Evolution of the eddy field in the Arctic Ocean's Canada Basin, 2005–2015

Author Posting. © American Geophysical Union, 2016. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 43 (2016): 8106–8114, doi:10.1002/2016GL069671.The eddy field across the Arctic Ocean's Canada Basin is analyzed using Ice-Tethered Profiler (ITP) and moored measurements of temperature, salinity, and velocity spanning 2005 to 2015. ITPs encountered 243 eddies, 98% of which were anticyclones, with approximately 70% of these having anomalously cold cores. The spatially and temporally varying eddy field is analyzed accounting for sampling biases in the unevenly distributed ITP data and caveats in detection methods. The highest concentration of eddies was found in the western and southern portions of the basin, close to topographic margins and boundaries of the Beaufort Gyre. The number of lower halocline eddies approximately doubled from 2005–2012 to 2013–2014. The increased eddy density suggests more active baroclinic instability of the Beaufort Gyre that releases available potential energy to balance the wind energy input; this may stabilize the Gyre spin-up and associated freshwater increase.National Science Foundation Division of Polar Programs Grant Number: 13500462017-02-0

Characterizing the eddy field in the Arctic Ocean halocline

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 119 (2014): 8800–8817, doi:10.1002/2014JC010488.Ice-Tethered Profilers (ITP), deployed in the Arctic Ocean between 2004 and 2013, have provided detailed temperature and salinity measurements of an assortment of halocline eddies. A total of 127 mesoscale eddies have been detected, 95% of which were anticyclones, the majority of which had anomalously cold cores. These cold-core anticyclonic eddies were observed in the Beaufort Gyre region (Canadian water eddies) and the vicinity of the Transpolar Drift Stream (Eurasian water eddies). An Arctic-wide calculation of the first baroclinic Rossby deformation radius Rd has been made using ITP data coupled with climatology; Rd ∼ 13 km in the Canadian water and ∼8 km in the Eurasian water. The observed eddies are found to have scales comparable to Rd. Halocline eddies are in cyclogeostrophic balance and can be described by a Rankine vortex with maximum azimuthal speeds between 0.05 and 0.4 m/s. The relationship between radius and thickness for the eddies is consistent with adjustment to the ambient stratification. Eddies may be divided into four groups, each characterized by distinct core depths and core temperature and salinity properties, suggesting multiple source regions and enabling speculation of varying formation mechanisms.Funding was provided by the National Science Foundation Polar Programs award ARC-1107623.2015-06-2

You Are My Way to the Universe: Critical Collective Research Through Feminist Community Building

In diesem Artikel stützen wir uns auf den feministischen Kommunitarismus, um eine Kritik an dem vorherrschenden neoliberalen Modell der Zusammenarbeit in der qualitativen Sozialforschung zu entwickeln. Wir argumentieren, dass feministische Theorien und Praktiken über Gemeinschaftsbildung und politischen Aktivismus das Potenzial haben, die stark institutionalisierte, individualistische und managerialistische Kultur von Zusammenarbeit zu überwinden. Feministische Einsichten können Wissenschaftler*innen helfen, sich in der kollaborativen Forschung zurechtzufinden und Schlüsselfragen wie Reflexivität, Konsensbildung, Wissensvalidierung und Gruppensolidarität anzugehen. Wir nutzen unsere eigene Arbeit im Feministischen Forschungskollektiv und im WomenWeLove-Projekt, um eine alternative Orientierung und einen kollektiven Weg zur Verwirklichung einer transformativen Forschung vorzustellen. Diese feministische Intervention gegen die neoliberale Forschungskultur trägt zu laufenden Überlegungen darüber bei, wie wir mithilfe der qualitativen Sozialforschung Wissen produzieren und warum wir dies in der gegenwärtigen historischen Situation tun sollten. Sie erweitert unsere Vorstellungen von der Verantwortung der Forschenden und schafft neue Möglichkeiten für Widerstand und Emanzipation.In this article, we draw on the scholarship of feminist communitarianism to develop a critique of the predominant neoliberal qualitative social research collaboration model. We argue that feminist theories and praxis about community building and political activism have the potential to transcend the highly institutionalized, individualistic, and managerialist collaborative culture. Feminist insights can help today's researchers navigate collaborative research and address key issues such as reflexivity, consensus formation, knowledge validation, and group solidarity. We use our own work in the Feminist Research Collective and in the WomenWeLove project to present an alternative orientation and a collective way to enact transformative research. This feminist intervention against the neoliberal research culture contributes to the ongoing reflections of how we produce knowledge via qualitative social research and why we shall do so in the current historical juncture, expands our imaginations of researchers' responsibilities, and engenders new possibilities for resistance and emancipation

