A Bidirectional Mendelian Randomization Study of Gut Microbiota and Cerebral Small Vessel Disease.

BACKGROUND: The causal nature of gut microbiota and cerebral small vessel disease (CSVD) is still obscure regardless of evidence supporting their observational correlations. OBJECTIVES: The primary objective of this research is to investigate the potentially pathogenic or protective causal impacts of specific gut microbiota on various neuroimaging subtypes of CSVD. METHODS: We obtained the latest summary-level genome-wide databases for gut microbiota and 9 CSVD traits. The univariable and multivariable Mendelian randomization (MR) studies were conducted to examine the possible causal link between exposure and outcome. Meanwhile, we conducted sensitivity analyses sequentially, containing the heterogeneity, pleiotropy, and leave-one-out analysis. Additionally, to clarify the potential bidirectional causality, the causality from CSVD traits to the identified gut microbiota was implemented through reverse MR analysis. RESULTS: The univariable MR analysis identified 22 genetically predicted bacterial abundances that were correlated with CSVD traits. Although conditioning on macronutrient dietary compositions, 2 suggestive relationships were retained using the multivariable MR analysis. Specifically, the class Negativicutes and order Selenomonadales exhibited a negative causal association with strictly lobar cerebral microbleeds, 1 neuroimaging trait of CSVD. There is insufficient evidence indicating the presence of heterogeneity and horizontal pleiotropy. Furthermore, the identified causal relationship was not driven by any single nucleotide polymorphism. The results of the reverse MR analysis did not reveal any statistically significant causality from CSVD traits to the identified gut microbiota. CONCLUSIONS: Our study indicated several suggestive causal effects from gut microbiota to different neuroimaging subtypes of CSVD. These findings provided a latent understanding of the pathogenesis of CSVD from the perspective of the gut-brain axis.

[C(NH2)3]6Mo7O24: A Guanidinium Molybdate as a UV Nonlinear Optical Crystal with Large Birefringence.

The key to searching novel nonlinear optical (NLO) crystals was effectively combining the NLO-active units to obtain a noncentrosymmetric structure. Nevertheless, the present predicament lies in the growing challenge of discovering novel crystals within conventional inorganic frameworks that surpass the properties of the current NLO materials. In view of this, researchers expanded their research focus to the organic-inorganic hybridization system; it is foreseeable to concentrate the advantages from several kinds of NLO-active units to acquire novel NLO crystals with superior properties. We herein report an organic-inorganic hybrid molybdate crystal, namely, [C(NH2)3]6Mo7O24 (GMO). It was successfully obtained via combining inorganic NLO-active MoO6 octahedra and organic π-conjugated [C(NH2)3]+ groups. GMO demonstrates a moderate second-harmonic-generation response, specifically measuring about 1.3 times the value of KDP. Additionally, it exhibits a significant birefringence value of 0.203 at the wavelength of 550 nm and possesses a wide band gap of 3.31 eV. Theoretical calculations suggest that the optical properties of the GMO are primarily influenced by the synergy effect of [C(NH2)3]+ groups between MoO6 octahedra.

[C(NH2)3][B(C2O2H4)2]: An Organic-Inorganic Hybrid Borate Containing Nonlinear-Optical Active Unit [B(C2O2H4)2]- with Solar-Blind-Region Optical Nonlinearity.

We herein report an unprecedented organic-inorganic hybrid borate incorporating a novel nonlinear-optical (NLO) active unit, namely, [C(NH2)3][B(C2O2H4)2]. The novel NLO active unit was derived from the condensation reaction between two glycol molecules and one (BO4)5- group. The title compound exhibits a moderate second-harmonic-generation effect (0.7 × KDP), a significant band gap (5.76 eV), and a suitable birefringence (0.078 at 550 nm). The optical properties are determined by the synergistic interaction between the C(NH2)3+ cation and the [B(C2O2H4)2]- group, as indicated by theoretical calculations.

