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Herein, we designed a series of guanidinobenzoic acid ester derivatives on the basis of approved AP drugs, such as nafamostat, gabexate and camostat, and evaluated their inhibitory effects on trypsin and anti-inflammatory activity. Among them, five compounds (6a, 6c–6e, 7j) showed excellent inhibitory effects on trypsin with IC50 values of 0.0756 μM to 0.1227 μM, which are more potent than nafamostat and gabexate. Moreover, compounds 6a, 6b and 6c also showed significant inhibitory potency against the pro-inflammatory molecule NO with IC50 values of 1.618 μM, 2.276 μM, and 3.022 μM, respectively. Consequently, the potential lead compounds simultaneously with anti-trypsin and anti-inflammatory activities were identified, which would profit further structural optimization for the treatment of AP. [ABSTRACT FROM AUTHOR]

Background: The September 11, 2001, catastrophe unleashed widespread destruction beyond the World Center (WTC), with fires and toxic gases leaving lasting impacts. First responders at Ground Zero faced prolonged exposure to hazardous particulate matter (PM), resulting in chronic health challenges. Among the multitude of health concerns, the potential association between the WTCPM and Alzheimer's disease (AD) has emerged as an area of intense inquiry, probing the intricate interplay between environmental factors and neurodegenerative diseases. Objective: We posit that a genetic predisposition to AD in mice results in dysregulation of the gut-brain axis following chronic exposure to WTCPM. This, in turn, may heighten the risk of AD-like symptoms in these individuals. Methods: 3xTg-AD and WT mice were intranasally administered with WTCPM collected at Ground Zero within 72 hours after the attacks. Working memory and learning and recognition memory were monitored for 4 months. Moreover, brain transcriptomic analysis and gut barrier permeability along with microbiome composition were examined. Results: Our findings underscore the deleterious effects of WTCPM on cognitive function, as well as notable alterations in brain genes associated with synaptic plasticity, pro-survival, and inflammatory signaling pathways. Complementary, chronic exposure to the WTCPM led to increased gut permeability in AD mice and altered bacteria composition and expression of functional pathways in the gut. Conclusions: Our results hint at a complex interplay between gut and brain axis, suggesting potential mechanisms through which WTCPM exposure may exacerbate cognitive decline. Identifying these pathways offers opportunities for tailored interventions to alleviate neurological effects among first responders. [ABSTRACT FROM AUTHOR]

Thyroid Eye Disease (TED) is an inflammatory autoimmune condition affecting the eyes, often associated with Graves' disease. Inflammation is important in TED, involving immune cells and orbital tissues. While inflammatory markers have been studied in other diseases, their role in TED is unclear. We included 734 participants from 5 eligible studies investigated associations between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) and TED. Initial analysis found no significant differences in these markers between TED and control groups. However, sensitivity analysis excluding an outlier study revealed significant differences in NLR, PLR, and MLR between groups, suggesting the potential association between these inflammatory markers and TED. More research is needed, but these findings indicate complex TED pathogenesis and that inflammation may offer insights for TED diagnosis and management. [ABSTRACT FROM AUTHOR]

Numerical techniques have been developed to study flow structures in the wake behind a tapered circular cylinder via computational fluid dynamics. The Reynolds number, based on the mean diameter of the tapered cylinder, is 4 × 103; here, the boundary layer on the cylinder surface is laminar before separating into a turbulent wake. In order to model this transient turbulent flow, a large eddy simulation was adopted and vortex-shedding frequencies were determined using the fast Fourier transform. The fundamental behaviors of the cellular distributions of vortex-shedding frequencies, mechanisms of vortex splitting and the vortex cell reorganization were addressed. Two constant-frequency vortex cells were observed in the operating Reynolds number, and the respective Strouhal numbers were validated experimentally. Numerical flow visualizations showed that the spanwise shedding vortices are well aligned, whereas the vortex splitting seems to disconnect vortex lines. The pressure coefficients at specific zones and angular positions of the tapered cylinder were illustrated to explore the correlation of pressure variation with vortex shedding. The results showed that the vortex splitting initiates and completes at boundary-layer separation. Furthermore, numerical techniques are elaborated on for readers to tackle similar problems. [ABSTRACT FROM AUTHOR]

