Genome-wide association studies (GWASs) have identified over 180 independent schizophrenia risk loci. Nevertheless, how the risk variants in the reported loci confer schizophrenia susceptibility ...remains largely unknown. Here we systematically investigate the gene regulatory mechanisms underpinning schizophrenia risk through integrating data from functional genomics (including 30 ChIP-Seq experiments) and position weight matrix (PWM). We identify 132 risk single nucleotide polymorphisms (SNPs) that disrupt transcription factor binding and we find that 97 of the 132 TF binding-disrupting SNPs are associated with gene expression in human brain tissues. We validate the regulatory effect of some TF binding-disrupting SNPs with reporter gene assays (9 SNPs) and allele-specific expression analysis (10 SNPs). Our study reveals gene regulatory mechanisms affected by schizophrenia risk SNPs (including widespread disruption of POLR2A and CTCF binding) and identifies target genes for mechanistic studies and drug development. Our results can be accessed and visualized at SZDB database ( http://www.szdb.org/ ).
This review summarizes the use of metal-organic frameworks (MOFs) as a versatile supramolecular platform to develop heterogeneous catalysts for a variety of organic reactions, especially for ...liquid-phase reactions. Following a background introduction about catalytic relevance to various metal-organic materials, crystal engineering of MOFs, characterization and evaluation methods of MOF catalysis, we categorize catalytic MOFs based on the types of active sites, including coordinatively unsaturated metal sites (CUMs), metalloligands, functional organic sites (FOS), as well as metal nanoparticles (MNPs) embedded in the cavities. Throughout the review, we emphasize the incidental or deliberate formation of active sites, the stability, heterogeneity and shape/size selectivity for MOF catalysis. Finally, we briefly introduce their relevance into photo- and biomimetic catalysis, and compare MOFs with other typical porous solids such as zeolites and mesoporous silica with regard to their different attributes, and provide our view on future trends and developments in MOF-based catalysis.
The contributions of MOFs to the field of heterogeneous supramolecular catalysis are comprehensively reviewed with regard to active sites, selectivity, as well as host-guest chemistry.
Abstract
The toxicity of lead perovskite hampers the commercialization of perovskite-based photovoltaics. While tin perovskite is a promising alternative, the facile oxidation of tin(II) to tin(IV) ...causes a high density of defects, resulting in lower solar cell efficiencies. Here, we show that tin(0) nanoparticles in the precursor solution can scavenge tin(IV) impurities, and demonstrate that this treatment leads to effectively tin(IV)-free perovskite films with strong photoluminescence and prolonged decay lifetimes. These nanoparticles are generated by the selective reaction of a dihydropyrazine derivative with the tin(II) fluoride additive already present in the precursor solution. Using this nanoparticle treatment, the power conversion efficiency of tin-based solar cells reaches 11.5%, with an open-circuit voltage of 0.76 V. Our nanoparticle treatment is a simple and broadly effective method that improves the purity and electrical performance of tin perovskite films.
This review introduces the syntheses of metal-organic framework (MOF) composites and their applications in CO2 capture and conversion, including CO2 chemical fixation, hydrogenation, photoreduction, ...electroreduction and photoelectroreduction.
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Reliable technologies for CO2 capture and conversion (C3) are of vital importance for the establishment of a sustainable society. Metal-organic framework (MOF) composites have shown their compelling potentials for C3 due to the plentiful reticular chemistry of MOF structures and the synergistic catalysis between MOFs and the functional guests. This review focuses on the syntheses and catalytic applications towards C3 of MOF composites, which is divided into three sections. The first section gives a brief introduction about synthetic strategies of MOF composites. The second section discusses the recent progress of MOF composites in C3, including CO2 chemical fixation, hydrogenation, photoreduction, electroreduction and photoelectroreduction. The third section summarizes the challenges and future prospects of MOF composites for C3. We hope that this review cannot only provide an inspiration for the rational design of MOF composites for C3, but also stimulate more and more research works in this emerging area.
During the past decade, genetic studies of schizophrenia have become one of the most exciting and fast-moving areas. Hundreds of genes implicated in schizophrenia have been identified by genetic, ...epigenetic, and gene expression studies. However, how to systematically and efficiently use these published data to pinpoint the causal genes becomes a major challenge in schizophrenia research. Here, we release an updated version of a comprehensive database for schizophrenia research, SZDB2.0 (
www.szdb.org
), which accompanies significant data expansion and feature improvements, as well as functionality optimization. Compared with the first version (SZDB), the current database has the following updates: (1) We added the newly published genome-wide association study (GWAS) of schizophrenia from CLOZUK + PGC, which is the largest GWAS for schizophrenia; (2) We included a polygenic risk score calculator; (3) In the refined “Gene” module of SZDB2.0, we collated genetic, gene expression, methylation, and integrative results of all available schizophrenia studies; (4) In the “CNV (copy number variation)” module, we collated the results of all 77 CNV publications about schizophrenia; (5) We also updated other data, including gene expression quantitative trait loci (eQTL), transcript QTL, methylation QTL, and protein–protein interaction data, based on the information from the latest literatures. We optimized the query interface of SZDB2.0 for a better visualization and data retrieval. The updated SZDB2.0 will advance the research of schizophrenia.
