Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity.

Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.

Molecular mechanisms underlying gene regulatory variation of maize metabolic traits.

Variation in gene expression levels is pervasive among individuals and races or varieties, and has substantial agronomic consequences, for example, by contributing to hybrid vigor. Gene expression level variation results from mutations in regulatory sequences (cis) and/or transcription factor (TF) activity (trans), but the mechanisms underlying cis and/or trans-regulatory variation of complex phenotypes remain largely unknown. Here, we investigated gene expression variation mechanisms underlying the differential accumulation of the insecticidal compounds maysin and chlorogenic acid in silks of two widely used maize (Zea mays) inbreds, B73 and A632. By combining transcriptomics and cistromics, we identified 1,338 silk direct targets of the maize R2R3-MYB TF Pericarp color1 (P1), consistent with it being a regulator of maysin and chlorogenic acid biosynthesis. Among these P1 targets, 464 showed allele-specific expression (ASE) between B73 and A632 silks. Allelic DNA-affinity purification sequencing identified 34 examples in which P1 allelic specific binding (ASB) correlated with cis-expression variation. From previous yeast one-hybrid studies, we identified nine TFs potentially implicated in the control of P1 targets, with ASB to 83 out of 464 ASE genes (cis) and differential expression of 4 out of 9 TFs between B73 and A632 silks (trans). These results provide a molecular framework for understanding universal mechanisms underlying natural variation of gene expression levels, and how the regulation of metabolic diversity is established.

Chemical interference with DSIF complex formation lowers synthesis of mutant huntingtin gene products and curtails mutant phenotypes.

Earlier work has shown that siRNA-mediated reduction of the SUPT4H or SUPT5H proteins, which interact to form the DSIF complex and facilitate transcript elongation by RNA polymerase II (RNAPII), can decrease expression of mutant gene alleles containing nucleotide repeat expansions differentially. Using luminescence and fluorescence assays, we identified chemical compounds that interfere with the SUPT4H-SUPT5H interaction and then investigated their effects on synthesis of mRNA and protein encoded by mutant alleles containing repeat expansions in the huntingtin gene (HTT), which causes the inherited neurodegenerative disorder, Huntington's Disease (HD). Here we report that such chemical interference can differentially affect expression of HTT mutant alleles, and that a prototypical chemical, 6-azauridine (6-AZA), that targets the SUPT4H-SUPT5H interaction can modify the biological response to mutant HTT gene expression. Selective and dose-dependent effects of 6-AZA on expression of HTT alleles containing nucleotide repeat expansions were seen in multiple types of cells cultured in vitro, and in a Drosophila melanogaster animal model for HD. Lowering of mutant HD protein and mitigation of the Drosophila "rough eye" phenotype associated with degeneration of photoreceptor neurons in vivo were observed. Our findings indicate that chemical interference with DSIF complex formation can decrease biochemical and phenotypic effects of nucleotide repeat expansions.

Genetic associations between bipolar disorder and brain structural phenotypes.

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

Risk factors for positive resection margins after endoscopic resection for gastrointestinal neuroendocrine tumors.

BACKGROUND: In recent years, the incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has remarkably increased due to the widespread use of screening gastrointestinal endoscopy. Currently, the most common treatments are surgery and endoscopic resection. Compared to surgery, endoscopic resection possesses a higher risk of resection margin residues for the treatment of GI-NETs. METHODS: A total of 315 patients who underwent surgery or endoscopic resection for GI-NETs were included. We analyzed their resection modality (surgery, ESD, EMR), margin status, Preoperative marking and Prognosis. RESULTS: Among 315 patients included, 175 cases underwent endoscopic resection and 140 cases underwent surgical treatment. A total of 43 (43/175, 24.57%) and 10 (10/140, 7.14%) patients exhibited positive resection margins after endoscopic resection and surgery, respectively. Multivariate regression analysis suggested that no preoperative marking and endoscopic treatment methods were risk factors for resection margin residues. Among the patients with positive margin residues after endoscopic resection, 5 patients underwent the radical surgical resection and 1 patient underwent additional ESD resection. The remaining 37 patients had no recurrence during a median follow-up of 36 months. CONCLUSIONS: Compared with surgery, endoscopic therapy has a higher margin residual rate. During endoscopic resection, preoperative marking may reduce the rate of lateral margin residues, and endoscopic submucosal dissection may be preferred than endoscopic mucosal resection. Periodical follow-up may be an alternative method for patients with positive margin residues after endoscopic resection.

