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ABSTRACT Aims/Introduction Diabetes mellitus is a traditional risk factor for heart failure (HF), and glycated albumin (GA) is a marker to assess short‐term glycemic control. Whether GA has prognostic significance in patients with HF remains unclear. Materials and Methods A total of 717 patients with HF were enrolled in the prospective cohort study. Patients were grouped by the normal upper limit of GA (17%). Kaplan–Meier analysis and Cox proportional hazards regression were used to evaluate the association between GA and prognosis. Results During a mean follow‐up of 387 days, 232 composite endpoint events of hospitalization for HF or all‐cause death occurred. Kaplan–Meier analysis showed a higher rate of adverse events in the higher GA group (GA >17%; log‐rank test P 17%: HR 1.36, 95% CI 1.03–1.80, P = 0.032). Restricted cubic splines showed a linear association between GA and adverse events (P for non‐linearity = 0.231). There was no significant difference in adverse outcome risk between those with diabetes and GA ≤17% and those without diabetes, whereas the prognosis was worse in those with diabetes and GA >17% (HR 1.56, 95% CI 1.16–2.11, P = 0.004). Compared to the group with normal levels of GA and glycated hemoglobin, the group with GA >17% and glycated hemoglobin >6.5% had a higher risk of adverse events (HR 1.49, 95% CI 1.06–2.10, P = 0.022). Conclusions GA was an independent predictor of HF prognosis. Combining GA and glycated hemoglobin might improve the predictive power of adverse outcomes in patients with HF.

Abstract Cell fate decisions remain poorly understood at the molecular level. Embryogenesis provides a unique opportunity to analyze molecular details associated with cell fate decisions. Works based on model organisms have provided a conceptual framework of genes that specify cell fate control, for example, transcription factors (TFs) controlling processes from pluripotency to immunity1. How TFs specify cell fate remains poorly understood. Here we report that SALL4 relies on NuRD (nucleosome-remodeling and deacetylase complex) to interpret BMP4 signal and decide cell fate in a well-controlled in vitro system. While NuRD complex cooperates with SALL4 to convert mouse embryonic fibroblasts or MEFs to pluripotency, BMP4 diverts the same process to an alternative fate, PrE (primitive endoderm). Mechanistically, BMP4 signals the dissociation of SALL4 from NuRD physically to establish a gene regulatory network for PrE. Our results provide a conceptual framework to explore the rich landscapes of cell fate choices intrinsic to development in higher organisms involving morphogen-TF-chromatin modifier pathways.

Abstract Cell fate is likely regulated by a common machinery, while components of this machine remain to be identified. Here we report the design and testing of engineered cell fate controller NanogBiD, fusing BiD or BRG1 interacting domain of SS18 with Nanog. NanogBiD promotes mouse somatic cell reprogramming efficiently in contrast to the ineffective native protein under multiple testing conditions. Mechanistic studies further reveal that it facilitates cell fate transition by recruiting the intended Brg/Brahma-associated factor (BAF) complex to modulate chromatin accessibility and reorganize cell state specific enhancers known to be occupied by canonical Nanog, resulting in precocious activation of multiple genes including Sall4, miR-302, Dppa5a and Sox15 towards pluripotency. Although we have yet to test our approach in other species, our findings suggest that engineered chromatin regulators may provide much needed tools to engineer cell fate in the cells as drugs era.

Abstract Pluripotent stem cells have the potential to generate embryo models that can recapitulate developmental processes in vitro. Large animals such as pigs may also benefit from stem-cell-based embryo models for improving breeding. Here, we report the generation of blastoids from porcine embryonic stem cells (pESCs). We first develop a culture medium 4FIXY to derive pESCs. We develop a 3D two-step differentiation strategy to generate porcine blastoids from the pESCs. The resulting blastoids exhibit similar morphology, size, cell lineage composition, and single-cell transcriptome characteristics to blastocysts. These porcine blastoids survive and expand for more than two weeks in vitro under two different culture conditions. Large animal blastoids such as those derived from pESCs may enable in vitro modeling of early embryogenesis and improve livestock species’ breeding practices.

