Comment Coordinators: Connecting Stakeholders and Regulatory Agencies

The Western Regional Integrated Pest Management (IPM) Center uses a new approach to provide effective and timely stakeholder input to USDA and EPA regarding pesticide use. The Western IPM Center has funded two positions, termed Comment Coordinators, to gather regional information to address use questions that arise as pesticides undergo re-registration review. Through this process, growers and Extension agents also become aware of potential issues with their crop-protection tools. Providing a voice for stakeholders within regulatory agencies strengthens existing Extension efforts. The concept of a dedicated interface between stakeholders and regulators is valuable in situations where stakeholder input is desired

Mutations in hepatitis C virus E2 located outside the CD81 binding sites lead to escape from broadly neutralizing antibodies but compromise virus infectivity.

Broadly neutralizing antibodies are commonly present in the sera of patients with chronic hepatitis C virus (HCV) infection. To elucidate possible mechanisms of virus escape from these antibodies, retrovirus particles pseudotyped with HCV glycoproteins (HCVpp) isolated from sequential samples collected over a 26-year period from a chronically infected patient, H, were used to characterize the neutralization potential and binding affinity of a panel of anti-HCV E2 human monoclonal antibodies (HMAbs). Moreover, AP33, a neutralizing murine monoclonal antibody (MAb) to a linear epitope in E2, was also tested against selected variants. The HMAbs used were previously shown to broadly neutralize HCV and to recognize a cluster of highly immunogenic overlapping epitopes, designated domain B, containing residues that are also critical for binding of viral E2 glycoprotein to CD81, a receptor essential for virus entry. Escape variants were observed at different time points with some of the HMAbs. Other HMAbs neutralized all variants except for the isolate 02.E10, obtained in 2002, which was also resistant to MAb AP33. The 02.E10 HCVpp that have reduced binding affinities for all antibodies and for CD81 also showed reduced infectivity. Comparison of the 02.E10 nucleotide sequence with that of the strain H-derived consensus variant, H77c, revealed the former to have two mutations in E2, S501N and V506A, located outside the known CD81 binding sites. Substitution A506V in 02.E10 HCVpp restored binding to CD81, but its antibody neutralization sensitivity was only partially restored. Double substitutions comprising N501S and A506V synergistically restored 02.E10 HCVpp infectivity. Other mutations that are not part of the antibody binding epitope in the context of N501S and A506V were able to completely restore neutralization sensitivity. These findings showed that some nonlinear overlapping epitopes are more essential than others for viral fitness and consequently are more invariant during earlier years of chronic infection. Further, the ability of the 02.E10 consensus variant to escape neutralization by the tested antibodies could be a new mechanism of virus escape from immune containment. Mutations that are outside receptor binding sites resulted in structural changes leading to complete escape from domain B neutralizing antibodies, while simultaneously compromising viral fitness by reducing binding to CD81

Letter to editor: A new core gross anatomy syllabus for medicine

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The Infrared Properties of Hickson Compact Groups

Compact groups of galaxies provide a unique environment to study the mechanisms by which star formation occurs amid continuous gravitational encounters. We present 2MASS (JHK), Spitzer IRAC (3.5-8 micron) and MIPS (24 micron) observations of a sample of twelve Hickson Compact Groups (HCGs 2, 7, 16, 19, 22, 31, 42, 48, 59, 61, 62, and 90) that includes a total of 45 galaxies. The near-infrared colors of the sample galaxies are largely consistent with being dominated by slightly reddened normal stellar populations. Galaxies that have the most significant PAH and/or hot dust emission (as inferred from excess 8 micron flux) also tend to have larger amounts of extinction and/or K-band excess and stronger 24 micron emission, all of which suggest ongoing star formation activity. We separate the twelve HCGs in our sample into three types based on the ratio of the group HI mass to dynamical mass. We find evidence that galaxies in the most gas-rich groups tend to be the most actively star forming. Galaxies in the most gas-poor groups tend to be tightly clustered around a narrow range in colors consistent with the integrated light from a normal stellar population. We interpret these trends as indicating that galaxies in gas-rich groups experience star formation and/or nuclear actively until their neutral gas consumed, stripped, or ionized. The galaxies in this sample exhibit a ``gap'' between gas-rich and gas-poor groups in infrared color space that is sparsely populated and not seen in the Spitzer First Look Survey sample. This gap may suggest a rapid evolution of galaxy properties in response to dynamical effects. These results suggest that the global properties of the groups and the local properties of the galaxies are connected.Comment: 34 pages, 26 figures, accepted for publication in AJ, higher quality images available in publicatio

