Abstract Left ventricular diastolic dysfunction (LVDD) is an early event associated with cardiovascular complications and poor prognosis in chronic kidney disease patients undergoing dialysis. In this study, we investigated whether diastolic dysfunction, measured by the E/E′ ratio, affects adverse outcomes in peritoneal dialysis (PD) patients (n = 148). Our results showed that patients with an E/E′ ratio ≥ 15 were more likely to be female, have a longer dialysis vintage, have significantly higher left atrial volume index and left atrial kinetic energy levels, have lower E′ levels and LV hypertrophy (LVH) degree, and have higher volume markers. Kaplan–Meier curves revealed that patients with a higher E/E′ ratio had worse survival and a higher risk of heart failure than those with a lower E/E′ ratio. Subgroup analysis demonstrated that non-diabetic patients with a higher E/E′ ratio had a higher risk of heart failure than those with a lower E/E′ ratio. Cox proportional hazard regression analysis indicated that the ECW/ICW ratio was strongly associated with LVDD and confirmed that the E/E′ ratio was an independent risk factor for overall death. Our study suggests that monitoring the E/E′ ratio in PD patients is important for improving their prognosis.
A 61-year-old woman was admitted for acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). At 1 week after standard treatments, the symptoms of pancreatitis disappeared. However, the patient could not eat anything, vomited repeatedly and developed recurrent biliary infections. Computed tomography (CT) revealed an enlarged pancreatic head (4 × 6 cm; [Fig. 1 a]). A jejunal tube and a nasogastric tube were introduced. The drainage volume was around 1500 ml/day and did not decrease in the following 2 months. Iodine swallow revealed an obstruction at the distal descending duodenum and the proximal horizontal duodenum ([Fig. 1 b]).
Tandem DNA repeats are often organized into heterochromatin that is crucial for genome organization and stability. Recent studies revealed that individual repeats within tandem DNA repeats can behave very differently. How DNA repeats are assembled into distinct heterochromatin structures remains poorly understood. Here, we developed a genome-wide genetic screen using a reporter gene at different units in a repeat array. This screen led to identification of a conserved protein Rex1BD required for heterochromatin silencing. Our structural analysis revealed that Rex1BD forms a four-helix bundle structure with a distinct charged electrostatic surface. Mechanistically, Rex1BD facilitates the recruitment of Clr6 histone deacetylase (HDAC) by interacting with histones. Interestingly, Rex1BD also interacts with the 14-3-3 protein Rad25, which is responsible for recruiting the RITS (RNA-induced transcriptional silencing) complex to DNA repeats. Our results suggest that coordinated action of Rex1BD and Rad25 mediates formation of distinct heterochromatin structure at DNA repeats via linking RNAi and HDAC pathways.
The centromere is a specialized chromosomal structure essential for chromosome segregation. Centromere dysfunction leads to chromosome segregation errors and genome instability. In most eukaryotes, centromere identity is specified epigenetically by CENP-A, a centromere-specific histone H3 variant. CENP-A replaces histone H3 in centromeres, and nucleates the assembly of the kinetochore complex. Mislocalization of CENP-A to non-centromeric regions causes ectopic assembly of CENP-A chromatin, which has a devastating impact on chromosome segregation and has been linked to a variety of human cancers. How non-centromeric regions are protected from CENP-A misincorporation in normal cells is largely unexplored. Here, we review the most recent advances on the mechanisms underlying the prevention of ectopic centromere formation, and discuss the implications in human disease.
Summary Histone phosphorylation is dynamically regulated during cell division, for example phosphorylation of histone H3 (H3)‐Ser10, H3‐Thr11 and H3‐Ser28. Here we analyzed maize ( Zea mays L) for Thr133‐phosphorylated histone H2A, which is important for spindle checkpoint control and localization of the centromere cohesion protector Shugoshin in mammals and yeast. Immunostaining results indicate that phosphorylated H2A‐Thr133 signals bridged those of the centromeric H3 histone variant CENH3 by using a plant displaying yellow fluorescent protein‐CENH3 signals and H2A‐Thr133 is phosphorylated in different cell types. During mitosis, H2A‐Thr133 phosphorylation becomes strong in metaphase and is specific to centromere regions but drops during later anaphase and telophase. Immunostaining for several maize dicentric chromosomes revealed that the inactive centromeres have lost phosphorylation of H2A‐Thr133. During meiosis in maize meiocytes, H2A phosphorylation becomes strong in the early pachytene stage and increases to a maximum at metaphase I. In the maize meiotic mutant afd1 (absence of first division), sister chromatids show equational separation at metaphase I, but there are no changes in H2A‐Thr‐133 phosphorylation during meiosis compared with the wild type. In sgo1 mutants, sister chromatids segregate randomly during meiosis II, and phosphorylation of H2A‐Thr‐133 is observed on the centromere regions during meiosis II. The availability of such mutants in maize that lack sister cohesion and Shugoshin indicate that the signals for phosphorylation are not dependent on cohesion but on centromere activity.
