Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2.

Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes that link substrate release and opening of the cytoplasmic gate and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.

Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.

Two pore channels are lysosomal cation channels with crucial roles in tumor angiogenesis and viral release from endosomes. Inhibition of the two-pore channel 2 (TPC2) has emerged as potential therapeutic strategy for the treatment of cancers and viral infections, including Ebola and COVID-19. Here, we demonstrate that antagonist SG-094, a synthetic analog of the Chinese alkaloid medicine tetrandrine with increased potency and reduced toxicity, induces asymmetrical structural changes leading to a single binding pocket at only one intersubunit interface within the asymmetrical dimer. Supported by functional characterization of mutants by Ca2+ imaging and patch clamp experiments, we identify key residues in S1 and S4 involved in compound binding to the voltage sensing domain II. SG-094 arrests IIS4 in a downward shifted state which prevents pore opening via the IIS4/S5 linker, hence resembling gating modifiers of canonical VGICs. These findings may guide the rational development of new therapeutics antagonizing TPC2 activity.

Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.

Structural characterization of human urea transporters UT-A and UT-B and their inhibition.

In this study, we present the structures of human urea transporters UT-A and UT-B to characterize them at molecular level and to detail the mechanism of UT-B inhibition by its selective inhibitor, UTBinh-14. High-resolution structures of both transporters establish the structural basis for the inhibitor's selectivity to UT-B, and the identification of multiple binding sites for the inhibitor will aid with the development of drug lead molecules targeting both transporters. Our study also discovers phospholipids associating with the urea transporters by combining structural observations, native MS, and lipidomics analysis. These insights improve our understanding of urea transporter function at a molecular level and provide a blueprint for a structure-guided design of therapeutics targeting these transporters.

Quantitative changes in mental health measures with 3MDR treatment for Canadian military members and veterans.

OBJECTIVE: Military members and veterans are at elevated risk of treatment-resistant posttraumatic stress disorder (TR-PTSD) due to higher rates of exposure to potentially traumatic events during the course of duty. Knowledge of TR-PTSD is limited, and specific protocols or evidence-based TR-PTSD therapies are lacking. Multimodal motion-assisted memory desensitization and reconsolidation (3MDR) therapy is an emerging intervention for combat-related TR-PTSD. The purpose of this study was to preliminarily assess the effectiveness of 3MDR in addressing TR-PTSD in Canadian military members and veterans. METHODS: This study is a longitudinal mixed-methods clinical trial. English-speaking military members and veterans aged 18-60 with TR-PTSD were recruited to participate. The intervention consisted of six sessions of 3MDR therapy. Quantitative data were collected pretreatment, posttreatment, and longitudinally at 1, 3, and 6 months after completion of 3MDR. RESULTS: Results from the first 11 participants to complete the 3MDR protocol exhibited statistically significant improvement (surviving multiple comparison correction) in clinically administered and self-reported scores for PTSD (CAPS-5 and PCL-5), moral injury (MISS-M-SF), depression (PHQ-9), anxiety (GAD-7), emotional regulation (DERS-18), and resilience (CD-RS-25). CONCLUSION: The preliminary and exploratory results from this clinical trial support the growing body of literature illustrating 3MDR as an effective treatment for military-related TR-PTSD. These results are notable given participants' previous lack of success with frontline psychotherapeutic and pharmacological interventions. Given that there are currently very limited treatment options for TR-PTSD, 3MDR could prove to be a valuable treatment option for military members and veterans with TR-PTSD.

New Life Through Disaster: A Thematic Analysis of Women's Experiences of Pregnancy and the 2016 Fort McMurray Wildfire.

