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BACKGROUND: Severe respiratory syncytial virus (RSV) pneumonia is a leading cause of hospitalization and morbidity in infants and young children. Early identification of severe RSV pneumonia is crucial for timely and effective treatment by pediatricians. Currently, no prediction model exists for identifying severe RSV pneumonia in children. METHODS: This study aimed to construct a diagnostic prediction model for severe RSV pneumonia in children using a machine learning algorithm. We analyzed data from the Gene Expression Omnibus (GEO) Series, including training dataset GSE246622 and testing dataset GSE105450, to identify differential genes between severe and mild-to-moderate RSV pneumonia in children. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the differential genes, followed by the construction of a protein-protein interaction (PPI) network. An artificial neural network (ANN) algorithm was then used to develop and validate a diagnostic prediction model for severe RSV pneumonia in children. RESULTS: We identified 34 differentially expressed genes between the severe and mild-to-moderate RSV pneumonia groups. Enrichment analysis revealed that these genes were primarily related to pathogenic infection and immune response. From the PPI network, we identified 10 hub genes and, using the random forest algorithm, screened out 20 specific genes. The ANN-based diagnostic prediction model achieved an area under the curve (AUC) value of 0.970 in the training group and 0.833 in the testing group, demonstrating the model's accuracy. CONCLUSIONS: This study identified specific biomarkers and developed a diagnostic model for severe RSV pneumonia in children. These findings provide a robust foundation for early identification and treatment of severe RSV pneumonia, offering new insights into its pathogenesis and improving pediatric care.

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WHO classified Helicobacter pylori as a Group I carcinogen for gastric cancer as early as 1994. However, despite the high prevalence of H. pylori infection, only about 3 % of infected individuals eventually develop gastric cancer, with the highly virulent H. pylori strains expressing cytotoxin-associated protein (CagA) and vacuolating cytotoxin (VacA) being critical factors in gastric carcinogenesis. It is well known that H. pylori infection is divided into two types in terms of the presence and absence of CagA and VacA toxins in serum, that is, carcinogenic Type I infection (CagA+/VacA+, CagA+/VacA-, CagA-/VacA+) and non-carcinogenic Type II infection (CagA-/VacA-). Currently, detecting the two carcinogenic toxins in active modes is mainly done by diagnosing their serological antibodies. However, the method is restricted by expensive reagents and intricate procedures. Therefore, establishing a rapid, accurate, and cost-effective way for serological profiling of carcinogenic H. pylori infection holds significant implications for effectively guiding H. pylori eradication and gastric cancer prevention. In this study, we developed a novel method by combining surface-enhanced Raman spectroscopy with the deep learning algorithm convolutional neural network to create a model for distinguishing between serum samples with Type I and Type II H. pylori infections. This method holds the potential to facilitate rapid screening of H. pylori infections with high risks of carcinogenesis at the population level, which can have long-term benefits in reducing gastric cancer incidence when used for guiding the eradication of H. pylori infections.

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Introduction: The brain's reward system (RS) reacts differently to pain and its alleviation. This study examined the correlation between RS activity and behavior during both painful and pain-free periods in individuals with primary dysmenorrhea (PDM) to elucidate their varying responses throughout the menstrual cycle. Methods: Ninety-two individuals with PDM and 90 control participants underwent resting-state functional magnetic resonance imaging (rsfMRI) scans during their menstrual and peri-ovulatory phases. Regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) analyses were used to evaluate RS responses. Psychological evaluations were conducted using the McGill Pain Questionnaire and the Pain Catastrophizing Scale. Results: ReHo analysis showed higher values in the left putamen and right amygdala of the PDM group during the peri-ovulatory phase compared to the menstrual phase. ALFF analysis revealed lower values in the putamen of the PDM group compared to controls, regardless of phase. ReHo and ALFF values in the putamen, amygdala, and nucleus accumbens were positively correlated with pain scales during menstruation, while ALFF values in the ventral tegmental area inversely correlated with pain intensity. Those with severe PDM (pain intensity ≥7) displayed distinct amygdala ALFF patterns between pain and pain-free phases. PDM participants also had lower ReHo values in the left insula during menstruation, with no direct correlation to pain compared to controls. Discussion: Our study highlights the pivotal role of the RS in dysmenorrhea management, exhibiting varied responses between menstrual discomfort and non-painful periods among individuals with PDM. During menstruation, the RS triggers mechanisms for pain avoidance and cognitive coping strategies, while it transitions to processing rewards during the peri-ovulatory phase. This demonstrates the flexibility of the RS in adapting to the recurring pain experienced by those with PDM.

