The lack of negative association between TE load and subgenome dominance in synthesized Brassica allotetraploids.

Polyploidization is important to the evolution of plants. Subgenome dominance is a distinct phenomenon associated with most allopolyploids. A gene on the dominant subgenome tends to express to higher RNA levels in all organs as compared to the expression of its syntenic paralogue (homoeolog). The mechanism that underlies the formation of subgenome dominance remains unknown, but there is evidence for the involvement of transposon/DNA methylation density differences nearby the genes of parents as being causal. The subgenome with lower density of transposon and methylation near genes is positively associated with subgenome dominance. Here, we generated eight generations of allotetraploid progenies from the merging of parental genomes Brassica rapa and Brassica oleracea. We found that transposon/methylation density differ near genes between the parental (rapa:oleracea) existed in the wide hybrid, persisted in the neotetraploids (the synthetic Brassica napus), but these neotetraploids expressed no expected subgenome dominance. This absence of B. rapa vs. B. oleracea subgenome dominance is particularly significant because, while there is no negative relationship between transposon/methylation level and subgenome dominance in the neotetraploids, the more ancient parental subgenomes for all Brassica did show differences in transposon/methylation densities near genes and did express, in the same samples of cells, biased gene expression diagnostic of subgenome dominance. We conclude that subgenome differences in methylated transposon near genes are not sufficient to initiate the biased gene expressions defining subgenome dominance. Our result was unexpected, and we suggest a "nuclear chimera" model to explain our data.

Mediation role of DNA methylation in association between handgrip strength and cognitive function in monozygotic twins.

Handgrip strength is a crucial indicator to monitor the change of cognitive function over time, but its mechanism still needs to be further explored. We sampled 59 monozygotic twin pairs to explore the potential mediating effect of DNA methylation (DNAm) on the association between handgrip strength and cognitive function. The initial step was the implementation of an epigenome-wide association analysis (EWAS) in the study participants, with the aim of identifying DNAm variations that are associated with handgrip strength. Following that, we conducted an assessment of the mediated effect of DNAm by the use of mediation analysis. In order to do an ontology enrichment study for CpGs, the GREAT program was used. There was a significant positive association between handgrip strength and cognitive function (ß = 0.194, P < 0.001). The association between handgrip strength and DNAm of 124 CpGs was found to be statistically significant at a significance level of P < 1 × 10-4. Fifteen differentially methylated regions (DMRs) related to handgrip strength were found in genes such as SNTG2, KLB, CDH11, and PANX2. Of the 124 CpGs, 4 within KRBA1, and TRAK1 mediated the association between handgrip strength and cognitive function: each 1 kg increase in handgrip strength was associated with a potential decrease of 0.050 points in cognitive function scores, mediated by modifications in DNAm. The parallel mediating effect of these 4 CpGs was -0.081. The presence of DNAm variation associated with handgrip strength may play a mediated role in the association between handgrip strength and cognitive function.

Schlafen 5 suppresses human immunodeficiency virus type 1 transcription by commandeering cellular epigenetic machinery.

Schlafen-5 (SLFN5) is an interferon-induced protein of the Schlafen family, which are involved in immune responses and oncogenesis. To date, little is known regarding its anti-HIV-1 function. Here, the authors report that overexpression of SLFN5 inhibits HIV-1 replication and reduces viral mRNA levels, whereas depletion of endogenous SLFN5 promotes HIV-1 replication. Moreover, they show that SLFN5 markedly decreases the transcriptional activity of HIV-1 long terminal repeat (LTR) via binding to two sequences in the U5-R region, which consequently represses the recruitment of RNA polymerase II to the transcription initiation site. Mutagenesis studies show the importance of nuclear localization and the N-terminal 1-570 amino acids fragment in the inhibition of HIV-1. Further mechanistic studies demonstrate that SLFN5 interacts with components of the PRC2 complex, G9a and Histone H3, thereby promoting H3K27me2 and H3K27me3 modification leading to silencing HIV-1 transcription. In concert with this, they find that SLFN5 blocks the activation of latent HIV-1. Altogether, their findings demonstrate that SLFN5 is a transcriptional repressor of HIV-1 through epigenetic modulation and a potential determinant of HIV-1 latency.

Cynarin ameliorates dextran sulfate sodium-induced acute colitis in mice through the STAT3/NF-κB pathway.

