San Diego, CA, United States
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.


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Firestein G.S.,University of California at San Diego | McInnes I.B.,University of Glasgow
Immunity | Year: 2017

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics. © 2017 Elsevier Inc.


Cepeda J.A.,University of California at San Diego
Journal of Acquired Immune Deficiency Syndromes | Year: 2017

BACKGROUND:: People who inject drugs (PWID) who are highly connected within their injection drug networks may be important HIV transmission nodes if they frequently share syringes with other PWID and are not engaged in HIV care. In India, HIV transmission fueled by injection drug use is increasing, however little is known about the associations between injection network size and syringe sharing and viral suppression. METHODS:: We recruited 14,481 PWID between October 2012 – December 2013 by respondent driven sampling across 15 sites in India. Interviewer-administered questionnaires assessed network characteristics, substance use, HIV testing experience, and access to health services. We used multilevel logistic regression modeling to evaluate the relationship between injection drug network size and 1) syringe sharing at last injection and 2) viral suppression among HIV-positive participants (<150 copies/ml). FINDINGS:: The median injection network size was 3 [IQR: 1-5] and 7% of participants injected with >10 members in the past 30 days. PWID who had >10 members in their network were 1.65 times (95% CI: 1.12 – 2.42, p=0.0111) more likely to have shared a syringe at last injection compared to those in the 0-1 members in their drug networks. Additionally, individuals with the largest injection drug networks were also 31% (95% CI: 0.53 – 0.90, p=0.006) less likely to be virally suppressed compared to individuals in the smallest injection drug networks. DISCUSSION:: Individuals with larger networks may be important in HIV transmission within injection drug networks since they were the most likely to engage in recent syringe sharing and least likely to be virally suppressed. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Sasik R.,University of California at San Diego
Nature Methods | Year: 2017

We developed a systematic approach to map human genetic networks by combinatorial CRISPR–Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Hoffman R.M.,University of California at San Diego
Cell Cycle | Year: 2017

We propose here a hypothesis of the cause of cancer that brings together fundamental changes in methyl-group metabolism resulting in methionine dependence and global DNA hypomethylation which destabilizes the genome leading to aneuploid karyotypes which evolve and stabilize into autonomous cancer. Experimental support for this hypothesis is that methioine dependence is a general metabolic defect in caner. Methionine dependence is due to excess use of methionene for aberrant transmethylation reactions that apparently divert methyl groups from DNA. The resulting global DNA hypomethylation is also a general phenomena in cancer. Global hypomethylation leads to an unstable genomes and aneuploid karyotypes, another general phenomena in cancer. The excessive and aberrant use of methionine in cancer is strongly observed in [11C]methionine PET imaging, where high uptake of [11C]methionine results in a very strong and selective tumor signal compared with normal tissue background. [11C]methionine is superior to [18C] fluorodeoxyglucose (FDG)-PET for PET imaging, suggesting methionine dependence is more tumor-specific than glucose dependence. © 2017 Taylor & Francis


Agarwal V.,University of California at San Diego
Nature Chemical Biology | Year: 2017

Naturally produced polybrominated diphenyl ethers (PBDEs) pervade the marine environment and structurally resemble toxic man-made brominated flame retardants. PBDEs bioaccumulate in marine animals and are likely transferred to the human food chain. However, the biogenic basis for PBDE production in one of their most prolific sources, marine sponges of the order Dysideidae, remains unidentified. Here, we report the discovery of PBDE biosynthetic gene clusters within sponge-microbiome-associated cyanobacterial endosymbionts through the use of an unbiased metagenome-mining approach. Using expression of PBDE biosynthetic genes in heterologous cyanobacterial hosts, we correlate the structural diversity of naturally produced PBDEs to modifications within PBDE biosynthetic gene clusters in multiple sponge holobionts. Our results establish the genetic and molecular foundation for the production of PBDEs in one of the most abundant natural sources of these molecules, further setting the stage for a metagenomic-based inventory of other PBDE sources in the marine environment. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Mo G.C.H.,University of California at San Diego
Nature Methods | Year: 2017

Compartmentalized biochemical activities are essential to all cellular processes, but there is no generalizable method to visualize dynamic protein activities in living cells at a resolution commensurate with cellular compartmentalization. Here, we introduce a new class of fluorescent biosensors that detect biochemical activities in living cells at a resolution up to threefold better than the diffraction limit. These 'FLINC' biosensors use binding-induced changes in protein fluorescence dynamics to translate kinase activities or protein–protein interactions into changes in fluorescence fluctuations, which are quantifiable through stochastic optical fluctuation imaging. A protein kinase A (PKA) biosensor allowed us to resolve minute PKA activity microdomains on the plasma membranes of living cells and to uncover the role of clustered anchoring proteins in organizing these activity microdomains. Together, these findings suggest that biochemical activities of the cell are spatially organized into an activity architecture whose structural and functional characteristics can be revealed by these new biosensors. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Nazarko T.Y.,University of California at San Diego
Autophagy | Year: 2017

Peroxisome biogenesis disorders (PBDs) is a group of diseases caused by mutations in one of the peroxins, proteins responsible for biogenesis of the peroxisomes. In recent years, it became clear that many peroxins (e.g., PEX3 and PEX14) play additional roles in peroxisome homeostasis (such as promoting autophagic degradation of peroxisomes or pexophagy), which are often opposite to their originally established functions in peroxisome formation and maintenance. Even more interesting, the peroxins that make up the peroxisomal AAA ATPase complex (AAA-complex) in yeast (Pex1, Pex6 and Pex15) or mammals (PEX1, PEX6, PEX26) are responsible for the downregulation of pexophagy. Moreover, this might be even their primary role in human: to prevent pexophagy by removing from the peroxisomal membrane the ubiquitinated peroxisomal matrix protein import receptor, Ub-PEX5, which is also a signal for the Ub-binding pexophagy receptor, NBR1. Remarkably, the peroxisomes rescued from pexophagy by autophagic inhibitors in PEX1G843D (the most common PBD mutation) cells are able to import matrix proteins and improve their biochemical function suggesting that the AAA-complex per se is not essential for the protein import function in human. This paradigm-shifting discovery published in the current issue of Autophagy has raised hope for up to 65% of all PBD patients with various deficiencies in the AAA-complex. Recognizing PEX1, PEX6 and PEX26 as pexophagy suppressors will allow treating these patients with a new range of tools designed to target mammalian pexophagy. © 2017 The Author(s). Published with license by Taylor & Francis


