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MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.

Although curricula teaching skills related to resilience are widely adopted, little is known about needs and attitudes regarding resilience training of undergraduate-medical-trainees in Middle-East-and-North-Africa-region. The purpose of this study is to investigate the value of an innovative curriculum developed through design-based-research to build resilience-skills among undergraduate-medical-trainees in the United-Arab-Emirates. Convergent-mixed-methods-study-design was utilized. Quantitative data collection was through controlled random group allocation conducted in one cohort of undergraduate medical students(n = 47). Students were randomly allocated into the respective resilience-skills-building-course(study-group) versus an unrelated curriculum(control-group). All students were tested at baseline(test-1), at end of 8-week course(test-2), and again 8 weeks after end of course(test-3). Then students crossed over to the opposite course and again tested at end of 8 weeks(test-4). Testing at four timepoints consisted of questionnaires related to burnout-Maslach-Burnout-Inventory; anxiety-General-Anxiety-Disorder-7; and resilience- Connor-Davidson-Resilience-Scale. Quantitative data were analysed descriptively and inferentially. Qualitative data, constituting of students' perception of their experience with the course, was captured using virtual-focus-group-sessions. Qualitative analysis was inductive. Generated primary inferences were merged using joint-display-analysis. Significant proportion of the students, at baseline, seemed to be at risk for burnout and anxiety, and would benefit from developing their resilience. There appeared to be no statistical differences in measures of burnout, anxiety, and resilience related to course delivery. Overall risk for anxiety among students increased following the COVID-19 lockdown. Qualitative analysis generated the 'Resilience-Skills'-Building-around-Undergraduate-Medical-Education-Transitions' conceptual model of five themes: Transitions, Adaptation, Added Value of course, Sustainability of effects of course, and Opportunities for improving course. Merging of findings led to a thorough understanding of how the resilience-skills'-building-course affected students' adaptability. This study indicates that a resilience-skills'-building-course may not instantly affect medical trainees' ratings of burnout, anxiety, and resilience. However, students likely engage with such an innovative course and its content to acquire and deploy skills to adapt to changes.

Medicine is one of the most demanding academic fields with an extensive curriculum that entails plenty of potential stressors. There is sufficient evidence that medical students are more prone to psychological distress when compared to their peer group of other disciplines. Despite the established need to prioritize resilience skills building within the medical curriculum, very few medical programmes in the Middle East and North Africa region (MENA) proactively empower the students to help themselves in sustaining their mental health. The purpose of the current study is to explore the perception of medical students in Dubai, United Arab Emirates (UAE) regarding their understanding of, and personal experience with building resilience, and their engagement with the content of an innovative curriculum-based resilience skills building course, designed in alignment with the constructivism theory of education. The current study utilized a qualitative phenomenological research design. The curriculum-based resilience skills building course, that was investigated as part of this study, is offered at a medical school in Dubai, UAE. A total of 37 students submitted reflective essays about resilience building, in general, and the respective course, in specific. The collected data was inductively analysed following a six-step framework. The qualitative analysis generated three interlinked themes, namely: Awareness, Application, and Appraisal. This study showed that integrating a resilience skills building course into medical curricula is likely to be positively appraised by the students, where it raises their level of awareness and likelihood of proactively applying the learned concepts in their daily lives. This is especially true when the course is anchored in constructivism experiential learning theory and designed to foster self-directed learning.

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. This study demonstrates the activation of a STAT3-independent healing pathway in response to mucosal injury which involves the co-receptor for IL-6 cytokines gp130 and downstream effectors Src, Yes, YAP and Notch. Beneficial effects of inflammation As well as activating innate and adaptive immunity, inflammation triggers tissue repair and regeneration through mechanisms that are largely unknown. This study demonstrates the activation of a STAT3-independent healing pathway in a mouse model of experimental colitis through a process involving gp130 (a co-receptor for interleukin-6 family cytokines) and the downstream effectors Src, Yes, YAP and Notch.