5NosoAE: a web server for nosocomial bacterial antibiogram investigation and epidemiology survey.

5NosoAE is a webserver that can be used for nosocomial bacterial analysis including the identification of similar strains based on antimicrobial resistance profiles (antibiogram) and the spatiotemporal distribution visualization and phylogenetic analysis of identified strains with similar antibiograms. The extensive use of antibiotics has caused many pathogenic bacteria to develop multiple drug resistance, resulting in clinical infection treatment challenges and posing a major threat to global public health. Relevant studies have investigated the key determinants of antimicrobial resistance in the whole-genome sequence of bacteria. However, a web server is currently not available for performing large-scale strain searches according to antimicrobial resistance profiles and visualizing epidemiological information including the spatiotemporal distribution, antibiogram heatmap, and phylogeny of identified strains. Here, we implemented these functions in the new server, referred to as 5NosoAE. This server accepts the genome sequence file in the FASTA format of five nosocomial bacteria, namely Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterococcus faecium and Staphylococcus aureus for query. All visualizations are implemented in JavaScript and PHP. This server will be useful for physicians and epidemiologists involved in research on infectious disease. The 5NosoAE platform is available at https://nosoae.imst.nsysu.edu.tw.

Langerhans cell histiocytosis in children with refractory diarrhoea and hypoalbuminaemia as the initial presentation: two case reports and a literature review.

Langerhans cell histiocytosis (LCH) involving the gastrointestinal tract is a rare condition for which clinical experience is limited. We describe the cases of two patients who initially presented with chronic diarrhoea, hypoproteinaemia, and intermittent fever. These findings suggest that in cases of refractory diarrhoea accompanied by recurrent hypoalbuminaemia, especially with abdominal rash, LCH should be considered. Gastrointestinal endoscopy, biopsy, and imaging studies are essential for obtaining a definitive diagnosis. This approach might be helpful for the early recognition of gastrointestinal tract involvement in LCH.

RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells.

RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.

Synthesis of 2-(pyridylvinyl)chromen-4-ones and their N-oxide analogs for assessment of their biological activities as anticancer agents.

2-Styrylchromones have been shown to possess a broad spectrum of biological activities. Replacing the carbon atom in 2-styrylchromones with a nitrogen atom in the benzene rings forms 2-(pyridylvinyl)chromen-4-ones (aza-2-styrylchromones). We have synthesized a series of novel 2-(pyridylvinyl)chromen-4-ones and their pyridine N-oxides to evaluate them as potential anticancer agents against human non-small-cell lung cancer cells (A549). Among the 18 synthesized molecules, compounds 18 and 8a exhibited comparable inhibitory effects to 5-fluorouracil and showed no toxicity against normal cells.

Coffee and tea consumption and dementia risk: The role of sex and vascular comorbidities.

BACKGROUND: Coffee and tea consumption has been linked to dementia. However, it remained unknown how sex and vascular risk factors modify the association. We aimed to investigate the association of coffee and tea consumption with dementia and whether sex and vascular comorbidities modified the association. METHODS: We included 278 elderly patients with Alzheimer's disease (AD) and 102 patients with vascular dementia (VaD) from three hospitals; controls (N = 468) were recruited during the same period. We collected the frequency and amount of coffee and tea consumption and the presence of vascular comorbidities. The multinomial logistic regression model was utilized to evaluate the association of coffee and tea consumption with dementia, stratified by sex and vascular comorbidities. RESULTS: Different combinations and quantities of coffee and tea consumption protected against AD and VaD. Consumption of ≥3 cups of coffee or tea per day was protective against AD [adjusted odds ratio (aOR) = 0.42; 95% confidence interval (CI) = 0.22-0.78)] and VaD (aOR = 0.42; 95% CI = 0.19-0.94). Stratified analyses showed that the protective effects of a higher quantity of coffee and tea against AD were more pronounced among females and individuals with hypertension. Consumption of either coffee or tea was associated with a decreased risk of VaD among diabetic participants (aOR = 0.23; 95% CI = 0.06-0.98). Hyperlipidemia modified the association of coffee or tea consumption on the risk of AD and VaD (both Pinteraction < 0.01). CONCLUSION: The risk of AD and VaD was lower with increased consumption of coffee and tea; the impact differed by sex and vascular comorbidities including hypertension, hyperlipidemia, and diabetes.