OBJECTIVE: Cynarin is a derivative of hydroxycinnamic acid presented in various medicinal plants, such as Cynara scolymus L. and Onopordum illyricum L. To date, the antioxidant and antihypertensive activities of cynarin have been reported. However, whether cynarin has a therapeutic impact on ulcerative colitis (UC) is unclear. Therefore, the aim of this study was to explore the potential effect of cynarin on dextran sulfate sodium (DSS)-induced acute colitis in vivo and on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced RAW264.7 and J774A.1 cellular inflammation model in vitro. METHODS AND RESULTS: In this study, we investigated that cynarin alleviated clinical symptoms in animal models, including disease activity index (DAI) and histological damage. Furthermore, cynarin can attenuate colon inflammation through decreasing the proportion of neutrophils in peripheral blood, reducing the infiltration of neutrophils, and macrophages in colon tissue, inhibiting the release of pro-inflammatory cytokines and suppressing the expression of STAT3 and p65. In cellular inflammation models, cynarin inhibited the expression of M1 macrophage markers, such as TNF-α, IL-1ß, and iNOS. Besides, cynarin suppressed the expression of STAT3 and p65 as well as the phosphorylation of STAT3, p65. Cynarin inhibited the polarization of RAW264.7 and J774A.1 cells toward M1 and alleviated LPS/IFN-γ-induced cellular inflammation. CONCLUSION: Considering these results, we conclude that cynarin mitigates experimental UC partially through inhibiting the STAT3/NF-кB signaling pathways and macrophage polarization toward M1. Accordingly, cynarin might be a potential and effective therapy for UC.

A cluster of transcripts identifies a transition stage initiating leafy head growth in heading morphotypes of Brassica.

Leaf heading is an important and economically valuable horticultural trait in many vegetables. The formation of a leafy head is a specialized leaf morphogenesis characterized by the emergence of the enlarged incurving leaves. However, the transcriptional regulation mechanisms underlying the transition to leaf heading remain unclear. We carried out large-scale time-series transcriptome assays covering the major vegetative growth phases of two headingBrassica crops, Chinese cabbage and cabbage, with the non-heading morphotype Taicai as the control. A regulatory transition stage that initiated the heading process is identified, accompanied by a developmental switch from rosette leaf to heading leaf in Chinese cabbages. This transition did not exist in the non-heading control. Moreover, we reveal that the heading transition stage is also conserved in the cabbage clade. Chinese cabbage acquired through domestication a leafy head independently from the origins of heading in other cabbages; phylogenetics supports that the ancestor of all cabbages is non-heading. The launch of the transition stage is closely associated with the ambient temperature. In addition, examination of the biological activities in the transition stage identified the ethylene pathway as particularly active, and we hypothesize that this pathway was targeted for selection for domestication to form the heading trait specifically in Chinese cabbage. In conclusion, our findings on the transcriptome transition that initiated the leaf heading in Chinese cabbage and cabbage provide a new perspective for future studies of leafy head crops.

Association of dietary mineral mixture with depressive symptoms: A combination of Bayesian approaches.

The relationships between mixtures of multiple minerals and depression have not been explored. Therefore, we analyzed the relationship between the mixture of nine dietary minerals [calcium (Ca), phosphorus, magnesium (Mg), iron (Fe), zinc, copper (Cu), sodium, potassium (K), and selenium (Se)] and depressive symptoms in the general population. We screened 20,342 participants from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. We fitted the general linear regression, Bayesian kernel machine regression (BKMR), and Bayesian semiparametric regression models to explore associations and interactions. We obtained the relative importance of dietary minerals by calculating posterior inclusion probabilities (PIPs). The dietary intakes of minerals were obtained using the 24-h dietary recall interview, and depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). The linear analysis showed that nine minerals were negatively associated with PHQ-9 scores. The BKMR analysis showed a negative association between the dietary mineral mixture and PHQ-9 scores, with Se having the largest PIP at 1.0000, followed by K (0.7784). We also observed potential interactions between Ca and Fe, Se and Fe, and K and Mg. Among them, the interaction of Ca and Fe had the largest PIP of 0.986. In addition, the overall effect was more pronounced in females than males, and Cu's PIP (0.8376) was higher in females. Two sensitivity analyses showed that our results were robust. Our study provides a basis for formulating nutritional intervention programs for depression in the future.