Circular RNA ZBTB46 depletion alleviates the progression of Atherosclerosis by regulating the ubiquitination and degradation of hnRNPA2B1 via the AKT/mTOR pathway.

BACKGROUND: CircZBTB46 has been identified as being associated with the risk of coronary artery disease (CAD) and has the potential to be a diagnostic biomarker for CAD. However, the specific function and detailed mechanism of circZBTB46 in CAD are still unknown. METHODS: The expression levels and properties of circRNAs were examined using qRT‒PCR, RNA FISH, and subcellular localization analysis. ApoE-/- mice fed a high-fat diet were used to establish an atherosclerosis model. HE, Masson, and Oil Red O staining were used to analyze the morphological features of the plaque. CCK-8, Transwell, and wound healing assays, and flow cytometric analysis were used to evaluate cell proliferation, migration, and apoptosis. RNA pull-down, silver staining, mass spectrometry analysis, and RNA-binding protein immunoprecipitation (RIP) were performed to identify the interacting proteins of circZBTB46. RESULTS: CircZBTB46 is highly conserved and is significantly upregulated in atherosclerotic lesions. Functional studies revealed that knockdown of circZBTB46 significantly decreased the atherosclerotic plaque area, attenuating the progression of atherosclerosis. In addition, silencing circZBTB46 inhibited cell proliferation and migration and induced apoptosis. Mechanistically, circZBTB46 physically interacted with hnRNPA2B1 and suppressed its degradation, thereby regulating cell functions and the formation of aortic atherosclerotic plaques. Additionally, circZBTB46 was identified as a functional mediator of PTEN-dependent regulation of the AKT/mTOR signaling pathway and thus affected cell proliferation and migration and induced apoptosis. CONCLUSION: Our study provides the first direct evidence that circZBTB46 functions as an important regulatory molecule for CAD progression by interacting with hnRNPA2B1 and regulating the PTEN/AKT/mTOR pathway.

The splicing factor DHX38 enables retinal development through safeguarding genome integrity.

DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, we demonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.

Altered dynamic functional network connectivity and topological organization variance in patients with white matter hyperintensities.

White matter hyperintensities (WMHs) of presumed vascular origin are important imaging biomarkers of cerebral small vessel disease (CSVD). Previous studies have verified abnormal functional brain networks in CSVD. However, most of these studies rely on static functional connectivity, and only a few focus on the varying severity of the WMHs. Hence, our study primarily explored the disrupted dynamic functional network connectivity (dFNC) and topological organization variance in patients with WMHs. This study included 38 patients with moderate WMHs, 47 with severe WMHs, and 68 healthy controls (HCs). Ten independent components were chosen using independent component analysis based on resting-state functional magnetic resonance imaging. The dFNC of each participant was estimated using sliding windows and k-means clustering. We identified three reproducible dFNC states. Among them, patients with WMHs had a significantly higher occurrence in the sparsely connected State 1, but a lower occurrence and shorter duration in the positive and stronger connected State 3. Regarding topological organization variance, patients with WMHs showed higher variance in local efficiency but not global efficiency compared to HCs. Among the WMH subgroups, patients with severe WMHs showed similar but more obvious alterations than those with moderate WMHs. These altered network characteristics indicated an imbalance between the functional segregation and integration of brain networks, which was correlated with global cognition, memory, executive functions, and visuospatial abilities. Our study confirmed aberrant dFNC state metrics and topological organization variance in patients with moderate-to-severe WMHs; thus, it might provide a new pathway for exploring the pathogenesis of cognitive impairment.

The Role of Social Norms and Personal Costs on Pro-Environmental Behavior: The Mediating Role of Personal Norms.

