Positioning Heterochromatin at the Nuclear Periphery Suppresses Histone Turnover to Promote Epigenetic Inheritance.

In eukaryotes, heterochromatin is generally located at the nuclear periphery. This study investigates the biological significance of perinuclear positioning for heterochromatin maintenance and gene silencing. We identify the nuclear rim protein Amo1NUPL2 as a factor required for the propagation of heterochromatin at endogenous and ectopic sites in the fission yeast genome. Amo1 associates with the Rix1PELP1-containing RNA processing complex RIXC and with the histone chaperone complex FACT. RIXC, which binds to heterochromatin protein Swi6HP1 across silenced chromosomal domains and to surrounding boundary elements, connects heterochromatin with Amo1 at the nuclear periphery. In turn, the Amo1-enriched subdomain is critical for Swi6 association with FACT that precludes histone turnover to promote gene silencing and preserve epigenetic stability of heterochromatin. In addition to uncovering conserved factors required for perinuclear positioning of heterochromatin, these analyses elucidate a mechanism by which a peripheral subdomain enforces stable gene repression and maintains heterochromatin in a heritable manner.

SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract.

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.

Paradoxical Mitophagy Regulation by PINK1 and TUFm.

Aberrant mitophagy has been implicated in a broad spectrum of disorders. PINK1, Parkin, and ubiquitin have pivotal roles in priming mitophagy. However, the entire regulatory landscape and the precise control mechanisms of mitophagy remain to be elucidated. Here, we uncover fundamental mitophagy regulation involving PINK1 and a non-canonical role of the mitochondrial Tu translation elongation factor (TUFm). The mitochondrion-cytosol dual-localized TUFm interacts with PINK1 biochemically and genetically, which is an evolutionarily conserved Parkin-independent route toward mitophagy. A PINK1-dependent TUFm phosphoswitch at Ser222 determines conversion from activating to suppressing mitophagy. PINK1 modulates differential translocation of TUFm because p-S222-TUFm is restricted predominantly to the cytosol, where it inhibits mitophagy by impeding Atg5-Atg12 formation. The self-antagonizing feature of PINK1/TUFm is critical for the robustness of mitophagy regulation, achieved by the unique kinetic parameters of p-S222-TUFm, p-S65-ubiquitin, and their common kinase PINK1. Our findings provide new mechanistic insights into mitophagy and mitophagy-associated disorders.

LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.

TAT-beclin1 treatment accelerates the development of atherosclerotic lesions in ApoE-deficient mice.

The importance of autophagy in atherosclerosis has garnered significant attention regarding the potential applications of autophagy inducers. However, the impact of TAT-Beclin1, a peptide inducer of autophagy, on the development of atherosclerotic plaques remains unclear. Single-cell omics analysis indicates a notable reduction in GAPR1 levels within fibroblasts, stromal cells, and macrophages during atherosclerosis. Tat-beclin1 (T-B), an autophagy-inducing peptide derived from Beclin1, could selectively bind to GAPR1, relieving its inhibition on Beclin1 and thereby augmenting autophagosome formation. To investigate its impact on atherosclerosic plaque progression, we established the ApoE-/- mouse model of carotid atherosclerotic plaques. Surprisingly, intravenous administration of Tat-beclin1 dramatically accelerated the development of carotid artery plaques. Immunofluorescence analysis suggested that macrophage aggregation and autophagosome formation within atherosclerotic plaques were significantly increased upon T-B treatment. However, immunofluorescence and transmission electron microscopy (TEM) analysis revealed a reduction in autophagy flux through lysosomes. In vitro, the interaction between T-B and GAPR1 was confirmed in RAW264.7 cells, resulting in the increased accumulation of p62/SQSTM1 and LC3-II in the presence of ox-LDL. Additionally, T-B treatment elevated the protein levels of p62/SQSTM1, LC3-II, and cleaved caspase 1, along with the secretion of IL-1ß in response to ox-LDL exposure. In summary, our study underscores that T-B treatment amplifies abnormal autophagy and inflammation, consequently exacerbating atherosclerotic plaque development in ApoE-/- mice.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

Large-Area Near-Infrared Emission Enhancement on Single Upconversion Nanoparticles by Metal Nanohole Array.

