a trial dataset involving 3680 patients with recent noncardioembolic ischemic stroke aged ≥35 years recruited from 56 centers between September 1996 and May 2003 and followed for 2 years. Subjects were categorized based on their mean in-trial SBP value as low-normal (<120 mm Hg), high-normal (120 to <140 mm Hg), or high (>140 mm Hg). The primary outcome was stroke. Multivariate analyses used competing-risks Cox regression models. The rate of recurrent stroke was 9.1% in the low-normal group, 6.7% in the high-normal group, and 10% in the high group. The difference in recurrent stroke rate between the low-normal and high-normal groups was more prominent within the first 6 months (low-normal, 4.5%; high-normal, 2.5%; high, 3.4%) than after 6 months (low-normal, 4.6%; high-normal, 4.2%; high, 6.6%). Over the study period, compared with the high-normal group, the risk of the primary outcome trended higher in the low-normal group (adjusted hazard ratio, 1.47; 95% confidence interval, 0.94-2.29; P =.09) and was higher in the high group (adjusted hazard ratio, 1.39; 95% confidence interval, 1.08-1.79; P =.01). These results support the recently described pattern of increased risk of recurrent stroke in patients with low-normal SBP levels, especially within the first 6 months after first stroke. However, this study likely was not sufficiently powered to detect more than a strong statistical trend underlying this relationship. © 2013 by National Stroke Association. Source


Creel S.C.,University of California at San Diego
Child Development | Year: 2012

A crucial part of language development is learning how various social and contextual language-external factors constrain an utterance's meaning. This learning process is poorly understood. Five experiments addressed one hundred thirty-one 3- to 5-year-old children's use of one such socially relevant information source: talker characteristics. Participants learned 2 characters' favorite colors; then, those characters asked participants to select colored shapes, as eye movements were tracked. Results suggest that by preschool, children use voice characteristics predictively to constrain a talker's domain of reference, visually fixating the talker's preferred color shapes. Indicating flexibility, children used talker information when the talker made a request for herself but not when she made a request for the other character. Children's ease at using voice characteristics and possible developmental changes are discussed. © 2012 The Author. Child Development © 2012 Society for Research in Child Development, Inc. Source


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. Source


Frank M.C.,Stanford University | Barner D.,University of California at San Diego
Journal of Experimental Psychology: General | Year: 2012

Mental abacus (MA) is a system for performing rapid and precise arithmetic by manipulating a mental representation of an abacus, a physical calculation device. Previous work has speculated that MA is based on visual imagery, suggesting that it might be a method of representing exact number nonlinguistically, but given the limitations on visual working memory, it is unknown how MA structures could be stored. We investigated the structure of the representations underlying MA in a group of children in India. Our results suggest that MA is represented in visual working memory by splitting the abacus into a series of columns, each of which is independently stored as a unit with its own detailed substructure. In addition, we show that the computations of practiced MA users (but not those of control participants) are relatively insensitive to verbal interference, consistent with the hypothesis that MA is a nonlinguistic format for exact numerical computation. © 2011 American Psychological Association. Source


Chao L.,University of California at San Diego
PLoS Genetics | Year: 2010

Deleterious mutations appearing in a population increase in frequency until stopped by natural selection. The ensuing equilibrium creates a stable frequency of deleterious mutations or the mutational load. Here I develop the comparable concept of a damage load, which is caused by harmful non-heritable changes to the phenotype. A damage load also ensues when the increase of damage is opposed by selection. The presence of a damage load favors the evolution of asymmetrical transmission of damage by a mother to her daughters. The asymmetry is beneficial because it increases fitness variance, but it also leads to aging or senescence. A mathematical model based on microbes reveals that a cell lineage dividing symmetrically is immortal if lifetime damage rates do not exceed a threshold. The evolution of asymmetry allows the lineage to persist above the threshold, but the lineage becomes mortal. In microbes with low genomic mutation rates, it is likely that the damage load is much greater than the mutational load. In metazoans with higher genomic mutation rates, the damage and the mutational load could be of the same magnitude. A fit of the model to experimental data shows that Escherichia coli cells experience a damage rate that is below the threshold and are immortal under the conditions examined. The model estimates the asymmetry level of E. coli to be low but sufficient for persisting at higher damage rates. The model also predicts that increasing asymmetry results in diminishing fitness returns, which may explain why the bacterium has not evolved higher asymmetry. © 2010 Lin Chao. Source


Jackson R.S.,Georgetown University | Chang D.C.,University of California at San Diego | Freischlag J.A.,Johns Hopkins Medical Institutions
JAMA - Journal of the American Medical Association | Year: 2012

Context: Endovascular repair of abdominal aortic aneurysm (AAA) compared with open repair increases perioperative survival, but it is not known if it increases longterm survival. Objective: To compare long-term outcomes after open vs endovascular repair of AAA. Design, Setting, and Patients: Retrospective analysis of patients 65 years or older in the Medicare Standard Analytic File, 2003-2007, who underwent isolated repair of intact AAA. Cause of death was determined from the National Death Index. Main Outcome Measures: The primary outcome was all-cause mortality. Secondary outcomes were AAA-related mortality, hospital length of stay, 1-year readmission, repeat AAA repair, incisional hernia repair, and lower extremity amputation. Results: Of 4529 included patients, 703 were classified as having undergone open repair and 3826 as having undergone endovascular repair. Mean and median follow-up times were 2.6 (SD, 1.5) and 2.5 (interquartile range, 2.4) years, respectively. In unadjusted analysis, both all-cause mortality (173 vs 752; 89 vs 76/1000 person-years, P=.04) and AAA-specific mortality (22 vs 28; 11.3 vs 2.8/1000 person-years, P<.001) were higher after open vs endovascular repair. After adjusting for emergency admission, age, calendar year, sex, race, and comorbidities, there was a higher risk of both all-cause mortality (hazard ratio [HR], 1.24 [95% CI, 1.05-1.47]; P=.01) and AAA-related mortality (HR, 4.37 [95% CI, 2.51-7.66]; P<.001) after open vs endovascular repair. The adjusted hospital length of stay was, on average, 6.5 days (95% CI, 6.0-7.0 days, P<.001) longer after open repair (mean, 10.4 days), compared with endovascular repair (mean, 3.6 days). Incidence of incisional hernia repair was higher after open AAA repair (19 vs 23; 12 vs 3 per 1000 person-years; adjusted HR, 4.45 [95% CI, 2.37-8.34, P<.001]), whereas the incidence of 1-year readmission (188 vs 1070; 274 vs 376/1000 person-years; adjusted HR, 0.96 [95% CI, 0.85-1.09, P=.52]), repeat AAA repair (15 vs 93; 9.7 vs 12.3/1000 person-years; adjusted HR, 0.80 [95% CI, 0.46-1.38, P=.42]), and lower extremity amputation (3 vs 25; 1.9 vs 3.3/1000 person-years; adjusted HR, 0.55 [95% CI, 0.16-1.86, P=.34]) did not differ by repair type. Conclusion: Among older patients with isolated intact AAA, use of open repair compared with endovascular repair was associated with increased risk of all-cause mortality and AAA-related mortality. ©2012 American Medical Association. All rights reserved. Source


Omilusik K.D.,University of California at San Diego
Current opinion in immunology | Year: 2013

Upon infection, CD8(+) T cells proliferate and differentiate into armed effector cells capable of eliminating the assaulting pathogen. Although the majority of the antigen-specific T cells will die as the immune response wanes, a few will survive indefinitely to establish the memory population and provide long-lived protection against reinfection. E protein transcription factors and their inhibitors, ID proteins, operate to balance expression of genes that control CD8(+) T cell differentiation through this process. Here, we discuss the role of ID2 and ID3 in promoting the generation and survival of effector and memory populations, particularly highlighting their reciprocal roles in shaping the CD8(+) T cell response unique to the inflammatory milieu. We further examine this coordinated control of gene expression in the context of additional transcription factors within the transcriptional network that programs CD8(+) effector and memory T cell differentiation. Copyright © 2013 Elsevier Ltd. All rights reserved. Source


Burgmann R.,University of California at Berkeley | Chadwell D.,University of California at San Diego
Annual Review of Earth and Planetary Sciences | Year: 2014

Seafloor geodetic techniques allow for measurements of crustal deformation over the ∼70% of Earth's surface that is inaccessible to the standard tools of tectonic geodesy. Precise underwater measurement of position, displacement, strain, and gravity poses technical, logistical, and cost challenges. Nonetheless, acoustic ranging; pressure sensors; underwater strain-, tilt- and gravimeters; and repeat multibeam sonar and seismic measurements are able to capture small-scale or regional deformation with approximately centimeter-level precision. Pioneering seafloor geodetic measurements offshore Japan, Cascadia, and Hawaii have substantially contributed to advances in our understanding of the motion and deformation of oceanic tectonic plates, earthquake cycle deformation in subduction zones, and the deformation of submarine volcanoes. Nontectonic deformation related to down-slope mass movement and underwater extraction of hydrocarbons or other resources represent other important targets. Recent technological advances promise further improvements in precision as well as the development of smaller, more autonomous, and less costly seafloor geodetic systems. © 2014 by Annual Reviews. All rights reserved. Source


Bradley J.S.,University of California at San Diego
Clinical Infectious Diseases | Year: 2010

Background. A need exists for new antimicrobial agents to treat neonates, infants, and children for hospitalacquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by nosocomial antibiotic-resistant pathogens. Current and clear guidance on approval of new agents for all pediatric age groups is lacking. Methods. Studies on HAP and VAP in the neonatal and pediatric age groups were collected using PubMed (National Library of Medicine). Published articles were reviewed for pediatric-specific definitions of HAP and VAP, diagnostic techniques, rates of disease, risk factors, characteristics, and outcomes. Results. Definitions of HAP and VAP in neonatal and pediatric age groups vary considerably. No well-studied, sensitive, and specific microbiologic testing techniques exist. Morbidity and mortality associated with VAP in neonates, infants, and children have been documented. Conclusions. Investigation and approval of new agents for HAP and VAP in all pediatric age groups is needed. A uniform definition of HAP and VAP is required that is relevant for clinical trials and balances the risks of experimental therapy and sampling procedures for study patients with potential benefits for both the patient under investigation and the hospitalized children who may develop nosocomial pneumonia. © 2010 by the Infectious Diseases Society of America. All rights reserved. Source


Broide D.H.,University of California at San Diego
Allergy and Asthma Proceedings | Year: 2010

The inflammatory response in the nasal mucosa in subjects with allergic rhinitis challenged intranasally with an allergen includes an immediate IgE-mediated mast cell response as well as a late-phase response characterized by recruitment of eosinophils, basophils, and T cells expressing Th2 cytokines including IL-4, a switch factor for IgE synthesis, and IL-5, an eosinophil growth factor. Recent advances have suggested that additional pathways may contribute to the pathophysiology of allergic rhinitis including local synthesis of IgE in the nasal mucosa, the epithelial expression of cytokines that regulate Th2 cytokine responses (i.e., thymic stromal lymphopoietin, IL-25, and IL-33), and the activation of histamine receptors other than H 1 and H 2 such as H 4-histamine receptors. This review focuses on briefly reviewing well-established pathways in the pathophysiology of allergic rhinitis and then updating knowledge on recent advances in the pathophysiology of allergic rhinitis. The review references information obtained from original articles published and available online on PubMed. In vitro and in vivo studies indicate that B cells in nasal mucosa can be induced to express IgE. Preclinical studies show an important role for epithelial-derived cytokines (thymic stromal lymphopoietin, IL-25, and IL-33) in regulating Th2 responses at mucosal surfaces, and for H 4-histamine receptors in mediating itching. In addition, regulatory T cells may play an important role in mediating active tolerance to allergens. An improved understanding of the pathophysiology of allergic rhinitis may provide important insight into novel therapeutic targets. Copyright © 2010, OceanSide Publications, Inc. Source


Taylor G.,Analog Devices Inc. | Galton I.,University of California at San Diego
IEEE Journal of Solid-State Circuits | Year: 2013

This paper presents a second-generation mostly-digital background- calibrated oversampling ADC based on voltage-controlled ring oscillators (VCROs). Its performance is in line with the best ΔΣ modulator ADCs published to date, but it occupies much less circuit area, is reconfigurable, and consists mainly of digital circuitry. Enhancements relative to the first-generation version include digitally background-calibrated open-loop V/I conversion in the VCRO to increase ADC bandwidth and enable operation from a single low-voltage power supply, quadrature coupled ring oscillators to reduce quantization noise, digital over-range correction to improve dynamic range and enable graceful overload behavior, and various circuit-level improvements. The ADC occupies 0.075 mm2 in a 65 nm CMOS process and operates from a single 0.9-1.2 V supply. Its sample-rate is tunable from 1.3 to 2.4 GHz over which the SNDR spans 70-75 dB, the bandwidth spans 5-37.5 MHz, and the minimum SNDR+ 10log(bandwidth/power dissipation) figure of merit (FOM) is 160 dB. © 1966-2012 IEEE. Source


Paulson A.S.,University of California at San Francisco | Tran Cao H.S.,The Surgical Center | Tempero M.A.,University of California at San Francisco | Lowy A.M.,University of California at San Diego
Gastroenterology | Year: 2013

Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5-10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of "borderline resectable pancreatic cancer" - a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future. © 2013 by the AGA Institute. Source


McCord G.C.,University of California at San Diego
European Physical Journal: Special Topics | Year: 2016

Understanding the costs that climate change will exact on society is crucial to devising an appropriate policy response. One of the channels through while climate change will affect human society is through vector-borne diseases whose epidemiology is conditioned by ambient ecology. This paper introduces the literature on malaria, its cost on society, and the consequences of climate change to the physics community in hopes of inspiring synergistic research in the area of climate change and health. It then demonstrates the use of one ecological indicator of malaria suitability to provide an order-of-magnitude assessment of how climate change might affect the malaria burden. The average of Global Circulation Model end-of-century predictions implies a 47% average increase in the basic reproduction number of the disease in today’s malarious areas, significantly complicating malaria elimination efforts. © 2016, EDP Sciences and Springer. Source


Zanetti M.,University of California at San Diego
Journal of Immunology | Year: 2015

Cellular immune responses that protect against tumors typically have been attributed to CD8 T cells. However, CD4 T cells also play a central role. It was shown recently that, in a patient with metastatic cholangiocarcinoma, CD4 T cells specific for a peptide from a mutated region of ERBB2IP could arrest tumor progression. This and other recent findings highlight new opportunities for CD4 T cells in cancer immunotherapy. In this article, I discuss the role and regulation of CD4 T cells in response to tumor Ags. Emphasis is placed on the types of Ags and mechanisms that elicit tumor-protective responses. I discuss the advantages and drawbacks of cancer immunotherapy through personalized genomics. These considerations should help to guide the design of next-generation therapeutic cancer vaccines. Copyright © 2015 by The American Association of Immunologists, Inc. Source


Wixted J.T.,University of California at San Diego | Mickes L.,Royal Holloway, University of London
Psychological Review | Year: 2014

The theoretical understanding of eyewitness identifications made from a police lineup has long been guided by the distinction between absolute and relative decision strategies. In addition, the accuracy of identifications associated with different eyewitness memory procedures has long been evaluated using measures like the diagnosticity ratio (the correct identification rate divided by the false identification rate). Framed in terms of signal-detection theory, both the absolute/relative distinction and the diagnosticity ratio are mainly relevant to response bias while remaining silent about the key issue of diagnostic accuracy, or discriminability (i.e., the ability to tell the difference between innocent and guilty suspects in a lineup). Here, we propose a signal-detection-based model of eyewitness identification, one that encourages the use of (and helps to conceptualize) receiver operating characteristic (ROC) analysis to measure discriminability. Recent ROC analyses indicate that the simultaneous presentation of faces in a lineup yields higher discriminability than the presentation of faces in isolation, and we propose a diagnostic feature-detection hypothesis to account for that result. According to this hypothesis, the simultaneous presentation of faces allows the eyewitness to appreciate that certain facial features (viz., those that are shared by everyone in the lineup) are non-diagnostic of guilt. To the extent that those non-diagnostic features are discounted in favor of potentially more diagnostic features, the ability to discriminate innocent from guilty suspects will be enhanced. © 2014 American Psychological Association. Source


Pershin Y.V.,University of South Carolina | Di Ventra M.,University of California at San Diego
Proceedings of the IEEE | Year: 2012

Memory effects are ubiquitous in nature and the class of memory circuit elementswhich includes memristive, memcapacitive, and meminductive systemsshows great potential to understand and simulate the associated physical processes. Here, we show that such elements can also be used in electronic schemes mimicking biologically inspired computer architectures, performing digital logic and arithmetic operations, and can expand the capabilities of certain quantum computation schemes. In particular, we will discuss some examples where the concept of memory elements is relevant to the realization of associative memory in neuronal circuits, spike-timing-dependent plasticity (STDP) of synapses, and digital and field-programmable quantum computing. © 1963-2012 IEEE. Source


Shearer P.,University of California at San Diego | Burgmann R.,University of California at Berkeley
Annual Review of Earth and Planetary Sciences | Year: 2010

The 2004 Sumatra-Andaman earthquake has been extensively studied because of its great size and devastating consequences. Large amounts of high-quality seismic, geodetic, and geologic data have led to a number of proposed models for its length, duration, fault geometry, rupture velocity, and slip history. The latest of these models vary in their details but now largely agree in their large-scale features, which include significant coseismic slip along the entire 1300-to 1500-km rupture, the bulk of which occurred fast enough to radiate seismic waves. The earthquake's enormous size has challenged conventional processing approaches and stimulated the development of new analysis and inversion methods, including multiple-source inversions, high-frequency body-wave imaging, and satellite observations of tsunami heights and gravity changes. The Sumatra megathrust earthquake was the largest in 40 years and is by far the best documented, but it does not seem fundamentally different in its properties from other large subduction-zone earthquakes. Copyright © 2010 by Annual Reviews. All rights reserved. Source


Dominguez G.,University of California at San Diego
Astrophysical Journal Letters | Year: 2010

The oldest solids formed in the solar system, calcium-aluminum inclusions, are 16O-enriched compared to chondrules, asteroids, Earth, and Mars. Based on the preliminary measurements of the solar wind by Genesis, the Sun also appears to be 16O-enriched. This distribution of oxygen isotopes in the solar system cannot be reconciled via conventional mass-dependent isotopic fractionation processes and instead require the existence and/or production of distinct 16O-enriched and 16O-depleted reservoirs in the early solar system. The origin of these distinct reservoirs is unknown, although several mechanisms have been proposed to date including the following: (1) the injection of pure 16O by a supernova into the protoplanetary disk or parent molecular cloud, (2) self-shielding of CO in the parent molecular cloud or protoplanetary disk, (3) symmetry-dependent chemical fractionation processes in the protoplanetary disk, and (4) Galactic chemical evolution. While some of these proposals have been ruled out, the validity of others is still open. Here I propose that the 16O-enriched and 16O-depleted reservoirs present in the early solar system originated in the parent molecular cloud via the heterogeneous chemical processes that form H2O, a significant oxygen reservoir, on the surface of interstellar (IS) dust grains in dense molecular clouds, the astrophysical setting where star formation is observed to occur. As a consequence, this model predicts that molecular cloud H2O and possibly other IS solids inherited from the molecular cloud were depleted in 16O compared to the bulk gas-phase O present, thus providing distinct 16O reservoirs at the earliest stages of planetary formation. © 2010. The American Astronomical Society. All rights reserved. Source


Paulus M.P.,University of California at San Diego
Depression and Anxiety | Year: 2013

Cognitive and affective processing has been the central focus of brain-related functions in psychology and psychiatry for many years. Much less attention has been paid to what could be considered the primary function of the brain, to regulate the function of the body. Recent developments, which include the conceptualization of interoception as a process consisting of integrating the information coming from the inside of the body in the central nervous system and the appreciation that complex emotional processes are fundamentally affected by the processing and regulation of somatic states, have profoundly changed the view of the function and dysfunction of the brain. This review focuses on the relationship between breathing and anxiety. Several anxiety disorders have been associated with altered breathing, perception of breathing, and response to manipulations of breathing. Both clinical and experimental research studies are reviewed that relate breathing dysfunctions to anxiety. Altered breathing may be useful as a physiological marker of anxiety as well as a treatment target using interoceptive interventions. © 2013 Wiley Periodicals, Inc. Source


Chhablani J.,University of California at San Diego
Investigative ophthalmology & visual science | Year: 2012

To evaluate the repeatability and reproducibility of manual choroidal volume (CV) measurements by spectral domain- optical coherence tomography (SD-OCT) using enhanced depth imaging (EDI). Sixty eyes of 32 patients with or without any ocular chorioretinal diseases were enrolled prospectively. Thirty-one choroidal scans were performed on each eye, centered at the fovea, using a raster protocol. Two masked observers demarcated choroidal boundaries by using built-in automated retinal segmentation software on two separate sessions. Observers were masked to each other's and their own previous readings. A standardized grid centered on the fovea was positioned automatically by OCT software, and values for average CVs and total CVs in three concentric rings were noted. The agreement between the intraobserver measurements or interobserver measurements was assessed using the concordance correlation coefficient (CCC). Bland-Altman plots were used to assess the clinically relevant magnitude of differences between inter- and intraobserver measurements. The interobserver CCC for the overall average CV was very high, 0.9956 (95% confidence interval [CI], 0.991-0.9968). CCCs for all three Early Treatment Diabetic Retinopathy Study concentric rings between two graders was 0.98 to 0.99 (95% CI, 0.97-0.98). Similarly intraobserver repeatability of two graders also ranged from 0.98 to 0.99. The interobserver coefficient of reproducibility was approximately 0.42 (95% CI, 0.34-0.5 mm(3)) for the average CV. CV measurement by manual segmentation using built-in automated retinal segmentation software on EDI-SD-OCT is highly reproducible and repeatable and has a very small range of variability. Source


Schmid-Schonbein G.W.,University of California at San Diego
Current Hypertension Reports | Year: 2012

One of the major challenges for hypertension research is to identify the mechanisms that cause the comorbidities encountered in many hypertensive patients, as seen in the metabolic syndrome. An emerging body of evidence suggests that human and experimental hypertensives may exhibit uncontrolled activity of proteinases, including the family of matrix metalloproteinases, recognized for their ability to restructure the extracellular matrix proteins and to play a role in hypertrophy. We propose a new hypothesis that provides a molecular framework for the comorbidities of hypertension, diabetes, capillary rarefaction, immune suppression, and other cell and organ dysfunctions due to early and uncontrolled extracellular receptor cleavage by active proteinases. The proteinase and signaling activity in hypertensives requires further detailed analysis of the proteinase expression, the mechanisms causing proenzyme activation, and identification of the proteinase substrate. This work may open the opportunity for reassessment of old interventions and development of new interventions to manage hypertension and its comorbidities. © 2011 Springer Science+Business Media, LLC. Source


Anstis S.,University of California at San Diego
Journal of Vision | Year: 2013

It is known that adaptation to a disk that flickers between black and white at 3-8 Hz on a gray surround renders invisible a congruent gray test disk viewed afterwards. This is contrast adaptation. We now report that adapting simply to the flickering circular outline of the disk can have the same effect. We call this "contour adaptation." This adaptation does not transfer interocularly, and apparently applies only to luminance, not color. One can adapt selectively to only some of the contours in a display, making only these contours temporarily invisible. For instance, a plaid comprises a vertical grating superimposed on a horizontal grating. If one first adapts to appropriate flickering vertical lines, the vertical components of the plaid disappears and it looks like a horizontal grating. Also, we simulated a Cornsweet (1970) edge, and we selectively adapted out the subjective and objective contours of a Kanisza (1976) subjective square. By temporarily removing edges, contour adaptation offers a new technique to study the role of visual edges, and it demonstrates how brightness information is concentrated in edges and propagates from them as it fills in surfaces. © 2013 ARVO. Source


Willert K.,University of California at San Diego | Nusse R.,Howard Hughes Medical Institute
Cold Spring Harbor Perspectives in Biology | Year: 2012

Wnt proteins comprise a major family of signaling molecules that orchestrate and influence a myriad of cell biological and developmental processes. Although our understanding of the role of Wnt signaling in regulating development and affecting disease, such as cancer, has been ever increasing, the study of the Wnt proteins themselves has been painstaking and slow moving. Despite advances in the biochemical characterization of Wnt proteins, many mysteries remain unsolved. In contrast to other developmental signaling molecules, such as fibroblast growth factors (FGF), transforming growth factors (TGFβ), and Sonic hedgehog (Shh), Wnt proteins have not conformed to many standard methods of protein production, such as bacterial overexpression, and analysis, such as ligand-receptor binding assays. The reasons for their recalcitrant nature are likely a consequence of the complex set of posttranslational modifications involving several highly specialized and poorly characterized processing enzymes. With the recent description of the first Wnt protein structure, the time is ripe to uncover and possibly resolve many of the remaining issues surrounding Wnt proteins and their interactions. Here we describe the process of maturation of Wnt from its initial translation to its eventual release from a cell and interactions in the extracellular environment. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Holland L.Z.,University of California at San Diego
Journal of Experimental Zoology Part B: Molecular and Developmental Evolution | Year: 2015

Morphological comparisons among extant animals have long been used to infer their long-extinct ancestors for which the fossil record is poor or non-existent. For evolution of the vertebrates, the comparison has typically involved amphioxus and vertebrates. Both groups are evolving relatively slowly, and their genomes share a high level of synteny. Both vertebrates and amphioxus have regulative development in which cell fates become fixed only gradually during embryogenesis. Thus, their development fits a modified hourglass model in which constraints are greatest at the phylotypic stage (i.e., the late neurula/early larva), but are somewhat greater on earlier development than on later development. In contrast, the third group of chordates, the tunicates, which are sister group to vertebrates, are evolving rapidly. Constraints on evolution of tunicate genomes are relaxed, and they have discarded key developmental genes and organized much of their coding sequences into operons, which are transcribed as a single mRNA that undergoes trans-splicing. This contrasts with vertebrates and amphioxus, whose genomes are not organized into operons. Concomitantly, tunicates have switched to determinant development with very early fixation of cell fates. Thus, tunicate development more closely fits a progressive divergence model (shaped more like a wine glass than an hourglass) in which the constraints on the zygote and very early development are greatest. This model can help explain why tunicate body plans are so very diverse. The relaxed constraints on development after early cleavage stages are correlated with relaxed constraints on genome evolution. The question remains: which came first? © 2014 Wiley Periodicals, Inc. Source


Feist A.M.,Gt Life Sciences, Inc. | Palsson B.O.,University of California at San Diego
Current Opinion in Microbiology | Year: 2010

Flux balance analysis (FBA) is a mathematical approach for analyzing the flow of metabolites through a metabolic network. To computationally predict cell growth using FBA, one has to determine the biomass objective function that describes the rate at which all of the biomass precursors are made in the correct proportions. Here we review fundamental issues associated with its formulation and use to compute optimal growth states. © 2010 Elsevier Ltd. All rights reserved. Source


Seyfarth S.,University of California at San Diego
Cognition | Year: 2014

Language-users reduce words in predictable contexts. Previous research indicates that reduction may be stored in lexical representation if a word is often reduced. Because representation influences production regardless of context, production should be biased by how often each word has been reduced in the speaker's prior experience. This study investigates whether speakers have a context-independent bias to reduce low-informativity words, which are usually predictable and therefore usually reduced. Content word durations were extracted from the Buckeye and Switchboard speech corpora, and analyzed for probabilistic reduction effects using a language model based on spontaneous speech in the Fisher corpus. The analysis supported the hypothesis: low-informativity words have shorter durations, even when the effects of local contextual predictability, frequency, speech rate, and several other variables are controlled for. Additional models that compared word types against only other words of the same segmental length further supported this conclusion. Words that usually appear in predictable contexts are reduced in all contexts, even those in which they are unpredictable. The result supports representational models in which reduction is stored, and where sufficiently frequent reduction biases later production. The finding provides new evidence that probabilistic reduction interacts with lexical representation. © 2014 Elsevier B.V. Source


Ellrott K.,University of California at San Diego
PLoS computational biology | Year: 2010

