Recently, male reproductive health has attracted extensive attention, with the adverse effects of circadian disruption on male fertility gradually gaining recognition. However, the mechanism by which circadian disruption leads to damage to male reproductive system remains unclear. In this review, we first summarized the dual regulatory roles of circadian clock genes on the male reproductive system: (1) circadian regulation of testosterone synthesis via the hypothalamic-pituitary-testicular (HPT) and hypothalamic-pituitary-adrenal (HPA) axes; (2) non-circadian regulation of spermatogenesis. Next, we further listed the possible mechanisms by which circadian disruption impairs male fertility, including interference with the oscillatory function of the reproductive system, i.e., synchronization of the HPT axis, crosstalk between the HPT axis and the HPA axis, as well as direct damage to germ cells by disturbing the non-oscillatory function of the reproductive system. Future research using spatiotemporal omics, epigenomic assays, and neural circuit mapping in studying the male reproductive system may provide new clues to systematically unravel the mechanisms by which circadian disruption affects male reproductive system through circadian clock genes.
Male ; Humans ; Animals ; Circadian Clocks/physiology* ; Hypothalamo-Hypophyseal System/physiology* ; Circadian Rhythm/genetics* ; Spermatogenesis/physiology* ; Pituitary-Adrenal System/physiology* ; Testis/physiology* ; Testosterone/biosynthesis* ; CLOCK Proteins ; Infertility, Male/physiopathology*

Objective To investigate the impact of sleep modes on the risk for diseases of the body systems.Methods Based on a subset of UK Biobank dataset comprising 87 617 participants,3 sleep dimensions including 6 sleep indicators were obtained through a wrist-worn accelerometer,that is sleep duration and onset,sleep rhythm(relative amplitude and stability),and sleep quality(sleep efficiency and number of awakenings).Latent profile analysis(LPA)was applied to identify and classify distinct sleep modes.Then their longitudinal medical records were the association between different sleep modes and the risk for 467 diseases.Results LPA identified 5 subgroups of unique sleep modes in the participants.Among the 5 subgroups,the subgroup 4 had relatively optimal levels in above sleep indicators.Compared to the subgroup 4,the other 4 subgroups exhibited variations in different sleep dimensions,with at least one indicator demonstrating an unfavorable trend.These subgroups also revealed differences in racial composition,shift work and social deprivation index.Moreover,there were notable differences in the risk of various system diseases among the subgroups(P<0.05).When compared to the subgroup 4,the other 4 subgroups exhibited an elevated risk for certain diseases(comprising a total of 126 diseases),with the diseases of the circulatory system,digestive system and musculoskeletal system most common.Among the 5 subgroups,the subgroup 2(shorter sleep duration and later sleep onset)and the subgroup 5(rhythm disorder)had the highest counts of associated risks,amounting to 85 and 91 types,respectively,but there was certain difference in their systematic composition.Conclusion There are different sleep modes within the participants,and the modes are potentially associated with an increased risk for diseases of body systems.Comprehensive interventions targeting overall sleep modes rather than single sleep indicator may yield obvious health benefits.

P53 is a key tumor suppressor gene,which is regulated in many ways.Zinc finger 148(ZNF148)and SP5,as zinc finger transcription factors(TFs),play important roles in tumor suppression and carcinogenesis.The regulatory relationship between these two TFs and p53 has not been reported.In this paper,Ishikawa and A549 cell lines with different p53 expression levels were used as research mod-els to explore the transcriptional regulation of the P53 gene by ZNF148 and SP5.The data showed that there were differences in the expression of ZNF148 and SP5 in the two cell lines.The mRNA expression of ZNF148 in Ishikawa was 1.9 times higher than that of A549,and the mRNA expression of SP5 in A549 was 802.4 times that of ZNF148.Data showed that in Ishikawa cells,the expression of P53 de-creased(81.8％)after ZNF148 knockdown,and increased(2.6 times)after SP5 overexpression.Transfection of si-SP5 and ZNF148 expression plasmids into A549 cells increased the mRNA expression of P53 by 6.6 times and 14.6 times,respectively.These results indicate that ZNF148 could activate,whereas SP5 could inhibit,P53 expression.The conserved cis-element of ZNF148 and SP5 TFs was found in the region of the P53 promoter by bioinformatics methods.The data from dual luciferase reporter gene assay showed that the luciferase activity of ZNF148 in Ishikawa and A549 cells was increased by 2.1-fold and 4.2-fold compared with the control group(P＜0.05).Compared with the control group,the normalized relative luciferase activity of transfected SP5 decreased by 77.1％and 35.7％(P＜0.05).However,when the cis-element of ZNF148 and SP5 was mutated,the effect disappeared.Further trans-fection of ZNF148 and SP5 with different ratios revealed that SP5 could reverse the transcriptional activa-tion of P53 by ZNF148.Studies have shown that ZNF148 shares a common site with SP5,and the ratio of the two TFs may influence the transcriptional activity of P53.The expression of the Wnt pathway and the cell proliferation rate after knockdown of ZNF148 and SP5 were further studied to explore the role of the two TFs.Our data show that ZNF148 and SP5 could regulate the transcriptional activity of P53,and their expression levels and interaction may be the key factors regulating P53 expression.