Single lanthanide (Ln) ion doped upconversion nanoparticles (UCNPs) exhibit great potential for biomolecule sensing and counting. Plasmonic structures can improve the emission efficiency of single UCNPs by modulating the energy transferring process. Yet, achieving robust and large-area single UCNP emission modulation remains a challenge, which obstructs investigation and application of single UCNPs. Here, we present a strategy using metal nanohole arrays (NHAs) to achieve energy-transfer modulation on single UCNPs simultaneously within large-area plasmonic structures. By coupling surface plasmon polaritons (SPPs) with higher-intermediate state (1D2 → 3F3, 1D2 → 3H4) transitions, we achieved a remarkable up to 10-fold enhancement in 800 nm emission, surpassing the conventional approach of coupling SPPs with an intermediate ground state (3H4 → 3H6). We numerically simulate the electrical field distribution and reveal that luminescent enhancement is robust and insensitive to the exact location of particles. It is anticipated that the strategy provides a platform for widely exploring applications in single-particle quantitative biosensing.

The cilia and flagella associated protein CFAP52 orchestrated with CFAP45 is required for sperm motility in mice.

Asthenozoospermia characterized by decreased sperm motility is a major cause of male infertility, but the majority of the etiology remains unknown. Here, we showed that the cilia and flagella associated protein 52 (Cfap52) gene was predominantly expressed in testis and its deletion in a Cfap52 knockout mouse model resulted in decreased sperm motility and male infertility. Cfap52 knockout also led to the disorganization of the midpiece-principal piece junction of the sperm tail but had no effect on the axoneme ultrastructure in spermatozoa. Furthermore, we found that CFAP52 interacted with the cilia and flagella associated protein 45 (CFAP45) and knockout of Cfap52 decreased the expression level of CFAP45 in sperm flagellum, which further disrupted the microtubule sliding produced by dynein ATPase. Together, our studies demonstrate that CFAP52 plays an essential role in sperm motility by interacting with CFAP45 in sperm flagellum, providing insights into the potential pathogenesis of the infertility of the human CFAP52 mutations.

Hypomorphic and hypermorphic mouse models of Fsip2 indicate its dosage-dependent roles in sperm tail and acrosome formation.

Loss-of-function mutations in multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes lead to decreased sperm motility and impaired male fertility. As an MMAF gene, the function of fibrous sheath-interacting protein 2 (FSIP2) remains largely unknown. In this work, we identified a homozygous truncating mutation of FSIP2 in an infertile patient. Accordingly, we constructed a knock-in (KI) mouse model with this mutation. In parallel, we established an Fsip2 overexpression (OE) mouse model. Remarkably, KI mice presented with the typical MMAF phenotype, whereas OE mice showed no gross anomaly except for sperm tails with increased length. Single-cell RNA sequencing of the testes uncovered altered expression of genes related to sperm flagellum, acrosomal vesicle and spermatid development. We confirmed the expression of Fsip2 at the acrosome and the physical interaction of this gene with Acrv1, an acrosomal marker. Proteomic analysis of the testes revealed changes in proteins sited at the fibrous sheath, mitochondrial sheath and acrosomal vesicle. We also pinpointed the crucial motifs of Fsip2 that are evolutionarily conserved in species with internal fertilization. Thus, this work reveals the dosage-dependent roles of Fsip2 in sperm tail and acrosome formation.

Network Meta-Analysis Indicates Superior Effects of Omega-3 Polyunsaturated Fatty Acids in Preventing the Transition to Psychosis in Individuals at Clinical High-Risk.

