Physiological Characteristics of Freestyle Snowboard and Freeski Athletes.

Purpose: To investigate the physiological characteristics of freestyle snowboard and freeski athletes and explore potential differences between males and females.

Methods: National-team athletes, snowboard (9 males, 21 [2.3] y; 8 females, 20 [4.

Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms.

Introduction: Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown.

Methods: We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1).

Two-color coincidence single-molecule pulldown for the specific detection of disease-associated protein aggregates.

Protein misfolding and aggregation is a characteristic of many neurodegenerative disorders, including Alzheimer's and Parkinson's disease. The oligomers generated during aggregation are likely involved in disease pathogenesis and present promising biomarker candidates. However, owing to their small size and low concentration, specific tools to quantify and characterize aggregates in complex biological samples are still lacking.

Total Pelvic Exenteration surgery - Considerations for healthcare professionals.

Background: Associated with considerable risk of morbidity, Total Pelvic Exenteration (TPE) is a life-altering procedure involving a significant prolonged recovery. As a result, and with the view of achieving the best outcomes and lessen short and long-term morbidities, a well-thought-out and coordinated multidisciplinary team approach, is crucial to the provision of safe and high-quality care.

Method: Using a nominal group technique and qualitative methodology, this article explores the current practices in the care of oncology patients who undergo TPE surgery, in a tertiary cancer centre, by highlighting considerations of a collaboratively multi-disciplinary team.

Molecular mechanisms of PI4K regulation and their involvement in viral replication.

Lipid phosphoinositides are master signaling molecules in eukaryotic cells and key markers of organelle identity. Because of these important roles, the kinases and phosphatases that generate phosphoinositides must be tightly regulated. Viruses can manipulate this regulation, with the Type III phosphatidylinositol 4-kinases (PI4KA and PI4KB) being hijacked by many RNA viruses to mediate their intracellular replication through the formation of phosphatidylinositol 4-phosphate (PI4P)-enriched replication organelles (ROs).

Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα.

Covalent protein kinase inhibitors exploit currently noncatalytic cysteines in the adenosine 5'-triphosphate (ATP)-binding site via electrophiles directly appended to a reversible-inhibitor scaffold. Here, we delineate a path to target solvent-exposed cysteines at a distance >10 Å from an ATP-site-directed core module and produce potent covalent phosphoinositide 3-kinase α (PI3Kα) inhibitors. First, reactive warheads are used to reach out to Cys862 on PI3Kα, and second, enones are replaced with druglike warheads while linkers are optimized.

Perioperative Transjugular Intrahepatic Portosystemic Shunt Is Associated With Decreased Postoperative Complications in Decompensated Cirrhotics Undergoing Abdominal Surgery.

Background: Operative risk in patients with cirrhosis is related to the severity of liver disease and nature of procedure. Pre and postoperative portal decompression via transjugular intrahepatic portosystemic shunt (TIPS) are logical approaches to facilitate surgery and improve postoperative outcomes. We compared postoperative outcomes of decompensated cirrhotics undergoing abdominal surgery either with or without perioperative TIPS placement.

Unilateral Maximal Isometric Hex Bar Pull Test: Within-Session Reliability and Lower Body Force Production in Male and Female Freeski Athletes.

The aim of the study was to (1) assess the within-session reliability of a unilateral isometric hex bar pull (UIHBP) maximal voluntary contraction (MVC) test and, (2) determine unilateral isometric absolute peak force (PF) and relative peak force (PF) values in freeski athletes. Twenty-one male and eight female academy to national team freeskiers performed the novel UIHBP MVC task on a force plate and PF and relative PF were assessed (1000 Hz). Within-session measures of PF offered high reliability on left and right limbs for males ( = 0.

Opportunistic postpartum depression symptom screening at well-child clinics in Alberta, 2012-2016.

Objectives: The study objective was to assess the reach and delivery of opportunistic postpartum depression (PPD) symptom screening at well-child clinic (WCC) immunization appointments in Alberta. The relationship between socio-demographic factors and PPD symptom screening status, and PPD symptom scores was explored.

Method: In this retrospective population-based cohort study, administrative health data from WCC immunization appointments were used to assess the PPD symptom screening delivery and scores from January 1, 2012 to December 31, 2016.

Structural Basis for Inhibitor Potency and Selectivity of Phosphatidylinositol 4-Kinase Inhibitors.

phosphatidylinositol 4-kinase (PI4K) has emerged as a promising new drug target for novel antimalarial therapeutics. In the absence of a reliable high-resolution three-dimensional structure, a homology model of PI4K was built as a tool for structure-based drug design. This homology model has been validated against three distinct chemical series of potent inhibitors using docking and energy minimizations to elucidate the interactions crucial for PI4K inhibition and potent antiplasmodium activity.