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Introduction: Primary dysmenorrhea (PDM), characterized by cyclic pain, may involve pain modulation within the reward system (RS). The Catechol-O-methyltransferase (COMT) Val158Met polymorphism, which significantly influences dopamine activity, is linked to the regulation of both acute and chronic pain. This study examines the differential neurodynamic modulation in the RS associated with COMT Val158Met polymorphisms during menstrual pain among PDM subjects. Method: Ninety-one PDM subjects underwent resting-state fMRI during menstruation and were genotyped for COMT Val158Met polymorphisms. The amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses were used to assess the RS response. Psychological evaluations included the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Anxiety Inventory, and Beck Depression Inventory. Result: Val/Val homozygotes (n = 50) and Met carriers (n = 41) showed no significant differences in McGill Pain Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory. However, Met carriers exhibited lower scores on the Pain Catastrophizing Scale. Distinct FC patterns was observed between Val/Val homozygotes and Met carriers, specifically between the nucleus accumbens (NAc) and prefrontal cortex, NAc and inferior parietal lobe, ventral tegmental area (VTA) and prefrontal cortex, VTA and precentral gyrus, and VTA and superior parietal lobe. Only Met carriers showed significant correlations between ALFF and FC values of the NAc and VTA with pain-related metrics (McGill Pain Questionnaire and Pain Catastrophizing Scale scores). NAc ALFF and NAc-prefrontal cortex FC values positively correlated with pain-related metrics, while VTA ALFF and VTA-prefrontal cortex and VTA-superior parietal lobe FC values negatively correlated with pain-related metrics. Discussion: This study reveals that the COMT Val158Met polymorphism results in genotype-specific functional changes in the brain's RS during menstrual pain. In Met carriers, engagement of these regions is potentially linked to motivational reward-seeking and top-down modulation. This polymorphism likely influences the RS's responses, significantly contributing to individual differences in pain regulation.

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Resveratrol (RSV) has been shown to prevent epithelial-mesenchymal transition (EMT) in different diseases by modulating several signaling pathways, and RSV can prevent EMT by modulating the signaling of the TGF-ß/Smad axis. In the development of renal ischemia‒reperfusion injury (RIRI), RSV and MSC-derived exosomes could ameliorate RIRI via different signaling pathways. In this study, we aimed to investigate the effect of RSV plus MSC-derived exosomes on the prognosis of RIRI. Quantitative real-time polymerase chain reaction (PCR) was performed to measure the expression of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA in TCMK-1 cells and mice under various conditions. HE and Masson staining were used to evaluate kidney injury and fibrosis in mice under various conditions. RSV effectively maintained the TGF-ß- and AA-induced upregulation of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA expression in TCMK-1 cells. Moreover, MSC-derived exosomes effectively reinforced the effect of RSV on reducing the TGF-ß- and AA-induced upregulation of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA expression in TCMK-1 cells. Furthermore, MSC-derived exosomes enhanced the capability of RSV to maintain the RIRI-induced increases in Cr and BUN, as well as the upregulation of E-CAD, SMA, COL10A1, VMT and MMP-7 mRNA expression in mice. In addition, MSC-derived exosomes enhanced the capability of RSV to decrease RIRI-induced kidney injury and fibrosis in mice. Our findings showed that the administration of MSC-derived exosomes and RSV could suppress the TGF-ß-induced epithelial-mesenchymal transition. This suppressive effect was promoted by the coadministration of MSC-derived exosomes and RSV.

