Interleukin 2-inducible T cell kinase (ITK) facilitates efficient egress of HIV-1 by coordinating Gag distribution and actin organization

AbstractInterleukin 2-inducible T cell kinase (ITK) influences T cell signaling by coordinating actin polymerization and polarization as well as recruitment of kinases and adapter proteins. ITK regulates multiple steps of HIV-1 replication, including virion assembly and release. Fluorescent microscopy was used to examine the functional interactions between ITK and HIV-1 Gag during viral particle release. ITK and Gag colocalized at the plasma membrane and were concentrated at sites of F-actin accumulation and membrane lipid rafts in HIV-1 infected T cells. There was polarized staining of ITK, Gag, and actin towards sites of T cell conjugates. Small molecule inhibitors of ITK disrupted F-actin capping, perturbed Gag-ITK colocalization, inhibited virus like particle release, and reduced HIV replication in primary human CD4+ T cells. These data provide insight as to how ITK influences HIV-1 replication and suggest that targeting host factors that regulate HIV-1 egress provides an innovative strategy for controlling HIV infection

Wee1-Regulated Apoptosis Mediated by the Crk Adaptor Protein in Xenopus Egg Extracts

Many of the biochemical reactions of apoptotic cell death, including mitochondrial cytochrome c release and caspase activation, can be reconstituted in cell-free extracts derived from Xenopus eggs. In addition, because caspase activation does not occur until the egg extract has been incubated for several hours on the bench, upstream signaling processes occurring before full apoptosis are rendered accessible to biochemical manipulation. We reported previously that the adaptor protein Crk is required for apoptotic signaling in egg extracts (Evans, E.K., W. Lu, S.L. Strum, B.J. Mayer, and S. Kornbluth. 1997. EMBO (Eur. Mol. Biol. Organ.) J. 16:230–241). Moreover, we demonstrated that removal of Crk Src homology (SH)2 or SH3 interactors from the extracts prevented apoptosis. We now report the finding that the relevant Crk SH2-interacting protein, important for apoptotic signaling in the extract, is the well-known cell cycle regulator, Wee1. We have demonstrated a specific interaction between tyrosine-phosphorylated Wee1 and the Crk SH2 domain and have shown that recombinant Wee1 can restore apoptosis to an extract depleted of SH2 interactors. Moreover, exogenous Wee1 accelerated apoptosis in egg extracts, and this acceleration was largely dependent on the presence of endogenous Crk protein. As other Cdk inhibitors, such as roscovitine and Myt1, did not act like Wee1 to accelerate apoptosis, we propose that Wee1–Crk complexes signal in a novel apoptotic pathway, which may be unrelated to Wee1's role as a cell cycle regulator

Vascular Health in American Football Players: Cardiovascular Risk Increased in Division III Players

Studies report that football players have high blood pressure (BP) and increased cardiovascular risk. There are over 70,000 NCAA football players and 450 Division III schools sponsor football programs, yet limited research exists on vascular health of athletes. This study aimed to compare vascular and cardiovascular health measures between football players and nonathlete controls. Twenty-three athletes and 19 nonathletes participated. Vascular health measures included flow-mediated dilation (FMD) and carotid artery intima-media thickness (IMT). Cardiovascular measures included clinic and 24 hr BP levels, body composition, VO2 max, and fasting glucose/cholesterol levels. Compared to controls, football players had a worse vascular and cardiovascular profile. Football players had thicker carotid artery IMT (0.49 ± 0.06 mm versus 0.46 ± 0.07 mm) and larger brachial artery diameter during FMD (4.3 ± 0.5 mm versus 3.7 ± 0.6 mm), but no difference in percent FMD. Systolic BP was significantly higher in football players at all measurements: resting (128.2 ± 6.4 mmHg versus 122.4 ± 6.8 mmHg), submaximal exercise (150.4 ± 18.8 mmHg versus 137.3 ± 9.5 mmHg), maximal exercise (211.3 ± 25.9 mmHg versus 191.4 ± 19.2 mmHg), and 24-hour BP (124.9 ± 6.3 mmHg versus 109.8 ± 3.7 mmHg). Football players also had higher fasting glucose (91.6 ± 6.5 mg/dL versus 86.6 ± 5.8 mg/dL), lower HDL (36.5±11.2 mg/dL versus 47.1±14.8 mg/dL), and higher body fat percentage (29.2±7.9% versus 23.2±7.0%). Division III collegiate football players remain an understudied population and may be at increased cardiovascular risk

Saliva urea nitrogen dipsticks to predict acute kidney injury in Malawian trauma patients