Dowdy S.F.,University of California at San Diego
Nature Biotechnology | Year: 2017

RNA-based therapeutics, such as small-interfering (siRNAs), microRNAs (miRNAs), antisense oligonucleotides (ASOs), aptamers, synthetic mRNAs and CRISPR-Cas9, have great potential to target a large part of the currently undruggable genes and gene products and to generate entirely new therapeutic paradigms in disease, ranging from cancer to pandemic influenza to Alzheimer's disease. However, for these RNA modalities to reach their full potential, they first need to overcome a billion years of evolutionary defenses that have kept RNAs on the outside of cells from invading the inside of cells. Overcoming the lipid bilayer to deliver RNA into cells has remained the major problem to solve for widespread development of RNA therapeutics, but recent chemistry advances have begun to penetrate this evolutionary armor. © 2017 Nature America, Inc., part of Springer Nature.


Hirsch J.E.,University of California at San Diego
Physical Review B - Condensed Matter and Materials Physics | Year: 2017

Momentum and energy conservation are fundamental tenets of physics, which valid physical theories have to satisfy. In the reversible transformation between superconducting and normal phases in the presence of a magnetic field, the mechanical momentum of the supercurrent has to be transferred to the body as a whole and vice versa, the kinetic energy of the supercurrent stays in the electronic degrees of freedom, and no energy is dissipated nor entropy is generated in the process. We argue on general grounds that to explain these processes it is necessary that the electromagnetic field mediates the transfer of momentum between electrons and the body as a whole, and this requires that when the phase boundary between normal and superconducting phases is displaced, a flow and counterflow of charge occurs in a direction perpendicular to the phase boundary. This flow and counterflow does not occur according to the conventional BCS-London theory of superconductivity, therefore we argue that within BCS-London theory the Meissner transition is a "forbidden transition." Furthermore, to explain the phase transformation in a way that is consistent with the experimental observations, requires that (i) the wave function and charge distribution of superconducting electrons near the phase boundary extend into the normal phase, and (ii) that the charge carriers in the normal state have holelike character. The conventional theory of superconductivity does not have these physical elements, the theory of hole superconductivity does. © 2017 American Physical Society.


Mehta S.,University of California at San Diego
Nature Chemical Biology | Year: 2017

Cyclic AMP (cAMP) and protein kinase A (PKA), classical examples of spatially compartmentalized signaling molecules, are critical axon determinants that regulate neuronal polarity and axon formation, yet little is known about micro-compartmentalization of cAMP and PKA signaling and its role in developing neurons. Here, we revealed that cAMP forms a gradient in developing hippocampal neurons, with higher cAMP levels in more distal regions of the axon compared to other regions of the cell. Interestingly, this cAMP gradient changed according to the developmental stage and depended on proper anchoring of PKA by A-kinase anchoring proteins (AKAPs). Disrupting PKA anchoring to AKAPs increased the cAMP gradient in early-stage neurons and led to enhanced axon elongation. Our results provide new evidence for a local negative-feedback loop, assembled by AKAPs, for the precise control of a growth-stage-dependent cAMP gradient to ensure proper axon growth. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Arimoto K.-I.,University of California at San Diego
Nature Structural and Molecular Biology | Year: 2017

Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK–STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. This mechanistic coupling of effector and negative-feedback functions of STAT2 may provide novel strategies for treatment of IFN-signaling-related human diseases. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Fu X.-D.,University of California at San Diego
Cell Research | Year: 2017

EGF, a well-studied mitogen for cancer cells, is revealed to induce an E3 ubiquitin ligase adaptor SPSB1, which recruits the Elongin B/C-Collin complex to trigger ubiquitylation of the negative splicing regulator hnRNP A1. This event is synergized with EGF-activated SR proteins to alter alternative splicing of a key small GTPase Rac1 to enhance cell migration, highlighting converging EGF signals on both negative and positive splicing regulators to jointly promote a key cancer pathway. © 2017 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences


Ghosh P.,University of California at San Diego
Aging | Year: 2017

Loss of cell polarity impairs organ development and function; it can also serve as one of the first triggers for oncogenesis. In 2006-2007 two groups simultaneously reported the existence of a special pathway for maintaining epithelial polarity in the face of environmental stressors. In this pathway, AMPK, a key sensor of metabolic stress stabilizes tight junctions, preserves cell polarity, and thereby, maintains epithelial barrier functions. Accumulating evidence since has shown that pharmacologic activation of AMPK by Metformin protects the epithelial barrier against multiple environmental and pathological stressful states and suppresses tumorigenesis. How AMPK protects the epithelium remained unknown until recently Aznar et al. identified GIV/Girdin as a novel effector of AMPK at the cell-cell junctions; phosphorylation of GIV at a single site by AMPK appears to be both necessary and sufficient for strengthening tight junctions and preserving cell polarity and epithelial barrier function in the face of energetic stress. Here we review the fundamentals of this specialized signaling pathway that buttresses cell-cell junctions against stress-induced collapse and discuss its pathophysiologic relevance in the context of a variety of diseases, including cancers, diabetes, aging, and the growing list of beneficial effects of the AMPK-activator, Metformin.


Cohen S.M.,University of California at San Diego
Journal of the American Chemical Society | Year: 2017

Metal-organic frameworks (MOFs) have rapidly grown into a major area of chemical research over the last two decades. MOFs represent the development of covalent chemistry “beyond the molecule” and into extended structures. MOFs also present an unprecedented scaffold for performing heterogeneous organic transformations in the solid state, allowing for deliberate and precise preparation of new materials. The development of these transformations has given rise to the “postsynthetic renaissance”, a suite of methods by which these materials can be transformed in a single-crystal-to-single-crystal manner. Postsynthetic modification, postsynthetic deprotection, postsynthetic exchange, postsynthetic insertion, and postsynthetic polymerization have exploited the unique features of both the organic and inorganic components of MOFs to create crystalline, porous solids of unique complexity and functionality. © 2017 American Chemical Society.


