Unveiling Promising Neuroimaging Biomarkers for Schizophrenia Through Clinical and Genetic Perspectives.

Schizophrenia is a complex and serious brain disorder. Neuroscientists have become increasingly interested in using magnetic resonance-based brain imaging-derived phenotypes (IDPs) to investigate the etiology of psychiatric disorders. IDPs capture valuable clinical advantages and hold biological significance in identifying brain abnormalities. In this review, we aim to discuss current and prospective approaches to identify potential biomarkers for schizophrenia using clinical multimodal neuroimaging and imaging genetics. We first described IDPs through their phenotypic classification and neuroimaging genomics. Secondly, we discussed the applications of multimodal neuroimaging by clinical evidence in observational studies and randomized controlled trials. Thirdly, considering the genetic evidence of IDPs, we discussed how can utilize neuroimaging data as an intermediate phenotype to make association inferences by polygenic risk scores and Mendelian randomization. Finally, we discussed machine learning as an optimum approach for validating biomarkers. Together, future research efforts focused on neuroimaging biomarkers aim to enhance our understanding of schizophrenia.

Two-sample Mendelian randomization analysis reveals causal relationships between blood lipids and venous thromboembolism.

Venous Thromboembolism (VTE) is a complex disease that can be classified into two subtypes: Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE. The MR results identified that fatty acid (FA) unsaturation traits (Ratio of bis-allylic bonds to double bonds in lipids, and Ratio of bis-allylic bonds to total fatty acids in lipids) were associated with VTE (OR [95% CI]: 1.21 [1.15-1.27]; 1.21 [1.13-1.30]), DVT (OR [95%CI]: 1.24 [1.16-1.33]; 1.26 [1.16-1.36]) and PE (OR [95%CI]: 1.18 [1.08-1.29]; 1.18 [1.09-1.27]). Phosphatidylcholines exhibit potential causal effects on VTE and PE. Phosphatidylcholine acyl-alkyl C40:4 (PC ae C40:4) was negatively associated with VTE (OR [95% CI]: 0.79 [0.73-0.86]), while phosphatidylcholine diacyl C42:6 (PC aa C42:6) and phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4) were positively associated with PE (OR [95%CI]: 1.44 [1.20-1.72]; 1.22 [1.10-1.35]). Additionally, we found that medium LDL had a protective effect on VTE. Our study indicates that higher FA unsaturation may increase the risk of VTE, DVT, and PE. Different types of phosphatidylcholine have either promotive or inhibitory effects on VTE and PE, contributing to a better understanding of the risk factors for VTE.

A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection.

Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.

The Causal Relationships Between Gut Microbiota, Brain Volume, and Intelligence: A Two-Step Mendelian Randomization Analysis.

BACKGROUND: Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence. METHODS: We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867). The inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. Considering the close relationship between brain volume and intelligence, we applied 2-step MR to evaluate whether the identified effect was mediated by regulating brain volume (N = 47,316). RESULTS: We found a risk effect of the genus Oxalobacter on intelligence (odds ratio = 0.968 change in intelligence per standard deviation increase in taxa; 95% CI, 0.952-0.985; p = 1.88 × 10-4) and a protective effect of the genus Fusicatenibacter on intelligence (odds ratio = 1.053; 95% CI, 1.024-1.082; p = 3.03 × 10-4). The 2-step MR analysis further showed that the effect of genus Fusicatenibacter on intelligence was partially mediated by regulating brain volume, with a mediated proportion of 33.6% (95% CI, 6.8%-60.4%; p = .014). CONCLUSIONS: Our results provide causal evidence indicating the role of the microbiome in intelligence. Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.

Scutellarin inhibits oleic acid induced vascular smooth muscle foam cell formation via activating autophagy and inhibiting NLRP3 inflammasome activation.

