Circadian rhythms are core regulatory mechanisms that evolved to align biological functions with the Earth's rotation. These rhythms are conserved across organisms from unicellular life to multicellular species and play essential roles in metabolism, immune responses, and sleep-wake cycle. Circadian disruptions are strongly associated with various diseases. Over the past decades, genetic studies in Drosophila and mice have identified key conserved clock genes and uncovered transcription-translation feedback loops governing circadian regulation. Additionally, rhythmic neurons in the brain integrate complex neural circuits to precisely regulate physiological and behavioral rhythms. This review highlights recent advances in understanding the neuronal circuit mechanisms of rhythmic neurons in the Drosophila brain and discusses future directions for translating circadian rhythm research into chronomedicine and precision therapies.
Animals ; Circadian Rhythm/genetics* ; Neurons/physiology* ; Drosophila/physiology* ; Brain/physiology* ; Nerve Net/physiology*

OBJECTIVE: To evaluate the association between erectile dysfunction (ED) and myocardial infarction (MI) using two sample Mendelian randomization. METHODS: A Mendelian randomization study was conducted using comprehensive data on ED and MI from extensive genome-wide association data. Using inverse variance weighted analysis for causal relationships, and correct for confounding factors using multivariate Mendelian randomization, the potential mediating effects were evaluated as well. Based on Genecard data, the genes related to ED and MI were identified. Molecular docking was used to reveal spontaneously bound drug molecules. RESULTS: Our study found that exposure to ED was a risk factor for MI (OR: 1.001 0, 95% CI: 1.000 2－1.001 8, P=0.017 7), which also held true in the validation dataset (OR: 1.028 5, 95% CI: 1.005 0－1.052 6, P=0.017 2). No statistically significant heterogeneity or horizontal pleiotropy was found. The results of reverse Mendelian randomization analysis showed any reverse causal relationship between ED and MI. In multivariate Mendelian randomization analysis, after excluding confounding factors (excluding triglycerides and high-density lipoprotein), the P-value remained less than 0.05, and the OR ranged from 1.000 1 to 1.000 7, indicating that ED was still a risk factor for MI. In the mediation analysis, it was found that the current mediation ratio of smoking to MI was 13.06%. In summary-data-based mendelian randomization analysis, it was found that the gene PTPN11 was a common target gene for MI and ED (OR=0.990, P<0.001). Subsequent molecular docking with sildenafil, clopidogrel, and dapoxetine could spontaneously bind to the PTPN11 gene receptor. CONCLUSION There is a causal relationship between ED and MI, with smoking as a potential mediating factor, and the gene PTPN11 being a co-target gene.
Humans ; Male ; Mendelian Randomization Analysis ; Myocardial Infarction/genetics* ; Erectile Dysfunction/complications* ; Risk Factors ; Genome-Wide Association Study ; Molecular Docking Simulation ; Polymorphism, Single Nucleotide

46XY simple gonadal hypoplasia, also known as Sweyer syndrome, patients often due to primary amenorrhea or pubertal secondary sex characteristics do not develop the doctor, its combined gonadal tumor is more likely, in the treatment process is often recommended prophylactic removal of gonads, postoperative hormone replacement therapy. We describe two patients diagnosed with Sweyer syndrome, one with gonadowlastoma and mature teratoma, and one with nodular Leydig cell hyperplasia and ectopic adrenal tissue, and reviews the literature.