The microbes that inhabit particular environments must be able to perform molecular functions that provide them with a competitive advantage to thrive in those environments. As most molecular functions are performed by proteins and are conserved between related proteins, we can expect that organisms successful in a given environmental niche would contain protein families that are specific for functions that are important in that environment. For instance, the human gut is rich in polysaccharides from the diet or secreted by the host, and is dominated by Bacteroides, whose genomes contain highly expanded repertoire of protein families involved in carbohydrate metabolism. To identify other protein families that are specific to this environment, we investigated the distribution of protein families in the currently available human gut genomic and metagenomic data. Using an automated procedure, we identified a group of protein families strongly overrepresented in the human gut. These not only include many families described previously but also, interestingly, a large group of previously unrecognized protein families, which suggests that we still have much to discover about this environment. The identification and analysis of these families could provide us with new information about an environment critical to our health and well being. Source


Geddis A.E.,University of California at San Diego
Seminars in Hematology | Year: 2010

The process of megakaryopoiesis and platelet production is complex, with the potential for regulation at multiple stages. Megakaryocytes are derived from the hematopoietic stem cell through successive lineage commitment steps, and they undergo a unique maturation process that includes polyploidization, development of an extensive internal demarcation membrane system, and finally formation of pro-platelet processes. Platelets are shed from these processes into vascular sinusoids within the bone marrow. Megakaryocyte differentiation is regulated both positively and negatively by transcription factors and cytokine signaling. Thrombopoietin (TPO) is the most important hematopoietic cytokine for platelet production. Clinically, acquired and inherited mutations affecting megakaryocytic transcription factors and thrombopoietin signaling have been identified in disorders of thrombocytopenia and thrombocytosis. © 2010 Elsevier Inc. Source


Mak R.H.,University of California at San Diego
Pediatric Nephrology | Year: 2010

Both vitamin D deficiency and vitamin D toxicity are associated with cardiovascular complications in chronic kidney disease (CKD). Clinical and experiment data indicate that the association of vitamin D levels with cardiovascular disease is best illustrated as a biphasic, or U-shaped, curve. Children and adolescents with CKD need vitamin D due to the demands of a growing skeleton, to prevent renal rickets. However, this therapy carries the risk of severe side effects and chronic toxicity. Observational studies show that vitamin D deficiency and toxicity are frequently present in patients with CKD. In view of the importance of cardiovascular complications for the long-term survival of young patients, these findings demand a judicious use of vitamin D preparations. In clinical practice, the therapeutic window is rather small, presenting a therapeutic challenge to avoid both vitamin D deficiency and toxicity. © 2010 IPNA. Source


Murphy T.W.,University of California at San Diego
Reports on Progress in Physics | Year: 2013

Lunar laser ranging has provided many of the best tests of gravitation since the first Apollo astronauts landed on the Moon. The march to higher precision continues to this day, now entering the millimeter regime, and promising continued improvement in scientific results. This review introduces key aspects of the technique, details the motivations, observables, and results for a variety of science objectives, summarizes the current state of the art, highlights new developments in the field, describes the modeling challenges, and looks to the future of the enterprise. © 2013 IOP Publishing Ltd. Source


Wagner P.D.,University of California at San Diego
European Respiratory Journal | Year: 2015

The field of pulmonary gas exchange is mature, with the basic principles developed more than 60 years ago. Arterial blood gas measurements (tensions and concentrations of O2 and CO2) constitute a mainstay of clinical care to assess the degree of pulmonary gas exchange abnormality. However, the factors that dictate arterial blood gas values are often multifactorial and complex, with six different causes of hypoxaemia (inspiratory hypoxia, hypoventilation, ventilation/perfusion inequality, diffusion limitation, shunting and reduced mixed venous oxygenation) contributing variably to the arterial O2 and CO2 tension in any given patient. Blood gas values are then usually further affected by the body's abilities to compensate for gas exchange disturbances by three tactics (greater O2 extraction, increasing ventilation and increasing cardiac output). This article explains the basic principles of gas exchange in health, mechanisms of altered gas exchange in disease, how the body compensates for abnormal gas exchange, and based on these principles, the tools available to interpret blood gas data and, quantitatively, to best understand the physiological state of each patient. This understanding is important because therapeutic intervention to improve abnormal gas exchange in any given patient needs to be based on the particular physiological mechanisms affecting gas exchange in that patient. Source


Holland N.D.,University of California at San Diego
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Older evolutionary scenarios for the origin of vertebrates often gave nervous systems top billing in accordance with the notion that a big-brained Homo sapiens crowned a tree of life shaped mainly by progressive evolution. Now, however, tree thinking positions all extant organisms equidistant from the tree’s root, and molecular phylogenies indicate that regressive evolution is more common than previously suspected. Even so, contemporary theories of vertebrate origin still focus on the nervous system because of its functional importance, its richness in characters for comparative biology, and its central position in the two currently prominent scenarios for the invertebrate-tovertebrate transition, which grew out of the markedly neurocentric annelid and enteropneust theories of the nineteenth century. Both these scenarios compare phyla with diverse overall body plans. This diversity, exacerbated by the scarcity of relevant fossil data, makes it challenging to establish plausible homologies between component parts (e.g. nervous system regions). In addition, our current understanding of the relation between genotype and phenotype is too preliminary to permit us to convert gene network data into structural features in any simpleway. These issues are discussed here with special reference to the evolution of nervous systems during proposed transitions from invertebrates to vertebrates. © 2015 The Author(s) Published by the Royal Society. All rights reserved. Source


Rudnick D.L.,University of California at San Diego
Annual Review of Marine Science | Year: 2016

Underwater gliders are autonomous underwater vehicles that profile vertically by changing their buoyancy and use wings to move horizontally. Gliders are useful for sustained observation at relatively fine horizontal scales, especially to connect the coastal and open ocean. In this review, research topics are grouped by time and length scales. Large-scale topics addressed include the eastern and western boundary currents and the regional effects of climate variability. The accessibility of horizontal length scales of order 1 km allows investigation of mesoscale and submesoscale features such as fronts and eddies. Because the submesoscales dominate vertical fluxes in the ocean, gliders have found application in studies of biogeochemical processes. At the finest scales, gliders have been used to measure internal waves and turbulent dissipation. The review summarizes gliders' achievements to date and assesses their future in ocean observation. © 2016 by Annual Reviews. All rights reserved. Source


Han S.K.,University of California at San Diego
Science signaling | Year: 2011

The skin is the largest sensory organ of the body. It is innervated by a diverse array of primary sensory neurons, including a heterogeneous subset of unmyelinated afferents called C fibers. C fibers, sometimes classified as nociceptors, can detect various painful stimuli, including temperature extremes. However, it is increasingly evident that these afferents respond to various pruritic stimuli and transmit information to the brain that is perceived as itch; this can subsequently drive scratching behavior. Although itch and pain are distinct sensations, they are closely related and can, under certain circumstances, antagonize each other. However, it is not clear precisely when, where, and how the processes generating these two sensations originate and how they are dissociated. Clues have come from the analysis of the activities of specific ligands and their receptors. New data indicate that specific pruritic ligands carrying both itch and pain information are selectively recognized by different G protein-coupled receptors (GPCRs), and this information may be transduced through different intracellular circuits in the same neuron. These findings raise questions about the intracellular mechanisms that preprocess and perhaps encode GPCR-mediated signals. Source


Saltiel A.R.,University of California at San Diego
Science Translational Medicine | Year: 2016

This review discusses current and future pharmacological approaches to the treatment of obesity, with a focus on the biological control of energy balance. Source


Bejar R.,University of California at San Diego
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2013

Establishing the prognosis for patients with myelodysplastic syndromes (MDS) is a key element of their care. It helps patients understand the severity of their disease and set expectations for their future. For physicians, an accurate estimate of prognosis drives decisions about the timing and choice of therapeutic options to consider. The International Prognostic Scoring System (IPSS) has been the standard tool for MDS risk stratification since it was released in 1997. It has been used to describe patients in pivotal clinical trials and is a key element of practice guidelines. Subsequent changes to the classification scheme for MDS and an underestimation of risk in some patients from the low and intermediate-1 categories have led to the development of several newer prognostic models. The most recent is the revised IPSS (IPSS-R), which addresses several of the perceived deficiencies of its predecessor. Despite their utility, none of the available prognostic systems incorporates disease-related molecular abnormalities such as somatic mutations. These lesions are present in the nearly all cases and many have been shown to improve upon existing prognostic models. However, the interpretation of somatic mutations can be challenging and it is not yet clear how best to combine them with clinical predictors of outcome. Here I review several prognostic scoring systems developed after the IPSS and describe the emerging use of molecular markers to refine risk stratification in the MDS patient population. Source


Rossier B.C.,University of Lausanne | Baker M.E.,University of California at San Diego | Studer R.A.,University College London
Physiological Reviews | Year: 2015

Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na+-K+-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin-aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na+-K+-ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases. © 2015 the American Physiological Society. Source


Wagner P.D.,University of California at San Diego
European Journal of Applied Physiology | Year: 2012

Exercise is the example par excellence of the body functioning as a physiological system. Conventionally we think of the O 2 transport process as a major manifestation of that system linking and integrating pulmonary, cardiovascular, hematological and skeletal muscular contributions to the task of getting O 2 from the air to the mitochondria, and this process has been well described. However, exercise invokes system responses at levels additional to those of macroscopic O 2 transport. One such set of responses appears to center on muscle intracellular PO 2, which falls dramatically from rest to exercise. At rest, it approximates 4 kPa, but during heavy endurance exercise it falls to about 0.4-0.5 kPa, an amazingly low value for a tissue absolutely dependent on the continual supply of O 2 to meet very high energy demands. One wonders why intracellular PO 2 is allowed to fall to such levels. The proposed answer, to be presented in the review, is that a low intramyocyte PO 2 is pivotal in: (a) optimizing oxygen's own physiological transport, and (b) stimulating adaptive gene expression that, after translation, enables greater exercise capacity-all the while maintaining PO 2 at levels sufficient to allow oxidative phosphorylation to operate sufficiently fast enough to support intense muscle contraction. Thus, during exercise, reductions of intracellular PO 2 to less than 1% of that in the atmosphere enables an integrated response that fundamentally and simultaneously optimizes physiological, biochemical and molecular events that support not only the exercise as it happens but the adaptive changes to increase exercise capacity over the longer term. © 2011 Springer-Verlag. Source


Graham R.,Monterey Bay Aquarium Research Institute | Cortes J.,University of California at San Diego
IEEE Transactions on Automatic Control | Year: 2012

This work deals with trajectory optimization for a robotic sensor network sampling a spatio-temporal random field. We examine the optimal sampling problem of minimizing the maximum predictive variance of the estimator over the space of network trajectories. This is a high-dimensional, multi-modal, nonsmooth optimization problem, known to be NP-hard even for static fields and discrete design spaces. Under an asymptotic regime of near-independence between distinct sample locations, we show that the solutions to a novel generalized disk-covering problem are solutions to the optimal sampling problem. This result effectively transforms the search for the optimal trajectories into a geometric optimization problem. Constrained versions of the latter are also of interest as they can accommodate trajectories that satisfy a maximum velocity restriction on the robots. We characterize the solution for the unconstrained and constrained versions of the geometric optimization problem as generalized multicircumcenter trajectories, and provide algorithms which enable the network to find them in a distributed fashion. Several simulations illustrate our results. © 2011 IEEE. Source


Cortes J.,University of California at San Diego
Systems and Control Letters | Year: 2012

This paper studies an optimal deployment problem for a network of robotic sensors moving in the real line. Given a spatial process of interest, each individual sensor sends a packet that contains a measurement of the process to a data fusion center. We assume that, due to communication limitations or hardware unreliability, only a fraction of the packets arrive at the center. Using convex analysis, nonsmooth analysis, and combinatorics, we show that, for various fractional rates of packet arrival, the optimal deployment configuration has the following features: agents group into clusters, clusters deploy optimally as if at least one packet from each cluster was guaranteed to reach the center, and there is an optimal cluster size for each fractional arrival rate. © 2011 Elsevier B.V. All rights reserved. Source


Vattani A.,University of California at San Diego
Discrete and Computational Geometry | Year: 2011

The k-means algorithm is a well-known method for partitioning n points that lie in the d-dimensional space into k clusters. Its main features are simplicity and speed in practice. Theoretically, however, the best known upper bound on its running time (i.e., nO(kd)) is, in general, exponential in the number of points (when kd=Ω(n/log n)). Recently Arthur and Vassilvitskii (Proceedings of the 22nd Annual Symposium on Computational Geometry, pp. 144-153, 2006) showed a super-polynomial worst-case analysis, improving the best known lower bound from Ω(n) to 2Ω(√n) with a construction in d=Ω(√n) dimensions. In Arthur and Vassilvitskii (Proceedings of the 22nd Annual Symposium on Computational Geometry, pp. 144-153, 2006), they also conjectured the existence of super-polynomial lower bounds for any d≥2. Our contribution is twofold: we prove this conjecture and we improve the lower bound, by presenting a simple construction in the plane that leads to the exponential lower bound 2Ω(n). © 2011 The Author(s). Source


Mizuno-Yamasaki E.,Gunma University | Rivera-Molina F.,Yale University | Novick P.,University of California at San Diego
Annual Review of Biochemistry | Year: 2012

Members of the Rab or ARFSar branches of the Ras GTPase superfamily regulate almost every step of intracellular membrane traffic. A rapidly growing body of evidence indicates that these GTPases do not act as lone agents but are networked to one another through a variety of mechanisms to coordinate the individual events of one stage of transport and to link together the different stages of an entire transport pathway. These mechanisms include guanine nucleotide exchange factor (GEF) cascades, GTPase-activating protein (GAP) cascades, effectors that bind to multiple GTPases, and positive-feedback loops generated by exchange factor-effector interactions. Together these mechanisms can lead to an ordered series of transitions from one GTPase to the next. As each GTPase recruits a unique set of effectors, these transitions help to define changes in the functionality of the membrane compartments with which they are associated. © 2012 by Annual Reviews. All rights reserved. Source


Dasgupta S.,University of California at San Diego
Theoretical Computer Science | Year: 2011

An active learner has a collection of data points, each with a label that is initially hidden but can be obtained at some cost. Without spending too much, it wishes to find a classifier that will accurately map points to labels. There are two common intuitions about how this learning process should be organized: (i) by choosing query points that shrink the space of candidate classifiers as rapidly as possible; and (ii) by exploiting natural clusters in the (unlabeled) data set. Recent research has yielded learning algorithms for both paradigms that are efficient, work with generic hypothesis classes, and have rigorously characterized labeling requirements. Here we survey these advances by focusing on two representative algorithms and discussing their mathematical properties and empirical performance. © 2010 Elsevier B.V. All rights reserved. Source


de Lecea L.,Stanford University | Huerta R.,University of California at San Diego
Frontiers in Pharmacology | Year: 2014

The hypocretin (Hcrt), also known as orexin, peptides are essential for arousal stability. Here we discuss background information about the interaction of Hcrt with other neuromodulators, including norepinephrine and acetylcholine probed with optogenetics. We conclude that Hcrt neurons integrate metabolic, circadian and limbic inputs and convey this information to a network of neuromodulators, each of which has a different role on the dynamic of sleep-to-wake transitions. This model may prove useful to predict the effects of orexin receptor antagonists in sleep disorders and other conditions. © 2014 de Lecea and Huerta. Source


Stahl S.M.,University of California at San Diego
CNS spectrums | Year: 2013

Guidelines for treating various conditions can be helpful in setting practice standards, but the presence of several sets of guidelines from different countries, experts, and settings, written at different times, can also create confusion. Here we provide a "guideline of guidelines" for the treatment of schizophrenia, or "meta-guidelines, which not only reconcile the various existing standards but also update them to include the use of several newer agents, most of which were marketed following the publication of existing standards. Source


Karin M.,University of California at San Diego | Clevers H.,Princess Maxima Center and Hubrecht Institute | Clevers H.,University Utrecht
Nature | Year: 2016

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies. © 2016 Macmillan Publishers Limited. All rights reserved. Source


Kristan W.B.,University of California at San Diego
Cell | Year: 2015

While some behavioral responses to a stimulus are invariant in animals, most are more likely to be variable or stochastic. In this issue, Gordus et al. illuminate a set of combinatorial neuronal activities that control the variability of a chemotactic behavior in response to an odor, providing a tractable system for understanding how stochastic circuit dynamics affect behavior. © 2015 Elsevier Inc. Source


Admani S.,University of California at San Diego
Current allergy and asthma reports | Year: 2014

Allergic contact dermatitis (ACD) is a type IV delayed hypersensitivity reaction. During the last decade, there has been a heightened awareness of this disease in the pediatric population. The gold standard for diagnosis is patch testing. The prevalence of positive patch tests in referred children with suspected ACD ranges from 27 to 95.6 %. The most common allergens in children in North America are nickel, neomycin, cobalt, fragrance, Myroxylon pereirae, gold, formaldehyde, lanolin/wool alcohols, thimerosal, and potassium dichromate. The relationship between ACD and atopic dermatitis (AD) is complicated with conflicting reports of prevalence in the literature; however, in a patient with dermatitis not responding to traditional therapies, or with new areas of involvement, ACD should be considered as part of the work-up. Source


Hoffman R.M.,University of California at San Diego
Cancer Discovery | Year: 2012

The effects of bacteria on patients with cancer have been observed for at least two centuries. Recent studies in animal models of cancer have shown effi cacy of both anaerobic bacteria such as Clostridia and Bifi dobacteria and facultative anaerobes such as Salmonella. In this issue of Cancer Discovery, Flentie and colleagues have identifi ed fi ve Salmonella promoters that are specifi cally stimulated by cancer cells as well as by acidic pH, a property of most tumors. One of these promoters (STM1787) was linked to a Shiga toxin gene and inserted in a wild-type Salmonella typhimurium strain, which showed in vivo antitumor effi cacy. Approaches to further improving the effi cacy of S. typhimurium with the use of tumor-targeting mutations are discussed. Because the barriers to effi cacy of standard therapy of cancer appear to be opportunities for bacterial cancer therapy, the future of bacterial therapy of cancer appears bright. © 2012 American Association for Cancer Research. Source


Baker M.E.,University of California at San Diego
FEBS Letters | Year: 2010

A key regulator of glucocorticoid action is 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD1), which catalyzes the conversion of cortisone to cortisol, the biologically active glucocorticoid. 11β-HSD1 is a paralog of 11β-HSD3, whose physiological function remains unclear. As reported here, 11β-HSD3 has orthologs in sea urchin, amphioxus and Ciona, while 11β-HSD1 first appears in sharks. Thus, 11β-HSD3 arose before the evolution of glucocorticoid signaling, suggesting different ancestral function(s) for 11β-HSD3. Four perplexing findings arise from this evolutionary analysis: (1) 11β-HSD1 is not present in a ray-finned fish genome, (2) zebrafish and fathead minnow contain two isoforms of 11β-HSD3; (3) neither rat nor mouse contain 11β-HSD3 and (4) amphioxus contains 16 11β-HSD3 paralogs. © 2010 Federation of European Biochemical Societies. Source


Buxton R.B.,University of California at San Diego
Reports on Progress in Physics | Year: 2013

Functional magnetic resonance imaging (fMRI) is a methodology for detecting dynamic patterns of activity in the working human brain. Although the initial discoveries that led to fMRI are only about 20 years old, this new field has revolutionized the study of brain function. The ability to detect changes in brain activity has a biophysical basis in the magnetic properties of deoxyhemoglobin, and a physiological basis in the way blood flow increases more than oxygen metabolism when local neural activity increases. These effects translate to a subtle increase in the local magnetic resonance signal, the blood oxygenation level dependent (BOLD) effect, when neural activity increases. With current techniques, this pattern of activation can be measured with resolution approaching 1 mm3 spatially and 1 s temporally. This review focuses on the physical basis of the BOLD effect, the imaging methods used to measure it, the possible origins of the physiological effects that produce a mismatch of blood flow and oxygen metabolism during neural activation, and the mathematical models that have been developed to understand the measured signals. An overarching theme is the growing field of quantitative fMRI, in which other MRI methods are combined with BOLD methods and analyzed within a theoretical modeling framework to derive quantitative estimates of oxygen metabolism and other physiological variables. That goal is the current challenge for fMRI: to move fMRI from a mapping tool to a quantitative probe of brain physiology. © 2013 IOP Publishing Ltd. Source


MacLeod D.T.,University of California at San Diego
Nature communications | Year: 2013

Herpes simplex virus type 1 is an important epithelial pathogen and has the potential for significant morbidity in humans. Here we demonstrate that a cell surface scavenger receptor, macrophage receptor with collagenous structure (MARCO), previously thought to enhance antiviral defense by enabling nucleic acid recognition, is usurped by herpes simplex virus type 1 and functions together with heparan sulphate proteoglycans to mediate adsorption to epithelial cells. Ligands of MARCO dramatically inhibit herpes simplex virus type 1 adsorption and infection of human keratinocytes and protect mice against infection. Herpes simplex virus type 1 glycoprotein C closely co-localizes with MARCO at the cell surface, and glycoprotein C binds directly to purified MARCO with high affinity. Increasing MARCO expression enhances herpes simplex virus type 1 infection while MARCO(-/-) mice have reduced susceptibility to infection by herpes simplex virus type 1. These findings demonstrate that herpes simplex virus type 1 binds to MARCO to enhance its capacity for disease, and suggests a new therapeutic target to alter pathogenicity of herpes simplex virus type 1 in skin infection. Source


Tong P.K.,University of California at San Diego
Health Economics | Year: 2011

This article investigates how a change in minimum nurse staffing regulation for California skilled nursing facilities (SNFs) affects nurse employment and how induced changes in nurse staffing affect patient mortality. In 2000, legislation increased the minimum nurse staffing standard and altered the calculation of nurse staffing, which created incentives to shift employment to lower skilled nurse labor. SNFs constrained by the new regulation increase absolute and relative hours worked by the lowest skilled type of nurse. Using this regulation change to instrument for measured nurse staffing levels, it is determined that increases in nurse staffing reduce on-site SNF patient mortality. Copyright © 2010 John Wiley & Sons, Ltd. Source


Sandborn W.J.,University of California at San Diego | Ghosh S.,University of Calgary | Panes J.,Institute dInvestigacions Biomediques August Pi i Sunyer | Vranic I.,Pfizer | Rousell S.,Pfizer
New England Journal of Medicine | Year: 2012

Background: Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation. Methods: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1. Results: The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.39), 3 mg (P = 0.55), 10 mg (P = 0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.76), 3 mg (P = 0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500. Conclusions: Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.) Copyright © 2012 Massachusetts Medical Society. Source


Rifkin D.E.,University of California at San Diego | Coca S.G.,Yale University | Kalantar-Zadeh K.,University of California at Los Angeles
Journal of the American Society of Nephrology | Year: 2012

Acute kidney injury (AKI) has been implicated as an independent risk factor for the development of CKD in recent observational studies. The presumption in the nephrology community is that this association represents a causal relationship. However, because of potential problems related to residual confounding (shared risk factors), ascertainment bias (sicker patients have more follow-up assessments), misclassification of exposure (problems with defining baseline kidney function and AKI representing a discrete event versus progression of renal disease), and misclassification of outcome (de novo CKD versus CKD progression), it is difficult to conclude with certainty that AKI is truly causal for CKD. In this review we highlight several of the Hill causality criteria to examine the existing evidence and point out the missing elements that preclude defining AKI as a cause of CKD in the general population.Only well-designed studies with rigorous assessment of kidney function in all participants (AKI and non-AKI) before and after the episode or hospitalization or randomized, controlled trials demonstrating that prevention or treatment of AKI reduces the incidence of subsequent CKD can clarify the causal nature of the AKI-CKD relationship. Copyright © 2012 by the American Society of Nephrology. Source


Helble T.A.,University of California at San Diego
The Journal of the Acoustical Society of America | Year: 2012

Conventional detection of humpback vocalizations is often based on frequency summation of band-limited spectrograms under the assumption that energy (square of the Fourier amplitude) is the appropriate metric. Power-law detectors allow for a higher power of the Fourier amplitude, appropriate when the signal occupies a limited but unknown subset of these frequencies. Shipping noise is non-stationary and colored and problematic for many marine mammal detection algorithms. Modifications to the standard power-law form are introduced to minimize the effects of this noise. These same modifications also allow for a fixed detection threshold, applicable to broadly varying ocean acoustic environments. The detection algorithm is general enough to detect all types of humpback vocalizations. Tests presented in this paper show this algorithm matches human detection performance with an acceptably small probability of false alarms (P(FA) < 6%) for even the noisiest environments. The detector outperforms energy detection techniques, providing a probability of detection P(D) = 95% for P(FA) < 5% for three acoustic deployments, compared to P(FA) > 40% for two energy-based techniques. The generalized power-law detector also can be used for basic parameter estimation and can be adapted for other types of transient sounds. Source


Medeiros F.A.,University of California at San Diego
Investigative ophthalmology & visual science | Year: 2012

To present and evaluate a new method of integrating risk factors into the analysis of rates of visual field progression in glaucoma. The study included 352 eyes of 250 glaucoma patients followed up for an average of 8.1 ± 3.5 years. Slopes of change over time were evaluated by the mean deviation (MD) from standard automated perimetry. For each eye, the follow-up time was divided into two equal periods: the first half was used to obtain the slopes of change and the second period was used to test the predictions. Slopes of change were calculated with two methods: the conventional approach of ordinary least squares (OLS) linear regression and a Bayesian regression model incorporating information on risk factors and presence of progressive optic disc damage on stereophotographs. The mean square error (MSE) of the predictions was used to compare the predictive performance of the different methods. Higher mean IOP, thinner central corneal thickness (CCT), and presence of progressive optic disc damage were associated with faster rates of MD change. Incorporation of risk factor information into the calculation of individual slopes of MD change with the Bayesian method resulted in better prediction of future MD values than with the OLS method (MSE: 4.31 vs. 8.03, respectively; P < 0.001). A Bayesian regression model incorporating structural and risk factor information into the estimation of glaucomatous visual field progression resulted in more accurate and precise estimates of slopes of functional change than the conventional method of OLS regression. (ClinicalTrials.gov number, NCT00221897.). Source


Sweeney S.E.,University of California at San Diego
Arthritis and rheumatism | Year: 2012

Innate immune responses activate synoviocytes and recruit inflammatory cells into the rheumatoid joint. Type I interferons (IFNs) play a role in autoimmunity, and IFN gene transcription is activated by IFN-regulatory factors (IRFs) in response to innate sensor recognition. The purpose of this study was to examine the effect of genetic deficiency of IRF-7 in a passive K/BxN serum-transfer model of arthritis. Passive-transfer arthritis was induced in IRF-7(-/-) mice, and additional groups were treated with IFNβ or poly(I-C). Clinical arthritis scoring, histologic assessment, micro-computed tomography, and synovial tissue quantitative polymerase chain reaction analysis were performed. Mouse serum was analyzed by enzyme-linked immunosorbent assay (ELISA). In the passive K/BxN serum-transfer model, arthritis severity was significantly increased in IRF-7(-/-) mice compared with wild-type (WT) mice. In addition, expression of IFNβ in synovium and serum was decreased, potentially contributing to increased arthritis. IRF-7(-/-) mice injected with replacement IFNβ had a decrease in arthritis. Poly(I-C) treatment diminished arthritis in IRF-7(-/-) mice, restored synovial IFNβ gene expression, and increased serum levels of IFNβ. In vitro studies demonstrated that poly(I-C) stimulation of fibroblast-like synoviocytes (FLS) from IRF-7(-/-) mice resulted in increased induction of proinflammatory gene expression as compared with FLS from WT mice; however, IFNβ expression was not significantly different. In contrast, peritoneal macrophages from IRF-7(-/-) mice showed significantly less induction of IFNβ in response to poly(I-C) stimulation. IRF-7 deficiency exacerbates arthritis and replacement treatment with IFNβ or poly(I-C) decreases arthritis severity. Both macrophage- and synoviocyte-specific roles of IRF-7 likely contribute to the increased arthritis. IRF-7 might play an antiinflammatory role in passive-transfer arthritis through regulation of macrophage IFNβ production. Copyright © 2012 by the American College of Rheumatology. Source


Ferreiro D.U.,Protein Physiology Laboratory | Komives E.A.,University of California at San Diego | Wolynes P.G.,Rice University
Quarterly Reviews of Biophysics | Year: 2014