Abnormalities in vascular smooth muscle cells (VSMCs) are pivotal in the pathogenesis of cardiovascular pathologies such as atherosclerosis and hypertension. Scutellarin (Scu), a flavonoid derived from marigold flowers, exhibits a spectrum of biological activities including anti-inflammatory, antioxidant, antitumor, immunomodulatory and antimicrobial effects. Notably, Scu has demonstrated the capacity to mitigate vascular endothelial damage and prevent atherosclerosis via its antioxidative properties. Nevertheless, the influence of Scu on the formation of VSMC-derived foam cells remains underexplored. In this study, Scu was evidenced to efficaciously attenuate oleic acid (OA)-induced lipid accumulation and the upregulation of adipose differentiation-associated protein Plin2 in a dose- and time-responsive manner. We elucidated that Scu effectively diminishes OA-provoked VSMC foam cell formation. Further, it was established that Scu pretreatment augments the protein expression of LC3B-II and the mRNA levels of Map1lc3b and Becn1, concurrently diminishing the protein levels of the NLRP3 inflammasome compared to the OA group. Activation of autophagy through rapamycin attenuated NLRP3 inflammasome protein expression, intracellular lipid droplet content and Plin2 mRNA levels. Scu also counteracted the OA-induced decrement of LC3B-II levels in the presence of bafilomycin-a1, facilitating the genesis of autophagosomes and autolysosomes. Complementarily, in vivo experiments revealed that Scu administration substantially reduced arterial wall thickness, vessel wall cross-sectional area, wall-to-lumen ratio and serum total cholesterol levels in comparison to the high-fat diet model group. Collectively, our findings suggest that Scu attenuates OA-induced VSMC foam cell formation through the induction of autophagy and the suppression of NLRP3 inflammasome activation.

Integrative high-throughput enhancer surveying and functional verification divulges a YY2-condensed regulatory axis conferring risk for osteoporosis.

The precise roles of chromatin organization at osteoporosis risk loci remain largely elusive. Here, we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated single-nucleotide polymorphisms (SNPs). We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) that linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs and prevailing osteoporosis-relevant regulatory roles for their chromatin interaction genes. Further motif enrichment and network mapping prioritized several putative, key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected one top-ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underline the roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help to better understand the intricate molecular regulatory mechanisms underlying osteoporosis risk loci.

Protoilludane-Type and Related Nor-Sesquiterpenes from Phellinus hartigii and Their Anti-Hypertrophic Activities in Rat Cardiomyocytes.

Three nor-sesquiterpenes, phellinharts A-C (1-3), isolated from Phellinus hartigii, exhibited unprecedented protoilludane and cerapicane-type structures. The structures of compounds 1-3 were elucidated via spectroscopic analysis, quantum chemical calculations, and X-ray diffraction. Potential biogenic pathways involving demethylation, ring cleavage, and rearrangement were proposed. Compounds 1-3 displayed potent anti-hypertrophic activities with low cytotoxicity (CC50 > 50 µM) in rat cardiomyocytes, underscoring their therapeutic potential.

A landscape of gene expression regulation for synovium in arthritis.

The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression.

Multi-tissue transcriptome-wide association study reveals susceptibility genes and drug targets for insulin resistance-relevant phenotypes.

AIM: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study. MATERIALS AND METHODS: We conducted a large-scale multi-tissue transcriptome-wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment-IR, fasting insulin) and lipid-relevant traits (high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis. RESULTS: We identified 1190 susceptibility genes causally associated with IR-relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR-related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR-related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk. CONCLUSIONS: Our study provided new insights into IR aetiology and avenues for therapeutic development.

An integrated hinged dual-probe for co-target fast switching imaging.

The diversity of functional applications of atomic force microscopes is the key to the development of nanotechnology. However, the single probe configuration of the traditional atomic force microscope restricts the realization of different application requirements for the same target area of a single sample, and the replacement of the working probe will lead to the loss of the target area. Here, the design, simulation, fabrication, and application of a unique atomic force microscope dual-probe are presented, which consists of a pair of parallel cantilevers with a narrow gap and a U-shaped hinged probe base. The Integrated Hinged Dual-Probe (IHDP) is developed specifically for fast switching of probes working in limited space and independent and precise manipulation of each probe. The deflection signal sensing of two cantilevers is achieved simultaneously by a single laser beam, and the decoupled independent cantilever deflection signals do not interfere with each other. The switching of the working probe is achieved by a piezoelectric ceramic with a 2 µm stroke and U-shaped hinge structure, which is fast and does not require tedious and repetitive spatial position calibration. By measuring standard grid samples, IHDP exhibits excellent measurement and characterization capabilities. Finally, a working probe switching imaging experiment was conducted on solidified rat cardiomyocytes, and the experimental process and imaging results demonstrated the superiority of IHDP in switching probe scanning imaging of the same target area of a single sample. The two probes of IHDP can undergo arbitrary functionalization modifications, which helps achieve multidimensional information acquisition for a single target.