The Ameliorative Effect of Berberine on Vascular Calcification by Inhibiting Endoplasmic Reticulum Stress.

ABSTRACT: Vascular calcification (VC), which currently cannot be prevented or treated, is an independent risk factor for cardiovascular events. We aimed to investigate the ameliorative effect of berberine on VC via the activation of Akt signaling and inhibition of endoplasmic reticulum stress (ERS). The VC model was induced by high-dose Vitamin D 3 in rats and beta-glycerophosphate in primary vascular smooth muscle cells of rat aortas, which were evaluated by Alizarin red staining to determine the calcium content and alkaline phosphatase activity. ERS was determined by the levels of GRP78 and CHOP, whereas that of the Akt signaling pathway was determined by the levels of phosphorylated Akt and GSK3ß. VC was significantly ameliorated by berberine treatment in vivo and in vitro, and the inhibition of ERS and the activation of the Akt/GSK3 signaling pathway. In the vascular smooth muscle cells of primary rats, tunicamycin, an ERS activator, blocked the ameliorative effect of berberine on VC and ERS, but not the activation of Akt/GSK3. The ameliorative effects of berberine on VC, ERS, and the Akt signaling pathway were all prevented by inhibitor IV. Four-phenylbutyric acid, an ERS inhibitor, can restore the ameliorative effect of berberine on VC and ERS that was blocked by inhibitor IV. Our results are the first to demonstrate the ameliorative effect of VC that was mediated by the activation of the Akt signaling pathway and inhibition of ERS. These results may provide a new pharmaceutical candidate for the prevention and treatment of VC.

Interventricular septum angle obtained from cardiac computed tomography for origin differentiation of outflow tract ventricular arrhythmia between left and right.

AIMS: Our objective was to explore whether the accuracy of the transitional zone index (TZI) for outflow tract ventricular arrhythmias (OT-VAs) origin is affected by cardiac rotation and the additive value of interventricular septum angle (IVSa) obtained from coronary computed tomography angiography (CCTA). METHODS: Standard 12-lead ECGs of OT-VAs with inferior axis in consecutive patients undergoing both CCTA examination and successful ablation were retrospectively analyzed. The IVSa was defined as an angle between the long axis of IVS and sagittal axis of the body from CCTA. RESULTS: 64 patients (31 men; mean age 54.2 ± 11.6 years) were enrolled. The OT-VAs exhibited right ventricular outflow tract origin in 46 (71.9%) patients and 36 (78.3%) were diagnosed correctly by TZI. The left ventricular outflow tract origin OT-VAs was observed in 18 (28.1%) patients and 16 (88.9%) were diagnosed correctly by TZI. The patients were then divided into TZI correct group (n = 52) and TZI incorrect group (n = 12). In the TZI incorrect group, 11/12 (91.7%) cases were R/S transition in lead V3 with the TZ score during premature ventricular contractions [2.8(2.5-3.4)], and the TZI between -1.5 and 0. The IVSa was significantly larger in the TZI incorrect group than correct group (52.0 ± 6.9° vs. 39.0 ± 6.1°; p < .0001). The IVSa ≥46° predicted TZI incorrect with 92% sensitivity, 94% specificity, and 94% accuracy. CONCLUSION: The IVSa is a novel cardiac rotation index that reliably improves TZI to differentiate the OT-VAs origin, especially for the OT-VAs with lead V3 R/S transition.

Space-variant Shack-Hartmann wavefront sensing based on affine transformation estimation.

The space-variant wavefront reconstruction problem inherently exists in deep tissue imaging. In this paper, we propose a framework of Shack-Hartmann wavefront space-variant sensing with extended source illumination. The space-variant wavefront is modeled as a four-dimensional function where two dimensions are in the spatial domain and two are in the Fourier domain with priors that both gently vary. Here, the affine transformation is used to characterize the wavefront space-variant function. Correspondingly, the zonal and modal methods are both escalated to adapt to four-dimensional representation and reconstruction. Experiments and simulations show double to quadruple improvements in space-variant wavefront reconstruction accuracy compared to the conventional space-invariant correlation method.

Alleviating the Influence of Circadian Rhythms and Drug Properties to the Release of Paliperidone Gel Matrix Tablets with Compression Coating Technology and Microenvironment Shaping.