Background: On May 3, 2016, residents of Fort McMurray Wood Buffalo, Alberta were evacuated due to an uncontrolled wildfire. The short-notice evacuation had destabilizing consequences for residents, including changes in routines, loss of control, and increased uncertainty. These consequences were especially detrimental to women who were pregnant or pre-conception during the evacuation. Pregnant and pre-conception women are particularly susceptible to a vast range of negative consequences during and post natural disasters, including elevated stress and higher incidence of pregnancy complications including gestational diabetes mellitus, pregnancy induced hypertension and C-section. The aim of this study was to understand the experiences, perceived stress and resilience of women who were pregnant during the wildfire. As well as to explore potential interventions to promote the health and enhance resilience of pregnant women and to assist in recovery after exposure to a natural disaster or other traumatic events. Methods: A qualitative thematic analysis of 16 narratives penned by pregnant women and recounted in Ashley Tobin's compilations 93/88,000 and 159 More/ 88,000: Stories of Evacuation, Re-Entry and the In-Between was conducted. Results: Analysis revealed five key themes: (1) experience of stress responses due to personal and external factors, (2) social connectedness and support as a facilitator of resilience, (3) performance of resilience-enhancing activities, (4) the roles of pregnancy and motherhood in the experiences of loss and resilience, and (5) the importance of home. Conclusion: Pregnant women have unique barriers that may negatively impact them during a natural disaster or other form of stressful event. They may benefit from assistance with navigating role transition during pregnancy, training in stress management strategies, and writing interventions to build resiliency and begin the process of recovery from trauma.

Workplace Reintegration Facilitator Training Program for Mental Health Literacy and Workplace Attitudes of Public Safety Personnel: Pre-Post Pilot Cohort Study.

BACKGROUND: Public safety personnel (PSP) impacted by operational stress injuries can find themselves needing both time off work and support reintegrating back into the workforce. Work reintegration programs have been introduced in PSP organizations to support those who aim to return to work. One such peer-led workplace reintegration program (RP) was created in 2009 by members of the Edmonton Police Service (EPS). The primary goal of the EPSRP is to assist PSP in returning to work as soon as possible following a critical incident, illness, or injury while diminishing the potential for long-term psychological injury. The EPSRP is delivered by peers through 3 interrelated components: (1) the Reintegration Program Facilitator Training (RPFT) Program; (2) a short-term Critical Incident RP; and (3) a long-term RP. There is a dire need for research that incorporates strong study designs to the determine long-term effectiveness of the program on increasing workplace reintegration, improving mental health knowledge, and creating culture change within PSP organizations. Simultaneously, the efficacy, effectiveness, and fidelity of the RPFT in providing the tools, mental health knowledge, and skills the RP peer facilitators will need for the RP must be evaluated. OBJECTIVE: The purpose of this quasi-experimental pre-post pilot cohort study is to evaluate the effectiveness of the EPSRPFT course on influencing mental health knowledge and attitudes of RPFT attendees who will be future RP peer facilitators. METHODS: This pre-post cohort study collected data via 2 questionnaires from RPFT participants (N=60) which included the Mental Health Knowledge Survey (MAKS) and the Open Minds Survey of Workplace Attitudes (OMSWA). Descriptive, parametric (sample t tests), and nonparametric (Wilcoxon signed rank tests) statistics were used to compare the pre- and post-RPFT results and to analyze results by gender and profession. RESULTS: Statistically significant changes were observed in pre-post questionnaire scores in the domains of mental health attitudes and knowledge. CONCLUSIONS: Although results are explorative, the RPFT may facilitate positive changes in workplace mental health attitudes and knowledge among PSP. It is hoped these findings will contribute to a broader evidence base that can inform changes to the program, practices, and policies, and inform decision-making regarding the EPSRP.

Neuroimaging predictors of longitudinal disability and cognition outcomes in multiple sclerosis patients: A systematic review and meta-analysis.

