Background
Elite athletes can experience a diverse range of symptoms following post-concussive injury. The impact of sport-related concussion on specific mental health outcomes is unclear in this ...population.
Objective
The aim was to appraise the evidence base regarding the association between sport-related concussion and mental health outcomes in athletes competing at elite and professional levels.
Methods
A systematic search of PubMed, EMBASE, SPORTDiscus, PsycINFO, Cochrane, and Cinahl databases was conducted.
Results
A total of 27 studies met inclusion criteria for review. Most of the included studies (67%,
n
= 18) were published in 2014 or later. Study methodology and reporting varied markedly. The extant research has been conducted predominantly in North America (USA,
n
= 23 studies; Canada,
n
= 3), often in male only (44.4%,
n
= 12) and college (70.4%,
n
= 19) samples. Depression is the most commonly studied mental health outcome (70.4%,
n
= 19 studies). Cross-sectional retrospective studies and studies including a control comparison tend to support an association between concussion exposure and depression symptoms, although several studies report that these symptoms resolved in the medium term (i.e. 1 month) post-concussion. Evidence for anxiety is mixed. There are insufficient studies to draw conclusions for other mental health domains.
Conclusion
Consistent with current recommendations to assess mood disturbance in post-concussive examinations, current evidence suggests a link between sports-related concussion and depression symptoms in elite athletes. Causation cannot be determined at this stage of enquiry because of the lack of well-designed, prospective studies. More research is required that considers a range of mental health outcomes in diverse samples of elite athletes/sports.
Ultrastructural analysis of hepatitis C virus particles Catanese, Maria Teresa; Uryu, Kunihiro; Kopp, Martina ...
Proceedings of the National Academy of Sciences - PNAS,
06/2013, Letnik:
110, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estimated 170 million people infected worldwide. Low yields, poor stability, and inefficient binding to conventional EM ...grids have posed significant challenges to the purification and structural analysis of HCV. In this report, we generated an infectious HCV genome with an affinity tag fused to the E2 envelope glycoprotein. Using affinity grids, previously described to isolate proteins and macromolecular complexes for single-particle EM, we were able to purify enveloped particles directly from cell culture media. This approach allowed for rapid in situ purification of virions and increased particle density that were instrumental for cryo-EM and cryoelectron tomography (cryo-ET). Moreover, it enabled ultrastructural analysis of virions produced by primary human hepatocytes. HCV appears to be the most structurally irregular member of the Flaviviridae family. Particles are spherical, with spike-like projections, and heterogeneous in size ranging from 40 to 100 nm in diameter. Exosomes, although isolated from unfractionated culture media, were absent in highly infectious, purified virus preparations. Cryo-ET studies provided low-resolution 3D structural information of highly infectious virions. In addition to apolipoprotein (apo)E, HCV particles also incorporate apoB and apoA-I. In general, host apolipoproteins were more readily accessible to antibody labeling than HCV glycoproteins, suggesting either lower abundance or masking by host proteins.
As interest in Animal-Assisted Interventions (AAI) grows, there is increasing need to differentiate informal activities from formal and professionally directed therapies, including mental health ...focussed Canine-Assisted Psychotherapy (CAP). There have been no reviews focusing exclusively on CAP and the distinct developmental period of adolescence. The aims of this study were to identify the characteristics of CAP interventions, their impacts and their acceptability, tolerability and feasibility for adolescents with mental health disorders.
A systematic review identified studies incorporating canines into mental health treatments for adolescents aged 10-19 years. Studies reporting qualitative or quantitative psychological or psychosocial outcomes were included.
Seven studies were scrutinised. Intervention characteristics varied, including a range of formats, settings, locations, doses, and facilitators. Information on the role of the canines in sessions was sparse. CAP had a positive impact on primary diagnoses and symptomatology, conferring additional benefits to standard treatments for internalising disorders, post-traumatic stress disorder, and equivalent effects for anxiety, anger and externalising disorders. CAP was associated with positive impacts on secondary factors including increased engagement and socialisation behaviours, and reductions in disruptive behaviours within treatment sessions. Global functioning also improved. There was insufficient evidence that CAP improved factors associated with self-esteem, subjective wellbeing, or coping. Good attendance and retention rates indicated high levels of acceptability. Moderate to high tolerability was also indicated. Feasibility may be limited by additional training and logistical requirements.
We recommend the development of theoretically informed, standardised (manualised) intervention protocols that may subsequently form the basis of efficacy and effectiveness testing. Such protocols should clearly describe canine-participant-facilitator interactions via a formalised nomenclature; spontaneous (animal-led), adjunctive (facilitator-led), and experiential (participant-led).
There is emerging evidence to suggest that CAP improves the efficacy of mental health treatments in self-selected adolescent populations via reductions in primary symptomatology, and via secondary factors that improve therapeutic processes and quality, such as engagement and retention.
