OBJECTIVE: Previous studies have shown that insomnia is closely related to erectile dysfunction（ED）. However, the causal relationship between them is still unclear. Mendelian randomization (MR) provides a new method for studying the relationship between the two, and the theory of heart-kidney interaction in TCM provides a new idea for exploring the causal relationship between them. METHODS: Based on the statistical data collected by genome-wide association studies (GWAS), the causal relationship between insomnia and ED was discussed by MR. Inverse variance weighted (IVW) is the main analysis method, and weighted median (WME), simple mode (SM), weighted mode (WM) and MR Egger method were the supplementary analysis to evaluate the causal effect. MR-Egger intercept test, Cochran Q test and leave-one-out method were used in sensitivity analysis to verify the reliability of MR results. RESULTS: Thirty-nine SNPs significantly related to insomnia were finally included for MR analysis. The results of IVW method in MR analysis showed that insomnia had a significant causal relationship with the increased risk of ED (OR = 3.111，95% CI= 1.566－6.181，P=1.193×10－3). The results obtained by MR-Egger method, WME method, WM method and SM method were consistent with IVW method in the direction of effect. The sensitivity results suggested that the results of this study were robust. CONCLUSION Our study reveals the causal relationship between insomnia and ED, which provides a new basis for future clinical practice and prevention and treatment of ED.
Causality ; Sleep Initiation and Maintenance Disorders/genetics* ; Erectile Dysfunction/genetics* ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Humans ; Male ; Heart/physiology* ; Kidney/physiology* ; Polymorphism, Single Nucleotide ; Data Interpretation, Statistical

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

Objective To investigate the prevalence of tension-type headache(TTH)in children and adolescents aged 0-19 years globally in 1990-2021,and to provide a basis for the prevention and treatment of TTH.Methods Based on the Global Burden of Disease Study data,the age-standardized prevalence distribution of TTH and its changing trend were analyzed among the children and adolescents aged 0-19 years,with different sexes,age groups,sociodemographic index(SDI)regions and countries/territories.Results The age-standardized prevalence rate(ASPR)of TTH in children and adolescents aged 0-19 globally in 2021 was 17 339.89/100 000,which was increased by 1.73%since 1990.The ASPR in females was slightly higher than that in males(1990:17 707.65/100 000 vs 16 403.78/100 000;2021:17 946.29/100 000 vs 16 763.09/100 000).The ASPR in adolescence was significantly higher than that in school-aged and preschool periods(1990:27 672.04/100 000 vs 10 134.16/100 000;2021:28 239.04/100 000 vs 10 059.39/100 000).Regions with high SDI exhibited a higher ASPR than the other regions,with significant differences in prevalence rates across different countries.From 1990 to 2021,there was a slight increase in global ASPR,with an average annual percentage change(AAPC)of 0.06%.Females experienced a smaller increase than males based on AAPC(0.04%vs 0.07%).There was reduction in ASPR in preschool and school-aged groups,with an AAPC of-0.02%,while there was a significant increase in ASPR in adolescence,with an AAPC of 0.07%.ASPR decreased in regions with low-middle and low levels of SDI,with an AAPC of-0.02%and-0.04%,respectively,while it increased in regions with middle SDI,with an AAPC of 0.24%.Conclusions There is a consistent increase in the ASPR of TTH in children and adolescents aged 0-19 years globally,with significant differences across sexes,age groups,SDI regions and countries/territories.

