The Relationship Between Chromosomal Polymorphism and Male Reproductive Abnormalities.

This study aims to investigate the association between chromosomal polymorphisms and abnormalities in male reproductive health. Within the period from January 2018 to December 2022, a cohort of 10,827 males seeking fertility services at our reproductive center was selected for inclusion in this study. Peripheral blood chromosomal karyotype analysis was conducted for each participant to identify carriers of chromosomal polymorphisms, who were subsequently categorized into a polymorphism group. Additionally, a control group was constituted by randomly selecting 1,630 patients exhibiting normal chromosomal karyotypes. The study conducted statistical analyses to compare clinical outcomes between the two groups, focusing on infertility, history of spontaneous miscarriage in partners, anomalies in reproductive development, fetal abnormalities, and sperm quality metrics. (1) Among the cohort of 10,827 males, chromosomal polymorphisms were identified in 1,622 participants, yielding a detection rate of 14.98%. This rate is significantly elevated in comparison to the baseline prevalence of 1.77% observed in the general population. (2) The predominant variant among these polymorphisms was related to the Y chromosome, accounting for 1,082 cases (66.71% of the polymorphic findings), corresponding to a detection rate of 9.99%. This is markedly higher than the approximate 0.09% prevalence noted within a normative demographic. (3) Statistical analysis revealed significant disparities between the chromosomal polymorphism group and the control group in several clinical outcomes. Notably, the rates of spontaneous abortion (18.06% vs. 1.35%), fetal anomalies (1.97% vs. 0.25%), and poor sperm quality (41.74% vs. 7.18%) were markedly higher in the polymorphism group. Additionally, incidences of testicular dysgenesis (2.28% vs. 0.92%) and hypogonadism in partners (0.62% vs. 0.37%) also demonstrated significant differences, underscoring the potential reproductive implications of chromosomal polymorphisms. The study establishes a significant link between chromosomal polymorphisms and critical reproductive outcomes, including male infertility, spontaneous miscarriages in partners, fetal anomalies, and reduced sperm quality. These findings highlight the clinical relevance of chromosomal polymorphisms in reproductive health assessments and suggest the necessity for their consideration in the diagnostic and therapeutic strategies for male reproductive disorders.

Proteomics Platform Reveals Broad-Spectrum Nanobodies for SARS-CoV-2 Variant Neutralization.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of different variants of concerns with immune evasion that have been prevalent over the past three years. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, have garnered interest in developing neutralizing antibodies due to their smaller size, structural stability, ease of production, high affinity, and low immunogenicity, among other characteristics. In this work, we describe an integrated proteomics platform for the high-throughput screening of nanobodies against different SARS-CoV-2 spike variants. To demonstrate this platform, we immunized a camel with subunit 1 (S1) of the wild-type spike protein and constructed a nanobody phage library. The binding and neutralizing activities of the nanobodies against 72 spike variants were then measured, resulting in the identification of two nanobodies (C-282 and C-39) with broad neutralizing activity against six non-Omicron variants (D614G, Alpha, Beta, Gamma, Delta, Kappa) and five Omicron variants (BA.1-5). Their neutralizing capability was validated using in vitro pseudovirus-based neutralization assays. All these results demonstrate the utility of our proteomics platform to identify new nanobodies with broad neutralizing capability and to develop a treatment for patients with SARS-CoV-2 variant infection in the future.

Temporal trends in prevalence and disability of chronic kidney disease caused by specific etiologies: an analysis of the Global Burden of Disease Study 2019.

BACKGROUND: The prevalence of disability in CKD is high. In this context the aim of the present study was to assess the  temporal trends of prevalence and disability progression for chronic kidney disease (CKD) caused by specific etiologies. METHODS: Using data from the Global Burden of Diseases Study (GBD) 2019, we examined the age-standardized rates of CKD prevalence and disability-adjusted life-years for different etiologies, including Type 1/2 diabetes mellitus (T1DM/T2DM), glomerulonephritis, and hypertension. We also calculated the average annual percentage changes to assess trends. Additionally, we utilized the joinpoint regression model to identify significant shifts over time. RESULTS: From 1990 to 2019, the global prevalence of CKD due to various etiologies exhibited an overall increasing trend, albeit with fluctuations. Notably, CKD due to T1DM, glomerulonephritis, and hypertension consistently demonstrated a significant upward trend across all continents, while the prevalence of CKD due to T2DM varied across continents. In terms of disability-adjusted life-years, CKD due to T2DM and hypertension exhibited a significant rising trend over the past 30 years. However, changes in age standardized disability-adjusted life-years for CKD due to different etiologies were not consistent across continents, with an upward trend observed in The Americas and a contrasting trend in Asia. Furthermore, both age-standardized prevalence rate and age standardized disability-adjusted life-year trends for CKD varied significantly across 204 countries and territories. Additionally, a negative association was observed between the Socio-demographic Index and the disability progression of CKD. CONCLUSION: The prevalence and disability burden of CKD caused by specific etiologies show substantial heterogeneity worldwide, highlighting significant disparities in the distribution of CKD. It is crucial to implement geographic and personalized strategies in different regions to alleviate the burden of CKD effectively.

