LRBmat: A Novel Gut Microbial Interaction and Individual Heterogeneity Inference Method for Colorectal Cancer

Many diseases are considered to be closely related to the changes in the gut microbial community, including colorectal cancer (CRC), which is one of the most common cancers in the world. The diagnostic classification and etiological analysis of CRC are two critical issues worthy of attention. Many methods adopt gut microbiota to solve it, but few of them simultaneously take into account the complex interactions and individual heterogeneity of gut microbiota, which are two common and important issues in genetics and intestinal microbiology, especially in high-dimensional cases. In this paper, a novel method with a Binary matrix based on Logistic Regression (LRBmat) is proposed to deal with the above problem. The binary matrix can directly weakened or avoided the influence of heterogeneity, and also contain the information about gut microbial interactions with any order. Moreover, LRBmat has a powerful generalization, it can combine with any machine learning method and enhance them. The real data analysis on CRC validates the proposed method, which has the best classification performance compared with the state-of-the-art. Furthermore, the association rules extracted from the binary matrix of the real data align well with the biological properties and existing literatures, which are helpful for the etiological analysis of CRC. The source codes for LRBmat are available at https://github.com/tsnm1/LRBmat

STW-MD: A Novel Spatio-Temporal Weighting and Multi-Step Decision Tree Method for Considering Spatial Heterogeneity in Brain Gene Expression Data

Motivation: Gene expression during brain development or abnormal development is a biological process that is highly dynamic in spatio and temporal. Due to the lack of comprehensive integration of spatial and temporal dimensions of brain gene expression data, previous studies have mainly focused on individual brain regions or a certain developmental stage. Our motivation is to address this gap by incorporating spatio-temporal information to gain a more complete understanding of the mechanisms underlying brain development or disorders associated with abnormal brain development, such as Alzheimer's disease (AD), and to identify potential determinants of response. Results: In this study, we propose a novel two-step framework based on spatial-temporal information weighting and multi-step decision trees. This framework can effectively exploit the spatial similarity and temporal dependence between different stages and different brain regions, and facilitate differential gene analysis in brain regions with high heterogeneity. We focus on two datasets: the AD dataset, which includes gene expression data from early, middle, and late stages, and the brain development dataset, spanning fetal development to adulthood. Our findings highlight the advantages of the proposed framework in discovering gene classes and elucidating their impact on brain development and AD progression across diverse brain regions and stages. These findings align with existing studies and provide insights into the processes of normal and abnormal brain development. Availability: The code of STW-MD is available at https://github.com/tsnm1/STW-MD.Comment: 11 pages, 6 figure

Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease

Peer reviewe

A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila

Phenotypes relevant to oxidative phosphorylation (OXPHOS) in eukaryotes are jointly determined by nuclear and mitochondrial DNA (mtDNA). Thus, in humans, the variable clinical presentations of mitochondrial disease patients bearing the same primary mutation, whether in nuclear or mitochondrial DNA, have been attributed to putative genetic determinants carried in the other genome, though their identity and the molecular mechanism(s) by which they might act remain elusive. Here we demonstrate cytoplasmic suppression of the mitochondrial disease-like phenotype of the Drosophila melanogaster nuclear mutant tko25t, which includes developmental delay, seizure sensitivity, and defective male courtship. The tko25t strain carries a mutation in a mitoribosomal protein gene, causing OXPHOS deficiency due to defective intramitochondrial protein synthesis. Phenotypic suppression was associated with increased mtDNA copy number and increased mitochondrial biogenesis, as measured by the expression levels of porin voltage dependent anion channel and Spargel (PGC1α). Ubiquitous overexpression of Spargel in tko25t flies phenocopied the suppressor, identifying it as a key mechanistic target thereof. Suppressor-strain mtDNAs differed from related nonsuppressor strain mtDNAs by several coding-region polymorphisms and by length and sequence variation in the noncoding region (NCR), in which the origin of mtDNA replication is located. Cytoplasm from four of five originally Wolbachia-infected strains showed the same suppressor effect, whereas that from neither of two uninfected strains did so, suggesting that the stress of chronic Wolbachia infection may provide evolutionary selection for improved mitochondrial fitness under metabolic stress. Our findings provide a paradigm for understanding the role of mtDNA genotype in human disease

A cytoplasmic suppressor of a nuclear mutation affecting mitochondrial functions in Drosophila

