The human FOXM1 homolog promotes basal progenitor cell proliferation and cortical folding in mouse.

Cortical expansion and folding are key processes in human brain development and evolution and are considered to be principal elements of intellectual ability. How cortical folding has evolved and is induced during embryo development is not well understood. Here, we show that the expression of human FOXM1 promotes basal progenitor cell proliferation and induces cortical thickening and folding in mice. Human-specific protein sequences further promote the generation of basal progenitor cells. Human FOXM1 increases the proliferation of neural progenitors by binding to the Lin28a promoter and increasing Lin28a expression. Furthermore, overexpression of LIN28A rescues the proliferation of human FOXM1 knockout neural progenitor cells. Together, our findings demonstrate that a human gene can increase the number of basal progenitor cells in mice, leading to brain size increase and gyrification, and may thus contribute to evolutionary brain development and cortical expansion.

Microglia homeostasis mediated by epigenetic ARID1A regulates neural progenitor cells response and leads to autism-like behaviors.

Microglia are resident macrophages of the central nervous system that selectively emerge in embryonic cortical proliferative zones and regulate neurogenesis by altering molecular and phenotypic states. Despite their important roles in inflammatory phagocytosis and neurodegenerative diseases, microglial homeostasis during early brain development has not been fully elucidated. Here, we demonstrate a notable interplay between microglial homeostasis and neural progenitor cell signal transduction during embryonic neurogenesis. ARID1A, an epigenetic subunit of the SWI/SNF chromatin-remodeling complex, disrupts genome-wide H3K9me3 occupancy in microglia and changes the epigenetic chromatin landscape of regulatory elements that influence the switching of microglial states. Perturbation of microglial homeostasis impairs the release of PRG3, which regulates neural progenitor cell self-renewal and differentiation during embryonic development. Furthermore, the loss of microglia-driven PRG3 alters the downstream cascade of the Wnt/ß-catenin signaling pathway through its interaction with the neural progenitor receptor LRP6, which leads to misplaced regulation in neuronal development and causes autism-like behaviors at later stages. Thus, during early fetal brain development, microglia progress toward a more homeostatic competent phenotype, which might render neural progenitor cells respond to environmental cross-talk perturbations.

TCF20 dysfunction leads to cortical neurogenesis defects and autistic-like behaviors in mice.

Recently, de novo mutations of transcription factor 20 (TCF20) were found in patients with autism by large-scale exome sequencing. However, how TCF20 modulates brain development and whether its dysfunction causes ASD remain unclear. Here, we show that TCF20 deficits impair neurogenesis in mouse. TCF20 deletion significantly reduces the number of neurons, which leads to abnormal brain functions. Furthermore, transcriptome analysis and ChIP-qPCR reveal that the DNA demethylation factor TDG is a downstream target gene of TCF20. As a nonspecific DNA demethylation factor, TDG potentially affects many genes. Combined TDG ChIP-seq and GO analysis of TCF20 RNA-Seq identifies T-cell factor 4 (TCF-4) as a common target. TDG controls the DNA methylation level in the promoter area of TCF-4, affecting TCF-4 expression and modulating neural differentiation. Overexpression of TDG or TCF-4 rescues the deficient neurogenesis of TCF20 knockdown brains. Together, our data reveal that TCF20 is essential for neurogenesis and we suggest that defects in neurogenesis caused by TCF20 loss are associated with ASD.

Genome-wide identification and characterization of R2R3-MYB genes in Medicago truncatula.

