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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.

While most literature examines the determinants of international student mobility on a single scale, either global, regional, or national, differences between various patterns are under-investigated. To address this gap, this article explores the determinants of international student mobility at three distinct levels: global, Asian-outward, and intra-Asian. Secondary data from international databases are collected to test the effects of economic, linguistic, educational, technological, and geographical factors at each level. Findings reveal significant variation between intra-Asian student mobility and the other two levels. More specifically, while pull factors of the destination countries are salient to global and Asian outward mobility, intra-Asian mobility is predominantly influenced by push factors of the source countries. We then interpret how differences in macro socio-economic conditions shape uneven mobility dynamics replicated at the global and regional levels. Suggestions for future research on Asian higher education and international student mobility are also presented.

Introduction: This study aimed to identify risk factors affecting outcomes in pediatric patients requiring emergent peritoneal dialysis (PD) for all causes, focusing on survival rates, kidney function recovery, PD duration, complications, and quality of life. Methods: A retrospective review was conducted on medical records of pediatric patients who received emergent bedside PD in the intensive care unit from January 2010 to February 2023. Thirty-four catheters were placed, with demographic, preoperative, and procedural data collected. MedCalc® Statistical Software was used for analysis with a significance level set at p < 0.05. Prophylactic antibiotics were administered prior to surgery, and catheters were placed using a consistent technique by a single team of pediatric surgeons. Results: The median age at catheter placement was 39 days (range 2–2,286), and the median body weight was 3.53 kg (range 1.2–48.8). The majority were male (64.7%), with 17.6% preterm. The most common indication for PD was acute kidney injury (AKI) (88.2%), followed by hyperammonemia, metabolic acidosis, and abdominal compartment syndrome. The median waiting period for PD placement was 1 day, and the median duration of PD was 7 days. Complications included dialysate leakage (22.8%) and catheter obstruction leading to PD discontinuation (31.4%). The mortality rate was high at 71.4%. Conclusion: It is advisable to advocate for the early initiation of PD in pediatric patients following cardiac surgery. AKI is a significant risk factor for mortality, while prematurity increases the risk of dialysate leakage. Omentectomy and the method of catheter exit did not significantly affect outcomes. The study's limitations highlight the need for larger prospective studies to better understand and improve emergent PD management in this vulnerable population. Plain Language Summary: In our study, we looked at medical records of young patients, from newborns to 18-year-olds, who needed an emergency procedure called peritoneal dialysis after heart surgery. Peritoneal dialysis is a treatment that cleans the blood when the kidneys can't do it properly. It involves placing a special tube in the belly to filter out waste using a cleansing fluid. We found that this emergency treatment was most often needed after complex surgery for heart problems present from birth. It is a serious situation, and unfortunately, many children did not survive. We learned that starting the dialysis treatment as soon as possible after surgery might help increase the chances of survival. We also noticed that some issues like infections or problems with the tube used in the treatment could lead to stopping the dialysis, which happened in about a third of the patients. Our goal was to understand what makes this emergency treatment work well or not. Knowing these factors can help doctors and medical teams improve how they care for very sick children after surgery and potentially save more lives. We hope that our findings will lead to better ways to manage and prevent problems that come up with this life-saving treatment. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) and microRNAs (miRs) have emerged as two important epigenetic factors in the regulation of vascular physiology. This study aimed to elucidate the relationship between HDACs and miRs in the hemodynamic modulation of endothelial cell (EC) dysfunction. We found that miR-10a has the lowest expression among all examined shear-responsive miRs in ECs under oscillatory shear stress (OS), and a relatively high expression under pulsatile shear stress (PS). PS and OS alter EC miR-10a expression to regulate the expression of its direct target GATA6 and downstream vascular cell adhesion molecule (VCAM)-1. PS induces the expression, nuclear accumulation, and association of retinoid acid receptor-α (RARα) and retinoid X receptor-α (RXRα). RARα and RXRα serve as a "director" and an "enhancer," respectively, to enhance RARα binding to RA-responsive element (RARE) and hence miR-10a expression, thus down-regulating GATA6/VCAM-1 signaling in ECs. In contrast, OS induces associations of "repressors" HDAC-3/5/7 with RARα to inhibit the RARα-directed miR-10a signaling. The flow-mediated miR-10a expression is regulated by Krüppel-like factor 2 through modulation in RARα-RARE binding, with the consequent regulation in GATA6/VCAM-1 in ECs. These results are confirmed in vivo by en face staining on the aortic arch vs. the straight thoracic aorta of rats. Our findings identify a mechanism by which HDACs and RXRα modulate the hormone receptor RARα to switch miR-10a expression and hence the proinflammatory vs. anti-inflammatory responses of vascular endothelium under different hemodynamic forces.