Background: Many low-resource settings have limited access to serum creatinine tests necessary for kidney disease identification. Among Malawian patients who are hospitalized after trauma, we evaluated the use of point-of-care saliva urea nitrogen (SUN) dipsticks to predict acute kidney injury (AKI). Methods: In a nested prospective cohort study, we enrolled hospitalized acute trauma patients aged ≥6 months to evaluate AKI (defined by KDIGO criteria) and the test characteristics of SUN to predict AKI. Results: Among 335 participants (approximately three-quarters able to expectorate and 34% aged ≤18 years), 12.5% (n = 42) developed AKI. At a SUN threshold of ≥40 mg/dL, a positive dipstick test was specific (99.3%) but insensitive (14.3%) in predicting AKI, with a positive predictive value of 75% and negative predictive value of 89%. At this threshold, 2.4% of participants were dipstick-positive (SUN+), and 75% of those had AKI. Reducing the SUN threshold to ≥30 mg/dL increased participants who were SUN+ to 5.0% (n = 16) but also increased the false positive rate and missed 79% (n = 33) of AKI cases. Stratified results showed better performance among adults than children and similar results when comparing participants who could and could not expectorate. There was moderate correlation between categorized BUN values and SUN (r = 0.53) but less agreement (weighted kappa 0.27; 95% CI 0.17–0.37). Conclusions: SUN dipstick testing has good specificity and negative predictive value for ruling out AKI, but poor sensitivity. We found similar results among those who could or could not expectorate a saliva sample

Questioning context: a set of interdisciplinary questions for investigating contextual factors affecting health decision making

Objective  To combine insights from multiple disciplines into a set of questions that can be used to investigate contextual factors affecting health decision making. Background  Decision‐making processes and outcomes may be shaped by a range of non‐medical or ‘contextual’ factors particular to an individual including social, economic, political, geographical and institutional conditions. Research concerning contextual factors occurs across many disciplines and theoretical domains, but few conceptual tools have attempted to integrate and translate this wide‐ranging research for health decision‐making purposes. Methods  To formulate this tool we employed an iterative, collaborative process of scenario development and question generation. Five hypothetical health decision‐making scenarios (preventative, screening, curative, supportive and palliative) were developed and used to generate a set of exploratory questions that aim to highlight potential contextual factors across a range of health decisions. Findings  We present an exploratory tool consisting of questions organized into four thematic domains – Bodies, Technologies, Place and Work (BTPW) – articulating wide‐ranging contextual factors relevant to health decision making. The BTPW tool encompasses health‐related scholarship and research from a range of disciplines pertinent to health decision making, and identifies concrete points of intersection between its four thematic domains. Examples of the practical application of the questions are also provided. Conclusions  These exploratory questions provide an interdisciplinary toolkit for identifying the complex contextual factors affecting decision making. The set of questions comprised by the BTPW tool may be applied wholly or partially in the context of clinical practice, policy development and health‐related research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86973/1/j.1369-7625.2010.00618.x.pd

Automation tools to support undertaking scoping reviews.

This paper describes several automation tools and software that can be considered during evidence synthesis projects and provides guidance for their integration in the conduct of scoping reviews. The guidance presented in this work is adapted from the results of a scoping review and consultations with the JBI Scoping Review Methodology group. This paper describes several reliable, validated automation tools and software that can be used to enhance the conduct of scoping reviews. Developments in the automation of systematic reviews, and more recently scoping reviews, are continuously evolving. We detail several helpful tools in order of the key steps recommended by the JBI's methodological guidance for undertaking scoping reviews including team establishment, protocol development, searching, de-duplication, screening titles and abstracts, data extraction, data charting, and report writing. While we include several reliable tools and software that can be used for the automation of scoping reviews, there are some limitations to the tools mentioned. For example, some are available in English only and their lack of integration with other tools results in limited interoperability. This paper highlighted several useful automation tools and software programs to use in undertaking each step of a scoping review. This guidance has the potential to inform collaborative efforts aiming at the development of evidence informed, integrated automation tools and software packages for enhancing the conduct of high-quality scoping reviews

NIH Workshop 2018: Towards Minimally-invasive or Non-invasive Approaches to Assess Tissue Oxygenation Pre- and Post-Transfusion