Drugging the Phosphoinositide 3-Kinase (PI3K) and Phosphatidylinositol 4-Kinase (PI4K) Family of Enzymes for Treatment of Cancer, Immune Disorders, and Viral/Parasitic Infections.

The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in regulating membrane trafficking and lipid transport within the cell. The class I phosphoinositide kinases which generate the critical lipid signal PIP are hyperactivated in numerous human pathologies including cancer, overgrowth syndromes, and primary immunodeficiencies.

Fibrosis improvement in patients with HCV treated with direct-acting antivirals.

Background And Aim: More prospective studies are needed to characterize fibrosis improvement in patients with hepatitis C virus (HCV) who are treated with direct-acting antivirals (DAAs). The aims of this study were to assess changes in elastography scores from baseline to 1-year follow-up in patients with HCV, to identify factors that were independently associated with improvement in fibrosis staging in patients who receive treatment, and to identify factors that were independently associated with no improvement in fibrosis staging among patients who achieved sustained virologic responses (SVR).

Methods: Ultrasound elastography and laboratory tests were performed and collected at baseline and at 1-year follow-up for patients who received HCV treatment and for those who did not receive treatment (n = 240).

Characterization of the c10orf76-PI4KB complex and its necessity for Golgi PI4P levels and enterovirus replication.

The lipid kinase PI4KB, which generates phosphatidylinositol 4-phosphate (PI4P), is a key enzyme in regulating membrane transport and is also hijacked by multiple picornaviruses to mediate viral replication. PI4KB can interact with multiple protein binding partners, which are differentially manipulated by picornaviruses to facilitate replication. The protein c10orf76 is a PI4KB-associated protein that increases PI4P levels at the Golgi and is essential for the viral replication of specific enteroviruses.

Diffusion of Excellence: Accelerating the Spread of Clinical Innovation and Best Practices across the Nation's Largest Health System.

The time it takes for clinical innovation and evidence-based practices to reach patients remains a major challenge for the health care sector. In 2015, the Veterans Health Administration (VHA) launched the Diffusion of Excellence Initiative aimed at aligning organizational resources with early-stage to midstage promising practices and innovations to replicate, scale, and eventually spread those with greatest potential for impact and positive outcomes. Using a 5-step systematic approach refined over time, frontline VHA staff have submitted more than 1676 practices since the initiative's inception, 47 of which have been selected as high-impact, Gold Status practices.

()-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: ()-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound ), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels.

Structural determinants of Rab11 activation by the guanine nucleotide exchange factor SH3BP5.

The GTPase Rab11 plays key roles in receptor recycling, oogenesis, autophagosome formation, and ciliogenesis. However, investigating Rab11 regulation has been hindered by limited molecular detail describing activation by cognate guanine nucleotide exchange factors (GEFs). Here, we present the structure of Rab11 bound to the GEF SH3BP5, along with detailed characterization of Rab-GEF specificity.

UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria.

The 2-aminopyridine MMV048 was the first drug candidate inhibiting phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant and clinical isolates.

The Molecular Basis of Aichi Virus 3A Protein Activation of Phosphatidylinositol 4 Kinase IIIβ, PI4KB, through ACBD3.

Phosphatidylinositol 4-kinase III beta (PI4KIIIβ) is an essential enzyme in mediating membrane transport, and plays key roles in facilitating viral infection. Many pathogenic positive-sense single-stranded RNA viruses activate PI4KIIIβ to generate phosphatidylinositol 4-phosphate (PI4P)-enriched organelles for viral replication. The molecular basis for PI4KIIIβ activation during viral infection has remained largely unclear.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase.

A multisite evaluation of summer camps for children with cancer and their siblings.

Summer camps for pediatric cancer patients and their families are ubiquitous. However, there is relatively little research, particularly studies including more than one camp, documenting outcomes associated with children's participation in summer camp. The current cross-sectional study used a standardized measure to examine the role of demographic, illness, and camp factors in predicting children's oncology camp-related outcomes.

Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase IIIβ.

Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics.

Type III phosphatidylinositol 4 kinases: structure, function, regulation, signalling and involvement in disease.

Many important cellular functions are regulated by the selective recruitment of proteins to intracellular membranes mediated by specific interactions with lipid phosphoinositides. The enzymes that generate lipid phosphoinositides therefore must be properly positioned and regulated at their correct cellular locations. Phosphatidylinositol 4 kinases (PI4Ks) are key lipid signalling enzymes, and they generate the lipid species phosphatidylinositol 4-phosphate (PI4P), which plays important roles in regulating physiological processes including membrane trafficking, cytokinesis and organelle identity.