Primary breast diffuse large B-cell lymphoma characterized by CNS relapse and successful hematopoietic stem cell transplantation salvage therapy.

BACKGROUND: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is rare, with a high incidence of central nervous system (CNS) relapse. This study aims to investigate clinical characteristics, prognostic factors, and outcomes in Taiwanese PB-DLBCL patients and review the literature on PB-DLBCL. METHODS: Thirty-one PB-DLBCL patients diagnosed between 2000 and 2021 were retrospectively enrolled for analysis. RESULTS: The median age was 49 (range 26-79) years. The complete remission (CR) rate was 90.3%. Nine (90%) of the ten patients who experienced relapse had CNS involvement at the time of relapse. The one-year, two-year, and five-year progression-free survival (PFS) rates were 86.6% (95% confidence interval [CI] 75.2-99.8), 75.8% (95% CI 61.6-93.2), and 45.1% (95% CI 29.5-68.9), respectively. The five-year overall survival (OS) rate was 64.1% (95 % CI 48.4-85.0). A stage-modified International Prognostic Index (mIPI) less than two (five-year PFS rate 52.5% vs. 17.1%, P = 0.02) and the achievement of CR after first-line treatment (two-year PFS rate 80.3% vs. 33.3%, P < 0.001) were significant favorable prognostic factors for PFS. Hematopoietic stem cell transplantation (HSCT) after the first relapse was associated with significantly improved post-relapse OS (five-year OS rate 85.7% vs. 20.0%, P = 0.02) and PFS (five-year PFS rate 85.7% vs. 20.0%, P = 0.02). CONCLUSION: Patients with low-risk mIPI scores, CR after first-line treatment, and those who underwent HSCT after the first relapse had significantly better survival. Intrathecal chemotherapy conferred no benefit in preventing CNS relapse. Further research is needed to assess frontline HSCT's effectiveness in improving outcomes and preventing CNS relapses in PB-DLBCL patients.

Beyond Spirometry: Linking Wasted Ventilation to Exertional Dyspnea in the Initial Stages of COPD.

Exertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics - as those in the initial stages of the disease - the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients' out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in "minor/trivial" COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV1.

ABCG2 Mediates Resistance to the Dual EGFR and PI3K Inhibitor MTX-211 in Cancer Cells.

MTX-211 is a first-in-class dual inhibitor of epidermal growth factor receptor (EGFR) and phosphoinositide-3 kinase (PI3K) signaling pathways with a compelling pharmaceutical profile and could enhance the effectiveness of mitogen-activated protein kinase kinase (MEK) inhibitor therapy in colorectal tumors with KRAS mutations. However, the specific mechanisms contributing to the acquired resistance to MTX-211 in human cancers remain elusive. Here, we discovered that the overexpression of the ATP-binding cassette (ABC) drug transporter ABCG2, a prevalent mechanism associated with multidrug resistance (MDR), could diminish the effectiveness of MTX-211 in human cancer cells. We showed that the drug efflux activity of ABCG2 substantially decreased the intracellular accumulation of MTX-211 in cancer cells. As a result, the cytotoxicity and effectiveness of MTX-211 in suppressing the activation of the EGFR and PI3K pathways were significantly attenuated in cancer cells overexpressing ABCG2. Moreover, the enhancement of the MTX-211-stimulated ATPase activity of ABCG2 and the computational molecular docking analysis illustrating the binding of MTX-211 to the substrate-binding sites of ABCG2 offered a further indication for the interaction between MTX-211 and ABCG2. In summary, our findings indicate that MTX-211 acts as a substrate for ABCG2, underscoring the involvement of ABCG2 in the emergence of resistance to MTX-211. This finding carries clinical implications and merits further exploration.

BML-111 inhibit H2O2-induced pyroptosis and osteogenic dysfunction of human periodontal ligament fibroblasts by activating the Nrf2/HO-1 pathway.