Abstract Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

Abstract Cell fate decision involves rewiring of the genome, but remains poorly understood at the chromatin level. Here, we report that chromatin remodeling complex NuRD participates in closing open chromatin in the early phase of somatic reprogramming. Sall4, Jdp2, Glis1 and Esrrb can reprogram MEFs to iPSCs efficiently, but only Sall4 is indispensable capable of recruiting endogenous components of NuRD. Yet knocking down NuRD components only reduces reprogramming modestly, in contrast to disrupting the known Sall4-NuRD interaction by mutating or deleting the NuRD interacting motif at its N-terminus that renders Sall4 inept to reprogram. Remarkably, these defects can be partially rescured by grafting NuRD interacting motif onto Jdp2. Further analysis of chromatin accessibility dynamics demonstrates that the Sall4-NuRD axis plays a critical role in closing the open chromatin in the early phase of reprogramming. Among the chromatin loci closed by Sall4-NuRD encode genes resistant to reprogramming. These results identify a previously unrecognized role of NuRD in reprogramming, and may further illuminate chromatin closing as a critical step in cell fate control.

Background: Inflammation is essential in cardiorenal syndrome, however there is still a lack of evidence proving the interaction between cardiac injury, renal dysfunction and the inflammatory response. This study aimed to illustrate the association between renal dysfunction and cardiac injury with a specific focus on the role of inflammation. Methods: A single-center, retrospective study included patients with heart failure admitted to the cardiovascular department from September 2019 to April 2022. Patients received cardiovascular magnetic resonance (CMR) imaging (T1 mapping and late gadolinium enhancement (LGE)). Demographic, creatinine and native T1 were analyzed using pearson correlation, linear regression and adjusted for confounders. Interaction and subgroup analysis were performed. Results: Finally, 50 validated heart failure (HF) patients (age 58.5 ± 14.8 years; 78.0% men) were included. Cardiac global native T1 for the high estimated glomeruar filtration rate (eGFR) group was 1117.0 ± 56.6 ms, and for the low eGFR group was 1096.5 ± 61.8 ms. Univariate analysis identified global native T1 (β = 0.16, 95% confidence interval (CI): 0.04–0.28, p = 0.014) and C-reactive protein (CRP) (β = 0.30, 95% CI: 0.15–0.45, p < 0.001) as determinants of creatinine. Multivariable linear regression analysis identified global native T1 (β = 0.12, 95% CI: 0.01–0.123, p = 0.040) as a determinant of creatinine while age and diabetes were adjusted. Significant interactions between CRP and global native T1 in relation to creatinine level (p for interaction = 0.005) were identified. Conclusions: Kidney dysfunction was associated with cardiac injury and inflammation, respectively. The interaction between myocardial injury and kidney dysfunction is contingent on the severity of the inflammatory response. Further studies were needed to identify the mechanisms of the inflammatory response in cardiorenal syndrome.

Trimetazidine has been reported to benefit patients with heart failure (HF) and angina. The impact of trimetazidine on non-ischemic HF remains unclear. We reviewed clinical trials to investigate whether trimetazidine could improve exercise endurance, life quality, and heart function in non-ischemic HF patients. We searched the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of science for randomized clinical trials published before April 30th, 2020; Studies limited to patients with non-ischemic HF, aged ≥18 years, comparing trimetazidine with conventional therapy with/without placebo. Outcome measurements included primary outcomes (6 minutes walking test (6-MWT)) and secondary outcomes (life quality scores, echocardiography parameters, biomarker, peak oxygen consumption). The follow-up period was longer than three months. This study was registered with international prospective register of systematic reviews (PROSPERO) (CRD42020182982). Six studies with 310 cases were included in this research. Trimetazidine significantly improved 6-MWT (weighted mean difference (WMD) = 48.51 m, 95% confidence interval (CI) [29.41, 67.61], p < 0.0001, I2 = 0%), left ventricle ejection fraction (LVEF) (WMD = 3.09%, 95% CI [1.09, 5.01], p = 0.002, I2 = 0%) at 3 months, and LVEF (WMD = 6.09%, 95% CI [3.76, 8.42], p < 0.0001, I2 = 12%) at 6 months. Furthermore, it reduced peak oxygen consumption (WMD = –2.24 mL/kg per minute, 95% CI [–4.09, –0.93], p = 0.02). This meta-analysis suggested that trimetazidine might be an effective strategy for improving exercise endurance and cardiac function in patients with non-ischemic HF.