Mendelian randomization analysis identifies a genetic casual association between circulating C-reactive protein and intracerebral hemorrhage.

BACKGROUND: The causal effect of C-reactive protein (CRP) on intracerebral hemorrhage (ICH) remains controversial. We discussed the causal association of CRP with ICH based on two-sample Mendelian randomization. METHODS: The data from two genome-wide association studies (GWAS) of European ancestry was extracted, including circulating CRP levels (204,402 individuals) and ICH (1,687 cases and 201,146 controls). The inverse variance weighted (IVW) method was primary tool to evaluate the causal relationship of circulating CRP levels on ICH risk. MR-Egger regression and MR-PRESSO global test were utilized to identify pleiotropy. Heterogeneity was discussed with Cochran's Q test. The leave-one-out analysis explored the reliability of the results. RESULTS: 54 SNPs were identified as instrumental variables (IVs) for circulating CRP levels, and these IVs had no significant horizontal pleiotropy, heterogeneity, or bias. MR analysis demonstrated a causal relationship between elevated circulating CRP levels and decreased risk of ICH (ORIVW = 0.828, 95% CI 0.692-0.992, P = 0.040). CONCLUSION: Elevated circulating CRP levels demonstrated a significant potentially protective causal relationship with risk of ICH.

Copolymers functionalized with quaternary ammonium compounds under template chain exhibit simultaneously efficient bactericidal and flocculation properties: Characterization, performance and mechanism.

In this work, novel multifunctional cationic template copolymers with flocculation and sterilization capabilities were synthesized using a low-pressure ultraviolet (LP-UV) template polymerization method for the removal of kaolin and Escherichia coli (E. coli) from water. The influence of template agents on the structural performance of the copolymers was evaluated through characterization, which showed that template copolymer TPADM possesses a higher cationic charge density and a more complex rough surface, contributing to better flocculation performance than that of the non-template copolymer CPADM. Under optimal experimental conditions, TPADM-1 exhibited removal rates of 98.45% for kaolin and 99% for E. coli (OD600 =0.04), marginally outperforming the non-template copolymer. Simultaneously, TPADM-1 produced good adaptability to kaolin and E. coli wastewater in terms of wide pH, speculating that charge neutralization, adsorption bridging, patching, and sweeping simultaneously dominate the flocculation mechanism. Interestingly, SEM and 3D-EEM analysis confirm that the sterilization of E. coli occurs through two distinct functions: initially adsorption followed by subsequent cell membrane rupture and leakage of cellular contents, ultimately leading to cell death. This research further confirms the feasibility of the designed novel multifunctional copolymers for achieving simultaneous disinfection and turbidity removal, demonstrating practical applicability in real water treatment processes.

Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization.

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurologic disorders characterized by progressive lower-extremity spasticity. Despite the identification of several HSP-related genes, many patients lack a genetic diagnosis. OBJECTIVES: The aims were to confirm the pathogenic role of biallelic COQ4 mutations in HSP and elucidate the clinical, genetic, and functional molecular features of COQ4-associated HSP. METHODS: Whole exome sequences of 310 index patients with HSP of unknown cause from three distinct populations were analyzed to identify potential HSP causal genes. Clinical data obtained from patients harboring candidate causal mutations were examined. Functional characterization of COQ4 variants was performed using bioinformatic tools, single-cell RNA sequencing, biochemical assays in cell lines, primary fibroblasts, induced pluripotent stem cell-derived pyramidal neurons, and zebrafish. RESULTS: Compound heterozygous variants in COQ4, which cosegregated with HSP in pedigrees, were identified in 7 patients from six unrelated families. Patients from four of the six families presented with pure HSP, whereas probands of the other two families exhibited complicated HSP with epilepsy or with cerebellar ataxia. In patient-derived fibroblasts and COQ4 knockout complementation lines, stable expression of these missense variants exerted loss-of-function effects, including mitochondrial reactive oxygen species accumulation, decreased mitochondrial membrane potential, and lower ubiquinone biosynthesis. Whereas differentiated pyramidal neurons expressed high COQ4 levels, coq4 knockdown zebrafish displayed severe motor dysfunction, reflecting motor neuron dysregulation. CONCLUSIONS: Our study confirms that loss-of-function, compound heterozygous, pathogenic COQ4 variants are causal for autosomal recessive pure and complicated HSP. Moreover, reduced COQ4 levels attributable to variants correspond with decreased ubiquinone biosynthesis, impaired mitochondrial function, and higher phenotypic disease severity. © 2023 International Parkinson and Movement Disorder Society.

