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.

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has posed a global challenge to the control of the coronavirus disease 2019 (COVID-19) pandemic. Therefore, developing countermeasures that broadly protect against SARS-CoV-2 and related sarbecoviruses is essential. Herein, we have developed a lipid nanoparticle (LNP)-encapsulated mRNA (mRNA-LNP) encoding the full-length Spike (S) glycoprotein of SARS-CoV-2 (termed RG001), which confers complete protection in a non-human primate model. Intramuscular immunization of two doses of RG001 in Rhesus monkey elicited robust neutralizing antibodies and cellular response against SARS-CoV-2 variants, resulting in significantly protected SARS-CoV-2-infected animals from acute lung lesions and complete inhibition of viral replication in all animals immunized with low or high doses of RG001. More importantly, the third dose of RG001 vaccination elicited effective neutralizing antibodies against current epidemic XBB and JN.1 strains and similar cellular response against SARS-CoV-2 Omicron variants (BA.1, XBB.1.16, and JN.1) were observed in immunized mice. All these results together strongly support the great potential of RG001 in preventing the infection of SARS-CoV-2 variants of concern (VOCs).

OBJECTIVE To investigate the bactericidal effect of levulinic acid-sodium dodecyl sulfate(LVA-SDS)on the strains of Mycobacterium abscessus,Mycobacterium chelonae and Mycobacterium fortuitum,and to provide a new method for the prevention of common pathogenic rapidly growing non-tuberculous mycobacteria(NTM)dis-ease.METHODS The minimum inhibitory concentration(MIC)and minimal bactericidal concentration(MBC)of LVA-SDS were detected by microculture method and suspension quantitative bactericidal test,respectively.Using 1000 mg/L chlorine-containing disinfectant(sodium hypochlorite)as the control,the killing effect of LVA-SDS at different times and concentrations on M.abscessus,M.chelonae and M.fortuitum were detected.RESULTS The MIC values of LVA-SDS against M.abscessus,M.chelonae and M.fortuitum were 0.0625%LVA+0.00625%SDS,0.03125%LVA+0.003125%SDS and 0.125%LVA+0.0125%SDS,respectively.The MBC values were 0.25%LVA+0.025%SDS,0.25%LVA+0.025%SDS,and 1%LVA+0.1%SDS,repectively.Within a cer-tain range,with the increase in LVA-SDS concentration and the extension of time(1-30 min),the bactericidal effect on M.abscessus,M.chelonae and M.fortuitum gradually enhanced.The killing rates of the 18%LVA+1.8%SDS for 5 minutes and the 6%LVA+0.6%SDS for 20 minutes to M.abscessus reached 100.00%;the kill-ing rates of the 18%LVA+1.8%SDS for 10 minutes and the 10%LVA+1%SDS for 25 minutes to M.chelo-nae reached 100.00%;while the killing rates of the 18%LVA+1.8%SDS for 5 minutes and the 6%LVA+0.6%SDS for 30 minutes to M.fortuitum reached 100.00%.Compared with 1000 mg/L chlorine-containing disin-fectant(sodium hypochlorite),LVA-SDS has equivalent bactericidal effects against M.abscessus and M.chelo-nae,and a better bactericidal effect against M.fortuitum.CONCLUSION LVA-SDS has a good bactericidal effect on M.abscessus,M.chelonae and M.fortuitum,and may be used in the disinfection of NTM in the future.

