Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

Objective To develop an ultra-sensitive nanoparticle contrast agent for magnetic resonance angiography(MRA),to establish a highly sensitive imaging method for complicated vascular structures,and to provide imaging evidence for precision diagnosis,treatment,prognosis,and individualized treatment of ischemic stroke.Methods A dual-modality MRA contrast agent was prepared through ligand exchange of ultra-small NaGdF4 nanocrystals synthesized via a high temperature method,with biocompatible polyethylene glycol(PEG-dp)ligands.The basic structure,morphology,size distribution,and relaxation rate of the NaGdF4 nano contrast agent were characterized using transmission electron microscopy(TEM),a particle size potential analyzer,and a 7.0 T small-animal MRI scanner.A total of 6 healthy male SPF-grade BALB/c mice were selected and randomly divided into two groups,a NaGdF4 group and a Gd-DTPA group.The mice in the two groups were injected with NaGdF4 nanoparticle contrast agent or clinical Gd-DTPA contrast agent(0.1 mmol Gd3+/kg)via the tail vein.MRA images were obtained using a 7.0 T small animal magnetic resonance imaging system before and after the injection.A total of 6 healthy male SPF-grade Sprague Dawley(SD)rats were selected to establish a right middle cerebral artery occlusion(rMCAO)model to simulate ischemic stroke.The rats were injected with NaGdF4 nano-contrast agent(0.1 mmol Gd3+/kg)via the tail vein.Before and after the injection,brain MRI images of the rats were obtained using a 7.0 T small animal magnetic resonance imaging system.The in vitro and in vivo biological safety of the nano contrast agent was verified through cytotoxicity and hemolysis experiments and HE staining.Results Uniform spherical oil-phase NaGdF4 nanocrystals with an average particle size of approximately(4.43±0.46)nm were successfully prepared.After ligand exchange,biocompatible water-phase nanocrystals were obtained with a hydrodynamic size of 16.1 nm and a surface potential of-1.9 mV.The relaxation performance of this nanocrystal contrast agent was significantly superior to that of the clinical contrast agent Gd-DTPA.The longitudinal molar relaxivity rate(r1)of the NaGdF4 nano contrast agent was 8.84 mM-1s-1,while the transverse molar relaxivity rate(r2)was 27.36 mM-1s-1,which were 1.96 times(4.52 mM-1s-1)and 3.37 times(8.13 mM-1s-1)those of Gd-DTPA,respectively.It also demonstrated excellent biocompatibility.NaGdF4-enhanced MRA achieved high-resolution vascular imaging and effectively enabled the differentiation of the ischemic area,infarct core,and ischemic penumbra in an animal model of ischemic stroke.Conclusion The multi-parameter MRA based on NaGdF4 nanoparticles provides critical imaging evidence for the clinical diagnosis and prognosis of ischemic stroke.

Objective To investigate the genetic association between nonalcoholic fatty liver disease(NAFLD)and type 2 diabetes mellitus(T2DM)using bidirectional two-sample Mendelian randomization(MR),as well as the causal relationship between NAFLD and T2DM across different body mass index(BMI)categories.Methods The data were derived from genome-wide association studies conducted in European populations,with a sample size of 32 941 cases for NAFLD,312 646 cases for T2DM,and 681 275 cases for BMI.The univariate and multivariate MR methods were used to assess the bidirectional causal relationship between NAFLD and T2DM in the general population and across different BMI subtypes.The methods of inverse-variance weighting,MR-Egger regression,constrained maximum likelihood and model averaging,and weighted median were used to conduct the MR analysis,and MR-Pleiotropy Residual Sum and Outlier,radial MR,the MR-Egger intercept method,and the Cochrane Q test were used for sensitivity analysis.Results The univariate MR analysis revealed a bidirectional causal relationship between NAFLD and T2DM in the general population(forward analysis:odds ratio[OR]=9.75,95%confidence interval[CI]:2.57-37.00,P＜0.001;reverse analysis:OR=1.01,95%CI:1.00-1.01,P＜0.01).After adjustment for BMI,the multivariate MR analysis showed that the causal relationship between NAFLD and T2DM remained significant in the general population(OR=33.12,95%CI:7.57-144.95,P＜0.000 1).The subgroup analysis showed a causal relationship between NAFLD and T2DM across all BMI subtypes(lean subgroup:OR=12.19,95%CI:3.35-44.40,P＜0.001;overweight subgroup:OR=4.30,95%CI:1.69-10.92,P＜0.01;obese subgroup:OR=1.67,95%CI:1.14-2.44,P＜0.01).Conclusion This study reveals the causal relationship between NAFLD and T2DM in the general population of NAFLD and across different BMI subtypes from a genetic perspective.

