More than two decades of intense research has provided a detailed understanding of hepatitis C virus (HCV), which chronically infects 2% of the world's population. This effort has paved the way for ...the development of antiviral compounds to spare patients from life-threatening liver disease. An exciting new era in HCV therapy dawned with the recent approval of two viral protease inhibitors, used in combination with pegylated interferon-α and ribavirin; however, this is just the beginning. Multiple classes of antivirals with distinct targets promise highly efficient combinations, and interferon-free regimens with short treatment duration and fewer side effects are the future of HCV therapy. Ongoing and future trials will determine the best antiviral combinations and whether the current seemingly rich pipeline is sufficient for successful treatment of all patients in the face of major challenges, such as HCV diversity, viral resistance, the influence of host genetics, advanced liver disease and other co-morbidities.
Wind blowing over sand on Earth produces decimeter-wavelength ripples and hundred-meter— to kilometer-wavelength dunes: bedforms of two distinct size modes. Observations from the Mars Science ...Laboratory Curiosity rover and the Mars Reconnaissance Orbiter reveal that Mars hosts a third stable wind-driven bedform, with meter-scale wavelengths. These bedforms are spatially uniform in size and typically have asymmetric profiles with angle-of-repose lee slopes and sinuous crest lines, making them unlike terrestrial wind ripples. Rather, these structures resemble fluid-drag ripples, which on Earth include water-worked current ripples, but on Mars instead form by wind because of the higher kinematic viscosity of the low-density atmosphere. A reevaluation of the wind-deposited strata in the Burns formation (about 3.7 billion years old or younger) identifies potential wind-drag ripple stratification formed under a thin atmosphere.
In this Review, we showcase the upsurge in the development and fundamental photophysical studies of more than 100 metal–organic frameworks (MOFs) as versatile stimuli-responsive platforms. The goal ...is to provide a comprehensive analysis of the field of photoresponsive MOFs while delving into the underlying photophysical properties of various classes of photochromic molecules including diarylethene, azobenzene, and spiropyran as well as naphthalenediimide and viologen derivatives integrated inside a MOF matrix as part of a framework backbone, as a ligand side group, or as a guest. In particular, the geometrical constraints, photoisomerization rates, and electronic structures of photochromic molecules integrated inside a rigid MOF scaffold are discussed. Thus, this Review reflects on the challenges and opportunities of using photoswitchable MOFs in next-generation multifunctional stimuli-responsive materials while highlighting their use in optoelectronics, erasable inks, or as the next generation of sensing devices.
To present an overview of the existing epidemiological evidence regarding the occurrence of mental health symptoms and disorders among current and former elite athletes.
Systematic review and ...meta-analysis.
Five electronic databases were searched from inception to November 2018: PubMed (MEDLINE), SportDiscus via EBSCO, PSycINFO via ProQuest, Scopus and Cochrane.
We included original quantitative studies that were written in English, were conducted exclusively among current or former elite athletes, and presented incidence or prevalence rates of symptoms of mental disorders.
Twenty-two relevant original studies about mental health symptoms and disorders among current elite athletes were included: they presented data especially on symptoms of distress, sleep disturbance, anxiety/depression and alcohol misuse. Meta-analyses comprising 2895 to 5555 current elite athletes showed that the prevalence of mental health symptoms and disorders ranged from 19% for alcohol misuse to 34% for anxiety/depression. Fifteen relevant original studies about mental health symptoms and disorders among former elite athletes were included: they similarly presented data especially about symptoms of distress, sleep disturbance, anxiety/depression and alcohol misuse. Meta-analyses comprising 1579 to 1686 former elite athletes showed that the prevalence of mental health symptoms and disorders ranged from 16% for distress to 26% for anxiety/depression.
Our meta-analyses showed that the prevalence of mental health symptoms and disorders ranged from 19% for alcohol misuse to 34% for anxiety/depression for current elite athletes, and from 16% for distress to 26% for anxiety/depression for former elite athletes.
Microtubules are dynamic polymers of αβ-tubulin that form diverse cellular structures, such as the mitotic spindle for cell division, the backbone of neurons, and axonemes. To control the ...architecture of microtubule networks, microtubule-associated proteins (MAPs) and motor proteins regulate microtubule growth, shrinkage, and the transitions between these states. Recent evidence shows that many MAPs exert their effects by selectively binding to distinct conformations of polymerized or unpolymerized αβ-tubulin. The ability of αβ-tubulin to adopt distinct conformations contributes to the intrinsic polymerization dynamics of microtubules. αβ-Tubulin conformation is a fundamental property that MAPs monitor and control to build proper microtubule networks.
The Genomic Data Storage (GDS) format provides efficient storage and retrieval of genotypes measured by microarrays and sequencing. We developed GENESIS to perform various single- and ...aggregate-variant association tests using genotype data stored in GDS format. GENESIS implements highly flexible mixed models, allowing for different link functions, multiple variance components and phenotypic heteroskedasticity. GENESIS integrates cohesively with other R/Bioconductor packages to build a complete genomic analysis workflow entirely within the R environment.
https://bioconductor.org/packages/GENESIS; vignettes included.