Biomolecules are the prime information processing elements of living matter. Most of these inanimate systems are polymers that compute their own structures and dynamics using as input seemingly random character strings of their sequence, following which they coalesce and perform integrated cellular functions. In large computational systems with finite interaction-codes, the appearance of conflicting goals is inevitable. Simple conflicting forces can lead to quite complex structures and behaviors, leading to the concept of frustration in condensed matter. We present here some basic ideas about frustration in biomolecules and how the frustration concept leads to a better appreciation of many aspects of the architecture of biomolecules, and especially how biomolecular structure connects to function by means of localized frustration. These ideas are simultaneously both seductively simple and perilously subtle to grasp completely. The energy landscape theory of protein folding provides a framework for quantifying frustration in large systems and has been implemented at many levels of description. We first review the notion of frustration from the areas of abstract logic and its uses in simple condensed matter systems. We discuss then how the frustration concept applies specifically to heteropolymers, testing folding landscape theory in computer simulations of protein models and in experimentally accessible systems. Studying the aspects of frustration averaged over many proteins provides ways to infer energy functions useful for reliable structure prediction. We discuss how frustration affects folding mechanisms. We review here how the biological functions of proteins are related to subtle local physical frustration effects and how frustration influences the appearance of metastable states, the nature of binding processes, catalysis and allosteric transitions. In this review, we also emphasize that frustration, far from being always a bad thing, is an essential feature of biomolecules that allows dynamics to be harnessed for function. In this way, we hope to illustrate how Frustration is a fundamental concept in molecular biology. Copyright © 2014 Cambridge University Press. Source


Gomez-Varela D.,University of California at San Diego
The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2012

Local control of calcium concentration within neurons is critical for signaling and regulation of synaptic communication in neural circuits. How local control can be achieved in the absence of physical compartmentalization is poorly understood. Challenging examples are provided by nicotinic acetylcholine receptors that contain α7 nicotinic receptor subunits (α7-nAChRs). These receptors are highly permeable to calcium and are concentrated on aspiny dendrites of interneurons, which lack obvious physical compartments for constraining calcium diffusion. Using functional proteomics on rat brain, we show that α7-nAChRs are associated with plasma membrane calcium-ATPase pump isoform 2 (PMCA2). Analysis of α7-nAChR function in hippocampal interneurons in culture shows that PMCA2 activity limits the duration of calcium elevations produced by the receptors. Unexpectedly, PMCA2 inhibition triggers rapid calcium-dependent loss of α7-nAChR clusters. This extreme regulatory response is mediated by CaMKII, involves proteasome activity, depends on the second intracellular loop of α7-nAChR subunits, and is specific in that it does not alter two other classes of calcium-permeable ionotropic receptors on the same neurons. A critical link is provided by the scaffold protein PSD-95 (postsynaptic density-95), which is associated with α7-nAChRs and constrains their mobility as revealed by single-particle tracking on neurons. The PSD-95 link is required for PMCA2-mediated removal of α7-nAChR clusters. This three-component combination of PMCA2, PSD-95, and α7-nAChR offers a novel mechanism for tight control of calcium dynamics in neurons. Source


Thode A.M.,University of California at San Diego
The Journal of the Acoustical Society of America | Year: 2012

An automated procedure has been developed for detecting and localizing frequency-modulated bowhead whale sounds in the presence of seismic airgun surveys. The procedure was applied to four years of data, collected from over 30 directional autonomous recording packages deployed over a 280 km span of continental shelf in the Alaskan Beaufort Sea. The procedure has six sequential stages that begin by extracting 25-element feature vectors from spectrograms of potential call candidates. Two cascaded neural networks then classify some feature vectors as bowhead calls, and the procedure then matches calls between recorders to triangulate locations. To train the networks, manual analysts flagged 219 471 bowhead call examples from 2008 and 2009. Manual analyses were also used to identify 1.17 million transient signals that were not whale calls. The network output thresholds were adjusted to reject 20% of whale calls in the training data. Validation runs using 2007 and 2010 data found that the procedure missed 30%-40% of manually detected calls. Furthermore, 20%-40% of the sounds flagged as calls are not present in the manual analyses; however, these extra detections incorporate legitimate whale calls overlooked by human analysts. Both manual and automated methods produce similar spatial and temporal call distributions. Source


Levin L.A.,University of California at San Diego
Proceedings. Biological sciences / The Royal Society | Year: 2012

Upon their initial discovery, hydrothermal vents and methane seeps were considered to be related but distinct ecosystems, with different distributions, geomorphology, temperatures, geochemical properties and mostly different species. However, subsequently discovered vents and seep systems have blurred this distinction. Here, we report on a composite, hydrothermal seep ecosystem at a subducting seamount on the convergent Costa Rica margin that represents an intermediate between vent and seep ecosystems. Diffuse flow of shimmering, warm fluids with high methane concentrations supports a mixture of microbes, animal species, assemblages and trophic pathways with vent and seep affinities. Their coexistence reinforces the continuity of reducing environments and exemplifies a setting conducive to interactive evolution of vent and seep biota. Source


Azad P.,University of California at San Diego
G3 (Bethesda, Md.) | Year: 2012

Hypoxia occurs in physiologic conditions (e.g. high altitude) or during pathologic states (e.g. ischemia). Our research is focused on understanding the molecular mechanisms that lead to adaptation and survival or injury to hypoxic stress using Drosophila as a model system. To identify genes involved in hypoxia tolerance, we screened the P-SUP P-element insertion lines available for all the chromosomes of Drosophila. We screened for the eclosion rates of embryos developing under 5% O(2) condition and the number of adult flies surviving one week after eclosion in the same hypoxic environment. Out of 2187 lines (covering ~1870 genes) screened, 44 P-element lines representing 44 individual genes had significantly higher eclosion rates (i.e. >70%) than those of the controls (i.e. ~7-8%) under hypoxia. The molecular function of these candidate genes ranged from cell cycle regulation, DNA or protein binding, GTP binding activity, and transcriptional regulators. In addition, based on pathway analysis, we found these genes are involved in multiple pathways, such as Notch, Wnt, Jnk, and Hedgehog. Particularly, we found that 20 out of the 44 candidate genes are linked to Notch signaling pathway, strongly suggesting that this pathway is essential for hypoxia tolerance in flies. By employing the UAS/RNAi-Gal4 system, we discovered that genes such as osa (linked to Wnt and Notch pathways) and lqf (Notch regulator) play an important role in survival and development under hypoxia in Drosophila. Based on these results and our previous studies, we conclude that hypoxia tolerance is a polygenic trait including the Notch pathway. Source


Sievenpiper D.F.,University of California at San Diego
IEEE Antennas and Wireless Propagation Letters | Year: 2011

Non-Foster circuits such as negative capacitors can be used to create superluminal waveguides for broadband leaky-wave antennas. The negative capacitors effectively cancel part of the dielectric constant within the waveguide to provide a broadband relative permittivity between 0 and 1. When used as a leaky-wave antenna, the beam angle is independent of frequency over a broad bandwidth because the waveguide provides a frequency-independent phase velocity greater than the vacuum speed of light. Thus, this approach eliminates beam squint, which is a primary drawback of passive leaky-wave antenna designs. Simulation results using ideal negative capacitors are presented, and the effects of causality are analyzed. © 2006 IEEE. Source


Doherty T.A.,University of California at San Diego
Journal of Leukocyte Biology | Year: 2015

The conventional paradigm of type 2 inflammatory responses is characterized by activation of CD4+ Th2 cells that produce IL-4, IL-5, and IL-13, resulting in tissue eosinophil infiltration, mucus metaplasia, AHR, and IgE production. However, the recent discovery of ILC2s in mice and humans has brought forth a novel pathway in type 2 immunity that may work independent of, or in concert with, adaptive Th2 responses. ILC2s were described initially as lineage-negative lymphocytes that produce high levels of Th2 cytokines IL-5 and IL-13 in response to IL-25 and IL-33 and promote protection against helminth infections. More recent investigations have identified novel upstream regulators, as well as novel ILC2 products. ILC2s are found in mucosal surfaces, including respiratory tract and skin, and studies from experimental asthma and atopic dermatitis models support a role for ILC2s in promoting type 2 inflammatory responses. There are many unanswered questions about the role of ILC2s in chronic allergic diseases, including how ILC2s or upstream pathways can be targeted for therapy. As ILC2s are not antigen specific and may be activated after exposures to a variety of infectious agents and irritants thought to contribute to respiratory and skin diseases, future strategies to target ILC2 function in human disease may be promising. Our intent is to identify priority areas for ILC2 translational research based on basic research insights. © Society for Leukocyte Biology. Source


Kauffman A.S.,University of California at San Diego
Journal of Neuroendocrinology | Year: 2010

The brains of males and females differ anatomically and physiologically, including sex differences in neurone size or number, synapse morphology and specific patterns of gene expression. Brain sex differences may underlie critical sex differences in physiology or behaviour, including several aspects of reproduction, such as the timing of sexual maturation (earlier in females than males) and the ability to generate a preovulatory gonadotrophin surge (in females only). The reproductive axis is controlled by afferent pathways that converge upon forebrain gonadotrophin-releasing hormone (GnRH) neurones, but GnRH neurones are not sexually dimorphic. Although most reproductive sex differences probably reflect sex differences in the upstream circuits and factors that regulate GnRH secretion, the key sexually-dimorphic factors that influence reproductive status have remained poorly defined. The recently-identified neuropeptide kisspeptin, encoded by the Kiss1 gene, is an important regulator of GnRH secretion, and Kiss1 neurones in rodents are sexually dimorphic in specific hypothalamic populations, including the anteroventral periventricular nucleus-periventricular nucleus continuum (AVPV/PeN) and the arcuate nucleus (ARC). In the adult AVPV/PeN, Kiss1 neurones are more abundant in females than males, representing a sex difference that is regulated by oestradiol signalling during critical periods of postnatal and pubertal development. By contrast, Kiss1 neurones in the ARC are not sexually differentiated in adult rodents but, in mice, the regulation of ARC Kiss1 cells by gonadal hormone-independent factors is sexually dimorphic during prepubertal development. These various sex differences in hypothalamic Kiss1 neurones may relate to known sex differences in reproductive physiology, such as puberty onset and positive feedback. © 2010 The Author. Journal Compilation © 2010 Blackwell Publishing Ltd. Source


Shearer P.M.,University of California at San Diego
Journal of Geophysical Research: Solid Earth | Year: 2012

Using two recent high-resolution earthquake catalogs, I examine clustering in California seismicity by plotting the average rate of earthquakes as a function of both space and time from target events of M 2 to 5. Comparisons between pre-and post-target event activity can be used to resolve earthquake-to-earthquake triggering associated with target events of different magnitudes. The results are more complicated than predicted by computer simulations of earthquake triggering that begin with background events occurring at random times. In particular, at least some of the temporal clustering of seismicity at short scales (0.1 to 5km) does not appear to be caused by local earthquake triggering, but instead reflects an underlying physical process that temporarily increases the seismicity rate, such as is often hypothesized to drive earthquake swarms. Earthquake triggering for M < 4.5 earthquakes is only resolvable in average seismicity rates at times less than about one day and to distances of less than about 10km, and its linear density decreases as r-1.5 to r-2.5, significantly steeper than some previous studies have found. © 2012. American Geophysical Union. All Rights Reserved. Source


Keller N.,University of California at San Diego
Nature Physics | Year: 2016

In many viruses, molecular motors forcibly pack single DNA molecules to near-crystalline density into ∼50–100 nm prohead shells. Unexpectedly, we found that packaging frequently stalls in conditions that induce net attractive DNA–DNA interactions. Here, we present findings suggesting that this stalling occurs because the DNA undergoes a nonequilibrium jamming transition analogous to that observed in many soft-matter systems, such as colloidal and granular systems. Experiments in which conditions are changed during packaging to switch DNA–DNA interactions between purely repulsive and net attractive reveal strongly history-dependent dynamics. An abrupt deceleration is usually observed before stalling, indicating that a transition in DNA conformation causes an abrupt increase in resistance. Our findings suggest that the concept of jamming can be extended to a single polymer molecule. However, compared with macroscopic samples of colloidal particles we find that single DNA molecules jam over a much larger range of densities. We attribute this difference to the nanoscale system size, consistent with theoretical predictions for jamming of attractive athermal particles. © 2016 Nature Publishing Group Source


Morgan E.E.,University of California at San Diego
Journal of acquired immune deficiency syndromes (1999) | Year: 2012

To determine whether HIV infection and aging act synergistically to disrupt everyday functioning. Cross-sectional factorial study of everyday functioning in the context of HIV serostatus and age (≤40 years vs. ≥50 years). One hundred three HIV+ and 87 HIV- participants were administered several measures of everyday functioning, including self-report indices of health-related quality of life (HRQoL) and instrumental and basic activities of daily living (IADLs and BADLs), and objective measures of functioning, including employment and Karnofsky Performance Scale ratings. Significant interaction effects of HIV and aging were observed for IADL and BADL declines, and for Karnofsky Performance Scale ratings (Ps < 0.05), independent of potentially confounding factors. Follow-up contrasts revealed significantly worse functioning in the older HIV+ group for most functional outcome measures relative to the other study groups (Ps < 0.05). A significant interaction effect was also observed on the emotional functioning HRQoL subscale, and additive effects of both age and HIV were observed for the physical functioning and general health perceptions HRQoL subscales (Ps < 0.05). Significant predictors of poorer functioning in the older HIV+ group included current major depressive disorder for all outcomes, and comorbid medical conditions, lower estimated premorbid functioning, neurocognitive impairment, and nadir CD4 count for selected outcomes. Findings suggest that older age may exacerbate the adverse effects of HIV on daily functioning, which highlights the importance of evaluating and monitoring the functional status of older HIV-infected adults. Early detection of functional difficulties could facilitate delivery of compensatory strategies (eg, cognitive remediation) or assistive services. Source


Gopal D.,University of California at San Diego
Advances in experimental medicine and biology | Year: 2012

Intervertebral disc (IVD) degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to degeneration of the disc and surrounding area. Degeneration of the disc is considered to be a normal process of aging, but can accelerate faster than expected or be precipitated by other factors. The scientific community has come a long way in understanding the biological basis and interpreting the lifestyle implications of IVD degeneration. Of all the diseases of the intervertebral disc, degeneration is the most common and has earned much attention due to its diversity in presentation and potential multiorgan involvement. We will provide a brief overview of the anatomic, cellular, and molecular structure of the IVD, and delve into the cellular and molecular pathophysiology surrounding IVD degeneration. We will then highlight some of the newest developments in stem cell, protein, and genetic therapy for IVD degeneration. Source


Zhu Q.,University of California at San Diego
Journal of Fluids and Structures | Year: 2012

By using a two-dimensional numerical approach, we investigate the response of a purely passive flapping foil flow energy harvester in a linear shear flow. Our focus is to prove that in such conditions the device is still capable of undergoing periodically oscillatory responses induced by flow-induced instability as it does in uniform incoming flows. Our simulations show that this regular and predictable response, essential for reliable energy harvesting, is achieved over a range of geometric and mechanical parameters when the shear rate is relatively small. It disappears when the shear rate is large. Other responses, such as tumbling motions and irregular motions, are also identified and mapped in the parametric space. The performance of the system, characterized by its energy harvesting efficiency (i.e., the percentage of the incoming flow energy flux captured by the system), is found to be comparable to that in the uniform-flow case. © 2012 Elsevier Ltd. Source


We developed a Markov model of cardiac thin filament activation that accounts for interactions among nearest-neighbor regulatory units (RUs) in a spatially explicit manner. Interactions were assumed to arise from structural coupling of adjacent tropomyosins (Tms), such that Tm shifting within each RU was influenced by the Tm status of its neighbors. Simulations using the model demonstrate that this coupling is sufficient to produce observed cooperativity in both steady-state and dynamic force-Ca(2+) relationships. The model was further validated by comparison with reported responses under various conditions including inhibition of myosin binding and the addition of strong-binding, non-force-producing myosin fragments. The model also reproduced the effects of 2.5 mM added P(i) on Ca(2+)-activated force and the rate of force redevelopment measured in skinned rat myocardial preparations. Model analysis suggests that Tm-Tm coupling potentiates the activating effects of strongly-bound cross-bridges and contributes to force-Ca(2+) dynamics of intact cardiac muscle. The model further predicts that activation at low Ca(2+) concentrations is cooperatively inhibited by nearest neighbors, requiring Ca(2+) binding to >25% of RUs to produce appreciable levels of force. Without excluding other putative cooperative mechanisms, these findings suggest that structural coupling of adjacent Tm molecules contributes to several properties of cardiac myofilament activation. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved. Source


Das A.,ViaSat Inc | Rao B.D.,University of California at San Diego
IEEE Transactions on Signal Processing | Year: 2012

Accurate signal-to-noise ratio (SNR) and noise variance estimation are extremely important aspects of receiver design in multiple-input multiple-output (MIMO) systems. Typically, these parameters are estimated using known pilot/training symbols. However, significant improvements may be made by using both the known pilot symbols as well as the unknown data symbols. In this paper, we address SNR and noise variance estimation of MIMO systems for both a data aided (DA) model, a non-data aided (NDA) model, as well as a mixed model that uses known and unknown data symbols. The Craḿr-Rao lower bound (CRLB) and modified Craḿr-Rao lower bound (MCRLB) for MIMO SNR and MIMO noise variance estimation are determined for digital constellations such as BPSK, QPSK, 8PSK, and 16QAM. Maximum-likelihood estimators are derived in closed form for the DA model. For the NDA model, closed form approximations are derived in addition to iterative expectation-maximization (EM) algorithm based estimators, all of which are demonstrated to perform very close to the CRLB. © 2012 IEEE. Source


Eckmann L.,University of California at San Diego
Current topics in microbiology and immunology | Year: 2011

NF-κB is well characterized as a primary mediator of inflammatory responses during infection and immune reactions, but it has recently become evident that NF-κB also mediates a potent cytoprotective, homeostatic function under basal conditions. This role is especially evident in the mammalian intestine, which is challenged not only with a range of microbial pathogens, but is also in constant contact with potent proinflammatory commensal bacteria and their products. Present data lead to the overall conclusion that antiapoptotic actions of NF-κB in intestinal epithelial cells dominate tissue responses to many acute inflammatory and injurious challenges, whereas proinflammatory and cell survival functions of NF-κB in macrophages and T cells govern chronic intestinal inflammation. This review focuses on the protective and homeostatic functions of NF-κB, and the importance of NF-κB in determining host-microbe interactions in the intestinal tract. Source


Friedlander S.F.,University of California at San Diego
Seminars in cutaneous medicine and surgery | Year: 2010

The demographic profile of facial acne vulgaris has changed during the past several decades; 12 years of age is no longer the low end of the "normal" range for onset of acne. The available epidemiologic evidence raises more questions than it answers regarding the etiology of this downward shift. More study is needed to clarify whether the trend toward an earlier onset of puberty in the United States has influenced the clinical picture of acne. Additional research will help advance understanding of the spectrum of pathophysiologic changes in acne in younger pediatric patients and whether it varies from that found in individuals in whom the onset of acne occurs at approximately 12 years of age or later. Copyright (c) 2010 Elsevier Inc. All rights reserved. Source


Karten H.J.,University of California at San Diego
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

The organization of the non-mammalian forebrain had long puzzled neurobiologists. Unlike typical mammalian brains, the telencephalon is not organized in a laminated ‘cortical’ manner, with distinct cortical areas dedicated to individual sensory modalities or motor functions. The two major regions of the telencephalon, the basal ventricular ridge (BVR) and the dorsal ventricular ridge (DVR), were loosely referred to as being akin to the mammalian basal ganglia. The telencephalon of non-mammalian vertebrates appears to consist of multiple ‘subcortical’ groups of cells. Analysis of the nuclear organization of the avian brain, its connections, molecular properties and physiology, and organization of its pattern of circuitry and function relative to that of mammals, collectively referred to as ‘evolutionary connectomics’, revealed that only a restricted portion of the BVR is homologous to the basal ganglia of mammals. The remaining dorsal regions of the DVR, wulst and arcopallium of the avian brain contain telencephalic inputs and outputs remarkably similar to those of the individual layers of the mammalian ‘neocortex’, hippocampus and amygdala, with instances of internuclear connections strikingly similar to those found between cortical layers and within radial ‘columns’ in the mammalian sensory and motor cortices. The molecular properties of these ‘nuclei’ in birds and reptiles are similar to those of the corresponding layers of the mammalian neocortex. The fundamental pathways and cell groups of the auditory, visual and somatosensory systems of the thalamus and telencephalon are homologous at the cellular, circuit, network and gene levels, and are of great antiquity.A proposed altered migration of these homologous neurons and circuits during development is offered as a mechanism that may account for the altered configuration of mammalian telencephalae. © 2015 The Author(s) Published by the Royal Society. All rights reserved. Source


Holland L.Z.,University of California at San Diego
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2015

In the past 40 years, comparisons of developmental gene expression and mechanisms of development (evodevo) joined comparative morphology as tools for reconstructing long-extinct ancestral forms. Unfortunately, both approaches typically give congruent answers only with closely related organisms. Chordate nervous systems are good examples. Classical studies alone left open whether the vertebrate brain was a new structure or evolved from the anterior end of an ancestral nerve cord like that of modern amphioxus. Evodevo plus electron microscopy showed that the amphioxus brain has a diencephalic forebrain, small midbrain, hindbrain and spinal cord with parts of the genetic mechanisms for the midbrain/hindbrain boundary, zona limitans intrathalamica and neural crest. Evodevo also showed how extra genes resulting from whole-genome duplications in vertebrates facilitated evolution of new structures like neural crest. Understanding how the chordate central nervous system (CNS) evolved from that of the ancestral deuterostome has been truly challenging. The majority view is that this ancestor had a CNS with a brain that gave rise to the chordate CNS and, with loss of a discrete brain, to one of the two hemichordate nerve cords. The minority view is that this ancestor had no nerve cord; those in chordates and hemichordates evolved independently. New techniques such as phylostratigraphy may help resolve this conundrum. © 2015 The Author(s) Published by the Royal Society. All rights reserved. Source


Kesari S.,University of California at San Diego
Seminars in Oncology | Year: 2011

Glioblastoma (GBM) is a highly malignant brain cancer characterized by uncontrolled cellular proliferation, diffuse infiltration, a tendency for necrosis, significant angiogenesis, intense resistance to apoptosis, and widespread genomic aberrations. Prognosis is poor and treatments are largely palliative, although there are subsets of patients that have prolonged survival. Greater understanding of the tumor biology of GBM has been achieved in the past decade, leading to the prospect of novel targeted therapies and biomarker-based individualization of therapy. The goal of this review is to describe the tumor biology and pathologic features of GBM, guidelines for classification and diagnosis, the current status of prognostic and predictive biomarkers, and the role of the blood-brain barrier in delivering therapy for GBM. © 2011 Elsevier Inc. All rights reserved. Source


Jaffe J.S.,University of California at San Diego
Optics Express | Year: 2010

In this article, the utility of structured illumination in order to enhance the contrast and subsequent range capability of an underwater imaging system is explored. The proposed method consists of transmitting a short pulse of light in a grid like pattern that consists of multiple, narrow, delta-function like beams. The grid pattern can be arranged in either a onedimensional line or an area as a two-dimensional pattern. Scanning the pattern in time results in the sequential illumination of the entire scene. The receiving system architecture imposes the exact same, grid-like pattern sensitivity on the reflected light with a simple subsequent superposition of the time-sequenced images. The system can be viewed as a parallel implementation of a Laser Line Scan System where multiple beams are projected and received instead of a single one. The performance enhancement over more conventional systems that project either a sheet or an area of light is compared for a challenging underwater environment via computer simulations. The resulting images are analyzed as a function of the spacing between the projected light beams to characterize contrast and resolution. The results indicate that reasonable gains are obtainable for close spacing between the beams while quite significant gains are predicted for larger ones. Structured illumination systems can therefore collect images more rapidly than systems that scan a single beam; however with concomitant trade-offs in contrast and resolution. © 2010 Optical Society of America. Source


Letendre S.,University of California at San Diego
Topics in Antiviral Medicine | Year: 2011

HIV-associated neurocognitive disorder (HAND) is the result of neural damage caused by HIV replication and immune activation. Potent antiretroviral therapy has reduced the prevalence of severe HAND but not mild to moderate HAND. Brief symptom questionnaires, screening tests, and neuropsychological tests can be used with relative ease in the clinic to identify cognitive and neurologic deficits and to track patient status. Increasing data on pharmacokinetics of antiretrovirals in cerebrospinal fluid (CSF) have permitted formulation of central nervous system (CNS) penetrationeffectiveness (CPE) rankings for single drugs and combinations. Available data indicate that regimens with higher CPE scores are associated with lower HIV RNA levels in CSF and improvement in neurocognitive functioning. © 2011, IAS-USA. Source


Wang J.,University of California at San Diego
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2012

This review article discusses the use of synthetic catalytic nano motors for cargo manipulations and for developing miniaturized lab-on-chip systems based on autonomous transport. The ability of using chemically-powered artificial nanomotors to capture, transport and release therapeutic payloads or nanostructured biomaterials represents one of the next major prospects for nanomotor development. The increased cargo-towing force of such self-propelled nanomotors, along with their precise motion control within microchannel networks, versatility and facile functionalization, pave the way to new integrated functional lab-on-a-chip powered by active transport and perform a series of tasks. Such use of cargo-towing artificial nanomotors has been inspired by on-chip kinesin molecular shuttles. Functionalized nano/microscale motors can thus be used to pick a selected nano/microscale chemical or biological payload target at the right place, transport and deliver them to a target location in a timely manner. Key challenges for using synthetic nanomachines for driving transport processes along microchannel networks are discussed, including loading and unloading of cargo and precise motion control, along with recent examples of related cargo manipulation processes and guided transport in lab-on-a-chip formats. The exciting research area of cargo-carrying catalytic man-made nanomachines is expected to grow rapidly, to lead to new lab-on-a-chip formats and to provide a wide range of future microchip opportunities. © 2012 The Royal Society of Chemistry. Source


Gille S.T.,University of California at San Diego
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2014

Observed long-term warming trends in the Southern Ocean have been interpreted as a sign of increased poleward eddy heat transport or of a poleward displacement of the entire Antarctic Circumpolar Current (ACC) frontal system. The two-decadelong record from satellite altimetry is an important source of information for evaluating the mechanisms governing these trends. While several recent studies have used sea surface height contours to index ACC frontal displacements, here altimeter data are instead used to track the latitude of mean ACC transport. Altimetric height contours indicate a poleward trend, regardless of whether they are associated with ACC fronts. The zonally averaged transport latitude index shows no long-term trend, implying that ACC meridional shifts determined from sea surface height might be associated with large-scale changes in sea surface height more than with localized shifts in frontal positions. The transport latitude index is weakly sensitive to the Southern Annular Mode, but is uncorrelated with El Niño/Southern Oscillation. © 2014 The Author(s) Published by the Royal Society. Source


Constable S.,University of California at San Diego
Geophysics | Year: 2010

Marine controlled-source electromagnetic (CSEM) surveying has been in commercial use for predrill reservoir appraisal and hydrocarbon exploration for years. Although a recent decrease has occurred in the number of surveys and publications associated with this technique, the method has become firmly established as an important geophysical tool in the offshore environment. This is a consequence of two important aspects associated with the physics of the method: First, it is sensitive to high electrical resistivity, which, although not an unambiguous indicator of hydrocarbons, is an important property of economically viable reservoirs. Second, although the method lacks the resolution of seismic wave propagation, it has a much better intrinsic resolution than potential-field methods such as gravity and magnetic surveying, which until now have been the primary nonseismic data sets used in offshore exploration. Although by many measures marine CSEM is still in its infancy, the reliability and noise floors of the instrument systems have improved significantly over the last decade, and interpretation methodology has progressed from simple anomaly detection to 3D anisotropic inversion of multicomponent data using some of the world's fastest supercomputers. Research directions presently include tackling the airwave problem in shallow water by applying time-domain methodology, continuous profiling tools, and the use of CSEM for reservoir monitoring during production. © 2010 Society of Exploration Geophysicists. Source


Mehta R.L.,University of California at San Diego
Kidney International | Year: 2010