Objective To analyze the application of ADOPT(attitude,definition,open mind,planning,try it out)model in parturients with gestational diabetes.Methods A total of 120 parturients with gestational diabetes admitted to Nantong Maternal and Child Health Hospital from January 2022 to February 2023 were selected as research objects.They were divided into control group and observation group according to the admission order,with 60 cases in each group.The mean age of parturients in the control group was(28.35±5.06)years(range,24-35 years).The mean age of parturients in the observation group was(28.29±5.33)years(range,23-36 years).The control group received conventional care,and the observation group were given ADOPT mode.The psychological resilience scale score,diabetes self-efficacy scale score,and blood glucose level before the intervention and at 7 d of intervention,as well as the incidence of adverse pregnancy outcomes were compared between the two groups.Results Before the intervention,there was no significant difference in the maternal psychological resilience scale score,diabetes self-efficacy scale score or blood glucose level between two groups(all P>0.05).At 7 d of intervention,the scores of maternal health knowledge rating scale and diabetes self-efficacy scale of the observation group were higher than those of the control group,and fasting blood glucose and 2-hour postprandial blood glucose in the observation group were lower than those in the control group(all P<0.05).After the intervention,the incidence of adverse pregnancy outcomes in the observation group(6.67%in parturients,5.00%in newborns)was lower than that in the control group(20.00%in parturients,16.67%in newborns)(P<0.05).Conclusion The ADOPT model can significantly improve the psychological resilience,strengthen self-efficacy,effectively control blood glucose level,and reduce the incidence of adverse pregnancy outcomes in parturients with gestational diabetes.

Objective:To investigate the diagnostic value of thyroid imaging report and data system (TIRADS) combined with BRAF V600E mutation detection in differentiating uncertain thyroid nodules by using fine needle aspiration cytology (FNAC), and to analyze the role of TIRADS classification in screening the nodules needed to be routinely detected for BRAF V600E mutation.Methods:The clinicopathological data of 337 thyroid nodules patients diagnosed with TIRADS classification, FNAC Bethesda classification, BRAF V600E mutation detection and postoperative histopathology from the Second Hospital of Hebei Medical University between January 2018 and August 2021 were retrospectively analyzed. The role of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation detection alone and the combined detection in the differentiation of benign and malignant thyroid nodules was also analyzed.Results:The postoperative histopathological result was regarded as the gold standard. The sensitivity of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation for thyroid cancer diagnosis was 76.0%, 88.1% and 80.4% respectively, and the corresponding specificity was 84.0%, 96.0% and 100.0%, respectively. Histologically, 37 (62.7%) of 59 nodules with FNAC uncertainty were malignant nodules after the surgery. The sensitivity and accuracy of BRAF V600E mutation detection in the diagnosis of FNAC uncertain nodules were 51.4% and 69.5%, respectively, while the sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were 86.5% and 84.7%, respectively. The sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were both improved ( P values were 0.002 and 0.049, respectively). The positive rate of BRAF V600E mutation in thyroid nodules increased step by step with the rise of risk degree in TIRADS classification, and the type 3 cases were lower than those in type 4a cases [14.3% (1/7) vs. 68.6% (24/35), P = 0.012], and there were no statistically significant differences among the adjacent groups above 4a (all P > 0.05). Conclusions:TIRADS combined with BRAF V600E mutation detection can improve the sensitivity and accuracy in the diagnosis of FNAC uncertain thyroid nodules. The BRAF V600E mutation rate of TIRADS 4a and above nodules is high, so routine detection is recommended.

OBJECTIVE: To carry out prenatal diagnosis for a fetus with normal ultrasonographic finding at 20 weeks' gestation but a copy number variant(CNV) of 13q indicated by non-invasive prenatal test (NIPT). METHODS: Karyotyping analysis and chromosomal CNV assay were carried out on the amniotic fluid sample. Parental peripheral blood sample was collected for chromosomal analysis. Detailed fetal ultrasound scan was carried out to rule out structural abnormalities of the fetus. RESULTS: The fetus was detected with a heterozygous 10.14 Mb deletion at 13q21.1q21.32, which has originated from the phenotypically normal mother. No apparent karyotypic abnormality was detected in the fetus and its parents. No ultrasonic abnormality was found in the fetus. CONCLUSION Both the fetus and its mother have carried a heterozygous 10.14 Mb deletion at 13q21.1q21.32 and presented normal phenotypes.Combined with literature review, the segmental deletion was judged to be a benign variant.
Female ; Genetic Counseling ; Humans ; Karyotyping ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Ultrasonography, Prenatal

OBJECTIVE: To explore the genetic etiology in four patients with hyperbilirubinemia, and discuss the correlation between clinical characteristics and molecular basis. METHODS: The data of clinical manifestation and auxiliary examinations were collected. Genomic DNA of the four patients was extracted and analyzed by next-generation sequencing using the panel including genes involved in hereditary metabolic liver diseases. Suspected variants were verified by Sanger sequencing. RESULTS: All of the four patients were males with normal liver enzymes. It was revealed that all the patients had heterozygous variants, among which c.3011C>T, c.2443C>T and c.2556del were the variants which have not been reported previously. CONCLUSION All of the patients were diagnosed as Dubin-Johnson syndrome (DJS) caused by ABCC2 gene variants. The novel variants add to the spectrum of genetic variants of the disease. Because of the favorite prognosis, precise diagnosis can greatly reduce the psychological pressure of patients and avoid excessive treatments. At the same time, it could provide pertinent genetic counseling for the families.
DNA ; Female ; Heterozygote ; Humans ; Jaundice, Chronic Idiopathic/genetics* ; Male ; Multidrug Resistance-Associated Protein 2 ; Multidrug Resistance-Associated Proteins/genetics* ; Phenotype

