PharmGWAS: a GWAS-based knowledgebase for drug repurposing.

Leveraging genetics insights to promote drug repurposing has become a promising and active strategy in pharmacology. Indeed, among the 50 drugs approved by FDA in 2021, two-thirds have genetically supported evidence. In this regard, the increasing amount of widely available genome-wide association studies (GWAS) datasets have provided substantial opportunities for drug repurposing based on genetics discoveries. Here, we developed PharmGWAS, a comprehensive knowledgebase designed to identify candidate drugs through the integration of GWAS data. PharmGWAS focuses on novel connections between diseases and small-molecule compounds derived using a reverse relationship between the genetically-regulated expression signature and the drug-induced signature. Specifically, we collected and processed 1929 GWAS datasets across a diverse spectrum of diseases and 724 485 perturbation signatures pertaining to a substantial 33609 molecular compounds. To obtain reliable and robust predictions for the reverse connections, we implemented six distinct connectivity methods. In the current version, PharmGWAS deposits a total of 740 227 genetically-informed disease-drug pairs derived from drug-perturbation signatures, presenting a valuable and comprehensive catalog. Further equipped with its user-friendly web design, PharmGWAS is expected to greatly aid the discovery of novel drugs, the exploration of drug combination therapies and the identification of drug resistance or side effects. PharmGWAS is available at https://ngdc.cncb.ac.cn/pharmgwas.

Gene expression imputation and cell-type deconvolution in human brain with spatiotemporal precision and its implications for brain-related disorders.

As the most complex organ of the human body, the brain is composed of diverse regions, each consisting of distinct cell types and their respective cellular interactions. Human brain development involves a finely tuned cascade of interactive events. These include spatiotemporal gene expression changes and dynamic alterations in cell-type composition. However, our understanding of this process is still largely incomplete owing to the difficulty of brain spatiotemporal transcriptome collection. In this study, we developed a tensor-based approach to impute gene expression on a transcriptome-wide level. After rigorous computational benchmarking, we applied our approach to infer missing data points in the widely used BrainSpan resource and completed the entire grid of spatiotemporal transcriptomics. Next, we conducted deconvolutional analyses to comprehensively characterize major cell-type dynamics across the entire BrainSpan resource to estimate the cellular temporal changes and distinct neocortical areas across development. Moreover, integration of these results with GWAS summary statistics for 13 brain-associated traits revealed multiple novel trait-cell-type associations and trait-spatiotemporal relationships. In summary, our imputed BrainSpan transcriptomic data provide a valuable resource for the research community and our findings help further studies of the transcriptional and cellular dynamics of the human brain and related diseases.

CeDR Atlas: a knowledgebase of cellular drug response.

Drug response to many diseases varies dramatically due to the complex genomics and functional features and contexts. Cellular diversity of human tissues, especially tumors, is one of the major contributing factors to the different drug response in different samples. With the accumulation of single-cell RNA sequencing (scRNA-seq) data, it is now possible to study the drug response to different treatments at the single cell resolution. Here, we present CeDR Atlas (available at https://ngdc.cncb.ac.cn/cedr), a knowledgebase reporting computational inference of cellular drug response for hundreds of cell types from various tissues. We took advantage of the high-throughput profiling of drug-induced gene expression available through the Connectivity Map resource (CMap) as well as hundreds of scRNA-seq data covering cells from a wide variety of organs/tissues, diseases, and conditions. Currently, CeDR maintains the results for more than 582 single cell data objects for human, mouse and cell lines, including about 140 phenotypes and 1250 tissue-cell combination types. All the results can be explored and searched by keywords for drugs, cell types, tissues, diseases, and signature genes. Overall, CeDR fine maps drug response at cellular resolution and sheds lights on the design of combinatorial treatments, drug resistance and even drug side effects.

Iron-inhibited autophagy via transcription factor ZFP27 in Parkinson's disease.

