Blood Pressure and Penumbral Sustenance in Stroke from Large Vessel Occlusion

The global burden of stroke remains high, and of the various subtypes of stroke, large vessel occlusions (LVOs) account for the largest proportion of stroke-related death and disability. Several randomized controlled trials in 2015 changed the landscape of stroke care worldwide, with endovascular thrombectomy (ET) now the standard of care for all eligible patients. With the proven success of this therapy, there is a renewed focus on penumbral sustenance. In this review, we describe the ischemic penumbra, collateral circulation, autoregulation, and imaging assessment of the penumbra. Blood pressure goals in acute stroke remain controversial, and we review the current data and suggest an approach for induced hypertension in the acute treatment of patients with LVOs. Finally, in addition to reperfusion and enhanced perfusion, efforts focused on developing therapeutic targets that afford neuroprotection and augment neural repair will gain increasing importance. ET has revolutionized stroke care, and future emphasis will be placed on promoting penumbral sustenance, which will increase patient eligibility for this highly effective therapy and reduce overall stroke-related death and disability

Genetic determinants of gut microbiota composition and bile acid profiles in mice.

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions

Ex-vivo changes in amino acid concentrations from blood stored at room temperature or on ice: implications for arginine and taurine measurements

Background: Determination of the plasma concentrations of arginine and other amino acids is important for understanding pathophysiology, immunopathology and nutritional supplementation in human disease. Delays in processing of blood samples cause a change in amino acid concentrations, but this has not been precisely quantified. We aimed to describe the concentration time profile of twenty-two amino acids in blood from healthy volunteers, stored at room temperature or on ice.Methods: Venous blood was taken from six healthy volunteers and stored at room temperature or in an ice slurry. Plasma was separated at six time points over 24 hours and amino acid levels were determined by high-performance liquid chromatography.Results: Median plasma arginine concentrations decreased rapidly at room temperature, with a 6% decrease at 30 minutes, 25% decrease at 2 hours and 43% decrease at 24 hours. Plasma ornithine increased exponentially over the same period. Plasma arginine was stable in blood stored on ice, with a < 10% change over 24 hours. Plasma taurine increased by 100% over 24 hours, and this change was not prevented by ice. Most other amino acids increased over time at room temperature but not on ice.Conclusion: Plasma arginine concentrations in stored blood fall rapidly at room temperature, but remain stable on ice for at least 24 hours. Blood samples taken for the determination of plasma amino acid concentrations either should be placed immediately on ice or processed within 30 minutes of collection

Modulatory Role for Retinoid-related Orphan Receptor α in Allergen-induced Lung Inflammation

Rationale: Nuclear receptors play a critical role in the regulation of inflammation, thus representing attractive targets for the treatment of asthma

Genetic mapping of microbial and host traits reveals production of immunomodulatory lipids by Akkermansia muciniphila in the murine gut.

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes

Annotation of the Drosophila melanogaster euchromatic genome: a systematic review

BACKGROUND: The recent completion of the Drosophila melanogaster genomic sequence to high quality and the availability of a greatly expanded set of Drosophila cDNA sequences, aligning to 78% of the predicted euchromatic genes, afforded FlyBase the opportunity to significantly improve genomic annotations. We made the annotation process more rigorous by inspecting each gene visually, utilizing a comprehensive set of curation rules, requiring traceable evidence for each gene model, and comparing each predicted peptide to SWISS-PROT and TrEMBL sequences. RESULTS: Although the number of predicted protein-coding genes in Drosophila remains essentially unchanged, the revised annotation significantly improves gene models, resulting in structural changes to 85% of the transcripts and 45% of the predicted proteins. We annotated transposable elements and non-protein-coding RNAs as new features, and extended the annotation of untranslated (UTR) sequences and alternative transcripts to include more than 70% and 20% of genes, respectively. Finally, cDNA sequence provided evidence for dicistronic transcripts, neighboring genes with overlapping UTRs on the same DNA sequence strand, alternatively spliced genes that encode distinct, non-overlapping peptides, and numerous nested genes. CONCLUSIONS: Identification of so many unusual gene models not only suggests that some mechanisms for gene regulation are more prevalent than previously believed, but also underscores the complex challenges of eukaryotic gene prediction. At present, experimental data and human curation remain essential to generate high-quality genome annotations

Regulation of Na+/K+ ATPase Transport Velocity by RNA Editing

Editing of Na+/K+ ATPase mRNAs modulates the Na+/K+ pump's turnover rate by selectively targeting the release of the final sodium to the outside

Protocols for Endovascular Stroke Treatment Diminish the Weekend Effect Through Improvements in Off-Hours Care

Introduction: The weekend effect is a well-recognized phenomenon in which patient outcomes worsen for acute strokes presenting outside routine business hours. This is attributed to non-uniform availability of services throughout the week and evenings and, though described for intravenous thrombolysis candidates, is poorly understood for endovascular stroke care. We evaluated the impact of institutional protocols on the weekend effect, and the speed and outcome of endovascular therapy as a function of time of presentation.Method: This study assesses a prospective observational cohort of 129 consecutive patients. Patients were grouped based on the time of presentation during regular work hours (Monday through Friday, 07:00–19:00 h) vs. off-hours (overnight 19:00–07:00 h and weekends) and assessed for treatment latency and outcome.Results: Treatment latencies did not depend on the time of presentation. The door to imaging interval was comparable during regular and off-hours (median time 21 vs. 19 min, respectively, p < 0.50). Imaging to groin puncture was comparable (71 vs. 71 min, p < 1.0), as were angiographic and functional outcomes. Additionally, treatment intervals decreased with increased protocol experience; door-to-puncture interval significantly decreased from the first to the fourth quarters of the study period (115 vs. 94 min, respectively, p < 0.006), with the effect primarily seen during off-hours with a 28% reduction in median door-to-puncture times.Conclusions: Institutional protocols help diminish the weekend effect in endovascular stroke treatment. This is driven largely by improvement in off-hours performance, with protocol adherence leading to further decreases in treatment intervals over time

Dealing with femtorisks in international relations

The contemporary global community is increasingly interdependent and confronted with systemic risks posed by the actions and interactions of actors existing beneath the level of formal institutions, often operating outside effective governance structures. Frequently, these actors are human agents, such as rogue traders or aggressive financial innovators, terrorists, groups of dissidents, or unauthorized sources of sensitive or secret information about government or private sector activities. In other instances, influential .actors. take the form of climate change, communications technologies, or socioeconomic globalization. Although these individual forces may be small relative to state governments or international institutions, or may operate on long time scales, the changes they catalyze can pose significant challenges to the analysis and practice of international relations through the operation of complex feedbacks and interactions of individual agents and interconnected systems. We call these challenges "femtorisks," and emphasize their importance for two reasons. First, in isolation, they may be inconsequential and semiautonomous; but when embedded in complex adaptive systems, characterized by individual agents able to change, learn from experience, and pursue their own agendas, the strategic interaction between actors can propel systems down paths of increasing, even global, instability. Second, because their influence stems from complex interactions at interfaces of multiple systems (e.g., social, financial, political, technological, ecological, etc.), femtorisks challenge standard approaches to risk assessment, as higher-order consequences cascade across the boundaries of socially constructed complex systems. We argue that new approaches to assessing and managing systemic risk in international relations are required, inspired by principles of evolutionary theory and development of resilient ecological systems