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This research focused on evaluating the clinical results of patients suffering from pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP), who received treatment with either ceftazidime-avibactam (CZA) alone or in combination with other antibiotics. From January 2020 to December 2023, we retrospectively analyzed CRKP-related pneumonia patients treated in two Chinese tertiary hospitals. Mortality was measured at 14 and 30 days as the primary outcome. Secondary outcomes included the 14-day microbiological cure rate and the 14-day clinical cure rate. Factors contributing to clinical failure were evaluated via both univariate analysis and multivariate logistic regression. To account for confounding factors, propensity score matching (PSM) was utilized. Among the 195 patients with CRKP infections, 103 (52.8 %) received CZA combination therapy, and 92 (47.2 %) patients received CZA monotherapy. The combination therapy group exhibited superior clinical and microbiological cure rates compared to the monotherapy group, with a 14-day clinical cure rate of 60.1 % vs. 45.7 % (P = 0.042) and a 14-day microbiological cure rate of 72.8 % vs. 58.6 % (P = 0.038), respectively. Combination therapy reduced mortality rates at 14 days (7.8 % vs. 17.4 %, P = 0.041), but not at 30 days (14.6 % vs. 25.0 %, P = 0.066). Even after using PSM, the group treated with the CZA combination continued to had a lower mortality rate at 14 days (5.9 % vs. 17.6 %, P = 0.039). The 14-day clinical cure rate for the combination therapy group was 63.2 %, and the 14-day microbial cure rate was 77.9 %. Both of these statistics were notably greater than those observed in the monotherapy group. Furthermore, the multivariate logistic regression model indicated a significant link between combination therapy and a decrease in clinical failure. Carbapenems were noted to be the most effective class of concomitant agents. Our findings indicate that patients with pneumonia due to CRKP benefit from combination treatment of CZA rather than monotherapy; administering carbapenem in combination with CZA in the early stages could provide considerable survival benefits.

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Although the Omicron variant has been associated with greater transmissibility and tropism of the upper respiratory tract, the clinical and pathogenic features of patients infected with the Omicron variant during an outbreak in China have been unclear. Adults with COVID-19 were retrospectively enrolled from seven medical centers in Guangzhou, China, and clinical information and specimens ( BALF, sputum, and throat swabs) from participants were collected. Conventional detection methods, metagenomics next-generation sequencing (mNGS), and other methods were used to detect pathogens in lower respiratory tract samples. From December 2022 to January 2023, we enrolled 836 patients with COVID-19, among which 56.7% patients had severe/critical illness. About 91.4% of patients were infected with the Omicron strain (BA.5.2). The detection rate of possible co-infection pathogens was 53.4% by mNGS, including Klebsiella pneumoniae (16.3%), Aspergillus fumigatus (12.2%), and Pseudomonas aeruginosa (11.8%). The co-infection rate was 19.5%, with common pathogens being Streptococcus pneumoniae (11.5%), Haemophilus influenzae (9.2%), and Adenovirus (6.9%). The superinfection rate was 75.4%, with common pathogens such as Klebsiella pneumoniae (26.1%) and Pseudomonas aeruginosa (19.4%). Klebsiella pneumoniae (27.1%% vs 6.1%, P < 0.001), Aspergillus fumigatus (19.6% vs 5.3%, P = 0.001), Acinetobacter baumannii (18.7% vs 4.4%, P = 0.001), Pseudomonas aeruginosa (16.8% vs 7.0%, P = 0.024), Staphylococcus aureus (14.0% vs 5.3%, P = 0.027), and Streptococcus pneumoniae (0.9% vs 10.5%, P = 0.002) were more common in severe cases. Co-infection and superinfection of bacteria and fungi are common in patients with severe pneumonia associated with Omicron variant infection. Sequencing methods may aid in the diagnosis and differential diagnosis of pathogens. IMPORTANCE: Our study has analyzed the clinical characteristics and pathogen spectrum of the lower respiratory tract associated with co-infection or superinfection in Guangzhou during the outbreak of the Omicron strain, particularly after the relaxation of the epidemic prevention and control strategy in China. This study will likely prompt further research into the specific issue, which will benefit clinical practice.

