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.

OBJECTIVE: To evaluate the clinical significance of a hemizygous c.1042-10G>C variant of the SLC9A7 gene NM_001257291.2) previously identified in individuals with neurodevelopmental disorders, and to provide an evidence-based guidance for prenatal genetic counseling. METHODS: Four families presented at the Medical Genetics Center of Henan Provincial People's Hospital between December 2022 and July 2024 were included in this study. Phenotypic information and biological samples were collected from family members. Genomic DNA was extracted and subjected to whole-exome sequencing and copy number variation analysis to identify candidate pathogenic variants. Sanger sequencing was performed for familial co-segregation analysis. Reverse-transcription PCR was used to assess the RNA splicing pattern of the variant in peripheral blood samples. Quantitative PCR was employed to analyze the expression profiles of various SLC9A7 transcripts in fetal brain tissue and peripheral blood samples. Pathogenicity of the variant was classified based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Henan Provincial People's Hospital (Ethics No.: 2021-171). RESULTS: Six hemizygous males carrying the SLC9A7 c.1042-10G>C variant were identified among the four families, which included three adult males and two male infants with normal phenotypes. Only one affected male from family 3 exhibited global developmental delay, short neck, webbed neck, ocular dysplasia, and congenital corneal leukoma. He also had a history of perinatal asphyxia and carried an additional hemizygous variant HUWE1 c.12283C>G. Reverse-transcription PCR showed no aberrant splicing in heterozygous or hemizygous carriers compared to healthy controls, suggesting that the variant does not affect RNA splicing. Quantitative PCR revealed that NM_001257291.2 is the predominant transcript expressed in fetal brain tissue and peripheral blood. CONCLUSION The SLC9A7 c.1042-10G>C variant does not alter RNA splicing and is present in multiple phenotypically normal males, which supported its classification as a benign variant.
Humans ; Male ; Female ; Genetic Counseling ; Pedigree ; Adult ; DNA Copy Number Variations/genetics* ; Sodium-Hydrogen Exchangers/genetics* ; Exome Sequencing

OBJECTIVE: To investigate the clinical phenotype and genetic characteristics of an infertile woman carrying a novel PADI6 gene variant. METHODS: An infertile woman who visited the Medical Genetics Center of Henan Provincial People's Hospital on April 29, 2024 was selected as the study subject. Clinical data of the proband and her family members were collected. Peripheral blood samples were obtained from the proband and her husband for genomic DNA extraction. Whole-exome sequencing (WES) was performed. Candidate variant was verified among the family members by Sanger sequencing. The pathogenicity of candidate variant was classified according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants. Relevant literature on the pathogenic variants of the PADI6 gene was reviewed for genotype-phenotype correlation analysis. This study was approved by the Medical Ethics Committee of Henan Provincial People's Hospital (Ethics No.: 2021-171). RESULTS: The proband was a 35-year-old woman who underwent two oocyte retrieval cycles, yielding a total of five oocytes, with all embryos arrested at day 3 post-fertilization. WES identified a homozygous PADI6 variant, c.367+4_367+7del. In vitro splicing assay confirmed that this variant can cause skipping of exon 3, leading to a frameshift and alterations in the protein structure or premature termination of translation. Literature review identified 12 relevant publications, and the PADI6 c.367+4_367+7del was determined to be a novel variant. CONCLUSION The homozygous PADI6 c.367+4_367+7del variant probably underlay the pathogenesis of infertility in the proband.
Humans ; Female ; Infertility, Female/genetics* ; Adult ; Protein-Arginine Deiminase Type 6/genetics* ; Pedigree ; Exome Sequencing ; Mutation

