p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage

UV-light-induced DNA damage affects RNA metabolism but the underlying signalling pathways are largely unexplored. Here, the authors show that UV light triggers p38-MK2-mediated phosphorylation of the NELF complex, promoting its release from chromatin and concurrent transcriptional elongation

In vivo partial cellular reprogramming enhances liver plasticity and regeneration.

Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration

Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity

Gene regulation in mammals involves a complex interplay between promoters and distal regulatory elements that function in concert to drive precise spatiotemporal gene expression programs. However, the dynamics of the distal gene regulatory landscape and its function in the transcriptional reprogramming that underlies neurogenesis and neuronal activity remain largely unknown. Here, we performed a combinatorial analysis of genome-wide data sets for chromatin accessibility (FAIRE-seq) and the enhancer mark H3K27ac, revealing the highly dynamic nature of distal gene regulation during neurogenesis, which gets progressively restricted to distinct genomic regions as neurons acquire a post-mitotic, terminally differentiated state. We further find that the distal accessible and active regions serve as target sites for distinct transcription factors that function in a stage-specific manner to contribute to the transcriptional program underlying neuronal commitment and maturation. Mature neurons respond to a sustained activity of NMDA receptors by epigenetic reprogramming at a large number of distal regulatory regions as well as dramatic reorganization of super-enhancers. Such massive remodeling of the distal regulatory landscape in turn results in a transcriptome that confers a transient loss of neuronal identity and gain of cellular plasticity. Furthermore, NMDA receptor activity also induces many novel prosurvival genes that function in neuroprotective pathways. Taken together, these findings reveal the dynamics of the distal regulatory landscape during neurogenesis and uncover novel regulatory elements that function in concert with epigenetic mechanisms and transcription factors to generate the transcriptome underlying neuronal development and activity

Effect of Palonosetron in the Prevention of Spinal Anaesthesia-induced Hypotension and Bradycardia: A Randomised Controlled Trial

Introduction: Spinal Anaesthesia (SA) is frequently associated with hypotension, which is due to sympathectomy causing vasodilation, leading to relative hypovolemia. This decrease in venous return to the heart causes a decrease in left ventricular filling pressure, leading to the activation of the Bezold-Jarisch Reflex (BJR), which causes bradycardia. This response is mediated by mechanoreceptors and chemoreceptors present on the heart walls. These chemoreceptors are mediated through serotonin (5-HT). Therefore, the activation of 5-HT3 receptors at sensory vagal nerve endings in the heart causes hypotension and bradycardia. Aim: To assess the efficacy of Palonosetron in attenuating spinal anaesthesia-induced hypotension and bradycardia. Materials and Methods: The trial was a parallel-design, randomised, double-blind controlled trial conducted over two years, from February 2021 to August 2022 in the Department of Anaesthesiology, Kalinga Institution of Medical Sciences (KIMS), Bhubaneswar, Odisha, India, among patients undergoing spinal anaesthesia for various surgeries. The patients were divided into two groups based on the type of medication received: Group APalonosetron group and Group B- the saline group. Computergenerated random number generator software was used for randomisation. At a 1:1 ratio, 150 patients were chosen (75 in each group). Baseline assessment of haemodynamic parameters was performed, followed by continuous monitoring. The drug was administered 10 minutes prior to spinal anaesthesia, and the haemodynamic parameters (Heart Rate [HR], Systolic Blood Pressure [SBP], Diastolic Blood Pressure [DBP], and Mean Arterial Pressure [MAP]) were monitored. Continuous variables are expressed as mean±Standard Deviation (SD). The Student’s t-test was used to compare the difference between the two groups, and categorical variables are expressed as frequency and percentage, with comparisons done using the Chi-square test. A p-value of <0.05 was considered statistically significant. Results: The mean age of Group A and Group B was 40.88 and 42.14, respectively. Significant haemodynamic changes (hypotension) were observed following induction in Group B (28 [37.3%]) compared to Group A (9 [12%]). Consumption of vasopressors and intravenous (i.v.) fluids was significantly higher in Group B compared to Group A. The incidence of bradycardia in Group A and Group B was 15 (20%) and 18 (24%), respectively. Postoperative Nausea and Vomiting (PONV) in Group A and Group B were 3 (4%) and 8 (10.7%), respectively. Conclusion: Based on the present study, the prophylactic administration of 0.075 mg Palonosetron 10 minutes before subarachnoid block is effective in attenuating the incidence of spinal anaesthesia-induced hypotension and bradycardia. There is also decreased consumption of vasopressors and a lower incidence of PONV.

FBXO32 promotes microenvironment underlying epithelial-mesenchymal transition via CtBP1 during tumour metastasis and brain development

Epithelial-to-mesenchymal transition (EMT) regulates both processes of organism development and changes in cell state causing disease. Here, the authors show that an E3 ubiquitin ligase, FBXO32, regulates EMT via CtBP1 and the transcriptional program, and also mediates cancer metastatic burden and neurogenesis