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Cervical cancer is a kind of tumor related to chronic HPV infection. Currently, the treatment of cervical cancer is guided mainly by clinicopathological factors. The role of tumor microenvironment in the prognosis and treatment of cervical cancer has been ignored. We aimed to use bioinformatics to identify the molecular subtypes in cervical cancer and construct a predictive nomogram combining a matrix-immune signature (MIS) and clinicopathological factors to support treatment decisions. Two cervical cancer subtypes with different prognoses were identified based on matrix- and immune-genes in TCGA-CESC. The MIS was developed using Cox regression and Lasso algorithm and verified in the Cancer Genome Characterization Initiative (CGCI) using time-dependent receiver operating characteristic (ROC) curve analysis. Multivariable analysis identified lymph node metastases, lymphovascular space invasion, and the MIS as independent prognostic factors, which were used to construct the predictive nomogram. The areas under the ROC curve of the model were 0.872, 0.879, and 0.803 for the 1-, 3-, and 5-year periods, respectively. The C-index was 0.845. Calibration curves confirmed the excellent prognosis prediction of the nomogram. The nomogram indicted a 3-year survival rate of > 90% in patients with a total score > 110.1. The constructed predictive nomogram has significant implications for prognostic assessment and treatment selection in cervical cancer.

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OBJECTIVE: Pregnancy care can improve maternal pregnancy outcomes. Cluster nursing, an evidence-based, patient-centered model, enhances pregnancy care, can provide patients with high-quality nursing services, has been widely used in clinical practice in recent years. However, most previous studies evaluated cluster nursing program only for a single clinical scenario. In this study, we developed and implemented a antenatal cluster care program for various prenatal issues faced by puerpera to analyze its application effect. METHODS: This is a historical before and after control study. 89 expectant mothers who had their prenatal information files registered in the outpatient department of a grade III, level A hospital from June 2020 to September 2021 were finally enrolled in observation group, and received prenatal cluster management. Another set of 89 expectant mothers from January 2019 to December 2019 were included in the control group and received traditional routine prenatal management. The effect of cluster nursing management on maternal delivery and postpartum rehabilitation was evaluated and compared between the two groups. RESULTS: Compared with the control group, the observation group had a significantly higher natural delivery rate, better neonatal prognosis, higher rates of exclusive breastfeeding, lower incidence of postpartum complications, shorter postpartum hospital stay, better postpartum health status, and higher satisfaction with nursing services. Compared with before intervention, the SAS and SDS scores of the observation group showed significant improvement after intervention. CONCLUSION: Antenatal cluster care is beneficial to improve maternal and neonatal outcomes, and can have positive effects on natural pregnancy and breastfeeding, while improving the multimedia health education ability of medical care and emphasizing the importance of social support.

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Straw, as a kind of biomass waste, has the advantages of low cost and abundant storage, which makes it a promising renewable resource. Using rice straw as a carbon source, carbon nanosheets were prepared by a two-step carbonization method combining low-temperature pyrolysis and low-temperature hydrothermal, and they were used as H2S removal agents. The results showed that during the two-step carbonization process, the adsorption performance of carbon nanosheets for H2S showed a tendency of enhancing and then weakening with the increase of pyrolysis temperature in the first step, and the sulfur capacity could reach 3.1 mg/g at the maximum of the pyrolysis temperature of 200 °C, which was superior to or close to that of the modified or activated carbon. The XPS, EPR, and CO2-TPD tests showed that the surface of carbon nanosheets was alkaline, containing a large number of hydroxyl groups and the presence of phenoxy persistent free radicals or semiquinone persistent free radicals. It was analyzed that the direct or indirect oxidation of H2S by the persistent radicals under an alkaline environment could convert the -2-valent sulfur into -1-, 0- and +6-valent sulfur to realize the adsorption and removal of H2S. This work, while offering the possibility of utilizing carbon nanosheets made from straw as a material for H2S adsorption and removal, also expands the application of straw waste in exhaust gas treatment.