Microbial corrosion behavior of pipeline steels in simulation environment of natural gas transportation pipeline.

Bacteria are introduced into natural gas transmission pipelines through water-driven gas extraction, which can exacerbate the occurrence of pipeline corrosion. This study utilized a micro-reactor to design a simulated corrosion environment that mimics natural gas gathering and transportation pipelines. The objective was to investigate the corrosion behavior of X80 pipeline steel under the combined effects of CO2, Cl-, sulfate reducing bacteria (SRB), and iron bacteria (IOB). Additionally, it aimed to elucidate the influence mechanisms of these two microorganisms on corrosion. Under a humid environment with a total pressure of 8.5 MPa and a partial pressure of CO2 at 0.85 MPa, the corrosion rate of X80 pipeline steel was observed to follow the sequence: IOB > control (asepsis) > SRB + IOB > SRB. During the initial stages of corrosion, highly active IOB becomes the primary factor contributing to corrosion. As corrosion progresses, the concentration of dissolved oxygen in the SRB system gradually decreases while SRB activity intensifies, leading to the formation of FeS through the process of corrosion. The corrosion current density (icorr) exhibited a significant decrease, thereby intensifying localized corrosion of the corrosion products beneath the film. This resulted in a maximum pitting depth of 113.5 µm. Research on the behavior of microbial-enhanced corrosion provides significant guidance in the development and implementation of protective coatings.

Downward trends in the global burden of congenital complete hearing loss in children younger than five years from 1990 to 2030.

Background: The global epidemiological data on congenital hearing loss in children is sparse. We aimed to analyse the trends in the burden of complete hearing loss caused by congenital birth defects in children younger than five years from 1990 to 2030. Methods: Using data from the Global Burden of Disease (GBD) Study 2019, we reported the counts and rates of prevalence and years lived with disability (YLD) by age, sex, and sociodemographic index (SDI). We also forecasted the prevalence rates until 2030 through the autoregressive integrated moving average (ARIMA) and Bayesian age-period-cohort (BAPC) models. Results: We observed a global prevalence rate of 15.4 (95% uncertainty interval (UI) = 5.8 to 33.8) and a YLD rate of 3.3 (95% UI = 1.1 to 7.1) per 100 000 population in 2019, with both showing downward trends from 1990 to 2019. Regionally, Oceania had the highest prevalence (47.2; 95% UI = 18.8 to 96.6) and YLD (10; 95% UI = 3.2 to 22.8) rates, while Central Europe had the lowest rates. Nationally, the prevalence (85.0; 95% UI = 36.8 to 166.8) and YLD (17.9; 95% UI = 6.6 to 36.9) rates were highest in Myanmar and lowest in Peru. Only the United States of America (2.6%; 95% UI = -4.6 to 14.4) and Norway (0.6%; 95% UI = -6.7 to 16.2) showed upward trends. Compared to girls, the prevalence and YLD rates were higher for boys at global, regional, and five SDI quintile levels, except for Eastern Sub-Saharan Africa. At the global level, downward trends were predicted in prevalence rates from 2019 to 2030 between boys and girls. Conclusions: Although the global burden of childhood congenital complete hearing loss showed inequalities across locations, sexes, and age groups, we found decreases in the global prevalence rates between 1990 and 2019 and predicted decreases from 2019 to 2030. Better prevention of infectious aetiologies, improving genetic diagnoses, and hearing restoration could alleviate this burden.

Expression patterns and immunological characterization of PANoptosis -related genes in gastric cancer.

