👤 K Song

The development of a broad repertoire of T cells in the immune system requires interaction of T cell receptors expressed by immature T cells with peptide/major histocompatibility complexes (MHCs) displayed by specialized epithelial cells in the thymus, in a process called T cell positive selection. Thymic epithelial cells (TECs) display unique antigen processing machinery which shapes the collection of self-peptides that drive positive selection. In our recent studies, we explored the contribution of the lipid kinase PIK3C3/VPS34 to the generation of positively selecting peptides in TECs. We found that TEC-specific PIK3C3/VPS34 facilitates the positive selection of CD4 but not CD8 T lineage cells, in a mechanism independent of its role in canonical macroautophagy/autophagy. Instead, we propose that PIK3C3/VPS34 alters vesicle trafficking in TECs that modulates lysosomal protease activity which, in turn, controls the generation of MHC class II-presented peptides optimized for positive selection of CD4 T cells. Show less

miRNA is a noncoding RNA found in recent years and more than one third of human genes are the target of miRNAs. miR-624, located on human chromosome 14, is associated with tumorigenesis. However, the role of miR-624 in human hepatocarcinogenesis is still unclear. Herein, our results indicate that miR-624 accelerates the growth of liver cancer cells Show less

Extravillous trophoblast (EVT) cell invasion is a tightly regulated process that requires for a normal pregnancy. The epithelial-mesenchymal transition (EMT) has been implicated in EVT cell invasion. Growth differentiation factor-8 (GDF-8), a member of the transforming growth factor-beta (TGF-β) superfamily, is expressed in the human placenta and promotes EVT cell invasion by upregulating the expression of matrix metalloproteinase 2 (MMP2). However, the underlying molecular mechanism of GDF-8-induced MMP2 expression remains undetermined. Therefore, the present study aims to examine the role of Snail and Slug, the EMT-related transcriptional regulators, in GDF-8-stimulated MMP2 expression and cell invasion in HTR-8/SVneo human EVT cell line and primary cultures of human EVT cells. HTR-8/SVneo and primary cultures of human EVT cells were used to examine the effect of GDF-8 on MMP2 expression and explore the underlying mechanism. For gene silencing and overexpression, the HTR-8/SVneo cell line was used to make the experiments more technically feasible. The cell invasiveness was measured by Matrigel-coated transwell invasion assay. GDF-8 stimulated MMP2 expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effect of GDF-8 on MMP2 expression was blocked by the inhibitor of TGF-β type-I receptors, SB431542. Treatment with GDF-8 upregulated Snail and Slug expression in both HTR-8/SVneo and primary EVT cells. The stimulatory effects of GDF-8 on Snail and Slug expression were blocked by pretreatment of SB431542 and siRNA-mediated knockdown of SMAD4. Interestingly, using the siRNA knockdown approach, our results showed that Snail but not Slug was required for the GDF-8-induced MMP2 expression and cell invasion in HTR-8/SVneo cells. The reduction of MMP2 expression in the placentas with preeclampsia (PE) was also observed. These findings discover the physiological function of GDF-8 in the human placenta and provide important insights into the regulation of MMP2 expression in human EVT cells. Video Abstract. Show less

The Melanocortin-3 receptor (MC3R) and Melanocortin-4 receptor (MC4R), two members of the key hypothalamic neuropeptide signaling, function as complex mediators to control the central appetitive and energy homeostasis. The melanocortin 2 receptor accessory protein 2 (MRAP2) is well-known for its modulation on the trafficking and signaling of MC3R and MC4R in mammals. In this study, we cloned and elucidated the pharmacological profiles of MRAP2 on the regulation of central melanocortin signaling in a relatively primitive poikilotherm amphibian species, the Mexican axolotl ( Show less