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Introduction: Percussionists stand out for their expertise in rhythm, with the network for musical rhythm (NMR) serving a vital neurological function in their improvisation, which is deeply rooted in comprehensive musical knowledge. Our research examines the central representations of various improvisation tactics used by percussionists and investigates the interactions between the NMR and other relevant neural networks. Methods: Twenty-five percussionists participated in functional magnetic resonance imaging (fMRI) sessions, which included two cognitive strategies of improvisation. Structural improvisation (SIMP) emphasized rhythmic patterns, while free improvisation (FIMP) focused on musical spontaneity. Sight-reading scenario served as the reference condition. Paired t-tests were utilized for comparative analyses. Results: The findings revealed a dynamic interplay characterized by increased activity in the executive control network and NMR, along with decreased activity in the default mode network during SIMP. During FIMP, heightened activity was observed in the executive control network, NMR, limbic, and memory systems. In both SIMP vs. sight-reading and FIMP vs. sight-reading comparisons, the visual network's activity decreased, a trend also observed in the comparative analysis of FIMP vs. SIMP. Discussion: In SIMP, percussionists leverage external rhythmic signals, resulting in heightened NMR and ECN activity and reduced DMN activity. In contrast, FIMP is characterized by a rise in activity within the NMR, ECN, limbic system, memory system, and reward system, underscoring the vital roles of motivation and memory in the rapid production of spontaneous musical ideas within set frameworks. The diminished activity in the visual network during FIMP compared to SIMP suggests less reliance on visual stimuli in FIMP. These findings suggest that various improvisational tactics may engage different neural pathways.

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BACKGROUND: An association has been observed between primary biliary cholangitis (PBC) and systemic rheumatic diseases (SRDs) in observational studies, however the exact causal link remains unclear. We aimed to evaluate the causal effects of PBC on SRDs through Mendelian randomization (MR) analysis. METHODS: The genome-wide association study (GWAS) summary data were obtained from MRC IEU OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as instrumental variables. Inverse variance weighted was used as the main approach to evaluate the causal effects of PBC on Sjögren syndrome (SS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by MR‒Egger intercept test and Cochran's Q value, respectively. RESULTS: PBC had causal effects on SS (OR = 1.177, P = 8.02e-09), RA (OR = 1.071, P = 9.80e-04), SLE (OR = 1.447, P = 1.04e-09), SSc (OR = 1.399, P = 2.52e-04), MCTD (OR = 1.306, P = 4.92e-14), and PM (OR = 1.416, P = 1.16e-04). Based on the MR‒Egger intercept tests, horizontal pleiotropy was absent (all P values > 0.05). The robustness of our results was further enhanced by the leave-one-out method. CONCLUSIONS: Our research has provided new insights into PBC and SRDs, indicating casual effects on various SRDs.

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BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a rare and serious condition, and severe APIP (SAPIP) can lead to pancreatic necrosis, abscess, multiple organ dysfunction, and other adverse maternal and infant outcomes. Therefore, early identification or prediction of SAPIP is important. AIM: To assess factors for early identification or prediction of SAPIP. METHODS: The clinical data of patients with APIP were retrospectively analyzed. Patients were classified with mild acute pancreatitis or severe acute pancreatitis, and the clinical characteristics and laboratory biochemical indexes were compared between the two groups. Logical regression and receiver operating characteristic curve analyses were performed to assess the efficacy of the factors for identification or prediction of SAPIP. RESULTS: A total of 45 APIP patients were enrolled. Compared with the mild acute pancreatitis group, the severe acute pancreatitis group had significantly increased (P < 0.01) heart rate (HR), hemoglobin, neutrophil ratio (NEUT%), and neutrophil-lymphocyte ratio (NLR), while lymphocytes were significantly decreased (P < 0.01). Logical regression analysis showed that HR, NEUT%, NLR, and lymphocyte count differed significantly (P < 0.01) between the groups. These may be factors for early identification or prediction of SAPIP. The area under the curve of HR, NEUT%, NLR, and lymphocyte count in the receiver operating characteristic curve analysis was 0.748, 0.732, 0.821, and 0.774, respectively. The combined analysis showed that the area under the curve, sensitivity, and specificity were 0.869, 90.5%, and 70.8%, respectively. CONCLUSION: HR, NEUT%, NLR, and lymphocyte count can be used for early identification or prediction of SAPIP, and the combination of the four factors is expected to improve identification or prediction of SAPIP.