Background: Pro-environmental behavior necessitates individuals to make personal sacrifices, such as spending more money on environmentally-friendly products to benefit the environment. Realistically, individuals may not be willing to engage in pro-environmental behavior based self-interest. The increase in personal pro-environmental behavior has become an urgent issue in the field of environmental psychology. Purpose: The present study adopted green consumption paradigm to explore the internal mechanisms of pro-environmental behavior at different personal costs, the role of social and personal norms on pro-environmental behavior, which can promote individual pro-environmental behavior. Methods: In our experiment, participants first were instructed to read texts unrelated and related to social norms in sequence. Participants subsequently completed the product choice task, which involved making choices between buying green (eco-friendly) products or cheaper (self-interested) common products, a method to measure pro-environment behavior. Finally, the participants completed the personal norms scale and social norms check. Results: The findings of present study indicated that pro-environmental behavior decreased as personal costs increased. However, social norms effectively promoted individuals' pro-environmental behavior, and personal norms played a mediating role at high personal costs. Conclusion: Our findings indicate that individuals tend to choose cheaper common products that are harmful to the natural environment in self-interest. However, we discuss the implications for the use of social norms as a social marketing technique, which extends the Norm Activation Model.

Rice kinesin-related protein STD1 and microtubule-associated protein MAP65-5 cooperatively control microtubule bundling.

MAIN CONCLUSIONS: STD1 specifically interacts with MAP65-5 in rice and they cooperatively control microtubule bundles in phragmoplast expansion during cell division. Microtubules play critical roles during the cell cycle progression in the plant cell. We previously reported that STEMLESS DWARF 1 (STD1), a kinesin-related protein, was localized specifically to the phragmoplast midzone during telophase to regulate the lateral expansion of phragmoplast in rice (Oryza sativa). However, how STD1 regulates microtubule organization remains unknown. Here, we found that STD1 interacted directly with MAP65-5, a member of the microtubule-associated proteins (MAPs). Both STD1 and MAP65-5 could form homodimers and bundle microtubules individually. Compared with MAP65-5, the microtubules bundled by STD1 were disassembled completely into single microtubules after adding ATP. Conversely, the interaction of STD1 with MAP65-5 enhanced the microtubule bundling. These results suggest STD1 and MAP65-5 might cooperatively regulate microtubule organization in the phragmoplast at telophase.

[C(NH2)2NHNO2][C(NH2)3](NO3)2: A Mixed Organic Cationic Hybrid Nitrate with an Unprecedented Nonlinear-Optical-Active Unit.

We herein report a mixed organic cationic hybrid nitrate, namely, [C(NH2)2NHNO2][C(NH2)3](NO3)2 (1). It was successfully achieved via combining three different planar groups: [(C(NH2)2NHNO2]+, C(NH2)3+, and NO3-. First-principles calculations confirm that the [(C(NH2)2NHNO2]+ group is an excellent cationic nonlinear-optical (NLO)-active unit. The title compound exhibits a moderate second-harmonic-generation (SHG) response (1.5 × KDP), a wide band gap (3.58 eV), and a suitable birefringence of 0.071 at 550 nm. Theoretical calculations indicate that the synergy effect between the [(C(NH2)2NHNO2]+ and C(NH2)3+ groups dominates the SHG process.

C(NH2)3(I3O8)(HI3O8)(H2I2O6)(HIO3)4·3H2O: An Unprecedented Asymmetric Guanidinium Polyiodate with a Strong Second-Harmonic-Generation Response and a Wide Band Gap.

Herein, we report an unprecedented asymmetric guanidinium polyiodate, namely, C(NH2)3(I3O8)(HI3O8)(H2I2O6)(HIO3)4·3H2O (1). The title compound was obtained via the hybridization of polyiodate anions and planar π-conjugated C(NH2)3+; meanwhile, its strong second-harmonic-generation (SHG) response (2.1 × KDP, where KDP = KH2PO4) and wide band gap (3.89 eV) were mainly dominated by the synergy effect of the aforementioned structural units.

Identifying the neural marker of chronic sciatica using multimodal neuroimaging and machine learning analyses.

Introduction: Sciatica is a pain disorder often caused by the herniated disk compressing the lumbosacral nerve roots. Neuroimaging studies have identified functional abnormalities in patients with chronic sciatica (CS). However, few studies have investigated the neural marker of CS using brain structure and the classification value of multidimensional neuroimaging features in CS patients is unclear. Methods: Here, structural and resting-state functional magnetic resonance imaging (fMRI) was acquired for 34 CS patients and 36 matched healthy controls (HCs). We analyzed cortical surface area, cortical thickness, amplitude of low-frequency fluctuation (ALFF), regional homogeneity (REHO), between-regions functional connectivity (FC), and assessed the correlation between neuroimaging measures and clinical scores. Finally, the multimodal neuroimaging features were used to differentiate the CS patients and HC individuals by support vector machine (SVM) algorithm. Results: Compared to HC, CS patients had a larger cortical surface area in the right banks of the superior temporal sulcus and rostral anterior cingulate; higher ALFF value in the left inferior frontal gyrus; enhanced FCs between somatomotor and ventral attention network. Three FCs values were associated with clinical pain scores. Furthermore, the three multimodal neuroimaging features with significant differences between groups and the SVM algorithm could classify CS patients and HC with an accuracy of 90.00%. Discussion: Together, our findings revealed extensive reorganization of local functional properties, surface area, and network metrics in CS patients. The success of patient identification highlights the potential of using artificial intelligence and multimodal neuroimaging markers in chronic pain research.

Impaired Inter-Hemispheric Functional Connectivity during Resting State in Female Patients with Migraine.

The application of voxel-mirrored homotopic connectivity (VMHC) analysis to study the central mechanism of migraine has been limited. Furthermore, little is known about inter-hemispheric functional connectivity (FC) alterations during resting state in female patients with migraine. This study aimed to investigate potential interictal VMHC impairments in migraine without aura (MwoA) patients and the relationship between connectivity alterations and clinical parameters. Resting-state functional magnetic resonance imaging data and clinical information were acquired from 43 female MwoA patients and 43 matched healthy controls. VMHC analysis was used to compare differences between these two groups, and brain regions showing significant differences were chosen as a mask to perform a seed-based FC group comparison. Subsequent correlation analysis was conducted to explore the relationship between abnormal inter-hemispheric FC and clinical data. Compared with healthy controls, female MwoA patients revealed significantly decreased VMHC in the bilateral cerebellum; cuneus; and lingual, middle occipital, precentral and postcentral gyri. Seed-based FC analysis indicated disrupted intrinsic connectivity in the cerebellum, and default mode, visual and sensorimotor network. These VMHC and FC abnormalities were negatively correlated with clinical indexes including duration of disease, migraine days and visual analogue scale. These inter-hemispheric FC impairments and correlations between abnormal VMHC and FC and clinical scores may improve our understanding of the central mechanism of female-specific migraine.

Dhx38 is required for the maintenance and differentiation of erythro-myeloid progenitors and hematopoietic stem cells by alternative splicing.

Mutations that occur in RNA-splicing machinery may contribute to hematopoiesis-related diseases. How splicing factor mutations perturb hematopoiesis, especially in the differentiation of erythro-myeloid progenitors (EMPs), remains elusive. Dhx38 is a pre-mRNA splicing-related DEAH box RNA helicase, for which the physiological functions and splicing mechanisms during hematopoiesis currently remain unclear. Here, we report that Dhx38 exerts a broad effect on definitive EMPs as well as the differentiation and maintenance of hematopoietic stem and progenitor cells (HSPCs). In dhx38 knockout zebrafish, EMPs and HSPCs were found to be arrested in mitotic prometaphase, accompanied by a 'grape' karyotype, owing to the defects in chromosome alignment. Abnormal alternatively spliced genes related to chromosome segregation, the microtubule cytoskeleton, cell cycle kinases and DNA damage were present in the dhx38 mutants. Subsequently, EMPs and HSPCs in dhx38 mutants underwent P53-dependent apoptosis. This study provides novel insights into alternative splicing regulated by Dhx38, a process that plays a crucial role in the proliferation and differentiation of fetal EMPs and HSPCs.

