Search

Preterm birth is a major challenge in pregnancy worldwide. Prematurity is the leading cause of death in infants and may result in severe complications. Nearly half of preterm births are spontaneous, but do not have recognizable causes. This study investigated whether the maternal gut microbiome and associated functional pathways might play a key role in spontaneous preterm birth (sPTB). Two hundred eleven women carrying singleton pregnancies were enrolled in this mother-child cohort study. Fecal samples were freshly collected at 24–28 weeks of gestation before delivery, and the 16S ribosomal RNA gene was sequenced. Microbial diversity and composition, core microbiome, and associated functional pathways were then statistically analyzed. Demographic characteristics were collected using records from the Medical Birth Registry and questionnaires. The result showed that the gut microbiome of mothers with over-weight (BMI ≥ 24) before pregnancy have lower alpha diversity than those with normal BMI before pregnancy. A higher abundance of Actinomyces spp. was filtered out from the Linear discriminant analysis (LDA) effect size (LEfSe), Spearman correlation, and random forest model, and was inversely correlated with gestational age in sPTB. The multivariate regression model showed that the odds ratio of premature delivery was 3.274 [95% confidence interval (CI): 1.349; p = 0.010] in the group with over-weight before pregnancy with a cutoff Hit% > 0.022 for Actinomyces spp. The enrichment of Actinomyces spp. was negatively correlated with glycan biosynthesis and metabolism in sPTB by prediction from the Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) platform. Maternal gut microbiota showing a lower alpha diversity, increased abundance of Actinomyces spp., and dysregulated glycan metabolism may be associated with sPTB risk.

Recent research using Eye Movement analysis with Hidden Markov Models (EMHMM) has reported that in face recognition, participants who look more at the eyes in addition to the face center (the analytic pattern) have better recognition performance than those looking mainly at the face center (the holistic pattern). Here we examined the mechanisms underlying the advantage of the analytic pattern through an Event-Related Potential (ERP) examination with simultaneous recording of EEG and eye movement. Using EMHMM, we identified nose-focused and eyes-focused eye movement patterns from participants. As compared with participants using nose-focused patterns, those with eyes-focused patterns showed increased N170 amplitude, reduced P2 amplitude, increased N250 amplitude, and prolonged P300 latency, suggesting that they may have engaged more in local face processing, perceived faces as less typical, developed richer perceptual memory representations, and engaged more in stimulus evaluation processes. Importantly, optimal face recognition performance was associated with a mixture of nose- and eyes-focused eye movement patterns and an intermediate level of P300 latency. Also, among all behavioral and ERP measures, eye movement pattern uniquely predicted participants’ recognition performance. Further regression analysis showed that eye movement pattern could be predicted by a combination of Tower of London task performance and ERP P2 amplitude. These results suggest that the optimal face recognition performance involves a balance between global and local face processing, and eye movement pattern is a multifaceted measure that reflects individual differences in both executive function and quality of perceptual representation, making it a unique predictor for recognition performance.

Background Catecholamine-storm is considered the major cause of enterovirus 71-associated cardiopulmonary death. To elucidate the effect of milrinone on cardiac mitochondria and death, a rat model of catecholamine-induced heart failure was investigated. Methods Young male Spray-Dawley rats received a continuous intravenous infusion of norepinephrine then followed by co-treatment with and without milrinone or esmolol. Vital signs were monitored and echocardiography was performed at indicated time points. At the end of experiments, hearts were extracted to study mitochondrial function, biogenesis, and DNA copy numbers. Results Hypernorepinephrinemia induced persistent tachycardia, hypertension, and high mortality and significantly impaired the activities of the electron transport chain and suppressed mitochondrial DNA copy number, mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator 1-α. Norepinephrine-induced hypertension could be significantly suppressed by milrinone and esmolol. Milrinone improved but esmolol deteriorated the survival rate. The left ventricle was significantly enlarged shortly after norepinephrine infusion but later gradually reduced in size by milrinone. The impairment and suppression of mitochondrial function could be significantly reversed by milrinone but not by esmolol. Conclusions Milrinone may protect the heart via maintaining mitochondrial function from hypernorepinephrinemia. This study warrants the importance of milrinone and the preservation of mitochondrial function in the treatment of catecholamine-induced death. Impact Milrinone may protect the heart from hypernorepinephrinemia-induced death via maintaining myocardial mitochondrial activity, function, and copy number.Maintenance of cardiac mitochondrial function may be a potential therapeutic strategy in such catecholamine-induced heart failure.