Parkinson's disease (PD) is a challenge because of the ageing of the population and the disease's complicated pathogenesis. Accumulating evidence showed that iron and autophagy were involved in PD. Nevertheless, the molecular mechanism and role of iron and autophagy in PD are not yet elucidated. In the present study, it was shown that PD mice had significant motor dysfunction, increased iron content, less dopamine neurons and more α-synuclein accumulation in the substantia nigra. Meanwhile, PD mice treated with deferoxamine exhibited less iron content, relieved the dyskinesia and had a significant increase in dopamine neurons and a significant decrease in α-synuclein. Autophagy induced by LC3 was inhibited in PD models with iron treatment. Following verification showed that iron aggregation restrained insulin-like growth factor 2 (IGF2) and transcription factor zinc finger protein 27 (ZFP27) in PD models. In addition, LC3-induced autophagy flux was reduced with ZFP27 knockdown. Furthermore, ZFP27 affected autophagy by regulating LC3 promoter activity. These data suggest that iron deposition inhibits IGF2 and ZFP27 to reduce LC3-induced autophagy, and ultimately decrease dopamine neurons, accelerating PD progression. Our findings provide a novel insight that ZFP27-mediated iron-related autophagy and IGF2 may activate the downstream kinase gene to trigger autophagy in the PD model.

Beneficial Rhizobacterium Triggers Induced Systemic Resistance of Maize to Gibberella Stalk Rot via Calcium Signaling.

Gibberella stalk rot (GSR) caused by the fungus Fusarium graminearum is a devastating disease of maize (Zea mays L.), but we lack efficient methods to control this disease. Biological control agents, including beneficial microorganisms, can be used as an effective and eco-friendly approach to manage crop diseases. For example, Bacillus velezensis SQR9, a bacterial strain isolated from the rhizosphere of cucumber plants, promotes growth and suppresses diseases in several plant species. However, it is not known whether and how SQR9 affects maize resistance to GSR. In this study, we found that treatment with SQR9 increased maize resistance to GSR by activating maize induced systemic resistance (ISR). RNA-seq and quantitative reverse transcription-PCR analysis showed that phenylpropanoid biosynthesis, amino acid metabolism, and plant-pathogen interaction pathways were enriched in the root upon colonization by SQR9. Also, several genes associated with calcium signaling pathways were up-regulated by SQR9 treatment. However, the calcium signaling inhibitor LaCl3 weakened the SQR9-activated ISR. Our data suggest that the calcium signaling pathway contributes to maize GSR resistance via the activation of ISR induced by SQR9. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

A study on the current state and equity level of social participation ability among older adults in Henan Province, China.

BACKGROUND: The social participation ability among older adults (SPAOA) plays an important role in enhancing their quality of life and utilization of medical services. This study aimed to evaluate the current state and equity level of SPAOA in Henan Province, China, as well as explore the factors associated with the current state and equity level of SPAOA. METHODS: This study analyzed data from the "2019 Henan Provincial Older Adults Ability Assessment Survey", which included 4,593 older people (over 60 years old). The relationships among the SPAOA indicators were explored using the Structural Equation Model (SEM). The Dynamic Material Element Analysis (DMA) and Logistic Regression (LR) were used to examine the current state of SPAOA and its associated factors. The equity level of SPAOA and its correlated factors were determined using the concentration index and T Theil index. RESULTS: SPAOA received an overall score of 91.89 ± 9.83. Daily living, perception ability and mental state were positively correlated with SPAOA (r = 0.13, 0.83, 0.11, all P < 0.05). Results of LR indicated that the most significant predictors of SPAOA were age, education level, pre-retirement occupation, and income (all P < 0.05). The concentration index of SPAOA based on age and income were -0.0058 and 0.0096, respectively. SPAOA had a total T Theil index of 0.030-0.031, and the contribution rate of the difference within the group was greater than 94%. CONCLUSIONS: While the overall level of SPAOA has been demonstrated to be outstanding, persons with a higher educational level and income are likely to benefit the most. The observed unequal distribution of SPAOA is primarily related to disparities in age or income within the group. To better serve older adults and improve their position and equity in terms of social participation ability, policymakers could emphasize older males with little income who live in urban areas, as well as unhealthy older females who live in rural residences.

Overexpression of miR-1306-5p, miR-3195, and miR-3914 Inhibits Ameloblast Differentiation through Suppression of Genes Associated with Human Amelogenesis Imperfecta.

Amelogenesis imperfecta is a congenital form of enamel hypoplasia. Although a number of genetic mutations have been reported in humans, the regulatory network of these genes remains mostly unclear. To identify signatures of biological pathways in amelogenesis imperfecta, we conducted bioinformatic analyses on genes associated with the condition in humans. Through an extensive search of the main biomedical databases, we found 56 genes in which mutations and/or association/linkage were reported in individuals with amelogenesis imperfecta. These candidate genes were further grouped by function, pathway, protein-protein interaction, and tissue-specific expression patterns using various bioinformatic tools. The bioinformatic analyses highlighted a group of genes essential for extracellular matrix formation. Furthermore, advanced bioinformatic analyses for microRNAs (miRNAs), which are short non-coding RNAs that suppress target genes at the post-transcriptional level, predicted 37 candidates that may be involved in amelogenesis imperfecta. To validate the miRNA-gene regulation association, we analyzed the target gene expression of the top seven candidate miRNAs: miR-3195, miR-382-5p, miR-1306-5p, miR-4683, miR-6716-3p, miR-3914, and miR-3935. Among them, miR-1306-5p, miR-3195, and miR-3914 were confirmed to regulate ameloblast differentiation through the regulation of genes associated with amelogenesis imperfecta in AM-1 cells, a human ameloblastoma cell line. Taken together, our study suggests a potential role for miRNAs in amelogenesis imperfecta.

Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression.

BACKGROUND: Heart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Although numerous advances have been made, its representative molecular signatures remain largely unknown, especially the role of genes in HF progression. The aim of the present prospective follow-up study was to reveal potential biomarkers associated with the progression of heart failure. METHODS: We generated multi-level transcriptomic data from a cohort of left ventricular heart tissue collected from 21 HF patients and 9 healthy donors. By using Masson staining to calculate the fibrosis percentage for each sample, we applied lasso regression model to identify the genes associated with fibrosis as well as progression. The genes were further validated by immunohistochemistry (IHC) staining in the same cohort and qRT-PCR using another independent cohort (20 HF and 9 healthy donors). Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma level in a validation cohort (139 HF patients) for predicting HF progression. RESULTS: Based on the multi-level transcriptomic data, we examined differentially expressed genes [mRNAs, microRNAs, and long non-coding RNAs (lncRNAs)] in the study cohort. The follow-up functional annotation and regulatory network analyses revealed their potential roles in regulating extracellular matrix. We further identified several genes that were associated with fibrosis. By using the survival time before transplantation, COL1A1 was identified as a potential biomarker for HF progression and its upregulation was confirmed by both IHC and qRT-PCR. Furthermore, COL1A1 content ≥ 256.5 ng/ml in plasma was found to be associated with poor survival within 1 year of heart transplantation from heart failure [hazard ratio (HR) 7.4, 95% confidence interval (CI) 3.5 to 15.8, Log-rank p value < 1.0 × 10- 4]. CONCLUSIONS: Our results suggested that COL1A1 might be a plasma biomarker of HF and associated with HF progression, especially to predict the 1-year survival from HF onset to transplantation.

Targeting iron-metabolism:a potential therapeutic strategy for pulmonary fibrosis.

Iron homeostasisis is integral to normal physiological and biochemical processes of lungs. The maintenance of iron homeostasis involves the process of intake, storage and output, dependening on iron-regulated protein/iron response element system to operate tightly metabolism-related genes, including TFR1, DMT1, Fth, and FPN. Dysregulation of iron can lead to iron overload, which increases the virulence of microbial colonisers and the occurrence of oxidative stress, causing alveolar epithelial cells to undergo necrosis and apoptosis, and form extracellular matrix. Accumulated iron drive iron-dependent ferroptosis to exacerbated pulmonary fibrosis. Notably, the iron chelator deferoxamine and the lipophilic antioxidant ferritin-1 have been shown to attenuate ferroptosis and inhibit lipid peroxidation in pulmonary fibrosis. The paper summarises the regulatory mechanisms of dysregulated iron metabolism and ferroptosis in the development of pulmonary fibrosis. Targeting iron metabolism may be a potential therapeutic strategy for the prevention and treatment of pulmonary fibrosis.

Chitosan alleviates symptoms of Parkinson's disease by reducing acetate levels, which decreases inflammation and promotes repair of the intestinal barrier and blood-brain barrier.

ABSTRACT: Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically short-chain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood-brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood-brain barriers, thereby alleviating symptoms of Parkinson's disease.

Valeric acid reduction by chitosan oligosaccharide induces autophagy in a Parkinson's disease mouse model.

Parkinson's disease (PD) is a central nervous system disease with the highest disability and mortality rate worldwide, and it is caused by a variety of factors. The most common medications for PD have side effects with limited therapeutic outcomes. Many studies have reported that chitosan oligosaccharide (COS) crossed blood-brain barrier to achieve a neuroprotective effect in PD. However, the role of COS in PD remains unclear. The present study demonstrated that COS increased dopaminergic neurons in the substantia nigra (SN) and ameliorated dyskinesia in a PD mouse model. Moreover, COS reduced gut microbial diversity and faecal short-chain fatty acids. Valeric acid supplementation enhanced the inflammatory response in the colon and SN, and it reversed COS - suppressed dopamine neurons damage. Autophagy was involved in COS modulating inflammation through valeric acid. These results suggest that COS reduces bacterial metabolites - valeric acid, which diminishes inflammation via activating autophagy, ultimately alleviating PD.

Astragalus polysaccharide protects experimental colitis through an aryl hydrocarbon receptor-dependent autophagy mechanism.

BACKGROUND AND PURPOSE: Disruption of intestinal barriers plays a vital role in the pathogenesis of colitis. The aryl hydrocarbon receptor (AhR) is a recognition sensor that mediates intestinal immune homeostasis and minimizes intestinal inflammation. Astragalus polysaccharide (APS) exerts pharmacological actions in colitis; however, the mechanism has not been elucidated. We investigated whether APS protects through AhR-dependent autophagy. EXPERIMENTAL APPROACH: The symptoms of dextran sulfate sodium (DSS)-induced colitis in mice involving intestinal barrier function and inflammatory injury were evaluated after APS administration. Intestinal-specific Becn1 conditional knockout (Becn1 cKO) mice were constructed and compared with wild-type mice. Autophagy and the effects of APS were investigated after the deactivation of AhRs. The relationship between APS-induced AhRs and autophagic Becn1 was investigated using a dual-luciferase reporter system and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction assay. Caco-2 cells were used to investigate inflammatory responses and AhR-dependent autophagy. KEY RESULTS: APS improved intestinal barrier function in inflammatory injury in colitis mice. APS triggered autophagic flow; however, knockout of Becn1 in the gut increased susceptibility to colitis, leading to diminished epithelial barrier function and severe intestinal inflammation, impairing the protective effects of APS. Mechanistically, APS-triggered autophagy depends on AhR expression. Activated AhR binds to the promoter Becn1 to operate transcription of genes involved in anti-inflammation and intestinal barrier repair, while deactivation of AhR correlated with intestinal inflammation and the therapeutic function of APS. CONCLUSIONS AND IMPLICATIONS: APS protects colitis mice by targeting autophagy, especially as the AhR stimulates the repair of damaged intestinal barrier functions.

Ferroptosis Mediates Pulmonary Fibrosis: Implications for the Effect of Astragalus and Panax notoginseng Decoction.

Objective: To investigate the mechanism through which Astragalus and Panax notoginseng decoction (APD) facilitates the treatment of ferroptosis-mediated pulmonary fibrosis. Materials and Methods: First, the electromedical measurement systems were used to measure respiratory function in mice; the lungs were then collected for histological staining. Potential pharmacologic targets were predicted via network pharmacology. Finally, tests including immunohistochemistry, reverse transcription-quantitative polymerase chain reaction, and western blotting were used to evaluate the relative expression levels of collagen, transforming growth factor ß, α-smooth muscle actin, hydroxyproline, and ferroptosis-related genes (GPX4, SLC7A11, ACSL4, and PTGS2) and candidates involved in the mediation of pathways associated with ferroptosis (Hif-1α and EGFR). Results: APD prevented the occurrence of restrictive ventilation dysfunction induced by ferroptosis. Extracellular matrix and collagen fiber deposition were significantly reduced when the APD group compared with the model group; furthermore, ferroptosis was attenuated, expression of PTGS2 and ACSL4 increased, and expression of GPX4 and SLC7A11 decreased. In the APD group, the candidates related to the mediation of ferroptosis (Hif-1α and EGFR) decreased compared with the model group. Discussion and Conclusions. APD may ameliorate restrictive ventilatory dysfunction through the inhibition of ferroptosis. This was achieved through the attenuation of collagen deposition and inflammatory recruitment in pulmonary fibrosis. The underlying mechanisms might involve Hif-1α and EGFR.

The BMAL1/HIF2A heterodimer modulates circadian variations of myocardial injury.

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide1-6. Clinical studies have demonstrated that the severity of cardiac injury following myocardial infarction exhibits a circadian pattern, with larger infarct sizes and poorer outcomes in patients experiencing morning onset myocardial infarctions7-14. However, the molecular mechanisms that govern circadian variations of myocardial injury remain unclear. Here, we show that BMAL114-20, a core circadian transcription factor, orchestrates diurnal variability in myocardial injury. Unexpectedly, BMAL1 modulates circadian-dependent cardiac injury by forming a transcriptionally active heterodimer with a non-canonical partner, hypoxia-inducible factor 2 alpha (HIF2A)6,21-23, in a diurnal manner. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2A/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1, which enables the crosstalk between circadian rhythms and hypoxia signaling. Furthermore, we identified amphiregulin (AREG) as a rhythmic transcriptional target of the BMAL1/HIF2A heterodimer, critical for regulating circadian variations of myocardial injury. Finally, pharmacologically targeting the BMAL1/HIF2A-AREG pathway provides effective cardioprotection, with maximum efficacy when aligned with the pathway's circadian trough. Our findings not only uncover a novel mechanism governing the circadian variations of myocardial injury but also pave the way for innovative circadian-based treatment strategies, potentially shifting current treatment paradigms for myocardial infarction.

Dynamic cellular changes in acute kidney injury caused by different ischemia time.

Ischemia reperfusion injury (IRI), often related to surgical procedures, is one of the important causes of acute kidney injury (AKI). To decipher the dynamic process of AKI caused by IRI (with prolonged ischemia phase), we performed single-cell RNA sequencing (scRNA-seq) of clinically relevant IRI murine model with different ischemic intervals. We discovered that Slc5a2hi proximal tubular cells were susceptible to AKI and highly expressed neutral amino acid transporter gene Slc6a19, which was dramatically decreased over the time course. With the usage of mass spectrometry-based metabolomic analysis, we detected that the level of neutral amino acid isoleucine dropped off in AKI mouse plasma metabolites. And the reduction of plasma isoleucine was also verified in patients with cardiac surgery-associated acute kidney injury (CSA-AKI). The findings advanced the understanding of dynamic process of AKI and introduced reduction of isoleucine as a potential biomarker for CSA-AKI.

Deciphering mechanisms of cardiomyocytes and non-cardiomyocyte transformation in myocardial remodeling of permanent atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it significantly increases the risk of cardiovascular complications and morbidity, even with appropriate treatment. Tissue remodeling has been a significant topic, while its systematic transcriptional signature remains unclear in AF. OBJECTIVES: Our study aims to systematically investigate the molecular characteristics of AF at the cellular-level. METHODS: We conducted single-nuclei RNA-sequencig (snRNA-seq) analysis using nuclei isolated from the left atrial appendage (LAA) of AF patients and sinus rhythm. Pathological staining was performed to validate the key findings of snRNA-seq. RESULTS: A total of 30 cell subtypes were identified among 80, 592 nuclei. Within the LAA of AF, we observed a specific subtype of dedifferentiated cardiomyocytes (CMs) characterized by reduced expression of cardiac contractile proteins (TTN and TRDN) and heightened expression of extracellular-matrix related genes (COL1A2 and FBN1). Transcription factor prediction analysis revealed that gene expression patterns in dedifferentiated CMs were primarily regulated by CEBPG and GISLI. Additionally, we identified a distinct subtype of endothelial progenitor cells (EPCs) demonstrating elevated expression of PROM1 and KDR, a population decreased within the LAA of AF. Epicardial adipocytes disclosed a reduced release of the anti-inflammatory and anti-fibrotic factor PRG4, and an augmented secretion of VEGF signals targeting CMs. Additionally, we noted accumulation of M2-like macrophages and CD8+ T cells with high pro-inflammatory score in LAA of AF. Furthermore, the analysis of intercellular communication revealed specific pathways related to AF, such as inflammation, extracellular matrix, and vascular remodeling signals. CONCLUSIONS: This study has discovered the presence of dedifferentiated CMs, a decrease in endothelial progenitor cells, a shift in the secretion profile of adipocytes, and an amplified inflammatory response in AF. These findings could offer crucial insights for future research on AF and serve as valuable references for investigating novel therapeutic approaches for AF.

Exploring drug combinations in genetic interaction network.

BACKGROUND: Drug combination that consists of distinctive agents is an attractive strategy to combat complex diseases and has been widely used clinically with improved therapeutic effects. However, the identification of efficacious drug combinations remains a non-trivial and challenging task due to the huge number of possible combinations among the candidate drugs. As an important factor, the molecular context in which drugs exert their functions can provide crucial insights into the mechanism underlying drug combinations. RESULTS: In this work, we present a network biology approach to investigate drug combinations and their target proteins in the context of genetic interaction networks and the related human pathways, in order to better understand the underlying rules of effective drug combinations. Our results indicate that combinatorial drugs tend to have a smaller effect radius in the genetic interaction networks, which is an important parameter to describe the therapeutic effect of a drug combination from the network perspective. We also find that drug combinations are more likely to modulate functionally related pathways. CONCLUSIONS: This study confirms that the molecular networks where drug combinations exert their functions can indeed provide important insights into the underlying rules of effective drug combinations. We hope that our findings can help shortcut the expedition of the future discovery of novel drug combinations.

Identification of Survival-Related Genes in Acute Myeloid Leukemia (AML) Based on Cytogenetically Normal AML Samples Using Weighted Gene Coexpression Network Analysis.

The prognosis of acute myeloid leukemia (AML) remains a challenge. In this study, we applied the weighted gene coexpression network analysis (WGCNA) to find survival-specific genes in AML based on 42 adult CN-AML samples from The Cancer Genome Atlas (TCGA) database. Eighteen hub genes (ABCA13, ANXA3, ARG1, BTNL8, C11orf42, CEACAM1, CEACAM3, CHI3L1, CRISP2, CYP4F3, GPR84, HP, LTF, MMP8, OLR1, PADI2, RGL4, and RILPL1) were found to be related to AML patient survival time. We then compared the hub gene expression levels between AML peripheral blood (PB) samples (n = 162) and control healthy whole blood samples (n = 337). Seventeen of the hub genes showed lower expression levels in AML PB samples. The gene expression analysis was also done among AML BM (bone marrow) samples of different stages: diagnosis (n = 142), posttreatment (n = 42), and recurrent (n = 12) stages. The results showed a significant increase of ANXA3, CEACM1, RGL4, RILPL1, and HP in posttreatment samples compared to diagnosis and/or recurrent samples. Transcription factor (TF) prediction of the hub genes suggested LTF as the top hit, overlapping 10 hub genes, while LTF itself is just one of the hub genes. Also, 3671 correlation links were shown between 128 mRNAs and 209 lncRNAs found in survival time-related modules. Generally, we identified candidate mRNA biomarkers based on CN-AML data which can be extensively used in AML prognosis. In addition, we mapped their potential regulatory mechanisms with correlated lncRNAs, providing new insights into potential targets for therapies in AML.

Protective Effects of Polysaccharides in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are characterized by progressive degeneration and necrosis of neurons, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease and others. There are no existing therapies that correct the progression of these diseases, and current therapies provide merely symptomatic relief. The use of polysaccharides has received significant attention due to extensive biological activities and application prospects. Previous studies suggest that the polysaccharides as a candidate participate in neuronal protection and protect against NDs. In this review, we demonstrate that various polysaccharides mediate NDs, and share several common mechanisms characterized by autophagy, apoptosis, neuroinflammation, oxidative stress, mitochondrial dysfunction in PD and AD. Furthermore, this review reveals potential role of polysaccharides in vitro and in vivo models of NDs, and highlights the contributions of polysaccharides and prospects of their mechanism studies for the treatment of NDs. Finally, we suggest some remaining questions for the field and areas for new development.

Causal Inference of Genetic Variants and Genes in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal progressive multisystem disorder with limited therapeutic options. Although genome-wide association studies (GWASs) have revealed multiple ALS susceptibility loci, the exact identities of causal variants, genes, cell types, tissues, and their functional roles in the development of ALS remain largely unknown. Here, we reported a comprehensive post-GWAS analysis of the recent large ALS GWAS (n = 80,610), including functional mapping and annotation (FUMA), transcriptome-wide association study (TWAS), colocalization (COLOC), and summary data-based Mendelian randomization analyses (SMR) in extensive multi-omics datasets. Gene property analysis highlighted inhibitory neuron 6, oligodendrocytes, and GABAergic neurons (Gad1/Gad2) as functional cell types of ALS and confirmed cerebellum and cerebellar hemisphere as functional tissues of ALS. Functional annotation detected the presence of multiple deleterious variants at three loci (9p21.2, 12q13.3, and 12q14.2) and highlighted a list of SNPs that are potentially functional. TWAS, COLOC, and SMR identified 43 genes at 24 loci, including 23 novel genes and 10 novel loci, showing significant evidence of causality. Integrating multiple lines of evidence, we further proposed that rs2453555 at 9p21.2 and rs229243 at 14q12 functionally contribute to the development of ALS by regulating the expression of C9orf72 in pituitary and SCFD1 in skeletal muscle, respectively. Together, these results advance our understanding of the biological etiology of ALS, feed into new therapies, and provide a guide for subsequent functional experiments.