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The gut microbiota, a pivotal component of the intestinal mucosal barrier, is critical for host resistance to enteric pathogen infection. Here, we report a novel function of the potentially probiotic Lactococcus garvieae strain LG1 (L. garvieae strain LG1) in maintaining intestinal mucosal barrier integrity and protecting against foodborne Clostridium perfringens (C. perfringens) infection. L. garvieae was isolated from the intestinal contents of Chinese Mongolian sheep (MS) and exhibited potential probiotic properties. In a C. perfringens enterocolitis model, L. garvieae-pretreated mice were less susceptible to C. perfringens infection compared with Phosphate buffered solution (PBS)-pretreated mice, which manifested as higher survival rates, lower pathogen loads, less weight loss, mild clinical symptoms and intestinal damage, and minor inflammation. Further mechanistic analysis showed that L. garvieae could ameliorate the disruption of intestinal permeability and maintain the integrity of the intestinal mucosal barrier by promoting the expression of tight junction proteins and mucoproteins. Moreover, L. garvieae was also able to facilitate antimicrobial peptide expression and ameliorate dysbiosis of the gut microbiota caused by C. perfringens. Together, these findings highlight the prospect of immunomodulatory potentially probiotic L. garvieae and might offer valuable strategies for prophylaxis and/or treatment of pathogenic C. perfringens mucosal infection. IMPORTANCE: C. perfringens necrotic enteritis leads to losses of about US $2 billion to the poultry industry worldwide every year. Worse, US Centers for Disease Control and Prevention (CDC) has estimated that C. perfringens causes nearly 1 million foodborne illnesses in the United States annually. Nowadays, the treatment recommendation is a combination of a broad-spectrum synergistic penicillin with clindamycin or a carbapenem, despite growing scientific concern over antibiotic resistance. The global understanding of the gut microbiome for C. perfringens infection may provide important insights into the intervention. L. garvieae originated from Mongolian sheep intestine, exhibited potentially probiotic properties, and was able to limit C. perfringens enterocolitis and pathogenic colonization. Importantly, we found that L. garvieae limits C. perfringens invasion via improving intestinal mucosal barrier function. Also, L. garvieae alleviates C. perfringens-induced gut microbiota dysbiosis. It allowed us to convince that utilization of probiotics to promote protective immunity against pathogens infection is of pivotal importance.

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Megalurothrips usitatus Bagnall, an important pest of bean plants, is primarily managed with synthetic insecticides. M. usitatus has developed considerable resistance to various insecticides in multiple cowpea-growing areas in Hainan Province, China, posing challenges to its control in the field. Light control technology is a potentially effective physical control method for M. usitatus. The vision of thrips is highly sensitive to UV light, whereas other biological characteristics remain unknown. Therefore, this study evaluated the effects of ultraviolet light on the biological characteristics of M. usitatus. Results showed that the egg, larval, and pupal stages of M. usitatus were significantly shortened, and the emergence rate (79.59%) and adult survival rate (77.95%) were reduced under a devoid of UV light environment (UV-), compared with the full-spectrum light (control treatment group, CK) (p < 0.05). However, the single spawning quantity and total amount of spawning were significantly higher, and the sex ratio (57%) was the highest under UV- (p < 0.05). Single UV light (UV+) only affected the pupation rate. Also, the antioxidant enzymes, polyphenol oxidase, superoxide dismutase (SOD), and peroxidase activities were significantly and negatively correlated with the progression of generations under UV-, whereas catalase and SOD activities were significantly and positively correlated with the progression of generations under UV+. The UV- light conditions significantly interfered with the behavior selection of M. usitatus. The results of this study showed that the adaptability of M. usitatus populations would be greatly reduced in the absence of ultraviolet light, providing a theoretical basis for the control of M. usitatus populations.