Whether and when to intervene and with which therapeutic agent are key questions physicians face daily in managing patients. Biomarkers are emerging to define the course of acute kidney injury and offer an opportunity to provide targeted interventions. The EARLYARF study by Endre et al. provides a glimpse of the challenges and opportunities that lie ahead. © 2010 International Society of Nephrology. Source


Gross A.M.,University of California at San Diego
Nature Genetics | Year: 2014

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease. Source


McCarthy M.J.,University of California at San Diego
Journal of Affective Disorders | Year: 2010

Background: Public health statistics are often released too late to affect reversible societal factors affecting suicide. Increasingly, internet search volume is used in epidemiology, but this method has not yet been applied to suicide. Methods: Google internet search engine activity for suicide-related terms from the years 2004-2009 was measured and correlated to available suicide and intentional self-injury data from the Centers of Disease Control (CDC). Results: Google search volumes correlated to CDC statistics for both suicide and self-injury, but in patterns that differed by age. Whereas internet search activity was negatively correlated to the suicide rate in the general population, it was positively correlated to both intentional self-injury and completed suicides among youth. Conclusions: Monitoring changes in search volumes on the internet may provide an early indicator of suicide risk within the population. Furthermore, youth may utilize the internet in ways that differ from the general population with respect to suicide. © 2009 Elsevier B.V. All rights reserved. Source


Sharma K.,University of California at San Diego | Sharma K.,Veterans Medical Research Foundation
Diabetes | Year: 2015

The concept that excess superoxide production from mitochondria is the driving, initial cellular response underlying diabetes complications has been held for the past decade. However, results of antioxidant-based trials have been largely negative. In the present review, the data supporting mitochondrial superoxide as a driving force for diabetic kidney, nerve, heart, and retinal complications are reexamined, and a new concept for diabetes complications - mitochondrial hormesis - is presented. In this view, production of mitochondrial superoxide can be an indicator of healthy mitochondria and physiologic oxidative phosphorylation. Recent data suggest that in response to excess glucose exposure or nutrient stress, there is a reduction of mitochondrial superoxide, oxidative phosphorylation, and mitochondrial ATP generation in several target tissues of diabetes complications. Persistent reduction of mitochondrial oxidative phosphorylation complex activity is associated with the release of oxidants from nonmitochondrial sources and release of proinflammatory and profibrotic cytokines, and a manifestation of organ dysfunction. Restoration of mitochondrial function and superoxide production via activation of AMPK has now been associated with improvement in markers of renal, cardiovascular, and neuronal dysfunction with diabetes. With this Perspective, approaches that stimulate AMPK and PGC1a via exercise, caloric restriction, and medications result in stimulation of mitochondrial oxidative phosphorylation activity, restore physiologic mitochondrial superoxide production, and promote organ healing. © 2015 by the American Diabetes Association. Source


Shih P.B.,University of California at San Diego
Molecular Psychiatry | Year: 2015

Individuals with anorexia nervosa (AN) restrict eating and become emaciated. They tend to have an aversion to foods rich in fat. Because epoxide hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared with controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment.Molecular Psychiatry advance online publication, 31 March 2015; doi:10.1038/mp.2015.26. © 2015 Macmillan Publishers Limited Source


David M.,University of California at San Diego
Journal of Interferon and Cytokine Research | Year: 2010

Plants rely heavily on an adaptive RNA degradation system mediated by an RNA interference mechanism to combat viral infection, whereas mammals fight infection with specific antibodies and lymphocytes that are adapted to specific viral antigens, and also employ nonadaptive defenses, such as production of interferons (IFNs) that block viral replication and stimulate the host immune response. Therefore, the IFN system represents an integral part of the mammalian antiviral innate immunity, and it is not surprising to find that cellular, IFN-regulated microRNAs contribute to this antiviral defense. In contrast, virus-encoded microRNAs target host cell factors that are either required for the induction of IFNs after pathogen recognition, or are involved in the cellular responses to these pleiotropic cytokines. © Copyright 2010, Mary Ann Liebert, Inc. Source


Swerdlow N.R.,University of California at San Diego
Schizophrenia Research | Year: 2011

New findings are rapidly revealing an increasingly detailed image of neural- and molecular-level dysfunction in schizophrenia, distributed throughout interconnected cortico-striato-pallido-thalamic circuitry. Some disturbances appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, resulting in a substantial loss of, or failure to develop, both cells and/or appropriate connectivity across widely dispersed brain regions. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and epigenetic events. Given these complex and variable hard-wired circuit disturbances, it is worth considering how new and emerging findings can be integrated into actionable treatment models. This paper suggests that future efforts towards developing more effective therapeutic approaches for the schizophrenias should diverge from prevailing models in genetics and molecular neuroscience, and focus instead on a more practical three-part treatment strategy: 1) systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements, used in concert with 2) medications that specifically target cognitive mechanisms engaged by these rehabilitative psychotherapies, and 3) antipsychotic medications that target nodal or convergent circuit points within the limbic-motor interface, to constrain the scope and severity of psychotic exacerbations and thereby facilitate engagement in cognitive rehabilitation. The use of targeted cognitive rehabilitative psychotherapy plus synergistic medication has both common sense and time-tested efficacy with numerous other neuropsychiatric disorders. © 2011 Elsevier B.V. Source


Stein M.B.,University of California at San Diego | Sareen J.,University of Manitoba
New England Journal of Medicine | Year: 2015

A 46-year-old married woman presents with insomnia, headaches, muscle tension, and back pain. She describes a long-term pattern of worrying about several life situations, including health, finances, and her job, and she notes increased anxiety associated with her teenager's leaving home to attend college. She drinks alcohol daily to reduce the tension and help her sleep. In reviewing her history, you note that she has visited your office many times over the past year because of physical symptoms. What do you advise? Source


Griffin J.H.,Scripps Research Institute | Zlokovic B.V.,University of California at San Diego | Mosnier L.O.,University of Southern California
Blood | Year: 2015

The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC's activation of these G protein-coupled receptors differs completely from thrombin's activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies. © 2015 by The American Society of Hematology. Source


Schug A.,University of California at San Diego
Methods in enzymology | Year: 2010

Two-component signal transduction systems enable cells in bacteria, fungi, and plants to react to extracellular stimuli. A sensor histidine kinase (SK) detects such stimuli with its sensor domains and transduces the input signals to a response regulator (RR) by trans-phosphorylation. This trans-phosphorylation reaction requires the formation of a complex formed by the two interacting proteins. The complex is stabilized by transient interactions. The nature of the transient interactions makes it challenging for experimental techniques to gain structural information. X-ray crystallography requires stable crystals, which are difficult to grow and stabilize. Similarly, the mere size of these systems proves problematic for NMR. Theoretical methods can, however, complement existing data. The statistical direct coupling analysis presented in the previous chapter reveals the interacting residues at the contact interface of the SK/RR pair. This information can be combined with the structures of the individual proteins in molecular dynamical simulation to generate structural models of the complex. The general approach, referred to as MAGMA, was tested on the sporulation phosphorelay phosphotransfer complex, the Spo0B/Spo0F pair, delivering crystal resolution accuracy. The MAGMA method is described here in a step-by-step explanation. The developed parameters are transferrable to other SK/RR systems. Copyright © 2010 Elsevier Inc. All rights reserved. Source


Young W.R.,University of California at San Diego
Journal of Physical Oceanography | Year: 2010

Anew seawater Boussinesq system is introduced, and it is shown that this approximation to the equations of motion of a compressible binary solution has an energy conservation law that is a consistent approximation to the Bernoulli equation of the full system. The seawater Boussinesq approximation simplifies the mass conservation equation to Δ. u = 0, employs the nonlinear equation of state of seawater to obtain the buoyancy force, and uses the conservative temperature introduced by McDougall as a thermal variable. The conserved energy consists of the kinetic energy plus the Boussinesq dynamic enthalpy h‡, which is the integral of the buoyancy with respect to geopotential height Z at a fixed conservative temperature and salinity. In the Boussinesq approximation, the full specific enthalpy h is the sum of four terms: McDougall's potential enthalpy, minus the geopotential g0Z, plus the Boussinesq dynamic enthalpy h‡, and plus the dynamic pressure. The seawater Boussinesq approximation removes the large and dynamically inert contributions to h, and it reveals the important conversions between kinetic energy and h‡. © 2010 American Meteorological Society. Source


Feddersen F.,University of California at San Diego
Journal of Atmospheric and Oceanic Technology | Year: 2010

High-quality measurements of the turbulent dissipation rate ∈ are required to diagnose field surf-zone turbulence budgets. Quality control (QC) methods are presented for estimating surf zone ∈ with acoustic Doppler velocimeter (ADV) data. Bad ADV velocity data points are diagnosed with both the ADV signal strength (SS) and correlation (CORR). The fraction of bad SS data points (δSS) depends inversely upon the wave-amplitude-normalized transducer distance below the mean sea surface. The fraction of bad CORR data points δCORR can be elevated when δSS is low. The δCORR depends inversely upon the wave-amplitude normalized sensing volume distance below the mean sea surface, and also increases with increased wave breaking, consistent with turbulence- and bubble-induced Doppler noise. Velocity spectra derived from both "patched" and "interpolated" time series are used to estimate ∈. Two QC tests, based upon the properties of a turbulent inertial subrange, are used to reject bad ∈ data runs. The first test checks that the vertical velocity spectrum's power-law exponent is near -5/3. The second test checks that a ratio R of horizontal and vertical velocity spectra is near 1. Over all δCORR, 70% of the patched and interpolated data runs pass these tests. However, for larger δCORR.0.1 (locations higher in the water column), 50% more patched than interpolated data runs pass the QC tests. Previous QC methods designed for wave studies are not appropriate for ∈ QC. The results suggest that ∈ can be consistently estimated over the lower 60% of the water column and>0.1 mabove the bed within a saturated surf zone. © 2010 American Meteorological Society. Source


Sosinsky G.E.,University of California at San Diego
Channels (Austin, Tex.) | Year: 2011

Pannexins, a class of membrane channels, bear significant sequence homology with the invertebrate gap junction proteins, innexins and more distant similarities in their membrane topologies and pharmacological sensitivities with the gap junction proteins, connexins. However, the functional role for the pannexin oligomers, or pannexons, is different from connexin oligomers, the connexons. Many pannexin publications have used the term "hemichannels" to describe pannexin oligomers while others use the term "channels" instead. This has led to confusion within the literature about the function of pannexins that promotes the idea that pannexons serve as gap junction hemichannels and thus have an assembly and functional state as gap junctional intercellular channels. Here we present the case that unlike the connexin gap junction intercellular channels, so far, pannexin oligomers have repeatedly been shown to be channels that are functional in single membranes, but not as intercellular channel in appositional membranes. Hence, they should be referred to as channels and not hemichannels. Thus, we advocate that in the absence of firm evidence that pannexins form gap junctions, the use of the term "hemichannel" be discontinued within the pannexin literature. Source


Dunn F.A.,University of California at San Diego
Journal of Neuroscience | Year: 2015

Structural changes underlying neurodegenerative diseases include dismantling of synapses, degradation of circuitry, and even massive rewiring. Our limited understanding of synapse dismantling stems from the inability to control the timing and extent of cell death. In this study, selective ablation of cone photoreceptors in live mouse retina and tracking of postsynaptic partners at the cone-to-ON cone bipolar cell synapse reveals that early reaction to cone loss involves rapid and local changes in postsynaptic glutamate receptor distribution. Glutamate receptors disappear with a time constant of 2 h. Furthermore, binding of glutamate receptors by agonists and antagonists is insufficient to rescue glutamate receptor loss, suggesting that receptor allocation depends on the physical presence of cones. These findings demonstrate that the initial step in synapse disassembly involves postsynaptic receptor loss rather than dendritic retraction, providing insight into the early stages of neurodegenerative disease. © 2015 the authors. Source


Understanding the historical biogeography of this global biodiversity hotspot is as important to long-term conservation goals as ecology and evolution are to understanding current patterns and processes. Today's geography is, however, misleading and typical of only ~2% of the last million years; >90% of that time the region's land area was 1.5-2.0 times larger as mean sea levels were 62 m below today's, climates were cooler, and extensive forests and savanna covered the emerged Sunda plains. The region's land area varied two-fold as sea levels fluctuated up to ±50 m with each of ~50 Pleistocene glacial cycles, and forests expanded and contracted with oscillations in land area and seasonality. This dynamic geographic history is relevant to the development of biogeographic regionalism and shows that it is today's forests that are refugial, not those of the Last Glacial Maximum. This history affects how species will adapt or shift their ranges in response to global warming and further decreases in land area (submergence of low-lying coastal areas) during the 21st century. The alternative is mass species extinction. The biota is also threatened by the continued destruction of forest, destruction of Mekong River flood-pulse based ecosystems, and continued human population growth. Human biogeography will become more important in conservation planning as tens of millions of people who depend on protected area forests, riverine ecosystems, and coastal habitats become environmental refugees. Conservation scientists need to become more involved in regional ecological education, environmental stewardship, and ecosystem-based adaptation to sustain as much as possible of this rich biota and the ecological services it provides. © The Author(s) 2010. Source


La Spada A.R.,University of California at San Diego | Taylor J.P.,St Jude Childrens Research Hospital
Nature Reviews Genetics | Year: 2010

Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, such as RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade and has shown that the autophagy pathway has an important role in the degradation of misfolded proteins ĝ€" two themes that are likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalysing new lines of study that should not only elucidate molecular mechanisms of disease but also highlight opportunities for therapeutic intervention for these currently untreatable disorders. © 2010 Macmillan Publishers Limited. All rights reserved. Source


Prigge M.J.,University of California at San Diego | Bezanilla M.,University of Massachusetts Amherst
Development | Year: 2010

The moss Physcomitrella patens has recently emerged as a powerful genetically tractable model plant system. As a member of the bryophytes, P. patens provides a unique opportunity to study the evolution of a myriad of plant traits, such as polarized cell growth, gametophyte-to-sporophyte transitions, and sperm-to-pollen transition. The availability of a complete genome sequence, together with the ability to perform gene targeting efficiently in P. patens has spurred a flurry of elegant reverse genetic studies in this plant model that address a variety of key questions in plant developmental biology. © 2010. Published by The Company of Biologists Ltd. Source


Ilfeld B.M.,University of California at San Diego
Expert Opinion on Pharmacotherapy | Year: 2013

Introduction: The duration of postsurgical pain greatly outlasts the duration of analgesia (typically < 12 h) following single administration of traditional formulations of local anesthetics. Bupivacaine, one of the most widely studied and extensively used local anesthetics, is now available in a liposomal formulation that has shown promise of providing postsurgical analgesia for a duration of up to 72 h when administered as part of a peripheral (e.g., femoral) or neuraxial (e.g., epidural) nerve block. However, it is currently approved for administration in the surgical site. Areas covered: This publication provides an overview of liposome bupivacaine and its potential utility in peripheral nerve blocks and epidural administration. Expert opinion: The potential to provide postoperative analgesia lasting 3 days with a single administration at the time of surgery holds considerable promise. This modality could have distinct advantages over currently available techniques, such as continuous perineural local anesthetic infusion, as it would preclude the need for a catheter and pump. However, potential risks and benefits of liposome bupivacaine in peripheral and neuraxial nerve blocks must be further elucidated in surgical populations, and US Food and Drug Administration (FDA) approval must be granted for these indications. Until FDA approval is provided, the use of liposome bupivacaine in peripheral and neuraxial nerve blocks must be considered investigational. © 2013 Informa UK, Ltd. Source


Nigam S.K.,University of California at San Diego
Stem Cells Translational Medicine | Year: 2013

Branching morphogenesis is critical to the development of organs such as kidney, lung, mammary gland, prostate, pancreas, and salivary gland. Essentially, an epithelial bud becomes an iterative tip-stalk generator (ITSG) able to form a tree of branching ducts and/or tubules. In different organs, branching morphogenesis is governed by similar sets of genes. Epithelial branching has been recapitulated in vitro (or ex vivo) using three-dimensional cell culture and partial organ culture systems, and several such systems relevant to kidney tissue engineering are discussed here. By adapting systems like these it may be possible to harness the power inherent in the ITSG program to propagate and engineer epithelial tissues and organs. It is also possible to conceive of a universal ITSG capable of propagation that may, by recombination with organ-specific mesenchymal cells, be used for engineering many organ-like tissues similar to the organ from which themesenchymecells were derived, or toward which they are differentiated (from stem cells). The three-dimensional (3D) branched epithelial structure could act as a dynamic branching cellular scaffold to establish the architecture for the rest of the tissue. Another strategy-that of recombining propagated organ-specific ITSGs in 3D culture with undifferentiated mesenchymal stem cells-is also worth exploring. If feasible, such engineered tissues may be useful for the ex vivo study of drug toxicity, developmental biology, and physiology in the laboratory. Over the long term, they have potential clinical applications in the general fields of transplantation, regenerative medicine, and bioartificial medical devices to aid in the treatment of chronic kidney disease, diabetes, and other diseases. © AlphaMed Press 2013. Source


Nitz D.A.,University of California at San Diego
Journal of Neurophysiology | Year: 2011

Similarities and differences in the visual content, scale, and shape of environmental boundaries for two environments have been extensively examined for their impact on the recurrence of spatially specific hippocampal firing patterns across environments and across multiple regions of a single environment. Although the shapes of paths taken through an environment are known to impact hippocampal firing patterns within any single region of a single environment, it is not known to what extent path shape and scale can impact firing pattern recurrence across two environments and across multiple regions of a single environment. This question was addressed in the present work where the spatial firing patterns of hippocampal CA1 neurons were examined as rats traversed differently shaped spiral paths centered on the same position within a visually observable curtained enclosure. On such tracks, firing fields for CA1 neurons were found to recur across multiple subregions of a single path and across similarly positioned regions of different paths. Both within and across different spiral tracks, the extent of such pattern recurrence was strongly influenced by similarity in the specific sequences of movement directions and locomotor behaviors engendered by different path shapes. The findings demonstrate that the shapes of paths taken through an environment can robustly and dynamically alter both the scale of spatially specific CA1 firing fields and the extent to which they recur across environments. © 2011 the American Physiological Society. Source


Reinagel P.,University of California at San Diego
PLoS ONE | Year: 2013

Animals must continuously evaluate sensory information to select the preferable among possible actions in a given context, including the option to wait for more information before committing to another course of action. In experimental sensory decision tasks that replicate these features, reaction time distributions can be informative about the implicit rules by which animals determine when to commit and what to do. We measured reaction times of Long-Evans rats discriminating the direction of motion in a coherent random dot motion stimulus, using a self-paced two-alternative forced-choice (2-AFC) reaction time task. Our main findings are: (1) When motion strength was constant across trials, the error trials had shorter reaction times than correct trials; in other words, accuracy increased with response latency. (2) When motion strength was varied in randomly interleaved trials, accuracy increased with motion strength, whereas reaction time decreased. (3) Accuracy increased with reaction time for each motion strength considered separately, and in the interleaved motion strength experiment overall. (4) When stimulus duration was limited, accuracy improved with stimulus duration, whereas reaction time decreased. (5) Accuracy decreased with response latency after stimulus offset. This was the case for each stimulus duration considered separately, and in the interleaved duration experiment overall. We conclude that rats integrate visual evidence over time, but in this task the time of their response is governed more by elapsed time than by a criterion for sufficient evidence. © 2013 Pamela Reinagel. Source


Taylor M.B.,University of California at San Diego
IEEE Micro | Year: 2013

Because of the breakdown of Dennard scaling, the percentage of a silicon chip that can switch at full frequency drops exponentially with each process generation. This utilization wall forces designers to ensure that, at any point in time, large fractions of their chips are effectively 'dark silicon'-that is, significantly underclocked or idle for large periods of time. As exponentially larger fractions of a chip's transistors become dark, silicon area becomes an exponentially cheaper resource relative to power and energy consumption. This shift is driving a new class of architectural techniques that 'spend' area to 'buy' energy efficiency. All these techniques seek to introduce new forms of heterogeneity into the computational stack. This article begins by examining four promising directions-the 'four horsemen'-that have emerged as top contenders for thriving in the dark silicon age. Each direction carries with its virtues deep-seated restrictions that require a careful understanding of the underlying trade-offs and benefits. Furthermore, the author proposes a set of evolutionary dark silicon design principles and examines how one of the 'darkest' computing architectures of all, the human brain, trades off energy and area in ways that provide potential insights into more revolutionary directions for computer architecture. © 2013 IEEE. Source


Guo X.,University of California at San Diego | Wang X.-F.,Duke University
Cell | Year: 2012

An unexpected role for a Mediator subunit, MED12, in resistance to multiple anticancer agents is revealed by Huang et al. Loss of MED12 confers drug resistance by activating transforming growth factor β (TGF-β) signaling. Inhibition of the TGF-β pathway resensitizes cells to therapeutic drugs, suggesting a new combinatorial cancer treatment. © 2012 Elsevier Inc. Source


Wang J.,University of California at San Diego
Biosensors and Bioelectronics | Year: 2015

Self-propelled nanomotors offer considerable promise for developing novel biosensing protocols involving 'on-the-fly' recognition events. This article reviews recent advances in using catalytic nanomotors for bioaffinity sensing and for isolating target biomolecules and cells from complex biological samples. A variety of receptors, attached to self-propelled nanoscale motors, can thus move around the sample and, along with the generated microbubbles, lead to greatly enhanced fluid transport and accelerated recognition process. Such operation addresses the challenges imposed by the slow analyte transport in designing sensitive bioaffinity assays. The recognition element can be attached onto the motor surface or embedded in the motor material itself. Receptor-functionalized nanomotors based on different biomolecular interactions have thus been shown extremely useful for rapid target isolation from complex biological samples without preparatory and washing steps. Tubular microengine microtransporters, functionalized with antibody, ss-DNA, aptamer or lectin receptors, are particularly useful for direct detection and isolation of proteins, nucleic acids, proteins or cancer cells. Micromotors with 'built-in' recognition, exploiting the selective binding properties of the outer layer of such micronegines, can also be used. Greatly enhanced analyte-receptor interactions can also be achieved through the increased fluid transport associated with the movement of unmodified micromotors. The attractive features of the new motion-based bioaffinity sensing and separation protocols open up new opportunities for diverse biomedical, environmental and security applications. © 2015 Elsevier B.V. Source


Lubarda V.A.,University of California at San Diego
Journal of the Mechanics and Physics of Solids | Year: 2010

The constitutive analysis of the mechanical response of thin elastic membranes under inplane deformation is presented by using the multiplicative decomposition of the deformation gradient into its areal and distortional parts. Specific results are obtained for the EvansSkalak form of the strain energy function. The solution to the problem of radial stretching of a hollow circular membrane obeying this constitutive model is then derived. The stress concentration factor is determined as a function of the relative hole size and the magnitude of the applied tension. The tension boundary is identified above which no compressive stress appears in the membrane. The limit boundary is introduced below which the membrane cannot support the applied loading without unstable wrinkling. For the loading between the tension and the limit boundary, nonuniformly distributed infinitesimal wrinkles appear within the inner portion of the membrane, carrying radial tension but no circumferential stress (tension field). The specific form of the strain energy function is used to describe this behavior, and to calculate the amount of the membrane area absorbed by infinitesimal wrinkles. The wrinkled portion is surrounded by the outer portion of the membrane carrying both radial and circumferential stresses. The limit boundary is reached when wrinkles spread throughout the membrane. It is shown that for a sufficiently large tension at the outer boundary, the wrinkling does not spread throughout the membrane no matter how large the applied tension at the inner boundary of the membrane is, provided that no rupture takes place. The limiting extent of the tension field in such cases is calculated. The linearized version of the analysis is characterized by a closed form solution. © 2010 Elsevier Ltd. All rights reserved. Source


McKittrick J.,University of California at San Diego | Shea-Rohwer L.E.,Sandia National Laboratories
Journal of the American Ceramic Society | Year: 2014

The wavelength down conversion approach to solid-state lighting (SSL) uses down conversion materials to produce visible light when excited by near-UV or blue emission from InGaN LEDs. This review discusses two classes of down conversion materials: phosphors and semiconductor quantum dots (QDs). Strong absorption of the excitation wavelength; high luminous efficacy of radiation, which enables white light with a high color rendering index and a low correlated color temperature; high quantum efficiency; and thermal and chemical stability are some of the criteria for down converters used in SSL. This review addresses the challenges in the development of down converters that satisfy all these criteria. We will discuss the advantages and disadvantages of several phosphor compositions for blue and near-UV LEDs. The use of core/shell architectures to improve the photoluminescence and moisture resistance of phosphors is presented. QDs are another class of down conversion materials for near-UV and blue LEDs. Strategies to improve the photostability and reduce the thermal quenching of QDs include strain-graded core/shell interfaces and alloying. We discuss Cd-containing II-VI QDs, and Cd-free III-V and I-III-VI QDs and their potential for SSL applications. Finally, a description of different methods to integrate the phosphors and QDs with the LED is given. © 2014 The American Ceramic Society. Source


West J.B.,University of California at San Diego
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2014

Humphry Davy (1778–1829) has an interesting place in the history of respiratory gases because the Pneumatic Institution in which he did much of his early work signaled the end of an era of discovery. The previous 40 years had seen essentially all of the important respiratory gases described, and the Institution was formed to exploit their possible value in medical treatment. Davy himself is well known for producing nitrous oxide and demonstrating that its inhalation could cause euphoria and heightened imagination. His thinking influenced the poets Samuel Taylor Coleridge and William Wordsworth, and perhaps we can claim that our discipline colored the poetry of the Romantic Movement. Davy was also the first person to measure the residual volume of the lung. The Pneumatic Institution was the brainchild of Thomas Beddoes, who had trained in Edinburgh under Joseph Black, who discovered carbon dioxide. Later Davy moved to the Royal Institution in London formed, in part, to diffuse the knowledge of scientific discoveries to the general public. Davy was a brilliant lecturer and developed an enthusiastic following. In addition he exploited the newly described electric battery to discover several new elements. He also invented the safety lamp in response to a series of devastating explosions in coal mines. Ultimately Davy became president of the Royal Society, a remarkable honor for somebody with such humble origins. Another of his important contributions was to introduce Michael Faraday (1791–1867) to science. Faraday became one of the most illustrious British scientists of all time. © 2014 the American Physiological Society. Source


Christman K.L.,University of California at San Diego
Science Translational Medicine | Year: 2012

Injection of a growth factor in a self-assembling nanof ber scaf old has the potential to create a suitable microenvironment and recruit endogenous cells for cardiac repair (Lin et al., this issue). Source


Kadonaga J.T.,University of California at San Diego
Wiley Interdisciplinary Reviews: Developmental Biology | Year: 2012

The RNA polymerase II core promoter is sometimes referred to as the gateway to transcription. The core promoter is generally defined to be the stretch of DNA that directs the initiation of transcription. This simple description belies a complex multidimensional regulatory element, as there is considerable diversity in core promoter structure and function. Core promoters can be viewed at the levels of DNA sequences, transcription factors, and biological networks. Key DNA sequences are known as core promoter elements, which include the TATA box, initiator (Inr), polypyrimidine initiator (TCT), TFIIB recognition element (BRE), motif ten element (MTE), and downstream core promoter element (DPE) motifs. There are no universal core promoter elements that are present in all promoters. Different types of core promoters are transcribed by different sets of transcription factors and exhibit distinct properties, such as specific interactions with transcriptional enhancers, that are determined by the presence or absence of particular core promoter motifs. Moreover, some core promoter elements have been found to be associated with specific biological networks. For instance, the TCT motif is dedicated to the transcription of ribosomal protein genes in Drosophila and humans. In addition, nearly all of the Drosophila Hox genes have a DPE motif in their core promoters. The complexity of the core promoter is further seen in the relation among transcription initiation patterns, the stability or lability of transcriptional states, and the organization of the chromatin structure in the promoter region. Hence, the current data indicate that the core promoter is a critical component in the regulation of gene activity. © 2011 Wiley Periodicals, Inc. Source


West J.B.,University of California at San Diego
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2014