Acetylation dependent translocation of EWSR1 regulates CHK2 alternative splicing in response to DNA damage.

Ewing sarcoma breakpoint region 1 (EWSR1) is a member of FET (FUS/EWSR1/TAF15) RNA-binding family of proteins. The Ewing sarcoma oncoprotein EWS-FLI1 has been extensively studied, while much less is known about EWSR1 itself, especially the potential role of EWSR1 in response to DNA damage. Here, we found that UV irradiation induces acetylation of EWSR1, which is required for its nucleoli translocation. We identified K423, K432, K438, K640, and K643 as the major acetylation sites, p300/CBP and HDAC3/HDAC10 as the major acetyltransferases and deacetylases, respectively. Mechanically, UV-induced EWSR1 acetylation repressed its interaction with spliceosomal component U1C, which caused abnormal splicing of CHK2, suppressing the activity of CHK2 in response to UV irradiation. Taken together, our findings uncover acetylation as a novel regulatory modification of EWSR1, and is essential for its function in DNA damage response.

Involvement of the High-Osmolarity Glycerol Pathway of Saccharomyces Cerevisiae in Protection against Copper Toxicity.

Although essential for life, copper is also potentially toxic in concentrations that surpass physiological thresholds. The high-osmolarity glycerol pathway of yeast is the main regulator of adaptive responses and is known to play crucial roles in the responses to various stressors. The objective of this research is to determine whether the HOG pathway could be activated and to investigate the possible interplay of the HOG pathway and oxidative stress due to copper exposure. In this research, we demonstrate that copper could induce oxidative stress, including the elevated concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA). Increased combination with GSH, increased intracellular SOD activity, and the up-regulation of relevant genes can help cells defend themselves against oxidative toxicity. The results show that copper treatment triggers marked and prolonged Hog1 phosphorylation. Significantly, oxidative stress generated by copper toxicity is essential for the activation of Hog1. Activated Hog1 is translocated to the nucleus to regulate the expressions of genes such as CTT1, GPD1, and HSP12, among others. Furthermore, copper exposure induced significant G1-phase cell cycle arrest, while Hog1 partially participated in the regulation of cell cycle progression. These novel findings reveal another role for Hog1 in the regulation of copper-induced cellular stress.

Antimicrobial Effects of Novel H2O2-Ag+ Complex on Membrane Damage to Staphylococcus aureus, Escherichia coli O157:H7, and Salmonella Typhimurium.

ABSTRACT: Diseases caused by harmful microorganisms pose a serious threat to human health. Safe and environmentally friendly disinfectants are, therefore, essential in preventing and controlling such pathogens. This study aimed to investigate the antimicrobial activity and mechanism of a novel hydrogen peroxide and silver (H2O2-Ag+) complex (HSC) in combatting Staphylococcus aureus ATCC 29213, Escherichia coli O157:H7 NCTC 12900, and Salmonella Typhimurium SL 1344. The MICs and MBCs against S. aureus were found to be 0.014% H2O2-3.125 mg/L Ag+, and for both E. coli O157:H7 and Salmonella Typhimurium they were 0.028% H2O2-6.25 mg/L Ag+. Results of the time-kill trial suggest that HSC could inhibit the growth of the tested bacteria, because 99.9% of viable cells were killed following treatment at 1 MIC for 3 h. The mechanism of antibacterial action of HSC was found to include the disruption of the bacterial cell membrane, followed by reduction of intracellular ATP concentration and inhibition of the activity of antioxidases, superoxide dismutase, and catalase. The enhanced bactericidal effect of hydrogen peroxide combined with silver indicates a potential for its application in environmental disinfection, particularly in the food industry.

A fundamental landscape of fungal biogeographical patterns across the main Chinese wine-producing regions and the dominating shaping factors.