MYB is a large family of plant transcription factors. Its function has been identified in several plants, while there are few reports in Medicago truncatula. In this study, we used RNA-seq data to analyze and identify R2R3-MYB genes in the genome of Medicago truncatula. Phylogenetic analysis classified 150 MtMYB genes into 21 subfamilies with homologs. Out of the 150 MtMYB genes, 139 were distributed among 8 chromosomes, with tandem duplications (TD) and segment duplications (SD). Microarray data were used for functional analysis of the MtMYB genes during growth and developmental processes providing evidence for a role in tissues differentiation, seed development processes, and especially the nodulation process. Furthermore, we investigated the expression of MtMYB genes in response to abiotic stresses using RNA-seq data, which confirmed the critical roles in signal transduction and regulation processes under abiotic stress. We used quantitative real-time PCR (qRT-PCR) to validate expression profiles. The expression pattern of M. truncatula MYB genes under different abiotic stress conditions suggest that some may play a major role in cross-talk among different signal transduction pathways in response to abiotic stresses. Our study will serve as a foundation for future research into the molecular function of M. truncatula R2R3-MYB genes.

Transcriptome sequencing and expression profiling of genes involved in the response to abiotic stress in Medicago ruthenica.

Medicago ruthenica is a perennial forage legume with the remarkable ability to survive under unfavorable environmental conditions. It has been identified as an excellent species of Medicago that can adapt to various environmental stresses including low temperature, drought, and salinity. To investigate its potential as a genetic resource, we performed transcriptome sequencing and analysis in M. ruthenica under abiotic stresses. We generated >120 million reads from six cDNA libraries, resulting in 79,249 unique transcripts, most of which were highly similar to transcripts from M. truncatula (44,608, 56.3%) and alfalfa (M. sativa, 48,023, 60.6%). Based on gene expression profiles, 2,721 transcripts were identified as abiotic stress responsive genes which were predicted to be mainly involved in phytohormone signaling pathways, transcriptional regulation, and ROS-scavenging. These results suggest that they play critical roles in the response to abiotic stress. In summary, we identified genes in our transcriptome dataset involved in the regulation of the abiotic stress response in M. ruthenica which will provide a valuable resource for the future identification and functional analysis of candidate genes for adaption to unfavorable conditions. The genes identified here could be also useful for improving stress tolerance traits in alfalfa through molecular breeding in the future.

Transcriptome sequencing analysis of alfalfa reveals CBF genes potentially playing important roles in response to freezing stress.

Alfalfa (Medicago sativa L.) is an important perennial forage, with high nutritional value, which is widely grown in the world. Because of low freezing tolerance, its distribution and production are threatened and limited by winter weather. To understand the complex regulation mechanisms of freezing tolerance in alfalfa, we performed transcriptome sequencing analysis under cold (4 °C) and freezing (-8 °C) stresses. More than 66 million reads were generated, and we identified 5767 transcripts differentially expressed in response to cold and/or freezing stresses. These results showed that these genes were mainly classified as response to stress, transcription regulation, hormone signaling pathway, antioxidant, nodule morphogenesis, etc., implying their important roles in response to cold and freezing stresses. Furthermore, nine CBF transcripts differentially expressed were homologous to CBF genes of Mt-FTQTL6 site, conferring freezing tolerance in M. truncatula, which indicated that a genetic mechanism controlling freezing tolerance was conservative between M. truncatula and M. sativa. In summary, this transcriptome dataset highlighted the gene regulation response to cold and/or freezing stresses in alfalfa, which provides a valuable resource for future identification and functional analysis of candidate genes in determining freezing tolerance.

Gasdermin D Mediated Mitochondrial Metabolism Orchestrate Neurogenesis Through LDHA During Embryonic Development.

Regulatory cell death is an important way to eliminate the DNA damage that accompanies the rapid proliferation of neural stem cells during cortical development, including pyroptosis, apoptosis, and so on. Here, the study reports that the absence of GSDMD-mediated pyroptosis results in defective DNA damage sensor pathways accompanied by aberrant neurogenesis and autism-like behaviors in adult mice. Furthermore, GSDMD is involved in organizing the mitochondrial electron transport chain by regulating the AMPK/PGC-1α pathway to target Aifm3. This process promotes a switch from oxidative phosphorylation to glycolysis. The perturbation of metabolic homeostasis in neural progenitor cells increases lactate production which acts as a signaling molecule to regulate the p38MAPK pathway. And activates NF-𝜿B transcription to disrupt cortex development. This abnormal proliferation of neural progenitor cells can be rescued by inhibiting glycolysis and lactate production. Taken together, the study proposes a metabolic axis regulated by GSDMD that links pyroptosis with metabolic reprogramming. It provides a flexible perspective for the treatment of neurological disorders caused by genotoxic stress and neurodevelopmental disorders such as autism.