Funding Acknowledgements Type of funding sources: None. Background Hyperkalemia is a common complication and increases the risk of cardiac arrhythmias and mortality in patients with type 2 diabetes (T2DM), especially in those with diabetic nephropathy. We investigated the risk of hyperkalemia in patients initiated on SGLT2 inhibitors versus DPP-4 inhibitors among patients with T2DM. Methods This study included patients with T2DM who initiated on SGLT2 inhibitors or DPP-4 inhibitors between January 01, 2015 and December 31, 2019 from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System [CDARS]). A multivariable cox proportional hazards analysis, adjusting for key confounders, was used to compare the risk of central laboratory-determined hyperkalemia (serum potassium ≥6.0mmol/L) and hypokalemia (serum potassium Results 10193 new users of SGLT2 inhibitors were matched to 17305 new users of DPP-4 inhibitors. During the 2-year follow-up, there were 104 hyperkalemia events (incident rate [IR] = 5.17 per 1000 person-years) among SGLT2 inhibitors and 306 events (IR = 9.09 per 1000 person-years) among DPP-4 inhibitors, of which SGLT2 inhibitors were associated with a lower risk of incident hyperkalemia (Adjusted HR: 0.66 [95%CI 0.53-0.83], p Conclusion SGLT2 inhibitors reduced incident hyperkalemia, but without increasing incident hypokalemia compared to DPP-4 inhibitors.

Funding Acknowledgements Type of funding sources: None. Background/Introduction The landscape of aortic valve replacement (AVR) has evolved dramatically over the years, but long-term outcomes have yet to be comprehensively explored. Purpose To compare long-term mortality among three AVR techniques: transcatheter (TAVI), minimally invasive (MIAVR), and conventional surgical AVR (CAVR). Methods An electronic literature search was performed for randomized controlled trials (RCTs) comparing TAVI to CAVR, and RCTs or propensity score-matched (PSM) studies comparing MIAVR to CAVR or MIAVR to TAVI. Individual patient data for all-cause mortality was derived from graphical reconstruction of digitized Kaplan-Meier curves. Pairwise comparisons followed by network meta-analysis were conducted. Sensitivity analyses were performed in the TAVI arm for high risk and low/intermediate risk as well as transfemoral (TF-TAVI) patients. Results A total of 27 studies involving 16,554 patients were included. In the pairwise comparison of TAVI versus CAVR, TAVI showed superior mortality to CAVR until 39.5 months, beyond which there was no significant difference in longer term mortality. When restricted to TF-TAVI versus CAVR, consistent mortality benefit favoring TAVI was seen (shared-frailty hazard ratio [HR]=1.17, 95%CI=1.03-1.33, p=0.016). In the network meta-analysis involving majority PSM data, MIAVR was associated with significantly lower mortality than TAVI (HR=0.69, 95%CI=0.59-0.82) and CAVR (HR=0.68, 95%CI=0.58-0.80); this significant association was not seen when compared to TF-TAVI patients. Conclusions An initial short-medium term mortality benefit for TAVI over CAVR was noted but this benefit was attenuated over the longer term. In the subset of TF-TAVI patients, this long-term mortality benefit persisted, suggesting that non-TF techniques are associated with higher mortality. Amongst majority PSM data, MIAVR showed improved mortality compared to TAVI and CAVR but this was not seen in the TF-TAVI subset. This suggests that MIAVR may have a role in treating patients who are ineligible for TF-TAVI in experienced centers, and future RCTs are needed to conclusively validate this.

