A Cation-π Interaction Discriminates among Sodium Channels That Are Either Sensitive or Resistant to Tetrodotoxin Block

Voltage-gated sodium channels control the upstroke of the action potential in excitable cells of nerve and muscle tissue, making them ideal targets for exogenous toxins that aim to squelch electrical excitability. One such toxin, tetrodotoxin (TTX), blocks sodium channels with nanomolar affinity only when an aromatic Phe or Tyr residue is present at a specific location in the external vestibule of the ion-conducting pore. To test whether TTX is attracted to Tyr401 of NaV1.4 through a cation-{pi} interaction, this aromatic residue was replaced with fluorinated derivatives of Phe using in vivo nonsense suppression. Consistent with a cation-{pi} interaction, increased fluorination of Phe401, which reduces the negative electrostatic potential on the aromatic face, caused a monotonic increase in the inhibitory constant for block. Trifluorination of the aromatic ring decreased TTX affinity by ~50-fold, a reduction similar to that caused by replacement with the comparably hydrophobic residue Leu. Furthermore, we show that an energetically equivalent cation-{pi} interaction underlies both use-dependent and tonic block by TTX. Our results are supported by high level ab initio quantum mechanical calculations applied to a model of TTX binding to benzene. Our analysis suggests that the aromatic side chain faces the permeation pathway where it orients TTX optimally and interacts with permeant ions. These results are the first of their kind to show the incorporation of unnatural amino acids into a voltage-gated sodium channel and demonstrate that a cation-{pi} interaction is responsible for the obligate nature of an aromatic at this position in TTX-sensitive sodium channels

Appetite Suppressants as Adjuncts for Weight Loss

Phentermine and diethylpropion are appetite suppressants approved for use in the United States as adjuncts in the treatment of obesity. These agents demonstrate a modest weight loss benefit when combined with dietary modifications and exercise. (Strength of Recommendation: B, based on a randomized trial and a meta-analysis.) No current evidence is available on the long-term risks and benefits of these medications, or the most appropriate time to initiate appetite suppressant therapy as part of a comprehensive weight management program

Social Work, Politics, and Social Policy Education: Applying a Multidimensional Framework of Power

The call to promote social justice sets the social work profession in a political context. In an effort to enhance social workers’ preparedness to engage in political advocacy, this article calls on educators to integrate a broad theoretical understanding of power into social policy curricula. We suggest the use of a multidimensional conceptualization of power that emphasizes mechanisms of decision making, agenda control, and attitude formation. We then apply these mechanisms to demonstrate how two prominent features of contemporary politics—party polarization and racially biased attitudes—affect the ability of social workers to influence policy. Finally, we suggest content that social work educators can integrate to prepare future social workers to engage in strategic and effective social justice advocacy

Adaptation of Human Influenza Viruses to Swine

A large diversity of influenza A viruses (IAV) within the H1N1/N2 and H3N2 subtypes circulates in pigs globally, with different lineages predominating in specific regions of the globe. A common characteristic of the ecology of IAV in swine in different regions is the periodic spillover of human seasonal viruses. Such human viruses resulted in sustained transmission in swine in several countries, leading to the establishment of novel IAV lineages in the swine host and contributing to the genetic and antigenic diversity of influenza observed in pigs. In this review we discuss the frequent occurrence of reverse-zoonosis of IAV from humans to pigs that have contributed to the global viral diversity in swine in a continuous manner, describe host-range factors that may be related to the adaptation of these human-origin viruses to pigs, and how these events could affect the swine industry

Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer

Epithelial-mesenchymal transition (EMT) is an essential developmental program that becomes reactivated in adult tissues to promote the progression of cancer. EMT has been largely studied by examining the beginning epithelial state or the ending mesenchymal state without studying the intermediate stages. Recent studies using trophoblast stem (TS) cells paused in EMT have defined the molecular and epigenetic mechanisms responsible for modulating the intermediate “metastable” stages of EMT. Targeted inactivation of MAP3K4, knockdown of CBP or overexpression of SNAI1 in TS cells induced similar metastable phenotypes. These TS cells exhibited epigenetic changes in the histone acetylation landscape that cause loss of epithelial maintenance while preserving self-renewal and multipotency. A similar phenotype was found in claudin-low breast cancer cells with properties of EMT and stemness. This intersection between EMT and stemness in TS cells and claudin-low metastatic breast cancer demonstrates the usefulness of developmental EMT systems to understand EMT in cancer