Electric Field-Controlled Magneto-Optical Kerr Effect in A-Type Antiferromagnetic Fe2CX2 (X = F, Cl) and Its Janus Monolayer.

The magneto-optical Kerr effect (MOKE) is a powerful probe of magnetism and has recently gained new attention in antiferromagnetic (AFM) materials. Through extensive first-principles calculations and group theory analysis, we have identified Fe2CX2 (X = F, Cl) and Janus Fe2CFCl monolayers as ideal A-type collinear AFM materials with high magnetic anisotropy and Néel temperatures. By applying a vertical external electrical field (Ef) of 0.2 V/Å, the MOKE is activated for Fe2CF2 and Fe2CCl2 monolayers without changing their magnetic ground state, and the maximum Kerr rotation angles are 0.13 and 0.08°, respectively. Due to the out-of-plane spontaneous polarization, the intrinsic and nonvolatile MOKE is found in the Janus Fe2CFCl monolayer and the maximal Kerr rotation angle without external electronic field is 0.25°. Moreover, the intrinsic built-in electronic field also gives origin to more robust A-type AFM ordering and reversible Kerr angle against external Ef. Our study suggests that Ef is an effective tool for controlling MOKE in two-dimensional (2D) AFM materials. This research opens the possibility of related studies and applications in AFM spintronics.

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study.

BACKGROUND: Stroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain. METHODS: We performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke. Summary data of 587 brain IDPs (up to 33,224 individuals) from the UK Biobank and five stroke types (sample size range from 301,663 to 446,696, case number range from 5,386 to 40,585) from the MEGASTROKE consortium were used. RESULTS: Forward MR indicated 14 IDPs belong to projection fibers or association fibers were associated with stroke. For example, higher genetically determined mean diffusivity (MD) in the right external capsule was causally associated with an increased risk of small vessel stroke (IVW OR = 2.76, 95% CI 2.07 to 3.68, P = 5.87 × 10-12). Reverse MR indicated that genetically determined higher risk of any ischemic stroke was associated with increased isotropic or free water volume fraction (ISOVF) in body of corpus callosum (IVW ß = 0.23, 95% CI 0.14 to 0.33, P = 3.22 × 10-7). This IDP is a commissural fiber and it is not included in the IDPs identified by forward MR. CONCLUSIONS: We identified 14 IDPs with statistically significant evidence of causal effects on stroke or stroke subtypes. We also identified potential causal effects of stroke on one IDP of commissural fiber. These findings might guide further work toward identifying preventative strategies at the brain imaging levels.

Mesenchymal stem/stromal cells-derived exosomes for osteoporosis treatment.

Osteoporosis is a systemic bone disease, which leads to decreased bone mass and an increased risk of fragility fractures. Currently, there are many anti-resorption drugs and osteosynthesis drugs, which are effective in the treatment of osteoporosis, but their usage is limited due to their contraindications and side effects. In regenerative medicine, the unique repair ability of mesenchymal stem cells (MSCs) has been favored by researchers. The exosomes secreted by MSCs have signal transduction and molecular delivery mechanisms, which may have therapeutic effects. In this review, we describe the regulatory effects of MSCs-derived exosomes on osteoclasts, osteoblasts, and bone immunity. We aim to summarize the preclinical studies of exosome therapy in osteoporosis. Furthermore, we speculate that exosome therapy can be a future direction to improve bone health.

Application of Hi-C technology in three-dimensional genomics research and disease pathogenesis analysis.

3D genomics aims to investigate the spatial structure of chromatin in the nucleus on the basis of genomic sequences, gene structures and relevant regulatory elements. The spatial organization of chromosomes is fundamental for gene expression regulation. Recent advances of high-throughput chromosome conformation capture (Hi-C) technology and its derivatives, has enabled capture of chromatin architecture with high resolution. In this review, we summarize the development and applications of various technologies of 3D genomes in disease research, particularly in the elucidation of pathogenic mechanisms in cancers and other systemic disorders.

Straight and twisted open nodal-line phonon states in the CaI2 family of materials.