Objective:To investigate the clinical characteristics and genetic etiology of fetal Dandy-Walker spectrum (DWS) anomalies.Methods:This retrospective cohort study analyzed 28 fetuses with ultrasonographically confirmed DWS (ten classic Dandy-Walker malformations and 18 Dandy-Walker variants) at the First Affiliated Hospital, Zhengzhou University from January 2019 to June 2024. All cases underwent systematic ultrasonographic evaluation. Genetic analyses included chromosomal karyotyping alone ( n=4) or combined with copy number variation sequencing (CNV-seq) ( n=10). Descriptive statistics and Chi-square tests (or Fisher's exact test) with Bonferroni correction were applied. Results:(1) Among 28 fetuses, seven (25.0%) had isolated DWS and 21 (75.0%) non-isolated DWS. Central nervous system anomalies were most common (53.6%, 15/28). (2) Karyotyping identified abnormalities in four cases (4/14), including two triploidies, one case of mosaicism for a derivative chromosome der(1;10), and one 17p deletion. CNV-seq detected anomalies in six cases (25.0%, 6/24), four of which were missed by karyotyping: 3q23 deletion (encompassing ZIC1/ ZIC4), 13q11 duplication, and other critical variants. (3) Combined testing yielded a higher detection rate (28.6%, 8/28) than karyotyping alone (4/14, χ2=4.62, P=0.032) or CNV-seq alone (25.0%, 6/24, χ2=4.83, P=0.028) ( P=0.048 and 0.044 after Bonferroni correction). Conclusions:DWS demonstrates significant genetic heterogeneity, primarily involving chromosomal numerical anomalies (e.g., triploidy) and copy number variations (e.g., 3q23 deletion). Combined karyotyping and CNV-seq improves detection rates of genetic abnormalities.

To investigate the malignant progression and molecular mechanism of KHSRP regulating esophageal squamous cell carcinoma(ESCC) through the JAK1/STAT3 signaling axis.

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
Core Binding Factor Alpha 2 Subunit/genetics* ; Humans ; Leukemia, Myeloid, Acute/pathology* ; Jumonji Domain-Containing Histone Demethylases/chemistry* ; Gene Expression Regulation, Leukemic ; Oxidoreductases, N-Demethylating/genetics* ; Cell Line, Tumor

Objective To explore the application value of improving the operation method of the coaxial microcatheter system to increase the recanalization rate of long-segment occluded blood vessels in the lower extremity arteries.Methods Eleven patients with long-segment occlusion of the lower extremity arteries were selected.Firstly,the angiographic catheter was sent to about 3-4 cm proximal to the occluded segment to provide support and direction control of the coaxial microcatheter system.Then,the microcathe-ter was sent to about 1 cm proximal to the occluded segment through the angiographic catheter,and the microguide wire was sent to the occluded segment,making the tip of the guide wire closely adhere to the occluded segment.The guide wire was fixed by using the guide wire controller to ensure that the guide wire in the blood vessel was always about 1 cm exposed outside the microcatheter.Meanwhile,the microcatheter and the microguide wire were rotated to make the tip form a"spring"shape similar to that of a pipe-line dredging machine,so that the coaxial microcatheter system could pass through the occluded segment of the blood vessel in this shape.After confirmed that the microcatheter had entered the lumen of the distal outflow tract blood vessel,the subsequent interven-tional treatment was completed according to the conventional method.Results Eleven patients with long-segment occluded blood vessels in the lower extremity arteries were successfully treated with improving the operation method of the coaxial microcatheter system to dredge the occluded segment,and completed the interventional treatment of the affected limb blood vessels without vascu-lar rupture,vascular bleeding or arterial dissection.Conclusion Using the improved operation method of the coaxial microcatheter system to dredge the long-segment occluded blood vessels of the lower extremity arteries is simple,safe and has a high success rate,which is worthy of clinical promotion.

Objective:To investigate the association between blood selenium levels and sex hormones in Chinese men aged 18-79 years.Methods:Data were derived from the China National Human Biomonitoring survey conducted in 2017-2018, with a final sample size of 5 414 men. General demographic characteristics, behavioral habits, and dietary frequency were collected through questionnaires and physical examinations. Fasting blood samples were collected to measure blood lead, serum testosterone, and estradiol levels. Complex sampling linear regression models were used to analyze the associations between blood selenium levels and testosterone, estradiol, and the testosterone/estradiol ratio, adjusting for confounding factors including age, education level, marital status, smoking status, alcohol consumption, seafood intake, soy product intake, protein supplement intake, BMI, and diabetes status.Results:The mean age of the 5 414 participants was (46.85±27.91) years; 4 774 (91.65%) were of Han ethnicity and 4 505 (86.68%) were married. The median ( Q1, Q3) blood selenium concentration in men was 97.80 (80.64, 116.99) μg/L. After adjusting for confounding factors, the complex sampling linear regression model revealed negative associations between blood selenium levels and both testosterone levels and the testosterone/estradiol ratio, with a significant linear trend ( Ptrend<0.05). Compared with the Q1 group, the β (95% CI) values for testosterone in the Q2, Q3, and Q4 groups were -0.02 (-0.06 to 0.02), -0.03 (-0.08 to 0.01), and -0.06 (-0.09 to -0.02), respectively. Similarly, the β (95% CI) values for the testosterone/estradiol ratio in the Q2, Q3, and Q4 groups were -0.01 (-0.03 to 0.02), -0.01 (-0.04 to 0.04), and -0.03 (-0.06 to -0.01), respectively. Subgroup analysis indicated stronger associations between blood selenium levels and testosterone/estradiol levels in non-smoking and obese men (BMI≥28 kg/m2). Conclusion:Blood selenium levels are negatively associated with testosterone levels and the testosterone/estradiol ratio in Chinese adult males.