Tsimikas S.,University of California at San Diego
Journal of the American College of Cardiology | Year: 2017

Evidence that elevated lipoprotein(a) (Lp[a]) levels contribute to cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS) is substantial. Development of isoform-independent assays, in concert with genetic, epidemiological, translational, and pathophysiological insights, have established Lp(a) as an independent, genetic, and likely causal risk factor for CVD and CAVS. These observations are consistent across a broad spectrum of patients, risk factors, and concomitant therapies, including patients with low-density lipoprotein cholesterol <70 mg/dl. Statins tend to increase Lp(a) levels, possibly contributing to the “residual risk” noted in outcomes trials and at the bedside. Recently approved proprotein convertase subtilisin/kexin-type 9 inhibitors and mipomersen lower Lp(a) 20% to 30%, and emerging RNA-targeted therapies lower Lp(a) >80%. These approaches will allow testing of the “Lp(a) hypothesis” in clinical trials. This review summarizes the current landscape of Lp(a), discusses controversies, and reviews emerging therapies to reduce plasma Lp(a) levels to decrease risk of CVD and CAVS. © 2017 The Author


Varki A.,University of California at San Diego
Glycobiology | Year: 2017

Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences. © The Author 2016.


Herrick N.,University of California at San Diego
Medicine and Science in Sports and Exercise | Year: 2017

Basketball and volleyball attract individuals with a characteristic biophysical profile, mimicking features of Marfan Syndrome (MFS). Consequently, identification of these abnormalities can be lifesaving. PURPOSE: To determine how physical examination, echocardiography, and genetic screening can identify elite volleyball players with a previously undiagnosed aortopathy. METHODS: We have performed cardiac screening on 90 US Volleyball National Team members and identified four individuals with dilated sinuses of Valsalva. This case series reports on three individuals who underwent a comprehensive genetics evaluation, including gene sequencing. RESULTS: Cardiac screening combined with genetic testing can identify previously undiagnosed tall athletes with an aortopathy, in the absence of non-cardiac findings of a connective tissue disorder. Subject #1 had a revised Ghent systems (RGS) score of 2 and a normal aortopathy gene panel. Subject #2 had a RGS score of 1 and genetic testing revealed a de novo disease causing mutation in the gene encoding fibrillin-1 (FBN1). Subject #3 had a RGS score of 4.0 and had a normal aortopathy gene panel. CONCLUSIONS: Despite variable clinical features of MFS, dilated sinuses of Valsalva were found in 4.9% of the athletes. A disease-causing mutation in the FBN1 gene was identified in Subject #2, who had the lowest RGS but the largest aortic root measurement. Subjects #1 and #3, with the highest RGS, had a normal aortopathy gene panel. Our findings provide further evidence suggesting that a cardiac evaluation, including a screening echocardiogram, should be performed on all elite tall adult athletes independent of other physical findings. Genetic testing should be considered for athletes with dilated sinuses of Valsalva (male >4.2cm, female >3.4cm), regardless of other extra-cardiac findings. © 2017 American College of Sports Medicine


OBJECTIVE:: Higher plasma soluble CD163 (sCD163), shed by monocytes and macrophages, correlates with neurocognitive impairment in human immunodeficiency virus (HIV) infection. We hypothesized that higher antemortem plasma or cerebrospinal fluid sCD163 would be associated with greater postmortem neurodegeneration and/or microgliosis. DESIGN:: Retrospective, postmortem observational study. METHODS:: We measured sCD163 levels in antemortem plasma (n?=?54) and cerebrospinal fluid (n?=?32) samples from 74 HIV participants (median 5 months before death) who donated their brains to research at autopsy. Postmortem, we quantified markers of synaptodendritic damage (microtubule-associated protein 2 [MAP2], synaptophysin [SYP]), microgliosis (HLA-DR, ionized calcium binding adaptor molecule 1), astrocytosis (glial fibrillary acidic protein) and impaired protein clearance (beta-amyloid) in frontal cortex, hippocampus, putamen, and internal capsule. Multivariable least-squares regression was used to evaluate the association between plasma or cerebrospinal fluid sCD163 and histological measures, correcting for multiple comparisons. RESULTS:: Higher plasma sCD163 was associated with lower MAP2 in frontal cortex (B?=?−0.23, 95% CI −0.41 to −0.06, p?=?0.04), putamen (B?=?0.32, 95% CI −0.52 to −0.12, p?=?0.02), and hippocampus (B?=?−0.23, 95% CI −0.35 to −0.10, p?=?0.01), and with lower SYP in hippocampus (B?=?−0.25, 95% CI −0.42 to −0.03, p?=?0.02) but not putamen or frontal cortex (p?>?0.05). Higher plasma sCD163 was associated with higher HLA-DR in putamen (B?=?0.17, 95% CI 0.08 to 0.26, p?=?0.008). Cerebrospinal fluid sCD163 was not associated with any histological measure (p?>?0.05). CONCLUSIONS:: Higher plasma sCD163 in life is associated with greater synaptodendritic damage and microglial activation in cortical and subcortical brain regions. Copyright © 2017 Wolters Kluwer Health, Inc.