Introduction: Human cytomegalovirus (HCMV) is the most common viral infection seen in newborns. The major route of transmission for acquired human cytomegalovirus infection is breast milk from mothers who are HCMV seropositive to the infants. Thus, a rapid, economical, and simple method to perform HCMV test in breast milk is crucial and necessary for preventing acquired HCMV infection, especially in underdeveloped regions with limited laboratory resources. Methods: In this study, an effective technique for the detection of HCMV was constructed by combining multienzyme isothermal rapid amplification (MIRA) and lateral flow chromatography strip (LFD). Primers for the conserved HCMV sequence UL83 were utilized for MIRA-LFD testing. Results: Our results showed that the entire MIRA reaction could be completed in 12 minutes at 37°C, and LFD outcomes could be observed visibly after 10 minutes. The detection sensitivity of this method reached 50 copy/ml. Samples of breast milk were examined to compare MIRA-LFD and conventional qPCR. The accuracy of MIRA-LFD was 100%. Discussion: The straightforward, rapid, economic features of the test can provide the significant advantages for the prevention of breast milk-acquired cytomegalovirus infection, particularly in resource-limited locations with high seroprevalence of cytomegalovirus. [ABSTRACT FROM AUTHOR]

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Spatial transcriptomics provides valuable insights into gene expression within the native tissue context, effectively merging molecular data with spatial information to uncover intricate cellular relationships and tissue organizations. In this context, deciphering cellular spatial domains becomes essential for revealing complex cellular dynamics and tissue structures. However, current methods encounter challenges in seamlessly integrating gene expression data with spatial information, resulting in less informative representations of spots and suboptimal accuracy in spatial domain identification. We introduce stCluster, a novel method that integrates graph contrastive learning with multi-task learning to refine informative representations for spatial transcriptomic data, consequently improving spatial domain identification. stCluster first leverages graph contrastive learning technology to obtain discriminative representations capable of recognizing spatially coherent patterns. Through jointly optimizing multiple tasks, stCluster further fine-tunes the representations to be able to capture complex relationships between gene expression and spatial organization. Benchmarked against six state-of-the-art methods, the experimental results reveal its proficiency in accurately identifying complex spatial domains across various datasets and platforms, spanning tissue, organ, and embryo levels. Moreover, stCluster can effectively denoise the spatial gene expression patterns and enhance the spatial trajectory inference. The source code of stCluster is freely available at https://github.com/hannshu/stCluster. [ABSTRACT FROM AUTHOR]

We have reported previously that during hypoxia exposure, the expression of mature miR-17~92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo. Here, we investigated the mechanisms regulating this biphasic expression of miR-17~92 in PASMC in hypoxia. We measured the level of primary miR17~92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3% O2, 6 h) induced the level of primary miR-17~92, whereas long-term hypoxia exposure (3% O2, 24 h) decreased its level, suggesting a biphasic regulation of miR17~92 expression at the transcriptional level. We found that short-term hypoxia-induced upregulation of miR-17~92 was hypoxiainducible factor 1α (HIF1α) and E2F1 dependent. Two HIF1α binding sites on miR-17~92 promoter were identified. We also found that long-term hypoxia-induced suppression of miR-17~92 expression could be restored by silencing of p53. Mutation of the p53-binding sites in the miR-17~92 promoter increased miR-17~92 promoter activity in both normoxia and hypoxia. Our findings suggest that the biphasic transcriptional regulation of miR-17~92 during hypoxia is controlled by HIF1/E2F1 and p53 in PASMC: during short-term hypoxia exposure, stabilization of HIF1 and induction of E2F1 induce the transcription of miR-17~92, whereas during long-term hypoxia exposure, hyperphosphorylation of p53 suppresses the expression of miR-17~92. NEW & NOTEWORTHY We showed that the biphasic transcriptional regulation of miR-17~92 during hypoxia is controlled by two distinct mechanisms: during short-term hypoxia exposure, induction of HIF1 and E2F1 upregulates miR-17~92. Longer hypoxia exposure induces hyperphosphorylation of p53 at ser15, which leads to its binding to miR-17~92 promoter and inhibition of its expression. Our findings provide novel insights into the spatiotemporal regulation of miR-17~92 that may play a role in the development of human lung diseases including pulmonary hypertension (PH). [ABSTRACT FROM AUTHOR]