Vesicoureteral reflux grading from voiding cystourethrograms is highly subjective with low reliability. We aimed to demonstrate improved reliability for vesicoureteral reflux grading with simple and machine learning approaches using ureteral tortuosity and dilatation on voiding cystourethrograms.Voiding cystourethrograms were collected from our institution for training and 5 external data sets for validation. Each voiding cystourethrogram was graded by 5-7 raters to determine a consensus vesicoureteral reflux grade label and inter- and intra-rater reliability was assessed. Each voiding cystourethrogram was assessed for 4 features: ureteral tortuosity, proximal, distal, and maximum ureteral dilatation. The labels were then assigned to the combination of the 4 features. A machine learning-based model, qVUR, was trained to predict vesicoureteral reflux grade from these features and model performance was assessed by AUROC (area under the receiver-operator-characteristic).A total of 1,492 kidneys and ureters were collected from voiding cystourethrograms resulting in a total of 8,230 independent gradings. The internal inter-rater reliability for vesicoureteral reflux grading was 0.44 with a median percent agreement of 0.71 and low intra-rater reliability. Higher values for each feature were associated with higher vesicoureteral reflux grade. qVUR performed with an accuracy of 0.62 (AUROC=0.84) with stable performance across all external data sets. The model improved vesicoureteral reflux grade reliability by 3.6-fold compared to traditional grading (In a large pediatric population from multiple institutions, we show that machine learning-based assessment for vesicoureteral reflux improves reliability compared to current grading methods. qVUR is generalizable and robust with similar accuracy to clinicians but the added prognostic value of quantitative measures warrants further study.

Background Despite numerous promising trials, catheter ablation is still regarded as a second-line alternative to antiarrhythmic drugs (AAD) in the treatment of paroxysmal atrial fibrillation (PAF). There remains a role for a broad comparison of the effectiveness of various ablation therapies against each other, and versus AAD. Purpose To conduct a systematic review and network meta-analysis of ablation therapies and AAD in the treatment of PAF. Ablation therapies were hypothesized to be superior to AAD in preventing atrial fibrillation (AF) recurrence. Methods An electronic literature search was conducted to retrieve randomized controlled trials or propensity score-matched studies comparing freedom from AF recurrence among any combination of ablation modalities or AAD. Kaplan-Meier curves and risk tables for this outcome were graphically reconstructed to extract individual patient data (IPD). A Frequentist network meta-analysis (NMA) was performed using the derived hazard ratios (HRs) of each study to compare various ablation therapies and AAD. Two separate NMAs were also conducted with restricted mean survival time (RMST) analysis, using RMST absolute differences and ratios, in light of violation of the proportional-hazards assumption. Treatment strategies were ranked using P-scores. Pairwise comparisons were also performed between treatment pairs with three or more studies reporting direct comparisons. Results Across 24 studies comparing six ablation therapies, comprising 5274 patients, Frequentist NMA-derived HRs of AF recurrence compared to AAD were 0.35 (95% CI: 0.26–0.48) for cryoballoon ablation (CBA), 0.33 (95% CI: 0.25–0.45) for radiofrequency ablation (RFA), 0.21 (95% CI: 0.09–0.49) for combined CBA and RFA, 0.20 (95% CI: 0.11–0.39) for hot-balloon ablation (HBA), 0.44 (95% CI: 0.16–1.22) for laser-balloon ablation, and 0.33 (95% CI: 0.19–0.56) for pulmonary vein ablation catheter. RMST-based NMAs similarly showed a significant benefit of all ablation therapies over AAD in preventing AF recurrence. Although none of the HRs between pairs of ablation modalities were significant, P-scores for HBA and combined CBA and RFA were consistently higher than those of other treatments. Independent pairwise comparisons of RFA and CBA versus AAD were greatly in favor of ablation (shared-frailty HR=0.24, 95% CI: 0.19–0.31, p Conclusions To our knowledge, this is the first network meta-analysis comparing a wide range of ablation therapies to AAD, synthesizing IPD from high-quality studies in three separate NMA models. The advantage of ablation therapies over AAD in preventing AF recurrence was consistently found across all three models. This strongly suggests that ablation should replace AAD as the first-line treatment for PAF in patients who are fit for the procedure. Moreover, the promising results of HBA underscore the need for more high-quality trials to be conducted. Funding Acknowledgement Type of funding sources: None.