Efficacy and safety of combined Chinese and western medicine in the treatment of metabolic syndrome: A network meta-analysis of randomized controlled trials.

Objectives: To comprehensively analyze the randomized controlled clinical trials of integrated traditional Chinese medicine (TCM) and western medicine in the treatment of metabolic syndrome (MetS), and to explore the clinical efficacy and safety of different TCM combined with western medicine for MetS. The purpose of this study is to provide specific suggestions for clinical guidance in the treatment of MetS. Methods: A comprehensive literature review was conducted across several databases, including China Knowledge Network, Wanfang Data, VIP Information, China Biomedical Literature Service System, Embase, PubMed, and Web of Science, up to October 2023. The scope of this review was confined to RCTs focusing on the treatment of metabolic syndrome through an integrated approach of TCM and Western medicine. The primary efficacy endpoints analyzed were clinical efficacy, fasting blood glucose (FBG), triglyceride (TG), and high-density lipoprotein (HDL). Data synthesis and analysis were performed using Stata 16 and RevMan 5.4 for both traditional and network meta-analyses. Results: The findings from both traditional and network meta-analyses reveal that the combination of JiangZhiHuoXue pills (JZHX) + Conventional Western Medicine (CWM) significantly reduces FBG levels. Similarly, the AnShenNingXin capsules (ASNX) + CWM combination markedly lowers TG levels, while the FuFangQiMa capsules (FFQM) + CWM combination shows enhanced efficacy in elevating HDL levels. Notably, the combination of KangNing capsules (KNJN) + CWM demonstrates a more pronounced clinical effect compared to CWM/placebo alone. Conclusions: The study concludes that the synergistic combination of TCM and Western medicine exhibits superior therapeutic benefits in treating MetS compared to CWM/Placebo treatments alone. The combinations of JZHX, AXNX, FFQM, and KNJN with CWM emerge as potentially effective treatments.

Mechanisms of regulation of glycolipid metabolism by natural compounds in plants: effects on short-chain fatty acids.

BACKGROUND: Natural compounds can positively impact health, and various studies suggest that they regulate glucose‒lipid metabolism by influencing short-chain fatty acids (SCFAs). This metabolism is key to maintaining energy balance and normal physiological functions in the body. This review explores how SCFAs regulate glucose and lipid metabolism and the natural compounds that can modulate these processes through SCFAs. This provides a healthier approach to treating glucose and lipid metabolism disorders in the future. METHODS: This article reviews relevant literature on SCFAs and glycolipid metabolism from PubMed and the Web of Science Core Collection (WoSCC). It also highlights a range of natural compounds, including polysaccharides, anthocyanins, quercetins, resveratrols, carotenoids, and betaines, that can regulate glycolipid metabolism through modulation of the SCFA pathway. RESULTS: Natural compounds enrich SCFA-producing bacteria, inhibit harmful bacteria, and regulate operational taxonomic unit (OTU) abundance and the intestinal transport rate in the gut microbiota to affect SCFA content in the intestine. However, most studies have been conducted in animals, lack clinical trials, and involve fewer natural compounds that target SCFAs. More research is needed to support the conclusions and to develop healthier interventions. CONCLUSIONS: SCFAs are crucial for human health and are produced mainly by the gut microbiota via dietary fiber fermentation. Eating foods rich in natural compounds, including fruits, vegetables, tea, and coarse fiber foods, can hinder harmful intestinal bacterial growth and promote beneficial bacterial proliferation, thus increasing SCFA levels and regulating glucose and lipid metabolism. By investigating how these compounds impact glycolipid metabolism via the SCFA pathway, novel insights and directions for treating glucolipid metabolism disorders can be provided.

