139 research outputs found

    Advances in Architectures and Tools for FPGAs and their Impact on the Design of Complex Systems for Particle Physics

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    The continual improvement of semiconductor technology has provided rapid advancements in device frequency and density. Designers of electronics systems for high-energy physics (HEP) have benefited from these advancements, transitioning many designs from fixed-function ASICs to more flexible FPGA-based platforms. Today’s FPGA devices provide a significantly higher amount of resources than those available during the initial Large Hadron Collider design phase. To take advantage of the capabilities of future FPGAs in the next generation of HEP experiments, designers must not only anticipate further improvements in FPGA hardware, but must also adopt design tools and methodologies that can scale along with that hardware. In this paper, we outline the major trends in FPGA hardware, describe the design challenges these trends will present to developers of HEP electronics, and discuss a range of techniques that can be adopted to overcome these challenges

    Evaluating Neighborhood, Social, and Genetic Influences on Precursors of Alcohol Use Risk Behavior in African American Adolescents

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    Background: Using a socioecological framework, we examined neighborhood and social stressors in concert with genetic risk for alcohol dependence in relation to externalizing behaviors, important precursors to alcohol-related problems. Methods: We used data from African American adolescents and their caregivers in the Gene, Environment, and Neighborhood Initiative, a subsample of the Mobile Youth and Poverty Study. Participants for the current analyses included 112 adolescents who reported ever having at least one full drink of alcohol. Empirical Bayes scores were used to estimate neighborhood-level violence and transitions. Multivariate models tested main effects and then interactions of family stressors, discrimination, and genetic risk with the neighborhood variables. Results: In the main effects model, adolescent externalizing behaviors were positively associated with greater family stressors, more racial discrimination experiences, and genetic liability, while neighborhood variables were nonsignificant. We found three significant interactions. Specifically, the joint effects of neighborhood violence and transitions and between these neighborhood variables and family stressors were significantly associated with externalizing behaviors. Conclusions: Our findings suggest genetic liability and complex interactions between neighborhood context and social stressors are important contributors that should be considered in the development of early prevention programs for adolescents who live in economically disadvantaged areas

    Blockade ofthe negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis

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    INTRODUCTION: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. METHODS: Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. RESULTS: Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. CONCLUSIONS: Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered

    Tethering Telomeric Double- and Single-stranded DNA-binding Proteins Inhibits Telomere Elongation

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    Mammalian telomeres are composed of G-rich repetitive double-stranded (ds) DNA with a 3' single-stranded (ss) overhang and associated proteins that together maintain chromosome end stability. Complete replication of telomeric DNA requires de novo elongation of the ssDNA by the enzyme telomerase, with telomeric proteins playing a key role in regulating telomerase-mediated telomere replication. In regards to the protein component of mammalian telomeres, TRF1 and TRF2 bind to the dsDNA of telomeres, whereas POT1 binds to the ssDNA portion. These three proteins are linked through either direct interactions or by the proteins TIN2 and TPP1. To determine the biological consequence of connecting telomeric dsDNA to ssDNA through a multiprotein assembly, we compared the effect of expressing TRF1 and POT1 in trans versus in cis in the form of a fusion of these two proteins, on telomere length in telomerase-positive cells. When expressed in trans these two proteins induced extensive telomere elongation. Fusing TRF1 to POT1 abrogated this effect, inducing mild telomere shortening, and generated looped DNA structures, as assessed by electron microscopy, consistent with the protein forming a complex with dsDNA and ssDNA. We speculate that such a protein bridge between dsDNA and ssDNA may inhibit telomerase access, promoting telomere shortening

    Macondo crude oil from the Deepwater Horizon oil spill disrupts specific developmental processes during zebrafish embryogenesis