Periodontitis is an inflammatory disease that is characterized by progressive destruction of the periodontium and causes tooth loss in adults.Periodontitis is known to be associated with dysbiosis of the oral microflora,which is often linked to various diseases.However,the complexity of plaque microbial communities of periodontitis,antibiotic resistance,and enhanced virulence make this disease difficult to treat.In this study,using metagenomic shotgun sequencing,we inves-tigated the etiology,antibiotic resistance genes(ARGs),and virulence genes(VirGs)of periodontitis.We revealed a significant shift in the composition of oral microbiota as well as several functional pathways that were represented significantly more abundantly in periodontitis patients than in con-trols.In addition,we observed several positively selected ARGs and VirGs with the Ka/Ks ratio＞1 by analyzing our data and a previous periodontitis dataset,indicating that ARGs and VirGs in oral microbiota may be subjected to positive selection.Moreover,5 of 12 positively selected ARGs and VirGs in periodontitis patients were found in the genomes of respiratory tract pathogens.Of note,91.8％of the background VirGs with at least one non-synonymous single-nucleotide polymorphism for natural selection were also from respiratory tract pathogens.These observations suggest a potential association between periodontitis and respiratory infection at the gene level.Our study enriches the knowledge of pathogens and functional pathways as well as the positive selection of antibiotic resistance and pathogen virulence in periodontitis patients,and provides evidence at the gene level for an association between periodontitis and respiratory infection.

Objective:To investigate the association of blood oxidative stress level with hypertriglyceridemia in the elderly aged 65 years and older in China.Methods:A total of 2 393 participants aged 65 years and older were recruited in 9 longevity areas from Heathy Aging and Biomarkers Cohort Study, during 2017 to 2018. Information on demographics characteristic, life style and health status were collected by questionnaire and physical examination, and venous blood was collected to detect the levels of blood oxidative stress and hypertriglyceridemia. The linear or non-linear association between oxidative stress and hypertriglyceridemia was described by restrictive cubic splines (RCS) fitting multiple linear regression model. The generalized linear mixed effect model was conducted to assess the association between oxidative stress and hypertriglyceridemia.Results:A total of 2 393 participants, mean age was 84.6 years, the youngest was 65 and the oldest was 112, the male was 47.9%(1 145/2 393), the triglyceride level was (1.4±0.8) mmol/L. The hypertriglyceridemia detection rate was 9.99%(239/2 393). The results of multiple linear regression model with restrictive cubic spline fitting showed that MDA level was linear association with triglyceride level; SOD level was nonlinear association with triglyceride level. MDA level had significantly association with hypertriglyceridemia, and the corresponding OR value was 1.063 (95% CI: 1.046,1.081) with 1 nmol/ml increment of blood MDA; SOD level had significantly association with hypertriglyceridemia, and the corresponding OR value was 0.986(95% CI: 0.983,0.989) with 1 U/ml increment of blood SOD. Conclusion:Among the elderly aged 65 and older in 9 longevity areas in China, MDA and SOD levels were associated with the risk of hypertriglyceridemia.

Objective:To investigate the association between blood lead concentrations and cognition impairment among Chinese older adults aged 65 or over.Method:Data was collected in 9 longevity areas from Heathy Aging and Biomarkers Cohort Study between 2017 and 2018. This study included 1 684 elderly aged 65 years and older. Information about demographic characteristics, socioeconomic factors, health status and cognitive function score of respondents were collected by questionnaire survey and physical examination. Venous blood of the subjects was collected to detect the blood lead concentration. Subjects were stratified into four groups ( Q 1- Q 4) by quartile of blood lead concentration. Multivariate logistic regression model was used to analyze the association between blood lead concentration and cognitive impairment. The linear or non-linear association between blood lead concentration and cognitive impairment were described by restrictive cubic splines (RCS). Results:Among the 1 684 respondents, 843 (50.1%) were female and 191 (11.3%) suffered from cognition impairment. After adjusting for confounding factors, the OR value and 95% CI of cognition impairment was 1.05 (1.01-1.10) for every 10 μg/L increase in blood lead concentration in elderly; Compared with the elderly in Q 1, the elderly with higher blood lead concentration had an increased risk of cognitive impairment. The OR value and 95% CIof Q2, Q3 and Q4 groups were 1.19 (0.69-2.05), 1.45 (0.84-2.51) and 1.92 (1.13-3.27), respectively. Conclusion:Higher blood lead concentration is associated with cognitive impairment among the elderly aged 65 years and older in 9 longevity areas in China.