The interest in covalent drugs has resurged in recent decades, spurring the development of numerous specialized computational docking tools to facilitate covalent ligand design and screening. Herein, we present CarsiDock-Cov, a new paradigm distinguishing itself as the first deep learning (DL)-guided approach for covalent docking. CarsiDock-Cov retains the core components of its non-covalent predecessor, leveraging a DL model pretrained on millions of docking complexes to predict protein-ligand distance matrices, along with a dedicated-designed geometric optimization procedure to convert these distances into refined binding poses. Additionally, it incorporates several key enhancements specifically tailored to optimize the protocol for covalent docking applications. Our approach has been extensively validated on multiple public datasets regarding the docking and screening of covalent ligands, and the results indicate that our approach not only achieves comparably improved applicability compared to its non-covalent predecessor, but also exhibits competitive performance against various state-of-the-art covalent docking tools. Collectively, our approach represents a significant advance in covalent docking methodology, offering an automated and efficient solution that shows considerable promise for accelerating covalent drug discovery and design.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Norovirus is the global leading cause of epidemic and endemic acute gastroenteritis in people of all ages.To inves-tigate the genetic diversity of GⅡ genogroup noroviruses linked to clustered infections in northeast Chongqing,we collected anal swabs or environmental smears from 11 norovirus outbreaks during 2021-2022.Norovirus RNA was detected by quantitative real-time PCR(qRT-PCR),and partial viral RdRp/capsid genes were amplified by reverse transcription PCR(RT-PCR)and sequenced.Among samples from 11 outbreaks in 4 districts and counties,55 strains of GⅡ genogroup norovirus were detected.Six genotypes were identified with an online norovirus genotyping tool(http://www.rivm.nl/mpf/norovirus/typingtool).Genotype GⅡ.17[P17]was associated with four outbreaks;the co-circulating GⅡ.17[P17]and GⅡ.1[P16]caused another out-break;GⅡ.6[P7]and GⅡ.8[P8]respectively were linked to two outbreaks;and GⅡ.3[P12]and GⅡ.2[P16]respectively ac-counted for one outbreak.Phylogenetic analysis also indicated that 55 GⅡ genogroup strains formed five clusters,with norovir-uses of identical genotypes from diverse events belonging to the same cluster,and that genetically distinct genotypes from di-verse events belonged to different clusters.Therefore,our results revealed that multiple genotypes associated with norovirus outbreaks were circulating in northeast Chongqing,and GⅡ.17[P17]was the predominant genotype linked to these out-breaks during 2021-2022.Most norovirus outbreak events were caused by single sources,and genetic relationships were demonstrated among noroviruses of identical genotypes from diverse events.

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.
Animals ; Mice ; Corticotropin-Releasing Hormone/metabolism* ; Nucleus Accumbens/metabolism* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Sleep ; Sleep Wake Disorders ; Stress, Psychological/complications*

The aim of this study was to evaluate the roles of interleukin (IL)-17A in risk stratification and prognosis of patients with sepsis-associated acute kidney injury (SAKI). Methods: We enrolled 146 sepsis patients (84 non-SAKI and 62 SAKI patients) admitted to the emergency department from November 2020 to November 2021. Patients with SAKI were differentiated based on the severity of acute kidney injury. All clinical parameters were evaluated upon admission before administering antibiotic treatment. Inflammatory cytokines were assessed using flow cytometry and the Pylon 3D automated immunoassay system (ET Healthcare). In addition, a receiver operating characteristic (ROC) curve was utilized to determine the prognostic values of IL-17A in SAKI. Results: The levels of creatinine, IL-2, IL-4, IL-6, IL-17A, tumor necrosis factor alpha, C-reactive protein, and procalcitonin (PCT) were significantly higher in the SAKI group than in the non-SAKI group (p < 0.05). The level of IL-17A revealed significant differences among stages 1, 2, and 3 in SAKI patients (p < 0.05). The mean levels of PCT, IL-4, and IL-17A were significantly higher in the non-survival group than in the survival group in SAKI patients (p < 0.05). In addition, the area under the ROC curve of IL-17A was 0.811. Moreover, the IL-17A cutoff for differentiating survivors from non-survivors was 4.7 pg/mL, of which the sensitivity and specificity were 77.4% and 71.0%, respectively. Conclusion: Elevated levels of IL-17A could predict that SAKI patients are significantly prone to worsening kidney injury with higher mortality. The usefulness of IL-17A in treating SAKI requires further research.