The influence of circadian rhythms is an important content in oral dosage form study which is shown as different pH conditions and gastrointestinal dynamics in the gastrointestinal tract. The purpose of this study was to alleviate the influence of circadian rhythms and drug properties to the release of gel matrix tablets in vitro and in vivo. In this study, the compression coating technology and microenvironment shaping were utilized to achieve the alleviation of the influence of circadian rhythms and drug properties. The compression coating technology was used to alleviate the influence of gastrointestinal dynamics, and microenvironment shaping was used to alleviate the interference of different pH condition variations. The self-made compression coating tablet could maintain a consistent release rate in different pH conditions and different dynamic environments in vitro for 24 h. In vivo, the pharmacokinetic parameters Cmax and Tmax were 3701.675 ng/mL and 24 h, respectively, and the release effect in vivo was similar to the paliperidone osmotic pump tablet with the ability to alleviate the influence of circadian rhythms. The correlation coefficient R2 was 0.9914 for the self-made paliperidone compression coating tablet in vitro-in vivo correlation. The interference caused by circadian rhythms was alleviated so that the compression coating technology with microenvironment shaping could replace the osmotic pump technology with easier preparation process and cheaper costs in vitro and in vivo and achieve the effect of alleviating the interference of circadian rhythms.

Current innovations in nutraceuticals and functional foods for intervention of non-alcoholic fatty liver disease.

As innovations in global agricultural production and food trading systems lead to major dietary shifts, high morbidity rates from non-alcoholic fatty liver disease (NAFLD), accompanied by elevated risk of lipid metabolism-related complications, has emerged as a growing problem worldwide. Treatment and prevention of NAFLD and chronic liver disease depends on the availability of safe, effective, and diverse therapeutic agents, the development of which is urgently needed. Supported by a growing body of evidence, considerable attention is now focused on interventional approaches that combines nutraceuticals and functional foods. In this review, we summarize the pathological progression of NAFLD and discuss the beneficial effects of nutraceuticals and the active ingredients in functional foods. We also describe the underlying mechanisms of these compounds in the intervention of NAFLD, including their effects on regulation of lipid homeostasis, activation of signaling pathways, and their role in gut microbial community dynamics and the gut-liver axis. In order to identify novel targets for treatment of lipid metabolism-related diseases, this work broadly explores the molecular mechanism linking nutraceuticals and functional foods, host physiology, and gut microbiota. Additionally, the limitations in existing knowledge and promising research areas for development of active interventions and treatments against NAFLD are discussed.

APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling.

The apelin receptor (APLNR) is a GPCR involved in many pathophysiological processes; however, the correlation between APLNR expression and nasopharyngeal carcinoma (NPC) has not been reported. In this study, we used cDNA microarray data to determine APLNR expression levels in NPC tissues. We found that APLNR expression was reduced in NPC tissues compared with noncancerous nasopharyngeal epithelial tissues. Subsequently, a large-scale sample of 1015 tissues was used to validate this discovery and explore the relationship between APLNR expression and prognosis of NPC. Expression levels of APLNR in NPC tissues were indeed down-regulated. Furthermore, positive expression of APLNR in NPC predicted a better prognosis (disease-free survival: P = 0.001; overall survival: P < 0.001). Moreover, ingenuity pathway analysis revealed that an indirect interaction existed between APLNR and retinoic acid (RA) in the cancer regulatory network. Consistently, after treatment with all-trans-RA (ATRA), we found that APLNR was significantly up-regulated in NPC cell lines (5-8F and HNE1), and proliferation of NPC cells was inhibited. Cell cycle arrest occurred in the G0/G1 phase. In contrast, knockdown of APLNR diminished ATRA-induced growth inhibition of NPC cells. In addition, we surprisingly found that APLNR also played an important role in migration and invasion of NPC. Wound-healing and Transwell assays revealed that APLNR overexpression led to reduced migratory and invasive properties in 2 NPC cell lines. Western blot results revealed that hallmarks of epithelial-mesenchymal transition (EMT) were altered as well, suggesting that APLNR was capable of inhibiting EMT in NPC cells. Our study further demonstrated that low expression of APLNR promoted EMT in NPC cells by activating the PI3K-protein kinase B-mammalian target of rapamycin signaling pathway. Taken together, our data suggest that APLNR could potentially predict prognosis for patients with NPC and inhibit proliferation, migration, invasion, and EMT in nasopharyngeal cancer cells.-Liu, Y., Liu, Q., Chen, S., Liu, Y., Huang, Y., Chen, P., Li, X., Gao, G., Xu, K., Fan, S., Zeng, Z., Xiong, W., Tan, M., Li, G., Zhang, W. APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling.