Defining the ligand-dependent proximatome of the sigma 1 receptor

Sigma 1 Receptor (S1R) is a therapeutic target for a wide spectrum of pathological conditions ranging from neurodegenerative diseases to cancer and COVID-19. S1R is ubiquitously expressed throughout the visceral organs, nervous, immune and cardiovascular systems. It is proposed to function as a ligand-dependent molecular chaperone that modulates multiple intracellular signaling pathways. The purpose of this study was to define the S1R proximatome under native conditions and upon binding to well-characterized ligands. This was accomplished by fusing the biotin ligase, Apex2, to the C terminus of S1R. Cells stably expressing S1R-Apex or a GFP-Apex control were used to map proximal proteins. Biotinylated proteins were labeled under native conditions and in a ligand dependent manner, then purified and identified using quantitative mass spectrometry. Under native conditions, S1R biotinylates over 200 novel proteins, many of which localize within the endomembrane system (endoplasmic reticulum, Golgi, secretory vesicles) and function within the secretory pathway. Under conditions of cellular exposure to either S1R agonist or antagonist, results show enrichment of proteins integral to secretion, extracellular matrix formation, and cholesterol biosynthesis. Notably, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) displays increased binding to S1R under conditions of treatment with Haloperidol, a well-known S1R antagonist; whereas Low density lipoprotein receptor (LDLR) binds more efficiently to S1R upon treatment with (+)-Pentazocine ((+)-PTZ), a classical S1R agonist. Furthermore, we demonstrate that the ligand bound state of S1R correlates with specific changes to the cellular secretome. Our results are consistent with the postulated role of S1R as an intracellular chaperone and further suggest important and novel functionalities related to secretion and cholesterol metabolism

A rhombohedral ferroelectric phase in epitaxially strained Hf0.5Zr0.5O2 thin films

Hafnia-based thin films are a favoured candidate for the integration of robust ferroelectricity at the nanoscale into next-generation memory and logic devices. This is because their ferroelectric polarization becomes more robust as the size is reduced, exposing a type of ferroelectricity whose mechanism still remains to be understood. Thin films with increased crystal quality are therefore needed. We report the epitaxial growth of Hf0.5Zr0.5O2 thin films on (001)-oriented La0.7Sr0.3MnO3/SrTiO3 substrates. The films, which are under epitaxial compressive strain and predominantly (111)-oriented, display large ferroelectric polarization values up to 34 mu C cm(-2) and do not need wake-up cycling. Structural characterization reveals a rhombohedral phase, different from the commonly reported polar orthorhombic phase. This finding, in conjunction with density functional theory calculations, allows us to propose a compelling model for the formation of the ferroelectric phase. In addition, these results point towards thin films of simple oxides as a vastly unexplored class of nanoscale ferroelectrics.</p

Identification of plasminogen-binding sites in Streptococcus suis enolase that contribute to bacterial translocation across the blood-brain barrier

Streptococcus suis is an emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, S. suis must cross the blood-brain barrier (BBB) comprising blood vessels that vascularize the central nervous system (CNS). The BBB is highly selective due to interactions with other cell types in the brain and the composition of the extracellular matrix (ECM). Purified streptococcal surface enolase, an essential enzyme participating in glycolysis, can bind human plasminogen (Plg) and plasmin (Pln). Plg has been proposed to increase bacterial traversal across the BBB via conversion to Pln, a protease which cleaves host proteins in the ECM and monocyte chemoattractant protein 1 (MCP1) to disrupt tight junctions. The essentiality of enolase has made it challenging to unequivocally demonstrate its role in binding Plg/Pln on the bacterial surface and confirm its predicted role in facilitating translocation of the BBB. Here, we report on the CRISPR/Cas9 engineering of S. suis enolase mutants eno261, eno252/253/255, eno252/261, and eno434/435 possessing amino acid substitutions at in silico predicted binding sites for Plg. As expected, amino acid substitutions in the predicted Plg binding sites reduced Plg and Pln binding to S. suis but did not affect bacterial growth in vitro compared to the wild-type strain. The binding of Plg to wild-type S. suis enhanced translocation across the human cerebral microvascular endothelial cell line hCMEC/D3 but not for the eno mutant strains tested. To our knowledge, this is the first study where predicted Plg-binding sites of enolase have been mutated to show altered Plg and Pln binding to the surface of S. suis and attenuation of translocation across an endothelial cell monolayer in vitro

Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced METpositive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C-trough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) >= 6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN >= 6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the (ClinicalTrials.gov Identifier: NCT01324479).

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for&nbsp;95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines

Digital approaches to enhancing community engagement in clinical trials.

Digital approaches are increasingly common in clinical trial recruitment, retention, analysis, and dissemination. Community engagement processes have contributed to the successful implementation of clinical trials and are crucial in enhancing equity in trials. However, few studies focus on how digital approaches can be implemented to enhance community engagement in clinical trials. This narrative review examines three key areas for digital approaches to deepen community engagement in clinical trials-the use of digital technology for trial processes to decentralize trials, digital crowdsourcing to develop trial components, and digital qualitative research methods. We highlight how digital approaches enhanced community engagement through a greater diversity of participants, and deepened community engagement through the decentralization of research processes. We discuss new possibilities that digital technologies offer for community engagement, and highlight potential strengths, weaknesses, and practical considerations. We argue that strengthening community engagement using a digital approach can enhance equity and improve health outcomes

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

Since the publication of the Society for Immunotherapy of Cancer\u27s (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients