Cerebral hemodynamics underlying ankle force sense modulated by high-definition transcranial direct current stimulation.

This study aimed to investigate the effects of high-definition transcranial direct current stimulation on ankle force sense and underlying cerebral hemodynamics. Sixteen healthy adults (8 males and 8 females) were recruited in the study. Each participant received either real or sham high-definition transcranial direct current stimulation interventions in a randomly assigned order on 2 visits. An isokinetic dynamometer was used to assess the force sense of the dominant ankle; while the functional near-infrared spectroscopy was employed to monitor the hemodynamics of the sensorimotor cortex. Two-way analyses of variance with repeated measures and Pearson correlation analyses were performed. The results showed that the absolute error and root mean square error of ankle force sense dropped more after real stimulation than after sham stimulation (dropped by 23.4% vs. 14.9% for absolute error, and 20.0% vs. 10.2% for root mean square error). The supplementary motor area activation significantly increased after real high-definition transcranial direct current stimulation. The decrease in interhemispheric functional connectivity within the Brodmann's areas 6 was significantly correlated with ankle force sense improvement after real high-definition transcranial direct current stimulation. In conclusion, high-definition transcranial direct current stimulation can be used as a potential intervention for improving ankle force sense. Changes in cerebral hemodynamics could be one of the explanations for the energetic effect of high-definition transcranial direct current stimulation.

ScRNA-seq reveals the spatiotemporal distribution of camptothecin pathway and transposon activity in Camptotheca acuminata shoot apexes and leaves.

Camptotheca acuminata Decne., a significant natural source of the anticancer drug camptothecin (CPT), synthesizes CPT through the monoterpene indole alkaloid (MIA) pathway. In this study, we used single-cell RNA sequencing (scRNA-seq) to generate datasets encompassing over 60,000 cells from C. acuminata shoot apexes and leaves. After cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Analysis of MIA pathway gene expression revealed that most of them exhibited heightened expression in proliferating cells (PCs) and vascular cells (VCs). In contrast to MIA biosynthesis in Catharanthus roseus, CPT biosynthesis in C. acuminata did not exhibit multicellular compartmentalization. Some putative genes encoding enzymes and transcription factors (TFs) related to the biosynthesis of CPT and its derivatives were identified through co-expression analysis. These include 19 cytochrome P450 genes, 8 O-methyltransferase (OMT) genes, and 62 TFs. Additionally, these pathway genes exhibited dynamic expression patterns during VC and EC development. Furthermore, by integrating gene and transposable element (TE) expression data, we constructed novel single-cell transcriptome atlases for C. acuminata. This approach significantly facilitated the identification of rare cell types, including peripheral zone cells (PZs). Some TE families displayed cell type specific, tissue specific, or developmental stage-specific expression patterns, suggesting crucial roles for these TEs in cell differentiation and development. Overall, this study not only provides novel insights into CPT biosynthesis and spatial-temporal TE expression characteristics in C. acuminata, but also serves as a valuable resource for further comprehensive investigations into the development and physiology of this species.

Genetic associations between bipolar disorder and brain structural phenotypes.

Patients with bipolar disorder (BD) and their first-degree relatives exhibit alterations in brain volume and cortical structure, whereas the underlying genetic mechanisms remain unclear. In this study, based on the published genome-wide association studies (GWAS), the extent of polygenic overlap between BD and 15 brain structural phenotypes was investigated using linkage disequilibrium score regression and MiXeR tool, and the shared genomic loci were discovered by conjunctional false discovery rate (conjFDR) and expression quantitative trait loci (eQTL) analyses. MiXeR estimated the overall measure of polygenic overlap between BD and brain structural phenotypes as 4-53% on a 0-100% scale (as quantified by the Dice coefficient). Subsequent conjFDR analyses identified 54 independent loci (71 risk single-nucleotide polymorphisms) jointly associated with BD and brain structural phenotypes with a conjFDR < 0.05, among which 33 were novel that had not been reported in the previous BD GWAS. Follow-up eQTL analyses in respective brain regions both confirmed well-known risk genes (e.g. CACNA1C, NEK4, GNL3, MAPK3) and discovered novel risk genes (e.g. LIMK2 and CAMK2N2). This study indicates a substantial shared genetic basis between BD and brain structural phenotypes, and provides novel insights into the developmental origin of BD and related biological mechanisms.

Anodal transcranial direct current stimulation enhances ankle force control and modulates the beta-band activity of the sensorimotor cortex.

This study aimed to investigate the cortical responses to the ankle force control and the mechanism underlying changes in ankle force control task induced by transcranial direct current stimulation (tDCS). Sixteen young adults were recruited, and they completed the electroencephalogram (EEG) assessment and high-definition tDCS (HD-tDCS) sessions. Root mean square (RMS) error was used to evaluate ankle force control task performance. Spectral power analysis was conducted to extract the average power spectral density (PSD) in the alpha (8-13 Hz) and beta (13-30 Hz) bands for resting state and tasking (i.e. task-PSD). The ankle force control task induced significant decreases in alpha and beta PSDs in the central, left, and right primary sensorimotor cortex (SM1) and beta PSD in the central frontal as compared with the resting state. HD-tDCS significantly decreased the RMS and beta task-PSD in the central frontal and SM1. A significant association between the percent change of RMS and the percent change of beta task-PSD in the central SM1 after HD-tDCS was observed. In conclusion, ankle force control task activated a distributed cortical network mainly including the SM1. HD-tDCS applied over SM1 could enhance ankle force control and modulate the beta-band activity of the sensorimotor cortex.

Balance Control Deficits are Associated With Diminished Ankle Force Sense, Not Position Sense, in Athletes with Chronic Ankle Instability.

OBJECTIVES: To compare balance control and ankle proprioception between athletes with and without chronic ankle instability (CAI). A further objective was to explore the relationship between balance control performance and ankle proprioception in athletes with CAI. DESIGN: Cross-sectional study. SETTINGS: Sports Rehabilitation Laboratory. PARTICIPANTS: Eighty-eight recreational athletes (47 CAI and 41 healthy control) were recruited. INTERVENTIONS: No applicable. MAIN OUTCOME MEASURES: Balance control performance was assessed using the sway velocity of the center of the pressure during the one-leg standing tasks. Ankle proprioception, including joint position sense and force sense, were tested using absolute error (AE) associated with joint position reproduction and force reproduction tasks in 4 directions, that is, plantarflexion, dorsiflexion, inversion, and eversion. RESULTS: Athletes with CAI performed significantly worse than those without CAI in balance control tasks. In addition, CAI athletes showed significantly worse joint position sense and force sense in all 3 movement directions tested (plantarflexion, inversion, and eversion). Correlation analysis showed that the AE of the plantarflexion force sense was significantly moderately correlated with medial-lateral sway velocity in the one-leg standing with eyes open and closed conditions (r=.372-.403, P=.006-.012), and the AE of inversion force sense was significantly moderately correlated with medial-lateral sway velocity in the one-leg standing with eyes open (r=.345, P=.018) in athletes with CAI, but the joint position sense measures were not (all P>0.05). CONCLUSIONS: Athletes with CAI showed significantly impaired balance control performance and diminished ankle proprioception. Deficit in force sense was deemed as a moderate predictor of one-leg standing balance control deficits in athletes with dominant-side injury CAI, whereas ankle position sense may be a small predictor.

Gray Matter Volumes Mediate the Relationship Between Disease Duration and Balance Control Performance in Chronic Ankle Instability.

The relationship between structural changes in the cerebral gray matter and diminished balance control performance in patients with chronic ankle instability (CAI) has remained unclear. This paper aimed to assess the difference in gray matter volume (GMV) between participants with CAI and healthy controls (HC) and to characterize the role of GMV in the relationship between disease duration and balance performance in CAI. 42 participants with CAI and 33 HC completed the structural brain MRI scans, one-legged standing test, and Y-balance test. Regional GMV was measured by applying voxel-based morphometry methods. The result showed that, compared with HC, participants with CAI exhibited lower GMV in multiple brain regions (familywise error [FWE] corrected p < 0.021). Within CAI only, but not in HC, lower GMV in the thalamus (ß = -0.53, p = 0.003) and hippocampus (ß = -0.57, p = 0.001) was associated with faster sway velocity of the center of pressure (CoP) in eyes closed condition (i.e., worse balance control performance). The GMV in the thalamus (percentage mediated [PM] = 32.02%; indirect effect ß = 0.119, 95% CI = 0.003 to 0.282) and hippocampus (PM = 33.71%; indirect effect ß = 0.122, 95% CI = 0.005 to 0.278) significantly mediated the association between the disease duration and balance performance. These findings suggest that the structural characteristics of the supraspinal elements is critical to the maintenance of balance control performance in individuals suffering from CAI, which deserve careful consideration in the management and rehabilitation programs in this population.

Identification of a psychiatric risk gene NISCH at 3p21.1 GWAS locus mediating dendritic spine morphogenesis and cognitive function.

BACKGROUND: Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported that single nucleotide polymorphisms spanning chromosome 3p21.1 showed significant associations with both schizophrenia and BD, and a risk SNP rs2251219 was in linkage disequilibrium with a human specific Alu polymorphism rs71052682, which showed enhancer effects on transcriptional activities using luciferase reporter assays in U251 and U87MG cells. METHODS: CRISPR/Cas9-directed genome editing, real-time quantitative PCR, and public Hi-C data were utilized to investigate the correlation between the Alu polymorphism rs71052682 and NISCH. Primary neuronal culture, immunofluorescence staining, co-immunoprecipitation, lentiviral vector production, intracranial stereotaxic injection, behavioral assessment, and drug treatment were used to examine the physiological impacts of Nischarin (encoded by NISCH). RESULTS: Deleting the Alu sequence in U251 and U87MG cells reduced mRNA expression of NISCH, the gene locates 180 kb from rs71052682, and Hi-C data in brain tissues confirmed the extensive chromatin contacts. These data suggested that the genetic risk of schizophrenia and BD predicted elevated NISCH expression, which was also consistent with the observed higher NISCH mRNA levels in the brain tissues from psychiatric patients compared with controls. We then found that overexpression of NISCH resulted in a significantly decreased density of mushroom dendritic spines with a simultaneously increased density of thin dendritic spines in primary cultured neurons. Intriguingly, elevated expression of this gene in mice also led to impaired spatial working memory in the Y-maze. Given that Nischarin is the target of anti-hypertensive agents clonidine and tizanidine, which have shown therapeutic effects in patients with schizophrenia and patients with BD in preliminary clinical trials, we demonstrated that treatment with those antihypertensive drugs could reduce NISCH mRNA expression and rescue the impaired working memory in mice. CONCLUSIONS: We identify a psychiatric risk gene NISCH at 3p21.1 GWAS locus influencing dendritic spine morphogenesis and cognitive function, and Nischarin may have potentials for future therapeutic development.

Reduced Vrk2 expression is associated with higher risk of depression in humans and mediates depressive-like behaviors in mice.

BACKGROUND: Genome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs on VRK2 as well as their roles in the illness are yet to be elucidated. METHODS: Based on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulating VRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice with Vrk2 repression. RESULTS: We identified a SNP rs2678907 located in the 5' upstream of VRK2 gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues. Using luciferase reporter gene assays and eQTL analyses, the depression risk allele of rs2678907 decreased enhancer activities and predicted lower VRK2 mRNA expression, which is consistent with the observations of reduced VRK2 level in the patients with major depression compared with controls. Notably, Vrk2-/- mice exhibited depressive-like behaviors compared to Vrk2+/+ mice and specifically repressing Vrk2 in the ventral hippocampus using adeno-associated virus (AAV) lead to consistent and even stronger depressive-like behaviors in mice. Compared with Vrk2+/+ mice, the density of mushroom and thin spines in the ventral hippocampus was significantly altered in Vrk2-/- mice, which is in line with the phosphoproteomic analyses showing dysregulated synapse-associated proteins and pathways in Vrk2-/- mice. CONCLUSIONS: Vrk2 deficiency mice showed behavioral abnormalities that mimic human depressive phenotypes, which may serve as a useful murine model for studying the pathophysiology of depression.

An alternative splicing hypothesis for neuropathology of schizophrenia: evidence from studies on historical candidate genes and multi-omics data.

Alternative splicing of schizophrenia risk genes, such as DRD2, GRM3, and DISC1, has been extensively described. Nevertheless, the alternative splicing characteristics of the growing number of schizophrenia risk genes identified through genetic analyses remain relatively opaque. Recently, transcriptomic analyses in human brains based on short-read RNA-sequencing have discovered many "local splicing" events (e.g., exon skipping junctions) associated with genetic risk of schizophrenia, and further molecular characterizations have identified novel spliced isoforms, such as AS3MTd2d3 and ZNF804AE3E4. In addition, long-read sequencing analyses of schizophrenia risk genes (e.g., CACNA1C and NRXN1) have revealed multiple previously unannotated brain-abundant isoforms with therapeutic potentials, and functional analyses of KCNH2-3.1 and Ube3a1 have provided examples for investigating such spliced isoforms in vitro and in vivo. These findings suggest that alternative splicing may be an essential molecular mechanism underlying genetic risk of schizophrenia, however, the incomplete annotations of human brain transcriptomes might have limited our understanding of schizophrenia pathogenesis, and further efforts to elucidate these transcriptional characteristics are urgently needed to gain insights into the illness-correlated brain physiology and pathology as well as to translate genetic discoveries into novel therapeutic targets.

Revisiting tandem repeats in psychiatric disorders from perspectives of genetics, physiology, and brain evolution.

Genome-wide association studies (GWASs) have revealed substantial genetic components comprised of single nucleotide polymorphisms (SNPs) in the heritable risk of psychiatric disorders. However, genetic risk factors not covered by GWAS also play pivotal roles in these illnesses. Tandem repeats, which are likely functional but frequently overlooked by GWAS, may account for an important proportion in the "missing heritability" of psychiatric disorders. Despite difficulties in characterizing and quantifying tandem repeats in the genome, studies have been carried out in an attempt to describe impact of tandem repeats on gene regulation and human phenotypes. In this review, we have introduced recent research progress regarding the genomic distribution and regulatory mechanisms of tandem repeats. We have also summarized the current knowledge of the genetic architecture and biological underpinnings of psychiatric disorders brought by studies of tandem repeats. These findings suggest that tandem repeats, in candidate psychiatric risk genes or in different levels of linkage disequilibrium (LD) with psychiatric GWAS SNPs and haplotypes, may modulate biological phenotypes related to psychiatric disorders (e.g., cognitive function and brain physiology) through regulating alternative splicing, promoter activity, enhancer activity and so on. In addition, many tandem repeats undergo tight natural selection in the human lineage, and likely exert crucial roles in human brain evolution. Taken together, the putative roles of tandem repeats in the pathogenesis of psychiatric disorders is strongly implicated, and using examples from previous literatures, we wish to call for further attention to tandem repeats in the post-GWAS era of psychiatric disorders.

Bidirectional genetic overlap between bipolar disorder and intelligence.

BACKGROUND: Bipolar disorder (BD) is a highly heritable psychiatric illness exhibiting substantial correlation with intelligence. METHODS: To investigate the shared genetic signatures between BD and intelligence, we utilized the summary statistics from genome-wide association studies (GWAS) to conduct the bivariate causal mixture model (MiXeR) and conjunctional false discovery rate (conjFDR) analyses. Subsequent expression quantitative trait loci (eQTL) mapping in human brain and enrichment analyses were also performed. RESULTS: Analysis with MiXeR suggested that approximately 10.3K variants could influence intelligence, among which 7.6K variants were correlated with the risk of BD (Dice: 0.80), and 47% of these variants predicted BD risk and intelligence in consistent allelic directions. The conjFDR analysis identified 37 distinct genomic loci that were jointly associated with BD and intelligence with a conjFDR < 0.01, and 16 loci (43%) had the same directions of allelic effects in both phenotypes. Brain eQTL analyses found that genes affected by the "concordant loci" were distinct from those modulated by the "discordant loci". Enrichment analyses suggested that genes related to the "concordant loci" were significantly enriched in pathways/phenotypes related with synapses and sleep quality, whereas genes associated with the "discordant loci" were enriched in pathways related to cell adhesion, calcium ion binding, and abnormal emotional phenotypes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between BD and intelligence and identified multiple genomic loci and risk genes. This study provides hints for the mesoscopic phenotypes of BD and relevant biological mechanisms, promoting the knowledge of the genetic and phenotypic heterogeneity of BD. The essential value of leveraging intelligence in BD investigations is also highlighted.

Natural and human factors influencing urban particulate matter concentrations in central heating areas with long-term wearable monitoring devices.

In northern China, central heating, as an important source of urban particulate matter (UPM), causes more than half of the air pollution during the heating season and has significant spatial-temporal heterogeneity. Owing to the limitations of stationary air monitoring networks, few studies distinguish between heating/non-heating seasons and few have been conducted in urban areas. However, fixed monitoring cannot accurately capture the dynamic exposure of residents to UPM, and there is a lack of comprehensive evaluation of the factors affecting UPM. Therefore, this study used wearable Sniffer 4D equipment to monitor the concentrations of UPM (PM1, PM2.5, and PM10) in selected typical areas of Shenyang City from March 2019 to February 2020. A random forest model was combined with land use and point-of-interest data to analyze the contributions and marginal effects of multiple influences on UPM, in both heating and non-heating seasons. The results showed that in the eastern part of the study area, UPM showed completely opposite spatial distribution characteristics during the two seasons. The concentrations of UPM were higher during the heating season than during the non-heating season. The results indicated that temperature and humidity were important factors in diffusing UPM. The production and operation of boilers were important for the production of UPM. In two-dimensional landscape pattern indices, the percentage of forest and Shannon diversity index were the first and second most important factors, respectively. The three-dimensional pattern of buildings had important effects on the transport and diffusion of UPM (landscape height range >100, floor area ratio >1.3, and landscape volume density >5). Wearable devices could monitor the real situation of residents' exposure to UPM and quantify the factors influencing the spatial-temporal distribution of UPM in an ecological sense. These results provide a scientific basis for urban planning and for health risk reduction for residents.

Starvation stress attenuates the miRNA-target interaction in suppressing breast cancer cell proliferation.

BACKGROUND: Emerging evidence has demonstrated the limited access to metabolic substrates as an effective approach to block cancer cell growth. The mechanisms remain unclear. Our previous work has revealed that miR-221/222 plays important role in regulating breast cancer development and progression through interaction with target gene p27. RESULTS: Herein, we determined the miRNA-mRNA interaction in breast cancer cells under induced stress status of starvation. Starvation stimulation attenuated the miR-221/222-p27 interaction in MDA-MB-231 cells, thereby increased p27 expression and suppressed cell proliferation. Through overexpression or knockdown of miR-221/222, we found that starvation-induced stress attenuated the negative regulation of p27 expression by miR-221/222. Similar patterns for miRNA-target mRNA interaction were observed between miR-17-5p and CyclinD1, and between mR-155 and Socs1. Expression of Ago2, one of the key components of RNA-induced silencing complex (RISC), was decreased under starvation-induced stress status, which took responsibility for the impaired miRNA-target interaction since addition of exogenous Ago2 into MDA-MB-231 cells restored the miR-221/222-p27 interaction in starvation condition. CONCLUSIONS: We demonstrated the attenuated interaction between miR-221/222 and p27 by starvation-induced stress in MDA-MB-231 breast cancer cells. The findings add a new page to the general knowledge of negative regulation of gene expression by miRNAs, also demonstrate a novel mechanism through which limited access to nutrients suppresses cancer cell proliferation. These insights provide a basis for development of novel therapeutic options for breast cancer.

Palladium-catalyzed regioselective synthesis of B(4,5)- or B(4)-substituted o-carboranes containing α,ß-unsaturated carbonyls.

With the help of a carboxylic acid directing group, Pd-catalyzed regioselective synthesis of B(4,5)- or B(4)-substituted o-carboranes containing α,ß-unsaturated carbonyls has been reported. The -COOH, removed during the course of the reaction, is responsible for controlling the regioselectivity. The desired products could be obtained in moderate to good yields.

YY1 mediates TGF-ß1-induced EMT and pro-fibrogenesis in alveolar epithelial cells.

Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-ß-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-ß treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-ß treatment. Enforced expression of YY1 can partly mimic the TGF-ß-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-ß-induced EMT and pro-fibrosis. In addition, the translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-ß treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.

Folate polyglutamylation is involved in chromatin silencing by maintaining global DNA methylation and histone H3K9 dimethylation in Arabidopsis.