Background and Objectives: This paper evaluates the efficacy and safety of ureteral access sheath (UAS) utilization in retrograde intrarenal surgery (RIRS). Materials and Methods: We searched PubMed, Embase, and the Cochrane Library up to 30 August 2023. The inclusion criteria comprised English-language original studies on RIRS with or without UAS in humans. The primary outcome was SFR, while the secondary outcomes included intraoperative and postoperative complications, the lengths of the operation and the hospitalization period, and the duration of the fluoroscopy. Subgroup analyses and a sensitivity analysis were performed. Publication bias was assessed using funnel plots and Egger's regression tests. Dichotomous variables were analyzed using odds ratios (ORs) with 95% confidence intervals (CIs), while mean differences (MDs) were employed for continuous variables. Results: We included 22 studies in our analysis. These spanned 2001 to 2023, involving 12,993 patients and 13,293 procedures. No significant difference in SFR was observed between the UAS and non-UAS groups (OR = 0.90, 95% CI 0.63–1.30, p = 0.59). Intraoperative (OR = 1.13, 95% CI 0.75–1.69, p = 0.5) and postoperative complications (OR = 1.29, 95% CI 0.89–1.87, p = 0.18) did not significantly differ between the groups. UAS usage increased operation times (MD = 8.30, 95% CI 2.51–14.10, p = 0.005) and fluoroscopy times (MD = 5.73, 95% CI 4.55–6.90, p < 0.001). No publication bias was detected for any outcome. Conclusions: In RIRS, UAS usage did not significantly affect SFR, complications, or hospitalization time. However, it increased operation time and fluoroscopy time. Routine UAS usage is not supported, and decisions should be patient-specific. Further studies with larger sample sizes and standardized assessments are needed to refine UAS utilization in RIRS. [ABSTRACT FROM AUTHOR]

This study aims to enhance the optical and thermal properties of cesium-based perovskite nanocrystals (NCs) through surface passivation with organic sulfonate (or sulfonic acid) ligands. Four different phenylated ligands, including sodium β-styrenesulfonate (SbSS), sodium benzenesulfonate (SBS), sodium p-toluenesulfonate (SPTS), and 4-dodecylbenzenesulfonic acid (DBSA), were employed to modify blue-emitting CsPbBr1.5Cl1.5 perovskite NCs, resulting in improved size uniformity and surface functionalization. Transmission electron microscopy and X-ray photoelectron spectroscopy confirmed the successful anchoring of sulfonate or sulfonic acid ligands on the surface of perovskite NCs. Moreover, the photoluminescence quantum yield increased from 32% of the original perovskite NCs to 63% of the SPTS-modified ones due to effective surface passivation. Time-resolved photoluminescence decay measurements revealed extended PL lifetimes for ligand-modified NCs, indicative of reduced nonradiative recombination. Thermal stability studies demonstrated that the SPTS-modified NCs retained nearly 80% of the initial PL intensity when heated at 60 °C for 10 min, surpassing the performance of the original NCs. These findings emphasize the optical and thermal stability enhancement of cesium-based perovskite NCs through surface passivation with suitable sulfonate ligands. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate physicians' awareness and knowledge towards pediatric nonalcoholic fatty liver disease (NAFLD) and their attitude toward change in nomenclature from NAFLD to metabolic dysfunction‐associated fatty liver disease (MAFLD) or metabolic dysfunction‐associated steatotic liver disease (MASLD) in China. Methods: The questionnaire survey contained five parts (characteristics of the participants, epidemiology, diagnosis, management of NAFLD, and attitudes toward the nomenclature of MAFLD/MASLD). The participants included 53 hepatologists, 88 gastroenterologists (GEs), 74 endocrinologists (ENDOs), 61 primary care physicians (PCPs), and 157 pediatricians across 31 municipalities, provinces and autonomous regions of China's mainland. Results: Hepatologists saw the largest number of pediatric NAFLD patients annually (median 9 [range 1–20]), with the lowest number by PCPs (even notwithstanding one patient annually). The primary sources of pediatric NAFLD knowledge were acquired via guidelines. Hepatologists had the highest total knowledge score among all five types of physicians. Approximately one‐third of nonspecialists (ENDOs and PCPs) considered liver biopsy necessary for pediatric NAFLD patients, and this percentage increased to half in specialists (hepatologists and GEs). For nonspecialists, the major barriers to the management of pediatric NAFLD were poor patient adherence to lifestyle modifications and lacking confidence in managing NAFLD. Above 90% physicians agreed to change the nomenclature NAFLD to MAFLD; however, they were not sure whether it could reduce the economic burden. Conclusions: Despite the epidemic of pediatric NAFLD in China, a significant knowledge gap remains in the identification, diagnosis, and treatment of pediatric NAFLD, particularly among frontline workers such as pediatricians and PCPs. More education programs should be carried out in the future. [ABSTRACT FROM AUTHOR]