The impact of participant mental health on attendance and engagement in a trial of behavioural weight management programmes: secondary analysis of the WRAP randomised controlled trial.

BACKGROUND: Low attendance and engagement in behavioural weight management trials are common. Mental health may play an important role, however previous research exploring this association is limited with inconsistent findings. We aimed to investigate whether mental health was associated with attendance and engagement in a trial of behavioural weight management programmes. METHODS: This is a secondary data analysis of the Weight loss referrals for adults in primary care (WRAP) trial, which randomised 1267 adults with overweight or obesity to brief intervention, WW (formerly Weight Watchers) for 12-weeks, or WW for 52-weeks. We used regression analyses to assess the association of baseline mental health (depression and anxiety (by Hospital Anxiety and Depression Scale), quality of life (by EQ5D), satisfaction with life (by Satisfaction with Life Questionnaire)) with programme attendance and engagement in WW groups, and trial attendance in all randomised groups. RESULTS: Every one unit of baseline depression score was associated with a 1% relative reduction in rate of WW session attendance in the first 12 weeks (Incidence rate ratio [IRR] 0.99; 95% CI 0.98, 0.999). Higher baseline anxiety was associated with 4% lower odds to report high engagement with WW digital tools (Odds ratio [OR] 0.96; 95% CI 0.94, 0.99). Every one unit of global quality of life was associated with 69% lower odds of reporting high engagement with the WW mobile app (OR 0.31; 95% CI 0.15, 0.64). Greater symptoms of depression and anxiety and lower satisfaction with life at baseline were consistently associated with lower odds of attending study visits at 3-, 12-, 24-, and 60-months. CONCLUSIONS: Participants were less likely to attend programme sessions, engage with resources, and attend study assessments when reporting poorer baseline mental health. Differences in attendance and engagement were small, however changes may still have a meaningful effect on programme effectiveness and trial completion. Future research should investigate strategies to maximise attendance and engagement in those reporting poorer mental health. TRIAL REGISTRATION: The original trial ( ISRCTN82857232 ) and five year follow up ( ISRCTN64986150 ) were prospectively registered with Current Controlled Trials on 15/10/2012 and 01/02/2018.The WRAP trial was funded by the National Prevention Research Initiative through research grant MR/J000493. The intervention was provided by WW (formerly Weight Watchers) at no cost via an MRC Industrial Collaboration Award. Five year follow up of the WRAP trial was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (RP-PG-0216-20010). RAJ, ALA, SJG, and SJS are supported by the Medical Research Council (MRC) (Grant MC_UU_00006/6). The University of Cambridge has received salary support in respect of SJG from the National Health Service in the East of England through the Clinical Academic Reserve. All funding bodies had no role in the design of the study and collection, analysis and interpretation of the data, and in the writing of the manuscript

Exercising Caution Upon Waking–Can Exercise Reduce Sleep Inertia?

Sleep inertia, the transitional state of reduced alertness and impaired cognitive performance upon waking, is a safety risk for on-call personnel who can be required to perform critical tasks soon after waking. Sleep inertia countermeasures have previously been investigated; however, none have successfully dissipated sleep inertia within the first 15 min following waking. During this time, on-call personnel could already be driving, providing advice, or performing other safety-critical tasks. Exercise has not yet been investigated as a sleep inertia countermeasure but has the potential to stimulate the key physiological mechanisms that occur upon waking, including changes in cerebral blood flow, the cortisol awakening response, and increases in core body temperature. Here, we examine these physiological processes and hypothesize how exercise can stimulate them, positioning exercise as an effective sleep inertia countermeasure. We then propose key considerations for research investigating the efficacy of exercise as a sleep inertia countermeasure, including the need to determine the intensity and duration of exercise required to reduce sleep inertia, as well as testing the effectiveness of exercise across a range of conditions in which the severity of sleep inertia may vary. Finally, practical considerations are identified, including the recommendation that qualitative field-based research be conducted with on-call personnel to determine the potential constraints in utilizing exercise as a sleep inertia countermeasure in real-world scenarios

