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ERI1 is a 3-to-5 exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3 end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

The Cu–15Ni–8Sn alloy ingot was prepared in the medium-frequency induction melting furnace. The hot extruded alloy was treated by solid solution at 840 °C for 60 min and aging at 400 °C for different times (0 miñ480 min). The effect of aging time on the evolution of the nanophase of Cu–15Ni–8Sn alloy and the strengthening-toughening mechanism were studied. The results show that at the beginning of aging, the alloy undergoes spinodal decomposition, the wavelength of the modulated structure is approximately 3∼7 nm, the ordered phase transformation of D022 and L12 occurs simultaneously, and the ordered phase size is approximately 5 nm. With the extension of aging time, the modulated structure became coarser, and the wavelength of the modulated structure increased to 5–9 nm. At the same time, the D022 ordered phase changed to the L12 ordered phase, and a continuous distribution of elliptical discontinuous precipitation appeared at the grain boundary. The ratio of the long and short axes of the discontinuous precipitation was approximately 4.7. In the late aging period, the D022 ordered phase was basically transformed into the L12 ordered phase, and discontinuous precipitation, which is incompatible with the matrix, extended into the crystal. After 120 min of aging at 400 °C, the hardness, strength, and elongation of the alloy are 105.4 HRB, 839.8 MPa and 9.6 %, respectively. The peak-aging states D022 and L12 coexist in an orderly phase at the nanoscale, and this nanoscale strengthening phase is completely integrated with the matrix, which improves the strength and toughness of the alloy. The research results can provide support for the development of high-performance copper alloys in the ocean.

Objective: To explore the epidemiological characteristics of hyperuricemia (HUA) in the metabolic syndrome (MS) and its different components in the physical examination population. Methods: Subjects who underwent medical check-ups at a hospital health management center from June 2021 to March 2023 were included in the study. To analyze the prevalence of HUA in MS and its different components, further, stratify the study population by gender and assess the serum uric acid (SUA) levels and prevalence of HUA in people with different numbers of MS components and the combination of MS components with the highest prevalence of HUA in both sexes. Logistic regression was used to analyze the risk of HUA in people with different numbers of MS components. Result: A total of 66,520 individuals were enrolled in the study. SUA levels (t= -82.947, P<0.001) and HUA prevalence (χ2 = 3421.632, P<0.001) were significantly higher in the MS group than in the Non-MS group. SUA levels and prevalence of HUA were significantly higher in abdominal obesity, hypertension, decreased HDL-C and evaluated TG than in normal subjects (P<0.001), while there were gender differences in SUA levels and HUA prevalence in diabetic patients, with significantly lower SUA levels and HUA prevalence in men with diabetes than in those with normal blood glucose, an opposite result in women. SUA levels and HUA prevalence gradually increased with the increasing number of MS components in women, whereas in men, such a trend was only observed in MS1-MS4. The combination of MS components with the highest prevalence of HUA was abdominal obesity + hypertension + decreased HDL-C + evaluated TG (54.35%) in men and abdominal obesity + hypertension + diabetes + decreased HDL-C + evaluated TG (41.46%) in women. Logistic regression analysis showed that after adjusting for gender, age and ethnicity, the risk of HUA increased with the number of MS components in women, while in men, the risk of HUA increased continuously from MS1-MS4. Further adjustment for BMI, elevated TC, elevated LDL-C, and coronary artery disease, the results remained consistent. Conclusion: MS and its components are risk factors for HUA in the physical examination population, with different combinations of MS components having different correlations with HUA, and the risk of developing HUA correlates with the number of abnormal MS components. [ABSTRACT FROM AUTHOR]

Climate change and human activities are important causes of runoff changes in watersheds. The Budyko hydrothermal coupled equilibrium equation is a common tool for runoff change analysis, because it takes into account certain physical causes on the one hand, and the parameters of the equation are simple on the other hand, so it has been widely used in runoff change attribution for a long time. However, the current research and application of Budyko' s formula for time-varying forms still need to be strengthened. Therefore, this paper first analyzes the trend and abrupt change of annual runoff in the study area by Mann-Kendall test and abrupt change test, and then constructs the time- varying Budyko formula based on the principle of hydrothermal coupling equilibrium, including linear, quadratic polynomial and physical mechanism, and uses Nash efficiency coefficient as the evaluation index to verify the most suitable. Finally, the contribution of precipitation, potential evapotranspiration and human activities to the runoff change is calculated, and the attribution analysis of the runoff change in the Liudong River basin is carried out. The results of this study show that the runoff of the river basin has been decreasing in recent years with the impact of climate change, with a significant change in 1997. A comparison of the sensitivity of precipitation, potential evapotranspiration and human activities to runoff show that the decrease in precipitation is the dominant factor in the decrease in runoff, with a contribution of 49%. Meanwhile, with the development of human economy and society and the construction of large water conservancy facilities, the influence of human activities on runoff changes in the basin is gradually emerging, with a contribution rate of about 26%. [ABSTRACT FROM AUTHOR]