New insights into the interplay between autophagy, gut microbiota and insulin resistance in metabolic syndrome.

Metabolic syndrome (MetS) is a widespread and multifactorial disorder, and the study of its pathogenesis and treatment remains challenging. Autophagy, an intracellular degradation system that maintains cellular renewal and homeostasis, is essential for maintaining antimicrobial defense, preserving epithelial barrier integrity, promoting mucosal immune response, maintaining intestinal homeostasis, and regulating gut microbiota and microbial metabolites. Dysfunctional autophagy is implicated in the pathological mechanisms of MetS, involving insulin resistance (IR), chronic inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, with IR being a predominant feature. The study of autophagy represents a valuable field of research with significant clinical implications for identifying autophagy-related signals, pathways, mechanisms, and treatment options for MetS. Given the multifactorial etiology and various potential risk factors, it is imperative to explore the interplay between autophagy and gut microbiota in MetS more thoroughly. This will facilitate the elucidation of new mechanisms underlying the crosstalk among autophagy, gut microbiota, and MetS, thereby providing new insights into the diagnosis and treatment of MetS.

Endothelial Cells Mediated by STING Regulate Oligodendrogenesis and Myelination During Brain Development.

Oligodendrocyte precursor cells (OPCs) migrate extensively using blood vessels as physical scaffolds in the developing central nervous system. Although the association of OPCs with the vasculature is critical for migration, the regulatory mechanisms important for OPCs proliferative and oligodendrocyte development are unknown. Here, a correlation is demonstrated between the developing vasculature and OPCs response during brain development. Deletion of endothelial stimulator of interferon genes (STING) disrupts angiogenesis by inhibiting farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and thereby reducing cholesterol synthesis. Furthermore, the perturbation of metabolic homeostasis in endothelial cells increases interleukin 17D production which mediates the signal transduction from endothelial cells to OPCs, which inhibits oligodendrocyte development and myelination and causes behavioral abnormalities in adult mice. Overall, these findings indicate how the endothelial STING maintains metabolic homeostasis and contributes to oligodendrocyte precursor cells response in the developing neocortex.

BCAT1 controls embryonic neural stem cells proliferation and differentiation in the upper layer neurons.

The regulation of neural stem cell (NSC) proliferation and differentiation during brain development is a precisely controlled process, with the production of different neuronal subtypes governed by strict timelines. Glutamate is predominantly used as a neurotransmitter by the subtypes of neurons in the various layers of the cerebral cortex. The expression pattern of BCAT1, a gene involved in glutamate metabolism, in the different layers of neurons has yet to be fully understood. Using single-cell data, we have identified seven different states of NSCs and found that state 4 is closely associated with the development of projection neurons. By inferring the developmental trajectory of different neuronal subtypes from NSC subsets of this state, we discovered that BCAT1 is involved in the regulation of NSC proliferation and differentiation and is specifically highly expressed in layer II/III and IV neurons. Suppression of BCAT1 through shRNA resulted in a reduction in NSC proliferation and an abnormal development of layer II/III and IV neurons. These findings provide new insights into the role of BCAT1 in the regulation of NSC behavior and neuronal development.

Role of fungal communities and their interaction with bacterial communities on carbon and nitrogen component transformation in composting with different phosphate additives.

