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The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1–277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1–277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1–277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD. [ABSTRACT FROM AUTHOR]

In China, studies have shown nosocomial infections contribute to increased mortality rates, prolonged hospital stays, and added financial burdens for patients. Previous studies have demonstrated that effective infection control training can enhance the quality of infection control practices, particularly in intensive care unit (ICU) settings. However, there is currently no universally accepted training mode or program that adequately addresses the specific needs of ICU medical staff regarding nosocomial infection control. The objective of this study was to develop a standardized training system for preventing and controlling hospital-acquired infections among new medical staff in the internal medicine ICU. Our methodology encompassed an extensive literature review, technical interviews focusing on key events, semi-structured in-depth interviews, and two rounds of Delphi expert correspondence. We employed intentional sampling to select 16 experts for the Delphi expert consultation. Indicators were chosen based on an average importance score of >3.5 and a coefficient of variation of <0.25. The weight of each indicator was determined using the analytic hierarchy process. The efficacy of the two rounds of questionnaires was also evaluated. Our findings revealed that the questionnaires achieved a 100% effective recovery rate, with expert authority coefficients of 0.96 and 0.90. The Kendall coordination coefficients for the first-, second-, and third-level indicators in the initial round of expert consultation questionnaires were 0.440, 0.204, and 0.386 (P < 0.001), respectively. In the second round of expert consultation questionnaires, the Kendall coordination coefficients for the first, second, and third-level indicators were 0.562, 0.467, and 0.556 (P < 0.001), respectively. The final training model consisted of four first-level indicators (hospital infection prevention and control training content, training methods/forms, assessment content, and evaluation indicators), 26 second-level indicators, and 44 third-level indicators. In conclusion, the proposed standardized training system for infection prevention and control among new medical staff in the internal medicine ICU is both scientifically sound and practical, which can contribute to improved patient safety, reduced healthcare costs, and enhanced overall quality of care in internal medicine ICUs. Moreover, it can serve as a framework for future training projects. [ABSTRACT FROM AUTHOR]

Ginsenoside 24-hydroxy-ginsengdiol (24-OH-PD), extracted from red ginseng, is a novel diol-type ginsenoside, strongly inhibits the growth of human T-cell acute lymphoblastic leukaemia (T-ALL) CCRF-CEM cells. Our research aimed at investigating the mechanism underlying this inhibition. Cell viability was determined using the cell counting kit-8 (CCK-8) assay, and NOD/SCID mice bearing CCRF-CEM cells were used to verify the therapeutic effect of 24-OH-PD on T-ALL in vivo. We equally analysed pathways related to 24-OH-PD in CCRF-CEM cells using RNA-Seq analysis. Cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) levels were detected by flow cytometry. The activity of caspase3 and caspase9 was detected by enzyme activity detection kits. The expression levels of apoptosis-related proteins and mRNA were determined through western blotting and quantitative reverse-transcription PCR assays (qRT-PCR). CCK-8 assay and animal xenograft experiments confirmed that 24-OH-PD significantly inhibited T-ALL in a dose-dependent manner, both in vivo and in vitro. RNA-Seq results suggest that mitochondria-mediated apoptosis pathway plays an important role in this process. Furthermore, intracellular ROS levels increased, mPTP opened, and ΔΨm decreased following 24-OH-PD treatment. Pretreatment with the antioxidant, NAC, reversed the effects of 24-OH-PD on apoptosis and ROS generation. Moreover, 24-OH-PD treatment increased the expression of Bax and caspase family members, thereby releasing cytochrome c (Cytc) and inducing apoptosis. Our findings showed that, 24-OH-PD induces apoptosis in CCRF-CEM cells by activating the mitochondrial-dependent apoptosis pathway through ROS accumulation. This inhibitory effect implies that 24-OH-PD could be further developed as treatment of T-ALL. [ABSTRACT FROM AUTHOR]

An accurate assessment of species diversity is a cornerstone of biology and conservation. The lynx spiders (Araneae: Oxyopidae) represent one of the most diverse and widespread cursorial spider groups, however their species richness in Asia is highly underestimated. In this study, we revised species diversity with extensive taxon sampling in Taiwan and explored species boundaries based on morphological traits and genetic data using a two-step approach of molecular species delimitation. Firstly, we employed a single COI dataset and applied two genetic distance-based methods: ABGD and ASAP, and two topology-based methods: GMYC and bPTP. Secondly, we further analyzed the lineages that were not consistently delimited, and incorporated H3 to the dataset for a coalescent-based analysis using BPP. A total of eight morphological species were recognized, including five new species, Hamataliwa cordivulvasp. nov., Hamat. leporaurissp. nov., Tapponia auriolasp. nov., T. parvasp. nov. and T. rarobulbussp. nov., and three newly recorded species, Hamadruas hieroglyphica (Thorell, 1887), Hamat. foveata Tang & Li, 2012 and Peucetia latikae Tikader, 1970. All eight morphological species exhibited reciprocally monophyletic lineages. The results of molecular-based delimitation analyses suggested a variety of species hypotheses that did not fully correspond to the eight morphological species. We found that Hamat. cordivulvasp. nov. and Hamat. foveata showed shallow genetic differentiation in the COI, but they were unequivocally distinguishable according to their genitalia. In contrast, T. parvasp. nov. represented a deep divergent lineage, while differences of genitalia were not detected. This study highlights the need to comprehensively employ multiple evidence and methods to delineate species boundaries and the values of diagnostic morphological characters for taxonomic studies in lynx spiders. [ABSTRACT FROM AUTHOR]