Miyakoshi M.,University of California at San Diego
Neuropsychopharmacology | Year: 2017

Computerized cognitive training is gaining empirical support for use in the treatment of schizophrenia (SZ). Although cognitive training is efficacious for SZ at a group level when delivered in sufficiently intensive doses (eg, 30–50 h), there is variability in individual patient response. The identification of biomarkers sensitive to the neural systems engaged by cognitive training interventions early in the course of treatment could facilitate personalized assignment to treatment. This proof-of-concept study was conducted to determine whether mismatch negativity (MMN), an event-related potential index of auditory sensory discrimination associated with cognitive and psychosocial functioning, would predict gains in auditory perceptual learning and exhibit malleability after initial exposure to the early stages of auditory cognitive training in SZ. MMN was assessed in N=28 SZ patients immediately before and after completing 1 h of a speeded time-order judgment task of two successive frequency-modulated sweeps (Posit Science ‘Sound Sweeps’ exercise). All SZ patients exhibited the expected improvements in auditory perceptual learning over the 1 h training period (p<0.001), consistent with previous results. Larger MMN amplitudes recorded both before and after the training exercises were associated with greater gains in auditory perceptual learning (r=−0.5 and r=−0.67, respectively, p’s<0.01). Significant pretraining vs posttraining MMN amplitude reduction was also observed (p<0.02). MMN is a sensitive index of the neural systems engaged in a single session of auditory cognitive training in SZ. These findings encourage future trials of MMN as a biomarker for individual assignment, prediction, and/or monitoring of patient response to procognitive interventions, including auditory cognitive training in SZ.Neuropsychopharmacology advance online publication, 22 March 2017; doi:10.1038/npp.2017.25. © 2017 American College of Neuropsychopharmacology


Holland D.,University of California at San Diego
Molecular Psychiatry | Year: 2017

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters—glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids—and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate ‘slow’ (G-protein-coupled receptors) and ‘fast’ (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an ‘associative’ disorder—a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways—and may unify a number of currently competing hypotheses of SCZ pathophysiology.Molecular Psychiatry advance online publication, 28 March 2017; doi:10.1038/mp.2017.33. © 2017 Macmillan Publishers Limited, part of Springer Nature.


Cameron N.,University of California at San Diego
International Journal of Obesity | Year: 2017

Background/objectives:Although several studies have reported associations between moderate to vigorous physical activity (MVPA), body fatness and visceral adipose tissue (VAT), the extent to which associations differ among Latinos and non-Latinos remains unclear. This study evaluated the associations between body composition and MVPA in Latino and non-Latino adults.Subjects/methods:An exploratory, cross-sectional analysis was conducted using baseline data collected from 298 overweight adults enrolled in a 12-month randomized controlled trial that tested the efficacy of text messaging to improve weight loss. MVPA, body fatness and VAT were assessed by waist-worn accelerometry, dual-energy x-ray absorptiometry (DXA), and DXA-derived software (GE CoreScan GE, Madison, WI, USA), respectively. Participants with <5 days of accelerometry data or missing DXA data were excluded; 236 participants had complete data. Multivariable linear regression assessed associations between body composition and MVPA per day, defined as time in MVPA, bouts of MVPA (time per bout ⩾10 min), non-bouts of MVPA (time per bout <10 min) and meeting the 150-min MVPA guideline. The modifying influence of ethnicity was modeled with a multiplicative interaction term.Results:The interaction between ethnicity and MVPA in predicting percent body fat was significant (P=0.01, 95% confidence interval (CI) (0.58, 4.43)) such that a given increase in MVPA was associated with a greater decline in total body fat in non-Latinos compared with Latinos (adjusted for age, sex and accelerometer wear time). There was no interaction between ethnicity and MVPA in predicting VAT (g) (P=0.78, 95% CI (−205.74, 273.17)) and body mass index (BMI) (P=0.18, 95% CI (−0.49, 2.26)).Conclusions:An increase in MVPA was associated with a larger decrease in body fat, but neither BMI nor VAT, in non-Latinos compared with Latinos. This suggests that changes in VAT and BMI in response to MVPA may be less influenced by ethnicity than is total body fatness.International Journal of Obesity advance online publication, 21 March 2017; doi:10.1038/ijo.2017.49. © 2017 Macmillan Publishers Limited, part of Springer Nature.


