Heavy metal ions exchange driven protein phosphorylation cascade functions in genomic instability in spermatocytes and male infertility.

DNA double-strand breaks (DSBs) are functionally linked to genomic instability in spermatocytes and to male infertility. The heavy metal cadmium (Cd) is known to induce DNA damage in spermatocytes by unknown mechanisms. Here, we showed that Cd ions impaired the canonical non-homologous end-joining (NHEJ) repair pathway, but not the homologous recombination (HR) repair pathway, through stimulation of Ser2056 and Thr2609 phosphorylation of DNA-PKcs at DSB sites. Hyper-phosphorylation of DNA-PKcs led to its premature dissociation from DNA ends and the Ku complex, preventing recruitment of processing enzymes and further ligation of DNA ends. Specifically, this cascade was initiated by the loss of PP5 phosphatase activity, which results from the dissociation of PP5 from its activating ions (Mn), that is antagonized by Cd ions through a competitive mechanism. In accordance, in a mouse model Cd-induced genomic instability and consequential male reproductive dysfunction were effectively reversed by a high dosage of Mn ions. Together, our findings corroborate a protein phosphorylation-mediated genomic instability pathway in spermatocytes that is triggered by exchange of heavy metal ions.

Development and validation of a Systemic Sclerosis Health Literacy Scale.

Background and aim: Health literacy levels are strongly associated with clinical outcomes and quality of life in patients with chronic diseases, and patients with limited health literacy often require more medical care and achieve poorer clinical outcomes. Among the large number of studies on health literacy, few studies have focused on the health literacy of people with systemic sclerosis (SSc), and there is no specific tool to measure health literacy in this group. Therefore, this study plans to develop a health literacy scale for patients with SSc. Methods: This study included 428 SSc patients from the outpatient and inpatient departments of the Department of Rheumatology and Immunology, the first affiliated Hospital of Anhui Medical University and the first affiliated Hospital of University of Science and Technology of China. The formulation of the scale was completed by forming the concept of health literacy of SSc patients, establishing the item pool, screening items, and evaluating reliability and validity. Classical measurement theory was used to screen items, factor analysis was used to explore the construct validity of the scale, and Cronbach's alpha coefficient was used to assess the internal consistency. Results: Our study population was predominantly middle-aged women, with a male to female ratio of 1:5.7 and a mean age of 51.57 ± 10.99. A SSc Health Literacy scale with 6 dimensions and 30 items was developed. The six dimensions are clinic ability, judgment/evaluation information ability, access to information ability, social support, treatment compliance and application information ability. The Cronbach's alpha coefficient of the scale is 0.960, retest reliability is 0.898, split-half reliability is 0.953, content validity is 0.983, which has good reliability and validity. Conclusion: The Systemic Sclerosis Health Literacy Scale may become a valid tool to evaluate the health literacy level of patients with SSc.

Synthesis and antitumor activity of erysolin and its metabolites.

Erysolin and its two metabolites which were found in blood, ERY-GSH and ERY-NAC, were synthesized by alkylation, amination, isothiocyanation and oxidation reactions from 1-bromo-4-chlorobutane and sodium methyl mercaptide. The reaction temperature, time, feed ratios and purification method were also optimized. The synthesis method was simple, green, safe and low-cost. Erysolin, ERY-GSH and ERY-NAC showed good antitumor activities against MCF-7, HeLa, HepG2, A549 and SW480 cells, which suggested that the antitumor mechanism of erysolin can also be clarified from its metabolites in addition to itself.

Bioinformatics analysis of markers based on m6 A related to prognosis combined with immune invasion of renal clear cell carcinoma.