Because blood transfusion is one of the most common therapeutic interventions in hospitalized patients, much recent research has focused on improving the storage quality in vitro of donor red blood cells (RBCs) that are then used for transfusion. However, there is a significant need for enhancing our understanding of the efficacy of the transfused RBCs in vivo. To this end, the NIH sponsored a one-and-a-half-day workshop that brought together experts in multiple disciplines relevant to tissue oxygenation (e.g., transfusion medicine, critical care medicine, cardiology, neurology, neonatology and pediatrics, bioengineering, biochemistry, and imaging). These individuals presented their latest findings, discussed key challenges, and aimed to construct recommendations for facilitating development of new technologies and/or biomarker panels to assess tissue oxygenation in a minimally-invasive to non-invasive fashion, before and after RBC transfusion. The workshop was structured into four sessions: (1) Global Perspective; (2) Organ Systems; (3) Neonatology; and (4) Emerging Technologies. The first day provided an overview of current approaches in the clinical setting, both from a global perspective, including the use of metabolomics for studying RBCs and tissue perfusion, and from a more focused perspective, including tissue oxygenation assessments in neonates and in specific adult organ systems. The second day focused on emerging technologies, which could be applied pre- and post-RBC transfusion, to assess tissue oxygenation in minimally-invasive or non-invasive ways. Each day concluded with an open-microphone discussion among the speakers and workshop participants. The workshop presentations and ensuing interdisciplinary discussions highlighted the potential of technologies to combine global “omics” signatures with additional measures (e.g., thenar eminence measurements or various imaging methods) to predict which patients could potentially benefit from a RBC transfusion and whether the ensuing RBC transfusion was effective. The discussions highlighted the need for collaborations across the various disciplines represented at the meeting to leverage existing technologies and to develop novel approaches for assessing RBC transfusion efficacy in various clinical settings. Although the Workshop took place in April, 2018, the concepts described and the ensuing discussions were, perhaps, even more relevant in April, 2020, at the time of writing this manuscript, during the explosive growth of the COVID-19 pandemic in the United States. Thus, issues relating to maintaining and improving tissue oxygenation and perfusion are especially pertinent because of the extensive pulmonary damage resulting from SARS-CoV-2 infection [1], compromises in perfusion caused by thrombotic-embolic phenomena [2], and damage to circulating RBCs, potentially compromising their oxygen-carrying capacity [3]. The severe end organ effects of SARS-CoV-2 infection mandate even more urgency for improving our understanding of tissue perfusion and oxygenation, improve methods for measuring and monitoring them, and develop novel ways of enhancing them

NIH Workshop 2018: Towards Minimally Invasive or Noninvasive Approaches to Assess Tissue Oxygenation Pre- and Post-transfusion

Because blood transfusion is one of the most common therapeutic interventions in hospitalized patients, much recent research has focused on improving the storage quality in vitro of donor red blood cells (RBCs) that are then used for transfusion. However, there is a significant need for enhancing our understanding of the efficacy of the transfused RBCs in vivo. To this end, the NIH sponsored a one-and-a-half-day workshop that brought together experts in multiple disciplines relevant to tissue oxygenation (eg, transfusion medicine, critical care medicine, cardiology, neurology, neonatology and pediatrics, bioengineering, biochemistry, and imaging). These individuals presented their latest findings, discussed key challenges, and aimed to identify opportunities for facilitating development of new technologies and/or biomarker panels to assess tissue oxygenation in a minimally-invasive to non-invasive fashion, before and after RBC transfusion

The Psychological Science Accelerator: Advancing Psychology through a Distributed Collaborative Network

Concerns have been growing about the veracity of psychological research. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions, or attempt to replicate prior research, in large, diverse samples. The PSA\u27s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time-limited), efficient (in terms of re-using structures and principles for different projects), decentralized, diverse (in terms of participants and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside of the network). The PSA and other approaches to crowdsourced psychological science will advance our understanding of mental processes and behaviors by enabling rigorous research and systematically examining its generalizability

PPARα L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males

<p>Abstract</p> <p>Background</p> <p>Of the five sub-phenotypes defining metabolic syndrome, all are known to have strong genetic components (typically 50–80% of population variation). Studies defining genetic predispositions have typically focused on older populations with metabolic syndrome and/or type 2 diabetes. We hypothesized that the study of younger populations would mitigate many confounding variables, and allow us to better define genetic predisposition loci for metabolic syndrome.</p> <p>Methods</p> <p>We studied 610 young adult volunteers (average age 24 yrs) for metabolic syndrome markers, and volumetric MRI of upper arm muscle, bone, and fat pre- and post-unilateral resistance training.</p> <p>Results</p> <p>We found the PPARα L162V polymorphism to be a strong determinant of serum triglyceride levels in young White males, where carriers of the V allele showed 78% increase in triglycerides relative to L homozygotes (LL = 116 ± 11 mg/dL, LV = 208 ± 30 mg/dL; p = 0.004). Men with the V allele showed lower HDL (LL = 42 ± 1 mg/dL, LV = 34 ± 2 mg/dL; p = 0.001), but women did not. Subcutaneous fat volume was higher in males carrying the V allele, however, exercise training increased fat volume of the untrained arm in V carriers, while LL genotypes significantly decreased in fat volume (LL = -1,707 ± 21 mm³, LV = 17,617 ± 58 mm³; p = 0.002), indicating a systemic effect of the V allele on adiposity after unilateral training. Our study suggests that the primary effect of PPARα L162V is on serum triglycerides, with downstream effects on adiposity and response to training.</p> <p>Conclusion</p> <p>Our results on association of PPARα and triglycerides in males showed a much larger effect of the V allele than previously reported in older and less healthy populations. Specifically, we showed the V allele to increase triglycerides by 78% (p = 0.004), and this single polymorphism accounted for 3.8% of all variation in serum triglycerides in males (p = 0.0037).</p