The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

China ; Humans ; Otolaryngology

Objective: To investigate oxidative stress-mediated damage to the epididymal epithelial tight junction protein ZO-1 and its impact on epididymal function in varicocele rats. METHODS: We randomly divided 45 male adolescent SD rats into three groups of equal number: sham operation (left renal vein exposed and isolated), experimental (left renal vein constricted and collaterals of the left spermatic vein fully ligated), and treatment (60-day intragastric administration of vitamin E at 150 mg/kg/d after modeling). At 60 days after modeling, we observed the histological changes in the left epididymis, detected the expressions of ZO-1 and other tight junction-related proteins by real-time quantitative PCR, immunohistochemistry, immunofluorescence staining and Western blotting, determined sperm motility, and measured the levels of superoxide dismutase (SOD), total antioxidant capacity (T-AOC), methylene dioxyamphetamine (MDA) and α-glucosidase (α-Glu) in the epididymal tissue of the rats. RESULTS: Compared with the rats of the sham operation group, those of the experimental group showed disorganized epithelial structure and decreased number of epithelial cells in the left epididymis, with some epithelial cells desquamated into the lumen. The expression of ZO-1 was significantly lower in the experimental than in the sham operation group (P < 0.05) but markedly upregulated after VE treatment (P < 0.05). In comparison with the sham operation group, the animals in the experimental group exhibited remarkably increased content of MDA in the epididymal tissue (［0.41 ± 0.05］ vs ［1.21 ± 0.18］ nmol/mg prot, P < 0.05) but decreased levels of SOD (［814.65 ± 73.64］ vs ［298.62 ± 67.84］ U/mg prot, P < 0.05), T-AOC (［0.84 ± 0.07］ vs ［0.24 ± 0.04］ nmol/mg prot, P < 0.05) and α-Glu (［11.72 ± 2.72］ vs ［5.82 ± 1.24］ U/mg prot, P < 0.05). VE treatment, however, remarkably reduced the content of MDA (［0.69 ± 0.12］ nmol/mg prot) and elevated the levels of SOD (［497.73 ± 48.03］ U/mg prot), T-AOC (［0.42 ± 0.06］ nmol/mg prot) and α-Glu (［9.11 ± 1.91］ U/mg prot) as compared with those in the experimental group (all P < 0.05). The percentage of progressively motile sperm was significantly lower in the experimental than in the sham operation group (［31.33 ± 6.32］% vs ［71.21 ± 5.21］%, P < 0.05), but markedly increased after VE treatment (［60.68 ± 5.31］%, P < 0.05). CONCLUSIONS Varicocele reduces the expression of the EETJ protein ZO-1 and impairs epididymal function via oxidative stress, while vitamin E can effectively upregulate the ZO-1 expression and improve epididymal function by decreasing oxidative stress in the epididymis of varicocele rats.

OBJECTIVE: To evaluate the feasibility and effectiveness of the totally extraperitoneal renal autotransplantation with boari flap-pelvis anastomosis in the treatment of upper urinary tract urothelial carcinoma (UTUC), and to review the experience of renal autotransplantation for UTUC treatment. METHODS: One case of applying the totally extraperitoneal renal autotransplantation with boari flap-pelvis anastomosis to the UTUC treatment was reported, and related literature was reviewed. The patient was a sixty-four-year old man who received right radical nephroureterectomy for right ureteral carcinoma 1 year before and diagnosed as left ureteral carcinoma(G2, high grade) this time. In order to preserve his renal function and avoid the shortness of common kidney-sparing surgery, a totally extraperitoneal procedure, including retroperitoneoscopic nephrectomy, ureterectomy, renal autotransplantation and Boari flap-pelvis anastomosis, was performed to the patient. RESULTS: The operation was completed successfully without perioperative complications. The renal function recovered to preoperative level within 1 week. No deterioration of renal function during the follow-up and no tumor recurrence was observed under cystoscopy at the 3-month postoperative consult. CONCLUSION The totally extraperitoneal renal autotransplantation with Boari flap-pelvis anastomosis is a feasible and effective treatment for UTUC. The innovative procedure has several advantages compared to the former ones. The extraperitoneal procedure results in significantly less pain, shorter hospital stay, decreased overall time to recovery and lower bowel complications risk without warm ischemia time extension. Meanwhile, the Boari flap-pelvis anastomosis simplifies the follow -up protocols and creates an easy route for cystoscopy and topical therapy. From the systematic clinical analysis, as well as the related literature review, it's been concluded that the renal autotransplantation can be a reasonable option for the patients who have UTUC in solitary kidney or have bilateral UTUC. This type of treatment possesses advantages of preservation of renal function and total resection of malignant lesions. But long-term data and large cohort study on renal function or tumor recurrence are still absent which will be necessary to confirm the advantages of this approach.
Anastomosis, Surgical ; Cohort Studies ; Humans ; Kidney Neoplasms ; Male ; Neoplasm Recurrence, Local ; Nephrectomy ; Pelvis ; Transplantation, Autologous ; Ureter ; Ureteral Neoplasms

