Walleye (Sander vitreus) are an ecologically important species managed for recreational, tribal, and commercial harvest. Walleye prefer cool water and low light conditions, and therefore changing ...water temperature and clarity potentially impacts walleye habitat and populations across the landscape. Using survey data collected from 1993 to 2018 from 312 lakes in Minnesota, we evaluated the relationship between thermal-optical habitat and the relative abundance of small (0-300 mm), medium (300450 mm), and large (450 + mm) walleye. Thermal-optical habitat was positively correlated with the relative abundance of small and medium walleye but not large walleye. Walleye were more abundant in larger, naturally reproducing lakes opposed to smaller, stocked lakes. Thermal-optical habitat changed in 59% of lakes since 1980 (26% increasing and 33% decreasing) and appears to be driven primarily by changes in water clarity and thus optical habitat area. Our study provides important insights into local and regional drivers that influence walleye populations that can be used to assist fisheries managers in setting population goals and managing harvest.
Here we seek to probe and understand the mechanical behavior of grain boundaries in pure Ta as a model bcc material using micropillar compression experiments. Three high angle grain boundaries are ...chosen with varying crystal orientations. Multiple bi-crystal pillars are prepared containing a single, nearly vertical grain boundary in the approximate center of the pillar and compared against their single crystalline pillar counterparts. The main phenomenon of interest was slip transmission or strain transfer in the bi-crystals which was considered to occur when slip traces aligned across the grain boundary. This occurred in two of the three bi-crystals. These observations were compared against two slip transmission factors, m'=cos(ψ)cos(κ) and LRB=cos(θ)cos(κ), where ψ,θ,andκ are the angles between the slip vectors, slip plane normals, and the intersection of the slip planes with the grain boundary from the slip systems on either side of the grain boundary. Additionally, transmission was compared against the stress-strain response and overall deformation (i.e., sheared boundary) of the bi-crystal. The transmission factors exhibited a consistent behavior with slip transmission occurring for high transmission factors and not occurring for low transmission factors. For example, slip transmission occurred for m'≥ 0.85 and did not occur for m'≤ 0.46. The engineering stress-strain response and overall deformation behavior did not show correlations with the presence or absence of slip transmission. High angle boundaries in bcc metals are shown to represent a diverse set of responses in bi-crystalline micropillar compression experiments.
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Natural killer (NK) cell‐mediated cytotoxicity is governed by the formation of a lytic immune synapse in discrete regulated steps, which give rise to an extensive array of cellular checkpoints in ...accessing NK cell‐mediated cytolytic defense. Appropriate progression through these cell biological steps is critical for the directed secretion of specialized secretory lysosomes and subsequent target cell death. Here we highlight recent discoveries in the formation of the NK cell cytolytic synapse as well as the molecular steps and cell biological checkpoints required for this essential host defense process.
The March 2014 issue contains a Special Feature on NK cell recognition of unconventional ligands. Natural Killer (NK) cells are bone marrow derived lymphocytes capable of mediating rapid effector responses following pathogen detection in mammals. The name “Natural Killer” derives from the ability of these cells to spontaneously lyse a large range of leukemia cell lines in vitro without prior sensitization. The reviews included in this Special Feature of Immunology and Cell Biology highlight the multifaceted roles of NK cells in detecting unconventional ligands and countering a large range of pathogens and malignancies. Covering a range of topics, including the way adhesion molecules and activating receptors are central to NK cell recognition of their targets, the reviews also highlight some of the challenges that lie ahead in harnessing NK cell function and advancing NK cell immunotherapy strategies to persistent infection, cancer and bone marrow transplantation. Immunology and Cell Biology thanks the coordinator of this Special Feature – Nicholas Huntington – for his planning and input. Further background information on this important topic is available through the accompanying web focus which links to related articles from across Nature Publishing Group.
To assess the role claudin-5, an endothelial cell (EC) tight junction protein, plays in establishing basal permeability levels in humans by comparing claudin-5 expression levels in situ and analyzing ...junctional organization and function in 2 widely used models of cultured ECs, namely human dermal microvascular (HDM)ECs and human umbilical vein (HUV)ECs.
By immunofluorescence microscopy, ECs more highly express claudin-5 (but equivalently express vascular endothelial-cadherin) in human dermal capillaries versus postcapillary venules and in umbilical and coronary arteries versus veins, correlating with known segmental differences in tight junction frequencies and permeability barriers. Postconfluent cultured HDMECs express more claudin-5 (but equivalent vascular endothelial-cadherin) and show higher transendothelial electric resistance and lower macromolecular flux than similarly cultured HUVECs. HDMEC junctions are more complex by transmission electron microscopy and show more continuous claudin-5 immunofluorescence than HUVEC junctions. Calcium chelation or dominant negative vascular endothelial-cadherin overexpression decreases transendothelial electric resistance and disrupts junctions in HUVECs, but not in HDMECs. Claudin-5 overexpression in HUVECs fails to increase transendothelial electric resistance or claudin-5 continuity, whereas claudin-5 knockdown in HDMECs, but not in HUVECs, reduces transendothelial electric resistance and increases antibody accessibility to junctional proteins.
Claudin-5 expression and junctional organization control HDMEC and arteriolar-capillary paracellular barriers, whereas HUVEC and venular junctions use vascular endothelial-cadherin.
The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist ...that links IL-22 to the crystallisable fragment (Fc) of human IgG
for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.
This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort).
The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients.
Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic.
NCT02749630.
Maintaining the health of aquatic systems is an essential component of sustainable catchment management, however, degradation of water quality and aquatic habitat continues to challenge scientists ...and policy‐makers. To support management and restoration efforts aquatic system models are required that are able to capture the often complex trajectories that these systems display in response to multiple stressors. This paper explores the abilities and limitations of current model approaches in meeting this challenge, and outlines a strategy based on integration of flexible model libraries and data from observation networks, within a learning framework, as a means to improve the accuracy and scope of model predictions. The framework is comprised of a data assimilation component that utilizes diverse data streams from sensor networks, and a second component whereby model structural evolution can occur once the model is assessed against theoretically relevant metrics of system function. Given the scale and transdisciplinary nature of the prediction challenge, network science initiatives are identified as a means to develop and integrate diverse model libraries and workflows, and to obtain consensus on diagnostic approaches to model assessment that can guide model adaptation. We outline how such a framework can help us explore the theory of how aquatic systems respond to change by bridging bottom‐up and top‐down lines of enquiry, and, in doing so, also advance the role of prediction in aquatic ecosystem management.
Key Points:
New demands are being made for aquatic ecosystem prediction
We outline a framework for model use within environmental observatories for aquatic systems
Improved model systems able to predict ecosystem services can better support management
RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are ...unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.
We report the discovery of a convenient and efficient method for the synthesis of highly substituted 1,6-naphthyridines. A tandem nitrile hydration/cyclization procedure was developed to access ...1,6-naphthyridine-5,7-diones under mild conditions. Subsequently, we have found that ditriflation of these intermediates provides 1,6-naphthyridine-5,7-ditriflates which are bench-stable but highly reactive intermediates that can be engaged in one-pot difunctionalization reactions leading to diverse drug-like products in rapid fashion.
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