Phenotypes relevant to oxidative phosphorylation (OXPHOS) in eukaryotes are jointly determined by nuclear and mitochondrial DNA (mtDNA). Thus, in humans, the variable clinical presentations of mitochondrial disease patients bearing the same primary mutation, whether in nuclear or mitochondrial DNA, have been attributed to putative genetic determinants carried in the other genome, though their identity and the molecular mechanism(s) by which they might act remain elusive. Here we demonstrate cytoplasmic suppression of the mitochondrial disease-like phenotype of the Drosophila melanogaster nuclear mutant tko25t, which includes developmental delay, seizure sensitivity, and defective male courtship. The tko25t strain carries a mutation in a mitoribosomal protein gene, causing OXPHOS deficiency due to defective intramitochondrial protein synthesis. Phenotypic suppression was associated with increased mtDNA copy number and increased mitochondrial biogenesis, as measured by the expression levels of porin voltage dependent anion channel and Spargel (PGC1α). Ubiquitous overexpression of Spargel in tko25t flies phenocopied the suppressor, identifying it as a key mechanistic target thereof. Suppressor-strain mtDNAs differed from related nonsuppressor strain mtDNAs by several coding-region polymorphisms and by length and sequence variation in the noncoding region (NCR), in which the origin of mtDNA replication is located. Cytoplasm from four of five originally Wolbachia-infected strains showed the same suppressor effect, whereas that from neither of two uninfected strains did so, suggesting that the stress of chronic Wolbachia infection may provide evolutionary selection for improved mitochondrial fitness under metabolic stress. Our findings provide a paradigm for understanding the role of mtDNA genotype in human disease

雷公藤红素通过靶向核受体Nur77促进损伤线粒体自噬而抑制炎症反应

文章简介线粒体在细胞死亡、自噬、免疫和炎症中起着不可或缺的作用。前期研究发现,孤儿核受体Nur77通过靶向线粒体诱导细胞凋亡。本文报道了Nur77作为具有抗炎作用的雷公藤红素的直接靶点,介导雷公藤红素通过自噬清除损伤线粒体,抑制炎症反应而达到治疗炎症疾病包括肥胖症的功能。研究人员发现,雷公藤红素的结合

Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways

Sivelestat sodium (SIV), a neutrophil elastase inhibitor, is mainly used for the clinical treatment of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). However, studies investigating the effects of SIV treatment of ALI are limited. Therefore, this study investigated the potential molecular mechanism of the protective effects of SIV against ALI. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with tumor necrosis factor α (TNF-α), and male Sprague-Dawley rats were intratracheally injected with Klebsiella pneumoniae (KP) and treated with SIV, ML385, and anisomycin (ANI) to mimic the pathogenetic process of ALI in vitro and in vivo, respectively. The levels of inflammatory cytokines and indicators of oxidative stress were assessed in vitro and in vivo. The wet/dry (W/D) ratio of lung tissues, histopathological changes, inflammatory cells levels in bronchoalveolar lavage fluid (BALF), and survival rates of rats were analyzed. The JNK/NF-κB (p65) and Nrf2/HO-1 levels in the HPMECs and lung tissues were analyzed by western blot and immunofluorescence analyses. Administration of SIV reduced the inflammatory factors levels, intracellular reactive oxygen species (ROS) production, and malondialdehyde (MDA) levels and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissues. Meanwhile, SIV alleviated pathological injuries, decreased the W/D ratio, and inflammatory cell infiltration in lung tissue. In addition, SIV also inhibited the activation of JNK/NF-κB signaling pathway, promoted nuclear translocation of Nrf2, and upregulated the expression of heme oxygenase 1 (HO-1). However, ANI or ML385 significantly reversed these changes. SIV effectively attenuated the inflammatory response and oxidative stress. Its potential molecular mechanism was related to the JNK/NF-κB activation and Nrf2/HO-1 signaling pathway inhibition. This further deepened the understanding of the protective effects of SIV against ALI

Gene Expression in a Drosophila Model of Mitochondrial Disease

Background A point mutation in the Drosophila gene technical knockout (tko), encoding mitoribosomal protein S12, was previously shown to cause a phenotype of respiratory chain deficiency, developmental delay, and neurological abnormalities similar to those presented in many human mitochondrial disorders, as well as defective courtship behavior. Methodology/Principal Findings Here, we describe a transcriptome-wide analysis of gene expression in tko25t mutant flies that revealed systematic and compensatory changes in the expression of genes connected with metabolism, including up-regulation of lactate dehydrogenase and of many genes involved in the catabolism of fats and proteins, and various anaplerotic pathways. Gut-specific enzymes involved in the primary mobilization of dietary fats and proteins, as well as a number of transport functions, were also strongly up-regulated, consistent with the idea that oxidative phosphorylation OXPHOS dysfunction is perceived physiologically as a starvation for particular biomolecules. In addition, many stress-response genes were induced. Other changes may reflect a signature of developmental delay, notably a down-regulation of genes connected with reproduction, including gametogenesis, as well as courtship behavior in males; logically this represents a programmed response to a mitochondrially generated starvation signal. The underlying signalling pathway, if conserved, could influence many physiological processes in response to nutritional stress, although any such pathway involved remains unidentified. Conclusions/Significance These studies indicate that general and organ-specific metabolism is transformed in response to mitochondrial dysfunction, including digestive and absorptive functions, and give important clues as to how novel therapeutic strategies for mitochondrial disorders might be developed.Public Library of Scienc