The aim of the study was to compare the succession of fungal community and their interaction with bacterial community during pig manure composting with different phosphate additives and further to identify microbial roles on the transformation of carbon and nitrogen (C&N) components and compost maturity. The results showed that the composition of fungal community was significantly affected by pH in composting and acidic phosphate might postpone the C&N degradation process. Network analysis showed that phosphate additives, especially acidic additives, could increase the interaction of microbial community but acidic phosphate decreased the core fungi:bacteria ratio. Redundancy analysis indicated that the interactions between bacterial and fungal communities played more roles than individual contribution of bacteria or fungi for C&N conversion of composting. Structural equation modeling suggested that bacterial community was positively directly correlated to C&N loss and the participation of fungal community significantly benefited the maturity of composting. pH exhibited a great intermediated role for driving C&N conversion, maturity, and safety of composts by regulating bacterial and fungal community in composting with phosphate addition, which suggested a fast-composting way based on pH regulation by additives.

Co-inoculation of phosphate-solubilizing bacteria and phosphate accumulating bacteria in phosphorus-enriched composting regulates phosphorus transformation by facilitating polyphosphate formation.

This study aimed to explore the impact of co-inoculating phosphate-solubilizing bacteria (PSB) and phosphate accumulating bacteria (PAB) on phosphorus forms transformation, microbial biomass phosphorus (MBP) and polyphosphate (Poly-P) accumulation, bacterial community composition in composting, using high throughput sequencing, PICRUSt 2, network analysis, structural equation model (SEM) and random forest (RF) analysis. The results demonstrated PSB-PAB co-inoculation (T1) reduced Olsen-P content (1.4 g) but had higher levels of MBP (74.2 mg/kg) and Poly-P (419 A.U.) compared to PSB-only (T0). The mantel test revealed a significantly positive correlation between bacterial diversity and both bioavailable P and MBP. Halocella was identified as a key genus related to Poly-P synthesis by network analysis. SEM and RF analysis showed that pH and bacterial community had the most influence on Poly-P synthesis, and PICRUSt 2 analysis revealed inoculation of PAB increased ppk gene abundance in T1. Thus, PSB-PAB co-inoculation provides a new idea for phosphorus management.

Endothelial Arid1a deletion disrupts the balance among angiogenesis, neurogenesis and gliogenesis in the developing brain.

The vascular system and the neural system processes occur simultaneously, the interaction among them is fundamental to the normal development of the central nervous system. Arid1a (AT-rich interaction domain 1A), which encodes an epigenetic subunit of the SWI/SNF chromatin-remodelling complex, is associated with promoter-mediated gene regulation and histone modification. However, the molecular mechanism of the interaction between cerebrovascular and neural progenitor cells (NPCs) remains unclear. To generate Arid1acKO-Tie2 mice, Arid1afl/fl mice were hybridized with Tie2-Cre mice. The Angiogenesis, neurogenesis and gliogenesis were studied by immunofluorescence staining and Western blotting. RNA-seq, RT-PCR, Western blotting, CO-IP and rescue experiments were performed to dissect the molecular mechanisms of Arid1a regulates fate determination of NPCs. We found that the absence of Arid1a results in increased the density of blood vessels, delayed neurogenesis and decreased gliogenesis, even after birth. Mechanistically, the deletion of Arid1a in endothelial cells causes a significant increase in H3k27ac and the secretion of maternal protein 2 (MATN2). In addition, matn2 alters the AKT/SMAD4 signalling pathway through its interaction with the NPCs receptor EGFR, leading to the decrease of SMAD4. SMAD complex further mediates the expression of downstream targets, thereby promoting neurogenesis and inhibiting gliogenesis. This study suggests that endothelial Arid1a tightly controls fate determination of NPCs by regulating the AKT-SMAD signalling pathway.

Human SERPINA3 induces neocortical folding and improves cognitive ability in mice.