BACKGROUND: Periodontitis is a common and harmful chronic inflammatory oral disease, characterized by the destruction of periodontal soft and hard tissues. The NLRP3 inflammasome-related pyroptosis and human periodontal ligament fibroblasts (hPDLFs) osteogenic dysfunction are involved in its pathogenesis. Studies have shown that lipoxin A4 is an endogenous anti-inflammatory mediator and BML-111 is a lipoxin A4 analog, which was found to have potent and durable anti-inflammatory effects in inflammatory diseases, but the mechanism remains unclear. The purpose of this study was to investigate whether BML-111 inhibits H2O2-induced dysfunction of hPDLFs, attenuates inflammatory responses, and identifies the underlying mechanisms. METHODS: The oxidative stress model was established with H2O2, and the cell proliferation activity was measured by CCK-8. ALP staining and alizarin red staining were used to detect the osteogenic differentiation capacity of cells; flow cytometry and ELISA were used to detect cell pyroptosis; we explored the effect of BML-111 on hPDLFs under oxidative stress by analyzing the results of PCR and Western blotting. The Nrf2 inhibitor ML385 was added to further identify the target of BML-111 and clarify its mechanism. RESULTS: BML-111 can alleviate the impaired cell proliferation viability induced by H2O2. H2O2 treatment can induce NLRP3 inflammasome-related pyroptosis, impairing the osteogenic differentiation capacity of hPDLFs. BML-111 can effectively alleviate H2O2-induced cellular dysfunction by activating the Nrf2/HO-1 signaling pathway. CONCLUSION: The results of this study confirmed the beneficial effects of BML-111 on H2O2-induced NLRP3 inflammasome-related pyroptosis in hPDLFs, and BML-111 could effectively attenuate the impaired osteogenic differentiation function. This beneficial effect is achieved by activating the Nrf2/HO-1 signaling pathway, therefore, our results suggest that BML-111 is a potential drug for the treatment of periodontitis.

Effectiveness of Chewing Gum on Nausea and Vomiting Following Postprocedure: A Systematic Review and Meta-Analysis.

PURPOSE: This study aimed to evaluate the effectiveness of chewing gum in reducing postprocedure nausea and vomiting. DESIGN: A systematic review and meta-analysis. METHODS: A systematic literature search was performed on MEDLINE Complete, EMBASE, CINAHL, PubMed, Web of Science, Academic Search Complete, and Cochrane Library databases from their inception to October 2, 2022. Methodological quality was assessed using the revised Cochrane Risk of Bias 2.0 tool for randomized trials. A meta-analysis was performed using a fixed-effects model to calculate pooled effects with Review Manager 5.4.1. FINDINGS: Twelve randomized trials encompassing 1,458 participants were pooled. The chewing gum intervention was effective in reducing vomiting (P = .007; risk ratio = 0.55; 95% Cl = 0.35-0.85), but not nausea (P = .14; risk ratio = 0.84; 95% Cl = 0.66-1.06). Thirty-minute sessions of gum chewing were significantly more effective in reducing vomiting than 15-minute sessions (P = .04; risk ratio = 0.31; 95% Cl = 0.1-0.93). CONCLUSIONS: The results indicate that repeated gum chewing sessions of at least 30 minutes may act as a nonpharmacological intervention for reducing vomiting. However, further studies are necessary to determine the outcomes of chewing gum interventions.

[Study on mechanism of Chinese Yam polysaccharide synergizing nucleoside analogues against hepatitis B virus through p38 MAPK signaling pathway].