Galen (129-c. 216 AD) was a key figure in the early development of Western physiology. His teachings incorporated much of the ancient Greek traditions including the work of Hippocrates and Aristotle. Galen himself was a well-educated Greco-Roman physician and physiologist who at one time was a physician to the gladiators in Pergamon. Later he moved to Rome, where he was associated with the Roman emperors Marcus Aurelius and Lucius Verus. The Galenical school was responsible for voluminous writings, many of which are still extant. One emphasis was on the humors of the body, which were believed to be important in disease. Another was the cardiopulmonary system, including the belief that part of the blood from the right ventricle could enter the left through the interventricular septum. An extraordinary feature of these teachings is that they dominated thinking for some 1,300 years and became accepted as dogma by both the State and Church. One of the first anatomists to challenge the Galenical teachings was Andreas Vesalius, who produced a magnificent atlas of human anatomy in 1543. At about the same time Michael Servetus described the pulmonary transit of blood, but he was burned at the stake for heresy. Finally, with William Harvey and others in the first part of the 17th century, the beginnings of modern physiology emerged with an emphasis on hypotheses and experimental data. Nevertheless, vestiges of Galen's teaching survived into the 19th century. © 2014 the American Physiological Society. Source


Thrush S.F.,NIWA - National Institute of Water and Atmospheric Research | Thrush S.F.,University of Genoa | Dayton P.K.,University of California at San Diego
Annual Review of Marine Science | Year: 2010

Modern fishing changes the ocean environment in many ways, including disturbing the sea floor, altering the food webs, and shifting many important ecosystem functions. Natural history, oceanographic, habitat, behavior, and ecological information must be integrated to implement meaningful ecosystem-based management. We discuss the urgent need to expand the concept of essential fish habitat to include important food-web relationships. The need for a broader perspective in terms of ecosystem function and the effects of interactive stressors is emphasized to maintain the vitality and resilience of valued ecosystems. Maintenance of multiple ecosystem functions is a key factor in the adaptive capacity of ecosystems to change. We argue that an ecological understanding of resilience embraces uncertainty and encourages multiple approaches to the management of humans such that ecosystem functions are maintained. © 2010 by Annual Reviews. Source


Constable S.,University of California at San Diego
Geophysical Prospecting | Year: 2013

We review and describe the electromagnetic transmitters and receivers used to carry out magnetotelluric and controlled source soundings in the marine environment. Academic studies using marine electromagnetic methods started in the 1970s but during the last decade these methods have been used extensively by the offshore hydrocarbon exploration industry. The principal sensors (magnetometers and non-polarizing electrodes) are similar to those used on land but magnetotelluric field strengths are not only much smaller on the deep sea-floor but also fall off more rapidly with increasing frequency. As a result, magnetotelluric signals approach the noise floor of electric field and induction coil sensors (0.1 nV/m and 0.1 pT) at around 1 Hz in typical continental shelf environments. Fluxgate magnetometers have higher noise than induction coils at periods shorter than 500 s but can still be used to collect sea-floor magnetotelluric data down to 40-100 s. Controlled source transmitters using electric dipoles can be towed continuously through the seawater or on the sea-bed, achieving output currents of 1000 A or more, limited by the conductivity of seawater and the power that can be transmitted down the cables used to tow the devices behind a ship. The maximum source-receiver separation achieved in controlled source soundings depends on both the transmitter dipole moment and on the receiver noise floor and is typically around 10 km in continental shelf exploration environments. The position of both receivers and transmitters needs to be navigated using either long baseline or short baseline acoustic ranging, while sea-floor receivers need additional measurements of orientations from compasses and tiltmeters. All equipment has to be packaged to accommodate the high pressure (up to 40 MPa) and corrosive properties of seawater. Usually receiver instruments are self-contained, battery powered and have highly accurate clocks for timekeeping, even when towed on the sea-floor or in the water column behind a transmitter. © 2013 European Association of Geoscientists & Engineers. Source


Ravits J.,University of California at San Diego
Experimental Neurology | Year: 2014

Amyotrophic lateral sclerosis (ALS) phenotypes such as limb ALS, bulbar ALS, primary lateral sclerosis and primary muscular atrophy are highly heterogeneous and exist on a continuum. These are largely determined by the neuroanatomy of the underlying pathological changes, which can be clinically imputed. Deconstructing these early in disease, before temporal-spatial summation induces complexity, shows that ALS begins focally at a seemingly random location and progresses contiguously. This suggests that focality and anatomic propagation of pathology are significant parts of pathogenesis-disease propagates over space as well as progresses over time. Focality and neuroanatomic propagation can explain how dominant genetic traits manifest with heterogeneous phenotypes, since the anatomic site of outbreak is a prime determinant of phenotype. Focality and neuroanatomic propagation can also explain why frontotemporal dementia (FTD), a neurodegeneration closely related to ALS, has heterogeneous phenotypes, since here too the anatomic site of the outbreak is a prime determinant of phenotype. There are two distinct types of neuroanatomic propagation: contiguous propagation, which occurs side-to-side regionally through the extracellular matrix independent of synaptic connection; and network propagation, which occurs end-to-end dependent on synaptic connections and axonal transmission in connected neuronal networks. The molecular basis of neuroanatomic propagation is unknown, although prion-like misfolding and templating of pathogenic proteins is a compelling unifying hypothesis. © 2014 Elsevier Inc. Source


Smith L.R.,University of California at San Diego
Developmental medicine and child neurology | Year: 2013

Satellite cells are the stem cells residing in muscle responsible for skeletal muscle growth and repair. Skeletal muscle in cerebral palsy (CP) has impaired longitudinal growth that results in muscle contractures. We hypothesized that the satellite cell population would be reduced in contractured muscle. We compared the satellite cell populations in hamstring muscles from participants with CP contracture (n=8; six males, two females; age range 6-15y; Gross Motor Function Classification System [GMFCS] levels II-V; 4 with hemiplegia, 4 with diplegia) and from typically developing participants (n=8; six males, two females, age range 15-18y). Muscle biopsies were extracted from the gracilis and semitendinosus muscles and mononuclear cells were isolated. Cell surface markers were stained with fluorescently conjugated antibodies to label satellite cells (neural cell adhesion molecule) and inflammatory and endothelial cells (CD34 and CD4 respectively). Cells were analyzed using flow cytometry to determine cell populations. After gating for intact cells a mean of 12.8% (SD 2.8%) were determined to be satellite cells in typically developing children, but only 5.3% (SD 2.3%; p<0.05) in children with CP. Hematopoietic and endothelial cell types were equivalent in typically developing children and children with CP (p>0.05) suggesting the isolation procedure was valid. A reduced satellite cell population may account for the decreased longitudinal growth of muscles in CP that develop into fixed contractures or the decreased ability to strengthen muscle in CP. This suggests a unique musculoskeletal disease mechanism and provides a potential therapeutic target for debilitating muscle contractures. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press. Source


Moore T.R.,University of California at San Diego
American Journal of Obstetrics and Gynecology | Year: 2010

Obesity and diabetes have become globally epidemic. The cause of this unprecedented rise in obesity is multifactorial, with inactivity, excessive calorie intake, and genetic factors implicated. More recent data indicate that exposure to diabetes during pregnancy increases the risk of childhood and adult obesity, diabetes, and cardiovascular disease. Evidence derived from recent randomized controlled trials indicates that gestational diabetes mellitus (GDM) treatment reduces newborn obesity and therefore may contribute to reducing the global prevalence of obesity and metabolic syndrome. Current evidence detailing increases in global prevalence of obesity was reviewed together with data evaluating the effectiveness of treatment of GDM. Development of new protocols for diagnosis and treatment of GDM may reduce population obesity and cardiovascular disease. © 2010 Mosby, Inc. All rights reserved. Source


West J.B.,University of California at San Diego
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2013

Antoine Lavoisier (1743-1794) was one of the most eminent scientists of the late 18th century. He is often referred to as the father of chemistry, in part because of his book Elementary Treatise on Chemistry. In addition he was a major figure in respiratory physiology, being the first person to recognize the true nature of oxygen, elucidating the similarities between respiration and combustion, and making the first measurements of human oxygen consumption under various conditions. Less well known are the contributions made by his wife, Marie-Anne Lavoisier. However, she was responsible for drawings of the experiments on oxygen consumption when the French revolution was imminent. These are of great interest because written descriptions are not available. Possible interpretations of the experiments are given here. In addition, her translations from English to French of papers by Priestley and others were critical in Lavoisier's demolition of the erroneous phlogiston theory. She also provided the engravings for her husband's textbook, thus documenting the extensive new equipment that he developed. In addition she undertook editorial work, for example in preparing his posthumous memoirs. The scientific collaboration of this husband-wife team is perhaps unique among the giants of respiratory physiology. © 2013 the American Physiological Society. Source


Shayevitz O.,University of California at San Diego | Feder M.,Tel Aviv University
IEEE Transactions on Information Theory | Year: 2011

In this paper, we introduce a fundamental principle for optimal communication over general memoryless channels in the presence of noiseless feedback, termed posterior matching. Using this principle, we devise a (simple, sequential) generic feedback transmission scheme suitable for a large class of memoryless channels and input distributions, achieving any rate below the corresponding mutual information. This provides a unified framework for optimal feedback communication in which the Horstein scheme (BSC) and the Schalkwijk-Kailath scheme (AWGN channel) are special cases. Thus, as a corollary, we prove that the Horstein scheme indeed attains the BSC capacity, settling a longstanding conjecture. We further provide closed form expressions for the error probability of the scheme over a range of rates, and derive the achievable rates in a mismatch setting where the scheme is designed according to the wrong channel model. Several illustrative examples of the posterior matching scheme for specific channels are given, and the corresponding error probability expressions are evaluated. The proof techniques employed utilize novel relations between information rates and contraction properties of iterated function systems. © 2011 IEEE. Source


Tarin D.,University of California at San Diego
Cancer and Metastasis Reviews | Year: 2013

Current cancer research focuses mainly upon the cancer cells in malignant tumours and is providing a growing database about aberrations in their genetic composition. However, tumours also contain non-cancerous host tissue, referred to as the stroma, which plays an active and indispensable role in tumour growth and influences the virulence of the neoplasm towards the host. Many cell types inhabit the stroma, amidst apparently inert fibrous and viscous matrix material, composed of complex polysaccharides, proteins and other molecules. Actually, all of these elements are in constant turnover, causing unpredictable evolution in the properties of the community. This article provides pathologic observations and data on reciprocal interactions between these stromal and neoplastic components of tumours and how they change during the course of the disease. Malignant progression depends upon dauntingly intricate communications between different specialised lineages within the cellular society, which enable rapid adaptation to changing circumstances. Opportunistic misuse of such communication networks enables tumour cells to recruit and incorporate adjacent normal stroma into their midst, so that they may grow, infiltrate and parasitise the host. The absolute dependency of primary tumours and metastases on their diverse stromal components for survival and their insatiable need to continuously recruit more stroma to support expansion, renders them vulnerable to strategies capable of disrupting the cellular interactions involved. This dependency is of critical importance for cancer therapy research, and proposed methods for turning this parasitic behaviour of tumours against themselves are suggested below. © 2013 Springer Science+Business Media New York. Source


Intriligator K.,University of California at San Diego
Journal of High Energy Physics | Year: 2014

Abstract: 6d QFTs are constrained by the analog of ’t Hooft anomaly matching: all anomalies for global symmetries and metric backgrounds are constants of RG flows, and for all vacua in moduli spaces. We discuss an anomaly matching mechanism for 6d N = (1, 0) theories on their Coulomb branch. It is a global symmetry analog of Green-Schwarz-West-Sagnotti anomaly cancellation, and requires the apparent anomaly mismatch to be a perfect square, (formula presented). Then ΔI8 is cancelled by making X4 an electric/magnetic source for the tensor multiplet, so background gauge field instantons yield charged strings. This requires the coefficients in X4 to be integrally quantized. We illustrate this for N = (2,0) theories. We also consider the N = (1, 0) SCFTs from N small E8 instantons, verifying that the recent result for its anomaly polynomial fits with the anomaly matching mechanism. © 2014, The Author(s). Source


Goldstein I.,University of California at San Diego
Journal of Women's Health | Year: 2010

Urogenital atrophy resulting from postmenopausal estrogen deficiency has numerous clinical effects, including vaginal dryness, sexual dysfunction, urinary incontinence, and recurrent urinary tract infections (UTIs), all of which can cause significant distress and reduction in quality of life. Although nearly one third to one half of postmenopausal women experience these symptoms, they are often overlooked because patients may be reluctant to discuss them and clinicians fail to screen for them. As these symptoms are unlikely to resolve without treatment, the prompt diagnosis and treatment of urogenital atrophy is essential. Estrogen therapy, administered either locally or systemically, provides significant relief from symptoms related to urogenital atrophy. However, systemic estrogen therapy is contraindicated in some women and may not be accepted in women without other menopausal symptoms. Local low-dose vaginal estrogen therapy, in the form of vaginal estrogen tablets, creams, or rings, has been shown to reduce dyspareunia and vaginal dryness, restore vaginal pH, and restore normal vaginal cytology. All forms of vaginal estrogen therapy are effective and well tolerated, although vaginal tablets and rings may have fewer adverse effects and have higher rates of adherence than creams. Copyright 2010, Mary Ann Liebert, Inc. Source


Doran N.,University of California at San Diego
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco | Year: 2011

A substantial number of adolescents are current and regular cigarette smokers, and there is a need to better understand factors that contribute to smoking behavior during these years. Sensation seeking (SS) is one factor that has consistently been associated with smoking, but less is known about mechanisms that may explain this relationship. The present study tested the hypothesis that high school students high in SS would report heavier cigarette smoking and that this relationship would be mediated by negative affect and by perceptions about the risks of smoking. Students (n = 1,688) participated in an annual survey of substance use and related attitudes and characteristics. As expected, higher SS was associated with greater levels of past 30-day (odds ratio [OR] = 1.46, p = .004) and lifetime (OR = 1.37, p = .004) smoking, particularly for males. Multiple mediation models indicated that effect of SS on both 30-day (combined indirect effect z = 5.38, p < .001) and lifetime (z = 6.14, p < .001) smoking was mediated by both negative affect and risk perception. These findings suggest a need for increasing the sensation value of anti-tobacco messages to increase their efficacy for high SS youth. High SS youth may also benefit from prevention efforts designed to teach healthy ways of coping with negative affect. Source


Arias-Castro E.,University of California at San Diego
IEEE Transactions on Information Theory | Year: 2011

In the context of clustering, we consider a generative model in a Euclidean ambient space with clusters of different shapes, dimensions, sizes, and densities. In an asymptotic setting where the number of points becomes large, we obtain theoretical guaranties for some emblematic methods based on pairwise distances: a simple algorithm based on the extraction of connected components in a neighborhood graph; hierarchical clustering with single linkage; and the spectral clustering method of Ng, Jordan, and Weiss. The methods are shown to enjoy some near-optimal properties in terms of separation between clusters and robustness to outliers. The local scaling method of Zelnik-Manor and Perona is shown to lead to a near-optimal choice for the scale in the first and third methods. We also provide a lower bound on the spectral gap to consistently choose the correct number of clusters in the spectral method. © 2011 IEEE. Source


Chapman C.D.,University of San Diego | Robertson-Anderson R.M.,University of California at San Diego
Physical Review Letters | Year: 2014

We optically drive a trapped microscale probe through entangled DNA at rates up to 100× the disentanglement rate (Wi≈100), then remove the trap and track subsequent probe recoil motion. We identify a unique crossover to the nonlinear regime at Wi≈20. Recoil dynamics display rate-dependent dilation and complex power-law healing of the reptation tube. The force response during strain exhibits key nonlinear features such as shear thinning and yielding with power-law rate dependence. Our results, distinctly nonclassical and in accord with recent theoretical predictions, reveal molecular dynamics governed by individual stress-dependent entanglements rather than chain stretching. © 2014 American Physical Society. Source


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. Source


Diamond-Stanic A.M.,University of California at San Diego | Rieke G.H.,University of Arizona
Astrophysical Journal | Year: 2012

We present estimates of black hole accretion rates (BHARs) and nuclear, extended, and total star formation rates for a complete sample of Seyfert galaxies. Using data from the Spitzer Space Telescope, we measure the active galactic nucleus (AGN) luminosity using the [O IV] λ25.89 μm emission line and the star-forming luminosity using the 11.3 μm aromatic feature and extended 24 μm continuum emission. We find that black hole growth is strongly correlated with nuclear (r < 1kpc) star formation, but only weakly correlated with extended (r > 1kpc) star formation in the host galaxy. In particular, the nuclear star formation rate (SFR) traced by the 11.3 μm aromatic feature follows a relationship with the BHAR of the form SFR ∞ M· 0.8 BH, with an observed scatter of 0.5 dex. This SFR-BHAR relationship persists when additional star formation in physically matched r = 1kpc apertures is included, taking the form SFR ∞ M · 0.8 BH. However, the relationship becomes almost indiscernible when total SFRs are considered. This suggests a physical connection between the gas on sub-kiloparsec and sub-parsec scales in local Seyfert galaxies that is not related to external processes in the host galaxy. It also suggests that the observed scaling between star formation and black hole growth for samples of AGNs will depend on whether the star formation is dominated by a nuclear or an extended component. We estimate the integrated black hole and bulge growth that occurs in these galaxies and find that an AGN duty cycle of 5%-10% would maintain the ratio between black hole and bulge masses seen in the local universe. © 2012. The American Astronomical Society. All rights reserved. Source


Spector D.H.,University of California at San Diego
Medical Microbiology and Immunology | Year: 2015

Human cytomegalovirus (HCMV) infection modulates the host cell cycle to create an environment that is optimal for viral gene expression, DNA replication, and production of infectious virus. The virus mostly infects quiescent cells and thus must push the cell into G1 phase of the cell cycle to co-opt the cellular mechanisms that could be used for DNA synthesis. However, at the same time, cellular functions must be subverted such that synthesis of viral DNA is favored over that of the host. The molecular mechanisms by which this is accomplished include altered RNA transcription, changes in the levels and activity of cyclin-dependent kinases, and other proteins involved in cell cycle control, posttranslational modifications of proteins, modulation of protein stability through targeted effects on the ubiquitin–proteasome degradation pathway, and movement of proteins to different cellular locations. When the cell is in the optimal G0/G1 phase, multiple signaling pathways are altered to allow rapid induction of viral gene expression once negative factors have been eliminated. For the most part, the cell cycle will stop prior to initiation of host cell DNA synthesis (S phase), although many cell cycle proteins characteristic of the S/G2/M phase accumulate. The environment of a cell progressing through the cell cycle and dividing is not favorable for viral replication, and HCMV has evolved ways to sense whether cells are in S/G2 phase, and if so, to prevent initiation of viral gene expression until the cells cycle back to G1. A major target of HCMV is the anaphase-promoting complex E3 ubiquitin ligase, which is responsible for the ubiquitination and subsequent degradation of cyclins A and B and other cell cycle proteins at specific phases in the cell cycle. This review will discuss the effects of HCMV infection on cell cycle regulatory pathways, with the focus on selected viral proteins that are responsible for these effects. © 2015, Springer-Verlag Berlin Heidelberg. Source


Aisen P.S.,University of California at San Diego
Neurobiology of Aging | Year: 2011

In recent years, advances in Alzheimer's disease (AD) biomarker research have provided powerful tools to improve trial design. In particular, biomarkers provide powerful methods for the selection of individuals with Alzheimer's disease prior to the onset of dementia. Data suggest that neuroimaging biomarkers will be useful as endpoints for trials in very early, even asymptomatic disease, though further work is necessary to establish validity for regulatory purposes. © 2011 Elsevier Inc. Source


Chambers C.,University of California at San Diego
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2011

Teratology Information Services (TIS) located throughout the world have long played a key role in screening for potential new human teratogens. Using a basic prospective cohort study design, TIS recruit pregnant women from among callers to the Services who have had an exposure of interest and at the same time identify an unexposed comparison group from the same pool of callers. Women in both groups are followed to pregnancy outcome and a range of adverse outcomes including major congenital anomalies, birth size, pregnancy loss, and preterm delivery are evaluated, while controlling for potential confounding. Particularly for rare exposures or newly marketed medications, TIS may be uniquely suited to gathering this information in a timely and efficient fashion. The primary limitation of these studies is the unknown representativeness of the volunteer sample, and the typical small to moderate sample sizes. Methods to increase the proportion of exposed pregnancies that are recruited should be developed. However, small sample size TIS studies, especially when considering new or rare exposures, often fulfill the important function of providing some reassurance to women who have already had the exposure of interest by ruling out major risks for teratogenicity, that is, on the order of thalidomide. Collaborations across TIS nationally and internationally help to address the sample size challenges. A formal collaboration between the TIS cohort study model with a case-control study design is also underway and will provide complementary strengths. © 2011 Wiley-Liss, Inc. Source


Hiller K.,University of Luxembourg | Metallo C.M.,University of California at San Diego
Current Opinion in Biotechnology | Year: 2013

Cancer is a disease of unregulated cell growth and survival, and tumors reprogram biochemical pathways to aid these processes. New capabilities in the computational and bioanalytical characterization of metabolism have now emerged, facilitating the identification of unique metabolic dependencies that arise in specific cancers. By understanding the metabolic phenotype of cancers as a function of their oncogenic profiles, metabolic engineering may be applied to design synthetically lethal therapies for some tumors. This process begins with accurate measurement of metabolic fluxes. Here we review advanced methods of quantifying pathway activity and highlight specific examples where these approaches have uncovered potential opportunities for therapeutic intervention. © 2012 Elsevier Ltd. Source


Lauga E.,University of California at San Diego
Soft Matter | Year: 2011

Locomotion on small scales is dominated by the effects of viscous forces and, as a result, is subject to strong physical and mathematical constraints. Following Purcell's statement of the scallop theorem which delimitates the types of swimmer designs which are not effective on small scales, we review the different ways the constraints of the theorem can be escaped for locomotion purposes. © The Royal Society of Chemistry 2011. Source


Hill L.,University of California at San Diego
Topics in Antiviral Medicine | Year: 2015

Direct-acting antiviral (DAA) drugs exhibit considerable variability in mechanisms of metabolism and the extent to which they are substrates, inhibitors, or inducers of cytochrome P450 enzymes or P-glycoprotein and other drug transporters. Thus, potential drug-drug interactions with other commonly used therapies also vary, as do the effects of renal and hepatic impairment on DAA drug exposure. Drug-drug interaction profiles and use in cases of renal or hepatic impairment are reviewed for the DAAs simeprevir; sofosbuvir; ledipasvir; the fixed-dose combination regimen of paritaprevir, ritonavir, and ombitasvir plus dasabuvir; and the investigational drugs daclatasvir and asunaprevir. This article summarizes a presentation by Lucas Hill, PharmD, at the IAS-USA continuing education program held in Chicago, Illinois, in October 2014. © 2015, IAS-USA. All rights reserved. Source


Lauga E.,University of California at San Diego
Physical Review Letters | Year: 2011

Purcell's scallop theorem states that swimmers deforming their shapes in a time-reversible manner ("reciprocal" motion) cannot swim. Using numerical simulations and theoretical calculations we show here that, in a fluctuating environment, reciprocal swimmers undergo, on time scales larger than that of their rotational diffusion, diffusive dynamics with enhanced diffusivities, possibly by orders of magnitude, above normal translational diffusion. Reciprocal actuation does therefore lead to a significant advantage over nonmotile behavior for small organisms such as marine bacteria. © 2011 American Physical Society. Source


Korte M.,Helmholtz Center Potsdam | Constable C.,University of California at San Diego
Physics of the Earth and Planetary Interiors | Year: 2011

Global geomagnetic field reconstructions on millennial time scales can be based on comprehensive paleomagnetic data compilations but, especially for older data, these still suffer from limitations in data quality and age controls as well as poor temporal and spatial coverage. Here we present updated global models for the time interval 0-3. ka where additions to the data basis mainly impact the South-East Asian, Alaskan, and Siberian regions. We summarize recent progress in millennial scale modelling, documenting the cumulative results from incremental modifications to the standard algorithms used to produce regularized time-varying spherical harmonic models spanning 1000. BC to 1990. AD: from 1590 to 1990. AD gauss coefficients from the historical gufm1 model supplement the paleomagnetic information; in addition to absolute paleointensities, calibrated relative paleointensity data from sediments are now routinely included; iterative data rejection and recalibration of relative intensity records from sediments ensure stable results; bootstrap experiments to generate uncertainty estimates for the model take account of uncertainties in both age and magnetic elements and additionally assess the impact of sampling in both time and space. Based on averaged results from bootstrap experiments, taking account of data and age uncertainties, we distinguish more conservative model estimates CALS3k.nb representing robust field structure at the core-mantle boundary from relatively high resolution models CALS3k.n for model versions n= 3 and 4. We assess the impact of newly available data and modifications to the modelling method by comparing the previous CALS3k.3, the new CALS3k.4, and the conservative new model, CALS3k.4b. We conclude that with presently available data it is not feasible to produce a model that is equally suitable for relatively high-resolution field predictions at Earth's surface and robust reconstruction of field evolution, avoiding spurious structure, at the core-mantle boundary (CMB). We presently consider CALS3k.4 the best high resolution model and recommend the more conservative lower resolution version for studies of field evolution at the CMB. © 2011 Elsevier B.V. Source


In previous studies, we have demonstrated that spinal grafting of human or rat fetal spinal neural precursors leads to amelioration of spasticity and improvement in ambulatory function in rats with spinal ischemic injury. In the current study, we characterize the survival and maturation of three different human embryonic stem (ES) cell line-derived neural precursors (hNPCs) once grafted into ischemia-injured lumbar spinal cord in rats or in naive immunosuppressed minipigs. Proliferating HUES-2, HUES-7, or HUES-9 colonies were induced to form embryoid bodies. During the nestin-positive stage, the rosettes were removed and CD184(+)/CD271(-)/CD44(-)/CD24(+) population of ES-hNPCs FAC-sorted and expanded. Male Sprague-Dawley rats with spinal ischemic injury or naive immunosuppressed Gottingen-Minnesota minipigs received 10 bilateral injections of ES-NPCs into the L2-L5 gray matter. After cell grafting, animals survived for 2 weeks to 4.5 months, and the presence of grafted cells was confirmed after staining spinal cord sections with a combination of human-specific (hNUMA, HO14, hNSE, hSYN) or nonspecific (DCX, MAP2, CHAT, GFAP, APC) antibodies. In the majority of grafted animals, hNUMA-positive grafted cells were identified. At 2-4 weeks after grafting, double-labeled hNUMA/DCX-immunoreactive neurons were seen with extensive DCX(+) processes. At survival intervals of 4-8 weeks, hNSE(+) neurons and expression of hSYN was identified. Some hSYN-positive terminals formed putative synapses with the host neurons. Quantitative analysis of hNUMA(+) cells at 2 months after grafting showed comparable cell survival for all three cell lines. In the presence of low-level immunosuppression, no grafted cell survival was seen at 4.5 months after grafting. Spinal grafting of proliferating pluripotent HUES-7 cells led to consistent teratoma formation at 2-6 weeks after cell transplantation. These data show that ES-derived, FAC-sorted NPCs can represent an effective source of human NPCs to be used in CNS cell replacement therapies. Source


We report the fabrication of a three dimensional branched ZnO/Si heterojunction nanowire array by a two-step, wafer-scale, low-cost, solution etching/growth method and its use as photoelectrode in a photoelectrochemical cell for high efficiency solar powered water splitting. Specifically, we demonstrate that the branched nanowire heterojunction photoelectrode offers improved light absorption, increased photocurrent generation due to the effective charge separation in Si nanowire backbones and ZnO nanowire branching, and enhanced gas evolution kinetics because of the dramatically increased surface area and decreased radius of curvature. The branching nanowire heterostructures offer direct functional integration of different materials for high efficiency water photoelectrolysis and scalable photoelectrodes for clean hydrogen fuel generation. Source


Liu-Bryan R.,University of California at San Diego
Immunology and Cell Biology | Year: 2010

Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in the joint. Recent studies have significantly advanced our knowledge on the understanding of mechanisms underlying MSU crystal-induced inflammation. MSU crystals act as a 'danger signal' that can be recognized by pattern recognition receptors both at cell surface and cytoplasm, indicating the importance of innate immunity in gout. This review focuses on the critical role of intracellular NALP3 inflammasome in MSU crystal-induced inflammation. © 2010 Australasian Society for Immunology Inc. All rights reserved. Source