DNA methylation and repressive histone Histone3 Lysine9 (H3K9) dimethylation correlate with chromatin silencing in plants and mammals. To identify factors required for DNA methylation and H3K9 dimethylation, we screened for suppressors of the repressor of silencing1 (ros1) mutation, which causes silencing of the expression of the RD29A (RESPONSE TO DESSICATION 29A) promoter-driven luciferase transgene (RD29A-LUC) and the 35S promoter-driven NPTII (NEOMYCIN PHOSPHOTRANSFERASE II) transgene (35S-NPTII). We identified the folylpolyglutamate synthetase FPGS1 and the known factor DECREASED DNA METHYLATION1 (DDM1). The fpgs1 and ddm1 mutations release the silencing of both RD29A-LUC and 35S-NPTII. Genome-wide analysis indicated that the fpgs1 mutation reduces DNA methylation and releases chromatin silencing at a genome-wide scale. The effect of fpgs1 on chromatin silencing is correlated with reduced levels of DNA methylation and H3K9 dimethylation. Supplementation of fpgs1 mutants with 5-formyltetrahydrofolate, a stable form of folate, rescues the defects in DNA methylation, histone H3K9 dimethylation, and chromatin silencing. The competitive inhibitor of methyltransferases, S-adenosylhomocysteine, is markedly upregulated in fpgs1, by which fpgs1 reduces S-adenosylmethionine accessibility to methyltransferases and accordingly affects DNA and histone methylation. These results suggest that FPGS1-mediated folate polyglutamylation is required for DNA methylation and H3K9 dimethylation through its function in one-carbon metabolism. Our study makes an important contribution to understanding the complex interplay among metabolism, development, and epigenetic regulation.

The multicellular compartmentation of plant specialized metabolism.

The phenomenon of multicellular compartmentation in biosynthetic pathways has been documented for only a limited subset of specialized metabolites, despite its hypothesized significance in facilitating plant survival and adaptation to environmental stress. Transporters that shuttle metabolic intermediates between cells are hypothesized to be integral components enabling compartmentalized biosynthesis. Nevertheless, our understanding of the multicellular compartmentation of plant specialized metabolism and the associated intermediate transporters remains incomplete. The emergence of single-cell and spatial multiomics techniques holds promise for shedding light on unresolved questions in this field, such as the prevalence of multicellular compartmentation across the plant kingdom and the specific types of specialized metabolites whose biosynthetic pathways are prone to compartmentation. Advancing our understanding of the mechanisms underlying multicellular compartmentation will contribute to improving the production of specialized target metabolites through metabolic engineering or synthetic biology.

A computational model for potential microbe-disease association detection based on improved graph convolutional networks and multi-channel autoencoders.

Introduction: Accumulating evidence shows that human health and disease are closely related to the microbes in the human body. Methods: In this manuscript, a new computational model based on graph attention networks and sparse autoencoders, called GCANCAE, was proposed for inferring possible microbe-disease associations. In GCANCAE, we first constructed a heterogeneous network by combining known microbe-disease relationships, disease similarity, and microbial similarity. Then, we adopted the improved GCN and the CSAE to extract neighbor relations in the adjacency matrix and novel feature representations in heterogeneous networks. After that, in order to estimate the likelihood of a potential microbe associated with a disease, we integrated these two types of representations to create unique eigenmatrices for diseases and microbes, respectively, and obtained predicted scores for potential microbe-disease associations by calculating the inner product of these two types of eigenmatrices. Results and discussion: Based on the baseline databases such as the HMDAD and the Disbiome, intensive experiments were conducted to evaluate the prediction ability of GCANCAE, and the experimental results demonstrated that GCANCAE achieved better performance than state-of-the-art competitive methods under the frameworks of both 2-fold and 5-fold CV. Furthermore, case studies of three categories of common diseases, such as asthma, irritable bowel syndrome (IBS), and type 2 diabetes (T2D), confirmed the efficiency of GCANCAE.

Shared genetic architecture and causal relationship between sleep behaviors and lifespan.

Poor sleep health is associated with a wide array of increased risk for cardiovascular, metabolic and mental health problems as well as all-cause mortality in observational studies, suggesting potential links between sleep health and lifespan. However, it has yet to be determined whether sleep health is genetically or/and causally associated with lifespan. In this study, we firstly studied the genome-wide genetic association between four sleep behaviors (short sleep duration, long sleep duration, insomnia, and sleep chronotype) and lifespan using GWAS summary statistics, and both sleep duration time and insomnia were negatively correlated with lifespan. Then, two-sample Mendelian randomization (MR) and multivariable MR analyses were applied to explore the causal effects between sleep behaviors and lifespan. We found that genetically predicted short sleep duration was causally and negatively associated with lifespan in univariable and multivariable MR analyses, and this effect was partially mediated by coronary artery disease (CAD), type 2 diabetes (T2D) and depression. In contrast, we found that insomnia had no causal effects on lifespan. Our results further confirmed the negative effects of short sleep duration on lifespan and suggested that extension of sleep may benefit the physical health of individuals with sleep loss. Further attention should be given to such public health issues.