Radiation Induces Metabolic Dysregulation in Pulmonary Fibroblasts

Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we hypothesized that ionizing radiation would cause aerobic glycolytic metabolic dysregulation in primary human lung fibroblasts. Results: Primary non-fibrotic HLFs exposed to irradiation exhibited significant upregulation of Pyruvate Dehydrogenase Kinase (PDK1 (0.5 – 3-fold, p\u3c0.05) and LDHA (1.4-fold, p\u3c0.05). Cell viability was unaffected by increased radiation dose. Conclusions: Radiation increased fibroblast expression of genes involved in fibrotic phenotypes (αSMA) and aerobic glycolysis (PDK1 and LDHA), in a similar pattern to that seen in IPF fibroblasts. The metabolic changes are closely associated with creating a profibrotic extracellular environment in IPF by promoting an acidic environment. Our evidence suggests this phenomenon can be driven by radiation in lung fibroblasts and affirm that glycolytic reprogramming may also be a hallmark of radiation-induced fibrosis. Further understanding of the common mechanisms that create this metabolic shift could provide novel therapeutics for fibrosis treatment.https://scholarscompass.vcu.edu/gradposters/1158/thumbnail.jp

Hepatic Proprotein Convertases Modulate HDL Metabolism

SummaryThe risk of atherosclerosis is inversely associated with plasma levels of high-density lipoprotein cholesterol (HDL-C). However, HDL metabolism is incompletely understood, and there are few effective approaches to modulate HDL-C levels. Here we show that inhibition in the liver of the classical proprotein convertases (PCs), but not the atypical PCs S1P and PCSK9, decreases plasma HDL-C levels. This metabolic effect of hepatic PCs is critically dependent on expression of endothelial lipase (EL), an enzyme that directly hydrolyzes HDL phospholipids and promotes its catabolism. Hepatic PCs reduce EL function through direct inactivating cleavage of EL as well as through activating cleavage of angiopoietin-like protein 3 (ANGPTL3), an endogenous inhibitor of EL. Thus, inhibition of hepatic PCs results in increased EL activity, leading to reduced HDL-C as well as impaired reverse cholesterol transport. The hepatic PC–ANGPTL3–EL–HDL pathway is therefore a novel mechanism controlling HDL metabolism and cholesterol homeostasis

Adaptation of Proteins to the Cold in Antarctic Fish: A Role for Methionine?

The evolution of antifreeze glycoproteins has enabled notothenioid fish to flourish in the freezing waters of the Southern Ocean. Whereas successful at the biodiversity level to life in the cold, paradoxically at the cellular level these stenothermal animals have problems producing, folding, and degrading proteins at their ambient temperatures of -1.86 °C. In this first multi-species transcriptome comparison of the amino acid composition of notothenioid proteins with temperate teleost proteins, we show that, unlike psychrophilic bacteria, Antarctic fish provide little evidence for the mass alteration of protein amino acid composition to enhance protein folding and reduce protein denaturation in the cold. The exception was the significant overrepresentation of positions where leucine in temperate fish proteins was replaced by methionine in the notothenioid orthologues. We hypothesize that these extra methionines have been preferentially assimilated into the genome to act as redox sensors in the highly oxygenated waters of the Southern Ocean. This redox hypothesis is supported by analyses of notothenioids showing enrichment of genes associated with responses to environmental stress, particularly reactive oxygen species. So overall, although notothenioid fish show cold-associated problems with protein homeostasis, they may have modified only a selected number of biochemical pathways to work efficiently below 0 °C. Even a slight warming of the Southern Ocean might disrupt the critical functions of this handful of key pathways with considerable impacts for the functioning of this ecosystem in the future

Zircon as a tracer of plumbing processes in an active magmatic system: insights from mingled magmas of the 2010 dome collapse, Montserrat, Lesser Antilles Arc, Caribbean