BACKGROUND: The efficacy of pharmacological and nutritional interventions in individuals at clinical high risk for psychosis (CHR-P) remains elusive. This study aims to investigate the efficacy of pharmacological and nutritional interventions in CHR-P and whether these interventions can enhance the efficacy of psychological treatments. METHODS: We systematically reviewed data from 5 databases until July 24, 2021: PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, and WanFang Data. The primary outcome was the transition to psychosis. Network meta-analyses were conducted at 3 time points (6, 12, and ≥24 months) considering both pharmacological/nutritional interventions alone and its combination with psychotherapy. RESULTS: Out of 11 417 identified references, 21 studies were included, comprising 1983 participants. CHR-P participants receiving omega-3 polyunsaturated fatty acids treatment were associated with a lower probability of transition compared with placebo/control at 6 months (odds ratio [OR] = 0.07, 95% confidence interval [CI] = .01 to .054), 12 months (OR = 0.14, 95% CI = .03 to .66), and ≥24 months (OR = 0.16, 95% CI = .05 to .54). Moreover, risperidone plus psychotherapy was associated with a lower likelihood of transition at 6 months compared with placebo/control plus psychotherapy, but this result was not sustained over longer durations. CONCLUSION: Omega-3 polyunsaturated fatty acids helped in preventing transitions to psychosis compared with controls. PROSPERO REGISTRATION NUMBER: CRD42021256209.

Shared molecular mechanisms and transdiagnostic potential of neurodevelopmental disorders and immune disorders.

The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross-trait meta-analysis revealed 154 genome-wide significant loci, including 8 novel pleiotropic loci. Significant associations were observed for 30 loci with both types of diseases. Pathway analysis on the candidate genes at these loci revealed common pathways shared by the two types of diseases, including neural signaling, inflammatory response, and PI3K-Akt signaling pathway. In addition, 26 of the 30 lead SNPs were associated with blood cell traits. Neurodevelopmental disorders exhibit complex polygenic architecture, with a subset of individuals being at a heightened genetic risk for both neurodevelopmental and immune disorders. The identification of pleiotropic loci has important implications for exploring opportunities for drug repurposing, enabling more accurate patient stratification, and advancing genomics-informed precision in the medical field of neurodevelopmental disorders.

Impact of trophectoderm biopsy for preimplantation genetic testing on obstetric and neonatal outcomes: a meta-analysis.

OBJECTIVE: This study aimed to investigate whether trophectoderm biopsy for preimplantation genetic testing is associated with an increased risk of adverse obstetrical and neonatal outcomes compared with conventional in vitro fertilization or intracytoplasmic sperm injection without preimplantation genetic testing. DATA SOURCES: Entries between January 1990 and August 2022 were searched using MEDLINE, Embase, Web of Science, the Cochrane Library, and Google Scholar. STUDY ELIGIBILITY CRITERIA: Publications comparing the outcomes of pregnancies after preimplantation genetic testing using trophectoderm biopsy and in vitro fertilization or intracytoplasmic sperm injection were included. Only human studies with a cohort or case-control design or randomized controlled trials were eligible for inclusion. METHODS: The study selection process was performed independently by 2 investigators. The quality of the observational studies was assessed using the Newcastle-Ottawa Scale, and the Cochrane risk-of-bias tool version 2 was used to grade the level of bias in randomized controlled trials. The pooled odds ratio and 95% confidence interval were calculated using a random-effects model when substantial heterogeneity occurred (indicated by I2 of >50% and P<.1). Otherwise, a fixed-effects model was used. RESULTS: This meta-analysis included 13 studies involving 11,469 live births after preimplantation genetic testing treatment with trophectoderm biopsy before embryo transfer and 20,438 live births after in vitro fertilization or intracytoplasmic sperm injection only. The odds ratio of preterm delivery was higher in the trophectoderm-biopsied group than in the routine in vitro fertilization or intracytoplasmic sperm injection group (pooled odds ratio, 1.12; 95% confidence interval, 1.03-1.21); however, the difference did not exist after sensitivity analysis (odds ratio, 0.97; 95% confidence interval, 0.84-1.11). The risk of low birthweight did not increase among the biopsied pregnancies (pooled odds ratio, 1.01; 95% confidence interval, 0.85-1.20). No marked difference was observed in the risk of other obstetrical or neonatal outcomes between the biopsy and control groups. Furthermore, no difference was noted in the perinatal outcomes between trophectoderm-biopsied and nonbiopsied groups in the subgroup analyses by intracytoplasmic sperm injection, frozen-thawed transfer, or single embryo transfer. CONCLUSION: Trophectoderm biopsy for preimplantation genetic testing treatment did not alter the risk of obstetrical or neonatal outcomes compared with conventional in vitro fertilization or intracytoplasmic sperm injection without preimplantation genetic testing. However, this study was limited by the large observational evidence base, and more randomized controlled trials are needed to further confirm these findings.

