Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular ...diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders, and, of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling because these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of "inhibiting the inhibitors," increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis, and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy, and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.
Heralded by Soviet propaganda as the "Path to the Future," the Baikal-Amur Mainline Railway (BAM) represented the hopes and dreams of Brezhnev and the Communist Party elite of the late Soviet era. ...Begun in 1974, and spanning approximately 2,000 miles after twenty-nine years of halting construction, the BAM project was intended to showcase the national unity, determination, skill, technology, and industrial might that Soviet socialism claimed to embody. More pragmatically, the Soviet leadership envisioned the BAM railway as a trade route to the Pacific, where markets for Soviet timber and petroleum would open up, and as an engine for the development of Siberia.
Despite these aspirations and the massive commitment of economic resources on its behalf, BAM proved to be a boondoggle-a symbol of late communism's dysfunctionality-and a cruel joke to many ordinary Soviet citizens. In reality, BAM was woefully bereft of quality materials and construction, and victimized by poor planning and an inferior workforce. Today, the railway is fully complete, but remains a symbol of the profligate spending and inefficiency that characterized the Brezhnev years.
InBrezhnev's Folly,Christopher J. Ward provides a groundbreaking social history of the BAM railway project. He examines the recruitment of hundreds of thousands of workers from the diverse republics of the USSR and other socialist countries, and his extensive archival research and interviews with numerous project workers provide an inside look at the daily life of the BAM workforce. We see firsthand the disorganization, empty promises, dire living and working conditions, environmental damage, and acts of crime, segregation, and discrimination that constituted daily life during the project's construction. Thus, perhaps, we also see the final irony of BAM: that the most lasting legacy of this misguided effort to build Soviet socialism is to shed historical light on the profound ills afflicting a society in terminal decline.
We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) to produce reactive oxygen species (ROS) in a ...process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This triggers a burst of Ca²⁺ sparks, the elementary Ca²⁺ release events in heart. Although this stretch-dependent "tuning" of RyRs increases Ca²⁺ signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca²⁺ sparks to trigger arrhythmogenic Ca²⁺ waves. In the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca²⁺ release from the SR. X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca²⁺ release in the heart and offers fresh therapeutic possibilities.
Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type 1 (HIV-1), these include widely expressed ...restriction factors, such as APOBEC3 proteins, TRIM5-α, BST2 (refs 4, 5) and SAMHD1 (refs 6, 7), as well as additional factors that are stimulated by type 1 interferon (IFN). Here we use both ectopic expression and gene-silencing experiments to define the human dynamin-like, IFN-induced myxovirus resistance 2 (MX2, also known as MXB) protein as a potent inhibitor of HIV-1 infection and as a key effector of IFN-α-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has equivalent or reduced effects on divergent simian immunodeficiency viruses, and does not inhibit other retroviruses such as murine leukaemia virus. The Capsid region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step, with both the nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed. Finally, human MX1 (also known as MXA), a closely related protein that has long been recognized as a broadly acting inhibitor of RNA and DNA viruses, including the orthomyxovirus influenza A virus, does not affect HIV-1, whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilization may represent a new therapeutic approach for the treatment of HIV/AIDS.
In preimplantation mammalian development the transcription factor Sox2 (SRY-related HMG-box gene 2) forms a complex with Oct4 and functions in maintenance of self-renewal of the pluripotent inner ...cell mass (ICM). Previously it was shown that Sox2-/- embryos die soon after implantation. However, maternal Sox2 transcripts may mask an earlier phenotype. We investigated whether Sox2 is involved in controlling cell fate decisions at an earlier stage.
We addressed the question of an earlier role for Sox2 using RNAi, which removes both maternal and embryonic Sox2 mRNA present during the preimplantation period. By depleting both maternal and embryonic Sox2 mRNA at the 2-cell stage and monitoring embryo development in vitro we show that, in the absence of Sox2, embryos arrest at the morula stage and fail to form trophectoderm (TE) or cavitate. Following knock-down of Sox2 via three different short interfering RNA (siRNA) constructs in 2-cell stage mouse embryos, we have shown that the majority of embryos (76%) arrest at the morula stage or slightly earlier and only 18.7-21% form blastocysts compared to 76.2-83% in control groups. In Sox2 siRNA-treated embryos expression of pluripotency associated markers Oct4 and Nanog remained unaffected, whereas TE associated markers Tead4, Yap, Cdx2, Eomes, Fgfr2, as well as Fgf4, were downregulated in the absence of Sox2. Apoptosis was also increased in Sox2 knock-down embryos. Rescue experiments using cell-permeant Sox2 protein resulted in increased blastocyst formation from 18.7% to 62.6% and restoration of Sox2, Oct4, Cdx2 and Yap protein levels in the rescued Sox2-siRNA blastocysts.
We conclude that the first essential function of Sox2 in the preimplantation mouse embryo is to facilitate establishment of the trophectoderm lineage. Our findings provide a novel insight into the first differentiation event within the preimplantation embryo, namely the segregation of the ICM and TE lineages.
Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus in the later phases of the infection is often predominantly macrophage-tropic and this tropism ...contributes to a chronic inflammatory and immune activation state that is observed in HIV patients. Pattern recognition receptors of the innate immune system are the key molecules that recognise HIV and mount the inflammatory responses in macrophages. The innate immune response against HIV-1 is potent and elicits caspase-1-dependent pro-inflammatory cytokine production of IL-1β and IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating this response little is known about the pattern recognition receptors that trigger the "priming" signal for inflammasome activation, the NLRs involved or the HIV components that trigger the response. Using a combination of siRNA knockdowns in monocyte derived macrophages (MDMs) of different TLRs and NLRs as well as chemical inhibition, it was demonstrated that HIV Vpu could trigger inflammasome activation via TLR4/NLRP3 leading to IL-1β/IL-18 secretion. The priming signal is triggered via TLR4, whereas the activation signal is triggered by direct effects on Kv1.3 channels, causing K+ efflux. In contrast, HIV gp41 could trigger IL-18 production via NAIP/NLRC4, independently of priming, as a one-step inflammasome activation. NAIP binds directly to the cytoplasmic tail of HIV envelope protein gp41 and represents the first non-bacterial ligand for the NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets to resolve specific inflammatory pathologies associated with HIV-1 infection in macrophages.
Abstract
Motivation
High throughput next generation sequencing (NGS) has become exceedingly cheap, facilitating studies to be undertaken containing large sample numbers. Quality control (QC) is an ...essential stage during analytic pipelines and the outputs of popular bioinformatics tools such as FastQC and Picard can provide information on individual samples. Although these tools provide considerable power when carrying out QC, large sample numbers can make inspection of all samples and identification of systemic bias a challenge.
Results
We present ngsReports, an R package designed for the management and visualization of NGS reports from within an R environment. The available methods allow direct import into R of FastQC reports along with outputs from other tools. Visualization can be carried out across many samples using default, highly customizable plots with options to perform hierarchical clustering to quickly identify outlier libraries. Moreover, these can be displayed in an interactive shiny app or HTML report for ease of analysis.
Availability and implementation
The ngsReports package is available on Bioconductor and the GUI shiny app is available at https://github.com/UofABioinformaticsHub/shinyNgsreports.
Supplementary information
Supplementary data are available at Bioinformatics online.
Urinary extracellular vesicles (uEVs) are released by cells throughout the nephron and contain biomolecules from their cells of origin. Although uEV-associated proteins and RNA have been studied in ...detail, little information exists regarding uEV glycosylation characteristics. Surface glycosylation profiling by flow cytometry and lectin microarray was applied to uEVs enriched from urine of healthy adults by ultracentrifugation and centrifugal filtration. The carbohydrate specificity of lectin microarray profiles was confirmed by competitive sugar inhibition and carbohydrate-specific enzyme hydrolysis. Glycosylation profiles of uEVs and purified Tamm Horsfall protein were compared. In both flow cytometry and lectin microarray assays, uEVs demonstrated surface binding, at low to moderate intensities, of a broad range of lectins whether prepared by ultracentrifugation or centrifugal filtration. In general, ultracentrifugation-prepared uEVs demonstrated higher lectin binding intensities than centrifugal filtration-prepared uEVs consistent with lesser amounts of co-purified non-vesicular proteins. The surface glycosylation profiles of uEVs showed little inter-individual variation and were distinct from those of Tamm Horsfall protein, which bound a limited number of lectins. In a pilot study, lectin microarray was used to compare uEVs from individuals with autosomal dominant polycystic kidney disease to those of age-matched controls. The lectin microarray profiles of polycystic kidney disease and healthy uEVs showed differences in binding intensity of 6/43 lectins. Our results reveal a complex surface glycosylation profile of uEVs that is accessible to lectin-based analysis following multiple uEV enrichment techniques, is distinct from co-purified Tamm Horsfall protein and may demonstrate disease-specific modifications.
Situating Motivation Nolen, Susan Bobbitt; Horn, Ilana Seidel; Ward, Christopher J.
Educational psychologist,
07/2015, Volume:
50, Issue:
3
Journal Article
Peer reviewed
This article describes a situative approach to studying motivation to learn in social contexts. We begin by contrasting this perspective to more prevalent psychological approaches to the study of ...motivation, describing epistemological and methodological differences that have constrained conversation between theoretical groups. We elaborate on issues of the unit of analysis, the conceptualization of contexts, and the role of identity as a central construct. Finally, we argue that the design of learning environments and interventions to change learning environments are informed by attention to the relationships among meanings, identities, and motives in context. We illustrate our argument with examples of design-based research and design-based implementation research focused on motivation to learn in children and adults.
Marine microbes exhibit seasonal cycles in community composition, yet the key drivers of these patterns and microbial population fidelity to specific environmental conditions remain to be determined. ...To begin addressing these questions, we characterized microbial dynamics weekly for 3 years at a temperate, coastal site with dramatic environmental seasonality. This high-resolution time series reveals that changes in microbial community composition are not continuous; over the duration of the time series, the community instead resolves into distinct summer and winter profiles with rapid spring and fall transitions between these states. Here, we show that these community shifts involve switching between closely related strains that exhibit either summer or winter preferences. Moreover, taxa repeat this process annually in both this and another temperate coastal time series, suggesting that this phenomenon may be widespread in marine ecosystems. To address potential biogeochemical impacts of these community changes, PICRUSt-based metagenomes predict seasonality in transporters, photosynthetic proteins, peptidases and carbohydrate metabolic pathways in spite of closely related summer- and winter-associated taxa. Thus, even small temperature shifts, such as those predicted by climate change models, could affect both the structure and function of marine ecosystems.
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