This project has received funding from the European Union's Hori-zon 2020 research and innovation programme under the Marie Skodowska-Curie grant agreement No. 749611 (JHS) . We also ac-knowledge funding from the Natural Environment Research Council Isotope Geoscience Facilities Steering Committee, grant IP-1746-1117 (JB) . The work has been financially supported by the Spanish grant CGL 2017-84469-P (JHS) . Funding for open access charge: Universidad de Granada/CBUA. Alexander Varychev at the University of Heidelberg, Germany, and Jeremy Rushton at the British Geological Survey, U.K., are thanked for help with analytical work. Jose Luis Macias is thanked for editorial handling. We are obliged to two anonymous reviewers for the time and effort they took to help us improve the clarity and rigour of our interpretations. 19Soufriere Hills Volcano, Montserrat, erupted from 1995 to 2010, with activity including dome growth, destructive pyroclastic density currents and Vulcanian explosions. Monitoring data, such as gas emissions, show the system is still in a state of unrest. The recent eruptions provide an opportunity to study, in real time, a complex subduction-related subvolcanic transaustal melt-mush reservoir, its magma fluxes, and the timing of crystal and melt storage prior to eruptive paroxysms. How and when mush destabilisation occurs prior to volcanic eruptions continues to be a question of intense debate. Evidence of mafic magma intrusion, a potential eruptive trigger, is preserved in enclaves with quenched and diffuse margins that are mingled with crystal-rich andesite. Here, in this first study of Soufriere Hills Volcano zircon, we report zircon ages and compositions for mafic-intermediate enclaves and host andesites from the most recent dome collapse in 2010 to place temporal constraints on magma reservoir processes. Zircon U-238-Th-230 ages disequilibrium crystallisation ages ranging between c. 2-250 ka constrain the longevity of the magmatic plumbing system. Uniform Hf isotopes, epsilon Hf 11.3 +/- 12 to 14.6 +/- 1.5, indicate invariant compositions that are typical for island arc magma sources. Zircon trace element concentrations and Ti-in-zircon crystallisation temperatures indicate crystallisation in isolated, small-volume, lenses with variable fractions of melt of heterogeneous compositions. We suggest amalgamation of assorted crystal cargoes from these lenses occurred prior to eruption during mush destabilisation triggered by mafic magma recharge. Zircon textures, on the other hand, shed light on recent centimetre-scale magma mingling immediately prior to eruption. Euhedral-subhedral zircon is preferentially preserved in or near quenched contacts of the least-evolved enclave and host andesite. By contrast, reheating of the andesite by the mafic magma recharge in the presence of zircon-undersaturated melts promoted zircon resorption. This led to the formation of subhedral-anhedral corroded zircon that is typical in the host andesite mush. Zircon thus reveals processes ranging from 100,000s of years of andesite storage to short-term partial destruction in response to transient heating and magma mixing events.European Commission 749611Natural Environment Research Council Isotope Geoscience Facilities Steering Committee IP-1746-1117Spanish Government CGL 2017-84469-PUniversidad de Granada/CBU

Acceptability of a Novel Smartphone Application for Rhythm Evaluation in Patients with Atrial Fibrillation

Background: Investigators at UMass Medical School and WPI co-developed a novel smartphone application (app), PULSESMART, that detects atrial fibrillation (AF). AF is the world’s most common, serious heart rhythm problem. In its early stages, most cases of AF are paroxysmal (pAF), making them difficult to identify early in the course of disease. Long-term cardiac monitoring is frequently needed to diagnose and prevent complications from AF, such as stroke. Home monitoring for AF can be clinically impactful but existing technologies have cost or methodological limitations. Data are needed on the potential acceptability and usability of heart rhythm monitoring applications. Aim: Our aim was to examine patient acceptability of using a pAF detection app. Methods: 52 patients with pAF underwent rhythm assessment using the app and completed a standardized questionnaire. We looked specifically at responses to 3 questions: 1) how easy was it to use? 2) How important could it be for you? And 3) to what extent does it fit into your daily life? Results: The mean age was 68.5 years and 69% female. The majority of patients reported the app was easy to use (73%), could be important to them and their health (84%), and would fit into their daily lives (78%). Conclusions: After use of the pAF detection app, most patients reported positively. The results suggest that older persons with, or at risk for, pAF may benefit from smartphone-based arrhythmia detection platforms. Further work is needed to assess the feasibility of at-home or in-clinic app use