In industrial production,the expression level of drug proteins in Chinese hamster ovary cells(CHO)is influenced by many factors:the regulatory elements on transcription and translation,the ge-nomic integration sites,and the expression system.Transcription,as the first step of gene expression,largely affects protein expression,and the promoter plays a crucial role in the initiation of transcription.Most of the promoters were screened through transient transfection or random integration,but the presence of unclear copy number or random integration sites makes it difficult to accurately evaluate the promoter activity.To some extent,site-specific integration can reduce the impact of positional effects on exogenous genes and may potentially increase the expression level of exogenous genes.In the early stage of our re-search,multiple sites that can stably express exogenous proteins were identified and verified in the CHO cell genome.In this study,one of these sites(2c6)was selected for the evaluation of promoter activity.The CRISPR/Cas9 gene editing technique was used to site-specifically integrate the reporter gene(EG-FP)regulated by the simian virus early promoter(SV40),mouse elongation factor-1α(mEF-1α),chicken β-actin(cACTB)promoter,and human phosphoglycerate kinase promoter(hPGK)into the 2c6 site,respectively.The mean fluorescence intensity of the cells was analyzed by flow cytometry,and the mRNA level of EGFP was detected by qPCR to comprehensively evaluate the activity of the promoter.The results showed that the activities of the mEF-1α and mACTB promoters were better than those of SV40 and hPGK.The results of the secondary flow cytometry sorting showed that site-specific integration can more accurately evaluate the activity of the promoter in the CHO cell expression system.

OBJECTIVES: To investigate the clinical characteristics, pathological features, treatment regimen, and prognosis of children with lupus nephritis (LN) and thrombotic microangiopathy (TMA), as well as the treatment outcome of these children and the clinical and pathological differences between LN children with TMA and those without TMA. METHODS: A retrospective analysis was conducted on 12 children with LN and TMA (TMA group) who were admitted to the Department of Nephrology, Children's Hospital of Nanjing Medical University, from December 2010 to December 2021. Twenty-four LN children without TMA who underwent renal biopsy during the same period were included as the non-TMA group. The two groups were compared in terms of clinical manifestations, laboratory examination results, and pathological results. RESULTS: Among the 12 children with TMA, 8 (67%) had hypertension and 3 (25%) progressed to stage 5 chronic kidney disease. Compared with the non-TMA group, the TMA group had more severe tubulointerstitial damage, a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score at onset, and higher cholesterol levels (P<0.05). There were no significant differences between the two groups in the percentage of crescent bodies and the levels of hemoglobin and platelets (P>0.05). CONCLUSIONS There is a higher proportion of individuals with hypertension among the children with LN and TMA, as well as more severe tubulointerstitial damage. These children have a higher SLEDAI score and a higher cholesterol level.
Child ; Humans ; Lupus Nephritis/complications* ; Kidney/pathology* ; Retrospective Studies ; Thrombotic Microangiopathies/therapy* ; Prognosis ; Hypertension/complications* ; Cholesterol ; Lupus Erythematosus, Systemic

Chuanxiong Rhizoma (CX, the dried rhizome of Ligusticum wallichii Franch.), a well-known traditional Chinese medicine, is clinically used for treating cardiovascular, cerebrovascular and hepatobiliary diseases. Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies. Currently, little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells (HSCs). The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous, alkaloid, phenolic acid and phthalide extracts of CX (CX_AE, CX_AL, CX_PA and CX_PHL) and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury. The active compounds of different CX extracts were identified by UPLC-MS/MS. A cholestatic liver injury mouse model induced by bile duct ligation (BDL), and transforming growth factor-β (TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes (HIBECs) and HSC cell line (LX-2 cells) were used for in vivo and in vitro studies. Histological and other biological techniques were also applied. The results indicated that CX_AE, CX_AL and CX_PHL significantly reduced ductular reaction (DR) and improved liver fibrosis in the BDL mice. Meanwhile, both CX_AE and CX_PHL suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β. CX_PHL suppressed the transcription and transfer of plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) from the 'DR-like' cholangiocytes to activated HSCs. Mechanistically, the inhibition of PAI-1 and FN by CX_PHL was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3, followdd by the suppression of histone 3 lysine 9 acetylation (H3K9ac)-mediated transcription in cholangiocytes. In conclusion, CX_PHL exerts stronger anti-cholestatic activity in vivo and in vitro than other CX extracts, and its protective effect on the intracellular communication between cholangiocytes and HSCs is achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.