Objective:To investigate the relationship between the severity of pharyngolaryngeal sensory impairment and swallowing biomechanics as well as the risk of penetration-aspiration in patients with dysphagia following infratentorial stroke.Methods:This retrospective cross-sectional study enrolled 51 patients with dysphagia following infratentorial stroke hospitalized in the Department of Rehabilitation Medicine of The Third Affiliated Hospital of Sun Yat-sen University between January 2022 and December 2023. Participants were categorized into three groups: normal sensation group [15 males, 2 females; age range 29-76 (56.0±13.3)years], diminished sensation group[16 males, 3 females; age range 38-80(62.0±11.8)years], and absent sensation group [14 males, 1 female; age range 44-75 (60.0±9.7)years]. All patients underwent laryngoscopy and videofluoroscopic swallowing study, which included pharyngolaryngeal sensory testing and Penetration-Aspiration Scale assessment. Swallowing temporal parameters were quantitatively analyzed. Group comparisons for different variable types were conducted using the Chi-square test, one-way ANOVA, and the Kruskal-Wallis test. The correlation between sensory groups and Penetration-Aspiration Scale scores was assessed using Spearman′s correlation analysis. Logistic regression was employed to analyze the impact of pharyngolaryngeal sensory function on penetration-aspiration events.Results:Among the 51 patients, 33.33% (17/51) had normal pharyngolaryngeal sensation, while, 66.67% (34/51) exhibited sensory impairment. The normal sensation group exhibited a significantly longer laryngeal vestibule closure (LVC) time [792 (643, 1 205) ms] compared to the diminished [528 (380, 776) ms] and absent sensation groups [380 (322, 404) ms] ( H=6.502, P=0.039). Additionally, the upper esophageal sphincter opening time was longer in the normal sensation group than in the absent sensation group [528 (371, 710) ms vs 182 (0, 710) ms, H=6.003, P=0.049]. Correlation analysis indicated a significant negative correlation between the severity of sensory impairment and Penetration-Aspiration Scale scores ( r=-0.366, P=0.008). Logistic regression analysis demonstrated that greater sensory impairment was an independent risk factor for penetration-aspiration ( OR=9.29, 95%CI=1.57-54.77, P=0.014). Conclusion:Pharyngolaryngeal sensory deficits are common after infratentorial stroke dysphagia and are significantly associated with impaired swallowing biomechanics and increased aspiration risk. The severity of sensory deficit is a key determinant of penetration-aspiration risk, highlighting its value in risk stratification and therapeutic decision-making for dysphagia.