Effect of Continuous Positive Airway Pressure on Blood Pressure in Patients with Resistant Hypertension and Obstructive Sleep Apnea: An Updated Meta-analysis.

PURPOSE OF REVIEW: The effect of continuous positive airway pressure (CPAP) on resistant hypertension in patients at high risk with obstructive sleep apnea (OSA) needs further investigation. We aimed to determine the effect of CPAP on blood pressure in patients with resistant hypertension and OSA. Databases including PubMed, EMBASE, MEDLINE, the Cochrane Library, and CMB were searched. Data were pooled using a random-effects or fixed-effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). RECENT FINDINGS: A total of 12 trials and 718 participants were included. Compared with control, CPAP significantly reduced 24-h systolic blood pressure (SBP) (WMD: - 5.92 mmHg [ - 8.72, - 3.11]; P＜0.001), 24-h diastolic blood pressure (DBP) (WMD: - 4.44 mmHg [- 6.26 , - 2.62]; P ＜0.001),  daytime SBP (WMD: - 5.76 mmHg [ - 9.16, - 2.36]; P ＜0.001),  daytime DBP (WMD: - 3.92 mmHg [- 5.55, - 2.30];  nighttime SBP (WMD: - 4.87 mmHg [ - 7.96 , - 1.78]; P = 0.002), and nighttime DBP (WMD: - 2.05 mmHg [- 2.99, - 1.11]; P＜0.001) in patients with resistant hypertension and OSA. CPAP improved the blood pressure both in the short (＜3 months) and long term (≥ 3 months). No significant impact on mean heart rate was noted (WMD: -2.76 beats per min [- 7.50, 1.97]; P = 0.25). CPAP treatment was associated with BP reduction in patients with resistant hypertension and OSA.

Association of SGLT2 inhibitor dapagliflozin with risks of acute kidney injury and all-cause mortality in acute myocardial infarction patients.

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have well-documented effects in reducing hospitalization or cardiovascular mortality, while the association of SGLT2 inhibitor dapagliflozin (DAPA) and the risk of acute kidney injury (AKI) in acute myocardial infarction (AMI) patients has not been comprehensively investigated. Therefore, we aimed to assess the association between DAPA and AKI risk in AMI patients after percutaneous coronary intervention (PCI) therapy. METHODS: Using the Changzhou Acute Myocardial Infarction Registry database, we retrospectively included AMI patients from January 2017 to August 2021 and analyzed the risk of AKI and all-cause mortality after PCI therapy. The patients were divided into two groups according to the use of DAPA (DAPA group and Ctrl group). Patients in the DAPA group started to use DAPA after admission and continued its use during hospitalization and follow-up period. Baseline characteristics were balanced between the two groups with a propensity score matching (PSM) analysis. The outcome was AKI within 7 days after PCI and all-cause mortality during a follow-up of 2 years. Univariate and multivariate logistic regression analyses were used to assess the association between DAPA and AKI risk. RESULTS: A total of 1839 AMI patients undergoing PCI were enrolled. DAPA was used in 278 (15.1%) patients. Postoperative AKI occurred in 351 (19.1%) cases. A 1:1 PSM analysis was used to reduce confounding factors. The multivariate stepwise regression analysis showed that DAPA (odds ratio, OR 0.66; 95% confidence interval, CI 0.44-0.97; P = 0.036) was an independent protective factor in the entire cohort. After matching, the use of DAPA in AMI patients was independently associated with a decline of AKI risk (OR 0.32; 95% CI, 0.19-0.53; P < 0.001) after hospital admission. Meanwhile, there were significant differences in mortality between the DAPA group and Ctrl group (2.5% vs. 7.6%, P = 0.012). CONCLUSION: SGLT2 inhibitor DAPA was associated with lower risks of incident AKI and all-cause mortality in AMI patients after PCI therapy.