BACKGROUND: Cross-sectional magnetic resonance imaging (MRI) studies have generated substantial evidence relating neuroimaging abnormalities to clinical and cognitive decline in multiple sclerosis (MS). Longitudinal neuroimaging studies may have additional value for predicting future cognitive deficits or clinical impairment, potentially leading to earlier interventions and better disease management. We conducted a meta-analysis of longitudinal studies using neuroimaging to predict cognitive decline (i.e. the Symbol Digits Modalities Test, SDMT) and disability outcomes (i.e. the Expanded Disability Status Scale, EDSS) in MS. METHODS: Our systematic literature search yielded 64 relevant publications encompassing 105 distinct sub-analyses. We performed a multilevel random-effects meta-analysis to estimate overall effect size for neuroimaging's ability to predict longitudinal cognitive and clinical decline, and a meta-regression to investigate the impact of distinct study factors on pooled effect size. RESULTS: In the EDSS analyses, the meta-analysis yielded a medium overall pooled effect size (Pearson's correlation coefficient r = 0.42, 95% CI [0.37; 0.46]). The meta-regression further indicated that analyses exclusively evaluating gray matter tissue had significantly stronger effect sizes than analyses of white matter tissue or whole brain analyses (p < 0.05). No other study factors significantly influenced the pooled effect size (all p > 0.05). In the SDMT analyses, the meta-analysis yielded a medium overall pooled effect size (r = 0.47, 95% CI [0.32; 0.60]). The meta-regression found no significant study factors influencing the pooled effect size. CONCLUSION: The present findings indicate that brain imaging is a medium predictor of longitudinal change in both disability progression (EDSS) and cognitive decline (SDMT). These findings reinforce the need for further longitudinal studies standardizing methods, using multimodal approaches, creating data consortiums, and publishing more complete datasets investigating MRI modalities to predict longitudinal disability and cognitive decline.

Resilient Parents Resilient Communities: A Pilot Study Trialing the Bounce Back and Thrive! Resilience-Training Program With Military Families.

INTRODUCTION: The resilience of Canadian military families (CMFs) - the main support of the Canadian Armed Forces service members (SMs) - is imperative. The Canadian Armed Forces aims to ensure that SMs and their families are resilient and SMs ready to respond when called upon for combat, peacekeeping or pandemic/disaster-response. Family concerns, however, can realistically distract SMs from the mission, potentially compromising themselves, their unit and the mission. Resilience-training programs such as Bounce Back and Thrive! (BBT) can help families manage the realities of military life. OBJECTIVE: This pilot study aimed to evaluate suitability of BBT implementation by Military Family Resource Centers (MFRCs), including whether BBT: (1) fosters resilience-building among parents, (2) facilitates CMF resilience-building, (3) can be contextualized for CMFs, and (4) supports MFRCs in cultivating a culture of resilience. METHODS: An exploratory qualitative design was used. BBT was offered to parents face-to-face. Participants completed focus groups after the first 6 sessions, final 4 sessions, and one-year post-intervention. Data was thematically analyzed. RESULTS: Nine military parents participated. Four major themes resulted: (1) military parent resilience-building, (2) CMF resilience-building, (3) BBT program feedback and contextualization, and (4) MFRCs as community resilience hubs. DISCUSSION: BBT enabled parents to gain a new perspective on resilience, engage in dialogue and intentionally role model resilience skills. Military-specific BBT contextualization and online-delivery formats would increase suitability and access for CMFs. Access to resilience programs delivered through MFRCs would support CMFs. Further research is warranted.

Enhancing Resilience in Canadian Military Families and Communities: A Qualitative Analysis of the Reaching In Reaching Out and Bounce Back and Thrive! Resiliency Skills Training Programs.

Introduction: A new vision of resilience and well-being for Canadian military service members (SMs), Veterans and their families has been championed by the Canadian Armed Forces (CAF) and Veterans Affairs Canada (VAC). Operationalizing this vision, which aims to support those who serve/have served and their families as they navigate life during and post-service, requires the support of service providers (SPs). Training SPs to deliver complementary resilience-training programs Reaching In… Reaching Out (RIRO; for adults working with parents of young children) and Bounce Back and Thrive! (BBT; for parents of children aged 0-8 years of age) may support this vision. Objective: To assess the appropriateness of RIRO/BBT trainer training for SPs, and RIRO and BBT resilience-training for military populations and families. Methods: This qualitative descriptive study involved the delivery of RIRO/BBT trainer training to SPs (n = 20), followed by focus groups (n = 6) with SPs and organisational leaders (n = 4). Focus groups were recorded, and data were transcribed and thematically-analysed. Results: Several themes emerged: (1) RIRO/BBT trainer training enabled SPs to model resilience and deliver the resilience-training programs, (2) training was appropriate and adaptable for the CAF and SMs/CMFs, and (3) training could support the development of resilient communities. Discussion: RIRO/BBT trainer training and RIRO and BBT resilience-training programs use a holistic, integrated, experiential, and community approach to resilience-building and align with CAF and VAC initiatives. Once contextualised, such programs could support resilience-building in the military context.