Home > Press > Geoffrey Beach: Drawn to explore magnetism: Materials researcher is working on the magnetic memory of the future Abstract: Geoffrey Beach has been tinkering and building things most of his life, including some 50 model rockets that he built and launched while in high school in Oklahoma. But it wasn’t until his undergraduate studies in physics that he zeroed in on the topic that has dominated his research ever since: the study of magnetism and how to control it. In his work, Beach combines the deep, theoretical understanding of a physicist with an engineer’s passion for building and refining the devices needed to carry out his investigations. “In high school and college, I was always interested in physics,” says Beach, who is an associate professor in MIT’s Department of Materials Science and Engineering, where he earned tenure in 2015. He received his bachelor’s degree from Caltech, where his interest in magnetism first came into focus. During those college years studying physics, “everyone there wanted to work on gravity,” he says. “I liked the theoretical aspect, but I’ve always been a very hands-on person. I always liked to build things, and I really like to see how things work.” Beach had an extra incentive to pursue his chosen field of physics: His father, a paper-industry executive, put Beach to work at a paper mill during his summer vacations, and chose for his son the hardest and dirtiest jobs to ensure he wasn’t getting any special treatment. “So I ended spending the summer up on the roof, cleaning out air-conditioning units in 100-degree heat,” Beach recalls. Looking for a more career-building alternative, he sent out “a lot of requests” to many faculty members, seeking a summer job. One of those requests struck paydirt — and opened up a whole new avenue of study for Beach. “There was a professor working on condensed matter and magnetic materials, who responded,” he says. She set him up in a lab that gave him his introduction to the study of exotic magnetic processes. Beach learned a variety of lab techniques and how to use specialized equipment, and then proceeded to figure out how to modify the equipment and develop new methods. “I realized that doing these things, I really could get my hands into every aspect” of the research, trying to unravel the properties of various newly developed materials, he says. “I loved it. I had found what I enjoyed doing.” “Interfaces control everything” Beach went to the University of California at San Diego for his doctorate, working in the industry-sponsored Center for Magnetic Recording Research, which covered all aspects of digital data storage, from the magnetic materials themselves to the signal-processing technology needed to process the data. “I was very intrigued by the magnetism problems,” he says, “but also by the utility of what I would do there, to address a real, pressing problem,” since magnetic recording is such a fundamental part of everything from computers to entertainment systems. One of the key insights he gained from that work was the crucial role of boundaries between materials. “Interfaces control everything,” he says. “If you want to control and design material properties, you don’t start with the bulk material, you put dissimilar materials adjacent to one another.” Such interfaces that don’t occur naturally are “the interesting places where things can happen.” While at UCSD, he worked on developing novel thin-film magnetic nanocomposites, with interfaces between metals and oxides, which turned out to have exceptionally fast response times for data recording. He met his wife Kanna Shimuzu as an undergraduate, and they got married while they were in graduate school. After they both earned their PhDs, she found a job with IBM in Austin, Texas, and he looked for a position in the area. He quickly found a postdoc opening at the University of Texas that fit his interests, working on thin-film magnetism. He and Shimuzu “finally got to live together, for the first time since we got married,” he says, after having spent their graduate school years commuting to be together on weekends. (She had been at Stanford University, about 470 miles away from San Diego). While in Texas, they had their first child, Emma. Alyssa, their second daughter, was born the day before Beach had his first interview at MIT. Shimuzu is now an engineer at working at Amazon. Controlling magnetism electrically It was at UT Austin that Beach began in earnest his investigation of how fast the poles of a magnetic material can be reversed — a key objective for enabling next-generation data systems for computers whose processing speeds continue to increase at a rapid pace. “That’s where I started to get into magnetization dynamics: How do materials respond to stimuli? How fast can magnetic materials respond?” he says. These dynamic effects turned out to work very differently as materials get down to nanoscale (billionths of a meter) sizes, Beach found. While in Texas, he studied new materials whose magnetic properties could be altered electrically — a field now known as spintronics. Until that time, “In all of history, if you wanted to control a magnetic material, you needed another magnet,” he says, but these new materials could be changed by just applying a voltage. “Once you can do things electrically, you can wire these things together into a circuit, and you can start to manipulate information this way without anything physically moving, and without using magnets.” That’s a big advantage, because it’s very hard to make very small, useful magnets; the magnetic field disperses around them. At the time, “these ideas of using electron properties in a material to control magnetism were just coming into fruition,” he says. His experiments with tiny wires, just a few nanometers in diameter, showed that when the wire was composed of two oppositely magnetized segments joined together, interesting things could happen at the boundary where the two segments meet. That boundary could be pushed and pulled one way or the other by passing current through the wire — changes that could be used to encode data. What’s more, he found that wires could be made with many segments in a row, and all the boundaries could be controlled in this way, so this could provide a way of encoding a number of data bits in a single, minuscule wire. But there were limitations: The system required too much current to be practical. When Beach was hired for a faculty position at MIT in 2008, these kind of moving magnetic domains quickly became a major focus of his research. “The crux of my research now is to design more complex materials in which we can go around what seemed to be fundamental simple principles, by using the complexity of materials, and properties that emerge at designed interfaces, to really use materials science to overcome these limits and really explore new physics in materials,” he says. For example, Beach and his co-workers have found that a kind of magnetic virtual particle can be created in these designed interfaces, and can be used to store and retrieve data at rates that are already comparable to those of conventional systems, but whose variants may have the potential to be much faster. “There are many thousands of combinations of materials and interfaces that we can create,” he says. “So with this wealth of material structures, rather than relying on the few materials that nature has given us, we can now design materials and their magnetic properties to exhibit the characteristics that we want.” That’s just one of many projects that Beach and his students continue to work on, in which creating and manipulating the interfaces between “simple, boring” materials can produce properties that are exciting, novel, and potentially useful for a wide variety of applications. “The possibilities are more or less endless, as far as we’re concerned,” he says. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


Now, the 23-year-old software engineer, who joined Pinterest in 2015, is helping 150 million monthly active users on the social bookmarking site tap into their creative side. Zhang works on the tech firm's search product team, which consists of 30 percent women engineers. She built the Android version of a new feature the company is testing called Lens, allowing users to discover more ideas by snapping a photo of an object in real life. "I think as an engineer it's really important to have inspiration to keep you going and work on a product that you really love," she said. Zhang, who is also a singer in Mino the band, sat down with The Mercury News to chat about the company's visual search efforts. This interview has been edited for clarity and length. Q: How would you describe your job as a software engineer at Pinterest? A: I work on the search product team, and we're responsible for all the user-facing aspects of search. We work on Android, iOS and web. The most recent project I worked on was Pinterest Lens and before that I worked on search recommendations, which are recommendations you get from your search results that kind of pivot you to search for other things as well. Q: Pinterest Lens basically allows you to snap a photo and then you get a list of recommended pins. How is the beta testing of the product going so far? A: It's going very well. We've got a lot of people posting what photos they've snapped on Twitter and recipes they've found from Pinterest Lens. We've also gotten a lot of people who take selfies of themselves to get their celebrity look-alikes. We discovered that people really like the suggestions we give from Pinterest Lens. If you took a picture of an avocado and got pictures of more avocados, they didn't find that very helpful. They wanted more context like avocado recipes. We've gotten a lot of people really excited about (Lens) on Twitter and social media. Q: If you're searching online, normally you would just type it into a search bar instead of taking a photo. How do you change consumer behavior? A: I think a lot of Pinners find a lot of ideas when they're on their computer. We wanted them to get ideas in the real world. I feel like Pinterest is not a search engine where you type in something and you get an answer. It's more, 'I'm curious and I don't know what I'm going to get as results.' I think Pinterest Lens really helps with that. Here's a type of furniture I really like, I don't know what it's called, but I'm curious about it, so let me take a picture of it and get some ideas. Q: Sometimes people take photos at a weird angle, or it's blurry. How is Pinterest tackling that problem? A: We have some tools to address it on the front end and the back end. In the app, if you are in a dark setting, we will turn on the auto flash setting for you. Then we also have back-end detection where we will detect whether an image is blurry or dark and then basically show a (notification) telling you we can't see in the dark or ask you to stay still. We have image detection that will tell you our results aren't going to be great because you're moving around too much or your image is too dark. Q: How would you define your own personal style? Do you still use Pinterest frequently now that you work here? A: I definitely do. Even when I'm working, I get distracted sometimes. If I see something I'm interested in, then I'll just click on the pin and go to related pins. I'm kind of stuck in a hole where I keep on looking for things. Because Pinterest is so visual, it's a tool that really helps you discover your personal style rather than share stuff about yourself. I discovered that I really like minimal style with clothing and also home decorations. I've definitely gotten a lot of ideas on how to decorate my house through Pinterest. Q: Do you use Pinterest differently as a musician? A: The band I have right now tries to promote ourselves in a way that's visually appealing. So I use Pinterest a lot for flyer ideas and for cover art album ideas. I feel like most of the music inspiration I get is through listening to music. Q: In 2016, only 20 percent of Pinterest engineers were women, and the company also fell short of its hiring goals for women engineers. As a woman engineer at Pinterest, why do you think tech companies are struggling to get more women in this field? A: If we introduced coding and these concepts at an early age, we wouldn't necessarily relate engineering to being a male-dominated field. I was lucky because my mom is also an engineer, so she definitely taught me how to code at an early age. It was always a possibility for me. I kind of learned how to code through using Neopets. I would make a webpage for my pets using HTML. At Pinterest, I feel that everyone is very open-minded and doesn't differentiate between engineer and female engineer. I have a lot of responsibility and ownership over projects that have a big impact on the product. Q: Where do you think visual search will be headed next? Do you see Pinterest going beyond photos? Will we one day be searching through videos or even virtual reality for pins? A: I think right now we're really trying to show you that object in a bigger context and give you more ideas of actions to take. For example, if you take a picture of a clock. We're trying to show you how to style that clock in your house and other homes with the same clock and what they look like. We're just trying to give you some suggestions on where to take action for that particular object. Definitely, in the future, I think there are a lot of opportunities for visual search at Pinterest. Previous jobs: Engineering intern at HP, Android intern at Yahoo, computer science and engineering tutor for Introduction to Computer Science classes at University of California at San Diego 1. I went to eight elementary schools because I moved around frequently as a child. 2. When I'm not coding, I'm probably doing something musical. I've had experience playing classical violin in high school and singing in an a cappella group in college. Now I'm writing songs for and singing in my band, which performs jazz-inspired pop and contemporary R&B.; 3. I've lived in three states after immigrating here from China: Iowa, Tennessee and California. 4. Along with Chinese, other foreign languages I speak include Japanese and Korean, which I studied in high school. 5. My favorite food apart from my mom's food is Korean food.