COVID-19 remains a challenge worldwide, and testing of asymptomatic individuals remains critical to pandemic control measures. Starting March 2020, a total of 7497 hospital employees were tested at least weekly for SARS CoV-2; the cumulative incidence of asymptomatic infections was 5.64%. Consistently over a 14-month period half of COVID-19 infections (414 of 820, total) were detected through the asymptomatic screening program, a third of whom never developed any symptoms during follow-up. Prompt detection and isolation of these cases substantially reduced the risk of potential workplace and outside of workplace transmission. COVID-19 vaccinations of the workforce were initiated in December 2020. Twenty-one individuals tested positive after being fully vaccinated (3.9 per 1000 vaccinated). Most (61.9%) remained asymptomatic and in majority (75%) the virus could not be sequenced due to low template RNA levels in swab samples. Further routine testing of vaccinated asymptomatic employees was stopped and will be redeployed if needed; routine testing for those not vaccinated continues. Asymptomatic SARS-CoV-2 testing, as a part of enhanced screening, monitors local dynamics of the COVID-19 pandemic and can provide valuable data to assess the ongoing impact of COVID-19 vaccination and SARS-CoV-2 variants, inform risk mitigation, and guide adaptive, operational planning including titration of screening strategies over time, based on infection risk modifiers such as vaccination. [ABSTRACT FROM AUTHOR]

This study delves into the complex dynamics of ethical leadership's influence on employees' pro-social rule-breaking behavior, taking into account the mediating role of psychological capital and the moderating effect of moral identity. Using data collected from nursing staff in Pakistani hospitals and analyzed through PLS SEM, the study yielded unexpected results. Contrary to the initial hypotheses, the findings reveal a positive relationship between ethical leadership and employees' pro-social rule-breaking behavior within organizational settings. Furthermore, the study identifies psychological capital as a key mediator in this relationship, while moral identity emerges as a crucial moderator. These results challenge the conventional perception of ethical leadership as an exclusively positive form of leadership and underscore its unintended consequences. Moreover, they underscore the significance of employees' psychological processes and individual differences in unraveling this paradoxical relationship. These results have the potential to reshape how organizations view ethical leadership and consider the unintended outcomes it may generate. Future research can build upon these findings to explore the boundaries and contextual factors that influence the effects of ethical leadership, ultimately contributing to a more comprehensive understanding of leadership dynamics in diverse organizational settings. [ABSTRACT FROM AUTHOR]

Effective surface disinfection is crucial for preventing the spread of pathogens in hospitals. Standard UltraViolet-C (UV-C) lamps have been widely used for this purpose, but their disinfection efficiency under real-world conditions is not well understood. To fill this gap, the influence of the power of the ultraviolet radiator, source-sample distance, and exposure time on the performance of UV-C lamps against Escherichia coli and Staphylococcus epidermidis were experimentally determined in the laboratory and hospital. The obtained results showed that the UV irradiance and, thus, the UV-C disinfection efficiency decreased significantly at distances greater than 100 cm from the UV-C lamp. Moreover, increasing the total power of the radiators does not improve the performance of UV-C lamps under real conditions. The UV-C disinfection efficiency greater than 90% was achieved only under laboratory conditions at a close distance from the UV-C lamp, i.e., 10 cm. These findings provide novel insights into the limitations of UV-C lamps in real-world conditions and highlight the need for more effective disinfection strategies in hospitals. [ABSTRACT FROM AUTHOR]

Early identification of safe and efficacious disease targets is crucial to alleviating the tremendous cost of drug discovery projects. However, existing experimental methods for identifying new targets are generally labor-intensive and failure-prone. On the other hand, computational approaches, especially the machine learning-based frameworks, have shown remarkable application potential in drug discovery. In this work, we propose Progeni, a novel machine learning-based framework for target identification. In addition to fully exploiting the known heterogeneous biological networks from various sources, Progeni integrates literature evidence about the relations between biological entities to construct a probabilistic knowledge graph. Graph neural networks are then employed in Progeni to learn the feature embeddings of biological entities to facilitate the identification of biologically relevant target candidates. A comprehensive evaluation of Progeni demonstrated its superior predictive power over the baseline methods on the target identification task. In addition, our extensive tests showed that Progeni exhibited high robustness to the negative effect of exposure bias, a common phenomenon in recommendation systems, and effectively identified new targets that can be strongly supported by the literature. Moreover, our wet lab experiments successfully validated the biological significance of the top target candidates predicted by Progeni for melanoma and colorectal cancer. All these results suggested that Progeni can identify biologically effective targets and thus provide a powerful and useful tool for advancing the drug discovery process. Author summary: The selection of a disease target, a biological entity with which potential drugs interact to treat diseases, is often the first step of a drug discovery project. Known to be extremely costly, drug discovery projects spend tremendous resources on failed drug instances, most of which result from inadequate choices of targets. To help address the costliness problem of drug discovery, we developed a machine learning-based framework that identifies biologically effective targets using a probabilistic knowledge graph built from both biological network data and literature evidence. Our method not only outperforms state-of-the-art baseline methods on the target prediction task, but can also identify targets with high biological relevance, as shown by the strong support of the literature for the predicted target candidates and wet lab experiments that validate the significance of the predicted target candidates for melanoma and colorectal cancer, These results suggest that our method can identify effective targets and therefore benefit drug discovery. [ABSTRACT FROM AUTHOR]