The structure of bi­cyclo­[3.3.0]octane-endo-3,endo-7-diol and bi­cyclo­[3.3.0]octane-endo-3,exo-7-diol, C8H14O2 form 2:1 co-crystals in the monoclinic P21/n space group rather than undergoing separation by means of fractional recrystallization or column chromatography., Reduction of bi­cyclo­[3.3.0]octane-3,7-dione yields a mixture of the endo-3,endo-7-diol and endo-3, exo-7-diol (C8H14O2) isomers (5 and 6). These form (5)2·(6) co-crystals in the monoclinic P21/n space group (with Z = 6, Z′ = 1.5) rather than undergoing separation by means of fractional recrystallization or column chromatography. The mol­ecule of 5 occupies a general position, whereas the mol­ecule of 6 is disordered over two orientations across a centre of symmetry with occupancies of 0.463 (2) and 0.037 (2). Individual diol hy­droxy groups associate around a pseudo-threefold screw axis by means of hydrogen bonding. The second hy­droxy group of each diol behaves in a similar manner, generating a three-dimensional hydrogen-bonded network structure. This hydrogen-bond connectivity is identical to that present in three known helical tubuland diol–hydro­quinone co-crystals, and the new crystal structure is even more similar to two homologous aliphatic diol co-crystals.

Collective phenomena in solids can be sensitive to the dimensionality of the system; a case of special interest is VSe2, which shows a (r7 x r3) charge density wave (CDW) in the single layer with the three-fold symmetry in the normal phase spontaneously broken, in contrast to the (4 x 4) in-plane CDW in the bulk. Angle-resolved photoemission spectroscopy (ARPES) from VSe2 ranging from a single layer to the bulk reveals the evolution of the electronic structure including the Fermi surface contours and the CDW gap. At a thickness of two layers, the ARPES maps are already nearly bulklike, but the transition temperature TC for the (4 x 4) CDW is much higher than the bulk value of 110 K. These results can be understood as a result of dimensional crossover of phonon instability driven by a competition of nesting vectors. Our study provides key insights into the CDW mechanisms and offers a perspective in the search and control of emergent phases in quantum materials.

Maternal nutrition has a key role in the developmental programming of adult disease. Excessive maternal fructose intake contributes to offspring hypertension. Newly discovered evidence supports the idea that early-life gut microbiota are connected to hypertension later in life. Short-chain fatty acids (SCFAs), butyrate, and propionate are microbiota-derived metabolites, also known as postbiotics. The present study aimed to determine whether maternal butyrate or propionate supplementation can protect offspring from hypertension using a maternal high-fructose (HF) diet rat model. Female Sprague Dawley rats were allocated during pregnancy and lactation to (1) regular chow (ND); (2) 60% high-fructose diet (HF); (3) HF diet plus butyrate (HFB, 400 mg/kg/day); and (4) HF diet plus propionate (HFP, 200 mmol/L). Male offspring were sacrificed at 12 weeks of age. The maternal HF diet impaired the offspring’s BP, which was prevented by perinatal butyrate or propionate supplementation. Both butyrate and propionate treatments similarly increased plasma concentrations of propionic acid, isobutyric acid, and valeric acid in adult offspring. Butyrate supplementation had a more profound impact on trimethylamine N-oxide metabolism and nitric oxide parameters. Whilst propionate treatment mainly influenced gut microbiota composition, it directly altered the abundance of genera Anaerovorax, Lactobacillus, Macellibacteroides, and Rothia. Our results shed new light on targeting gut microbiota through the use of postbiotics to prevent maternal HF intake-primed hypertension, a finding worthy of clinical translation.

Adolescent idiopathic scoliosis (AIS) disrupts spinal alignment and increases the intrinsic demand for active stabilization to maintain postural stability. Understanding the paraspinal muscle fatigability and its effects on spinal alignment and kinematics informs the importance of paraspinal muscle endurance for postural stability. This study aims to investigate the effects of fatigue of thoracic erector spinae on the spinal muscle activity and spinal kinematics in individuals with scoliosis. Spinal muscle activity, posture and mobility measured by electromyography and surface tomography were compared between 15 participants with scoliosis and 15 age- and gender-matched healthy controls during unilateral shoulder flexion and abduction with and without holding a 2-kg weight and performed before and after a fatigue task (prone isometric chest raise). No between-groups difference was found for the spinal extensor endurance. Erector spinae activity at the convex side of AIS group was significantly higher than that at their concave side and than that of healthy controls during shoulder elevations, regardless of the fatigue status. Significant decreases in translational and rotational mobility were found at convex side of AIS group during weighted abduction tasks after fatigue. In contrast, a significant increase in rotational mobility was demonstrated at convex side of AIS participants during weighted flexion tasks after fatigue. Our results revealed a comparable level of spinal extensor endurance between individuals with or without AIS. The increase in muscle activation post-fatigue provides no additional active postural stability but may increase the risk of back pain over the convex side in individuals with scoliosis. Findings highlight imbalances in muscles and the potential implications in optimising neuromuscular activation and endurance capacity in the rehabilitation for AIS patients. Future research is needed to investigate if endurance training of the convex-sided back extensors could optimize the impaired neuromuscular control in the AIS patients.