Chemotherapy is one of the common treatment methods for breast cancer, but chemoresistance is a severe challenge. Caffeic acid phenethyl ester (CAPE) is an active ingredient of propolis extract and has been shown to have a variety of beneficial effects, and its potential as a treatment for breast cancer is worth exploring. The effects of CAPE on doxorubicin (DOX) resistance were determined by cell counting kit‐8 (CCK‐8) assay, colony‐formation assay, and flow cytometry. Oil Red O staining and the detection of free fatty acids, triglycerides, phospholipids, and cholesterol were performed to assess the status of lipid metabolism. Quantitative polymerase chain reaction (qPCR) and western blotting were applied to investigate the molecules involved in lipid metabolism and the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/sterol regulatory element binding protein 1 (SREBP1) pathway. CAPE treatment reversed DOX resistance in breast cancer cells and suppressed their lipid metabolism. In addition, CAPE combined with DOX remarkably suppressed SREBP1 expression in part by inhibiting Akt/mTOR pathway activation. Furthermore, by inhibiting lipid metabolism, partly via the Akt/mTOR/SREBP1 pathway, CAPE ultimately reversed DOX resistance in breast cancer. Our results suggest that CAPE treatment reversed DOX resistance in breast cancer cells, at least in part by inhibiting Akt/mTOR/SREBP1 pathway‐mediated lipid metabolism, indicating that CAPE may be an effective substance to assist in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the impact of different blood pressure control statuses on newly developed left bundle branch block (LBBB). METHODS A retrospective cohort study was conducted. A total of 88,553 Kailuan employees who underwent health examinations from July 2006 to October 2007 were recruited and categorized into non-hypertension and hypertension groups based on their blood pressure values and hypertension history at the beginning of follow-up. The hypertensive patients were further divided into two groups: the initial blood pressure-controlled group and the initial blood pressure-uncontrolled group based on the blood pressure values at the beginning of follow-up. Based on the blood pressure readings at the end of the follow-up, patients with initially uncontrolled blood pressure were categorized into two groups: those with controlled blood pressure and those with uncontrolled blood pressure. The impact of different blood pressure control statuses on the occurrence of newly developed LBBB was analyzed using a multifactorial Cox proportional hazards model. Stratified analyses by age and gender were performed, along with sensitivity analyses excluding participants with diabetes, chronic kidney disease (CKD), heart attack, or heart failure. RESULTS The non-hypertension group comprised 50,505 individuals, while the hypertension group comprised 38,048 individuals. Among the hypertensives, 2,607 patients had controlled blood pressure, and 35,441 patients had uncontrolled blood pressure at the beginning of follow-up. Among the patients with uncontrolled initial blood pressure, 10,658 patients had controlled blood pressure and 24,783 patients had uncontrolled blood pressure at the end of follow-up. Over a follow-up period of (10.15 ± 3.44) years, a total of 1,014 cases of LBBB occurred. The incidence density of LBBB was 0.80/1,000 person-years in the non-hypertension group, 1.58/1,000 person-years in the hypertension group (Log-Rank test P  < 0.001), 1.04/1,000 person-years in the initial blood pressure-controlled group, 1.62/1,000 person-years in the initial blood pressure uncontrolled group, 1.32/1,000 person-years in the follow-up blood pressure-controlled group, and 1.76/1,000 person-years in the follow-up blood pressure uncontrolled group. The results of the multifactorial Cox proportional hazards model analysis showed that adjusting for various influencing factors, compared with the non-hypertension group, the hazard ratio (HR) of developed LBBB was 1.42 (95% confidence interval [CI]: 1.24–1.62) in the hypertension group, and which was 0.97 (0.66–1.44) and 1.45 (1.27–1.66) in the initial blood pressure-controlled and uncontrolled group, 1.27 (1.04–1.54) and 1.53 (1.33–1.77) in the follow-up blood pressure-controlled and uncontrolled group, respectively. CONCLUSION Hypertension serves as a risk factor for newly developed LBBB, and achieving blood pressure control standards can reduce the risk of new-onset LBBB. [ABSTRACT FROM AUTHOR]