Design, synthesis, and evaluation of novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile compounds as Zika inhibitors.

The prevalence of Zika virus (ZIKV) has become widespread in recent years. ZIKV infection is associated with severe congenital CNS malformations in both newborns and adults. However, neither vaccines nor therapeutics are available to control ZIKV infection until now. We started by hit screening our in-house small molecule library, then designed, synthesized, and evaluated a new class of 1, 4-bibenzylsubstituted piperazine derivatives for their cytopathic effect (CPE) protection effect in a ZIKV-infected Vero E6 cellular assay. A preliminary structure-activity relationship study identified five novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile analogs with obvious CPE reduction effects against ZIKV at micromolar concentrations. Moreover, compound 3p exerted a significant antiviral effect on both Zika RNA replication and virus protein expression in a dose-dependent manner at low micromolar concentrations. This study demonstrated the potential of a novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile scaffold for the development of anti-ZIKV candidates.

Cell permeable HMGB1-binding heptamer peptide ameliorates neurovascular complications associated with thrombolytic therapy in rats with transient ischemic stroke.

BACKGROUND: Blood-brain barrier (BBB) breakdown and inflammatory responses are the major causes of tissue-type plasminogen activator (tPA)-induced hemorrhagic transformation (HT), while high-mobility group box 1 (HMGB1) exacerbates inflammatory damage to BBB during the process of brain ischemia/reperfusion. This study aimed to investigate the change of HMGB1 after thrombolytic therapy and whether blocking HMGB1 could ameliorate the neurovasculature complications secondary to tPA treatment in stroke rats. METHODS: Sera from acute stroke patients and rats with thrombolytic therapy were collected to investigate HMGB1 secretion. Male Sprague-Dawley rats with 2 h or 4.5 h middle cerebral artery occlusion were continuously infused with tPA followed by administration of membrane permeable HMGB1-binding heptamer peptide (HBHP). The mortality rate, neurological score, HT, brain swelling, BBB permeability, and inflammatory factors were determined. RESULTS: The results revealed that HMGB1 levels were elevated in both stroke patients and rats after tPA treatment. Blocking HMGB1 signaling by HBHP in the rat model of 4.5 h brain ischemia significantly attenuated tPA-related complications, including mortality rate, the degree of hemorrhage, brain swelling, neurological deficits, BBB impairment, microglia activation, and the expressions of inflammatory cytokines. CONCLUSIONS: tPA treatment might induce HMGB1 secretion while blocking HMGB1 with HBHP could markedly reduce the risk of thrombolysis-associated brain hemorrhage and mortality through attenuating BBB damage and inflammatory reactions. These results indicate that HMGB1 may potentiate the risk of HT in tPA administration and that blocking HMGB1 signaling would be helpful in preventing complications brought by thrombolysis in ischemic stroke. TRIAL REGISTRATION: http://www.chictr.org.cn . Unique identifier: ChiCTR-OOC-16010052. Registered 30 November 2016.

A comparative analysis of human plasma and serum proteins by combining native PAGE, whole-gel slicing and quantitative LC-MS/MS: Utilizing native MS-electropherograms in proteomic analysis for discovering structure and interaction-correlated differences.