Nazarko T.Y.,University of California at San Diego
Autophagy | Year: 2014

Like other selective autophagy pathways, the selective autophagy of peroxisomes, pexophagy, is controlled by receptor protein complexes (RPCs). The pexophagic RPC in Pichia pastoris consists of several proteins: Pex3 and Pex14 ligands in the peroxisomal membrane, Atg30 receptor, Atg11, and Atg17 scaffolds, and the phagophore protein Atg8. Recently, we identified a new component of the pexophagic RPC, Atg37, which is involved in the assembly of this complex. Atg37 is an integral peroxisomal membrane protein (PMP) that binds Pex3 and Atg30, but not Pex14 or Atg8. In the absence of Atg37, the recognition of Pex3 and recruitment of Atg17 by Atg30 are normal. However, the recruitment of Atg11 is severely affected suggesting that the role of Atg37 is to facilitate the Atg30-Atg11 interaction. Palmitoyl-CoA competes with Atg30 for the acyl-CoA binding domain of Atg37 in vitro and might regulate the dynamics of the pexophagic RPC in vivo. The human counterpart of Atg37, ACBD5, also localizes to peroxisomes and is specifically required for pexophagy. Therefore, it is tempting to speculate that ACBD5/ATG37 regulates the assembly of the pexophagic RPC in mammalian cells. © 2014 Landes Bioscience. Source


Chen X.,University of California at Davis | Varki A.,University of California at San Diego
ACS Chemical Biology | Year: 2010

Sialic acids are a subset of nonulosonic acids, which are ninecarbon α-keto aldonic acids. Natural existing sialic acid-containing structures are presented in different sialic acid forms, various sialyl linkages, and on diverse underlying glycans. They play important roles in biological, pathological, and immunological processes. Sialobiology has been a challenging and yet attractive research area. Recent advances in chemical and chemoenzymatic synthesis, as well as large-scale E. coli cell-based production, have provided a large library of sialoside standards and derivatives in amounts sufficient for structure-activity relationship studies. Sialoglycan microarrays provide an efficient platform for quick identification of preferred ligands for sialic acid-binding proteins. Future research on sialic acid will continue to be at the interface of chemistry and biology. Research efforts not only will lead to a better understanding of the biological and pathological importance of sialic acids and their diversity but also could lead to the development of therapeutics. © 2010 American Chemical Society. Source


Lin J.Y.,University of California at San Diego
Experimental Physiology | Year: 2010

Channelrhodopsins (ChRs) are light-activated channels from algae that provide these organisms with fast sensors to visible light for phototaxis. Since its discovery, channelrhodopsin-2 (ChR2) has been used as a research tool to depolarize membranes of excitable cells with light. Subsequent chimeragenesis, mutagenesis and bioinformatic approaches have introduced additional ChR variants, such as channelrhodopsin-2 with H134R mutation (ChR2/H134R), channelrhodopsin-2 with E123T mutation (ChETA), Volvox carteri channelrhodopsin-1 (VChR1), Volvox carteri channelrhodopsin-2 (VChR2), channelrhodopsin-2 with C128 or D156A mutations (ChR2/C128X/D156A), chimera D (ChD), chimera EF (ChEF) and chimera EF with I170V mutation (I170V). Each of these ChR variuants has unique features and limitations, but there are few resources summarizing and comparing these ChRs in a systematic manner. In this review, the seven following key properties of ChRs that have significant influences on their effectiveness as research tools are examined: conductance, selectivity, kinetics, desensitization, light sensitivity, spectral response and membrane trafficking. Using this information, valuable qualities and deficits of each ChR variant are summarized. Optimal uses and potential future improvements of ChRs as optogenetic tools are also discussed. © 2010 The Author. Journal compilation © 2010 The Physiological Society. Source


Hendrix C.S.,University of Denver | Haggard S.,University of California at San Diego
Journal of Peace Research | Year: 2015

The 2014 IPCC report concludes that changes in precipitation and temperature could cause global food prices to nearly double by 2050. Anecdotal evidence of riots during the global food price spikes of 2007–08 and 2010–11 raises the more general question of whether global food prices affect patterns of contentious politics in developing countries. Drawing on a dataset of urban unrest in 55 major cities in 49 Asian and African countries for the period 1961–2010, we find the effect of global food prices on protests and rioting is contingent on regime type: democracies are more prone to urban unrest during periods of high food prices than autocracies. We show that this is due both to the more permissive political opportunity structure in democratic systems and to systematic differences in food policy across regimes of different types. Relative to autocracies, democracies pursue policies that are more favorable to the rural sector and less favorable to the cities. The findings have longer-run implications. To the extent that climate change will make many developing countries more dependent on food imports, and that prices could rise and be more volatile, we suggest another vector by which climate change may affect political unrest. Our findings highlight the importance of both political institutions and policy choices in mediating global shocks. © The Author(s) 2015 Source


Josefowicz S.Z.,Howard Hughes Medical Institute | Josefowicz S.Z.,Rockefeller University | Lu L.-F.,Howard Hughes Medical Institute | Lu L.-F.,University of California at San Diego | Rudensky A.Y.,Howard Hughes Medical Institute
Annual Review of Immunology | Year: 2012

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cellmediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells. © 2012 by Annual Reviews. All rights reserved. Source


Montal M.,University of California at San Diego
Annual Review of Biochemistry | Year: 2010

Botulinum neurotoxin (BoNT), the causative agent of botulism, is acknowledged to be the most poisonous protein known. BoNT proteases disable synaptic vesicle exocytosis by cleaving their cytosolic SNARE (soluble NSF attachment protein receptor) substrates. BoNT is a modular nanomachine: an N-terminal Zn 2+-metalloprotease, which cleaves the SNAREs; a central helical protein-conducting channel, which chaperones the protease across endosomes; and a C-terminal receptor-binding module, consisting of two subdomains that determine target specificity by binding to a ganglioside and a protein receptor on the cell surface and triggering endocytosis. For BoNT, functional complexity emerges from its modular design and the tight interplay between its component modules a partnership with consequences that surpass the simple sum of the individual component's action. BoNTs exploit this design at each step of the intoxication process, thereby achieving an exquisite toxicity. This review summarizes current knowledge on the structure of individual modules and presents mechanistic insights into how this protein machine evolved to this level of sophistication. Understanding the design principles underpinning the function of such a dynamic modular protein remains a challenging task. © 2010 by Annual Reviews. All rights reserved. Source


Goddard J.D.,University of California at San Diego
Applied Mechanics Reviews | Year: 2014

This is a survey of the interesting phenomenology and the prominent regimes of granular flow, followed by a unified mathematical synthesis of continuum modeling. The unification is achieved by means of "parametric" viscoelasticity and hypoplasticity based on elastic and inelastic potentials. Fully nonlinear, anisotropic viscoelastoplastic models are achieved by expressing potentials as functions of the joint isotropic invariants of kinematic and structural tensors. These take on the role of evolutionary parameters or "internal variables," whose evolution equations are derived from the internal balance of generalized forces. The resulting continuum models encompass most of the mechanical constitutive equations currently employed for granular media. Moreover, these models are readily modified to include Cosserat and other multipolar effects. Several outstanding questions are identified as to the contribution of parameter evolution to dissipation; the distinction between quasielastic and inelastic models of material instability; and the role of multipolar effects in material instability, dense rapid flow, and particle migration phenomena. Copyright © 2014 by ASME. Source


Goddard J.D.,University of California at San Diego
Acta Mechanica | Year: 2014

Following is an elaboration on D. G. B. Edelen's (1972-1973) nonlinear generalization of the classical Rayleigh-Onsager dissipation potentials and the implications for the models of viscoplasticity. A brief derivation is given via standard vector calculus of Edelen's potentials and the associated non-dissipative or "gyroscopic" forces and fluxes. It is also shown that certain extensions of Edelen's formulae can be obtained by means of a recently proposed source-flux relation or "inverse divergence," a generalization of the classical Gauss-Maxwell construct. The Legendre-Fenchel duality of Edelen's potentials is explored, with important consequences for rate-independent friction or plasticity. The use of dissipation potentials serves to facilitate the development of viscoplastic constitutive equations, a point illustrated here by the special cases of Stokesian fluid-particle suspensions and granular media. In particular, we consider inhomogeneous systems with particle migration coupled to gradients in particle concentration, strain rate, and fabric. Employing a mixture-theoretic treatment of Stokesian suspensions, one is able to identify particle stress as the work conjugate of the global deformation of the particle phase. However, in contrast to past treatments, this stress is not assumed to be a privileged driving force for particle migration. A comparison is made with models based on extremal dissipation or entropy production. It is shown that such models yield the correct dissipative components of force or flux but generally fail to capture certain non-dissipative, but mechanically relevant components. The significance of Edelen's gyroscopic forces and their relation to reactive constraints or other reversible couplings is touched upon. When gyroscopic terms are absent, one obtains a class of strongly dissipative or hyperdissipative materials whose quasi-static mechanics are governed by variational principles based on dissipation potential. This provides an interesting analog to elastostatic variational principles based on strain energy for hyperelastic materials and to the associated material instabilities arising from loss of convexity. © 2014 Springer-Verlag Wien. Source


Cartwright N.,University of California at San Diego
Preventive Medicine | Year: 2011

To what extent do the results of randomized controlled trials inform our predictions about the effectiveness of potential policy interventions? This crucial question is often overlooked in discussions about evidence-based policy. The view I defend is that the arguments that lead from the claim that a program works somewhere to a prediction about the effectiveness of this program as it will be implemented here rests on many premises, most of which cannot be justified by the results of randomized controlled trials. Randomized controlled trials only provide indirect evidence for effectiveness, and we need much more than just randomized- controlled-trial results to make reliable predictions. © 2011 Elsevier Inc. Source


Rus D.,Massachusetts Institute of Technology | Tolley M.T.,University of California at San Diego
Nature | Year: 2015

Conventionally, engineers have employed rigid materials to fabricate precise, predictable robotic systems, which are easily modelled as rigid members connected at discrete joints. Natural systems, however, often match or exceed the performance of robotic systems with deformable bodies. Cephalopods, for example, achieve amazing feats of manipulation and locomotion without a skeleton; even vertebrates such as humans achieve dynamic gaits by storing elastic energy in their compliant bones and soft tissues. Inspired by nature, engineers have begun to explore the design and control of soft-bodied robots composed of compliant materials. This Review discusses recent developments in the emerging field of soft robotics. © 2015 Macmillan Publishers Limited. All rights reserved. Source


Kauffman A.S.,University of California at San Diego
Molecular and Cellular Endocrinology | Year: 2010

The status of the neuroendocrine reproductive axis differs dramatically during various stages of development, and also differs in several critical ways between the sexes, including its earlier pubertal activation in females than males and the presence of neural circuitry that generates preovulatory hormone surges in females but not males. The reproductive axis is controlled by various hormonal and neural pathways that converge upon forebrain gonadotropin-releasing hormone (GnRH) neurons, and many of the critical age and sex differences in the reproductive axis likely reflect differences in the " upstream" circuits and factors that regulate the GnRH system. Recently, the neural kisspeptin system has been implicated as an important regulator of GnRH neurons. Here I discuss the evidence supporting a critical role of kisspeptin signaling at different stages of life, including early postnatal and pubertal development, as well as in adulthood, focusing primarily on information gleaned from mammalian studies. I also evaluate key aspects of sexual differentiation and development of the brain as it relates to the Kiss1 system, with special emphasis on rodents. In addition to discussing recent advances in the field of kisspeptin biology, this paper will highlight a number of unanswered questions and future challenges for kisspeptin investigators, and will stress the importance of studying the kisspeptin system in both males and females, as well as in multiple species. © 2010 Elsevier Ireland Ltd. Source


Solinas G.,University of Fribourg | Karin M.,University of California at San Diego
FASEB Journal | Year: 2010

Inflammation is thought to underlie the pathogenesis of many chronic diseases. It is now established that obesity results in a state of chronic low-grade inflammation thought to contribute to several metabolic disorders, including insulin resistance and pancreatic islet dysfunction. The protein kinases JNK1 and IKKβ have been found to serve as critical molecular links between obesity, metabolic inflammation, and disorders of glucose homeostasis. The precise mechanisms of these linkages are still being investigated. However, as we discuss here, JNK1 and IKKβ are activated by almost all forms of metabolic stress that have been implicated in insulin resistance or islet dysfunction. Furthermore, both JNK1 and IKKβ are critically involved in the promotion of diet-induced obesity, metabolic inflammation, insulin resistance, and β-cell dysfunction. Understanding the molecular mechanisms by which JNK1 and IKKβ mediate obesity-induced metabolic stress is likely to be of importance for the development of new treatments for a variety of obesity-associated diseases. © FASEB. Source


Matthay K.K.,University of California at San Francisco | George R.E.,Dana-Farber Cancer Institute | Yu A.L.,University of California at San Diego
Clinical Cancer Research | Year: 2012

Neuroblastoma, the most common extracranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease and have a 5-year event-free survival of <50%. New approaches with targeted therapy may improve efficacy without increased toxicity. In this review we evaluate 3 promising targeted therapies: (i) 131I- metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of neuroblastomas; (ii) immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, which is expressed on 98% of neuroblastoma cells; and (iii) inhibitors of anaplastic lymphoma kinase (ALK), a tyrosine kinase that is mutated or amplified in ∼10% of neuroblastomas and expressed on the surface of most neuroblastoma cells. Early-phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of ∼30%, but the technical aspects of administering large amounts of radioactivity in young children and limited access to this agent have hindered its incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also shown activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small-molecule inhibitor of ALK has shown promising preclinical activity for neuroblastoma and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma. ©2012 AACR. Source


Hagood J.S.,University of California at San Diego
Physiology | Year: 2014

The lung develops from a very simple outpouching of the foregut into a highly complex, finely structured organ with multiple specialized cell types that are required for its normal physiological function. During both the development of the lung and its remodeling in the context of disease or response to injury, gene expression must be activated and silenced in a coordinated manner to achieve the tremendous phenotypic heterogeneity of cell types required for homeostasis and pathogenesis. Epigenetic mechanisms, consisting of DNA base modifications such as methylation, alteration of histones resulting in chromatin modification, and the action of noncoding RNA, control the regulation of information "beyond the genome" required for both lung modeling and remodeling. Epigenetic regulation is subject to modification by environmental stimuli, such as oxidative stress, infection, and aging, and is thus critically important in chronic remodeling disorders such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), broncho-pulmonary dysplasia (BPD), and pulmonary hypertension (PH). Technological advances have made it possible to evaluate genome-wide epigenetic changes (epigenomics) in diseases of lung remodeling, clarifying existing pathophysi-ological paradigms and uncovering novel mechanisms of disease. Many of these represent new therapeutic targets. Advances in epigenomic technology will accelerate our understanding of lung development and remodeling, and lead to novel treatments for chronic lung diseases. © 2014 Int. Union Physiol. Sci./Am. Physiol. Soc. Source


Yang L.,U.S. National Cancer Institute | Karin M.,University of California at San Diego
Cell Death and Differentiation | Year: 2014

Loss or silencing of tumor suppressors (TSs) promotes neoplastic transformation and malignant progression. To date, most work on TS has focused on their cell autonomous effects. Recent evidence, however, demonstrates an important noncell autonomous role for TS in the control of tumor-associated inflammation. We review evidence from clinical data sets and mouse model studies demonstrating enhanced inflammation and altered tumor microenvironment (TME) upon TS inactivation. We discuss clinical correlations between tumor-associated inflammation and inactivation of TS, and their therapeutic implications. This review sets forth the concept that TS can also suppress tumor-associated inflammation, a concept that provides new insights into tumor-host interactions. We also propose that in some cases the loss of TS function in cancer can be overcome through inhibition of the resulting inflammatory response, regardless whether it is a direct or an indirect consequence of TS loss. © 2015 Macmillan Publishers Limited. Source


Fu X.-D.,University of California at San Diego | Ares M.,University of California at Santa Cruz
Nature Reviews Genetics | Year: 2014

Sequence-specific RNA-binding proteins (RBPs) bind to pre-mRNA to control alternative splicing, but it is not yet possible to read the 'splicing code' that dictates splicing regulation on the basis of genome sequence. Each alternative splicing event is controlled by multiple RBPs, the combined action of which creates a distribution of alternatively spliced products in a given cell type. As each cell type expresses a distinct array of RBPs, the interpretation of regulatory information on a given RNA target is exceedingly dependent on the cell type. RBPs also control each other's functions at many levels, including by mutual modulation of their binding activities on specific regulatory RNA elements. In this Review, we describe some of the emerging rules that govern the highly context-dependent and combinatorial nature of alternative splicing regulation. © 2014 Macmillan Publishers Limited. Source


Kis K.,University of California at San Diego
Expert reviews in molecular medicine | Year: 2011

During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, which occurs in hypertrophic scars or tissue fibrosis, results in a loss of function. Many reviews outline the cellular and molecular features of myofibroblasts and their roles in a variety of diseases. This review focuses on the origins of myofibroblasts and the factors that control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts originate mostly from tissue-resident fibroblasts, and also from epithelial and endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, which promotes their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT-β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated. Source


Encalada S.E.,Scripps Research Institute | Goldstein L.S.B.,University of California at San Diego
Annual Review of Biophysics | Year: 2014

Axonal transport is indispensable for the distribution of vesicles, organelles, messenger RNAs (mRNAs), and signaling molecules along the axon. This process is mediated by kinesins and dyneins, molecular motors that bind to cargoes and translocate on microtubule tracks. Tight modulation of motor protein activity is necessary, but little is known about the molecules and mechanisms that regulate transport. Moreover, evidence suggests that transport impairments contribute to the initiation or progression of neurodegenerative diseases, or both, but the mechanisms by which motor activity is affected in disease are unclear. In this review, we discuss some of the physical and biophysical properties that influence motor regulation in healthy neurons. We further discuss the evidence for the role of transport in neurodegeneration, highlighting two pathways that may contribute to transport impairment-dependent disease: genetic mutations or variation, and protein aggregation. Understanding how and when transport parameters change in disease will help delineate molecular mechanisms of neurodegeneration. Copyright © 2014 by Annual Reviews. All rights reserved. Source


Stiles J.,University of California at San Diego
Developmental Psychobiology | Year: 2012

This special section emphasizes three key factors relevant to understanding brain responses to injury. First, it is important to consider the impact of injury on brain networks rather then just the localized neuropathology. In contrast to older localizationist models, neural systems views emphasize that the effects of localized injury cascade through the neural system altering function at multiple levels. Thus, effective remediation must accommodate the multiple effects of brain injury. Second, the role of neural plasticity in the brain response to injury is critical. Rehabilitation implies that neural system is adaptive and capable of changing in response to input. Thus exploiting the brain's inherent plasticity is central to remediation. Finally, the timing of injury is an essential consideration. Adult injury disrupts stable neural systems and plasticity operates to regain functional balance. In contrast, early injury affects fundamental development processes and alters the emerging organization and functioning of neural systems. © 2012 Wiley Periodicals, Inc. Source


Matzkin L.M.,University of Alabama in Huntsville | Matzkin L.M.,University of California at San Diego
Molecular Ecology | Year: 2012

In the presence of environmental change, natural selection can shape the transcriptome. Under a scenario of environmental change, genotypes that are better able to modulate gene expression to maximize fitness will tend to be favoured. Therefore, it is important to examine gene expression at the population level to distinguish random or neutral gene expression variation from the pattern produced by natural selection. This study investigates the natural variation in transcriptional response to a cactus host shift utilizing the mainland Sonora population of Drosophila mojavensis. Drosophila mojavensis is a cactophilic species composed of four cactus host populations endemic to the deserts of North America. Overall, the change in cactus host was associated with a significant reduction in larval viability as well as the differential expression of 21% of the genome (3109 genes). Among the genes identified were a set of genes previously known to be involved in xenobiotic metabolism, as well as genes involved in cellular energy production, oxidoreductase/carbohydrate metabolism, structural components and mRNA binding. Interestingly, of the 3109 genes whose expression was affected by host use, there was a significant overrepresentation of genes that lacked an orthologous call to the D. melanogaster genome, suggesting the possibility of an accelerated rate of evolution in these genes. Of the genes with a significant cactus effect, the majority, 2264 genes, did not exhibit a significant cactus-by-line interaction. This population-level approach facilitated the identification of genes involved in past cactus host shifts. © 2012 Blackwell Publishing Ltd. Source


Cooper D.C.,University of California at San Diego
Annals of behavioral medicine : a publication of the Society of Behavioral Medicine | Year: 2010

BACKGROUND: Although objective and subjective indicators of socioeconomic status (SES) are linked to cardiovascular disease (CVD), little is known about their relationship to endothelial dysfunction, which often precedes CVD. PURPOSE: This study examined how objective and subjective SES relate to brachial artery flow-mediated dilation (FMD). METHODS: FMD was assessed in 72 healthy adults (mean age 36 years). The MacArthur Scale of Subjective Social Status assessed perceived social standing in the USA (SSS-USA) and local community (SSS-Community). Objective SES measures included income and the Hollingshead Two-Factor Index of Social Position (education, occupation). RESULTS: Adjusted regressions revealed that SSS-Community positively correlated with FMD (p < 0.05) and explained 8% of the variance. No other SES measures were significant for FMD. The association between FMD and SSS-Community remained significant (p < 0.01) after adjustment for objective SES and other covariates. CONCLUSIONS: Lower subjective social status in one's community may be linked to CVD via impaired vasodilation. Source


Huffaker A.,University of California at San Diego
Current Opinion in Insect Science | Year: 2015

Over 20 years ago the peptide systemin was discovered to be an integral regulator of anti-herbivore defense responses in Solanaceous plants. However, other peptides of similar function have remained elusive. Plant Elicitor Peptides (Peps) were initially discovered in Arabidopsis as mediators of basal immune responses protective against invading pathogens. Recently a Pep from maize, ZmPep3, was demonstrated to be a potent regulator of anti-herbivore defenses. ZmPep3 was as active as the Lepidopteran elicitor N-linolenoyl-l-glutamine (Gln-18:3) in stimulating volatile emission and accumulation of defense transcripts and metabolites, resulting in both attraction of the parasitoid Cotesia marginiventris and suppressed growth of Spodoptera exigua larvae. Orthologues of Peps in Solanaceous and Fabaceous plants also trigger emission of herbivore-associated volatiles, indicating that Peps have a conserved role as regulators of plant defense against herbivores in diverse species. This conservation of a peptide signal and cognate receptor for activation of plant defense responses reveals a widespread regulatory motif and provides opportunities for manipulation of plant resistance. Source


Background: Both vertebroplasty and balloon kyphoplasty have been described for treatment of vertebral compression fractures. Vertebroplasty is known for its high leakage rate compared with balloon kyphoplasty. In vitro studies have shown that high-viscosity cements significantly decrease the incidence of cement leakage and increase the predictability of cement fill in cancellous bonelike substrates compared with low-viscosity cements. Objective: This study compares the incidence and pattern of cement leakage in cases treated with standard balloon kyphoplasty (BKP) and a novel vertebral augmentation procedure, radiofrequency targeted vertebral augmentation (RF-TVA). Study Design: Retrospective evaluation of postoperative radiographs. Setting: Single center inpatient and outpatient population. Methods: Two methods of vertebral augmentation were utilized. Conventional bipedicular BKP and RF-TVA, a novel unipedicular technique which uses a navigational osteotome to create targeted, bone sparing cavities and RF energy to deliver an ultra-high viscosity cement at a consistent rate via a remote controlled, automated hydraulic delivery system. Postoperative radiographs of patients treated with the 2 techniques were critically analyzed for the incidence and location of cement leakage. Eighty consecutive patients with 106 treated levels were included. Thirty-five patients with 49 levels in the BKP and 45 patients with 57 levels in RF-TVA group were evaluated. Results: Leakages less than 1-2 mm were not reported since they may not represent any clinical significance. In the BKP group, 6 leakages (12%) were reported (3 discal, 2 venous, one paravaertebral, and no epidural). In the RF-TVA group, a total of 3 leakages (5%) were reported, (one discal, 2 venous, no paravaertebral or epidural). Using contingency analysis for leakage per level, there was a statistical difference for leakage between RF-TVA and standard BKP, P < 0.01. Limitations: Retrospective study, single center. Conclusions: The RF-TVA technique may provide an approximately 50% reduction in leakage rate when compared to standard BKP. This may be related to the combination of controlled delivery of radiofrequency activated (high viscosity) cement at a fixed, low rate of delivery into sitespecific channels created using a navigational osteotome. Additionally, based on the unipedicular access and remotely controlled cement delivery RF-TVA may decrease procedural invasiveness and physician radiation exposure, respectively. Institutional Review: This study was approved by the Institutional Review Board. Source


Talley L.D.,University of California at San Diego
Oceanography | Year: 2013

The overturning pathways for the surface-ventilated North Atlantic Deep Water (NADW) and Antarctic Bottom Water (AABW) and the diffusively formed Indian Deep Water (IDW) and Pacific Deep Water (PDW) are intertwined. The global overturning circulation (GOC) includes both large wind-driven upwelling in the Southern Ocean and important internal diapycnal transformation in the deep Indian and Pacific Oceans. All three northern-source Deep Waters (NADW, IDW, PDW) move southward and upwell in the Southern Ocean. AABW is produced from the denser, salty NADW and a portion of the lighter, low oxygen IDW/PDW that up wells above and north of NADW. The remaining upwelled IDW/PDW stays near the surface, moving into the subtropical thermoclines, and ultimately sources about one-third of the NADW. Another third of the NADW comes from AABW upwelling in the Atlantic. The remaining third comes from AABW upwelling to the thermocline in the Indian-Pacific. Atlantic cooling associated with NADW formation (0.3 PW north of 32°S; 1 PW = 1015 W) and Southern Ocean cooling associated with AABW formation (0.4 PW south of 32°S) are balanced mostly by 0.6 PW of deep diffusive heating in the Indian and Pacific Oceans; only 0.1 PW is gained at the surface in the Southern Ocean. Thus, while an adiabatic model of NADW global overturning driven by winds in the Southern Ocean, with buoyancy added only at the surface in the Southern Ocean, is a useful dynamical idealization, the associated heat changes require full participation of the diffusive Indian and Pacific Oceans, with a basin-averaged diffusivity on the order of the Munk value of 10-4 m2 s-1. © 2013 by The Oceanography Society. All rights reserved. Source


Daneman R.,University of California at San Diego | Prat A.,University of Montreal
Cold Spring Harbor Perspectives in Biology | Year: 2015

Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood–brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved. Source


West J.B.,University of California at San Diego
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2013

In 1953 Frank Low published the first high-resolution electron micrographs of the human pulmonary blood-gas barrier. These showed that a structure only 0.3-fxm thick separated the capillary blood from the alveolar gas, immediately suggesting that the barrier might be vulnerable to mechanical failure if the capillary pressure increased. However, it was 38 years before stress failure was recognized. Initially it was implicated in the pathogenesis of High Altitude Pulmonary Edema, but it was soon clear that stress failure of pulmonary capillaries is common. The vulnerability of the blood-gas barrier is a key factor in the evolution of the pulmonary circulation. As evolution progressed from the ancestors of fishes to amphibians, reptiles, and finally birds and mammals, two factors challenged the integrity of the barrier. One was the requirement for the barrier to become increasingly thin because of the greater oxygen consumption. The other was the high pulmonary capillary pressures that were inevitable before there was complete separation of the pulmonary and systemic circulations. © 2013 the American Physiological Society. Source


Selverston A.I.,University of California at San Diego
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

There are now a reasonable number of invertebrate central pattern generator (CPG) circuits described in sufficient detail that a mechanistic explanation of how they work is possible. These small circuits represent the best-understood neural circuits with which to investigate how cell-tocell synaptic connections and individual channel conductances combine to generate rhythmic and patterned output. In this review, some of the main lessons that have appeared from this analysis are discussed and concrete examples of circuits ranging from single phase to multiple phase patterns are described. While it is clear that the cellular components of any CPG are basically the same, the topology of the circuits have evolved independently to meet the particular motor requirements of each individual organism and only a few general principles of circuit operation have emerged. The principal usefulness of small systems in relation to the brain is to demonstrate in detail how cellular infrastructure can be used to generate rhythmicity and form specialized patterns in a way that may suggest how similar processes might occur in more complex systems. But some of the problems and challenges associated with applying data from invertebrate preparations to the brain are also discussed. Finally, I discuss why it is useful to have well-defined circuits with which to examine various computational models that can be validated experimentally and possibly applied to brain circuits when the details of such circuits become available. © 2010 The Royal Society. Source