The incidence rate of renal cell carcinoma (RCC) is about 3% of all adult cancers. Of these, the Kidney clear cell renal cell carcinoma (KIRC) is the most common type, accounting for about 70%-75% of RCC. KIRC is difficult to be detected in time clinically. KIRC still has no effective treatment at this stage. We combined high-throughput bioinformatics analysis to obtained the structural sequence transcriptome data, relevant clinical information, and m6 A gene map of KIRC patients from genomics TCGA database. Pearson's correlation analysis was used to explore m6 A related gene long noncoding RNAs (lncRNAs), and then univariate Cox regression analysis was performed to screen the prognostic role of KIRC patients. Lasso-Cox regression was performed to establish the lncRNAs risk model associated with m6 A.LINC02154 and AC016773.2, Z98200.2, AL161782.1, EMX2OS, AC021483.2, CD27-AS1, AC006213.3 were iidentif. Compared with the low-risk group, the overall survival of patients in the high-risk group was significantly worse. Analyzing whether there are differences in immune cells between high-risk and low-risk subgroups. There were CD4 memory resting, Monocytes, Macrophages M1, Dendritic cells activated, Mast cells resting, which had higher infiltrations in the low-risk group. We performed Go enrichment analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis and gene set enrichment analysis enrichment analysis. Overall, our results suggest that the component of m6A-related lncRNAs in the prognostic signal may be a key mediator in the immune microenvironment of KIRC, which represents a promising therapeutic effect.

Urinary Creatinine Concentrations and Its Explanatory Variables in General Chinese Population: Implications for Creatinine Limits and Creatinine Adjustment.

Objective: The study aimed to analyze the applicability of the World Health Organization's exclusionary guidelines for Urinary creatinine (Ucr) in the general Chinese population, and to identify Ucr related factors. Methods: We conduct a cross-sectional study using baseline data from 21,167 participants in the China National Human Biomonitoring Program. Mixed linear models and restricted cubic splines (RCS) were used to analyze the associations between explanatory variables and Ucr concentration. Results: The geometric mean and median concentrations of Ucr in the general Chinese population were 0.90 g/L and 1.01 g/L, respectively. And 9.36% samples were outside 0.3-3.0 g/L, including 7.83% below the lower limit and 1.53% above the upper limit. Middle age, male, obesity, smoking, higher frequency of red meat consumption and chronic kidney disease were associated significantly with higher concentrations of Ucr. Results of the RCS showed Ucr was positively and linearly associated with body mass index, inversely and linearly associated with systolic blood pressure, diastolic blood pressure, triglycerides level, and glomerular filtration rate, and were non-linearly associated with triiodothyronine. Conclusion: The age- and gender-specific cut-off values of Ucr that determine the validity of urine samples in the general Chinese population were recommended. To avoid introducing bias into epidemiologic associations, the potential predictors of Ucr observed in the current study should be considered when using Ucr to adjust for variations in urine dilution.

Community Structure and Diversity of Hymenopteran Parasitoids of Chromatomyia horticola (Diptera: Agromyzidae) in Different Habitats in Changchun, China.

The community structure and diversity of hymenopteran parasitoids of the agromyzid leafminer Chromatomyia horticola (Diptera: Agromyzidae) were studied in agricultural, urban, and natural habitats in Changchun, Northeast China. In agricultural habitats, a total of 3,380 individuals and 19 species were collected, and the dominant species were Diglyphus isaea (Walker) (Hymenoptera: Eulophidae) (71.15%) and Chrysocharis pentheus (Walker) (Hymenoptera: Eulophidae) (12.10%). In urban habitats, a total of 5,996 individuals and 21 species were collected. There were three dominant species, C. pentheus (26.68%), Chrysocharis phryne (Walker) (Hymenoptera: Eulophidae) (22.18%), and D. isaea (22.13%). In natural habitats, a total of 1,566 individuals and 26 species were collected. There were three dominant species, C. pentheus (30.52%), D. isaea (15.52%), and Pediobius metallicus (Nees) (Hymenoptera: Eulophidae) (12.26%). The diversity indices of the parasitoid community in urban and natural habitats were higher than that in agricultural habitats, and the richness index in natural habitats was higher than that in agricultural and urban habitats. These results suggest that there are differences in the community composition and dynamics of parasitoids in different habitats. Hymenopteran parasitoids of C. horticola are less abundant in natural habitats; however, species richness is greater, and can be used as a species reserve for biological control.