MS identification has long been used for PAGE-separated protein bands, but global and systematic quantitation utilizing MS after PAGE has remained rare and not been reported for native PAGE. Here we reported on a new method combining native PAGE, whole-gel slicing and quantitative LC-MS/MS, aiming at comparative analysis on not only abundance, but also structures and interactions of proteins. A pair of human plasma and serum samples were used as test samples and separated on a native PAGE gel. Six lanes of each sample were cut, each lane was further sliced into thirty-five 1.1 mm × 1.1 mm squares and all the squares were subjected to standardized procedures of in-gel digestion and quantitative LC-MS/MS. The results comprised 958 data rows that each contained abundance values of a protein detected in one square in eleven gel lanes (one plasma lane excluded). The data were evaluated to have satisfactory reproducibility of assignment and quantitation. Totally 315 proteins were assigned, with each protein assigned in 1-28 squares. The abundance distributions in the plasma and serum gel lanes were reconstructed for each protein, named as "native MS-electropherograms". Comparison of the electropherograms revealed significant plasma-versus-serum differences on 33 proteins in 87 squares (fold difference > 2 or < 0.5, p < 0.05). Many of the differences matched with accumulated knowledge on protein interactions and proteolysis involved in blood coagulation, complement and wound healing processes. We expect this method would be useful to provide more comprehensive information in comparative proteomic analysis, on both quantities and structures/interactions.

Analysis of low-density lipoprotein-associated proteins using the method of digitized native protein mapping.

The method of digitized native protein mapping, combining nondenaturing micro 2DE, grid gel-cutting, and quantitative LC-MS/MS (in data-independent acquisition mode, or MS(E) ), was improved by using a new MS/MS mode, ion mobility separation enhanced-MS(E) (HDMS(E) ), and applied to analyze the area of human plasma low-density lipoprotein (LDL). An 18 mm × 4.8 mm rectangular area which included LDL on a nondenaturing micro 2D gel of human plasma was grid-cut into 72 square gel pieces and subjected to quantitative LC-MS/MS. Compared with MS(E) , HDMS(E) showed significantly higher performance, by assigning 50% more proteins and detecting each protein in more squares. A total of 253 proteins were assigned with LC-HDMS(E) and the quantity distribution of each was reconstructed as a native protein map. The maps showed that Apo B-100 was the most abundant protein in the grid-cut area, concentrated at pI ca. 5.4-6.1 and apparent mass ca. 1000 kDa, which corresponded to four gel pieces, squares 39-42. An Excel macro was prepared to search protein maps which showed protein quantity peaks localized within this concentrated region of Apo B-100. Twenty-two proteins out of the 252 matched this criterion, in which 19 proteins have been reported to be associated with LDL. This method only requires several microliters of a plasma sample and the principle of the protein separation is totally different from the commonly used ultracentrifugation. The results obtained by this method would provide new insights on the structure and function of LDL.

Global mapping of rat plasma proteins with a native proteomic approach using nondenaturing micro 2DE and quantitative LC-MS/MS.

Plasma samples from adult male rats were separated by nondenaturing micro 2DE and a reference gel was selected, on which 136 CBB-stained spots were numbered and subjected to in-gel digestion and quantitative LC-MS/MS. The analysis provided the assignment of 1-25 (average eight) non-redundant proteins in each spot and totally 199 proteins were assigned in the 136 spots. About 40% of the proteins were detected in more than one spot and 15% in more than ten spots. We speculate this complexity arose from multiple causes, including protein heterogeneity, overlapping of protein locations and formation of protein complexes. Consequently, such results could not be appropriately presented as a conventional 2DE map, i.e. a list or a gel pattern with one or a few proteins annotated to each spot. Therefore, the LC-MS/MS quantity data was used to reconstruct the gel distribution of each protein and a library containing 199 native protein maps was established for rat plasma. Since proteins that formed a complex would migrate together during the nondenaturing 2DE and thus show similar gel distributions, correlation analysis was attempted for similarity comparison between the maps. The protein pairs showing high correlation coefficients included some well-known complexes, suggesting the promising application of native protein mapping for interaction analysis. With the importance of rat as the most commonly used laboratory animal in biomedical research, we expect this work would facilitate relevant studies by providing not only a reference library of rat plasma protein maps but a means for functional and interaction analysis.

An association study of TOLL and CARD with leprosy susceptibility in Chinese population.