Jordan A.S.,University of Melbourne | Jordan A.S.,Institute for Breathing and Sleep | McSharry D.G.,Harvard University | Malhotra A.,Harvard University | Malhotra A.,University of California at San Diego
The Lancet | Year: 2014

Obstructive sleep apnoea is an increasingly common disorder of repeated upper airway collapse during sleep, leading to oxygen desaturation and disrupted sleep. Features include snoring, witnessed apnoeas, and sleepiness. Pathogenesis varies; predisposing factors include small upper airway lumen, unstable respiratory control, low arousal threshold, small lung volume, and dysfunctional upper airway dilator muscles. Risk factors include obesity, male sex, age, menopause, fluid retention, adenotonsillar hypertrophy, and smoking. Obstructive sleep apnoea causes sleepiness, road traffic accidents, and probably systemic hypertension. It has also been linked to myocardial infarction, congestive heart failure, stroke, and diabetes mellitus though not definitively. Continuous positive airway pressure is the treatment of choice, with adherence of 60-70%. Bi-level positive airway pressure or adaptive servo-ventilation can be used for patients who are intolerant to continuous positive airway pressure. Other treatments include dental devices, surgery, and weight loss. Source


Key K.,University of California at San Diego
Surveys in Geophysics | Year: 2012

The past decade has been a period of rapid growth for marine electromagnetic (EM) methods, predominantly due to the industrial adoption and promotion of EM as a valuable tool for characterizing offshore hydrocarbon reservoirs. This growth is illustrated by a database of marine EM publications spanning from the early developments in the 1960's to the present day; while over 300 peer-reviewed papers on marine EM have been published to date, more than half of these papers have been published within the last decade. This review provides an overview of these recent developments, covering industrial and academic use of marine EM for resource exploration and tectonic investigations, ranging from acquisition technology and modeling approaches to new physical and geological insights learned from recent data sets. © 2011 Springer Science+Business Media B.V. Source


Kavanaugh A.,University of California at San Diego
Clinical and Experimental Rheumatology | Year: 2012

Recently, the concept of "treat-to-target" has emerged as a topic of great interest in rheumatology, particularly as regards the therapeutic approach to patients with rheumatoid arthritis RA). From observational data as well data from controlled clinical trials, there is a body of evidence supporting this idea. Thus, closely monitoring RA patients and adjusting therapies with the goal of achieving the lowest disease activity possible can result in optimal outcomes for patients. Based on the success in RA, interest in adopting a treatto-target approach in other rheumatic conditions, including psoriatic arthritis (PsA) has arisen. It would appear logical that some data from "treat-totarget" approaches in RA may readily be extrapolated to PsA, particularly as it relates to PsA patients with polyarticular peripheral arthritis. However, PsA is a heterogeneous disorder, with involvement in areas quite distinct from RA, including the skin and nails, the axial spine, and the entheses. Therefore, developing a treat-to-target strategy in PsA will require additional disease specific considerations to optimise its implementation. © Copyright Clinical and Experimental Rheumatology 2012. Source


Baumgart D.C.,TU Berlin | Sandborn W.J.,University of California at San Diego
The Lancet | Year: 2012

Crohn's disease is a relapsing systemic inflammatory disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations and associated immune disorders. Genome wide association studies identified susceptibility loci that - triggered by environmental factors - result in a disturbed innate (ie, disturbed intestinal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response and autophagy, impaired recognition of microbes by pattern recognition receptors, such as nucleotide binding domain and Toll like receptors on dendritic cells and macrophages) and adaptive (ie, imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota. We discuss the epidemiology, immunobiology, amd natural history of Crohn's disease; describe new treatment goals and risk stratification of patients; and provide an evidence based rational approach to diagnosis (ie, work-up algorithm, new imaging methods [ie, enhanced endoscopy, ultrasound, MRI and CT] and biomarkers), management, evolving therapeutic targets (ie, integrins, chemokine receptors, cell-based and stem-cell-based therapies), prevention, and surveillance. © 2012 Elsevier Ltd. Source


Hauser F.,University of California at San Diego | Horie T.,Okayama University
Plant, Cell and Environment | Year: 2010

Increasing soil salinity is a serious threat to agricultural productions worldwide in the 21st century. Several essential Na+ transporters such as AtNHX1 and AtSOS1 function in Na+ tolerance under salinity stress in plants. Recently, evidence for a new primary salt tolerance mechanism has been reported, which is mediated by a class of HKT transporters both in dicots such as Arabidopsis and monocot crops such as rice and wheat. Here we present a review on vital physiological functions of HKT transporters including AtHKT1;1 and OsHKT1;5 in preventing shoot Na+ over-accumulation by mediating Na+ exclusion from xylem vessels in the presence of a large amount of Na+ thereby protecting leaves from salinity stress. Findings of the HKT2 transporter sub-family are also updated in this review. Subjects regarding function and regulation of HKT transporters, which need to be elucidated in future research, are discussed. © 2009 Blackwell Publishing Ltd. Source


Janowsky D.S.,University of California at San Diego
Current Psychiatry Reports | Year: 2011

The adrenergic-cholinergic balance hypothesis of mania and depression suggests that depression may be due to an over-activity or a hypersensitivity to central acetylcholine. From this hypothesis, it is logical that scopolamine, a centrally acting antimuscarinic agent, would be useful as an antidepressant. Authors, working at the Intramural Program at NIMH in Bethesda Maryland have shown that intravenous scopolamine is a rapidly acting, effective antidepressant and have than replicated this finding. They now report that this antidepressant effect occurs in bipolar, as well as unipolar depressed patients. The clinical and theoretical implications of this findng for difficult to treat bipolar depressed patients is considerable, and the finding is in need of independent replication. © Springer Science+Business Media, LLC 2011. Source


Webster M.A.,University of Nevada, Reno | Macleod D.I.A.,University of California at San Diego
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

The appearance of faces can be strongly affected by the characteristics of faces viewed previously. These perceptual after-effects reflect processes of sensory adaptation that are found throughout the visual system, but which have been considered only relatively recently in the context of higher level perceptual judgements. In this review, we explore the consequences of adaptation for human face perception, and the implications of adaptation for understanding the neural-coding schemes underlying the visual representation of faces. The properties of face after-effects suggest that they, in part, reflect response changes at high and possibly face-specific levels of visual processing. Yet, the form of the after-effects and the norm-based codes that they point to show many parallels with the adaptations and functional organization that are thought to underlie the encoding of perceptual attributes like colour. The nature and basis for human colour vision have been studied extensively, and we draw on ideas and principles that have been developed to account for norms and normalization in colour vision to consider potential similarities and differences in the representation and adaptation of faces. © 2011 The Royal Society. Source


Shpyrko O.G.,University of California at San Diego
Journal of Synchrotron Radiation | Year: 2014

In recent years, X-ray photon correlation spectroscopy (XPCS) has emerged as one of the key probes of slow nanoscale fluctuations, applicable to a wide range of condensed matter and materials systems. This article briefly reviews the basic principles of XPCS as well as some of its recent applications, and discusses some novel approaches to XPCS analysis. It concludes with a discussion of the future impact of diffraction-limited storage rings on new types of XPCS experiments, pushing the temporal resolution to nanosecond and possibly even picosecond time scales. © 2014 International Union of Crystallography. Source


Saier Jr. M.H.,University of California at San Diego
Journal of Molecular Microbiology and Biotechnology | Year: 2013

The prokaryotic cell was once thought of as a 'bag of enzymes' with little or no intracellular compartmentalization. In this view, most reactions essential for life occurred as a consequence of random molecular collisions involving substrates, cofactors and cytoplasmic enzymes. Our current conception of a prokaryote is far from this view. We now consider a bacterium or an archaeon as a highly structured, nonrandom collection of functional membrane-embedded and proteinaceous molecular machines, each of which serves a specialized function. In this article we shall present an overview of such microcompartments including (1) the bacterial cytoskeleton and the apparati allowing DNA segregation during cell division; (2) energy transduction apparati involving light-driven proton pumping and ion gradient-driven ATP synthesis; (3) prokaryotic motility and taxis machines that mediate cell movements in response to gradients of chemicals and physical forces; (4) machines of protein folding, secretion and degradation; (5) metabolosomes carrying out specific chemical reactions; (6) 24-hour clocks allowing bacteria to coordinate their metabolic activities with the daily solar cycle, and (7) proteinaceous membrane compartmentalized structures such as sulfur granules and gas vacuoles. Membrane-bound prokaryotic organelles were considered in a recent Journal of Molecular Microbiology and Biotechnology written symposium concerned with membranous compartmentalization in bacteria [J Mol Microbiol Biotechnol 2013;23:1-192]. By contrast, in this symposium, we focus on proteinaceous microcompartments. These two symposia, taken together, provide the interested reader with an objective view of the remarkable complexity of what was once thought of as a simple noncompartmentalized cell. Copyright © 2013 S. Karger AG, Basel. Source


Asch R.G.,University of California at San Diego | Asch R.G.,Princeton University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Climate change has prompted an earlier arrival of spring in numerous ecosystems. It is uncertain whether such changes are occurring in Eastern Boundary Current Upwelling ecosystems, because these regions are subject to natural decadal climate variability, and regional climate models predict seasonal delays in upwelling. To answer this question, the phenology of 43 species of larval fishes was investigated between 1951 and 2008 off southern California. Ordination of the fish community showed earlier phenological progression in more recent years. Thirty-nine percent of seasonal peaks in larval abundance occurred earlier in the year, whereas 18% were delayed. The species whose phenology became earlier were characterized by an offshore, pelagic distribution, whereas species with delayed phenology were more likely to reside in coastal, demersal habitats. Phenological changes were more closely associated with a trend toward earlier warming of surface waters rather than decadal climate cycles, such as the Pacific Decadal Oscillation and North Pacific Gyre Oscillation. Species with long-term advances and delays in phenology reacted similarly to warming at the interannual time scale as demonstrated by responses to the El Niño Southern Oscillation. The trend toward earlier spawning was correlated with changes in sea surface temperature (SST) and mesozooplankton displacement volume, but not coastal upwelling. SST and upwelling were correlated with delays in fish phenology. For species with 20th century advances in phenology, future projections indicate that current trends will continue unabated. The fate of species with delayed phenology is less clear due to differences between Intergovernmental Panel on Climate Change models in projected upwelling trends. Source


Stevens C.F.,University of California at San Diego
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The fly olfactory system has a three-layer architecture: The fly's olfactory receptor neurons send odor information to the first layer (the encoder) where this information is formatted as combinatorial odor code, one which is maximally informative, with the most informative neurons firing fastest. This first layer then sends the encoded odor information to the second layer (decoder), which consists of about 2,000 neurons that receive the odor information and "break" the code. For each odor, the amplitude of the synaptic odor input to the 2,000 second-layer neurons is approximately normally distributed across the population, which means that only a very small fraction of neurons receive a large input. Each odor, however, activates its own population of large-input neurons and so a small subset of the 2,000 neurons serves as a unique tag for the odor. Strong inhibition prevents most of the second-stage neurons from firing spikes, and therefore spikes from only the small population of large-input neurons is relayed to the third stage. This selected population provides the third stage (the user) with an odor label that can be used to direct behavior based on what odor is present. Source


Radisic M.,University of Toronto | Christman K.L.,University of California at San Diego
Mayo Clinic Proceedings | Year: 2013

Heart failure after a myocardial infarction continues to be a leading killer in the Western world. Currently, there are no therapies that effectively prevent or reverse the cardiac damage and negative left ventricular remodeling process that follows a myocardial infarction. Because the heart has limited regenerative capacity, there has been considerable effort to develop new therapies that could repair and regenerate the myocardium. Although cell transplantation alone was initially studied, more recently, tissue engineering strategies using biomaterial scaffolds have been explored. In this review, we cover the different approaches to engineering the myocardium, including cardiac patches, which are in vitro-engineered constructs of functional myocardium, and injectable scaffolds, which can either encourage endogenous repair and regeneration or act as vehicles to support the delivery of cells and other therapeutics. © 2013 Mayo Foundation for Medical Education and Research. Source


Villa E.,University of California at San Diego | Lasker K.,Stanford University
Current Opinion in Structural Biology | Year: 2014

Cryo-electron microscopy is a central tool for studying the architecture of macromolecular complexes at subnanometer resolution. Interpretation of an electron microscopy map requires its computational integration with data about the structure's components from all available sources, notably atomic models. Selecting a protocol for EM density-guided integrative structural modeling depends on the resolution and quality of the EM map as well as the available complimentary datasets. Here, we review rigid, flexible, and de novo integrative fitting into EM maps and provide guidelines and considerations for the design of modeling experiments. Finally, we discuss efforts towards establishing unified criteria for map and model assessment and validation. © 2014 Elsevier Ltd. Source


Buckwalter J.F.,University of California at San Diego
IEEE Journal of Solid-State Circuits | Year: 2014

A 10 bit current-steering, digital-to-analog converter (DAC) is presented that delivers 6 VPP into a 100 Ω differential load. To realize high-voltage swings using fineline CMOS, a stacked-FET buffer is used to isolate the current source from the output load. The stacked-FET buffer degrades the linearity of the DAC. This work presents a Volterra analysis to capture the frequency-dependent behavior of the stacked-FET circuit that can be cascaded to quantify the linearity of an N-device stack. The power DAC is implemented in 45 nm CMOS SOI and the measured differential nonlinearity (DNL) and integral nonlinearity (INL) is better than 0.4 and 0.6 LSB, respectively. The DAC consumes 476 mW and achieves a peak SFDR of 73 dB and a minimum IM3 of -69 dBc. This DAC demonstrates the largest output swing and highest power efficiency for a high-resolution (> 8 bit), high-speed (> 100 MS/s) DAC. © 1966-2012 IEEE. Source


Loomis W.F.,University of California at San Diego
Developmental Biology | Year: 2015

Cells grow, move, expand, shrink and die in the process of generating the characteristic shapes of organisms. Although the structures generated during development of the social amoeba Dictyostelium discoideum look nothing like the structures seen in metazoan embryogenesis, some of the morphogenetic processes used in their making are surprisingly similar. Recent advances in understanding the molecular basis for directed cell migration, cell type specific sorting, differential adhesion, secretion of matrix components, pattern formation, regulation and terminal differentiation are reviewed. Genes involved in Dictyostelium aggregation, slug formation, and culmination of fruiting bodies are discussed. © 2015 Elsevier Inc. Source


Dudko O.K.,University of California at San Diego
Quarterly Reviews of Biophysics | Year: 2016

The capacity of biological macromolecules to act as exceedingly sophisticated and highly efficient cellular machines - switches, assembly factors, pumps, or motors - is realized through their conformational transitions, that is, their folding into distinct shapes and selective binding to other molecules. Conformational transitions can be induced, monitored, and manipulated by pulling individual macromolecules apart with an applied force. Pulling experiments reveal, for a given biomolecule, the relationship between applied force and molecular extension. Distinct signatures in the force-extension relationship identify a given biomolecule and thus serve as the molecule's 'mechanical fingerprints'. But, how can these fingerprints be decoded to uncover the energy barriers crossed by the molecule in the course of its conformational transition, as well as the associated timescales? This review summarizes a powerful class of approaches to interpreting single-molecule force spectroscopy measurements - namely, analytically tractable approaches. On the fundamental side, analytical theories have the power to reveal the unifying principles underneath the bewildering diversity of biomolecules and their behaviors. On the practical side, analytical expressions that result from these theories are particularly well suited for a direct fit to experimental data, yielding the important parameters that govern biological processes at the molecular level. © 2016 Cambridge University Press. Source


Gilmer T.,University of California at San Diego
Medical Care | Year: 2011

Objective: Healthcare reform will result in substantial numbers of newly insured, low-income adults with chronic conditions. This paper examines the costs of a chronic disease management program among newly insured adults with diabetes and/or hypertension. Research Design and Methods: Low-income adults with diabetes and/or hypertension were provided County-sponsored health insurance coverage and access to disease management. Health econometric methods were used to compare costs among participants in disease management to nonparticipants, both overall and in comparison between those who were newly insured versus previously insured under an alternative County-sponsored insurance product. Costs were also compared between those who qualified for County-sponsored coverage due to diabetes versus hypertension. Results: Annual inpatient costs were $1260 lower, and outpatient costs were $723 greater, among participants in disease management (P<0.001 each). Participants in disease management without previous County-sponsored coverage had higher pharmacy costs ($154, P=0.002) than nonparticipants; whereas participants with diabetes had marginally significant lower overall costs compared with nonparticipants ($-685, P=0.070). Conclusions: Disease management was successful in increasing the use of outpatient services among participants. The offsetting costs of the program suggest that disease management should be considered for some newly insured populations, especially for adults with diabetes. © 2011 by Lippincott Williams & Wilkins. Source


Steinberg D.,University of California at San Diego
Journal of Lipid Research | Year: 2013

This year marks the 100th anniversary of the publication of Anitschkow's classic paper proposing the central role of hypercholesterolemia in atherogenesis. We at the Journal of Lipid Research take this occasion to acknowledge the debt we all owe to Anitschkow and his colleagues for getting us on the right track. As discussed below in detail, his contributions were insightful and went well beyond simply pinpointing hypercholesterolemia as a major etiologic factor. Anitschkow's work led him to define most of the key elements in the initiation and evolution of lesions in animal models of atherogenesis. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc. Source


Goldstein P.S.,University of California at San Diego
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

The south central Andes is known as a region of enduring multiethnic diversity, yet it is also the cradle of one the South America's first successful expansive-state societies. Social structures that encouraged the maintenance of separate identities among coexistent ethnic groups may explain this apparent contradiction. Although the early expansion of the Tiwanaku state (A.D. 600-1000) is often interpreted according to a centralized model derived from Old World precedents, recent archaeological research suggests a reappraisal of the socio-political organization of Tiwanaku civilization, both for the diversity of social entities within its core region and for the multiple agencies behind its wider program of agropastoral colonization. Tiwanaku's sociopolitical pluralism in both its homeland and colonies tempers some of archaeology's global assumptions about the predominant role of centralized institutions in archaic states. Source


Cook G.S.,University of California at San Diego
Marine Ecology Progress Series | Year: 2011

Our understanding of the role dispersal plays in marine population dynamics is incomplete. One method used to quantify movement among populations is otolith microchemistry. A challenge with this method is gaining an understanding of the spatial and temporal variability of microchemistry that occurs over the course of a protracted spawning season. High-resolution sampling was used to explore the variability of elemental fingerprints of Hypsypops rubicundus at 6 rocky reefs spanning the southern California (USA) coastline from 3 June to 2 September 2008. Otolith microchemistry of 1101 larval fish and 72 juveniles was analyzed using a laser ablation inductively coupled plasma mass spectrometer. Within-reef elemental fingerprints were more similar than among-reef elemental fingerprints. The primary elements enabling discrimination among reefs and their relative contribution (%) to the elemental fingerprint of each reef were U (47%), Pb (31%), Ba (14%), Mg (9%), and Sr (1%). The 2 elements with the most consistent shifts in elemental chemistry from the onset to cessation of the spawning season were Ba (decreased across all study sites) and U (increased across all study sites). More than a third of the time (34%), the elemental fingerprint of a given reef was indistinguishable from the elemental fingerprint of a different reef later in the spawning season. When natal origins of juveniles were classified using microchemical data spanning the entire spawning season, the number of source populations and number of individuals predicted to have originated from actual source populations were underestimated. Researchers must utilize natural history information together with otolith microchemistry data to ensure that the natal origin of juveniles is assigned using data that account for both spatial and temporal changes in reef-specific elemental fingerprints. © Inter-Research 2011. Source


Devaraj N.K.,University of California at San Diego
Synlett | Year: 2012

There has been increasing interest in the use of tetrazines as partners in bioorthogonal inverse Diels-Alder cycloadditions. Although tetrazine cycloadditions possess several characteristics that make them attractive compared to alternative coupling strategies, the coupling partners, 1,2,4,5-tetrazines and strained alkenes and cycloalkynes, are not trivial to synthesize. The use of tetrazines and dienophiles in biological applications has required the development of new synthetic methodologies to create stable yet reactive probes conveniently. This paper addresses the synthetic milestones that have enabled and improved tetrazine cycloadditions as a popular form of bioorthogonal chemistry and highlights recent work from our lab that we believe has advanced the methodology available for the synthesis of tetrazines 1 and smaller strained cyclopropene dienophiles. 2 We also outline some future challenges and open questions that remain to be addressed. © Georg Thieme Verlag Stuttgart • New York. Source


Perissi V.,Howard Hughes Medical Institute | Jepsen K.,Howard Hughes Medical Institute | Glass C.K.,University of California at San Diego | Rosenfeld M.G.,Howard Hughes Medical Institute
Nature Reviews Genetics | Year: 2010

A crucial aspect of development, homeostasis and prevention of disease is the strict maintenance of patterns of gene repression. Gene repression is largely achieved by the combinatorial action of various enzymatic complexes known as co-repressor complexes that are recruited to DNA by transcription factors and often act through enzymatic modification of histone protein tails. Our understanding of how co-repressors act has begun to change over recent years owing to the increased availability of genome-scale data. Here, we consider specific strategies that underlie repression events for example, those mediated by the nuclear receptor co-repressor (NCoR, also known as NCOR1) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT, also known as NCOR2) co-repressor complexes and discuss emerging themes in gene repression. © 2010 Macmillan Publishers Limited. All rights reserved. Source


East P.L.,University of California at San Diego
Child Development Perspectives | Year: 2010

Despite the high numbers of children who provide care to family members in industrialized countries, relatively little is known about the impact of caregiving on children's development. In this article, issues related to children's caregiving, including a discussion of who provides care, the costs and benefits of caring, and directions for future research are reviewed. This review is intended to stimulate further study of this issue, particularly in clarifying who is most vulnerable to caregiving burden and understanding how caregiving affects children's lives and development. © 2010, Copyright the Author(s). Journal Compilation © 2010, Society for Research in Child Development. Source


Radic S.,University of California at San Diego
IEEE Journal on Selected Topics in Quantum Electronics | Year: 2012

Recent advances in parametric signal processing are described. Parametric mixer role in processing of high-speed signals is recognized and illustrated in analog and digital domains. Rate-scalable signal replication in efficient, wideband mixer was used to redefine traditional analog-to-digital conversion and channelizer architectures. The limits and practical challenges of the parametric mixer technology are discussed. © 2011 IEEE. Source


Jones K.L.,University of California at San Diego
Birth Defects Research Part C - Embryo Today: Reviews | Year: 2011

Prenatal exposure to alcohol has profound effects on many aspects of fetal development. Although alterations of somatic growth and specific minor malformations of facial structure are most characteristic, the effects of alcohol on brain development are most significant in that they lead to substantial problems with neurobehavioral development. Since the initial recognition of the fetal alcohol syndrome (FAS), a number of important observations have been made from studies involving both humans and animals. Of particular importance, a number of maternal risk factors have been identified, which may well be of relevance relative to the development of strategies for prevention of the FAS as well as intervention for those who have been affected. These include maternal age >30 years, ethnic group, lower socioeconomic status, having had a previously affected child, maternal under-nutrition, and genetic background. The purpose of this review is to discuss these issues as well as to set forth a number of questions that have not adequately been addressed relative to alcohol's effect on fetal development. Of particular importance is the critical need to identify the full spectrum of structural defects associated with the prenatal effects of alcohol as well as to establish a neurobehavioral phenotype. Appreciation of both of these issues is necessary to understand the full impact of alcohol on fetal development. © 2011 Wiley-Liss, Inc. Source


Chisholm A.D.,University of California at San Diego
Annual Review of Cell and Developmental Biology | Year: 2013

Axon regeneration after damage is widespread in the animal kingdom, and the nematode Caenorhabditis elegans has recently emerged as a tractable model in which to study the genetics and cell biology of axon regrowth in vivo. A key early step in axon regrowth is the conversion of part of a mature axon shaft into a growth cone-like structure, involving coordinated alterations in the microtubule, actin, and neurofilament systems. Recent attention has focused on microtubule dynamics as a determinant of axon-regrowth ability in several organisms. Live imaging studies have begun to reveal how the microtubule cytoskeleton is remodeled after axon injury, as well as the regulatory pathways involved. The dual leucine zipper kinase family of mixed-lineage kinases has emerged as a critical sensor of axon damage and plays a key role in regulating microtubule dynamics in the damaged axon. © 2013 by Annual Reviews. All rights reserved. Source


Keith B.,University of Pennsylvania | Johnson R.S.,University of California at San Diego | Simon M.C.,University of Pennsylvania
Nature Reviews Cancer | Year: 2012

Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1 α and HIF2 α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIF α isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1 α and HIF2 α in human neoplasia is warranted. © 2012 Macmillan Publishers Limited. All rights reserved. Source


West J.B.,University of California at San Diego
Physiology | Year: 2013

The recognition of barometric pressure was a critical step in the development of environmental physiology. In 1644, Evangelista Torricelli described the first mercury barometer in a remarkable letter that contained the phrase, "We live submerged at the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight." This extraordinary insight seems to have come right out of the blue. Less than 10 years before, the great Galileo had given an erroneous explanation for the related problem of pumping water from a deep well. Previously, Gasparo Berti had filled a very long lead vertical tube with water and showed that a vacuum formed at the top. However, Torricelli was the first to make a mercury barometer and understand that the mercury was supported by the pressure of the air. Aristotle stated that the air has weight, although this was controversial for some time. Galileo described a method of measuring the weight of the air in detail, but for reasons that are not clear his result was in error by a factor of about two. Torricelli surmised that the pressure of the air might be less on mountains, but the first demonstration of this was by Blaise Pascal. The first air pump was built by Otto von Guericke, and this influenced Robert Boyle to carry out his classical experiments of the physiological effects of reduced barometric pressure. These were turning points in the early history of high-altitude physiology. © 2013 Int. Union Physiol. Sci./Am. Physiol. Soc. Source


Pasquale E.B.,Sanford Burnham Institute for Medical Research | Pasquale E.B.,University of California at San Diego
Nature Reviews Cancer | Year: 2010

The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression. Eph gene mutations probably also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth, migration and invasion of cancer cells in culture as well as tumour growth, invasiveness, angiogenesis and metastasis in vivo. However, Eph signalling activities in cancer seem to be complex, and are characterized by puzzling dichotomies. Nevertheless, the Eph receptors are promising new therapeutic targets in cancer. © 2010 Macmillan Publishers Limited. All rights reserved. Source


Newton A.C.,University of California at San Diego
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010

Nestled at the tip of a branch of the kinome, protein kinase C (PKC) family members are poised to transduce signals emanating from the cell surface. Cell membranes provide the platform for PKC function, supporting the maturation of PKC through phosphorylation, its allosteric activation by binding specific lipids, and, ultimately, promoting the downregulation of the enzyme. These regulatory mechanisms precisely control the level of signalingcompetent PKC in the cell. Disruption of this regulation results in pathophysiological states, most notably cancer, where PKC levels are often grossly altered. This review introduces the PKC family and then focuses on recent advances in understanding the cellular regulation of its diacylglycerol-regulated members. Copyright © 2010 the American Physiological Society. Source


Marsden A.L.,University of California at San Diego
Annual Review of Fluid Mechanics | Year: 2014

Fluid mechanics plays a key role in the development, progression, and treatment of cardiovascular disease. Advances in imaging methods and patient-specific modeling now reveal increasingly detailed information about blood flow patterns in health and disease. Building on these tools, there is now an opportunity to couple blood flow simulation with optimization algorithms to improve the design of surgeries and devices, incorporating more information about the flow physics in the design process to augment current medical knowledge. In doing so, a major challenge is the need for efficient optimization tools that are appropriate for unsteady fluid mechanics problems, particularly for the optimization of complex patient-specific models in the presence of uncertainty. This article reviews the state of the art in optimization tools for virtual surgery, device design, and model parameter identification in cardiovascular flow and mechanobiology applications. In particular, it reviews trade-offs between traditional gradient-based methods and derivative-free approaches, as well as the need to incorporate uncertainties. Key future challenges are outlined, which extend to the incorporation of biological response and the customization of surgeries and devices for individual patients. Copyright © 2014 by Annual Reviews. All rights reserved. Source