Exercising Caution Upon Waking–Can Exercise Reduce Sleep Inertia?

Sleep inertia, the transitional state of reduced alertness and impaired cognitive performance upon waking, is a safety risk for on-call personnel who can be required to perform critical tasks soon after waking. Sleep inertia countermeasures have previously been investigated; however, none have successfully dissipated sleep inertia within the first 15 min following waking. During this time, on-call personnel could already be driving, providing advice, or performing other safety-critical tasks. Exercise has not yet been investigated as a sleep inertia countermeasure but has the potential to stimulate the key physiological mechanisms that occur upon waking, including changes in cerebral blood flow, the cortisol awakening response, and increases in core body temperature. Here, we examine these physiological processes and hypothesize how exercise can stimulate them, positioning exercise as an effective sleep inertia countermeasure. We then propose key considerations for research investigating the efficacy of exercise as a sleep inertia countermeasure, including the need to determine the intensity and duration of exercise required to reduce sleep inertia, as well as testing the effectiveness of exercise across a range of conditions in which the severity of sleep inertia may vary. Finally, practical considerations are identified, including the recommendation that qualitative field-based research be conducted with on-call personnel to determine the potential constraints in utilizing exercise as a sleep inertia countermeasure in real-world scenarios

Characterization of co-circulating swine influenza A viruses in North America and the identification of a novel H1 genetic clade with antigenic significance.

Multiple genetically and antigenically distinct hemagglutinin genes of the H1 and H3 influenza A virus (IAV) subtypes co-circulate in North American swine. This diversity has evolved by repeated transmission of IAVs from humans to swine and subsequent antigenic drift in swine. To understand the evolutionary dynamics of these diverse HA lineages in North American swine, we undertook a phylogenetic analysis of 1576 H1 and 607 H3 HA gene segments, as well as 834 N1 and 1293 N2 NA gene segments, and 2126 M gene segments. These data revealed yearly co-circulation of H1N1, H1N2, and H3N2 viruses, with three HA clades representing the majority of the HA sequences: of the H1 viruses, 42% were classified as H1δ1 and 40.6% were classified as H1γ; and of the H3 viruses 53% were classified as cluster IV-A H3N2. We detected a genetically distinct minor clade consisting of 37 H1 viruses isolated between 2003 and 2013, which we classified as H1γ-2. We estimated that this clade circulated in swine since approximately 1995, but it was not detected in swine until 2003. Though this clade only represents 1.07% of swine H1 sequences reported over the past 10 years, hemagglutination inhibition (HI) assays demonstrated that representatives of this clade of viruses are antigenically distinct, and, when measured using antigenic cartography, were as many as 7 antigenic units from other H1γ viruses. Therefore vaccines against the contemporary H1γ viruses are not likely to cross-protect against γ-2 viruses. The long-term circulation of these γ-2 viruses suggests that minor populations of viruses may be underreported in the national dataset given the long branch lengths and gaps in detections. The identification of these γ-2 viruses demonstrates the need for robust surveillance to capture the full diversity IAVs in swine in the USA and the importance of antigenic drift in the diversification and emergence of new antigenic variants in swine, which complicates vaccine design.Funding was provided by USDA-ARS and USDA355 APHIS-VS by the Supplemental Appropriations Act of 2009. NSL was funded by USDA-ARS SCA agreement number 58-3625-2-103F and the EC FP7 award number 259949. TKA was funded by USDA ARS SCA agreement number 58-3625-4-070.This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0168170215000799