Background: Accumulative studies have demonstrated the close relationship between tumor immunity and pyroptosis, apoptosis, and necroptosis. However, the role of PANoptosis in gastric cancer (GC) is yet to be fully understood. Methods: This research attempted to identify the expression patterns of PANoptosis regulators and the immune landscape in GC by integrating the GSE54129 and GSE65801 datasets. We analyzed GC specimens and established molecular clusters associated with PANoptosis-related genes (PRGs) and corresponding immune characteristics. The differentially expressed genes were determined with the WGCNA method. Afterward, we employed four machine learning algorithms (Random Forest, Support Vector Machine, Generalized linear Model, and eXtreme Gradient Boosting) to select the optimal model, which was validated using nomogram, calibration curve, decision curve analysis (DCA), and two validation cohorts. Additionally, this study discussed the relationship between infiltrating immune cells and variables in the selected model. Results: This study identified dysregulated PRGs and differential immune activities between GC and normal samples, and further identified two PANoptosis-related molecular clusters in GC. These clusters demonstrated remarkable immunological heterogeneity, with Cluster1 exhibiting abundant immune infiltration. The Support Vector Machine signature was found to have the best discriminative ability, and a 5-gene-based SVM signature was established. This model showed excellent performance in the external validation cohorts, and the nomogram, calibration curve, and DCA indicated its reliability in predicting GC patterns. Further analysis confirmed that the 5 selected variables were remarkably related to infiltrating immune cells and immune-related pathways. Conclusion: Taken together, this work demonstrates that the PANoptosis pattern has the potential as a stratification tool for patient risk assessment and a reflection of the immune microenvironment in GC.

Integration of metabolomics and machine learning revealed tryptophan metabolites are sensitive biomarkers of pemetrexed efficacy in non-small cell lung cancer.

BACKGROUND: Anti-folate drug pemetrexed is a vital chemotherapy medication for non-small cell lung cancer (NSCLC). Its response varies widely and often develops resistance to the treatment. Therefore, it is urgent to identify biomarkers and establish models for drug efficacy evaluation and prediction for rational drug use. METHODS: A total of 360 subjects were screened and 323 subjects were recruited. Using metabolomics in combination with machine learning methods, we are trying to select potential biomarkers to diagnose NSCLC and evaluate the efficacy of pemetrexed in treating NSCLC. Furtherly, we measured the concentration of eight metabolites in the tryptophan metabolism pathway in the validation set containing 201 subjects using a targeted metabolomics method with UPLC-MS/MS. RESULTS: In the discovery set containing 122 subjects, the metabolic profile of healthy controls (H), newly diagnosed NSCLC patients (ND), patients who responded well to pemetrexed treatment (S) and pemetrexed-resistant patients (R) differed significantly on the PLS-DA scores plot. Pathway analysis showed that glycine, serine and threonine metabolism occurred in every two group comparisons. TCA cycle, pyruvate metabolism and glycerolipid metabolism are the most significantly changed pathways between ND and H group, pyruvate metabolism was the most altered pathway between S and ND group, and tryptophan metabolism was the most changed pathway between S and R group. We found Random forest method had the maximum area under the curve (AUC) and can be easily interpreted. The AUC is 0.981 for diagnosing patients with NSCLC and 0.954 for evaluating pemetrexed efficiency. CONCLUSION: We compared eight mathematical models to evaluate pemetrexed efficiency for treating NSCLC. The Random forest model established with metabolic markers tryptophan, kynurenine and xanthurenic acidcan accurately diagnose NSCLC and evaluate the response of pemetrexed.

Structural basis of the human negative elongation factor NELF-B/C/E ternary complex.

Negative elongation factor (NELF) is a four-subunit transcription elongation factor that mainly functions in maintaining the paused state of RNA polymerase II in eukaryotes. Upon binding to Pol II, NELF works synergistically with DRB sensitivity-inducing factor (DSIF) and inhibits transcription elongation of Pol II, which subsequently retains a stably paused state 20-60 base pairs downstream of the promoter. The promoter-proximal pausing of Pol II caused by NELF is a general mechanism of transcriptional regulation for most signal-responsive genes. To date, structural studies have significantly advanced our understanding of the molecular mechanisms of NELF. However, a high quality structural model clarifying the interaction details of this complex is still lacking. In this study, we solved the high resolution crystal structure of the NELF-B/C/E ternary complex. We observed detailed interactions between subunits and identified residues important for the association between NELF-B and NELF-E. Our work presents a precise model of the NELF complex, which will facilitate our understanding of its in vivo function.