News Article | April 17, 2017
Site: www.eurekalert.org

Chapel Hill, NC - HIV cure research to date has focused on clearing the virus from T cells, a type of white blood cell that is an essential part of the immune system. Yet investigators in the Division of Infectious Diseases at the University of North Carolina School of Medicine have found the virus persists in HIV-infected macrophages. Macrophages are large white blood cells found in tissues throughout the body including the liver, lung, bone marrow and brain. The discovery of this additional viral reservoir has significant implications for HIV cure research. These findings were published in Nature Medicine on Monday, April 17. "These results are paradigm changing because they demonstrate that cells other than T cells can serve as a reservoir for HIV," said Jenna Honeycutt, Ph.D., lead-author and postdoctoral research associate in the UNC Division of Infectious Diseases. "The fact that HIV-infected macrophages can persist means that any possible therapeutic intervention to eradicate HIV might have to target two very different types of cells." Last spring, this laboratory lead by J. Victor Garcia, Ph. D., professor of medicine, microbiology and immunology at UNC School of Medicine, demonstrated the ability of tissue macrophages to support HIV replication in vivo in the total absence of human T cells. But how macrophages would respond to antiretroviral therapy (ART) and whether macrophages represented a reservoir for HIV after treatment were unknown. Macrophages are myeloid lineage cells that have been implicated in HIV pathogenesis and in the trafficking of virus into the brain. Using a humanized myeloid-only mouse (MoM) model devoid of T cells, Garcia and his team showed that ART strongly suppresses HIV replication in tissue macrophages. Yet when HIV treatment was interrupted, viral rebound was observed in one third of the animals. This is consistent with the establishment of persistent infection in tissue macrophages. "This is the first report demonstrating that tissue macrophages can be infected and that they respond to antiretroviral therapy," Honeycutt said. "In addition, we show that productively infected macrophages can persist despite ART; and most importantly, that they can reinitiate and sustain infection upon therapy interruption even in the absence of T cells -- the major target of HIV infection." Now that Garcia and his team know HIV persists in macrophages, the next step will be to determine what regulates HIV persistence in tissue macrophages, where in the body persistently infected macrophages reside during HIV treatment and how macrophages respond to possible therapeutic interventions aimed at eradicating HIV from the body. The UNC School of Medicine team collaborated with scientists in UNC's Department of Biostatistics, the Theoretical Division at Los Alamos National Laboratory, Veterans Affairs San Diego Healthcare System, and the Departments of Medicine and Pathology at the University of California at San Diego. This study was funded by the National Institute of Mental Health and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health. The mission of UNC's Institute for Global Health & Infectious Diseases is to harness the full resources of the University and its partners to solve global health problems, reduce the burden of disease, and cultivate the next generation of global health leaders. Learn more at http://www. .


Hoffman R.M.,Anticancer, Inc. | Hoffman R.M.,University of California at San Diego
Nature Reviews Cancer | Year: 2015

The majority of human solid tumours do not metastasize when grown subcutaneously in immunocompromised mice; this includes patient-derived xenograft (PDX) models. However, orthotopic implantation of intact tumour tissue can lead to metastasis that mimics that seen in patients. These patient-derived orthotopic xenograft (PDOX) models have a long history and might better recapitulate human tumours than PDX models. © 2015 Macmillan Publishers Limited. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 316.11K | Year: 2015