The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic ...landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.
How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary ...glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and a leading cause of disability worldwide. Though recent genome-wide association studies (GWAS) have identified ...multiple risk variants for MDD, how these variants confer MDD risk remains largely unknown. Here we systematically characterize the regulatory mechanism of MDD risk variants using a functional genomics approach. By integrating chromatin immunoprecipitation sequencing (ChIP-Seq) (from human brain tissues or neuronal cells) and position weight matrix (PWM) data, we identified 34 MDD risk SNPs that disrupt the binding of 15 transcription factors (TFs). We verified the regulatory effect of the TF binding-disrupting SNPs with reporter gene assays, allelic-specific expression analysis, and CRISPR-Cas9-mediated genome editing. Expression quantitative trait loci (eQTL) analysis identified the target genes that might be regulated by these regulatory risk SNPs. Finally, we found that NEGR1 (regulated by the TF binding-disrupting MDD risk SNP rs3101339) was dysregulated in the brains of MDD cases compared with controls, implying that rs3101339 may confer MDD risk by affecting NEGR1 expression. Our findings reveal how genetic variants contribute to MDD risk by affecting TF binding and gene regulation. More importantly, our study identifies the potential MDD causal variants and their target genes, thus providing pivotal candidates for future mechanistic study and drug development.
Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in achieving long survival of patients. ...MET fusion is a rare oncogenic factor, whose optimal detection and treatment are not well established. Here, we report on a 32-year-old female lung adenocarcinoma patient with positive PD-L1 and negative driver gene detected by DNA-based next-generation sequencing (NGS). A radical resection of the primary lesion after chemotherapy combined with PD-1 checkpoint inhibitor administration indicated primary immuno-resistance according to her pathological response and rapid relapse. A rare CD47-MET was detected by RNA-based NGS, which was confirmed by fluorescence in situ hybridization. Multiplex immunofluorescence revealed a PD-L1 related heterogeneous immunosuppressive microenvironment with little distribution of CD4+ T cells and CD8+ T cells. Savolitinib therapy resulted in a progression-free survival (PFS) of >12 months, until a new secondary resistance mutation in MET p.D1228H was detected by re-biopsy and joint DNA-RNA-based NGS after disease progression. In this case, CD47-MET fusion NSCLC was primarily resistant to immunotherapy, sensitive to savolitinib, and developed secondary MET p.D1228H mutation after targeted treatment. DNA-RNA-based NGS is useful in the detection of such molecular events and tracking of secondary mutations in drug resistance. To this end, DNA-RNA-based NGS may be of better value in guiding precise diagnosis and individualized treatment in this patient population.
To determine the impact of vitamin D on the occurrence and progression of intestinal disorders, the authors of this study have conducted a systematic review and meta-analysis.
Vitamin D regulates ...inflammation and immunity in association with reducing the disease symptoms of several gastrointestinal diseases, including inflammatory bowel diseases (IBD), Crohn's disease (CD), ulcerative colitis (UC), and colorectal cancer (CRC). However, the exact role of vitamin D in the occurrence and development of intestinal diseases is unclear so far.
The relevant studies were searched in PubMed and screened based on inclusion and exclusion criteria. The quality of full-text studies was assessed using National Heart, Lung, and Blood Institute (NIH) scale. The study was conducted as per the PRISMA guidelines. The overall estimate was calculated in terms of risk ratio with a 95% confidence interval. The publication bias was assessed qualitatively using a funnel plot, and heterogeneity among studies was calculated using I2 statistics. All analyses were done using RevMan 5.0.
The overall risk ratio using random effect model was found to be 0.89 (0.70, 1.12), which indicates the non-significant role of vitamin D in the occurrence and development of intestinal diseases as compared to the non-vitamin D group. However, after exclusion of studies with low and high sample sizes, a significant reduction in intestinal diseases was observed in the vitamin D group as compared to the non-vitamin D group. Further, no heterogeneity among the studies was observed.
Based on available evidence, vitamin D might play a significant role in the reduction of intestinal diseases; however, more studies with high sample sizes are required to draw a valid conclusion.
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