Structural Basis of the Transcriptional Elongation Factor Paf1 Core Complex from Saccharomyces eubayanus.

The multicomponent polymerase associated factor 1 (Paf1) complex (PAF1C) is an important transcription elongation factor that upregulates RNA polymerase II-mediated genome-wide transcription. PAF1C can regulate transcription through direct association with the polymerase or by impacting the chromatin structure epigenetically. In recent years, significant progress has been made in understanding the molecular mechanisms of PAF1C. However, high-resolution structures that can clarify the interaction details among the components of the complex are still needed. In this study, we evaluated the structural core of the yeast PAF1C containing the four components Ctr9, Paf1, Cdc73 and Rtf1 at high resolution. We observed the interaction details among these components. In particular, we identified a new binding surface of Rtf1 on PAF1C and found that the C-terminal sequence of Rtf1 dramatically changed during evolution, which may account for its different binding affinities to PAF1C among species. Our work presents a precise model of PAF1C, which will facilitate our understanding of the molecular mechanism and the in vivo function of the yeast PAF1C.

PIM2 Promotes the Development of Ovarian Endometriosis by Enhancing Glycolysis and Fibrosis.

Endometriosis is a common gynecological disorder characterized by the presence of the endometrial glands and the stroma outside the uterine cavity. The disease affects reproductive function and quality of life in women of reproductive age. Endometriosis is similar to tumors in some characteristics, such as glycolysis. PIM2 can promote the development of tumors, but the mechanism of PIM2 in endometriosis is still unclear. Therefore, our goal is to study the mechanism of PIM2 in endometriosis. Through immunohistochemistry, we found PIM2, HK2, PKM2, SMH (smooth muscle myosin heavy chain), Desmin, and α-SMA (α-smooth muscle actin) were strongly expressed in the ovarian endometriosis. In endometriotic cells, PIM2 enhanced glycolysis and fibrosis via upregulating the expression of PKM2. Moreover, the PIM2 inhibitor SMI-4a inhibited the development of endometriosis. And we established a PIM2 knockout mouse model of endometriosis to demonstrate the role of PIM2 in vivo. In summary, our study indicates that PIM2 promotes the development of endometriosis. PIM2 may serve as a promising therapeutic target for endometriosis.

Metabolomics analysis reveals cytotoxic effects of ouabain towards psoriatic keratinocytes via impairment of glutathione metabolism.

Ouabain is a cardiac glycoside long studied for treating heart diseases, but the attempts to evaluate its anti-psoriatic activity have not been reported. We aimed to explore the effects of ouabain on proliferation and metabolism towards psoriatic keratinocytes. In human HaCaT keratinocytes, ouabain potently decreased viability, promoted apoptosis and caused G2/M cycle arrest. Metabolomics analysis indicated that ouabain markedly impaired glutathione metabolism. The solute carrier family 7 member 11 (SLC7A11) is an amino acid transporter highly specific to cysteine, which is critical for glutathione synthesis. Ouabain downregulated SLC7A11, reduced cysteine uptake and subsequently inhibited glutathione synthesis, probably through inhibiting Akt/mTOR/beclin axis that regulate protein activity of SLC7A11. The impaired glutathione synthesis and oxidative stress caused by ouabain may contribute to its cytotoxicity towards psoriatic keratinocytes. Our results provide experimental evidence supporting further study of ouabain as a potential anti-psoriatic agent.

Structural Insights into the Distortion of the Ribosomal Small Subunit at Different Magnesium Concentrations.

Magnesium ions are abundant and play indispensable functions in the ribosome. A decrease in Mg2+ concentration causes 70S ribosome dissociation and subsequent unfolding. Structural distortion at low Mg2+ concentrations has been observed in an immature pre50S, while the structural changes in mature subunits have not yet been studied. Here, we purified the 30S subunits of E. coli cells under various Mg2+ concentrations and analyzed their structural distortion by cryo-electron microscopy. Upon systematically interrogating the structural heterogeneity within the 1 mM Mg2+ dataset, we observed 30S particles with different levels of structural distortion in the decoding center, h17, and the 30S head. Our model showed that, when the Mg2+ concentration decreases, the decoding center distorts, starting from h44 and followed by the shifting of h18 and h27, as well as the dissociation of ribosomal protein S12. Mg2+ deficiency also eliminates the interactions between h17, h10, h15, and S16, resulting in the movement of h17 towards the tip of h6. More flexible structures were observed in the 30S head and platform, showing high variability in these regions. In summary, the structures resolved here showed several prominent distortion events in the decoding center and h17. The requirement for Mg2+ in ribosomes suggests that the conformational changes reported here are likely shared due to a lack of cellular Mg2+ in all domains of life.