Dura cells in the etiopathogenesis of Crouzon syndrome: the effects of FGFR2 mutations in the dura cells on the proliferation of osteoblasts through the hippo/YAP mediated transcriptional regulation pathway.

BACKGROUND: FGFR2 (fibroblast growth factor receptor 2) mutations are implicated in the etiopathogenesis of syndromic craniosynostosis, and C278F- or C342Y-FGFR2 mutations can lead to Crouzon syndrome. The dura mater exerts crucial effects in the regulation of cranial suture development. However, the underlying mechanisms of these biological processes are rarely studied. This research explored and analyzed the biological function of FGFR2 overexpressed by dura cells on cranial osteoblasts. METHODS: Dura cells and cranial osteoblasts from C57BL/6 mice aged 6 days were obtained and cultured respectively. Lentivirus-FGFR2 constructs were engineered with C278F- and C342Y-FGFR2 mutations. The dura cells were infected with the constructs and co-cultured with osteoblasts in a trans-well system. Four experimental groups were established, namely the Oste group, the Oste+Dura-vector group, the Oste+Dura-C278F group, and the Oste+Dura-C342Y group. FACS, CCK8, and EdU assays were used to evaluate the osteoblast proliferation levels. Western blot and RT-qPCR were used to measure the expressions of the factors related to proliferation, differentiation, and apoptosis. Furthermore, the expression levels of the key factors in the Hippo/YAP-PI3K-AKT proliferation pathway were measured and analyzed. Finally, rescue experiments were performed with an RNA interfering assay. RESULTS: The proliferation and differentiation levels of the osteoblasts in the Oste+Dura-C278F and Oste+Dura-C342Y groups were significantly up-regulated, but the apoptosis levels in the four groups were not significantly different. The YAP, TEADs1-4, p-PI3K, and p-AKT1 expressions in the mutant FGFR2 groups were higher than the corresponding expressions in the control groups, and the results of the rescue experiments showed a reverse expression tendency, which further confirmed the effects of the FGFR2 mutations in the dura cells on the proliferation of the osteoblasts and the underlying possible mechanisms. CONCLUSION: Our studies suggest that the Crouzon mutations (C278F- and C342Y-) of FGFR2 in dura cells can enhance osteoblast proliferation and differentiation and might influence the pathogenesis of craniosynostosis by affecting the Hippo/YAP-PI3K-AKT proliferation signaling pathway.

Iron chelation suppresses secondary bleeding after intracerebral hemorrhage in angiotensin II-infused mice.

AIMS: Secondary bleeding and further hematoma expansion (HE) aggravate brain injury after intracerebral hemorrhage (ICH). The majority of HE results from hypertensive ICH. Previous study reported higher iron content in the brains of hypertensive patients. Iron overload exacerbates the risk of hemorrhagic transformation in thromboembolic stroke mice. Whether iron overload during the process of hypertension participates in secondary bleeding of hypertensive ICH remains unclear. METHODS: Hypertension was induced by continuous infusion of angiotensin II (Ang II) with an osmotic pump into C57BL/6 mice. ICH was simulated by intrastriatal injection of the liquid polymer Onyx-18. Iron chelation and iron overload was achieved by deferoxamine mesylate or iron dextran injection. Secondary bleeding was quantified by measuring the hemoglobin content in the ipsilateral brain hemisphere. RESULTS: Ang II-induced hypertensive mice showed increased iron accumulation in the brain and expanded secondary hemorrhage after ICH modeling. Moreover, iron chelation suppressed while iron overload aggravated secondary bleeding. Mechanistically, iron exacerbated the loss of contractile cerebral vascular smooth muscle cells (VSMCs), aggravated blood-brain barrier (BBB) leakage in Ang II-induced hypertensive mice, and increased glial and MMP9 accumulation after ICH. CONCLUSION: Iron overload plays a key role in secondary bleeding after ICH in Ang II-induced hypertensive mice. Iron chelation during the process of Ang II-induced hypertension suppresses secondary bleeding after ICH.