Association between triglyceride glucose and acute kidney injury in patients with acute myocardial infarction: a propensity score­matched analysis.

BACKGROUND: Acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) often indicates a poor prognosis. OBJECTIVE: This study aimed to investigate the association between the TyG index and the risk of AKI in patients with AMI. METHODS: Data were taken from the Medical Information Mart for Intensive Care (MIMIC) database. A 1:3 propensity score (PS) was set to match patients in the AKI and non-AKI groups. Multivariate logistic regression analysis, restricted cubic spline (RCS) regression and subgroup analysis were performed to assess the association between TyG index and AKI. RESULTS: Totally, 1831 AMI patients were included, of which 302 (15.6%) had AKI. The TyG level was higher in AKI patients than in non-AKI patients (9.30 ± 0.71 mg/mL vs. 9.03 ± 0.73 mg/mL, P < 0.001). Compared to the lowest quartile of TyG levels, quartiles 3 or 4 had a higher risk of AKI, respectively (Odds Ratiomodel 4 = 2.139, 95% Confidence Interval: 1.382-3.310, for quartile 4 vs. quartile 1, Ptrend < 0.001). The risk of AKI increased by 34.4% when the TyG level increased by 1 S.D. (OR: 1.344, 95% CI: 1.150-1.570, P < 0.001). The TyG level was non-linearly associated with the risk of AKI in the population within a specified range. After 1:3 propensity score matching, the results were similar and the TyG level remained a risk factor for AKI in patients with AMI. CONCLUSION: High levels of TyG increase the risk of AKI in AMI patients. The TyG level is a predictor of AKI risk in AMI patients, and can be used for clinical management.

Development and validation of a novel combinatorial nomogram model to predict in-hospital deaths in heart failure patients.

BACKGROUND: The purpose of this study was to develop a Nomogram model to identify the risk of all-cause mortality during hospitalization in patients with heart failure (HF). METHODS: HF patients who had been registered in the Medical Information Mart for Intensive Care (MIMIC) III and IV databases were included. The primary outcome was the occurrence of all-cause mortality during hospitalization. Two Logistic Regression models (LR1 and LR2) were developed to predict in-hospital death for HF patients from the MIMIC-IV database. The MIMIC-III database were used for model validation. The area under the receiver operating characteristic curve (AUC) was used to compare the discrimination of each model. Calibration curve was used to assess the fit of each developed models. Decision curve analysis (DCA) was used to estimate the net benefit of the predictive model. RESULTS: A total of 16,908 HF patients were finally enrolled through screening, of whom 2,283 (13.5%) presented with in-hospital death. Totally, 48 variables were included and analyzed in the univariate and multifactorial regression analysis. The AUCs for the LR1 and LR2 models in the test cohort were 0.751 (95% CI: 0.735∼0.767) and 0.766 (95% CI: 0.751-0.781), respectively. Both LR models performed well in the calibration curve and DCA process. Nomogram and online risk assessment system were used as visualization of predictive models. CONCLUSION: A new risk prediction tool and an online risk assessment system were developed to predict mortality in HF patients, which performed well and might be used to guide clinical practice.

Triclosan induces earlier puberty onset in female mice via interfering with L-type calcium channels and activating Pik3cd.