Chronic liver disease is rising in western countries and liver cirrhosis is the 12th leading cause of death worldwide. Simultaneously, use of gastric acid suppressive medications is increasing. Here, we show that proton pump inhibitors promote progression of alcoholic liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis in mice by increasing numbers of intestinal Enterococcus spp. Translocating enterococci lead to hepatic inflammation and hepatocyte death. Expansion of intestinal Enterococcus faecalis is sufficient to exacerbate ethanol-induced liver disease in mice. Proton pump inhibitor use increases the risk of developing alcoholic liver disease among alcohol-dependent patients. Reduction of gastric acid secretion therefore appears to promote overgrowth of intestinal Enterococcus , which promotes liver disease, based on data from mouse models and humans. Recent increases in the use of gastric acid-suppressive medications might contribute to the increasing incidence of chronic liver disease. Proton pump inhibitors (PPIs) reduce gastric acid secretion and modulate gut microbiota composition. Here Llorente et al . show that PPIs induce bacterial overgrowth of enterococci, which, in turn, exacerbate ethanol-induced liver disease both in mice and humans.

Ocean microbes contribute to biogeochemical cycles and ecosystem function, but they do so under top-down pressure imposed by viruses. While viruses are increasingly understood spatially and beginning to be incorporated into predictive modeling, high-frequency ocean virus dynamics remain understudied due to methodological challenges. Here we sampled stratified Bermuda Atlantic Time Series (BATS) waters for 112 hours at sub-daily 4- (surface) or 12- (deep chlorophyll maximum) hour intervals, purified viral particles from these samples, sequenced their metagenomes, and used the resulting data to characterize high-frequency virus community dynamics. Aggregated community diversity metrics changed with depth, but were not statistically significant temporally at a fixed location. However, finer-scale population-level analyses revealed both depth and temporal change, including physicochemical depth-driven differences and, in surface waters, thousands of viral populations that exhibited statistically significant diel rhythms. Statistical analyses revealed three main archetypes of temporal dynamics that themselves differed in abundance patterns, host predictions, viral taxonomy, and gene functions. Among these, highlights include viruses resembling an archetype with a night peaking pattern in activity that include an over-representation of viruses that putatively infect Prochlorococcus , a phototrophic cyanobacteria. Together, these efforts provide baseline community- and population-scale short-time-frame observations relevant to future climate state modeling.

Mild traumatic brain injury (mTBI) is a significant health burden among military service members. Although mTBI was once considered relatively benign compared to more severe TBIs, a growing body of evidence has demonstrated the devastating neurological consequences of mTBI, including chronic post-concussion symptoms and deficits in cognition, memory, sleep, vision, and hearing. The discovery of reliable biomarkers for mTBI has been challenging due to under-reporting and heterogeneity of military-related mTBI, unpredictability of pathological changes, and delay of post-injury clinical evaluations. Moreover, compared to more severe TBI, mTBI is especially difficult to diagnose due to the lack of overt clinical neuroimaging findings. Yet, advanced neuroimaging techniques using magnetic resonance imaging (MRI) hold promise in detecting microstructural aberrations following mTBI. Using different pulse sequences, MRI enables the evaluation of different tissue characteristics without risks associated with ionizing radiation inherent to other imaging modalities, such as X-ray-based studies or computerized tomography (CT). Accordingly, considering the high morbidity of mTBI in military populations, debilitating post-injury symptoms, and lack of robust neuroimaging biomarkers, this review (1) summarizes the nature and mechanisms of mTBI in military settings, (2) describes clinical characteristics of military-related mTBI and associated comorbidities, such as post-traumatic stress disorder (PTSD), (3) highlights advanced neuroimaging techniques used to study mTBI and the molecular mechanisms that can be inferred, and (4) discusses emerging frontiers in advanced neuroimaging for mTBI. We encourage multi-modal approaches combining neuropsychiatric, blood-based, and genetic data as well as the discovery and employment of new imaging techniques with big data analytics that enable accurate detection of post-injury pathologic aberrations related to tissue microstructure, glymphatic function, and neurodegeneration. Ultimately, this review provides a foundational overview of military-related mTBI and advanced neuroimaging techniques that merit further study for mTBI diagnosis, prognosis, and treatment monitoring.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.