Background:The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma;therefore,the use of morcellation is limited in the USA.A large sample study is necessary to assess the proportion of uterine malignant tumors found in patients with laparoscopic myomectomy.Methods:A national multicenter study was performed in China.From 2002 to 2014,33,723 cases were retrospectively selected.We calculated the prevalence and recorded the clinical characteristics of the patients with malignancy after morcellation application.A total of 62 cases were finally pathologically confirmed as malignant postoperatively.Additionally,the medical records of the 62 patients were analyzed in details.Results:The proportion of postoperative malignancy after morcellation application was 0.18％ (62/33,723) for patients who underwent laparoscopic myomectomy.Nearly 62.9％ (39/62) of patients had demonstrated blood flow signals in the uterine fibroids before surgery.And,23 (37.1％) patients showed rapid growth at the final preoperative ultrasound.With respect to the pathological types,38 (61.3％) patients had detectable endometrial stromal sarcoma,13 (21.0％) had detectable uterine leiomyosarcoma,only 3 (3.2％) had detectable carcinosarcoma,and 5 (8.1％) patients with leiomyoma had an undetermined malignant potential.Conclusions:The proportion of malignancy is low after using morcellation in patients who undergo laparoscopic myomectomy.Patients with fast-growing uterine fibroids and abnormal ultrasonic tumor blood flow should be considered for malignant potential,and morcellation should be avoided.

Swine influenza viruses (SwIVs) cause considerable morbidity and mortality in domestic pigs, resulting in a significant economic burden. Moreover, pigs have been considered to be a possible mixing vessel in which novel strains loom. Here, we developed and evaluated a novel M2e-multiple antigenic peptide (M2e-MAP) as a supplemental antigen for inactivated H3N2 vaccine to provide cross-protection against two main subtypes of SwIVs, H1N1 and H3N2. The novel tetra-branched MAP was constructed by fusing four copies of M2e to one copy of foreign T helper cell epitopes. A high-yield reassortant H3N2 virus was generated by plasmid based reverse genetics. The efficacy of the novel H3N2 inactivated vaccines with or without M2e-MAP supplementation was evaluated in a mouse model. M2e-MAP conjugated vaccine induced strong antibody responses in mice. Complete protection against the heterologous swine H1N1 virus was observed in mice vaccinated with M2e-MAP combined vaccine. Moreover, this novel peptide confers protection against lethal challenge of A/Puerto Rico/8/34 (H1N1). Taken together, our results suggest the combined immunization of reassortant inactivated H3N2 vaccine and the novel M2e-MAP provided cross-protection against swine and human viruses and may serve as a promising approach for influenza vaccine development.
Animals ; Antibodies, Viral/blood ; Antigens, Viral/genetics/*immunology ; Body Weight ; Cross Protection/*immunology ; Disease Models, Animal ; Epitopes, T-Lymphocyte/genetics/immunology ; Female ; Influenza A Virus, H3N2 Subtype/genetics/*immunology ; Influenza Vaccines/*immunology ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/*immunology/mortality/pathology/prevention & control ; Peptides/genetics/*immunology ; Random Allocation ; Survival Analysis ; Vaccines, Synthetic/immunology ; Virus Replication