Background: Mitral regurgitation (MR) has a high prevalence and aggravates hypoperfusion and hypoxia in heart failure (HF). Renal tubular epithelial cells are sensitive to hypoxia, and therefore tubulointerstitial damage is quite common in HF. However, the correlation between tubular dysfunction and MR has not been studied. The aim of this work was to evaluate the prognostic significance of urinary N-acetyl-β-d-glucosaminidase (uNAG), a biomarker of renal tubular damage, in patients with HF and MR. Methods: This was a prospective cohort study of 390 patients (mean age 64 years; 65.6% male) with uNAG measurement on admission (expressed as urinary NAG/urinary creatinine) and at least 1 year of follow-up data. The pre-defined primary endpoint was the composite of all-cause mortality or rehospitalization for HF after discharge. Cox regression analysis, restricted cubic splines, and subgroup analysis were used to investigate the prognostic value of uNAG modeled as a categorical (quartiles) or continuous (per SD increase) variable. Results: A total of 153 (39.23%) patients reached the composite endpoint over a median follow-up time of 1.2 years. The uNAG level correlated with the severity of HF and with the incidence of adverse events. In a multivariable Cox regression model, each SD (13.80 U/g⋅Cr) of increased uNAG was associated with a 17% higher risk of death or HF rehospitalization (95% confidence interval, 2–33%, p = 0.022), and a 19% higher risk of HF rehospitalization (p = 0.027). Subgroup analysis revealed the associations between uNAG and poor prognosis were only significant in younger patients (≤65 years) and in patients without obvious cardiovascular comorbidities. Conclusions: uNAG levels at admission were associated with the risk of adverse outcomes in patients with HF and MR. Additional studies are needed to further investigate the heart-kidney interaction.

Abstract Background Germline cells are important carriers of genetic and epigenetic information transmitted across generations in mammals. During the mammalian germline cell development cycle (i.e., the germline cycle), cell potency changes cyclically, accompanied by dynamic transcriptional changes and epigenetic reprogramming. Recently, to understand these dynamic and regulatory mechanisms, multiomic analyses, including transcriptomic and epigenomic analyses of DNA methylation, chromatin accessibility and histone modifications of germline cells, have been performed for different stages in human and mouse germline cycles. However, the long time span of the germline cycle and material scarcity of germline cells have largely limited the understanding of these dynamic characteristic changes. A tool that integrates the existing multiomics data and visualizes the overall continuous dynamic trends in the germline cycle can partially overcome such limitations. Results Here, we present GLEANER, a web server for GermLine cycle Expression ANalysis and Epigenetics Roadmap visualization. GLEANER provides a comprehensive collection of the transcriptome, DNA methylome, chromatin accessibility, and H3K4me3, H3K27me3, and H3K9me3 histone modification characteristics in human and mouse germline cycles. For each input gene, GLEANER shows the integrative analysis results of its transcriptional and epigenetic features, the genes with correlated transcriptional changes, and the overall continuous dynamic trends in the germline cycle. We further used two case studies to demonstrate the detailed functionality of GLEANER and highlighted that it can provide valuable clues to the epigenetic regulation mechanisms in the genetic and epigenetic information transmitted during the germline cycle. Conclusions To the best of our knowledge, GLEANER is the first web server dedicated to the analysis and visualization of multiomics data related to the mammalian germline cycle. GLEANER is freely available at http://compbio-zhanglab.org/GLEANER .

This study analyzes the recovery voltage changes when a low-voltage circuit breaker opens with load and short-circuit faults and explains the reignition types under different recovery voltages. Reignition probability models of a single-pole contact and three-pole contact under different reignition types are established. The variation law of the contact erosion amount with the arc starting phase angle is analyzed. The distribution characteristics of the electrical life under three reignition types are obtained by simulating the low-voltage circuit breaker electrical life with a random arc starting phase angle. The results show that the electrical life of contacts obviously decreases after reignition, and that the electrical life changes differently with different reignition types. Specifically, the electrical life of a single-pole contact and three-pole contact is reduced by different degrees for the same reignition type. Hence, the influence of reignition on the electrical life distribution characteristics of a low-voltage circuit breaker cannot be ignored.