Previous genome-wide association studies (GWASs) identified multiple susceptibility loci that have highlighted the important role of TLR (Toll-like receptor) and CARD (caspase recruitment domain) genes in leprosy. A large three-stage candidate gene-based association study of 30 TLR and 47 CARD genes was performed in the leprosy samples of Chinese Han. Of 4363 SNPs investigated, eight SNPs showed suggestive association (P < 0.01) in our previously published GWAS datasets (Stage 1). Of the eight SNPs, rs2735591 and rs4889841 showed significant association (P < 0.001) in an independent series of 1504 cases and 1502 controls (Stage 2), but only rs2735591 (next to BCL10) showed significant association in the second independent series of 938 cases and 5827 controls (Stage 3). Rs2735591 showed consistent association across the three stages (P > 0.05 for heterogeneity test), significant association in the combined validation samples (Pcorrected = 5.54 × 10(-4) after correction for 4363 SNPs tested) and genome-wide significance in the whole GWAS and validation samples (P = 1.03 × 10(-9), OR = 1.24). In addition, we demonstrated the lower expression of BCL10 in leprosy lesions than normal skins and a significant gene connection between BCL10 and the eight previously identified leprosy loci that are associated with NFκB, a major regulator of downstream inflammatory responses, which provides further biological evidence for the association. We have discovered a novel susceptibility locus on 1p22, which implicates BCL10 as a new susceptibility gene for leprosy. Our finding highlights the important role of both innate and adaptive immune responses in leprosy.

Identification of IL18RAP/IL18R1 and IL12B as leprosy risk genes demonstrates shared pathogenesis between inflammation and infectious diseases.

Of eight leprosy susceptibility loci identified by genome-wide association studies, five have been implicated in Crohn disease, suggesting a common genetic fingerprint between leprosy and inflammatory bowel disease (IBD). Here, we conducted a multiple-stage genetic association study of 133 IBD susceptibility loci in multiple leprosy samples (totaling 4,971 leprosy cases and 5,503 controls) from a Chinese population and discovered two associations at rs2058660 on 2q12.1 (p = 4.57 × 10(-19); odds ratio [OR] = 1.30) and rs6871626 on 5q33.3 (p = 3.95 × 10(-18); OR = 0.75), implicating IL18RAP/IL18R1 and IL12B as susceptibility genes for leprosy. Our study reveals the important role of IL12/IL18-mediated transcriptional regulation of IFN-γ production in leprosy, and together with previous findings, it demonstrates the shared genetic susceptibility between infectious and inflammatory diseases.

Critical gene signature and immunological characterization in peripheral vascular atherosclerosis: novel insights from mendelian randomization and transcriptomics.

Introduction: Peripheral vascular atherosclerosis (PVA) is a chronic inflammatory disease characterized by lipid accumulation in blood vessel walls, leading to vessel narrowing and inadequate blood supply. However, the molecular mechanisms underlying PVA remain poorly understood. In this study, we employed a combination of Mendelian randomization (MR) analysis and integrated transcriptomics to identify the critical gene signature associated with PVA. Methods: This study utilized three public datasets (GSE43292, GSE100927 and GSE28829) related to peripheral vascular atherosclerosis obtained from the Gene Expression Omnibus database. Instrumental variables (IVs) were identified through expression quantitative trait loci (eQTL) analysis, and two-sample MR analysis was performed using publicly available summary statistics. Disease critical genes were identified based on odds ratios and intersected with differentially expressed genes in the disease dataset. GSE28829 dataset was used to validate the screened disease critical genes. Functional enrichment analysis, GSEA analysis, and immune cell infiltration analysis were performed to further characterize the role of these genes in peripheral vascular atherosclerosis. Results: A total of 26,152 gene-related SNPs were identified as IVs, and 242 disease-associated genes were identified through MR analysis. Ten disease critical genes (ARHGAP25, HCLS1, HVCN1, RBM47, LILRB1, PLAU, IFI44L, IL1B, IFI6, and CFL2) were significantly associated with peripheral vascular atherosclerosis. Functional enrichment analysis using KEGG pathways revealed enrichment in the NF-kappa B signaling pathway and osteoclast differentiation. Gene set enrichment analysis further demonstrated functional enrichment of these genes in processes related to vascular functions and immune system activation. Additionally, immune cell infiltration analysis showed differential ratios of B cells and mast cells between the disease and control groups. The correlations analysis highlights the intricate interplay between disease critical genes and immune cells associated with PVA. Conclusion: In conclusion, this study provides new insights into the molecular mechanisms underlying PVA by identifying ten disease critical genes associated with the disease. These findings, supported by differential expression, functional enrichment, and immune system involvement, emphasize the role of these genes in vascular function and immune cell interactions in the context of PVA. These findings contribute to a better understanding of PVA pathogenesis and offer potential targets for further mechanistic exploration and therapeutic interventions.