Supplementary data are available at Bioinformatics online.
Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) chemistries exploit small electrophilic reagents that react with 2'-hydroxyl groups to interrogate RNA structure at ...single-nucleotide resolution. Mutational profiling (MaP) identifies modified residues by using reverse transcriptase to misread a SHAPE-modified nucleotide and then counting the resulting mutations by massively parallel sequencing. The SHAPE-MaP approach measures the structure of large and transcriptome-wide systems as accurately as can be done for simple model RNAs. This protocol describes the experimental steps, implemented over 3 d, that are required to perform SHAPE probing and to construct multiplexed SHAPE-MaP libraries suitable for deep sequencing. Automated processing of MaP sequencing data is accomplished using two software packages. ShapeMapper converts raw sequencing files into mutational profiles, creates SHAPE reactivity plots and provides useful troubleshooting information. SuperFold uses these data to model RNA secondary structures, identify regions with well-defined structures and visualize probable and alternative helices, often in under 1 d. SHAPE-MaP can be used to make nucleotide-resolution biophysical measurements of individual RNA motifs, rare components of complex RNA ensembles and entire transcriptomes.
Cellular bodies such as P bodies and PML nuclear bodies (PML NBs) appear to be phase-separated liquids organized by multivalent interactions among proteins and RNA molecules. Although many components ...of various cellular bodies are known, general principles that define body composition are lacking. We modeled cellular bodies using several engineered multivalent proteins and RNA. In vitro and in cells, these scaffold molecules form phase-separated liquids that concentrate low valency client proteins. Clients partition differently depending on the ratio of scaffolds, with a sharp switch across the phase diagram diagonal. Composition can switch rapidly through changes in scaffold concentration or valency. Natural PML NBs and P bodies show analogous partitioning behavior, suggesting how their compositions could be controlled by levels of PML SUMOylation or cellular mRNA concentration, respectively. The data suggest a conceptual framework for considering the composition and control thereof of cellular bodies assembled through heterotypic multivalent interactions.
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•Cellular bodies are organized by scaffolds and recruit clients•Clients bind to free sites in the scaffolds, and binding scales with client valency•Relative scaffold stoichiometries control client recruitment in switch-like fashion•Cells can control these parameters and thus regulate cellular body composition
What are the general principles that define the composition of phase-separated cellular bodies?
mRNAs can fold into complex structures that regulate gene expression. Resolving such structures de novo has remained challenging and has limited our understanding of the prevalence and functions of ...mRNA structure. We use SHAPE-MaP experiments in living E. coli cells to derive quantitative, nucleotide-resolution structure models for 194 endogenous transcripts encompassing approximately 400 genes. Individual mRNAs have exceptionally diverse architectures, and most contain well-defined structures. Active translation destabilizes mRNA structure in cells. Nevertheless, mRNA structure remains similar between in-cell and cell-free environments, indicating broad potential for structure-mediated gene regulation. We find that the translation efficiency of endogenous genes is regulated by unfolding kinetics of structures overlapping the ribosome binding site. We discover conserved structured elements in 35% of UTRs, several of which we validate as novel protein binding motifs. RNA structure regulates every gene studied here in a meaningful way, implying that most functional structures remain to be discovered.
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•E. coli mRNAs adopt highly diverse and complex structures•Translation is the main source of mRNA structural destabilization in cells•Translation efficiency is strongly correlated with ribosome-binding-site structure•Conserved structured elements found in 35% of UTRs
High-resolution probing of hundreds of genes in living E. coli cells reveals that bacterial mRNAs fold into highly diverse and complex structures and that these structures have widespread regulatory functions.
The current ‘state of play’ in supporting elite athlete mental health and wellbeing has centred mostly on building mental health literacy or awareness of the signs of mental ill-health amongst ...athletes. Such awareness is necessary, but not sufficient to address the varied mental health needs of elite athletes. We call for a new model of intervention and outline the backbone of a comprehensive mental health framework to promote athlete mental health and wellbeing, and respond to the needs of athletes who are at-risk of developing, or already experiencing mental health symptoms or disorders. Early detection of, and intervention for, mental health symptoms is essential in the elite sporting context. Such approaches help build cultures that acknowledge that an athlete’s mental health needs are as important as their physical health needs, and that both are likely to contribute to optimising the athlete’s overall wellbeing in conjunction with performance excellence. The proposed framework aims at (i) helping athletes develop a range of self-management skills that they can utilise to manage psychological distress, (ii) equipping key stakeholders in the elite sporting environment (such as coaches, sports medicine and high-performance support staff) to better recognise and respond to concerns regarding an athlete’s mental health and (iii) highlighting the need for specialist multi-disciplinary teams or skilled mental health professionals to manage athletes with severe or complex mental disorders. Combined, these components ensure that elite athletes receive the intervention and support that they need at the right time, in the right place, with the right person.
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