The structural basis of fatty acid elongation by the ELOVL elongases.

Very long chain fatty acids (VLCFAs) are essential building blocks for the synthesis of ceramides and sphingolipids. The first step in the fatty acid elongation cycle is catalyzed by the 3-keto acyl-coenzyme A (CoA) synthases (in mammals, ELOVL elongases). Although ELOVLs are implicated in common diseases, including insulin resistance, hepatic steatosis and Parkinson's, their underlying molecular mechanisms are unknown. Here we report the structure of the human ELOVL7 elongase, which comprises an inverted transmembrane barrel surrounding a 35-Å long tunnel containing a covalently attached product analogue. The structure reveals the substrate-binding sites in the narrow tunnel and an active site deep in the membrane. We demonstrate that chain elongation proceeds via an acyl-enzyme intermediate involving the second histidine in the canonical HxxHH motif. The unusual substrate-binding arrangement and chemistry suggest mechanisms for selective ELOVL inhibition, relevant for diseases where VLCFAs accumulate, such as X-linked adrenoleukodystrophy.

Decision-making capacity assessment education.

BACKGROUND/OBJECTIVES: As the elderly population and associated number of persons with dementia increase, so does the need for decision-making capacity assessments (DMCAs). Many healthcare professionals (HCPs), however, do not feel prepared to conduct DMCAs. We have provided 4-h DMCA workshops to HCPs since 2006 and offered physicians either a 3-h or 2-day DMCA workshop from 2013 to present. We evaluated the effectiveness of the workshops on self-reported key concepts of capacity. DESIGN: Pre-/post-test design. SETTING: DMCA workshops for physicians across Canada and HCPs within Alberta. PARTICIPANTS: Two hundred and eighty-one physicians and 835 HCPs. MEASUREMENTS: Pre-/post-workshop ratings on level of comfort with and understanding of 15 core DMCA concepts using 4-point Likert-type items. RESULTS: For the DMCA workshops among physicians, ten 3-h workshops were held in 2014-2015 with 166 participants and seven 2-day workshops, between 2014 and 2018, with 115 participants. With respect to the self-report on core DMCA concepts, at least 62.7% (range: 62.7%-89.6%) of physician participants had higher post-workshop ratings (sign test; p < 0.001) than pre-workshop ratings for all core DMCA concepts. For the DMCA workshops among HCPs, 4-h workshops were delivered to 835 HCP participants from 2008 to 2012. At least 49.6% of participants (range: 49.6%-78.9%) had increased post-workshop ratings (sign test; p < 0.001) for all level of comfort items with and understanding of core DMCA concepts. CONCLUSION: There is a need for DMCA training for physicians and HCPs. The content and method of the workshops are effective at enhancing self-reported level of comfort with and understanding of core DMCA concepts.

Companions in the Abyss: A Feasibility and Acceptability Study of an Online Therapy Group for Healthcare Providers Working During the COVID-19 Pandemic.

INTRODUCTION: In the context of the global pandemic of the SARS-CoV-2 coronavirus (COVID-19), healthcare providers (HCPs) have experienced difficult moral and ethical dilemmas. Research is highlighting the importance of moral injury (MI)-a trauma syndrome related to transgressing personal morals and values-in understanding the psychological harm and occupational impairment experienced by HCPs. To date, MI treatments have largely been developed for military personnel and veterans and rely on in-person one-on-one psychotherapy. PURPOSE: This project aims to explore the feasibility and acceptability of an evidence-informed online Acceptance and Commitment Therapy-based group therapy for MI in HCPs called "Accepting Moral Pain and Suffering for Healthcare Providers" (AMPS-HCP). METHOD: This feasibility and acceptability study included three separate phases with the first two phases focused on the development of the psychotherapeutic intervention and the third phase focused on the evaluation of the psychotherapeutic intervention. Eight participants (including registered nurses, practical nurses and respiratory therapists) completed seven 90-min sessions in an online group format. The focus of these sessions included ACT and MI psychoeducation and experientials. Qualitative semi-structured interview data was thematically analyzed while demographic and quantitative self-reported outcome data underwent descriptive analysis and non-parametric testing. RESULTS: Results show that the intervention was highly feasible and acceptable to healthcare providers who worked on the frontline during COVID-19. Feasibility (referrals, eligibility, retention, participation engagement) was strong (8 out of 10 participants; 80% vs. desired >70% eligibility) and overall, 80% of participants completed 71% of the intervention. Data further supported the applicability and acceptability of the intervention. Preliminary data suggests that AMPS-HCP may supports HCPs to address MI. DISCUSSION: This study is the first to report on the development and evaluation of an online MI group intervention for registered nurses, registered practical nurses, and respiratory therapists working during COVID-19. Results showed the use of both the online and group components of the intervention were acceptable and feasible during the third wave of COVID-19.