DESCRIPTION provided by applicant Activation of lung myofibroblasts LMF is responsible for the development of lung fibrosis in chronic lung diseases of all causes and remarkably LMF clearance by apoptosis may prevent development of lung fibrosis and lung injury and possibly allow recovery from reversal of lung fibrosis There is full agreement among tissue fibrosis experts that inhibiting o reversing myofibroblast activation the therapeutic target is critical fr the treatment of lung fibrosis Both preventing progression of lung fibrosis as well as possibly regression of lung fibrosis in spite of continued lung injury as we documented in our pre clinical studies are considered important clinical targets for patients with Idiopathic Pulmonary Fibrosis IPF Finally blocking the progression of lung fibrosis may decrease development of lung cancer The basis for our Research and Development is the development of novel andapos humanizedandapos peptoids not previously reported We created a library using analog synthesis to improve potential pitfalls for human therapy We have performed in a step wise manner assays to select the safest and most efficient andapos humanizedandapos peptoids including apoptosis assays in activated primary human myofibroblasts cell free caspase activation assays lung injury fibrogenesis models preliminary toxicology assays in mice We have developed novel and highly effective anti fibrotic peptoids in animal models with no evidences of immunogenicity in state of the art T cell assays and with exceptional stability in mouse microsomal systems and mouse blood The lead peptoid has excellent solubility in water These features should facilitate administration by inhalation with increased bioavailability to the LMF during clinical trials The proposed compounds markedly inhibit activation of human and mouse myofibroblast in culture These compounds were not toxic in the preliminary toxicology studies including pilot toxicogenomics to mice at least at fold the therapeutic dose The aims that are proposed for this Phase STTR are Specific Aim Efficacy of the Lead Peptoid in Lung Fibrosis Mouse Models Specific Aim Pharmacokinetics Single and Multiple doses in Mice and Stability Assays in vitro in Human Lung Microsomes and Human Plasma There is no medication for the treatment of lung fibrosis in IPF Completion of these tasks for the proposed compounds will allow us proceeding with a Phase STTR and clinical development in patients with IPF PUBLIC HEALTH RELEVANCE Idiopathic Pulmonary Fibrosis IPF through inflammation and injury induce the development of scar tissue in the lung this is called lung fibrosis Excessive lung fibrosis can result in lung dysfunction which accounts for the significant complications and mortality among the population with IPF The personal medical and financial burden of IPF to the USA is substantial as it is associated with a very poor prognosis and high mortality Additional knowledge gained by Xfibra with this work will facilitate the development of medication given by inhalation for the treatment of IPF The inhalation route of administration is simple highly feasible given the exceptional solubility and stability of the therapeutic compound and relatively inexpensive to produce


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 150.00K | Year: 2015

DESCRIPTION provided by applicant Dysbiosis refers to a condition with microbial imbalances within the human microbiome Yogurts are the best examples of using fermenting gut bacteria to rebalance the gut dysbiosis Our results demonstrate for the first time that Staphylococcus epidermidis S epidermidis a commensal bacterium of the human skin functions as a probiotic microorganism that employs fermentation to restrain the over growth of Propionibacterium acnes a skin opportunistic bacterium associated with acne vulgaris Like microbial competition in a ripening fruit we envision that S epidermidis and P acnes within an acne microenvironment compete with each other for the same carbon source of fermentation To intensify the ability of S epidermidis to andquot beatandquot out its competitor P acnes the a lactose monohydrate ALM a selective fermentation initiator will be used to exclusively trigger the fermentation of S epidermidis The concept of using S epidermidis fermentation against P acnes will be applied for {development of post antibiotic adjuvant therapy for treatment of acne vulgairs A short chain fatty acid SCFA with antimicrobial activity in the fermentative metabolites of S epidermidis will be formulated with clindamycin a commonly prescribed topical antibiotic for acne vulgaris The effects of SCFA on the suppression of P acnes growth and reduction of required doses of clindamycin will be investigated {We have recently obtained acne biopsies in collaboration with Dr Tissa R Hata a Director of the Dermatology Clinical Trials Unit at University of California San Diego UCSD These acne biopsies have been used to establish ex vivo acne explants The effectiveness of SCFA or the SCFA clindamycin combination on suppression of P acnes growth and reduction of pro inflammatory cytokines will be tested by using ex vivo acne explants } Three Specific Aims are proposed to validate our hypothesis In Specific Aim we will identify a SCFA for selectively eliminating P acnes without inhibiting S epidermidis {measure the concentrations of SCFAs in human ex vivo acne explants and determine an effective concentration of SCFA for suppression of P acnes growth In Specific Aim we will validate the essential role of probiotic S epidermidis in the inhibitio of P acnes growth in acne lesions compare the potency of SCFA against P acnes to that of antibiotic and develop SCFA as an antibiotic adjuvant In Specific Aim we will explore the possible disruptive effects of SCFA on skin commensals and examine the cytotoxicities of SCFA with without clindamycin to skin cells } In addition to developing a novel acne therapeutic { SCFA as post antibiotic adjuvant therapy } we emphasize the notion that {combination of antibiotics with probiotic derived metabolites may greatly reduce the side effects of antibiotics for treatment of acne vulgaris } PUBLIC HEALTH RELEVANCE Dysbiotic acne vulgaris is associated with the over growth of Propionibacterium acnes P acnes Our results have demonstrated that Staphylococcus epidermidis S epidermidis a Gram positive bacterium co existed with P acnes in an acne lesion can exploit the carbohydrate fermentation to inhibit the growth of P acnes Our approach here is to selectively amplify the fermentation activity of S epidermidis to rebalance the acne dysbiosis {and develop short chain fatty acids main ferment metabolites as post antibiotic adjuvant therapy for treatment of acne vulgaris }


Okumura C.Y.M.,Occidental College | Nizet V.,University of California at San Diego
Annual Review of Microbiology | Year: 2014

The development of a severe invasive bacterial infection in an otherwise healthy individual is one of the most striking and fascinating aspects of human medicine. A small cadre of gram-positive pathogens of the genera Streptococcus and Staphylococcus stand out for their unique invasive disease potential and sophisticated ability to counteract the multifaceted components of human innate defense. This review illustrates how these leading human disease agents evade host complement deposition and activation, impede phagocyte recruitment and activation, resist the microbicidal activities of host antimicrobial peptides and reactive oxygen species, escape neutrophil extracellular traps, and promote and accelerate phagocyte cell death through the action of pore-forming cytolysins. Understanding the molecular basis of bacterial innate immune resistance can open new avenues for therapeutic intervention geared to disabling specific virulence factors and resensitizing the pathogen to host innate immune clearance. Copyright © 2014 by Annual Reviews. All rights reserved.