With their ultrafast water transport and excellent molecule sieving properties, graphene oxide (GO)-based membranes show great potential in the membrane filtration field for water purification and molecular separation. However, the inability of uniform GO membranes to be produced on an industrial scale and their nonenvironmentally friendly reduction treatment are the bottleneck preventing their industrial applications. Herein, we report a scalable ultrathin uniform GO membrane fabrication technique. Ultrathin GO membranes with a large area of 30 × 80 cm2 and a thickness of a few nanometers were uniformly and facilely fabricated using a continuous process combining Mayer rod-coating and a short-time, high-power UV reduction. The interlayer spacing of the GO membrane could be effectively reduced and regulated to improve the salt rejection rate. The fabricated membrane showed superior water permeability of over 60.0 kg m-2 h-1 and a high separation efficiency of over 96.0% for a sodium sulfate (Na2SO4) solution. It also exhibited excellent mechanical stability under various harsh crossflow conditions. More importantly, the fabrication method developed here can be scaled up using a roll-to-roll industrial production process, which successfully solves the problem currently faced by GO membrane researchers and makes the industrial usage of GO membrane a reality.

Mitogen-activated protein kinase (MAPK) pathway plays a major role in pediatric low-grade gliomas (pLGGs). Immunohistochemistry with mutant-specific antibody, VE1, has appeared to be the most affordable and rapidly deployable method to identify tumors with aberrant MAPK signaling pathway, by highlighting tumor with BRAFV600E mutation. Nonetheless, positive staining cases but not associated with BRAFV600E mutation are also seen. We analyzed 62 pLGGs for the two commonest genetic aberrations in MAPK pathway: KIAA1549-BRAF fusion, using reverse-transcriptase polymerase chain reaction, and BRAFV600E mutation, using VE1 antibody and Sanger sequencing. We recorded a specificity and accuracy rate of 68.75% and 75%, respectively, for VE1, when strong cytoplasmic staining is observed. Interestingly, we observed that cells with ganglionic features frequently bind VE1 but not associated with BRAFV600E mutation. Such observation was also confirmed in four cases of differentiating neuroblastoma. This false positive staining may serve as an important confounder in the interpretation of VE1 immunoreactivity with major therapeutic implication. It is important to confirm the presence of BRAFV600E mutation by DNA-based method, especially in tumor entities not known to, or rarely harbor such mutations.

Background Cardiac troponin I (cTnI) has two flexible tails that control the cardiac cycle. The C-terminal tail, cTnI135–209, binds actin to shut off cardiac muscle contraction, whereas the competing calcium-dependent binding of the switch region, cTnI146–158, by cardiac troponin C (cTnC) triggers contraction. The N-terminal tail, cTnI1–37, regulates the calcium affinity of cTnC. cTnI is known to be susceptible to proteolytic cleavage by matrix metalloproteinase-2 (MMP-2) and calpain, two intracellular proteases implicated in ischemia-reperfusion injury. Methods Soluble fragments of cTnI containing its N- and C-terminal tails, cTnI1–77 and cTnI135–209, were highly expressed and purified from E. coli. We performed in vitro proteolysis studies of both constructs using liquid chromatography-mass spectrometry and solution NMR studies of the C-terminal tail. Results cTnI135–209 is intrinsically disordered, though it contains three regions with helical propensity (including the switch region) that acquire more structure upon actin binding. We identified three precise MMP-2 cleavage sites at cTnI P17-I18, A156-L157, and G199-M200. In contrast, calpain-2 has numerous cleavage sites throughout Y25-T30 and A152-A160. The critical cTnI switch region is targeted by both proteases. Conclusions Both N-terminal and C-terminal tails of cTnI are susceptible to cleavage by MMP-2 and calpain-2. Binding to cTnC or actin confers some protection to proteolysis, which can be understood in terms of their interactions as probed by NMR studies. General significance cTnI is an important marker of intracellular proteolysis in cardiomyocytes, given its many protease-specific cut sites, high natural abundance, indispensable functional role, and clinical use as gold standard biomarker of myocardial injury.