Durably antibacterial cotton fabrics coated by protamine via Schiff base linkages.

The development of antibacterial cotton fabrics with an overall performance is critical but remains challenging. In this study, we propose a facile method to prepare durable antibacterial cotton fabric without significant sacrifices of wearing comfortability. Cotton fabric is firstly oxidated to obtain dialdehyde groups, then treated with PM molecules to establish a PM coating on the fiber surfaces via Schiff base linkages. The resultant cotton fabrics show durably antibacterial activity, realizing high bacterial reduction rates against both E. coli and S. aureus higher than 99.99 %, and offering remarkable durabilities tolerable 50 washing cycles and 500 rubbing times. These fabrics also show reliable safety for human skin that proofed by a series of cytotoxicity tests with positive results. This work demonstrates an example of versatile strategy to impart effective antibacterial function with durable activity to cotton textiles, showing great potential for practical applications in functional textile fields.

Facile Strategy for Constructing Highly Thermally Conductive Epoxy Composites Based on a Salt Template-Assisted 3D Carbonization Nanohybrid Network.

The construction of an interconnected nanofiller network is critical for the preparation of highly effective thermal management composites, though it remains a challenge to eliminate the anisotropic thermal conductivity of the nanofiller-induced defective interfacial heat-flow efficiency. In this work, a facile and novel approach is proposed to optimize phonon transport by building a salt template-assisted three-dimensional (3D) carbonization nanohybrid network in an epoxy system. The advantage of the salt template relied on green and scalable merits to construct a 3D nanofiller network and supporting abundant holes for the introduction of a polymer matrix after washing. Meanwhile, the contained carbonization materials contributed to reducing the interfacial phonon scattering issues of the filler/filler and filler/polymer for an efficient heat-flow pathway. As a result of this effect, the prepared epoxy nano-composites presented a high thermal conductivity of 4.27 W/m K, resulting in a 1841% increase compared to the thermal conductivity of the pure epoxy resin. In addition, the epoxy composites exhibited good mechanical properties and thermal conductive performance during heating and cooling. Therefore, this study may provide new insights into the design and preparation of thermal management polymers to meet the applicational requirements of electronics.

Prevalence of and risk factors for diabetic retinopathy in residents with different types of abnormal glucose metabolism with or without hypertension: A suburban community-based cross-sectional study.

Aims: The present study examined the prevalence and risk factors for diabetic retinopathy (DR) in residents with abnormal glucose metabolism in a community. Methods: 6029 subjects were included and underwent standardized interviews and comprehensive examinations. Residents with diabetes were divided into nondiabetic retinopathy (NDR) and DR groups and non-hypertension and hypertension groups. Unconditional multivariate logistic regression models were used to analyze the risk factors for DR in different groups. Results: The prevalence of DR in diabetes was 9.9%, and the prevalence of retinopathy, which also has the typical signs of DRs, such as retinal microaneurysms, in prediabetes and normal glucose tolerance was 5.2% and 5.3%, respectively. An elevated waist-to-hip ratio (WHR) (female≥0.85, male≥0.9)[OR 1.683, 95% CI (1.016, 2.790)], systolic blood pressure (SBP)≥140 mmHg [OR 1.875, 95% CI (1.158, 3.034)], elevated HbA1c [OR 1.410, 95% CI (1.220, 1.629)], HbA1c ≥6.5% [OR 2.149, 95% CI (1.320, 3.498)], antidiabetic drug use [OR 3.798, 95% CI (2.209, 6.529)], elevated fasting blood glucose [OR 1.176, 95% CI (1.072, 1.289)], elevated postprandial blood glucose [OR 1.090, 95% CI (1.033, 1.150)] and nonspecific ST-T segment changes on electrocardiography [OR 2.555, 95% CI (1.556, 4.196)] were risk factors for DR. Duration of diabetes [OR 1.206, 95% CI (1.028, 1.415)], elevated WHR [OR 3.796, 95% CI (1.144, 12.603)], elevated waist circumference [OR 6.874, 95% CI (1.403, 33.665)], elevated HbA1c [OR 1.435, 95% CI (1.046, 1.970)], HbA1c ≥6.5% [OR 6.850, 95% CI (1.771, 26.501)], and concurrent metabolic syndrome [OR 3.975, 95% CI (1.144, 13.815)] were risk factors for DR in diabetes without hypertension, and elevated HbA1c [OR 1.395, 95% CI (1.183, 1.645)], HbA1c ≥6.5% [OR 1.745, 95% CI (1.027, 2.966)], use of antidiabetic drugs [OR 4.781, 95% CI (2.624, 8.711)], elevated fasting blood glucose [OR 1.146, 95% CI (1.034, 1.270)], elevated postprandial blood glucose [OR 1.083, 95% CI (1.020, 1.151)], and nonspecific ST-T segment changes on electrocardiography [OR 2.616, 95% CI (1.531, 4.469)] were risk factors for DR in diabetes with hypertension. Conclusion: Retinopathy was found in subjects with normal glucose tolerance and prediabetes. There were differences in risk factors for DR in diabetic patients with and without hypertension.

