H2B oncohistones cause homologous recombination defect and genomic instability through reducing H2B monoubiquitination in Schizosaccharomyces pombe.

Canonical oncohistones are histone H3 mutations in the N-terminal tail associated with tumors and affect gene expression by altering H3 post-translational modifications (PTMs) and the epigenetic landscape. Noncanonical oncohistone mutations occur in both tails and globular domains of all four core histones and alter gene expression by perturbing chromatin remodeling. However, the effects and mechanisms of noncanonical oncohistones remain largely unknown. Here we characterized 16 noncanonical H2B oncohistones in the fission yeast Schizosaccharomyces pombe. We found that seven of them exhibited temperature sensitivities and 11 exhibited genotoxic sensitivities. A detailed study of two of these onco-mutants H2BG52D and H2BP102L revealed that they were defective in homologous recombination (HR) repair with compromised histone eviction and Rad51 recruitment. Interestingly, their genotoxic sensitivities and HR defects were rescued by the inactivation of the H2BK119 deubiquitination function of Ubp8 in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex. The levels of H2BK119 monoubiquitination (H2Bub) in the H2BG52D and H2BP102L mutants are reduced in global genome and at local DNA break sites presumably due to enhanced recruitment of Ubp8 onto nucleosomes and are recovered upon loss of H2B deubiquitination function of the SAGA complex. Moreover, H2BG52D and H2BP102L heterozygotes exhibit genotoxic sensitivities and reduced H2Bub in cis. We therefore conclude that H2BG52D and H2BP102L oncohistones affect HR repair and genome stability via the reduction of H2Bub and propose that other noncanonical oncohistones may also affect histone PTMs to cause diseases.

The deletion of ppr2 interferes iron sensing and leads to oxidative stress response in Schizosaccharomyces pombe.

Pentatricopeptide repeat proteins are involved in mitochondrial both transcriptional and posttranscriptional regulation. Schizosaccharomyces pombe Ppr2 is a general mitochondrial translation factor that plays a critical role in the synthesis of all mitochondrial DNA-encoded oxidative phosphorylation subunits, which are essential for mitochondrial respiration. Our previous analysis showed that ppr2 deletion resulted in increased expression of iron uptake genes and caused ferroptosis-like cell death in S. pombe. In the present work, we showed that deletion of ppr2 reduced viability on glycerol- and galactose-containing media.Php4 is a transcription repressor that regulates iron homeostasis in fission yeast. We found that in the ppr2 deletion strain, Php4 was constitutively active and accumulated in the nucleus in the stationary phase. We also found that deletion of ppr2 decreased the ferroptosis-related protein Gpx1 in the mitochondria. Overexpression of Gpx1 improves the viability of Δppr2 cells. We showed that the deletion of ppr2 increased the production of ROS, downregulated heme synthesis and iron-sulfur cluster proteins, and induced stress proteins. Finally, we observed the nuclear accumulation of Pap1-GFP and Sty1-GFP, suggesting that Sty1 and Pap1 in response to cellular stress in the ppr2 deletion strain. These results suggest thatppr2 deletion may cause mitochondrial dysfunction, which is likely to lead to iron-sensing defect and iron starvation response, resulting in perturbation of iron homeostasis and increased hydroxyl radical production. The increased hydroxyl radical production triggers cellular responses in theppr2 deletion strain.

Effect of Electrical Impedance Tomography-Guided Early Mobilization in Patients After Major Upper Abdominal Surgery: Protocol for a Prospective Cohort Study.

Background: Pulmonary complications are common in patients after upper abdominal surgery, resulting in poor clinical outcomes and increased costs of hospitalization. Enhanced Recovery After Surgery Guidelines strongly recommend early mobilization post-operatively; however, the quality of the evidence is poor, and indicators for quantifying the effectiveness of early mobilization are lacking. This study will evaluate the effectiveness of early mobilization in patients undergoing an upper abdominal surgery using electrical impedance tomography (EIT). Specifically, we will use EIT to assess and compare the lung ventilation distribution among various regions of interest (ROI) before and after mobilization in this patient population. Additionally, we will assess the temporal differences in the distribution of ventilation in various ROI during mobilization in an effort to develop personalized activity programs for this patient population. Methods: In this prospective, single-center cohort study, we aim to recruit 50 patients after upper abdominal surgery between July 1, 2021 and June 30, 2022. This study will use EIT to quantify the ventilation distribution among different ROI. On post-operative day 1, the nurses will assist the patient to sit on the chair beside the bed. Patient's heart rate, blood pressure, oxygen saturation, respiratory rate, and ROI 1-4 will be recorded before the mobilization as baseline. These data will be recorded again at 15, 30, 60, 90, and 120 min after mobilization, and the changes in vital signs and ROI 1-4 values at each time point before and after mobilization will be compared. Ethics and Dissemination: The study protocol has been approved by the Institutional Review Board of Liaocheng Cardiac Hospital (2020036). The trial is registered at chictr.org.cn with identifier ChiCTR2100042877, registered on January 31, 2021. The results of the study will be presented at relevant national and international conferences and submitted to international peer-reviewed journals. There are no plans to communicate results specifically to participants. Important protocol modifications, such as changes to eligibility criteria, outcomes, or analyses, will be communicated to all relevant parties (including investigators, Institutional Review Board, trial participants, trial registries, journals, and regulators) as needed via email or in-person communication.

Effect of remimazolam besylate compared with propofol on the incidence of delirium after cardiac surgery: study protocol for a randomized trial.

BACKGROUND: Delirium is an acute cognitive disorder that presents with fluctuation in cognition, apathy, and non-organized thinking, resulting in increased morbidity, mortality, intensive care unit (ICU) stay, and total healthcare costs. In patients undergoing cardiac surgery, delirium also increases the risk of postoperative complications, such as respiratory insufficiency, sternum instability, and need for re-operation of the sternum. This study aims to understand the incidence of delirium in patients after cardiac surgery in patients sedated with remimazolam besylate versus propofol. METHODS: In this prospective, double-blind, randomized controlled clinical trial, we aim to recruit 200 patients undergoing cardiac surgery between January 1, 2021, and December 31, 2021, who will be randomized to receive either remimazolam besylate or propofol infusions postoperatively, until they are extubated. The primary outcome is the incidence of delirium within 5 days after surgery. Secondary outcomes include the time of delirium onset, duration of delirium, ICU length of stay, hospital length of stay, and mechanical ventilation time. DISCUSSION: The key objective of this study is to assess whether remimazolam besylate reduces the incidence of delirium in patients after cardiac surgery compared to propofol sedation. In this preliminary randomized controlled clinical trial, we will test the hypothesis that the use of remimazolam besylate lowers the incidence of delirium when compared to propofol in patients undergoing cardiac surgery. TRIAL REGISTRATION: chictr.org.cn ChiCTR2000038976. Registered on October 11, 2020.