Objective:To investigate the association between blood selenium levels and sex hormones in Chinese men aged 18-79 years.Methods:Data were derived from the China National Human Biomonitoring survey conducted in 2017-2018, with a final sample size of 5 414 men. General demographic characteristics, behavioral habits, and dietary frequency were collected through questionnaires and physical examinations. Fasting blood samples were collected to measure blood lead, serum testosterone, and estradiol levels. Complex sampling linear regression models were used to analyze the associations between blood selenium levels and testosterone, estradiol, and the testosterone/estradiol ratio, adjusting for confounding factors including age, education level, marital status, smoking status, alcohol consumption, seafood intake, soy product intake, protein supplement intake, BMI, and diabetes status.Results:The mean age of the 5 414 participants was (46.85±27.91) years; 4 774 (91.65%) were of Han ethnicity and 4 505 (86.68%) were married. The median ( Q1, Q3) blood selenium concentration in men was 97.80 (80.64, 116.99) μg/L. After adjusting for confounding factors, the complex sampling linear regression model revealed negative associations between blood selenium levels and both testosterone levels and the testosterone/estradiol ratio, with a significant linear trend ( Ptrend<0.05). Compared with the Q1 group, the β (95% CI) values for testosterone in the Q2, Q3, and Q4 groups were -0.02 (-0.06 to 0.02), -0.03 (-0.08 to 0.01), and -0.06 (-0.09 to -0.02), respectively. Similarly, the β (95% CI) values for the testosterone/estradiol ratio in the Q2, Q3, and Q4 groups were -0.01 (-0.03 to 0.02), -0.01 (-0.04 to 0.04), and -0.03 (-0.06 to -0.01), respectively. Subgroup analysis indicated stronger associations between blood selenium levels and testosterone/estradiol levels in non-smoking and obese men (BMI≥28 kg/m2). Conclusion:Blood selenium levels are negatively associated with testosterone levels and the testosterone/estradiol ratio in Chinese adult males.

Objective To explore the application value of improving the operation method of the coaxial microcatheter system to increase the recanalization rate of long-segment occluded blood vessels in the lower extremity arteries.Methods Eleven patients with long-segment occlusion of the lower extremity arteries were selected.Firstly,the angiographic catheter was sent to about 3-4 cm proximal to the occluded segment to provide support and direction control of the coaxial microcatheter system.Then,the microcathe-ter was sent to about 1 cm proximal to the occluded segment through the angiographic catheter,and the microguide wire was sent to the occluded segment,making the tip of the guide wire closely adhere to the occluded segment.The guide wire was fixed by using the guide wire controller to ensure that the guide wire in the blood vessel was always about 1 cm exposed outside the microcatheter.Meanwhile,the microcatheter and the microguide wire were rotated to make the tip form a"spring"shape similar to that of a pipe-line dredging machine,so that the coaxial microcatheter system could pass through the occluded segment of the blood vessel in this shape.After confirmed that the microcatheter had entered the lumen of the distal outflow tract blood vessel,the subsequent interven-tional treatment was completed according to the conventional method.Results Eleven patients with long-segment occluded blood vessels in the lower extremity arteries were successfully treated with improving the operation method of the coaxial microcatheter system to dredge the occluded segment,and completed the interventional treatment of the affected limb blood vessels without vascu-lar rupture,vascular bleeding or arterial dissection.Conclusion Using the improved operation method of the coaxial microcatheter system to dredge the long-segment occluded blood vessels of the lower extremity arteries is simple,safe and has a high success rate,which is worthy of clinical promotion.