Microtubules are dynamic polymers of αβ-tubulin that are essential for intracellular organization, organelle trafficking and chromosome segregation. Microtubule growth and shrinkage occur via ...addition and loss of αβ-tubulin subunits, which are biochemical processes. Dynamic microtubules can also engage in mechanical processes, such as exerting forces by pushing or pulling against a load. Recent advances at the intersection of biochemistry and mechanics have revealed the existence of multiple conformations of αβ-tubulin subunits and their central role in dictating the mechanisms of microtubule dynamics and force generation. It has become apparent that microtubule-associated proteins (MAPs) selectively target specific tubulin conformations to regulate microtubule dynamics, and mechanical forces can also influence microtubule dynamics by altering the balance of tubulin conformations. Importantly, the conformational states of tubulin dimers are likely to be coupled throughout the lattice: the conformation of one dimer can influence the conformation of its nearest neighbours, and this effect can propagate over longer distances. This coupling provides a long-range mechanism by which MAPs and forces can modulate microtubule growth and shrinkage. These findings provide evidence that the interplay between biochemistry and mechanics is essential for the cellular functions of microtubules.
Variational studies of the t-J model on the square lattice based on infinite projected-entangled pair states confirm an extremely close competition between a uniform d-wave superconducting state and ...different stripe states. The site-centered stripe with an in-phase d-wave order has an equal or only slightly lower energy than the stripe with antiphase d-wave order. The optimal stripe filling is not constant but increases with J/t. A nematic anisotropy reduces the pairing amplitude and the energies of stripe phases are lowered relative to the uniform state with increasing nematicity.
Interferon-stimulated gene (ISG) products take on a number of diverse roles. Collectively, they are highly effective at resisting and controlling pathogens. In this review, we begin by introducing ...interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production. Next, we describe ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the JAK-STAT pathway. Several ISGs that directly inhibit virus infection are described with an emphasis on those that impact early and late stages of the virus life cycle. Finally, we describe ongoing efforts to identify and characterize antiviral ISGs, and we provide a forward-looking perspective on the ISG landscape.
Hepatitis C virus, a major human pathogen, produces infectious virus particles with several unique features, such as an ability to interact with serum lipoproteins, a dizzyingly complicated process ...of virus entry, and a pathway of virus assembly and release that is closely linked to lipoprotein secretion. Here, we review these unique features, with an emphasis on recent discoveries concerning virus particle structure, virus entry and virus particle assembly and release.
Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be ...fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5′-ε region of HBV pregenomic RNA. In addition, RIG-I could also counteract the interaction of HBV polymerase (P protein) with the 5′-ε region in an RNA-binding dependent manner, which consistently suppressed viral replication. Liposome-mediated delivery and vector-based expression of this ε region-derived RNA in liver abolished the HBV replication in human hepatocyte-chimeric mice. These findings identify an innate-recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes.
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•Type III IFNs are predominantly induced in human hepatocytes during HBV infection•RIG-I senses the HBV genotype A, B, and C for the induction of type III IFNs•The 5′-ε region of HBV pgRNA is a key element for the RIG-I-mediated recognition•RIG-I counteracts the interaction of HBV P with pgRNA to suppress viral replication
The sensing mechanism of hepatitis B virus (HBV) and the subsequent signaling events remain to be fully clarified. Sato and colleagues demonstrate that the RNA sensor RIG-I not only senses HBV pregenomic RNA to preferentially induce type III interferon production but also counteracts the interaction of viral polymerase with the pregenomic RNA for antiviral defense against HBV.
Background
The physical impacts of elite sport participation have been well documented; however, there is comparatively less research on the mental health and psychological wellbeing of elite ...athletes.
Objective
This review appraises the evidence base regarding the mental health and wellbeing of elite-level athletes, including the incidence and/or nature of mental ill-health and substance use.
Methods
A systematic search of the PubMed, EMBASE, SPORTDiscus, PsycINFO, Cochrane and Google Scholar databases, up to and including May 2015, was conducted.
Results
The search yielded a total of 2279 records. Following double screening, 60 studies were included. The findings suggested that elite athletes experience a broadly comparable risk of high-prevalence mental disorders (i.e. anxiety, depression) relative to the general population. Evidence regarding other mental health domains (i.e. eating disorders, substance use, stress and coping) is less consistent. These results are prefaced, however, by the outcome of the quality assessment of the included studies, which demonstrated that relatively few studies (25 %) were well reported or methodologically rigorous. Furthermore, there is a lack of intervention-based research on this topic.
Conclusion
The evidence base regarding the mental health and wellbeing of elite athletes is limited by a paucity of high-quality, systematic studies. Nonetheless, the research demonstrates that this population is vulnerable to a range of mental health problems (including substance misuse), which may be related to both sporting factors (e.g. injury, overtraining and burnout) and non-sporting factors. More high-quality epidemiological and intervention studies are needed to inform optimal strategies to identify and respond to player mental health needs.
Human copy number variants (CNVs) account for genome variation an order of magnitude larger than single-nucleotide polymorphisms. Although much of this variation has no phenotypic consequences, some ...variants have been associated with disease, in particular neurodevelopmental disorders. Pathogenic CNVs are typically very large and contain multiple genes, and understanding the cause of the pathogenicity remains a major challenge. Here we show that pathogenic CNVs are significantly enriched for genes involved in development and genes that have greater evolutionary copy number conservation across mammals, indicative of functional constraints. Conversely, genes found in benign CNV regions have more variable copy number. These evolutionary constraints are characteristic of genes in pathogenic CNVs and can only be explained by dosage sensitivity of those genes. These results implicate dosage sensitivity of individual genes as a common cause of CNV pathogenicity. These evolutionary metrics suggest a path to identifying disease genes in pathogenic CNVs.
The 'tubulin-code' hypothesis proposes that different tubulin genes or post-translational modifications (PTMs), which mainly confer variation in the carboxy-terminal tail (CTT), result in unique ...interactions with microtubule-associated proteins for specific cellular functions. However, the inability to isolate distinct and homogeneous tubulin species has hindered biochemical testing of this hypothesis. Here, we have engineered 25 α/β-tubulin heterodimers with distinct CTTs and PTMs and tested their interactions with four different molecular motors using single-molecule assays. Our results show that tubulin isotypes and PTMs can govern motor velocity, processivity and microtubule depolymerization rates, with substantial changes conferred by even single amino acid variation. Revealing the importance and specificity of PTMs, we show that kinesin-1 motility on neuronal β-tubulin (TUBB3) is increased by polyglutamylation and that robust kinesin-2 motility requires detyrosination of α-tubulin. Our results also show that different molecular motors recognize distinctive tubulin 'signatures', which supports the premise of the tubulin-code hypothesis.
The landforms of northern Gale crater on Mars expose thick sequences of sedimentary rocks. Based on images obtained by the Curiosity rover, we interpret these outcrops as evidence for past fluvial, ...deltaic, and lacustrine environments. Degradation of the crater wall and rim probably supplied these sediments, which advanced inward from the wall, infilling both the crater and an internal lake basin to a thickness of at least 75 meters. This intracrater lake system probably existed intermittently for thousands to millions of years, implying a relatively wet climate that supplied moisture to the crater rim and transported sediment via streams into the lake basin. The deposits in Gale crater were then exhumed, probably by wind-driven erosion, creating Aeolis Mons (Mount Sharp).
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