Abstract Background During mammalian early embryogenesis, expression and epigenetic heterogeneity emerge before the first cell fate determination, but the programs causing such determinate heterogeneity are largely unexplored. Results Here, we present MethylTransition, a novel DNA methylation state transition model, for characterizing methylation changes during one or a few cell cycles at single-cell resolution. MethylTransition involves the creation of a transition matrix comprising three parameters that represent the probabilities of DNA methylation-modifying activities in order to link the methylation states before and after a cell cycle. We apply MethylTransition to single-cell DNA methylome data from human pre-implantation embryogenesis and elucidate that the DNA methylation heterogeneity that emerges at promoters during this process is largely an intrinsic output of a program with unique probabilities of DNA methylation-modifying activities. Moreover, we experimentally validate the effect of the initial DNA methylation on expression heterogeneity in pre-implantation mouse embryos. Conclusions Our study reveals the programmed DNA methylation heterogeneity during human pre-implantation embryogenesis through a novel mathematical model and provides valuable clues for identifying the driving factors of the first cell fate determination during this process.

Background: Iron deficiency is common in cardiovascular diseases (CVD), e.g., heart failure and coronary heart disease. Soluble transferrin receptor (sTfR) is a promising marker representing unmet cellular iron demands. However, whether higher serum sTfR is associated with increased risk of CVDs needs further investigation.Methods: In the present cross-sectional study, we analyzed data of 4,867 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2017–2018. Linear regression models were employed to identify possible correlations between sTfR and other characteristics. The association between sTfR and CVDs was assessed with univariable and multivariable logistics regression models.Results: The prevalence of CVDs was 9.5% among participants, and higher sTfR levels were found in participants with CVDs (p < 0.001). Linear regression models revealed positive associations between sTfR and age, body mass index, systolic blood pressure, glycated hemoglobulin A1c, and insulin resistance (all p < 0.001). In the multivariable logistics regression model, the adjusted odds ratio of sTfR for CVDs was 2.05 (per 1 log2 mg/L, 95% confidence interval: 1.03∼4.05, p = 0.046). Further subgroup analysis identified the associations of sTfR and CVDs were only significant in participants ≥60 years old, or with hypertension (all p < 0.05).Conclusion: Our study demonstrated that increased serum sTfR levels were associated with a high prevalence of cardiovascular diseases.

Background: Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF).Methods: This single-center, observational cohort study enrolled 183 AHF patients (de novo heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization.Results: During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 μmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2–55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively.Conclusion: Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management.

Background: Mitral regurgitation (MR) is one of the common complications of heart failure (HF). The prevalence and characteristics of MR are rarely investigated, especially in the Chinese population. Objectives: The purpose of this study was to determine the prevalence and characteristics of non-organic MR in HF patients and subgroups defined by ejection fraction. Methods: A single-center, hospital-based, and retrospective chart review study included patients with heart failure admitted to the cardiovascular department from January 2017 to April 2020. Demographic characteristics, laboratory results, and echocardiogram results before discharge were analyzed in different groups defined by left ventricular ejection fraction (EF) using logistic regression and adjusted for confounders. Results: Finally, 2418 validated HF patients (age 67.2 ± 13.5 years; 68.03% men) were included. The prevalence of MR was 32.7% in HF, 16.7% in HF with preserve EF patients, 28.4% in HF with mid-range EF patients and 49.7% in HF with reduced EF (HFrEF) patients. In the HF with preserved EF group, multivariable logistic regression showed that 4 factors associated with MR including EF (odds ratio (OR) 0.954 (0.928–0.981), p = 0.001), left ventricular posterior wall thickness in diastolic phase (LVPWd) (OR 0.274 (0.081–0.932), p = 0.038), left atrium (LA) dimension (OR 2.049 (1.631–2.576), p < 0.001) and age (OR 1.024 (1.007–1.041), p = 0.007). In the HF with midrange EF group, multivariable logistic regression showed that 3 factors associated with MR including LA dimension (OR 2.009 (1.427–2.829), p < 0.001), triglycerides (TG) (OR 0.552 (0.359–0.849), p = 0.007) and digoxin (OR 2.836 (1.624–4.951), p < 0.001). In the HFrEF group, multivariable logistic regression showed that 7 factors associated with MR including EF (OR 0.969 (0.949–0.990), p = 0.004), (OR 0.161 (0.067–0.387), p < 0.001), LA dimension (OR 2.289 (1.821–2.878), p < 0.001), age (OR 1.016 (1.004–1.027)), p = 0.009), TG (OR 0.746 (0.595–0.936), p = 0.011), diuretics (OR 0.559 (0.334–0.934), p = 0.026) and ICD (OR 1.898 (1.074–3.354), p = 0.027). Conclusions: HF patients had a high burden of MR, particularly in the HFrEF group. Worsen cardiac structure (LA dimension and LVPWd) and function (EF), age, and medical treatment strategy played essential roles in MR.