This study explore the molecular mechanism of the synergistic effect of Chinese Yam polysaccharides and nucleoside analogues(NAs) on hepatitis B virus(HBV) resistance. Different concentrations of Chinese Yam polysaccharide and entecavir were ad-ded to HepG2.2.15 cells. After the cytotoxicity was detected by cell counting kit-8(CCK-8), the optimal concentration and time of the two drugs to inhibit HepG2.2.15 cells were screened out. They were divided into control group, Chinese Yam polysaccharide group, entecavir group and combination drug group(Chinese Yam polysaccharide + entecavir). The drugs were added to HepG2.2.15 cells, ELISA was used to detect the effects of each group of drugs on the secretion of hepatitis B virus surface antigen(HBsAg) and hepatitis B virus e antigen(HBeAg) in cell supernatant, probe quantitative real-time PCR(probe qRT-PCR) was used to detect the effects of drugs on HBV-DNA in HepG2.2.15 cells, and Western blot was used to detect the effects of each group of drugs on the expression of p38 MAPK, p-p38 MAPK, NTCP proteins in HepG2.2.15 cells. The qRT-PCR was used to detect the effect of drugs on the expression of p38 MAPK and NTCP mRNA in HepG2.2.15 cells. The results showed that compared with control group, the concentrations of HBeAg and HBsAg in Chinese Yam polysaccharide group, entecavir group and combination group decreased(P<0.01 or P<0.001), and both of them inhibited HBV-DNA in HepG2.2.15 cells(P<0.01), and the HBV-DNA inhibition of HepG2.2.15 cells in the combination group was more obvious(P<0.001), and the protein expression levels of p-p38 MAPK and NTCP were significantly decreased(P<0.05 or P<0.01), the mRNA expression level of p38 MAPK increased, and the mRNA expression level of NTCP decreased(P<0.05 or P<0.01). To sum up, Chinese Yam polysaccharide can reduce the expression of NTCP protein and mRNA through p38 MAPK signaling pathway and cooperate with entecavir in anti-HBV.

Highly Selective Photocatalytic Synthesis of Acetic Acid at 0-25oC.

Acetic acid (AA), a vital compound in chemical production and materials manufacturing, is conventionally synthesized by starting with coal or methane through multiple steps including high-temperature transformations. Here we present a new synthesis of AA from ethane through photocatalytic selective oxidation of ethane by H2O2 at 0-25°C. The catalyst designed for this process comprises g-C3N4 with anchored Pd1 single-atom sites. In-situ studies and computational simulation suggest the immobilized Pd1 atom becomes positively charged under photocatalytic condition. Under photoirradiation, the holes on the Pd1 single-atom of OH-Pd1Å/g-C3N4 serves as a catalytic site for activating a C-H instead of C-C of C2H6 with a low activation barrier of 0.14 eV, through a concerted mechanism. Remarkably, the selectivity for synthesizing AA reaches 98.7%, achieved under atmospheric pressure of ethane at 0°C. By integrating photocatalysis with thermal catalysis, we introduce a highly selective, environmentally friendly, energy-efficient synthetic route for AA, starting from ethane, presenting a promising alternative for AA synthesis. This integration of photocatalysis in low-temperature oxidation demonstrates a new route of selective oxidation of light alkanes.

Exploring Camelina sativa lipid metabolism regulation by combining gene co-expression and DNA affinity purification analyses.

Camelina (Camelina sativa) is an annual oilseed plant that is gaining momentum as a biofuel cover crop. Understanding gene regulatory networks is essential to deciphering plant metabolic pathways, including lipid metabolism. Here, we take advantage of a growing collection of gene expression datasets to predict transcription factors (TFs) associated with the control of Camelina lipid metabolism. We identified approximately 350 TFs highly co-expressed with lipid-related genes (LRGs). These TFs are highly represented in the MYB, AP2/ERF, bZIP, and bHLH families, including a significant number of homologs of well-known Arabidopsis lipid and seed developmental regulators. After prioritizing the top 22 TFs for further validation, we identified DNA-binding sites and predicted target genes for 16 out of the 22 TFs tested using DNA affinity purification followed by sequencing (DAP-seq). Enrichment analyses of targets supported the co-expression prediction for most TF candidates, and the comparison to Arabidopsis revealed some common themes, but also aspects unique to Camelina. Within the top potential lipid regulators, we identified CsaMYB1, CsaABI3AVP1-2, CsaHB1, CsaNAC2, CsaMYB3, and CsaNAC1 as likely involved in the control of seed fatty acid elongation and CsaABI3AVP1-2 and CsabZIP1 as potential regulators of the synthesis and degradation of triacylglycerols (TAGs), respectively. Altogether, the integration of co-expression data and DNA-binding assays permitted us to generate a high-confidence and short list of Camelina TFs involved in the control of lipid metabolism during seed development.

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

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

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

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