Objectives Caregivers of hospitalized older adults experience elevated levels of stress and are at risk of poor health outcomes. There is a lack of screening tools based on self-reported caregiver variables incorporating both protective and risk factors, for early identification of at-risk caregivers. This study reports the development of a caregiver-centric screening tool to identify risk of depression at admission and predicts 3-month risk of depression and quality of life amongst caregivers of older adults with an unplanned admission. Design, Setting and Participants This prospective cohort study was conducted in the medical wards of a tertiary-care hospital from July 2015 to May 2017. We recruited family caregivers of patients aged 65 years and above who fulfilled the following criteria: a) unplanned admission, b) not residing in nursing homes; and c) requiring assistance in activities of daily living. Measurements We examined 11 candidate caregiver variables (mastery, burden and nine demographic variables). Risk of depression (score ≥8 on Hospital Anxiety and Depression Scale (HADS-D) depression subscale) was the primary outcome, and was assessed during the index admission. Logistic regression models were used to identify risk factors and risk scores (weights). The total risk scores were then stratified into three risk levels. Predictive validity of the screening tool was assessed using 3-months post-discharge risk of depression and health-related quality of life (HRQoL). Results The study included 274 caregiver-patient dyads. The mean (SD) age of the caregivers was 59 (10) years with 33.6% caregivers screening positive for risk of depression. The final model comprised three caregiver variables: mastery, burden and education. The total risk scores ranged from 0 to 6 and showed good discrimination (AUC:0.82, 95% CI: 0.77 to 0.87). Caregivers were classified into low-risk (0–1 points), intermediate-risk (2–4 points), and high-risk (5–6 points) groups, with corresponding rates of risk of depression (HADS-D≥8) of 10.7%, 44.6% and 73.3%, during admission. Relative risk rates of the intermediate- and high-risk group using the low-risk group as reference were 4.16 and 6.84 respectively. At 3-months post-discharge, the rates of caregivers at risk of depression or having poor HRQoL also increased corresponding to the three risk levels as per baseline, supporting the predictive validity of the tool. Conclusions/Implications The caregiver-centric tool is a novel, practical, self-administered, relatively brief caregiver-centric instrument that can be used for rapid screening and stratification of caregivers at risk of depression. Uniquely, the tool comprised of assessment of protective factor (mastery) in addition to risk factors to provide a holistic assessment of the caregiver. It can be incorporated as part of older adults’ admission evaluation so that prompt intervention can be rendered to their at-risk caregivers. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s12603-019-1197-7 and is accessible for authorized users.

Emerging evidence supports that hypertension can be programmed or reprogrammed by maternal nutrition. Maternal exposures during pregnancy, such as maternal nutrition or antibiotic use, could alter the offspring’s gut microbiota. Short-chain fatty acids (SCFAs) are the major gut microbiota-derived metabolites. Acetate, the most dominant SCFA, has shown its antihypertensive effect. Limited information exists regarding whether maternal acetate supplementation can prevent maternal minocycline-induced hypertension in adult offspring. We exposed pregnant Sprague Dawley rats to normal diet (ND), minocycline (MI, 50 mg/kg/day), magnesium acetate (AC, 200 mmol/L in drinking water), and MI + AC from gestation to lactation period. At 12 weeks of age, four groups (n = 8/group) of male progeny were sacrificed. Maternal acetate supplementation protected adult offspring against minocycline-induced hypertension. Minocycline administration reduced plasma acetic acid level, which maternal acetate supplementation prevented. Additionally, acetate supplementation increased the protein level of SCFA receptor G protein-coupled receptor 41 in the offspring kidneys. Further, minocycline administration and acetate supplementation significantly altered gut microbiota composition. Maternal acetate supplementation protected minocycline-induced hypertension accompanying by the increases in genera Roseburia, Bifidobacterium, and Coprococcus. In sum, our results cast new light on targeting gut microbial metabolites as early interventions to prevent the development of hypertension, which could help alleviate the global burden of hypertension.