The microbial terroir plays an indispensable role in the formation of regional wine characteristics. A fundamental landscape of the fungal biogeographical patterns across Chinese wine-producing regions was obtained by characterizing the fungal communities in spontaneous fermentation. After confirming the established national microbial terroir, the fungal heterogeneity was evaluated at different geographical levels. The result showed that the variation between the wineries was more evident than at a regional level. Moreover, the microbial comparability from various regions with similar climates or wineries within the same regions was revealed. Further discriminant analysis determined the specific fungal biomarkers in different regions, while the associated reverse identification model displayed reliable accuracy (>70%). Correlation analysis illustrated the primary role of the geoclimatic factors (>41%) in shaping the fungal geographical patterns, and the relationship between the microbiome and spontaneous fermentation performance. In addition to expanding the knowledge regarding wine microbes, these findings provided a new benchmark for harnessing the microbial terroir to enhance regional wine expression.

Genome-Wide Association Study of the Genetic Basis of Effective Tiller Number in Rice.

BACKGROUND: Effective tiller number (ETN) has a pivotal role in determination of rice (Oryza sativa L.) grain yield. ETN is a complex quantitative trait regulated by both genetic and environmental factors. Despite multiple tillering-related genes have been cloned previously, few of them have been utilized in practical breeding programs. RESULTS: In this study, we conducted a genome-wide association study (GWAS) for ETN using a panel of 490 rice accessions derived from the 3 K rice genomes project. Thirty eight ETN-associated QTLs were identified, interestingly, four of which colocalized with the OsAAP1, DWL2, NAL1, and OsWRKY74 gene previously reported to be involved in rice tillering regulation. Haplotype (Hap) analysis revealed that Hap5 of OsAAP1, Hap3 and 6 of DWL2, Hap2 of NAL1, and Hap3 and 4 of OsWRKY74 are favorable alleles for ETN. Pyramiding favorable alleles of all these four genes had more enhancement in ETN than accessions harboring the favorable allele of only one gene. Moreover, we identified 25 novel candidate genes which might also affect ETN, and the positive association between expression levels of the OsPILS6b gene and ETN was validated by RT-qPCR. Furthermore, transcriptome analysis on data released on public database revealed that most ETN-associated genes showed a relatively high expression from 21 days after transplanting (DAT) to 49 DAT and decreased since then. This unique expression pattern of ETN-associated genes may contribute to the transition from vegetative to reproductive growth of tillers. CONCLUSIONS: Our results revealed that GWAS is a feasible way to mine ETN-associated genes. The candidate genes and favorable alleles identified in this study have the potential application value in rice molecular breeding for high ETN and grain yield.

The Biogeography of Fungal Communities Across Different Chinese Wine-Producing Regions Associated With Environmental Factors and Spontaneous Fermentation Performance.

Chinese Marselan grapes are believed to possess the potential to become a characteristic regional variety, whose quality is internationally recognized. The fermentation-related mycobiota from six climatically diverse Marselan-producing regions in China were analyzed via high-throughput sequencing (HTS), while the influence of environmental factors was evaluated as well. The results implied that the phyla Ascomycota and genus Aureobasidium dominated the fungal communities in 166 Marselan must and fermented samples. Significant differences were detected in the fungal microbiota from the regions, as well as the wineries, while these discrepancies decreased as the fermentation progressed. Moreover, the discrepancy in fungal communities between the wineries exceeded the variation involving the regions. Geoclimatic elements (Gc) and physicochemical indexes (Pi) exerted a significant effect on the fungal must consortium, explaining 58.17% of the taxonomic information. Furthermore, a correlation was proposed between the spontaneous fermentation performance and their association with fungal taxonomic composition. In addition to depicting a fundamental landscape of fungal biogeography patterns across Chinese main wine-producing regions, we firstly proposed the correlation between the must polyphenol content and fungal microbiota, which may provide a new strategy for harnessing autochthonous "microbial terroir."