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Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.

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AIM: This study aimed to evaluate examinees' perceptions of the performance of student standardized patients (SPs) and to explore student SPs' experiences. BACKGROUND: Objective structured clinical examination (OSCE) is a standard approach to the task of evaluating students' clinical competency that relies on SPs. However, professional SPs are characterized by high costs and insufficient availability. Training students to serve as SPs can help address this lack of OSCE resources. However, only preliminary evidence regarding this process and its feasibility has been reported. DESIGN: We used a concurrent mixed-method study design that included quantitative surveys and qualitative group interviews. METHODS: Our sample consisted of two-year Bachelor of Nursing program students and trained student SPs who were recruited in May 2021. We used a 5-item performance evaluation tool to assess the SPs' performance. The reliability of this evaluation tool was indicated by a Cronbach's α coefficient of.95. Descriptive statistics were used to assess the examinees' satisfaction with the student SPs' performance using SPSS 28.0 software. We used a semi-structured interview guide during a group interview; the interview was transcribed verbatim and analyzed via thematic analysis with the assistance of Microsoft Word software. RESULTS: Eighty-two nursing school students responded to the survey and 10 student SPs were included in a group interview. Nursing school students rated SPs' performance favorably. The mean score assigned to the SPs on the performance scale was 4.41 out of 5. The student SPs described the challenges and benefits that they experienced regarding their role. The challenges they described included 1) staying true to my role, 2) overcoming a physically overwhelming role and 3) facing the threat of insecurity. However, the corresponding benefits included 1) gaining rewards, 2) advancing nursing competency and 3) experiencing a sense of accomplishment. CONCLUSION: After undergoing training, the SPs performed well. They experienced a variety of challenges and obtained certain benefits. In health care education, recruiting students to serve as SPs is feasible.

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Lead (Pb) is harmful to almost all organs, particularly the developmental neural system, and previous studies revealed oxidative stress played an important role in Pb neurotoxicity. Rutin, a type of flavonoid glycoside found in various plants and fruits, is widely used as a dietary supplement due to its antioxidant and anti-inflammatory properties, but whether rutin could protect against Pb neurotoxicity is unclear. In this study, we found rutin treatment significantly alleviated Pb-induced cell death, oxidative stress, and inflammation, resulting in cell survival. Moreover, rutin treatment promoted nuclear factor erythroid 2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and subsequently activated antioxidant and detoxifying enzymes expression including HO-1. Knocking down Nrf2 by siRNA transfection abolished this protection of rutin against Pb. Overall, rutin could alleviate Pb-induced oxidative stress, inflammation, and cell death by activating the Nrf2/antioxidant response elements (ARE) system.

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Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development. Defects in the process can result in severe organ mispositioning. Coiled-coil domain containing 141 (CCDC141) has been previously known as a centrosome-related gene, but its role in left-right (LR) asymmetry has not been characterized. In this study, we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects. The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways, cilia function, and Kupffer's vesicle formation. Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns, ccdc141-null mutants show no apparent abnormality, suggesting a genetic compensation response effect. In parallel, we observe a marked reduction in α-tubulin acetylation levels in the ccdc141 crispants. The treatment with histone deacetylase (HDAC) inhibitors, particularly the HDAC6 inhibitor, rescues the ccdc141 crispant phenotypes. Furthermore, exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations, with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G. Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns, identifying it as a candidate gene for laterality defects.

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