Objective:To analyze the effects of preoperative renin-angiotensin system inhibitor (RASi) use on postoperative renal function and short-term and long-term prognosis in patients undergoing coronary artery bypass grafting (CABG).Methods:A retrospective cohort analysis was conducted. Based on the registration study data of CABG patients at Fuwai Hospital, Chinese Academy of Medical Sciences, the clinical data of adult patients who underwent CABG from January 2013 to December 2022 were analyzed. Preoperative use of RASi (PreRASi) was defined as receiving RASi treatment within 48 hours before surgery. Postoperative acute kidney injury (AKI) was defined using the diagnostic criteria of Kidney Disease: Improving Global Outcomes (KDIGO). Demographic characteristics, past medical history, comorbidities, preoperative medication, preoperative laboratory test results, specific information on surgical procedures, and postoperative treatment related data were extracted. The primary endpoint was the incidence of postoperative AKI. Secondary endpoints included in-hospital all-cause mortality and all-cause mortality within the longest follow-up period. According to whether RASi was used before surgery, the patients were divided into PreRASi group and No-PreRASi group. The baseline data of the two groups were balanced by propensity score matching (PSM). Logistic regression model and Cox proportional hazards model were used to assess the correlation between PreRASi and postoperative AKI and clinical outcomes, and analyze the subgroups of hypertension and heart failure with preserved ejection fraction (HFpEF) in the cohort.Results:A total of 33?884 patients who underwent CABG were included, with a mean follow-up duration of (3.0±2.4) years and the longest follow-up duration up to 8.5 years. There were 9?128 cases (26.94%) in the PreRASi group and 24?756 cases (73.06%) in the No-PreRASi group. The incidence of postoperative AKI in the PreRASi group was 47.61% (4?346 cases), compared to 52.37% (12?964 cases) in the No-PreRASi group. Two groups were matched with 5?094 patients each. Compared to the No-PreRASi group, both before and after PSM, PreRASi was associated with a reduction of risk of postoperative AKI [before PSM: odds ratio ( OR) = 0.834, 95% confidence interval (95% CI) was 0.793-0.877, P < 0.001; after PSM: OR = 0.875, 95% CI was 0.808-0.948, P = 0.001]. Subgroup analysis of hypertensive and HFpEF patients showed that PreRASi was associated with a decreased risk of postoperative AKI before and after PSM. The in-hospital mortality for the PreRASi and No-PreRASi groups were 0.61% (56 cases) and 0.49% (121 cases), respectively. Analysis of the overall cohort and subgroups with hypertension and HFpEF showed no correlation between PreRASi and in-hospital mortality or longest follow-up mortality. Conclusion:The perioperative use of RASi can reduce the risk of postoperative AKI in patients undergoing CABG, has a certain renal protective effect, but is not associated with short-term or long-term death risk after surgery.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature. This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC. METHODS: Transcriptomic data of HGSOC patients' samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas (TCGA) database. Hub genes' immune landscapes were estimated by the Tumor Immune Estimation Resource (TIMER) database. Finally, using 25 HGSOC patients' cancer tissues and 10 normal fallopian tube tissues, immunohistochemistry (IHC) was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics (FIGO) stages. RESULTS: Fourteen DEGs, ADIPOQ , ALPK2 , BARX1 , CD37 , CNR2 , COL5A3 , FABP4 , FAP , GPR68 , ITGBL1 , MOXD1 , PODNL1 , SFRP2 , and TRAF3IP3 , were upregulated in metastatic tumors in every database while CADPS , GATA4 , STAR , and TSPAN8 were downregulated. ALPK2 , FAP , SFRP2 , GATA4 , STAR , and TSPAN8 were selected as hub genes significantly associated with survival and recurrence. All hub genes were correlated with tumor microenvironment infiltration, especially cancer-associated fibroblasts and natural killer (NK) cells. Furthermore, the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage, and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC ( P = 0.0002 and P = 0.0001, respectively). CONCLUSIONS This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses. We identified six hub genes that were correlated with the progression of HGSOC, particularly FAP and SFRP2 , which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.
Humans ; Female ; Ovarian Neoplasms/pathology* ; Prognosis ; Gene Expression Profiling ; Transcriptome ; Tumor Microenvironment ; Receptors, G-Protein-Coupled/therapeutic use* ; Tetraspanins/genetics* ; Protein Kinases ; Integrin beta1/therapeutic use*