Grant
Agency: National Aeronautics and Space Administration | Branch: | Program: STTR | Phase: Phase I | Award Amount: 124.98K | Year: 2014

The technical innovation proposed here expands upon early research into the viability of additive machining (AM) for liquid rocket engine components and other emerging capabilities to initiate TRL 6 flight test evaluations of candidate applications that could enhance the affordability of a small launch vehicle (SLV) booster stage. University of California, San Diego (USCD) has achieved success in applying 3D AM to fabricate a 200 lbf-thrust LOX/kerosene engine. Concurrently, the Garvey Spacecraft Corporation (GSC) team continues to make progress in the development and flight testing of key elements for a future low-cost nanosat launch vehicle (NLV). These NASA-sponsored NLV designs, concept of operations (CONOPS) and cost metrics based on actual flight operations now serve as references for evaluating emerging technologies like UCSD's AM engine(s) to implement an SLV first stage that achieves the aggressive cost, performance and sizing goals specified in the T1.02 subtopic description. This is exactly the same approach that was followed under a previous NASA STTR that successfully demonstrated a TRL 6 for an advanced CMC-lined ablative engine chamber. Phase I flight testing features a subscale host vehicle, while Phase II then follows with an SLV-scale prototype booster.


Meng Y.S.,University of California at San Diego | Arroyo-De Dompablo M.E.,Complutense University of Madrid
Accounts of Chemical Research | Year: 2013

To meet the increasing demands of energy storage, particularly for transportation applications such as plug-in hybrid electric vehicles, researchers will need to develop improved lithium-ion battery electrode materials that exhibit high energy density, high power, better safety, and longer cycle life. The acceleration of materials discovery, synthesis, and optimization will benefit from the combination of both experimental and computational methods. First principles (ab Initio) computational methods have been widely used in materials science and can play an important role in accelerating the development and optimization of new energy storage materials. These methods can prescreen previously unknown compounds and can explain complex phenomena observed with these compounds.Intercalation compounds, where Li + ions insert into the host structure without causing significant rearrangement of the original structure, have served as the workhorse for lithium ion rechargeable battery electrodes. Intercalation compounds will also facilitate the development of new battery chemistries such as sodium-ion batteries. During the electrochemical discharge reaction process, the intercalating species travel from the negative to the positive electrode, driving the transition metal ion in the positive electrode to a lower oxidation state, which delivers useful current. Many materials properties change as a function of the intercalating species concentrations (at different state of charge). Therefore, researchers will need to understand and control these dynamic changes to optimize the electrochemical performance of the cell. In this Account, we focus on first-principles computational investigations toward understanding, controlling, and improving the intrinsic properties of five well known high energy density Li intercalation electrode materials: layered oxides (LiMO2), spinel oxides (LiM2O4), olivine phosphates (LiMPO4), silicates-Li2MSiO4, and the tavorite-LiM(XO4)F (M = 3d transition metal elements). For these five classes of materials, we describe the crystal structures, the redox potentials, the ion mobilities, the possible phase transformation mechanisms, and structural stability changes, and the relevance of these properties to the development of high-energy, high-power, low-cost electrochemical systems. These results demonstrate the importance of computational tools in real-world materials development, to optimize or minimize experimental synthesis and testing, and to predict a material's performance under diverse conditions. © 2012 American Chemical Society.


Chang J.T.,University of California at San Diego | Wherry E.J.,University of Pennsylvania | Goldrath A.W.,University of California at San Diego
Nature Immunology | Year: 2014

Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream 'pioneering' factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy.


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.


Grant
Agency: Department of Energy | Branch: | Program: STTR | Phase: Phase I | Award Amount: 150.00K | Year: 2016

Replacement of petroleum based vehicles with fuel cell electric vehicles operating on hydrogen produced from domestically available resources would dramatically decrease emissions of greenhouse gases and other pollutants as well as reduce dependence on oil from politically volatile regions of the world. One major inhibitor to a hydrogen society is the lack of infrastructure, which requires hydrogen liquefaction refrigeration systems to provide safe and economical storage and transportation of this fuel. Statement of how this problem is being addressed: One of the more promising technologies of interest for hydrogen liquefaction is magnetic refrigeration due to its high efficiency. Magnetic Refrigeration utilizes the magnetocaloric effect (MCE), which is the temperature variation of a magnetic material after exposure to a magnetic field. A critical challenge of developing low cost magnetic refrigerators is the cost and availability of MCE materials, which are typically rare-earth and very expensive. Therefore, the focus of this proposal is to develop rare-earth free or low cost rare-earth MCE materials specifically for hydrogen liquefaction systems. Small changes in the composition of the MCE material shift its MCE response temperature, allowing optimization to the desired temperature range (~20K). The use of nano-grained structures allows broader temperature response range along with increased cooling capacity. During the Phase I effort, nano-grained compositions of low cost Mn-based Heusler alloys, and La-based alloys will be synthesized and optimized for near 20K refrigeration. Commercial Applications and Other Benefits: The proposed research has the potential to contribute to a fundamental understanding of MCE within nanoscience and also advance the state-of-the-art in refrigeration technologies. The proposed low cost MCE materials would reduce the MCE material cost for these systems by greater than 95%, offering an enormous commercial opportunity ((>$20M annual U.S. gross sales), and opening the door for reliable, low cost, and energy-efficient hydrogen liquefaction systems. Additionally, all working MCE materials developed during this research will be made commercially available for online purchase in small quantities. This will accelerate the development of innovative magnetic refrigeration technologies for all temperature applications: hydrogen liquefaction (20K), nitrogen liquefaction (80K), space applications (100-200K), and room temperature refrigeration and air conditioning. Key Words: Magnetocaloric Materials, Hydrogen Liquefaction, Magnetic Refrigeration, Nanomaterials


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

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

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