Neocortex expansion and folding are related to human intelligence and cognition, but the molecular and cellular mechanisms underlying cortical folding remain poorly understood. Here, we report that the human gene SERPINA3 is linked to gyrification. Specifically, the overexpression of SERPINA3 induced neocortical folding, increased the abundance of neurons, and improved cognitive abilities. Further, SERPINA3 promoted proliferation of the outer radial glia (oRG, also referred to as the basal radial glia) and increased the number of upper-layer neurons. The downstream target Glo1 was determined to be involved in SERPINA3-induced gyrification. Moreover, SERPINA3 increased the proliferation of oRG by binding to the Glo1 promoter. Assessment of behavior performance showed enhanced cognitive abilities in SERPINA3 knock-in mice. Our findings will enrich the understanding of neocortical expansion and gyrification and provide insights into possible treatments for intellectual disability and lissencephaly syndrome.

Histone Variants and Histone Modifications in Neurogenesis.

During embryonic brain development, neurogenesis requires the orchestration of gene expression to regulate neural stem cell (NSC) fate specification. Epigenetic regulation with specific emphasis on the modes of histone variants and histone post-translational modifications are involved in interactive gene regulation of central nervous system (CNS) development. Here, we provide a broad overview of the regulatory system of histone variants and histone modifications that have been linked to neurogenesis and diseases. We also review the crosstalk between different histone modifications and discuss how the 3D genome affects cell fate dynamics during brain development. Understanding the mechanisms of epigenetic regulation in neurogenesis has shifted the paradigm from single gene regulation to synergistic interactions to ensure healthy embryonic neurogenesis.

Fermentation improves the potentiality of capsicum in decreasing high-fat diet-induced obesity in C57BL/6 mice by modulating lipid metabolism and hormone response.

Capsicum has been proved to have anti-obesity effect. In this study, extracts from multi-strain coupled fermented capsicum (EFC) and from fresh capsicum (EC) were compared in their anti-obesity effect among these obese mice induced by high-fat diet (HFD), in order to exploring the potential mechanism of EFC for alleviating obesity. It has shown that the constituents of capsicum undergo transformation during fermentation. Obese mice in all experimental groups had similar energy absorption, and both EFC and EC relieved obesity, with better effect in the EFC group than in the EC group. Lower lipid and cholesterol were observed in serum, liver and feces in HFD-FC (HFD supplied with EFC)group compared to HFD-C (HFD supplied with EC) group. In addition, the HFD-FC group had less visceral fat and a smaller adipocyte size. The HFD-FC group exhibited better sensitivity to hormones, with lower levels of both leptin and insulin and higher ghrelin level. Expression of PPARα, CPT-1α, HSL and ACO were up-regulated, whereas PPARγ and C/EBPα were down-regulated significantly in the HFD-FC group compared to the HFD-C group. In summary, fermentation of Capsicum leads to a better effect on preventing fat accumulation and reducing lipid levels, which may be regulated by certain new contents in EFC that facilitate lipid metabolism and hormone response.

Transcriptome sequencing analysis of alfalfa reveals CBF genes potentially playing important roles in response to freezing stress

Abstract Alfalfa (Medicago sativa L.) is an important perennial forage, with high nutritional value, which is widely grown in the world. Because of low freezing tolerance, its distribution and production are threatened and limited by winter weather. To understand the complex regulation mechanisms of freezing tolerance in alfalfa, we performed transcriptome sequencing analysis under cold (4 °C) and freezing (-8 °C) stresses. More than 66 million reads were generated, and we identified 5767 transcripts differentially expressed in response to cold and/or freezing stresses. These results showed that these genes were mainly classified as response to stress, transcription regulation, hormone signaling pathway, antioxidant, nodule morphogenesis, etc., implying their important roles in response to cold and freezing stresses. Furthermore, nine CBF transcripts differentially expressed were homologous to CBF genes of Mt-FTQTL6 site, conferring freezing tolerance in M. truncatula, which indicated that a genetic mechanism controlling freezing tolerance was conservative between M. truncatula and M. sativa. In summary, this transcriptome dataset highlighted the gene regulation response to cold and/or freezing stresses in alfalfa, which provides a valuable resource for future identification and functional analysis of candidate genes in determining freezing tolerance.