Objective:To compare the clinical and prognostic characteristics of ovarian endometrioid carcinoma (OEC) patients with synchronous endometrial lesions and patients with pure OEC.Methods:A retrospective review of the medical records of patients received initial treatment and a postoperative pathological diagnosis of OEC at Peking University People′s Hospital between August 1998 and December 2017 were performed. According to the inclusion criteria, a total of 56 patients with OEC were included in the study, including 13 patients concurrent with simultaneous endometrial lesions (Group A) and 43 patients with pure OEC (Group B).Results:Patients with synchronous endometrial lesions accounted for 23% (13/56). Mean age of Group A at diagnosis was (44.9±8.3) years old, 2/13 of patients were postmenopausal, and no one had a history of hypertension, the first symptom of 5/13 people was irregular vaginal bleeding. Mean age of Group B patients at diagnosis was (52.7±10.2) years old, 53% (23/43) of patients were postmenopausal, and 28% (12/43) patients had the history of hypertension, the first symptom of 4 (9%, 4/43) people was irregular vaginal bleeding. The differences of age, menopause status, history of hypertension and initial symptoms between the two groups were statistically significant (all P<0.05). There were no significant differences in fertility history, dysmenorrhea history, age of menarche, history of endometriosis, preoperative and postoperative CA 125 level, International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, metastatic site and platinum-based chemotherapy drug resistance between the two groups (all P>0.05). The overall 5-year survival rate of OEC patients was 91.6%, and the overall 5-year progression-free survival rate was 76.6%. Among them, the 5-year survival rate of the OEC concurrent with simultaneous endometrial lesions group was 80.2%, and the pure OEC group was 93.4%; the 5-year progression-free survival rate of the OEC concurrent with simultaneous endometrial lesions group was 74.1%, and the 5-year progression-free survival rate of the pure OEC group was 77.3%. There were no significant differences between the two groups (all P>0.05). Multivariate analysis showed that the independent factors for the prognosis of OEC patients were FIGO stage ( P=0.006) and residual lesion size ( P=0.020). Conclusions:OEC patients have a high proportion of simultaneous endometrial lesions. OEC with simultaneous endometrial lesions are younger than patients with pure OEC. Synchronous endometrial lesions do not affect the prognosis of patients with OEC.

Objective:To investigate the association of time in range(TIR) with the severity of coronary artery disease and acute coronary syndrome in patients with type 2 diabetes mellitus.Methods:A total of 216 patients with type 2 diabetes mellitus and coronary heart disease were recruited and undergone anthropometric and biochemical measurements, continuous glucose monitoring, and calculation of SYNTAX score. TIR was defined as the percentage of time within the glucose range of 3.9-10.0 mmol/L during 24 h. Spearman correlation analysis and multivariate linear regression analysis were used to evaluate the correlation factors of SYNTAX score. Multivariate logistic regression analysis was used to analyze the association of TIR with the severity of coronary artery disease and acute coronary syndrome. Results:Compared with patients with mild coronary artery disease, TIR in patients with moderate to severe coronary artery disease was lower[(69.4±17.3)% vs (60.8±17.8)%, t=3.0, P=0.003], and HbA 1C of patients with moderate to severe coronary artery disease was higher [(9.6±1.7)% vs (8.8±1.6)%, t=3.3, P=0.001]. SYNTAX score was negatively correlated with TIR ( r=-0.251, P<0.01) and positively correlated with HbA 1C ( r=0.249, P<0.01). Moreover, compared with HbA 1C (standardized coefficients=0.181, P=0.007), TIR (standardized coefficients=-0.192, P=0.004) had a greater influence on SYNTAX score. Multivariate linear regression analysis showed that TIR, HbA 1C, duration of diabetes and smoking were independently correlated with SYNTAX score. Multivariate logistic regression analysis revealed that compared with TIR Q1, Q3 and Q4 were independent protective factors for moderate to severe coronary artery disease (respectively, OR=0.61 and 0.59, 95% CI 0.39-0.96 and 0.38-0.94, P=0.014 and 0.009) and acute coronary syndrome (respectively, OR=0.51 and 0.39, 95% CI 0.32-0.95 and 0.26-0.75, P=0.022 and 0.008). Conclusion:TIR was significantly and independently correlated with the severity of coronary artery disease and acute coronary syndrome in type 2 diabetes mellitus after controlling confounding factors. When TIR level was decreased, the severity of coronary artery disease was aggravated, and SYNTAX score and the risk of acute coronary syndrome was increased.

