Abnormal Default Mode Network Homogeneity in Treatment-Naive Patients With First-Episode Depression

Background and Objective: The default mode network (DMN) may be an important component involved in the broad-scale cognitive problems seen in patients with first-episode treatment-naive depression. Nevertheless, information is scarce regarding the changes in network homogeneity (NH) found in the DMN of these patients. Therefore, in this study, we explored the NH of the DMN in patients with first-episode treatment-naive depression.Methods: The study included 66 patients and 74 control participants matched by age, gender, educational level and health status who underwent resting-state functional magnetic resonance imaging (rs-fMRI) and the attentional network test (ANT). To assess data, the study utilizes NH and independent component analysis (ICA). Additionally, Spearman's rank correlation analysis is performed among significantly abnormal NH in depression patients and clinical measurements and executive control reaction time (ECRT).Results: In comparison with the control group, patients with first-episode treatment-naive depression showed lower NH in the bilateral angular gyrus (AG), as well as increased NH in the bilateral precuneus (PCu) and posterior cingulate cortex (PCC). Likewise, patients with first-episode treatment-naive depression had longer ECRT. No significant relation was found between abnormal NH values and the measured clinical variables.Conclusions: Our results suggest patients with first-episode treatment-naive depression have abnormal NH values in the DMN. This highlights the significance of DMN in the pathophysiology of cognitive problems in depression. Our study also found alterations in executive functions in patients with first-episode treatment-naive depression

SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense

Abstract Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose‐6‐phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH‐producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS. SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5‐dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation

Shared and non-shared sIgA-coated and uncoated bacteria in intestine of mother-infant pairs

preprintBackground The infant gut microbiota is critical for promoting and maintaining early life health. Bacteria coated by secretory immunoglobulin A (sIgA) may help commensal bacteria colonize the gastrointestinal tract. The study aimed to analyze the composition of sIgA-coated and sIgA-uncoated bacterial communities at genus level, and lactobacilli and bifidobacterial communities at species level in human breast milk (HBM), infant, and maternal feces. Results Eleven pregnant women were recruited successfully. HBM, infant feces during colostrum, transition, and mature stages, and maternal feces within the mature stage were collected. sIgA-coated and sIgAuncoated bacteria were separated with magnetic-activated cell sorting. Then 16S rRNA sequencing, bifidobacterial groEL gene sequencing, and lactobacilli groEL gene sequencing were performed to analyze the bacterial community. The richness of sIgA-coated bacteria was significantly higher than that of sIgA-uncoated bacteria in HBM. PCoA revealed that the compositions of sIgA-coated and sIgAuncoated bacteria were different among HBM, infant and maternal feces. The dominant sIgA-coated bacteria in those samples were Escherichia/shigella and the dominant sIgA-uncoated bacteria was Pseudomonas. Higher relative abundance of sIgA-uncoated Bifidobacterium was found in the three lactation stages in infant feces compared to the corresponding HBM, and a higher relative abundance of sIgA-uncoated Faecalibacterium was found in maternal feces compared to HBM and infant feces. For the bifidobacterial community, PCoA analysis revealed a significantly different Bifidobacterium composition only in the sIgA-uncoated segments of infant feces and maternal feces. sIgA-coated and sIgA-uncoated B. longum subsp. infantis and B. pseudocatenulatum was dominant in infant feces and maternal feces, respectively. Additionally, the relative abundance of sIgA-uncoated B. longum subsp. infantis was significantly higher in infant feces compared to that in maternal feces. For the Lactobacillus community, the composition was significantly different in infant and maternal feces, while at species level, L. paragasseri and L. mucosae were dominant in infant and maternal feces, respectively. Conclusion HBM, infant, and maternal feces showed distinct diversity and composition of both sIgA-coated and sIgAuncoated bacteria at genus level. Infant and maternal feces showed similar diversity and similar composition of Bifidobacterium at species level. The same Bifidobacterium species could be detected both in sIgA-coated and sIgA-uncoated for

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

l-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of l-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans