Epitaxial Growth and Processing of Compound Semiconductors

Contains an introduction and reports on three research projects.MIT Lincoln LaboratoryU.S. Air Force - Office of Scientific Research Grant F49620-96-1-0126National Science Foundation Grant DMR 94-00334Joint Services Electronics Progra

Epitaxial Growth and Processing of Compound Semiconductors

Contains an introduction and reports on six research projects.Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research University Research Initiative Subcontract N00014-92-J-1893Joint Services Electronics Program Grant DAAH04-95-1-0038National Center for Integrated Photonics Technology Contract 542-381National Science Foundation Grant DMR 92-02957MIT Lincoln Laboratory Contract BX-6085National Center for Integrated Photonics Technology Subcontract 542-383U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0126U.S. Navy - Office of Naval Research Grant N00014-91-J-1956National Science Foundation Grant DMR 94-0033

Upper ocean oxygenation dynamics from I/Ca ratios during the Cenomanian-Turonian OAE 2

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 30 (2015): 510–526, doi:10.1002/2014PA002741.Global warming lowers the solubility of gases in the ocean and drives an enhanced hydrological cycle with increased nutrient loads delivered to the oceans, leading to increases in organic production, the degradation of which causes a further decrease in dissolved oxygen. In extreme cases in the geological past, this trajectory has led to catastrophic marine oxygen depletion during the so-called oceanic anoxic events (OAEs). How the water column oscillated between generally oxic conditions and local/global anoxia remains a challenging question, exacerbated by a lack of sensitive redox proxies, especially for the suboxic window. To address this problem, we use bulk carbonate I/Ca to reconstruct subtle redox changes in the upper ocean water column at seven sites recording the Cretaceous OAE 2. In general, I/Ca ratios were relatively low preceding and during the OAE interval, indicating deep suboxic or anoxic waters exchanging directly with near-surface waters. However, individual sites display a wide range of initial values and excursions in I/Ca through the OAE interval, reflecting the importance of local controls and suggesting a high spatial variability in redox state. Both I/Ca and an Earth System Model suggest that the northeast proto-Atlantic had notably higher oxygen levels in the upper water column than the rest of the North Atlantic, indicating that anoxia was not global during OAE 2 and that important regional differences in redox conditions existed. A lack of correlation with calcium, lithium, and carbon isotope records suggests that neither enhanced global weathering nor carbon burial was a dominant control on the I/Ca proxy during OAE 2.Z.L. thanks NSF OCE 1232620. J.D.O. is supported by an Agouron Postdoctoral Fellowship. T.W.L. acknowledges support from the NSF-EAR and NASA-NAI. A.R. thanks the support of NERC via NE/J01043X/1.2015-11-1

Gas Source Molecular Beam Epitaxy of Compound Semiconductors

Contains an introduction and reports on seven research projects.Defense Advanced Research Projects Agency Subcontract 284-25041Joint Services Electronics Program Contract DAAL04-95-1-0038National Center for Integrated Photonic Technology Contract 542-381U.S. Army Research Office/ AASERT Contract DAAH04-93-G-0175National Science Foundation Grant DMR 92-02957Joint Services Electronics Program Grant DAAL04-95-1-0038National Science Foundation Grant DMR 90-22933National Science Foundation Grant DMR 92-02957National Center for Integrated Photonic Technology Contract 542-381MIT Lincoln LaboratoryNational Center for Integrated Photonic Technology Subcontract 542-383National Science Foundation DMR 94-0033

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Importance: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; Results: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration: ClinicalTrials.gov Identifier: NCT04297683</p

Emergency department clinical leads’ experiences of implementing primary care services where GPs work in or alongside emergency departments in the UK: a qualitative study

Background To manage increasing demand for emergency and unscheduled care NHS England policy has promoted services in which patients presenting to Emergency Departments (EDs) with non-urgent problems are directed to general practitioners (GPs) and other primary care clinicians working within or alongside emergency departments. However, the ways that hospitals have implemented primary care services in EDs are varied. The aim of this study was to describe ED clinical leads’ experiences of implementing and delivering ‘primary care services’ and ‘emergency medicine services’ where GPs were integrated into the ED team. Methods We conducted interviews with ED clinical leads in England (n = 19) and Wales (n = 2). We used framework analysis to analyse interview transcripts and explore differences across ‘primary care services’, ‘emergency medicine services’ and emergency departments without primary care services. Results In EDs with separate primary care services, success was reported when having a distinct workforce of primary care clinicians, who improved waiting times and flow by seeing primary care-type patients in a timely way, using fewer investigations, and enabling ED doctors to focus on more acutely unwell patients. Some challenges were: trying to align their service with the policy guidance, inconsistent demand for primary care, accessible community primary care services, difficulties in recruiting GPs, lack of funding, difficulties in agreeing governance protocols and establishing effective streaming pathways. Where GPs were integrated into an ED workforce success was reported as managing the demand for both emergency and primary care and reducing admissions. Conclusions Introducing a policy advocating a preferred model of service to address primary care demand was not useful for all emergency departments. To support successful and sustainable primary care services in or alongside EDs, policy makers and commissioners should consider varied ways that GPs can be employed to manage variation in local demand and also local contextual factors such as the ability to recruit and retain GPs, sustainable funding, clear governance frameworks, training, support and guidance for all staff. Whether or not streaming to a separate primary care service is useful also depended on the level of primary care demand

Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors

Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory “danger” signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A2A receptor (A2AR) antagonist, was administered 1 h before bilateral IRI in WT, A2AR KO (Adora2a–/–) or CD73–/– mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a–/– mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73–/– mice, which lack a 5′-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A2AR-and non-A2AR-dependent signaling pathways

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health