Compact photonic devices that integrate metasurfaces with light sources have been widely studied. However, experimental demonstrations of a higher efficiency of integration are still lacking. To enhance the efficiency of light sources integrated with metasurfaces, we employed a forward design optimization method and index matching between the light source and metasurface substrate to design metagratings. To optimize the overall diffraction efficiency, we manipulated the degrees of freedom in phase, the lattice constants, and the number of unit cells. The same material was utilized for the nanostructures and substrate (homo-metagrating) for index matching, while Si and GaAs materials were used for working at 1550 and 940 nm, respectively. The experimental homo-metagratings operating at 1550 nm and made of Si exhibited an overall average efficiency of 51.3% at diffraction angles of 60.3°. On the other hand, experimental homo-metagratings operating at 940 nm and made of GaAs exhibited an overall average efficiency of 52.4% at diffraction angles of 49.3°. This suggests that the future integration of metagratings with a polarization-specific laser can further enhance the overall diffraction efficiency. [ABSTRACT FROM AUTHOR]

RationaleIn atherosclerotic lesions, synthetic smooth muscle cells (sSMCs) induce aberrant microRNA (miR) profiles in endothelial cells (ECs) under flow stagnation. Increase in shear stress induces favorable miR modulation to mitigate sSMC-induced inflammation.ObjectiveTo address the role of miRs in sSMC-induced EC inflammation and its inhibition by shear stress.Methods and resultsCoculturing ECs with sSMCs under static condition causes initial increases of 4 anti-inflammatory miRs (146a/708/451/98) in ECs followed by decreases below basal levels at 7 days; the increases for miR-146a/708 peaked at 24 hours and those for miR-451/98 lasted for only 6 to 12 hours. Shear stress (12 dynes/cm(2)) to cocultured ECs for 24 hours augments these 4 miR expressions. In vivo, these 4 miRs are highly expressed in neointimal ECs in injured arteries under physiological levels of flow, but not expressed under flow stagnation. MiR-146a, miR-708, miR-451, and miR-98 target interleukin-1 receptor-associated kinase, inhibitor of nuclear factor-κB kinase subunit-γ, interleukin-6 receptor, and conserved helix-loop-helix ubiquitous kinase, respectively, to inhibit nuclear factor-κB signaling, which exerts negative feedback control on the biogenesis of these miRs. Nuclear factor-E2-related factor (Nrf)-2 is critical for shear-induction of miR-146a in cocultured ECs. Silencing either Nrf-2 or miR-146a led to increased neointima formation of injured rat carotid artery under physiological levels of flow. Overexpressing miR-146a inhibits neointima formation of rat or mouse carotid artery induced by injury or flow cessation.ConclusionsNrf-2-mediated miR-146a expression is augmented by atheroprotective shear stress in ECs adjacent to sSMCs to inhibit neointima formation of injured arteries.

This study aims to assess the global warming's impact on intense tropical cyclones (TCs) over the western North Pacific (WNP) through dynamical downscaling. 379 and 179 TCs reaching Category 1 in the High‐Resolution Atmospheric Model (HiRAM) are downscaled for use in the Weather Research and Forecasting (WRF) model at 5‐km horizontal resolution in the current climate (1979–2015) and for use in the Representative Concentration Pathways 8.5 (RCP8.5) in the future climate (2074–2100) scenarios, respectively. Inclusion of the downscaling simulations by WRF helps better reproduce the probability distribution of the TC's lifetime maximum intensity (LMI). In the warmer climate, the LMI of very intense TCs in WNP are projected to be stronger. Such an increase in intensity is statistically significant, and can be primarily explained by enhanced intensification rate. Meanwhile, TCs among the top 5% in LMI can reach higher intensities which cannot be attained in the current climate. After downscaling, the probability of WNP TCs reaching Category 4–5 increases by 6.5 percentage points in the late 21st century. This increase is 1.7 percentage points higher than the increase projected exclusively by HiRAM. Moreover, for TCs among the top 5% in LMI, a 233‐km and 300‐km westward shift of LMI locations is identified in the late 21st century for simulations with and without the downscaling approach, respectively. Both results suggest that very intense TCs would pose a higher threat to the WNP lands under global warming, as they become substantially stronger, and as their LMI locations migrate toward the coast. Plain Language Summary: This study assesses the impact of global warming on intense tropical cyclones (TCs) over the western North Pacific (WNP) through a dynamical downscaling approach, showing that inclusion of the downscaling simulations helps better reproduce the probability distribution of the TC lifetime maximum intensity (LMI). The very intense TCs would pose a higher threat to the WNP lands under global warming, as they become substantially stronger, and as their LMI locations migrate toward the coast. Key Points: Inclusion of the downscaled tropical cyclones (TCs) improves the probability distribution of TC's lifetime maximum intensity (LMI)There is a more substantial increase in the intensity of very intense TCs in a warmer futureAs global warming progresses, heightened TC intensity and their tendency to reach LMI closer to land jointly pose increased coastal threats [ABSTRACT FROM AUTHOR]