Based on first-principles calculations and symmetry analysis, we propose that trigonal CaI2 with the space group P3̄m1 possesses straight and twisted open nodal-line phonon states with linear dispersion. The symmetry analysis indicates that joint symmetry PT and rotational symmetry C3z protect the straight nodal lines along Γ-A and K-H while PT and mirror symmetry M010 (M110) maintain the twisted nodal lines that traverse Γ-M (Γ-K) and A-L (A-H). The calculated π Berry phase suggests that all the nodal lines are nontrivial and the corresponding drumhead-like surface states are clearly visible in the observation window, which is less than 6 THz, suggesting a significant chance for them to be measured using meV-resolution inelastic X-ray scattering. The distribution of the nodal lines in the Brillouin zone is also confirmed by the phononic tight-binding model. Furthermore, the isostructural compounds MgBr2 and MgI2 show similar phonon spectra and topological nontrivial surface states. This work provides promising candidates for investigating straight and twisted open nodal-line phonon states in a single material, which will facilitate future experimental observation.

Enhancer variants on chromosome 2p14 regulating SPRED2 and ACTR2 act as a signal amplifier to protect against rheumatoid arthritis.

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.

A two-dimensional PtS2/BN heterostructure as an S-scheme photocatalyst with enhanced activity for overall water splitting.

Photocatalytic hydrogen production from water is a sustainable solution to the environmental pollution and energy crises. Encouraged by the successful synthesis of PtS2 and BN nanosheets and their suitable band edges, we have designed a PtS2/BN bilayer heterojunction and investigated its electronic and optical properties for the first time based on hybrid DFT calculations. In this system, the built-in electric field and band edge bending can retain useful electrons on the conduction band of BN and holes on the valence band of PtS2, which endow this system with a stronger redox ability. Meanwhile, this electric field can efficiently separate photoinduced electron-hole pairs and improve the photocatalytic efficiency. Compared with BN and PtS2 single layers, the PtS2/BN heterojunction with its smaller bandgap can make better use of visible and infrared light. Additionally, we have studied the effect of applied strain on the electronic and optical properties. This work aims to provide a method for constructing high-efficiency BN-based photocatalysts and illuminating the electron migration mechanism in step-scheme (S-scheme) heterostructures. We have found that the PtS2/BN bilayer heterojunction is a promising S-scheme photocatalyst for overall water decomposition.

Lineage-selective super enhancers mediate core regulatory circuitry during adipogenic and osteogenic differentiation of human mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) can be differentiated into osteoblasts and adipocytes. During these processes, super enhancers (SEs) play important roles. Here, we performed comprehensive characterization of the SEs changes associated with adipogenic and osteogenic differentiation of hMSCs, and revealed that SEs changed more dramatically compared with typical enhancers. We identified a set of lineage-selective SEs, whose target genes were enriched with cell type-specific functions. Functional experiments in lineage-selective SEs demonstrated their specific roles in directed differentiation of hMSCs. We also found that some key transcription factors regulated by lineage-selective SEs could form core regulatory circuitry (CRC) to regulate each other's expression and control the hMSCs fate determination. In addition, we found that GWAS SNPs of osteoporosis and obesity were significantly enriched in osteoblasts-selective SEs or adipocytes-selective SEs, respectively. Taken together, our studies unveiled important roles of lineage-selective SEs in hMSCs differentiation into osteoblasts and adipocytes.

Mendelian randomization analyses support causal relationships between brain imaging-derived phenotypes and risk of psychiatric disorders.

Observational studies have reported the correlations between brain imaging-derived phenotypes (IDPs) and psychiatric disorders; however, whether the relationships are causal is uncertain. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the causalities between 587 reliable IDPs (N = 33,224 individuals) and 10 psychiatric disorders (N = 9,725 to 161,405). We identified nine IDPs for which there was evidence of a causal influence on risk of schizophrenia, anorexia nervosa and bipolar disorder. For example, 1 s.d. increase in the orientation dispersion index of the forceps major was associated with 32% lower odds of schizophrenia risk. Reverse MR indicated that only genetically predicted schizophrenia was positively associated with two IDPs, the cortical surface area and the volume of the right pars orbitalis. We established the BrainMR database ( http://www.bigc.online/BrainMR/ ) to share our results. Our findings provide potential strategies for the prediction and intervention for psychiatric disorder risk at the brain-imaging level.