Heart Neoplasms/genetics* ; Hemangiosarcoma/genetics* ; Humans ; Mediastinal Neoplasms ; Thymus Neoplasms

Prostate biopsy is the gold standard for the diagnosis of prostate cancer. In order to successfully and effectively complete the biopsy, clinicians should not only select the correct puncture method, but also pay attention to the pain control of patients undergoing puncture. It is necessary to select a reasonable anesthetic method for biopsy. The pain during biopsy comes from the skin, muscle and other structures in the puncture approach, and also comes from the prostate capsule. Therefore, the anesthesia emphasis of transperineal and transrectal biopsy approaches will also be different. The use of appropriate anesthesia is of great significance to improve the patient's cooperation and ensure the success rate of biopsy. With the continuous maturity of the technology and concept of prostate biopsy, a single anesthesia method has been unable to meet the actual anesthetic needs of biopsy, and the use of multi-site and multi-phase combined anesthesia for different sources of pain has become the mainstream anesthetic option.
Anesthesia ; Anesthesia, Local ; Biopsy ; Humans ; Image-Guided Biopsy/methods* ; Male ; Pain/pathology* ; Prostate/pathology* ; Prostatic Neoplasms/pathology*

AIM: To investigate the efficacy of anti-inflammatory treatment and anti-vascular endothelial growth factor(VEGF)treatment on different types of macular edema secondary to retinal vein occlusion(RVO-ME).

METHODS: The clinical data of RVO-ME patients who were treated in the Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University from 2019-06/2020-12 were retrospectively collected. A total of 108 cases(108 eyes)of RVO-ME patients were collected, including 52 cases(52 eyes)with cystoid macular edema(CME), 38 cases(38 eyes)with macular edema with serous retinal detachment(SRD), and 18 cases(18 eyes)with diffuse retinal thickening(DRT). Patients with various types of ME were further classified into anti-VEGF group and anti-inflammatory group. The observation metrics such as best corrected visual acuity(BCVA)and foveal thickness(CMT)before and 3mo after surgery were collected and compared in each group.

RESULTS: There was no difference in baseline data between the anti-VEGF group and the anti-inflammatory group in all types of ME patients(all P>0.05). Patients with CME in the anti-VEGF group in BCVA, CMT, and the sum of CME diameter after operation were different from that before operation(Z= -4.463, -4.541, -4.541, all P<0.001); the postoperative BCVA, CMT, and the sum of CME diameter in the anti-inflammatory group were significantly different from those before operation(Z= -3.743, -4.345, -4.372, all P<0.001); and there was no difference between the anti-VEGF group and the anti-inflammatory group in the postoperative CMT and the sum of CME diameter(Z= -1.017, -0.968, all P>0.05), but there was a difference in BCVA after operation in two groups(Z= -1.978, P<0.05). SRD patients in the anti-VEGF group had differences in postoperative BCVA, CMT, and SRD heights compared with preoperative ones(Z= -4.111, -4.198, -4.198, all P<0.01); the BCVA, CMT, and SRD height in the anti-inflammatory group after operation were different from those before operation(Z= -3.410, -3.408, -3.408, all P<0.05); and there was no difference in BCVA and CMT between the two groups after operation(Z= -0.857, -1.030, all P>0.05), but the postoperative SRD height in the anti-inflammatory group was significantly lower than that in the anti-VEGF group(Z= -2.117, P<0.05). DRT patients in the anti-VEGF group were significantly different in BCVA and CMT after operation compared with preoperative ones(Z= -2.207, -2.521, all P<0.05), and in the anti-inflammatory group after injection, BCVA and CMT were significantly different from preoperative ones(Z= -2.207, -2.521, all P<0.05). There were differences in BCVA and CMT after injection in the anti-inflammatory group compared with those before operation(Z= -2.207, -2.803, all P<0.05). There was no difference in postoperative BCVA and CMT between the two groups(Z= -0.359, -0.845, all P>0.05).

CONCLUSION: Anti-inflammatory and anti-VEGF treatments are effective for all kinds of ME in improving vision and reducing CMT. Anti-VEGF treatment is superior to anti-inflammatory treatment in improving BCVA of CME patients and is inferior to anti-inflammatory in decreasing SRD thickness of SRD patients.