The most common and deadly subtype of renal carcinoma is kidney renal clear cell carcinoma (KIRC), which accounts for approximately 75% of renal carcinoma. However, the main cause of death in KIRC patients is tumor metastasis. There are no obvious clinical features in the early stage of kidney cancer, and 25-30% of patients have already metastasized when they are first diagnosed. Moreover, KIRC patients whose local tumors have been removed by nephrectomy are still at high risk of metastasis and recurrence and are not sensitive to chemotherapy and radiotherapy, leading to poor prognosis. Therefore, early diagnosis and treatment of this disease are very important. KIRC-related patient datasets were downloaded from the GEO database and TCGA database. DEG screening and GO, KEGG and GSEA enrichment analysis was firstly conducted and then the LASSO and support vector machine (SVM) RFE algorithms were adopted to identify KIRC-associated key genes in training sets and validate them in the test set. The clinical prognostic analysis including the association between the expression of key genes and the overall survival, stage, grade across KIRC, the immune infiltration difference between normal samples and cancer samples, the correlation between the key genes and immune cells, immunomodulator, immune subtypes of KIRC were investigated in this research. We finally screened out 4 key genes, including ACPP, ANGPTL4, SCNN1G, SLC22A7. The expression of key genes show difference among normal samples and tumor samples, SCNN1G and SLC22A7 could be predictor of prognosis of patients. The expression of key genes was related with the abundance of tumor infiltration immune cells and the gene expression of immune checkpoint. This study screened the 4 key genes, which contributed to early diagnosis, prognosis assessment and immune target treatment of patients with KIRC. Show less

Small bowel adenocarcinoma (SBA) is a gastrointestinal malignancy with low incidence but poor prognosis, and its pathogenesis is still unclear. This study aimed to explore potential disease-causing biomarkers of SBA. The gene expression datasets of SBA and normal samples were downloaded from the Gene Expression Omnibus database. First, differential gene expression analysis and weighted gene coexpression network analysis (WGCNA) were performed. Common genes (CGs) were obtained by intersection of differentially expressed genes (DEGs) and optimal modal genes of WGCNA. Subsequently, a protein‒protein interaction network was established to screen hub genes, and target genes were obtained by Lasso regression analysis of hub genes. An SBA risk prediction model was established based on target genes. The prediction accuracy of the model was evaluated by the area under the receiver operating characteristic curve (AUC). The levels of immune cell infiltration and activation of immune pathways were compared between SBA and normal samples using the "ggpubr" and "reshape2" packages. A total of 1058 DEGs were identified. WGCNA showed that the signature gene in the brown module was significantly associated with SBA (p = 7E-17), and 469 CGs were obtained. Four target genes (APOA4, APOB, COL1A2, FN1) were identified and showed excellent prediction of SBA risk (AUC = 0.965). In addition, active dendritic cells and macrophages showed higher infiltration levels in SBA. Meanwhile, the APC_co_stimulation pathway and parainflammation pathway were strongly active in SBA. Four target genes (APOA4, APOB, COL1A2, FN1) may be involved in the pathogenesis of small bowel adenocarcinoma. Show less

Recently, clinical trials of adeno-associated virus-mediated replacement therapy have suggested long-term therapeutic effects for several genetic diseases of the liver, including hemophilia. However, there remain concerns regarding decreased therapeutic effects when the liver is regenerated or when physiological proliferation occurs. Although genome editing using the clustered regularly interspaced short palindromic repeats/Cas9 system provides an opportunity to solve this problem, low knock-in efficiency may limit its application for therapeutically relevant expression. Here, we identified a novel gene, Show less

Adipogenesis is a complex process controlled by intrinsic and extrinsic factors that regulate preadipocyte proliferation, adipogenic capacity and maturation of metabolic function. Here we show that insulin and IGF-1 receptors are essential for mature adipocyte survival and that deletion of both IR and IGF1R specifically in fat using a tamoxifen inducible-AdipoQ-Cre (Ai-DKO) leads to rapid and severe loss of adipocytes in all depots, associated with a metabolic syndrome characterized by hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver, and pancreatic beta cell proliferation. In this model, this pathological phenotype reverses over a few weeks, in large part, due to preadipocyte proliferation and adipose tissue regeneration. Incubation of preadipocytes with serum from the Ai-DKO mice in vitro stimulates cell proliferation, and this effect can be mimicked by conditioned media from liver slices of Ai-DKO mice, but not by media of cultured Ai-DKO adipocytes, indicating a hepatic origin of the growth factor. Proteomic analysis of serum reveals apolipoprotein C3 (APOC3), a protein secreted by liver, as one of the most upregulated proteins in the Ai-DKO mice. In vitro, purified and delipidated APOC3 stimulates preadipocyte proliferation, however, knockdown of hepatic APOC3 in vivo in Ai-DKO mice is not sufficient to block adipose regeneration. Thus, lipodystrophy is associated with presence of increased preadipocyte-stimulating growth factors in serum. Our study indicates that APOC3 is one contributing factor to preadipocyte proliferation, however, other still-unidentified circulating growth factors are also likely present in Ai-DKO mice. Identification of these factors may provide a new approach to regulation of adipose mass in health and disease. Show less