Abstract Heterochromatin is generally associated with the nuclear periphery, but how the spatial organization of heterochromatin is regulated to ensure epigenetic silencing remains unclear. Here we found that Sad1, an inner nuclear membrane SUN-family protein in fission yeast, interacts with histone H2A-H2B but not H3-H4. We solved the crystal structure of the histone binding motif (HBM) of Sad1 in complex with H2A-H2B, revealing the intimate contacts between Sad1 HBM and H2A-H2B. Structure-based mutagenesis studies revealed that the H2A-H2B-binding activity of Sad1 is required for the dynamic distribution of Sad1 throughout the nuclear envelope (NE). The Sad1-H2A-H2B complex mediates tethering telomeres and the mating-type locus to the NE. This complex is also important for heterochromatin silencing. Mechanistically, H2A-H2B enhances the interaction between Sad1 and HDACs, including Clr3 and Sir2, to maintain epigenetic identity of heterochromatin. Interestingly, our results suggest that Sad1 exhibits the histone-enhanced liquid-liquid phase separation property, which helps recruit heterochromatin factors to the NE. Our results uncover an unexpected role of SUN-family proteins in heterochromatin regulation and suggest a nucleosome-independent role of H2A-H2B in regulating Sad1’s functionality.
<i>Objective:</i> This study aims to comprehensively analyze the factors influencing the efficacy of bone marrow platelet-rich plasma (BMPRP) therapy in patients with type 2 diabetes mellitus. <i>Methods: </i>In this clinical investigation, autologous bone marrow was harvested from participants, followed by the isolation of BMPRP. Patients then underwent ultrasound-guided infusion of BMPRP directly into the pancreas. The follow-up period for evaluating treatment outcomes spanned one year, during which various factors potentially affecting the therapeutic effects were systematically analyzed. <i>Results: </i>A total of 49 patients diagnosed with type 2 diabetes mellitus received BMPRP pancreatic infusion as a treatment modality. Among these patients, 32 demonstrated a positive response to the therapy, while 17 experienced no significant improvement. Notably, in the effective treatment group, fasting blood glucose levels exhibited a significant reduction after one month of intervention. Additionally, glycosylated hemoglobin (HbA1c) levels showed a substantial decrease at the three-month mark, and a gradual decline in insulin dosage requirements was observed over time. In contrast, changes in C-peptide levels were not pronounced. Analysis of the ineffective treatment group revealed that these patients often had obesity, demonstrated minimal physical activity, and did not adhere to dietary recommendations for carbohydrate control. <i>Conclusion:</i> The findings suggest that BMPRP pancreatic infusion can improve pancreatic function and glycemic control in type 2 diabetes patients. However, for optimal outcomes, it is crucial to combine this therapy with a regimen that includes regular exercise and strict management of carbohydrate intake. This multifaceted approach promises to enhance the effectiveness of BMPRP therapy and contribute to better overall management of type 2 diabetes.
Type 2 diabetes mellitus is the most common form of endocrine disease in humans; genetic factors are known to contribute to the development of this disease. In this case-control study, we investigated the relationship between the -1082G/A, -819C/T, and -592C/A polymorphisms in interleukin 10 (IL-10) and the pathogenesis of type 2 diabetes mellitus in a Chinese population. Patients with type 2 diabetes mellitus (N = 228) and control subjects (N = 240) were recruited from the Department of Endocrinology at the People's Hospital of Linyi City, between September 2013 and April 2015. The IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Multivariate logistic regression analyses revealed that patients carrying the AA genotype of IL-10 -592C/A were at a higher risk of developing type 2 diabetes mellitus compared to those carrying the CC genotype [adjusted odds ratio (OR) = 1.74; 95% confidence interval (CI) = 1.03-2.95]. In addition, individuals carrying the A allele of IL-10 -592C/A showed a 1.34-fold higher risk of developing type 2 diabetes mellitus compared to those carrying the C allele (adjusted OR = 1.34; 95%CI = 1.03- 1.75). There was no significant correlation between the IL-10 -1082G/ A and -819C/T polymorphisms and risk of type 2 diabetes mellitus. In conclusion, this study shows that the -1082G/A polymorphism of IL-10 contributes to the onset of type 2 diabetes mellitus, and may be considered a biomarker for early screening of type 2 diabetes mellitus in the Chinese population studied here.
Significance Precise chromosome segregation relies on kinetochores. How kinetochores are precisely assembled on centromeres through the cell cycle remains poorly understood. Centromeres in most eukaryotes are epigenetically marked by nucleosomes containing the histone H3 variant, CENP-A. Here, we demonstrated that Ccp1, an anti–CENP-A loading factor, interacts with the N terminus of CENP-T to promote the assembly of the outer kinetochore Ndc80 complex. This work further suggests that competitive exclusion between Ccp1 and Ndc80 at the N terminus of CENP-T via phosphorylation ensures precise kinetochore assembly during mitosis. In addition, CENP-T is critical for Ccp1 centromeric localization, which in turn regulates CENP-A distribution. Our results reveal a previously unrecognized mechanism underlying kinetochore assembly through the cell cycle.
The maize (Zea mays) B centromere is composed of B centromere-specific repeats (ZmBs), centromere-specific satellite repeats (CentC), and centromeric retrotransposons of maize (CRM). Here we describe a newly formed B centromere in maize, which has lost CentC sequences and has dramatically reduced CRM and ZmBs sequences, but still retains the molecular features of functional centromeres, such as CENH3, H2A phosphorylation at Thr-133, H3 phosphorylation at Ser-10, and Thr-3 immunostaining signals. This new centromere is stable and can be transmitted to offspring through meiosis. Anti-CENH3 chromatin immunoprecipitation sequencing revealed that a 723-kb region from the short arm of chromosome 9 (9S) was involved in the formation of the new centromere. The 723-kb region, which is gene poor and enriched for transposons, contains two abundant DNA motifs. Genes in the new centromere region are still transcribed. The original 723-kb region showed a higher DNA methylation level compared with native centromeres but was not significantly changed when it was involved in new centromere formation. Our results indicate that functional centromeres may be formed without the known centromere-specific sequences, yet the maintenance of a high DNA methylation level seems to be crucial for the proper function of a new centromere.
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