P53 is a key tumor suppressor gene,which is regulated in many ways.Zinc finger 148(ZNF148)and SP5,as zinc finger transcription factors(TFs),play important roles in tumor suppression and carcinogenesis.The regulatory relationship between these two TFs and p53 has not been reported.In this paper,Ishikawa and A549 cell lines with different p53 expression levels were used as research mod-els to explore the transcriptional regulation of the P53 gene by ZNF148 and SP5.The data showed that there were differences in the expression of ZNF148 and SP5 in the two cell lines.The mRNA expression of ZNF148 in Ishikawa was 1.9 times higher than that of A549,and the mRNA expression of SP5 in A549 was 802.4 times that of ZNF148.Data showed that in Ishikawa cells,the expression of P53 de-creased(81.8％)after ZNF148 knockdown,and increased(2.6 times)after SP5 overexpression.Transfection of si-SP5 and ZNF148 expression plasmids into A549 cells increased the mRNA expression of P53 by 6.6 times and 14.6 times,respectively.These results indicate that ZNF148 could activate,whereas SP5 could inhibit,P53 expression.The conserved cis-element of ZNF148 and SP5 TFs was found in the region of the P53 promoter by bioinformatics methods.The data from dual luciferase reporter gene assay showed that the luciferase activity of ZNF148 in Ishikawa and A549 cells was increased by 2.1-fold and 4.2-fold compared with the control group(P＜0.05).Compared with the control group,the normalized relative luciferase activity of transfected SP5 decreased by 77.1％and 35.7％(P＜0.05).However,when the cis-element of ZNF148 and SP5 was mutated,the effect disappeared.Further trans-fection of ZNF148 and SP5 with different ratios revealed that SP5 could reverse the transcriptional activa-tion of P53 by ZNF148.Studies have shown that ZNF148 shares a common site with SP5,and the ratio of the two TFs may influence the transcriptional activity of P53.The expression of the Wnt pathway and the cell proliferation rate after knockdown of ZNF148 and SP5 were further studied to explore the role of the two TFs.Our data show that ZNF148 and SP5 could regulate the transcriptional activity of P53,and their expression levels and interaction may be the key factors regulating P53 expression.

Objective:To investigate the relationship between the severity of pharyngolaryngeal sensory impairment and swallowing biomechanics as well as the risk of penetration-aspiration in patients with dysphagia following infratentorial stroke.Methods:This retrospective cross-sectional study enrolled 51 patients with dysphagia following infratentorial stroke hospitalized in the Department of Rehabilitation Medicine of The Third Affiliated Hospital of Sun Yat-sen University between January 2022 and December 2023. Participants were categorized into three groups: normal sensation group [15 males, 2 females; age range 29-76 (56.0±13.3)years], diminished sensation group[16 males, 3 females; age range 38-80(62.0±11.8)years], and absent sensation group [14 males, 1 female; age range 44-75 (60.0±9.7)years]. All patients underwent laryngoscopy and videofluoroscopic swallowing study, which included pharyngolaryngeal sensory testing and Penetration-Aspiration Scale assessment. Swallowing temporal parameters were quantitatively analyzed. Group comparisons for different variable types were conducted using the Chi-square test, one-way ANOVA, and the Kruskal-Wallis test. The correlation between sensory groups and Penetration-Aspiration Scale scores was assessed using Spearman′s correlation analysis. Logistic regression was employed to analyze the impact of pharyngolaryngeal sensory function on penetration-aspiration events.Results:Among the 51 patients, 33.33% (17/51) had normal pharyngolaryngeal sensation, while, 66.67% (34/51) exhibited sensory impairment. The normal sensation group exhibited a significantly longer laryngeal vestibule closure (LVC) time [792 (643, 1 205) ms] compared to the diminished [528 (380, 776) ms] and absent sensation groups [380 (322, 404) ms] ( H=6.502, P=0.039). Additionally, the upper esophageal sphincter opening time was longer in the normal sensation group than in the absent sensation group [528 (371, 710) ms vs 182 (0, 710) ms, H=6.003, P=0.049]. Correlation analysis indicated a significant negative correlation between the severity of sensory impairment and Penetration-Aspiration Scale scores ( r=-0.366, P=0.008). Logistic regression analysis demonstrated that greater sensory impairment was an independent risk factor for penetration-aspiration ( OR=9.29, 95%CI=1.57-54.77, P=0.014). Conclusion:Pharyngolaryngeal sensory deficits are common after infratentorial stroke dysphagia and are significantly associated with impaired swallowing biomechanics and increased aspiration risk. The severity of sensory deficit is a key determinant of penetration-aspiration risk, highlighting its value in risk stratification and therapeutic decision-making for dysphagia.

Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.