Early Prediction Model for Critical Illness of Hospitalized COVID-19 Patients Based on Machine Learning Techniques.

Motivation: Patients with novel coronavirus disease 2019 (COVID-19) worsen into critical illness suddenly is a matter of great concern. Early identification and effective triaging of patients with a high risk of developing critical illness COVID-19 upon admission can aid in improving patient care, increasing the cure rate, and mitigating the burden on the medical care system. This study proposed and extended classical least absolute shrinkage and selection operator (LASSO) logistic regression to objectively identify clinical determination and risk factors for the early identification of patients at high risk of progression to critical illness at the time of hospital admission. Methods: In this retrospective multicenter study, data of 1,929 patients with COVID-19 were assessed. The association between laboratory characteristics measured at admission and critical illness was screened with logistic regression. LASSO logistic regression was utilized to construct predictive models for estimating the risk that a patient with COVID-19 will develop a critical illness. Results: The development cohort consisted of 1,363 patients with COVID-19 with 133 (9.7%) patients developing the critical illness. Univariate logistic regression analysis revealed 28 variables were prognosis factors for critical illness COVID-19 (p < 0.05). Elevated CK-MB, neutrophils, PCT, α-HBDH, D-dimer, LDH, glucose, PT, APTT, RDW (SD and CV), fibrinogen, and AST were predictors for the early identification of patients at high risk of progression to critical illness. Lymphopenia, a low rate of basophils, eosinophils, thrombopenia, red blood cell, hematocrit, hemoglobin concentration, blood platelet count, and decreased levels of K, Na, albumin, albumin to globulin ratio, and uric acid were clinical determinations associated with the development of critical illness at the time of hospital admission. The risk score accurately predicted critical illness in the development cohort [area under the curve (AUC) = 0.83, 95% CI: 0.78-0.86], also in the external validation cohort (n = 566, AUC = 0.84). Conclusion: A risk prediction model based on laboratory findings of patients with COVID-19 was developed for the early identification of patients at high risk of progression to critical illness. This cohort study identified 28 indicators associated with critical illness of patients with COVID-19. The risk model might contribute to the treatment of critical illness disease as early as possible and allow for optimized use of medical resources.

A TRIM66/DAX1/Dux axis suppresses the totipotent 2-cell-like state in murine embryonic stem cells.

2-cell-like cells (2CLCs)-which comprise only ∼1% of murine embryonic stem cells (mESCs)-resemble blastomeres of 2-cell-stage embryos and are used to investigate zygotic genome activation (ZGA). Here, we discovered that TRIM66 and DAX1 function together as negative regulators of the 2C-like state in mESCs. Chimeric assays confirmed that mESCs lacking TRIM66 or DAX1 function have bidirectional embryonic and extraembryonic differentiation potential. TRIM66 functions by recruiting the co-repressor DAX1 to the Dux promoter, and TRIM66's repressive effect on Dux is dependent on DAX1. A solved crystal structural shows that TRIM66's PHD finger recognizes H3K4-K9me3, and mutational evidence confirmed that TRIM66's PHD finger is essential for its repression of Dux. Thus, beyond expanding the scope of known 2CLC regulators, our study demonstrates that interventions disrupting TRIM66 or DAX1 function in mESCs yield 2CLCs with expanded bidirectional differentiation potential, opening doors for the practical application of these totipotent-like cells.