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    Background: The Deepwater Horizon disaster was the largest marine oil spill in history, and total vertical exposure of oil to the water column suggests it could impact an enormous diversity of ecosystems. The most vulnerable organisms are those encountering these pollutants during their early life stages. Water-soluble components of crude oil and specific polycyclic aromatic hydrocarbons have been shown to cause defects in cardiovascular and craniofacial development in a variety of teleost species, but the developmental origins of these defects have yet to be determined. We have adopted zebrafish, Danio rerio, as a model to test whether water accumulated fractions (WAF) of the Deepwater Horizon oil could impact specific embryonic developmental processes. While not a native species to the Gulf waters, the developmental biology of zebrafish has been well characterized and makes it a powerful model system to reveal the cellular and molecular mechanisms behind Macondo crude toxicity. Results: WAF of Macondo crude oil sampled during the oil spill was used to treat zebrafish throughout embryonic and larval development. Our results indicate that the Macondo crude oil causes a variety of significant defects in zebrafish embryogenesis, but these defects have specific developmental origins. WAF treatments caused defects in craniofacial development and circulatory function similar to previous reports, but we extend these results to show they are likely derived from an earlier defect in neural crest cell development. Moreover, we demonstrate that exposure to WAFs causes a variety of novel deformations in specific developmental processes, including programmed cell death, locomotor behavior, sensory and motor axon pathfinding, somitogenesis and muscle patterning. Interestingly, the severity of cell death and muscle phenotypes decreased over several months of repeated analysis, which was correlated with a rapid drop-off in the aromatic and alkane hydrocarbon components of the oil. Conclusions: Whether these teratogenic effects are unique to the oil from the Deepwater Horizon oil spill or generalizable for most crude oil types remains to be determined. This work establishes a model for further investigation into the molecular mechanisms behind crude oil mediated deformations. In addition, due to the high conservation of genetic and cellular processes between zebrafish and other vertebrates, our work also provides a platform for more focused assessment of the impact that the Deepwater Horizon oil spill has had on the early life stages of native fish species in the Gulf of Mexico and the Atlantic Ocean

    The Grizzly, April 16, 1991

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    Alcohol Policy Changes Discussed • Reimert Fire Breaks Up Sorority Rush: Deliberate or Accidental Still Unknown • Faculty Evaluates Frat Pledges Performance • Economics Conference Held • U.S.G.A. Minutes • Conflict and Creativity: ProTheatre Does it Again • Is Rock and Roll Really Dead? • REM: Out of Time • The Cider House Rules, Revisited • Religious Significance of David • Plaza Suite in Wismer • Jack Spinella Named New Basketball Coach • Men\u27s Track Falls to Hopkins • Men\u27s Lax Goes 1 and 1 This Week • Women Run Over Muhlenberg • Softball Splits • Golf Below Par • Student Input on Alcohol Policy Inadequate • Schafer Demands Opinion • Hold on to Your Key Money? • Letters: Apathy Dialog Proposed; Sorry, Harley; Thanks, Judd!; Weakly not Weekly • The Cutting Edge of Surgery • Electron Microscope to be Purchased With Kresge Grant • Help for Chronic Fatigue Sufferershttps://digitalcommons.ursinus.edu/grizzlynews/1276/thumbnail.jp

    Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

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    BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10(−4); OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10(−4); OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No

    The Grizzly, February 4, 1991

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    Ursinus Celebrates Black History Month • Welcome Back President Richter • Noted Psychologist to Speak at Ursinus Forum • Kirstin Border Crowned • Sophomore Scholarship Competition Announced • Operation Ursinus Cares • Peace Activist Speaks • Veteran Leads Discussion • King Swamp • The Dark Half • Organ Recital • Fact vs. Fiction • Wrestlers Take It To the Mat • Football Players Honored at Banquet • Swimmers Drown E-town • Martin Scores 1,00th Career Point • Hoopsters Fall to Hopkins • Donald R. Groff Named New Softball Coach • Peace Movement Needs Agenda • Why we are at War: The Opinion of One Informed Layperson • Garbage: A Terrible Thing to Waste • Chemistry of the Gulf Warhttps://digitalcommons.ursinus.edu/grizzlynews/1269/thumbnail.jp
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