Breast cancer is the most common malignancy among women across the globe. Recent studies have revealed that many long non-coding RNAs (lncRNAs) regulate the Wnt/β-catenin signaling pathway in several types of cancer. Hyperactivation of the Wnt/β-catenin pathway has been extensively presented in breast cancer and is involved in breast cancer progression. However, the underlying molecular mechanism remains elusive. In the current study, we found lncRNA RBM5-AS1 was remarkably upregulated in breast cancer cells and tissues. Overexpression of RBM5-AS1 facilitated proliferation, migration, invasion, EMT, and stemness maintenance of breast cancer cells in vitro and in vivo. Mechanism studies suggested that RBM5-AS1 could be transcriptionally activated by hypoxia-induced RUNX2. Upregulated RBM5-AS1 further activated the Wnt/β-catenin signaling by preventing β-catenin degradation and by helping organize β-catenin-TCF4 transcriptional complex. These findings suggested that RBM5-AS1, a regulator of Wnt/β-catenin signaling, plays a vital role in breast cancer initiation and progression, implicating its potential as a new target for breast cancer treatment. Show less

Triple ionic and electronic conductivity (TIEC) in cathode materials for protonic ceramic fuel cells (PCFCs) is a desirable feature that enhances the spatial expansion of active reaction sites for electrochemical oxygen reduction reaction. The realization of optimal TIEC in single-phase materials, however, is challenging. A facile route that facilitates the optimization of TIEC in PCFC cathodes is the strategic development of multiphase cathode materials. In this study, a cubic-rhombohedral TIEC nanocomposite material with the composition Ba(CeCo) Show less

Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumin, a major ingredient of traditional Chinese medicine, Curcuma Longa, has various pharmacological activities. Therefore, exploring clinical drugs based on the inhibition of AD pathological features is imperative. First, we utilized the HERB database and Swisstarget Prediction database to get the related targets of curcumin and intersected with the AD targets. The intersection targets were used to construct the protein-protein interaction network and performed gene ontology and kyoto encyclopedia of genes and genomes analyses. Further, we obtained targets of curcumin against AD-related tau and aβ pathology via the AlzData database. These targets were applied to perform GEO and receiver operating characteristic analyses. Finally, the reliability of the core targets was evaluated using molecular docking technology. We identified 49 targets of curcumin against AD, and kyoto encyclopedia of genes and genomes pathway enrichment analysis demonstrated that the Alzheimer disease pathway (has05010) was significantly enriched. Even more, we obtained 16 targets of curcumin-related Aβ and tau pathology. Among these targets, 8 targets involved the Alzheimer disease pathway and the biological process analyses showed that positive regulation of cytokine production (GO:0001819) was significantly enriched. Bioinformatic analyses indicated that HMOX1, CSF1R, NFKB1, GSK3B, BACE1, AR, or PTGS1 expression was significantly different compared to the control group in the AD patients. Finally, molecular docking studies suggested these genes have a good binding force with curcumin. In this study, we identified curcumin exerted the effect of treating AD by regulating multitargets and multichannels through the method of network pharmacology. Show less