Active learning promotes the capacity of problem solving and decision making among learners. Teachers who apply instructional processes toward active participation of learners help their students develop higher order thinking skills. Due to the recent paradigm shift toward adopting competency-based curricula in the education of healthcare professionals in India, there is an emergent need for physiology instructors to be trained in active-learning methodologies and to acquire abilities to promote these curriculum changes. To address these issues, a series of International Union of Physiological Sciences (IUPS) workshops on physiology education techniques in four apex centers in India was organized in November 2018 and November 2019. The “hands-on” workshops presented the methodologies of case-based learning, problem-based learning, and flipped classroom; the participants were teachers of basic sciences and human and veterinary medicine. The workshop series facilitated capacity building and creation of a national network of physiology instructors interested in promoting active-learning techniques. The workshops were followed by a brainstorming meeting held to assess the outcomes. The aim of this report is to provide a model for implementing a coordinated series of workshops to support national curriculum change and to identify the organizational elements essential for conducting an effective Physiology Education workshop. The essential elements include a highly motivated core organizing team, constant dialogue between core organizing and local organizing committees, a sufficient time frame for planning and execution of the event, and opportunities to engage students at host institutions in workshop activities.

Blood–brain barrier (BBB) disruption contributes to neurodegenerative diseases. Loss of tight junction (TJ) proteins in cerebral endothelial cells (ECs) is a leading cause of BBB breakdown. We recently reported that miR‐195 provides vasoprotection, which urges us to explore the role of miR‐195 in BBB integrity. Here, we found cerebral miR‐195 levels decreased with age, and BBB leakage was significantly increased in miR‐195 knockout mice. Furthermore, exosomes from miR‐195‐enriched astrocytes increased endothelial TJ proteins and improved BBB integrity. To decipher how miR‐195 promoted BBB integrity, we first demonstrated that TJ proteins were metabolized via autophagic–lysosomal pathway and the autophagic adaptor p62 was necessary to promote TJ protein degradation in cerebral ECs. Next, proteomic analysis of exosomes revealed miR‐195‐suppressed thrombospondin‐1 (TSP1) as a major contributor to BBB disruption. Moreover, TSP1 was demonstrated to activate selective autophagy of TJ proteins by increasing the formation of claudin‐5‐p62 and ZO1‐p62 complexes in cerebral ECs while TSP1 impaired general autophagy. Delivering TSP1 antibody into the circulation showed dose‐dependent reduction of BBB leakage by 20%–40% in 25‐month‐old mice. Intravenous or intracerebroventricular injection of miR‐195 rescued TSP1‐induced BBB leakage. Dementia patients with BBB damage had higher levels of serum TSP1 compared to those without BBB damage (p = 0.0015), while the normal subjects had the lowest TSP1 (p, The present study revealed that thrombospondin‐1 (TSP1) is a key factor for BBB leakage and miR‐195 protects BBB integrity. We showed that cerebral miR‐195 reduces with age and blood‐brain barrier (BBB) leakage is increased in miR‐195 knockout mice. miR‐195‐regulated thrombospondin‐1 impairs BBB via selective autophagy of tight junctions. Furthermore, circulating TSP1 was higher in BBB‐damaged patients, which implied TSP1 as a new biomarker of BBB damage.

Neurophysiological investigation of neural processes are hindered by the presence of large artifacts associated with eye movement. Although blind source separation (BSS)-based hybrid algorithms are useful for separating, identifying, and removing these artifacts from EEG, it remains unexamined to what extent neural signals can remain mixed with these artifact components, potentially resulting in unintended removal of critical neural signals. Here, we present a novel validation approach to quantitatively evaluate to what extent horizontal and vertical saccadic eye movement-related artifact components (H and V Comps) are indeed ocular in origin. To automate the identification of the H and V Comps recovered by the second-order blind identification (SOBI), we introduced a novel Discriminant ANd Similarity (DANS)-based method. Through source localization, we showed that over 95% of variance in the SOBI-DANS identified H and V Comps' scalp projections were ocular in origin. Through the analysis of saccade-related potentials (SRPs), we found that the H and V Comps' SRP amplitudes were finely modulated by eye movement direction and distance jointly. SOBI-DANS' component selection was in 100% agreement with human experts' selection and was 100% successful in component identification across all participants indicating a high cross-individual consistency or robustness. These results set the stage for future work to transform the to-be-thrown-away artifacts into signals indicative of gaze position, thereby providing readily co-registered eye movement and neural signal without using a separate eye tracker.