Virtual Reality-Based Treatment for Military Members and Veterans With Combat-Related Posttraumatic Stress Disorder: Protocol for a Multimodular Motion-Assisted Memory Desensitization and Reconsolidation Randomized Controlled Trial.

BACKGROUND: Military members are at elevated risk of operational stress injuries, including posttraumatic stress disorder (PTSD) and moral injury. Although psychotherapy can reduce symptoms, some military members may experience treatment-resistant PTSD. Multimodular motion-assisted memory desensitization and reconsolidation (3MDR) has been introduced as a virtual reality (VR) intervention for military members with PTSD related to military service. The 3MDR intervention incorporates exposure therapy, psychotherapy, eye movement desensitization and reconsolidation, VR, supportive counselling, and treadmill walking. OBJECTIVE: The objective of this study is to investigate whether 3MDR reduces PTSD symptoms among military members with combat-related treatment-resistant PTSD (TR-PTSD); examine the technology acceptance and usability of the Computer Assisted Rehabilitation ENvironment (CAREN) and 3MDR interventions by Canadian Armed Forces service members (CAF-SMs), veterans, 3MDR clinicians, and operators; and evaluate the impact on clinicians and operators of delivering 3MDR. METHODS: This is a mixed-methods waitlist controlled crossover design randomized controlled trial. Participants include both CAF-SMs and veterans (N=40) aged 18-60 years with combat-related TR-PTSD (unsuccessful experience of at least 2 evidence-based trauma treatments). Participants will also include clinicians and operators (N=12) who have been trained in 3MDR and subsequently utilized this intervention with patients. CAF-SMs and veterans will receive 6 weekly 90-minute 3MDR sessions. Quantitative and qualitative data will be collected at baseline and at 1, 3, and 6 months postintervention. Quantitative data collection will include multiomic biomarkers (ie, blood and salivary proteomic and genomic profiles of neuroendocrine, immune-inflammatory mediators, and microRNA), eye tracking, electroencephalography, and physiological data. Data from outcome measures will capture self-reported symptoms of PTSD, moral injury, resilience, and technology acceptance and usability. Qualitative data will be collected from audiovisual recordings of 3MDR sessions and semistructured interviews. Data analysis will include univariate and multivariate approaches, and thematic analysis of treatment sessions and interviews. Machine learning analysis will be included to develop models for the prediction of diagnosis, symptom severity, and treatment outcomes. RESULTS: This study commenced in April 2019 and is planned to conclude in April 2021. Study results will guide the further evolution and utilization of 3MDR for military members with TR-PTSD and will have utility in treating other trauma-affected populations. CONCLUSIONS: The goal of this study is to utilize qualitative and quantitative primary and secondary outcomes to provide evidence for the effectiveness and feasibility of 3MDR for treating CAF-SMs and veterans with combat-related TR-PTSD. The results will inform a full-scale clinical trial and stimulate development and adaptation of the protocol to mobile VR apps in supervised clinical settings. This study will add to knowledge of the clinical effectiveness of 3MDR, and provide the first comprehensive analysis of biomarkers, technology acceptance and usability, moral injury, resilience, and the experience of clinicians and operators delivering 3MDR. TRIAL REGISTRATION: ISRCTN Registry 11264368; http://www.isrctn.com/ISRCTN11264368. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/20620.

A lower X-gate in TASK channels traps inhibitors within the vestibule.

TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K2P) channel family-are found in neurons1, cardiomyocytes2-4 and vascular smooth muscle cells5, where they are involved in the regulation of heart rate6, pulmonary artery tone5,7, sleep/wake cycles8 and responses to volatile anaesthetics8-11. K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli12-15. Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation16. In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an 'X-gate'-created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues (243VLRFMT248) that are essential for responses to volatile anaesthetics10, neurotransmitters13 and G-protein-coupled receptors13. Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.

Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2.

Polycystin-2 (PC2) is a transient receptor potential (TRP) channel present in ciliary membranes of the kidney. PC2 shares a transmembrane fold with other TRP channels, in addition to an extracellular domain found in TRPP and TRPML channels. Using molecular dynamics (MD) simulations and cryoelectron microscopy we identify and characterize PIP2 and cholesterol interactions with PC2. PC2 is revealed to have a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel. A 3.0-Å structure reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are characterized by MD simulations. The two classes of lipid binding sites are compared with sites observed in other TRPs and in Kv channels. These findings suggest PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol, and position PC2 within an emerging model of the roles of lipids in the regulation and organization of ciliary membranes.

The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K.

Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.

Spirituality and Moral Injury Among Military Personnel: A Mini-Review.

Introduction: Moral injury (MI) results when military personnel are exposed to morally injurious events that conflict with their values and beliefs. Given the complexity of MI and its physical, emotional, social, and spiritual impact, a holistic approach is needed. While the biopsychosocial aspects of MI are more commonly addressed, less is known of the spiritual dimension and how to incorporate it into treatment that facilitates restoration of one's core self and mending of relationships with self, others, and the sacred/Transcendent. The purpose of this study was to gain a greater understanding of the relationship between spirituality/religion (S/R) and MI as experienced by military members and veterans and to consider how S/R might be better integrated into prevention and treatment strategies. Methods: A mini-review of peer-reviewed articles published between January 2000 and April 2018 regarding the relationship between spirituality and MI among military personnel and veterans was conducted. Results: Twenty-five articles were included in the final review. Five themes were identified and explored, including i) Spirituality: A potential cause of and protective factor against MI, ii) Self and identity: Lost and found, iii) Meaning-making: What once was and now is, iv) Spirituality as a facilitator of treatment for MI, and v) Faith communities: Possible sources of fragmentation or healing. Discussion: Findings identified a cyclical relationship between S/R and MI, whereby S/R can both mitigate and exacerbate MI, as well as be affected by it. Seen as a type of S/R struggle, the use of S/R-specific strategies [e.g., forgiveness, review of S/R beliefs, engagement in S/R practices, and (re)connection with S/R communities], integration of S/R perspectives into general interventions, and help from chaplains may support healing, self-regulation, and mending of relationships, moral emotions, and social connection. Further research is yet needed, however, regarding i) S/R orienting systems, interventions, practices, and rituals/ceremonies that might protect against and treat MI; ii) features of individuals who do/do not experience MI; iii) S/R assessment tools and interventions; and iv) ways to maximize the positive contributions of faith communities.

Corrections and connection to the community: A diagnostic and service program for incarcerated adult men with FASD.

Previous research has demonstrated that impaired social and adaptive behavior due to prenatal alcohol exposure can be associated with severe conduct disorders in adolescence, mental health concerns, school failure, employment difficulties, substance abuse, difficulty with the law, and incarceration. The Corrections and Connections to the Community research and service program was established to examine adult male offenders with frequent contact with the provincial corrections system. Individuals who participated in the program received neuropsychological testing, a functional assessment and a psychiatric interview. Results indicated that 90% of the participants identified within the spectrum of FASD. The functional profile indicated that many participants had impaired social functioning. A natural dichotomy emerged from the data which reflected those who connected early with the criminal justice system (65%) and those who did not connect within the 18 month project period. Significant differences emerged between those individuals who reconnected with the justice system and who also possessed a juvenile record and those who did not. Further analysis also indicated significant differences between scores on the Finger Tapping Test, Trail Making Test A, ILS and California Verbal Learning Test. Findings of this study highlight the importance of appropriate programming and services for incarcerated men with FASD.

A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels.

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K2P) channels, voltage-gated hERG (human ether-à-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design.