The deposition of β-amyloid (Aβ) in the brain plays a major role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated via amyloid precursor protein (APP) cleavage through the amyloidogenic pathway. In this pathway, β-secretase (BACE1) is the first and rate-limiting enzyme. Its expression increases through an unknown mechanism in patients with AD. Thus, the key regulatory mechanism of BACE1 in the AD process should be revealed to understand the pathogenesis of AD and explore the key treatment targets of AD. Here, APPswe/PS1dE9 (APP/PS1) mice were employed to observe the Krüppel-like factor 5 (KLF5) and BACE1 levels in the serum and brain tissues. HT22 cells were used to explore the relationship between KLF5 and BACE1. In this study, KLF5 was found to be a novel transcription factor that positively regulated BACE1 by binding to the BACE1 promoter. The KLF5 levels significantly increased not only in the CSF and serum of patients with AD but also in the brain tissue of APP/PS1 mice. They were closely related to cognitive capacity. KLF5 accelerated APP amyloidogenic metabolism and promoted Aβ synthesis through BACE1. Silencing BACE1 could block the KLF5-induced amyloidogenic process of APP. ML264 ameliorated the cognitive deficits and slowed down APP amyloidogenic cleavage in APP/PS1 mice. The findings above suggest that upregulation of KLF5 might be a critical element in AD progression by accelerating BACE1-mediated APP amyloidogenic cleavage. The inhibition of KLF5 or the combined inhibitory effect of KLF5 and the BACE1 promoter might be a potential strategy to prevent AD pathogenesis. Show less

Alzheimer's disease (AD) causes progressive decline of memory and cognitive deficits. Because of its complicated pathogenesis, the prevention and therapy of AD remain an enormous challenge. It has been reported that catalpol possessed neuroprotective effects against AD. However, the involved mechanism still needs to be intensively studied. Therefore, the effects of catalpol on N2a/APP695swe cells and APP/PS1 mice were identified in the current study. Catalpol could improve cytotoxicity according to CCK-8 assay and ameliorate cellular morphological changes in N2a/APP695swe cells. Neuronal structural damage in the hippocampal CA1 region of APP/PS1 AD mice was improved according to HE staining and immunohistochemistry of NeuN. Meanwhile, catalpol administration ameliorated cognitive deficits confirmed by behavior performance of APP/PS1 mice. Hoechst 33,342 staining and Annexin V-FITC/PI double staining demonstrated that catalpol could reduce apoptosis in N2a/APP695swe cells. Likewise, TUNEL staining also manifested that catalpol significantly reduced apoptosis in hippocampal CA1 region of APP/PS1 mice. Catalpol administration also could improve mitochondrial functions indicated by the ameliorative mitochondrial morphology, the decreased ROS generation, and the increased MMP in N2a/APP695swe cells. Subsequently, catalpol restrained oligomerization of Aβ Show less

The integration of metabolomics and transcriptomics may elucidate the correlation between the genotypic and phenotypic patterns in organisms. In equine physiology, various metabolite levels vary during exercise, which may be correlated with a modified gene expression pattern of related genes. Integrated metabolomic and transcriptomic studies in horses have not been conducted to date. The objective of this study was to detect the effect of moderate exercise on the metabolomic and transcriptomic levels in horses. In this study, using nuclear magnetic resonance (NMR) spectroscopy, we analyzed the concentrations of metabolites in muscle and plasma; we also determined the gene expression patterns of branched chain (alpha) keto acid dehydrogenase kinase complex ( Show less

Choline has been shown to exert atherogenic effects in Apoe Female APOE*3-Leiden.CETP mice were fed an atherogenic diet alone or supplemented with choline, butyrate or their combination for 16 weeks. Interestingly, choline protected against fat mass gain, increased the abundance of anti-inflammatory gut microbes, and increased the expression of gut microbial genes involved in TMA and TMAO degradation. Butyrate similarly attenuated fat mass gain and beneficially modulated the gut microbiome, as shown by increased abundance of anti-inflammatory and short chain fatty acid-producing microbes, and inhibited expression of gut microbial genes involved in lipopolysaccharide synthesis. Both choline and butyrate upregulated hepatic expression of flavin-containing monooxygenases, and their combination resulted in highest circulating TMAO levels. Nonetheless, choline, butyrate and their combination did not influence atherosclerosis development, and TMAO levels were not associated with atherosclerotic lesion size. While choline and butyrate have been reported to oppositely modulate atherosclerosis development in Apoe Show less

To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of GAgP group and control group was (27.5±5.2) years and (28.8±7.1) years respectively. There was significant difference in age between the two groups ( Show less

Idiopathic pulmonary fibrosis (IPF) is characterized by lung scarring and has no effective treatment. Fibroblast-to-myofibroblast differentiation and myofibroblast proliferation and migration are major clinical manifestations of this disease; hence, blocking these processes is a practical treatment strategy. Here, highly upregulated Show less

