Polycomb repressive complex 2 is critical for mouse cortical glutamatergic neuron development.

The Polycomb Repressive Complex 2 (PRC2) regulates corticogenesis, yet the consequences of mutations to this epigenetic modifier in the mature brain are poorly defined. Importantly, PRC2 core genes are haploinsufficient and causative of several human neurodevelopmental disorders. To address the role of PRC2 in mature cortical structure and function, we conditionally deleted the PRC2 gene Eed from the developing mouse dorsal telencephalon. Adult homozygotes displayed smaller forebrain structures. Single-nucleus transcriptomics revealed that glutamatergic neurons were particularly affected, exhibiting dysregulated gene expression profiles, accompanied by aberrations in neuronal morphology and connectivity. Remarkably, homozygous mice performed well on challenging cognitive tasks. In contrast, while heterozygous mice did not exhibit clear anatomical or behavioral differences, they displayed dysregulation of neuronal genes and altered neuronal morphology that was strikingly different from homozygous phenotypes. Collectively, these data reveal how alterations to PRC2 function shape the mature brain and reveal a dose-specific role for PRC2 in determining glutamatergic neuron identity.

Efficacy and safety of vibrating capsule in treatment of chronic idiopathic constipation: a systematic review and meta-analysis of randomized controlled trials.

Background: Multiple pharmacological interventions and modalities are available for managing chronic idiopathic constipation (CIC), with variable efficacy. Vibrating capsule (VC) is a device that has shown variable results in alleviating constipation by tactile stimulation of the colonic wall and inducing peristalsis. This meta-analysis is to investigate the efficacy and safety of this modality. Methods: Comprehensive literature search was performed through June 14th, 2023, on databases including Embase, PubMed/MEDLINE, Cochrane Central, Web of Science, Global Index Medicus, and Google Scholar. Core concepts of VC, constipation, and bowel movement were searched. The DerSimonian-Laird method and random effects model were utilized. We calculated odds ratio (OR) and mean difference (MD) for proportional and continuous variables, respectively, with 95% confidence interval (CI) and a P value of <0.05 considered statistically significant. Results: The search strategy yielded 117 articles. Four studies with 705 total patients were finalized comparing VC to placebo/sham treatment. The pooled complete spontaneous bowel movement (CSBM), defined as bowel movement without use of laxatives within the last 48 hours with sense of complete evacuation did not achieve statistical improvement with VC (MD =0.153; 95% CI: -0.218 to 0.523; P=0.422). However, spontaneous bowel movement (SBM), defined as bowel movement without use of laxatives within the last 48 hours, showed statistical improvement with VC (MD =0.159; 95% CI: 0.095 to 0.223; P<0.001). VC didn't show an increase in pooled adverse events (OR =1.431; 95% CI: 0.702 to 2.916; P=0.324). Conclusions: The systematic review and meta-analysis suggest that VC is safe and efficacious in some outcomes, however, larger randomized controlled trials (RCTs) and real-world data are needed to establish this.

A protocol for high-resolution episcopic microscopy and 3D volumetric analyses of the adult mouse brain.

The rapid evolution of different imaging modalities in the last two decades has enabled the investigation of the role of different genes in development and disease to be studied in a range of model organisms. However, selection of the appropriate imaging technique depends on a number of constraints, including cost, time, image resolution, size of the sample, computational complexity and processing power. Here, we use the adult mouse central nervous system to investigate whether High-Resolution Episcopic Microscopy (HREM) can provide an effective means to study the volume of individual subregions within the brain. We find that HREM can provide precise volume quantification of different structures within the mouse brain, albeit with limitations regarding the time involved for analysis and the necessity of some estimations.

Systematic analysis of the transcriptional landscape of melanoma reveals drug-target expression plasticity.

Metastatic melanoma originates from melanocytes of the skin. Melanoma metastasis results in poor treatment prognosis for patients and is associated with epigenetic and transcriptional changes that reflect the developmental program of melanocyte differentiation from neural crest stem cells. Several studies have explored melanoma transcriptional heterogeneity using microarray, bulk and single-cell RNA-sequencing technologies to derive data-driven models of the transcriptional-state change which occurs during melanoma progression. No study has systematically examined how different models of melanoma progression derived from different data types, technologies and biological conditions compare. Here, we perform a cross-sectional study to identify averaging effects of bulk-based studies that mask and distort apparent melanoma transcriptional heterogeneity; we describe new transcriptionally distinct melanoma cell states, identify differential co-expression of genes between studies and examine the effects of predicted drug susceptibilities of different cell states between studies. Importantly, we observe considerable variability in drug-target gene expression between studies, indicating potential transcriptional plasticity of melanoma to down-regulate these drug targets and thereby circumvent treatment. Overall, observed differences in gene co-expression and predicted drug susceptibility between studies suggest bulk-based transcriptional measurements do not reliably gauge heterogeneity and that melanoma transcriptional plasticity is greater than described when studies are considered in isolation.