Cash holding is an important strategic decision of enterprises. As a macro-level factor, economic policy uncertainty causes risks, affecting enterprises' cash holdings. Taking the quarterly financial data of China's A-share non-financial listed firms for 2010–2020 as a sample, this study adopts the OLS and fixed effect models to investigate how corporate cash holdings are affected by economic policy uncertainty. The findings indicate that economic policy uncertainty is directly proportional to the level of cash that listed corporations hold. The higher the uncertainty, the more cash the company holds. Among them, state-owned enterprises and the manufacturing industry are more significantly affected by economic policy uncertainty. Finally, considering the regional marketization level and the differences in financing constraints enterprises face, it is concluded through grouping empirical studies that enterprises located in regions with lower marketization levels are more susceptible to policy uncertainty, while financially constrained enterprises are more susceptible to economic policy uncertainty. The study of economic policy uncertainty is helpful to guide enterprises to realize the importance of coping strategies in advance under the background of intensifying economic policy uncertainty. Therefore, this paper proposes to introduce policies on the premise of fully considering the smoothness of the economy and the differences in the conditions of firms of different natures, as well as some proposals to alleviate financing constraints, reduce the adverse effects of uncertainty on firms, and bolster the marketization process. [ABSTRACT FROM AUTHOR]

Rapid and uniform seed germination is required for modern cropping system. Thus, it is important to optimize germination performance through breeding strategies in maize, in which identification for key regulators is needed. Here, we characterized an AP2/ERF transcription factor, ZmEREB92, as a negative regulator of seed germination in maize. Enhanced germination in ereb92 mutants is contributed by elevated ethylene signaling and starch degradation. Consistently, an ethylene signaling gene ZmEIL7 and an α-amylase gene ZmAMYa2 are identified as direct targets repressed by ZmEREB92. OsERF74, the rice ortholog of ZmEREB92, shows conserved function in negatively regulating seed germination in rice. Importantly, this orthologous gene pair is likely experienced convergently selection during maize and rice domestication. Besides, mutation of ZmEREB92 and OsERF74 both lead to enhanced germination under cold condition, suggesting their regulation on seed germination might be coupled with temperature sensitivity. Collectively, our findings uncovered the ZmEREB92-mediated regulatory mechanism of seed germination in maize and provide breeding targets for maize and rice to optimize seed germination performance towards changing climates. Author summary: Seed germination is a crucial step for agricultural production, yet the regulatory mechanism in many crops remains unclear. We demonstrated that ZmEREB92 negatively regulates maize seed germination in a temperature-sensitive manner. In suitable condition, ZmEREB92 is transcriptionally inhibited during imbibition, thereby releasing the expression of ZmEIL7 and ZmAMYa2 to enhance ethylene signaling and starch degradation, which ensures timely germination. When the temperature is low, the expression of ZmEREB92 is strongly induced after imbibition. The increased level of ZmEREB92 directly represses the transcription of ZmEIL7 and ZmAMYa2 by binding to their promoters, leading to inhibited seed germination. The rice ortholog of ZmEREB92, OsERF74, is functionally conserved in controlling seed germination in rice, and this orthologous gene pair show evidences of selection during maize and rice domestication. [ABSTRACT FROM AUTHOR]

The objection of this study was to investigate the effects of vindoline(VDL) on the cytochrome P450 (CYP 450) isoforms (CYP1A2, 2B, 2C11, 2D1 and 3A) in rats. Firstly, the rats were randomly divided into VDL pretreatment group and blank group, each group had six rats. VDL pretreatment group was administrated VDL (20 mg·kg-1) by oral gavage for fifteen days consecutively, and the equivalent CMC-Na solution without VDL was given to the blank group by gavage. Secondly, a cocktail of caffeine, bupropion, diclofenac, dextromethorphan and midazolam was then administered on the sixteenth day. Finally, blood samples were collected at the specified time point, and the plasma concentration of the probe drug was determined by UHPLC-QTOF-MS/MS. The effects of VDL on the activity of these CYP enzymes in rats were evaluated by pharmacokinetic parameters. VDL pretreatment group compared with the blank group, accelerated the metabolism of diclofenac, and weakened the metabolism of caffeine. These results suggested that VDL could induce the activity of CYP2C11, and inhibits the activity of CYP1A2, but had no significant effects on CYP2B, CYP2D1 and CYP3A. The results in this study can provide beneficial information for the later clinical application of VDL. [ABSTRACT FROM AUTHOR]