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a hub of the cholinergic anti-inflammatory pathway (CAP), is required for the treatment of inflammatory diseases. HIV-1 infection can upregulate the expression of α7 nAChR in T lymphocytes and affect the role of CAP. However, whether α7 nAChR regulates HIV-1 infection in CD4 Show less

Skin cutaneous melanoma (SKCM) is an extremely metastatic form of skin cancer. However, there are few valuable molecular biomarkers, and accurate diagnosis is still a challenge. Hypercoagulable state encourages the infiltration and development of tumor cells and is significantly associated with poor prognosis in cancer patients. However, the use of a coagulation-related gene (CRG) signature for prognosis in SKCM, on the other hand, has yet to be determined. We used data from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases to identify differentially expressed CRGs, then designed a prognostic model by using the LASSO algorithm, univariate and multivariate Cox regression analysis, and constructed a nomogram which was evaluated by calibration curves. Moreover, the Gene Expression Omnibus (GEO), GSE54467 was used as an independent validation. The correlation between risk score and clinicopathological characteristics, tumor microenvironment (TME), and immunotherapy was further analyzed. To develop a prognostic model, seven CRGs in SKCM patients related to overall survival (OS) were selected: ANG, C1QA, CFB, DUSP6, KLKB1, MMP7, and RABIF. According to the Kaplan-Meier survival analysis, an increased OS was observed in the low-risk group than in the high-risk group (P<0.05). Immunotherapy was much more beneficial in the low-risk group, as per immune infiltration, functional enrichment, and immunotherapy analysis. The prognosis of SKCM patients may now be predicted with the use of a CRG prognostic model, thus guiding the development of treatment plans for SKCM patients and promoting OS rates. Show less

The endothelial glycocalyx regulates vascular permeability, inflammation, and coagulation, and acts as a mechanosensor. The loss of glycocalyx can cause endothelial injury and contribute to several microvascular complications and, therefore, may promote diabetic retinopathy. Studies have shown a partial loss of retinal glycocalyx in diabetes, but with few molecular details of the changes in glycosaminoglycan (GAG) composition. Therefore, the purpose of our study was to investigate the effect of hyperglycemia on GAGs of the retinal endothelial glycocalyx. GAGs were isolated from rat retinal microvascular endothelial cells (RRMECs), media, and retinas, followed by liquid chromatography-mass spectrometry assays. Quantitative real-time polymerase chain reaction was used to study mRNA transcripts of the enzymes involved in GAG biosynthesis. Hyperglycemia significantly increased the shedding of heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA). There were no changes to the levels of HS in RRMEC monolayers grown in high-glucose media, but the levels of CS and HA decreased dramatically. Similarly, while HA decreased in the retinas of diabetic rats, the total GAG and CS levels increased. Hyperglycemia in RRMECs caused a significant increase in the mRNA levels of the enzymes involved in GAG biosynthesis (including EXTL-1,2,3, EXT-1,2, ChSY-1,3, and HAS-2,3), with these increases potentially being compensatory responses to overall glycocalyx loss. Both RRMECs and retinas of diabetic rats exhibited glucose-induced alterations in the disaccharide compositions and sulfation of HS and CS, with the changes in sulfation including N,6-O-sulfation on HS and 4-O-sulfation on CS. Show less