Objective To explore the correlation between pre-transplantation donor kidney biopsy and short-term renal function after transplantation.Methods This study include 240 kidney transplantation of donation after cardiac death (DCD) from July 2016 to April 2018.Banff's score of donor kidney biopsy was employed for estimating kidney status.Results No significant correlation existed between rate of glomerulosclerosis and delayed graft function (DGF) (P =0.815).The rate of glomerulosclerosis was significantly correlated with 1-week estimated glomerular filtration rate (eGFR) and discharge eGFR (P＜0.05).Based upon the glomerulosclerosis rate,the patients were divided into two groups ＜ 20％ (n =220) and ≥20％ (n =20),there was no significant inter-group difference in DGF,1-week eGFR or discharge eGFR (P＞0.05).Arterial fibrosis was significantly positively correlated with DGF and negatively with 1-week eGFR and discharge eGFR (P＜0.05).Statistically significant inter-group differences existed in 1-week eGFR and discharge eGFR that arterial fibrosis scores ＜ 2 (n =19) and ≥2 (n =41) (P＜0.05).Arteriolar hyalinosis score was negatively correlated with 1-week eGFR and discharge eGFR (P＜0.05).Based upon arteriolar hyalinosis scores,they were divided into two groups ＜ 2 (n =193) and ≥2 (n =47).There were significant inter-group differences in DGF,1-week eGFR and discharge eGFR (P＜0.05).Remuzzi scores were negatively correlated with 1-week eGFR and discharge eGFR (P＜0.05).Interstitial fibrosis was significantly positively correlated with DGF (P＜0.05) and negatively with 1-week eGFR and discharge eGFR (P＜0.05).Conclusions Donor kidney glomerulosclerosis rate affects short-term renal function of recipients after transplantation.However,using 20％ as a threshold value is limited in clinical practice.Arterial intimal fibrosis and arteriolar hyalinosis are important factors affecting short-term eGFR.Recipient kidneys with Remuzzi score ＞ 4 had poor renal function after transplantation.Interstitial fibrosis score may be used as a predictor of postoperative DGF and shortterm renal function recovery.It is expected to be discussed more extensively in literature.

Objective To amplify natural killer (NK) cells in vitro and explore its killing effect on ovarian cancer cells.Methods (1) The separation of NK cells and identification.A total of 20 ml peripheral blood of one healthy volunteer was collected in Nov.2015,Peking University People's Hospital.The peripheral blood mononuclear cells of normal volunteers were isolated,cultured in vitro and amplificated cultivation for 14 days with K562 cells transfected and expressing interleukin 21 (IL-21-K562) as nourish cells.The number and dynamic state of the growth cells were monitored during the cultured process.Cells were harvested and counted after 14 days cultured.The NK cells phenotypes were detected by flow cytometry.(2) The killing effect of NK cells on ovarian cancer cells:the ratio of effector cells (NK cells) and target cells (ovarian cancer cells and its control) was 50∶ 1,20∶ 1,10∶ 1,5∶1 or 1 ∶ 1,NK cells killing effect on ovarian cancer cells was detected by the lactate dehydrogenase (LDH) release experiments.Results (1) The results of NK cells establishment and phenotypic characterization:the cells were induced in vitro for 14 days by amplification culture.With the extension of incubation time,the number of NK cells increased constantly,from 2.0× 107 on day 0 to 5.1 × 109 on day 14.Obvious amplification of the total number of cells were detected for 255 times.Living cells unstained by trypan blue eventually reached 95％ above.Before and after the induction and amplification in vitro,the percentage of NK cells (CD3-CD56+cells) in CD3-cells were 2.33％ and 85.32％,respectively (P＜0.01),which covered the whole lymphocytes 1.06％ and 69.42％,respectively (P＜0.01),which showed that NK was the main cell type in the amplificated lymphocytes.(2) The killing rate of NK cells on ovarian cancer cells in vitro:the results detected by LDH release experiments showed that NK cells could performed strong nonspecific killing effect on ovarian cancer cell lines SKOV3,HOC1A,3AO and CAOV3,as well the normal ovarian cell line T29 and NK sensitive cell line K562,and the killing effect increased significantly along with the increase of effector cells and target cells ratio (P＜0.01).When the ratio was 1 ∶ 1,the killing rate was 37％ for K562,while the rate of killing of other cells was around 10％ (P＜0.05).When the effect-target ratio was 20∶1 and 50∶ 1,in addition to CAOV3 cells (more than 70％),NK cells had a kill rate of more than 80％ for other ovarian cancer cells lines and their control cell K562 and T29 cells (P＞0.05).Conclusion NK cells could be established in vitro and have a good non-specific killing effect on ovarian cancer cells.

This paper introduces the background, implication and construction of the county health services community (County medical alliance) model in Anhui Province under the background of new medical reform,and briefly introduces the relationship between medical insurance, enhancing the ability to upgrade and standardize services and medical treatment integration of the typical experience.It also analyses the challenges faced in the construction of medical syndicate, such as the mechanism of regional environmental restriction, compensation and assessment mechanisms which have not been established yet, and the sustainable development of information technology that has lagged behind, and put forward the policy suggestion to improve the construction of medical community, with a view to providing reference for the next work.