Triclosan (TCS) is a broad-spectrum antibacterial chemical widely presents in people's daily lives. Epidemiological studies have revealed that TCS exposure may affect female puberty development. However, the developmental toxicity after low-dose TCS continuous exposure remains to be confirmed. In our study, 8-week-old ICR female mice were continuously exposed to TCS (30, 300, 3000 µg/kg/day) or vehicle (corn oil) from 2 weeks before mating to postnatal day 21 (PND 21) of F1 female mice, while F1 female mice were treated with TCS intragastric administration from PND 22 until PND 56. Vaginal opening (VO) observation, hypothalamic-pituitary-ovarian (HPO) axis related hormones and genes detection, and ovarian transcriptome analysis were carried out to investigate the effects of TCS exposure on puberty onset. Meanwhile, human granulosa-like tumor cell lines (KGN cells) were exposed to TCS to further explore the biological mechanism of the ovary in vitro. The results showed that long-term exposure to low-dose TCS led to approximately a 3-day earlier puberty onset in F1 female mice. Moreover, TCS up-regulated the secretion of estradiol (E2) and the expression of ovarian steroidogenesis genes. Notably, ovarian transcriptomes analysis as well as bidirectional validation in KGN cells suggested that L-type calcium channels and Pik3cd were involved in TCS-induced up-regulation of ovarian-related hormones and genes. In conclusion, our study demonstrated that TCS interfered with L-type calcium channels and activated Pik3cd to up-regulate the expression of ovarian steroidogenesis and related genes, thereby inducing the earlier puberty onset in F1 female mice.

Relationships of infrared thermography temperature with core temperature in goat.

Rectal temperature is widely used as an indicator of animal health. However, rectal temperature is conventionally measured by an invasive method, which may reduce animal welfare. So, this study aimed to determine the relationships between the deep-body (core) temperature and body surface temperatures in goats and develop a linear regression equation to establish the core temperature based on body surface temperatures. Body surface temperatures (head, eye, muzzle, horn, back, scrotum and groin) of goats were measured by infrared thermography (IRT). Ambient temperatures were measured by digital thermometer. Core temperatures were measured by a digital vet thermometer. Pearson correlation analysis was used to analyze the relationship between body surface temperatures, ambient temperature, and core temperature. Simple linear regression analysis was used to develop core temperature assessment equations. Correlation analysis showed that groin temperature was highly correlated with core temperature, and low correlated with ambient temperature. The body surface temperature of other region was low correlated with core temperature, and highly correlated with ambient temperature. Regression analysis showed that the determination coefficient of core temperature assessment equation based on groin temperature was the highest (P < 0.0001, R2 = 0.55), and those based on surface temperature of other regions were low (P < 0.01, R2 ≤ 0.16). We concluded that body surface temperatures obtained by IRT could be used for the assessment of goat core temperature. The core temperature assessment equations developed by the temperature of the body surface, which is less affected by ambient temperature, was found to have a higher determination coefficient than the equations developed using body surface temperature that is more affected by ambient temperature.

Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2.

BACKGROUND: Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown. METHODS: We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)-specific, endothelial cell-specific, and myeloid cell-specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)- and CaPO4-induced AAA models. RESULTS: Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO4-induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs. CONCLUSIONS: Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.

Black Hole Spectroscopy by Mode Cleaning.

We formulate a Bayesian framework to analyze ringdown gravitational waves from colliding binary black holes and test the no-hair theorem. The idea hinges on mode cleaning-revealing subdominant oscillation modes by removing dominant ones using newly proposed "rational filters." By incorporating the filter into Bayesian inference, we construct a likelihood function that depends only on the mass and spin of the remnant black hole (no dependence on mode amplitudes and phases) and implement an efficient pipeline to constrain the remnant mass and spin without Markov chain Monte Carlo. We test ringdown models by cleaning combinations of different modes and evaluating the consistency between the residual data and pure noise. The model evidence and Bayes factor are used to demonstrate the presence of a particular mode and to infer the mode starting time. In addition, we design a hybrid approach to estimate the remnant black hole properties exclusively from a single mode using Markov chain Monte Carlo after mode cleaning. We apply the framework to GW150914 and demonstrate more definitive evidence of the first overtone by cleaning the fundamental mode. This new framework provides a powerful tool for black hole spectroscopy in future gravitational-wave events.