The single nucleotide polymorphisms (SNPs) in the fatty acid desaturases and elongases might associate with the endogenous synthesis of polyunsaturated fatty acids (PUFAs). However, the related epidemiological evidence is still conflicting. So we aimed to clearly evaluate the interactions between maternal DHA-rich n-3 PUFAs supplementation and the known 26 SNPs on the profiles of PUFAs in the colostrum using a Chinese birth cohort. Totally, 1050 healthy mother-infant pairs were enrolled in this study at gestational 6-8 weeks when they established their pregnancy files at Fuxing Hospital affiliated to Capital Medical University in Beijing from January to December 2018. Meanwhile, their venous blood samples were obtained for DNA extraction to detect the genotypes of SNPs in the Fads1, Fads2, Fads3, Elovl2 and Elovl5 using the Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry. Then the colostrum samples were collected to determine the profiles of PUFAs by gas chromatography. Maternal DHA-rich n-3 PUFAs supplementation from the early and middle pregnancy could reduce the infant BMI at birth, and impact the profiles of PUFAs in the colostrum, as higher n-3 PUFAs (EPA, DHA, DHA/ALA and DHA/EPA), lower n-6 PUFAs (AA and AA/LA) and ∑-6/n-3ΣPUFAs. Moreover, there were significant correlations between multiple SNPs and the profiles of n-6 PUFAs (rs76996928 for LA, rs174550, rs174553 and rs174609 for AA, rs174550 and rs76996928 for AA/LA) and n-3 PUFAs in the colostrum (rs174448, rs174537, rs174550, rs174553, rs174598, rs3168072, rs174455 and rs174464 for ALA, rs174550, rs174553 and rs174598 for EPA, rs174455 and rs174464 for DHA, rs174448 and rs3168072 for DHA/EPA) using the multiple linear regressions by adjusting the maternal age, gestational week, mode of delivery, infant sex and BMI at birth, and all these above significant SNPs had the cumulative effects on the profiles of PUFAs. Furthermore, the pairwise comparisons also showed the meaningful interactions between maternal DHA-rich n-3 PUFAs supplementation and related genotypes of SNPs (rs76996928 for LA, rs174598 for EPA, rs174448 for DHA and DHA/EPA) on the contents of PUFAs in the colostrum. Results from this birth cohort study proved that the pregnant women with the following SNPs such as Fads3 rs174455 T, Fads3 rs174464 A and Fads1 rs174448 G alleles should pay more attention on their exogenous DHA supplementation from the early and middle pregnancy for the blocked endogenous synthesis. This study was approved by the Ethics Committee of Beijing Pediatric Research Institution, Beijing Children's Hospital affiliated to Capital Medical University (2016-08), which was also registered at the website of http://www.chictr.org.cn/showproj.aspx?proj=4673 (No: ChiCTR-OCH-14004900). Show less

The effects of inflammation on post-stroke cognitive function are still unclear. This study investigated the correlation between the Th17-related cytokines in peripheral blood and post-stroke cognitive function after ischemic stroke in the subacute phase. A retrospective cohort study. Academic acute inpatient rehabilitation facility. One hundred and fourteen patients with first ischemic stroke were categorized as the poor cognitive recovery group ( All subjects received routine physical, occupational, and speech-language pathology therapy. Serum cytokines/chemokine (IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-17E, IL-17F, IL-21, IL-22, IL-23, IL-27, IL-28A, IL-31, IL-33, GM-CSF, IFN-γ, MIP-3 α, TNF-α, and TNF-β) levels were measured in duplicate using Human Th17 magnetic bead panel and multiplex array analysis (Luminex-200 system). The primary functional outcome was a gain in functional independence measure (FIM) cognitive subscore at discharge. The secondary outcome measures were FIM total score at discharge, length of stay in the hospital, and discharge destination. Cognitive Montebello Rehabilitation Factor Score (MRFS) and cognitive MRFS efficiency were calculated. Demographic and clinical characteristics were obtained from the medical record. The good cognitive recovery group had an interesting trend of higher IL-13 than the poor cognitive recovery group (good cognitive recovery group 257.82 ± 268.76 vs. poor cognitive recovery group 191.67 ± 201.82, Our preliminary findings suggested that the level of serum cytokines had minimal predictive value for the recovery of cognitive function during the subacute inpatient rehabilitation after stroke. Show less

Genome-wide association studies (GWAS) of Crohn's disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10-11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = -0.40[0.13], P = 2.6 × 10-3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli. Show less

IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. Here, we show that the activation of mast cells is negatively regulated by IL-27 signaling. We found that mice lacking IL-27Rα (WSX-1) displayed increased sensitivity to IgE-mediated skin allergic response and chronic airway inflammation. The bone marrow-derived mast cells (BMMCs) of IL-27Rα-deficient mouse showed greater high-affinity receptor Fc epsilon RI (FcεRI)-mediated activation with significantly enhanced degranulation and cytokine production. Mechanistically, the dysregulated signaling in IL-27Rα Show less

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1 Show less

Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases. Show less