Steiner R.W.,University of California at San Diego
American Journal of Transplantation | Year: 2010

Transplant centers medically evaluate potential living kidney donors in part to determine their baseline remaining lifetime risk for end stage renal disease (ESRD). If baseline risk is increased by the presence of a risk factor for ESRD, donation is often refused. However, as only about 13% of ESRD occurs in the general population by age 44, a normal medical evaluation cannot be expected to significantly reduce the 7% lifetime risk for a 'normal' 25-year-old black donor or the 2-3% risk for a similar white donor. About half of newly diagnosed ESRD in the United States occurs by age 65, and about half of that is from diabetic nephropathy, which takes about 25 years to develop. Therefore, the remaining baseline lifetime risk for ESRD is significantly lower in the normal, nondiabetic 55-year-old donor candidate. Some older donors with an isolated medical abnormality such as mild hypertension will be at lower or about the same overall baseline lifetime risk for ESRD as are young 'normal' donor candidates. Transplant centers use a 'normal for now' standard for accepting young donors, in place of the long-term risk estimates that must guide selection of all donors. © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons. Source


Yajima T.,University of California at San Diego
Future Microbiology | Year: 2011

Virus infection can inflict significant damage on cardiomyocytes through direct injury and secondary immune reactions, leading to myocarditis and dilated cardiomyopathy. While viral myocarditis or cardiomyopathy is a complication of systemic infection of cardiotropic viruses, most individuals infected with the viruses do not develop significant cardiac disease. However, some individuals proceed to develop severe virus-mediated heart disease. Recent studies have shown that viral infection of cardiomyocytes is required for the development of myocarditis and subsequent cardiomyopathy. This suggests that viral infection of cardiomyocytes can be an important step that determines the pathogenesis of viral myocarditis during systemic infection. Accordingly, this article focuses on potential defense mechanisms within the cardiomyocyte against virus infection. Understanding of the cardiomyocyte defense against invading viruses may give us novel insights into the pathophysiology of viral myocarditis, and enable us to develop innovative strategies of diagnosis and treatment for this challenging clinical entity. © 2011 Future Medicine Ltd. Source


Bode L.,University of California at San Diego
Glycobiology | Year: 2012

Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycans that are highly abundant in and unique to human milk. Originally, HMOs were discovered as a prebiotic "bifidus factor" that serves as a metabolic substrate for desired bacteria and shapes an intestinal microbiota composition with health benefits for the breast-fed neonate. Today, HMOs are known to be more than just "food for bugs". An accumulating body of evidence suggests that HMOs are antiadhesive antimicrobials that serve as soluble decoy receptors, prevent pathogen attachment to infant mucosal surfaces and lower the risk for viral, bacterial and protozoan parasite infections. In addition, HMOs may modulate epithelial and immune cell responses, reduce excessive mucosal leukocyte infiltration and activation, lower the risk for necrotizing enterocolitis and provide the infant with sialic acid as a potentially essential nutrient for brain development and cognition. Most data, however, stem from in vitro, ex vivo or animal studies and occasionally from association studies in mother-infant cohorts. Powered, randomized and controlled intervention studies will be needed to confirm relevance for human neonates. The first part of this review introduces the pioneers in HMO research, outlines HMO structural diversity and describes what is known about HMO biosynthesis in the mother's mammary gland and their metabolism in the breast-fed infant. The second part highlights the postulated beneficial effects of HMO for the breast-fed neonate, compares HMOs with oligosaccharides in the milk of other mammals and in infant formula and summarizes the current roadblocks and future opportunities for HMO research. © 2012 The Author. Source


Cortes C.J.,University of California at San Diego
Nature neuroscience | Year: 2014

Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR). We found that polyQ-AR reduced long-term protein turnover and impaired autophagic flux in motor neuron-like cells. Ultrastructural analysis of SBMA mice revealed a block in autophagy pathway progression. We examined the transcriptional regulation of autophagy and observed a functionally significant physical interaction between transcription factor EB (TFEB) and AR. Normal AR promoted, but polyQ-AR interfered with, TFEB transactivation. To evaluate physiological relevance, we reprogrammed patient fibroblasts to induced pluripotent stem cells and then to neuronal precursor cells (NPCs). We compared multiple SBMA NPC lines and documented the metabolic and autophagic flux defects that could be rescued by TFEB. Our results indicate that polyQ-AR diminishes TFEB function to impair autophagy and promote SBMA pathogenesis. Source


Bucher D.,University of California at San Diego
Chemical Physics Letters | Year: 2012

The synthesis of an endohedral C60 fullerene containing a single trapped H 2O molecule was recently achieved [K. Kurotobi and Y. Murata, Science 333 (2011) 613-616]. In this Letter, a computational study is conducted to determine the dynamic properties of the trapped water for a range of temperatures between 50 and 300 K. MD and ab initio MD (AIMD) simulations show that, in the absence of hydrogen bonds, the orientational relaxation of H 2O inside the fullerene cage is fast and nearly temperature independent. These properties could be exploited in the design of future nanotechnologies. © 2012 Elsevier B.V. All rights reserved. Source


Barreto F.S.,University of California at San Diego
Proceedings. Biological sciences / The Royal Society | Year: 2013

Aerobic energy production occurs via the oxidative phosphorylation pathway (OXPHOS), which is critically dependent on interactions between the 13 mitochondrial DNA (mtDNA)-encoded and approximately 70 nuclear-encoded protein subunits. Disruptive mutations in any component of OXPHOS can result in impaired ATP production and exacerbated oxidative stress; in mammalian systems, such mutations are associated with ageing as well as numerous diseases. Recent studies have suggested that oxidative stress plays a role in fitness trade-offs in life-history evolution and functional ecology. Here, we show that outcrossing between populations with divergent mtDNA can exacerbate cellular oxidative stress in hybrid offspring. In the copepod Tigriopus californicus, we found that hybrids that showed evidence of fitness breakdown (low fecundity) also exhibited elevated levels of oxidative damage to DNA, whereas those with no clear breakdown did not show significantly elevated damage. The extent of oxidative stress in hybrids appears to be dependent on the degree of genetic divergence between their respective parental populations, but this pattern requires further testing using multiple crosses at different levels of divergence. Given previous evidence in T. californicus that hybridization disrupts nuclear/mitochondrial interactions and reduces hybrid fitness, our results suggest that such negative intergenomic epistasis may also increase the production of damaging cellular oxidants; consequently, mtDNA evolution may play a significant role in generating postzygotic isolating barriers among diverging populations. Source


Esposito M.,University of Luxembourg | Ochoa M.A.,University of California at San Diego | Galperin M.,University of Luxembourg
Physical Review Letters | Year: 2015

We establish the foundations of a nonequilibrium theory of quantum thermodynamics for noninteracting open quantum systems strongly coupled to their reservoirs within the framework of the nonequilibrium Green's functions. The energy of the system and its coupling to the reservoirs are controlled by a slow external time-dependent force treated to first order beyond the quasistatic limit. We derive the four basic laws of thermodynamics and characterize reversible transformations. Stochastic thermodynamics is recovered in the weak coupling limit. © 2015 American Physical Society. Source


Wolkovich E.M.,National Center for Ecological Analysis And Synthesis | Cleland E.E.,University of California at San Diego
Frontiers in Ecology and the Environment | Year: 2011

Community ecologists have long recognized the importance of phenology (the timing of periodic life-history events) in structuring communities. Phenological differences between exotic and native species may contribute to the success of invaders, yet a general theory for how phenology may shape invasions has not been developed. Shifts toward longer growing seasons, tracked by plant and animal species worldwide, heighten the need for this analysis. The concurrent availability of extensive citizen-science and long-term datasets has created tremendous opportunities to test the relationship between phenology and invasion. Here, we (1) extend major theories within community and invasion biology to include phenology, (2) develop a predictive framework to test these theories, and (3) outline available data resources to test predictions. By creating an integrated framework, we show how new analyses of long-term datasets could advance the fields of community ecology and invasion biology, while developing novel strategies for invasive species management. Although we focus here on terrestrial plants, our framework has clear extensions to animal communities and aquatic ecosystems as well. © The Ecological Society of America. Source


Berger W.H.,University of California at San Diego
Annual Review of Marine Science | Year: 2011

Ocean history is largely read from deep-sea sediments, using microscopic fossils, notably foraminifers. Ice age fluctuations in the ocean's sediments provided for a new geologic understanding of climate change. The discovery of rapid decay of ice masses at the end of glacial periods was especially important, yielding rates of sea level rise reaching values of 1 to 2 m per century for millennia. Thanks to deep-ocean drilling, the overall planetary cooling trend in the Cenozoic was recognized as occurring in three large steps. The first step is at the EoceneOligocene boundary and is marked by a great change in sedimentation patterns; the second is in the middle Miocene, associated with a major pulse in the buildup of Antarctic ice masses and the intensification of upwelling regimes; and the third is within the late Pliocene and led into the northern ice ages. Evolution in the sea is linked to these various steps. Copyright © 2011 by Annual Reviews. All rights reserved. Source


Steiner R.W.,University of California at San Diego
Current Opinion in Nephrology and Hypertension | Year: 2012

Purpose of Review: Over the past two decades, steroid-free immunosuppression has become more widespread, but improvements in long-term kidney transplant survival have been modest, mandating scrutiny of our chronic regimens. Recent Findings: Current studies and commentary cautiously conclude that steroid-free regimens in low-risk patients seem acceptable for up to 5 years, although most studies are shorter. Patients who will develop chronic rejection cannot be identified prospectively and usually return to steroids. One center continues to report long-term steroid-free results that are comparable to or better than national Scientific Registry of Renal Transplant Recipients (SRTR) outcomes, even with 'older' drugs cyclosporine and azathioprine, reaffirming the need for well designed prospective studies. Some authorities question whether minimal side effects with current regimens justify steroid elimination. In low-risk populations, 'steroid-type' studies probably would suggest no short-term benefit of tacrolimus over cyclosporine, or mycophenolate over azathioprine. Summary: The data justifying steroid-free immunosuppression continue to be suboptimal. A larger question is whether to treat an entire population at medical risk or just the higher-risk subgroup that declares itself in the short term. 'Subgroup therapy' might well produce the same quandaries if applied to other accepted transplant immunosuppression. © 2012 Wolters Kluwer Health | Lippincott Williams and Wilkins. Source


Nie J.,University of California at San Diego
Mathematical Programming | Year: 2013

Consider the optimization problem of minimizing a polynomial function subject to polynomial constraints. A typical approach for solving it globally is applying Lasserre's hierarchy of semidefinite relaxations, based on either Putinar's or Schmüdgen's Positivstellensatz. A practical question in applications is: how to certify its convergence and get minimizers? In this paper, we propose flat truncation as a certificate for this purpose. Assume the set of global minimizers is nonempty and finite. Our main results are: (1) Putinar type Lasserre's hierarchy has finite convergence if and only if flat truncation holds, under some generic assumptions; the same conclusion holds for the Schmüdgen type one under weaker assumptions. (2) Flat truncation is asymptotically satisfied for Putinar type Lasserre's hierarchy if the archimedean condition holds; the same conclusion holds for the Schmüdgen type one if the feasible set is compact. (3) We show that flat truncation can be used as a certificate to check exactness of standard SOS relaxations and Jacobian SDP relaxations. © 2012 Springer and Mathematical Optimization Society. Source


Hiramatsu N.,University of California at San Diego
BioMetals | Year: 2010

Cadmium preferentially accumulates in the kidney, the major target for cadmium-related toxicity. Several underlying mechanisms are postulated, and reactive oxygen species (ROS) have been considered as crucial mediators for tissue injuries. In addition to oxidative stress, we recently disclosed that endoplasmic reticulum (ER) stress also plays a critical role. Cadmium causes ER stress in vitro and in vivo and mediates induction of apoptosis in target tissues. In this article, we describe a role for ER stress and involvement of particular branches of the unfolded protein response (UPR) in cadmium-triggered tissue injury, especially nephrotoxicity. We also discuss relationship between oxidative stress and ER stress, and involvement of selective ROS in the induction of pro-apoptotic branches of the UPR. © 2010 Springer Science+Business Media, LLC. Source


Molina N.,University of California at San Diego
American Journal of Public Health | Year: 2011

Throughout the 20th century, US public health and immigration policies intersected with and informed one another in the country's response to Mexican immigration. Three historical episodes illustrate how perceived racial differences influenced disease diagnosis: a 1916 typhus outbreak, the midcentury Bracero Program, and medical deportations that are taking place today. Disease, or just the threat of it, marked Mexicans as foreign, just as much as phenotype, native language, accent, or clothing. A focus on race rendered other factors and structures, such as poor working conditions or structural inequalities in health care, invisible. This attitude had long-term effects on immigration policy, as well as on how Mexicans were received in the United States. Source


Means J.D.,University of California at San Diego
Journal of Climate | Year: 2013

Precipitable water derived from archived global positioning system (GPS) zenith travel-time delays is used to describe the seasonal and interannual variation of the North American monsoon in California and Nevada. A 3-hourly dataset of precipitable water from 2003 to 2009, for over 500 sites in California and Nevada using temperature and pressure interpolated from the North American Regional Reanalysis (NARR), is constructed to study the temporal and spatial extent of the North American monsoon in the desert regions of California and Nevada. The statistical distribution of precipitable water values is shown to delineate the region that is most often affected by the monsoonal influence. A normalized precipitable water index is employed to indicate when the monsoon starts and stops and to investigate spatial variability. The GPS network provides much higher spatial resolution than other meteorological networks using surface-based methods, such as dewpoint criteria and rainfall, and is seen to contain comparable ability in capturing temporal variations. This dataset reveals the northwestward propagation of the monsoon onset both synoptically and seasonally. The GPS observations indicate that in the mean the decay of the monsoon is less well defined than the onset. Seven-year reanalysis 700-mb geopotential height composites for the monsoon onset and 3 days prior indicate that the onset of the monsoon is associated with a shift in the synoptic pattern characterized by upper-level high pressure building from the east and offshore troughing retreating to the northwest. © 2013 American Meteorological Society. Source


Chaisson M.J.,Pacific Biosciences | Tesler G.,University of California at San Diego
BMC Bioinformatics | Year: 2012

Background: Recent methods have been developed to perform high-throughput sequencing of DNA by Single Molecule Sequencing (SMS). While Next-Generation sequencing methods may produce reads up to several hundred bases long, SMS sequencing produces reads up to tens of kilobases long. Existing alignment methods are either too inefficient for high-throughput datasets, or not sensitive enough to align SMS reads, which have a higher error rate than Next-Generation sequencing.Results: We describe the method BLASR (Basic Local Alignment with Successive Refinement) for mapping Single Molecule Sequencing (SMS) reads that are thousands of bases long, with divergence between the read and genome dominated by insertion and deletion error. The method is benchmarked using both simulated reads and reads from a bacterial sequencing project. We also present a combinatorial model of sequencing error that motivates why our approach is effective.Conclusions: The results indicate that it is possible to map SMS reads with high accuracy and speed. Furthermore, the inferences made on the mapability of SMS reads using our combinatorial model of sequencing error are in agreement with the mapping accuracy demonstrated on simulated reads. © 2012 Chaisson and Tesler; licensee BioMed Central Ltd. Source


Witztum J.L.,University of California at San Diego | Lichtman A.H.,Harvard University
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. © 2014 by Annual Reviews. All rights reserved. Source


Edelman S.V.,University of California at San Diego
Diabetes technology & therapeutics | Year: 2010

BACKGROUND: This study assessed insulin dose and dosing patterns required to optimize glycemic control with an insulin pump in patients with type 2 diabetes. METHODS: In this 16-week, open-label, multicenter, pilot study, 56 insulin pump-naive patients treated at baseline with two or more oral antidiabetes agents (OADs), basal insulin with or without OADs, or basal-bolus insulin with or without OADs discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin doses were adjusted to optimize glycemic control with the simplest possible insulin regimen. Outcomes included total daily insulin dose, daily basal and bolus insulin doses, number of daily basal rates, hemoglobin A1C, fasting and postprandial glucose, patient-reported outcomes and rate of hypoglycemia. RESULTS: After 16 weeks of pump therapy, the mean +/- SD total daily insulin dose was 95 +/- 59 U. The percentage of the total daily insulin dose used as basal and as bolus delivery was 55% and 45%, respectively. Eighty-eight percent of patients were treated with two or fewer daily basal rates. Mean A1C was lowered by 1.2 +/- 1.2% (P < 0.001), and there was no severe hypoglycemia. Mean change in body weight was +1.9 +/- 3.3 kg (P < 0.001). Overall treatment preference improved with pump therapy compared to baseline. CONCLUSIONS: Insulin pump therapy using a simple dosing regimen significantly improved glycemic control in patients with type 2 diabetes. Patients experienced limited weight gain, there was no severe hypoglycemia, and overall treatment preference improved significantly. Source


Wang J.W.,University of California at San Diego
Developmental Neurobiology | Year: 2012

Most animals are endowed with an olfactory system that is essential for finding foods, avoiding predators, and locating mating partners. The olfactory system must encode the identity and intensity of behaviorally relevant stimuli in a dynamic environmental landscape. How is olfactory information represented? How is a large dynamic range of odor concentrations represented in the olfactory system? How is this representation modulated to meet the demands of different internal physiological states? Recent studies have found that sensory terminals are important targets for neuromodulation. The emerging evidence suggests that presynaptic inhibition scales with sensory input and thus provides a mechanism to increase dynamic range of odor representation. In addition, presynaptic facilitation could be a mechanism to alter behavioral responses in hungry animals. This review will focus on the GABA B (gamma-aminobutyric acid) receptor-mediated presynaptic inhibition, and neuropeptide-mediated presynaptic modulation in Drosophila. © 2011 Wiley Periodicals, Inc. Source


Tsimring L.S.,University of California at San Diego
Reports on Progress in Physics | Year: 2014

Noise permeates biology on all levels, from the most basic molecular, sub-cellular processes to the dynamics of tissues, organs, organisms and populations. The functional roles of noise in biological processes can vary greatly. Along with standard, entropy-increasing effects of producing random mutations, diversifying phenotypes in isogenic populations, limiting information capacity of signaling relays, it occasionally plays more surprising constructive roles by accelerating the pace of evolution, providing selective advantage in dynamic environments, enhancing intracellular transport of biomolecules and increasing information capacity of signaling pathways. This short review covers the recent progress in understanding mechanisms and effects of fluctuations in biological systems of different scales and the basic approaches to their mathematical modeling. © 2014 IOP Publishing Ltd. Source


Zanetti M.,University of California at San Diego
Nature Reviews Clinical Oncology | Year: 2016

Telomerase reverse transcriptase (TERT) is a self-antigen that is expressed constitutively in many tumours, and is, therefore, an important target for anticancer immunotherapy. In the past 10 years, trials of immunotherapy with TERT-based vaccines have demonstrated only modest benefits. In this Perspectives, I discuss the possible immunological reasons for this limited antitumour efficacy, and propose that advances in our understanding of the genetics and biology of the involvement of TERT in cancer provides the basis for renewed interest in TERT- based immunotherapy. Telomerase and TERT are expressed in cancer cells at every stage of tumour evolution, from the cancer stem cell to circulating tumour cells and tumour metastases. Many cancer types also harbour cells with mutations in the TERT promoter region, which increase transcriptional activation of this gene. These new findings should spur new interest in the development of TERT-based immunotherapies that are redesigned in line with established immunological considerations and working principles, and are tailored to patients stratified on the basis of TERT-promoter mutations and other underlying tumour characteristics. Thus, despite the disappointment of previous clinical trials, TERT offers the potential for personalized immunotherapy, perhaps in combination with immune-checkpoint inhibition. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Nakamura T.,Sanford Burnham Institute for Medical Research | Lipton S.A.,Sanford Burnham Institute for Medical Research | Lipton S.A.,University of California at San Diego
Cell Death and Differentiation | Year: 2011

The pathological processes of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases engender synaptic and neuronal cell damage. While mild oxidative and nitrosative (nitric oxide (NO)-related) stress mediates normal neuronal signaling, excessive accumulation of these free radicals is linked to neuronal cell injury or death. In neurons, N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and subsequent Ca 2+ influx can induce the generation of NO via neuronal NO synthase. Emerging evidence has demonstrated that S-nitrosylation, representing covalent reaction of an NO group with a critical protein thiol, mediates the vast majority of NO signaling. Analogous to phosphorylation and other posttranslational modifications, S-nitrosylation can regulate the biological activity of many proteins. Here, we discuss recent studies that implicate neuropathogenic roles of S-nitrosylation in protein misfolding, mitochondrial dysfunction, synaptic injury, and eventual neuronal loss. Among a growing number of S-nitrosylated proteins that contribute to disease pathogenesis, in this review we focus on S-nitrosylated protein-disulfide isomerase (forming SNO-PDI) and dynamin-related protein 1 (forming SNO-Drp1). Furthermore, we describe drugs, such as memantine and newer derivatives of this compound that can prevent both hyperactivation of extrasynaptic NMDARs as well as downstream pathways that lead to nitrosative stress, synaptic damage, and neuronal loss. © 2011 Macmillan Publishers Limited All rights reserved. Source


Sise M.J.,University of California at San Diego
Surgical Clinics of North America | Year: 2014

Acute mesenteric ischemia is uncommon and always occurs in the setting of preexisting comorbidities. Mortality rates remain high. The 4 major types of acute mesenteric ischemia are acute superior mesenteric artery thromboembolic occlusion, mesenteric arterial thrombosis, mesenteric venous thrombosis, and nonocclusive mesenteric ischemia, including ischemic colitis. Delays in diagnosis are common and associated with high rates of morbidity and mortality. Prompt diagnosis requires attention to history and physical examination, a high index of suspicion, and early contract CT scanning. Selective use of nonoperative therapy has an important role in nonocclusive mesenteric ischemia of the small bowel and colon. © 2014 Elsevier Inc. Source


Jeong K.,University of California at San Diego
BMC bioinformatics | Year: 2012

Automated database search engines are one of the fundamental engines of high-throughput proteomics enabling daily identifications of hundreds of thousands of peptides and proteins from tandem mass (MS/MS) spectrometry data. Nevertheless, this automation also makes it humanly impossible to manually validate the vast lists of resulting identifications from such high-throughput searches. This challenge is usually addressed by using a Target-Decoy Approach (TDA) to impose an empirical False Discovery Rate (FDR) at a pre-determined threshold x% with the expectation that at most x% of the returned identifications would be false positives. But despite the fundamental importance of FDR estimates in ensuring the utility of large lists of identifications, there is surprisingly little consensus on exactly how TDA should be applied to minimize the chances of biased FDR estimates. In fact, since less rigorous TDA/FDR estimates tend to result in more identifications (at higher 'true' FDR), there is often little incentive to enforce strict TDA/FDR procedures in studies where the major metric of success is the size of the list of identifications and there are no follow up studies imposing hard cost constraints on the number of reported false positives. Here we address the problem of the accuracy of TDA estimates of empirical FDR. Using MS/MS spectra from samples where we were able to define a factual FDR estimator of 'true' FDR we evaluate several popular variants of the TDA procedure in a variety of database search contexts. We show that the fraction of false identifications can sometimes be over 10× higher than reported and may be unavoidably high for certain types of searches. In addition, we further report that the two-pass search strategy seems the most promising database search strategy. While unavoidably constrained by the particulars of any specific evaluation dataset, our observations support a series of recommendations towards maximizing the number of resulting identifications while controlling database searches with robust and reproducible TDA estimation of empirical FDR. Source


Seki E.,Cedars Sinai Medical Center | Brenner D.A.,University of California at San Diego
Journal of Hepato-Biliary-Pancreatic Sciences | Year: 2015

Liver fibrosis occurs in response to any etiology of chronic liver injury including hepatitis B and C, alcohol consumption, fatty liver disease, cholestasis, and autoimmune hepatitis. Hepatic stellate cells (HSCs) are the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in the liver. Various inflammatory and fibrogenic pathways contribute to the activation of HSCs. Recent studies also discovered that liver fibrosis is reversible and activated HSCs can revert to quiescent HSCs when causative agents are removed. Although the basic research for liver fibrosis has progressed remarkably, sensitive and specific biomarkers as non-invasive diagnostic tools, and effective anti-fibrotic agents have not been developed yet. This review highlights the recent advances in cellular and molecular mechanisms of liver fibrosis, especially focusing on origin of myofibroblasts, inflammatory signaling, autophagy, cellular senescence, HSC inactivation, angiogenesis, and reversibility of liver fibrosis. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery. Source


Steinberg D.,University of California at San Diego
Journal of the American College of Cardiology | Year: 2010

The thesis advanced here is that we are initiating treatment of hypercholesterolemia (and other risk factors) too late in life. Initiating treatment at, for example, age 30 years instead of age 60 years might very well prevent not just 30% of events, as in the 5-year statin trials, but perhaps as many as 60%. © 2010 American College of Cardiology Foundation. Source


Aceves S.S.,University of California at San Diego
Digestive Diseases | Year: 2014

Chronic eosinophilic inflammation has been associated with tissue remodeling in a number of disease states including the hypereosinophilic syndrome (HES), asthma, and, more recently, eosinophilic esophagitis (EoE). Remodeling occurs in the epithelial and subepithelial esophageal tissue, and includes basal zone hyperplasia, epithelial mesenchymal transition, fibrosis, angiogenesis, and smooth muscle hypertrophy/hyperplasia. Previously, research on the clinical impacts of tissue remodeling has been limited by a paucity of human tissue. However, in EoE, recurrent biopsies are required for diagnosis and management. As such, investigators are able to study the associations between tissue changes and clinical disease features. A number of profibrotic and proangiogenic factors are elevated in EoE, including TGF-β1, CCL-18, FGF-9, VEGF, and VCAM-1. Both eosinophils and mast cells produce a number of these factors. TGF-β1 appears to be a master regulator of end-organ dysfunction in EoE and can cause esophageal epithelial mesenchymal transition, fibrosis, and smooth muscle contraction. The requirement for eosinophils, the eosinophilopoietic interleukin, IL-5, and the canonical TGF-β1 signaling pathway for EoE-associated fibrosis, has been invoked using gene-deficient mice. The clinical consequences of eosinophil-associated tissue fibrosis can be devastating, such as endomyocardial fibrosis and heart failure in HES. In EoE, tissue remodeling appears to be the mechanism for multiple cardinal disease complications including esophageal rigidity, strictures, narrowing, and food impactions, as well as the clinical hallmark of dysphagia. Therapies that may be able to reduce or reverse EoE-associated remodeling include topical corticosteroids, anti-IL-5, and food antigen avoidance. © 2014 S. Karger AG, Basel. Source


Ilfeld B.M.,University of California at San Diego
Anesthesia and Analgesia | Year: 2011

A continuous peripheral nerve block, also termed "perineural local anesthetic infusion," involves the percutaneous insertion of a catheter adjacent to a peripheral nerve, followed by local anesthetic administration via the catheter, providing anesthesia/analgesia for multiple days or even months. Continuous peripheral nerve blocks may be provided in the hospital setting, but the use of lightweight, portable pumps permits ambulatory infusion as well. This techniques most common application is providing analgesia after surgical procedures. However, additional indications include treating intractable hiccups; inducing a sympathectomy and vasodilation to increase blood flow after a vascular accident, digit transfer/replantation, or limb salvage; alleviating vasospasm of Raynaud disease; and treating peripheral embolism and chronic pain such as complex regional pain syndrome, phantom limb pain, trigeminal neuralgia, and cancer-induced pain. After trauma, perineural infusion can provide analgesia during transportation to a distant treatment center, or while simply awaiting surgical repair. Catheter insertion may be accomplished using many possible modalities, including nerve stimulation, ultrasound guidance, paresthesia induction, fluoroscopic imaging, and simple tactile perceptions ("facial click"). Either a nonstimulating epidural-type catheter may be used, or a "stimulating catheter" that delivers electrical current to its tip. Administered infusate generally includes exclusively long-acting, dilute, local anesthetic delivered as a bolus only, basal only, or basal-bolus combination. Documented benefits appear to be dependent on successfully improving analgesia, and include decreasing baseline/breakthrough/dynamic pain, supplement