Summary: Human naive pluripotent stem cells established from the epiblasts of preimplantation blastocysts provide a useful model for mechanistic studies of pluripotency regulation and lineage differentiation. Important advances have been made to optimize culture conditions and define molecular criteria for naive pluripotency. However, the identity of naive-specific surface markers and the underlying molecular mechanism of naive pluripotency regulation remain poorly understood. Here, we identify alkaline phosphatase placental-like 2 (ALPPL2) as a prominent naive-specific surface marker by systematic proteomic and transcriptomic analyses. Furthermore, we demonstrate that ALPPL2 is essential for both the establishment and maintenance of naive pluripotency. Moreover, we show that ALPPL2 can interact with the RNA-binding protein IGF2BP1 to stabilize the mRNA levels of the naive pluripotency transcription factors TFCP2L1 and STAT3 to regulate naive pluripotency. Overall, our study identifies a functional surface marker for human naive pluripotency, providing a powerful tool for human-naive-pluripotency-related mechanistic studies. : Bi et al. identify ALPPL2 as a functional surface marker specific for naive pluripotency that interacts with IGF2BP1 to regulate STAT3 and TFCP2L1 mRNA stability to affect naive pluripotency maintenance and establishment, providing a powerful tool for human-naive-pluripotency-related mechanistic studies. Keywords: naive pluripotency, ALPPL2, IGF2BP1, functional surface marker

Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental biology studies and therapeutic manipulations. However, the molecular mechanisms involved in the establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with the 5iLAF naïve induction strategy, integrative analysis of transcriptional and epigenetic dynamics across the transition from human fibroblasts to naïve iPSCs revealed ordered waves of gene network activation sharing signatures with those found during embryonic development from late embryogenesis to pre-implantation stages. More importantly, Transcriptional analysis showed a significant transient reactivation of transcripts with 8-cell-stage-like characteristics in the late stage of reprogramming, suggesting transient activation of gene network with human zygotic genome activation (ZGA)-like signatures during the establishment of naïve pluripotency. Together, Dissecting the naïve reprogramming dynamics by integrative analysis improves the understanding of the molecular features involved in the generation of naïve pluripotency directly from somatic cells.

An increasing number of single cell transcriptome and epigenome technologies, including single cell ATAC-seq (scATAC-seq), have been recently developed as powerful tools to analyze the features of many individual cells simultaneously. However, the methods and software were designed for one certain data type and only for single cell transcriptome data. A systematic approach for epigenome data and multiple types of transcriptome data is needed to control data quality and to perform cell-to-cell heterogeneity analysis on these ultra-high-dimensional transcriptome and epigenome datasets. Here we developed Dr.seq2, a Quality Control (QC) and analysis pipeline for multiple types of single cell transcriptome and epigenome data, including scATAC-seq and Drop-ChIP data. Application of this pipeline provides four groups of QC measurements and different analyses, including cell heterogeneity analysis. Dr.seq2 produced reliable results on published single cell transcriptome and epigenome datasets. Overall, Dr.seq2 is a systematic and comprehensive QC and analysis pipeline designed for parallel single cell transcriptome and epigenome data. Dr.seq2 is freely available at: http://www.tongji.edu.cn/~zhanglab/drseq2/ and https://github.com/ChengchenZhao/DrSeq2.

Nucleosome organization affects the accessibility of cis-elements to trans-acting factors. Micrococcal nuclease digestion followed by high-throughput sequencing (MNase-seq) is the most popular technology used to profile nucleosome organization on a genome-wide scale. Evaluating the data quality of MNase-seq data remains challenging, especially in mammalian. There is a strong need for a convenient and comprehensive approach to obtain dedicated quality control (QC) for MNase-seq data analysis. Here we developed CAM, which is a comprehensive QC pipeline for MNase-seq data. The CAM pipeline provides multiple informative QC measurements and nucleosome organization profiles on different potentially functional regions for given MNase-seq data. CAM also includes 268 historical MNase-seq datasets from human and mouse as a reference atlas for unbiased assessment. CAM is freely available at: http://www.tongji.edu.cn/~zhanglab/CAM.