A virally encoded superfamily-2 (SF2) helicase (NS3h) is essential for the replication of hepatitis C virus, a leading cause of liver disease worldwide. Efforts to elucidate the function of NS3h and ...to develop inhibitors against it, however, have been hampered by limited understanding of its molecular mechanism. Here we show x-ray crystal structures for a set of NS3h complexes, including ground-state and transition-state ternary complexes captured with ATP mimics (ADP·BeF₃ and Formula ). These structures provide, for the first time, three conformational snapshots demonstrating the molecular basis of action for a SF2 helicase. Upon nucleotide binding, overall domain rotation along with structural transitions in motif V and the bound DNA leads to the release of one base from the substrate base-stacking row and the loss of several interactions between NS3h and the 3' DNA segment. As nucleotide hydrolysis proceeds into the transition state, stretching of a "spring" helix and another overall conformational change couples rearrangement of the (d)NTPase active site to additional hydrogen-bonding between NS3h and DNA. Together with biochemistry, these results demonstrate a "ratchet" mechanism involved in the unidirectional translocation and define the step size of NS3h as one base per nucleotide hydrolysis cycle. These findings suggest feasible strategies for developing specific inhibitors to block the action of this attractive, yet largely unexplored drug target.
Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered ...antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has devastated the global economy and claimed more than 1.7 million lives, presenting an urgent global health crisis. ...To identify host factors required for infection by SARS-CoV-2 and seasonal coronaviruses, we designed a focused high-coverage CRISPR-Cas9 library targeting 332 members of a recently published SARS-CoV-2 protein interactome. We leveraged the compact nature of this library to systematically screen SARS-CoV-2 at two physiologically relevant temperatures along with three related coronaviruses (human coronavirus 229E HCoV-229E, HCoV-NL63, and HCoV-OC43), allowing us to probe this interactome at a much higher resolution than genome-scale studies. This approach yielded several insights, including potential virus-specific differences in Rab GTPase requirements and glycosylphosphatidylinositol (GPI) anchor biosynthesis, as well as identification of multiple pan-coronavirus factors involved in cholesterol homeostasis. This coronavirus essentiality catalog could inform ongoing drug development efforts aimed at intercepting and treating coronavirus disease 2019 (COVID-19) and help prepare for future coronavirus outbreaks.
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•SARS-CoV-2 host protein interactome CRISPR screens for SARS-CoV-2 and three coronaviruses•Parallel CRISPR screens uncover unique and shared coronavirus host factors•Numbers of interacting host proteins and functional interactors are not proportional•Identified SARS-CoV-2 host factors are expressed in relevant cells in the human airway
Building upon a published SARS-CoV-2 protein interactome, Hoffmann et al. use a custom CRISPR library to determine which of these interacting host proteins are essential for infection by SARS-CoV-2 virus as well as three seasonal coronaviruses. These factors represent potential targets to combat COVID-19 and perhaps future coronavirus outbreaks.
The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening ...studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
Abstract Dopamine (DA) is a key transmitter in the basal ganglia, yet DA transmission does not conform to several aspects of the classic synaptic doctrine. Axonal DA release occurs through vesicular ...exocytosis and is action potential- and Ca2+ -dependent. However, in addition to axonal release, DA neurons in midbrain exhibit somatodendritic release by an incompletely understood, but apparently exocytotic, mechanism. Even in striatum, axonal release sites are controversial, with evidence for DA varicosities that lack postsynaptic specialization, and largely extrasynaptic DA receptors and transporters. Moreover, DA release is often assumed to reflect a global response to a population of activities in midbrain DA neurons, whether tonic or phasic, with precise timing and specificity of action governed by other basal ganglia circuits. This view has been reinforced by anatomical evidence showing dense axonal DA arbors throughout striatum, and a lattice network formed by DA axons and glutamatergic input from cortex and thalamus. Nonetheless, localized DA transients are seen in vivo using voltammetric methods with high spatial and temporal resolution. Mechanistic studies using similar methods in vitro have revealed local regulation of DA release by other transmitters and modulators, as well as by proteins known to be disrupted in Parkinson's disease and other movement disorders. Notably, the actions of most other striatal transmitters on DA release also do not conform to the synaptic doctrine, with the absence of direct synaptic contacts for glutamate, GABA, and acetylcholine (ACh) on striatal DA axons. Overall, the findings reviewed here indicate that DA signaling in the basal ganglia is sculpted by cooperation between the timing and pattern of DA input and those of local regulatory factors. This article is part of a Special Issue entitled: Function and Dysfunction of the Basal Ganglia.
The host factor and interferon (IFN)-stimulated gene (ISG) product, zinc-finger antiviral protein (ZAP), inhibits a number of diverse viruses by usurping and intersecting with multiple cellular ...pathways. To elucidate its antiviral mechanism, we perform a loss-of-function genome-wide RNAi screen to identify cellular cofactors required for ZAP antiviral activity against the prototype alphavirus, Sindbis virus (SINV). In order to exclude off-target effects, we carry out stringent confirmatory assays to verify the top hits. Important ZAP-liaising partners identified include proteins involved in membrane ion permeability, type I IFN signaling, and post-translational protein modification. The factor contributing most to the antiviral function of ZAP is TRIM25, an E3 ubiquitin and ISG15 ligase. We demonstrate here that TRIM25 interacts with ZAP through the SPRY domain, and TRIM25 mutants lacking the RING or coiled coil domain fail to stimulate ZAP's antiviral activity, suggesting that both TRIM25 ligase activity and its ability to form oligomers are critical for its cofactor function. TRIM25 increases the modification of both the short and long ZAP isoforms by K48- and K63-linked polyubiquitin, although ubiquitination of ZAP does not directly affect its antiviral activity. However, TRIM25 is critical for ZAP's ability to inhibit translation of the incoming SINV genome. Taken together, these data uncover TRIM25 as a bona fide ZAP cofactor that leads to increased ZAP modification enhancing its translational inhibition activity.
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