Objective: To examine the association of body mass index (BMI) and waist circumference (WC) with frailty among oldest-old adults in China. Methods: A total of 7 987 people aged 80 years and older (oldest-old) who participated in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2017-2018 were included. Information on demographic characteristics, behavior pattern, diet, activities of daily living, cognitive function, health status, disease condition were collected by questionnaire and physical examination. Generalized linear mixed model and restricted cubic splines (RCS) were used to analyze the association of BMI and WC with frailty. Results: The mean age of all participants was 91.7 years, and their mean BMI and WC were (21.3±3.5) kg/m² and (82.9±10.5) cm, respectively. The proportion of male was 42.3% (3 377/7 987), and the proportion of people with frailty was 33.7% (2 664/7 987). After controlling confounding factors, compared with T₂ (19.1-22.1 kg/m²) of BMI, the OR (95%CI) of the female T₁ (<19.1 kg/m²) and T₃ (≥22.2 kg/m²) group was 1.39 (1.17-1.65) and 1.27 (1.07-1.52), respectively. Compared with T₂ (77-85 cm) of WC, the OR (95%CI) of female T₁ (<77 cm) and T₃ (≥86 cm) group was 1.20 (1.01-1.42) and 1.10 (0.93-1.31), respectively. The results of multiple linear regression model with restrictive cubic spline showed that there was a non-linear association of BMI and WC with frailty in female. Conclusion: There is a U-shaped association of BMI and WC with frailty in female participants.
Adult ; Male ; Female ; Humans ; Aged, 80 and over ; Waist Circumference ; Body Mass Index ; Frailty/epidemiology* ; Activities of Daily Living ; China/epidemiology* ; Risk Factors

OBJECTIVE: To establish the occupational exposure limit for trimethyltin chloride(TMT) in workplace air. METHODS:According to the GBZ/T 210.1-2008 Guide for Establishing Occupational Health Standards--Part 1: Occupational Exposure Limits for Airborne Chemicals in the Workplace, the relevant literatures on toxicology, population epidemiology and foreign occupational exposure limit of TMT were collected and analyzed. A total of 276 workers with TMT occupational exposure were selected as the exposure group and 25 workers without TMT occupational exposure were selected as the control group.Worksite survey of occupational health and occupational medical examination were carried out. Combined with the literature data, the occupational exposure limit of TMT in the workplace air was calculated by using the 90% medical reference level(internal exposure limit) of the urine TMT level of workers who exposed to TMT without moderate hypokalemia. RESULTS: The time-weighted average of TMT in the workplace air is 0.100 mg/m~3 and the short-term exposure limit is 0.200 mg/m~3 in the United States based on total organic tin. The highest concentration of TMT in the workplace air in Germany is 0.005 mg/m~3. The literature data analysis results showed that the incubation period of TMT poisoning is mostly 3-6 days, and the main symptoms of TMT poisoning are hypokalemia in the early stage, followed by neuropsychiatric symptoms such as headache, memory loss and aggressive behavior. The median(M) and the 0-100 th percentile(P_0-P_(100)) of exposure to TMT were 8.35(< 0.20-91.40) μg/m~3 in the exposure group. The individual TMT exposure level of workers in different positions from high to low were crushing, granulation, withdrawal and assembly positions. The M(P_0-P_(100)) of urinary TMT level in the exposure group was 16.94(<0.50-591.14) μg/L. There was a positive correlation between the individual TMT exposure level and urine TMT level in the exposure group(Spearman correlation coefficient=0.62, P<0.01). The detection rate of hypokalemia in the exposure group was higher than that in the control group(26.1% vs 4.0%, P < 0.05). However, there was no significant difference in the detection rate of moderate hypokalemia between the two groups(3.3% vs 0.0%, P>0.05). The 90% medical reference value of urine TMT was 89.90 μg/L in workers exposed to TMT without moderate hypokalemia. CONCLUSION: In order to prevent acute hypokalemia damage caused by TMT, we recommended that the occupational exposure limit of TMT in the workplace air should be set at 0.025 mg/m~3 in China, and this limit should be the maximum allowable concentration.

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.
Aged ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis ; Chemoradiotherapy ; Female ; Humans ; Male ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Recurrence, Local ; Programmed Cell Death 1 Receptor/antagonists & inhibitors* ; Rectal Neoplasms/therapy* ; Retrospective Studies ; Risk Factors ; Treatment Outcome

Arsenic is a potent toxic heavy metal found in the environment that can causes health problems, including liver disease in humans and animals. Chronic exposure to arsenic remains an environmental health problem worldwide, affecting hundreds of millions of people. Although the oxidative stress and apoptosis induced by arsenic have been confirmed, the underlying mechanism of apoptosis has not been fully elucidated. The purpose of this study is to investigate whether sodium arsenite (SA)induced liver toxicity is related to the regulation of DNA replication and repair pathways. The results of MTT and microscopy showed that SA has an inhibitory effect on the proliferation of human hepatocytes (L02), and this effect is time and concentration dependent. Flow cytometry detected the effects of different concentrations of SA on L02 cells. Compared with the control group, high concentrations of SA significantly affected the L02 cell cycle. In addition, RNA sequencing results showed that the differentially expressed genes in cells after SA treatment were concentrated in the DNA replication process and repair pathways. The effect of SA treatment on the expression of human RECQ DNA helicase and repair genes was further confirmed by Western blot and real-time quantitative PCR. In vitro study showed that SA treatment inhibited cell proliferation, and induced apoptosis as well as DNA damage and cell cycle arrest of human liver cell L02. Collectively, these results indicate that arsenic poisoning is related to the regulation of DNA replication and repair pathways, which provides insight for understanding the molecular mechanism of arsenic poisoning.