Objective
Due to the phenotypic heterogeneity and etiological complexity of bipolar disorder (BD), many patients do not respond well to the current medications, and developing novel effective ...treatment is necessary. Whether any BD genome‐wide association study (GWAS) risk genes were targets of existing drugs or novel drugs that can be repurposed in the clinical treatment of BD is a hot topic in the GWAS era of BD.
Methods
A list of 425 protein‐coding BD risk genes was distilled through the BD GWAS, and 4479 protein‐coding druggable targets were retrieved from the druggable genome. The overlapped genes/targets were subjected to further analyses in DrugBank, Pharos, and DGIdb datasets in terms of their FDA status, mechanism of action and primary indication, to identify their potential for repurposing.
Results
We identified 58 BD GWAS risk genes grouped as the druggable targets, and several genes were given higher priority. These BD risk genes were targets of antipsychotics, antidepressants, antiepileptics, calcium channel antagonists, as well as anxiolytics and analgesics, either existing clinically‐approved drugs for BD or the drugs than can be repurposed for treatment of BD in the future. Those genes were also likely relevant to BD pathophysiology, as many of them encode ion channel, ion transporter or neurotransmitter receptor, or the mice manipulating those genes are likely to mimic the phenotypes manifest in BD patients.
Conclusions
This study identifies several targets that may facilitate the discovery of novel treatments in BD, and implies the value of conducting GWAS into clinical translation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Whether risk genes of severe coronavirus disease 2019 (COVID-19) from genome-wide association study could play their regulatory roles by interacting with host genes that were interacted with ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins was worthy of exploration. In this study, we implemented a network-based approach by developing a user-friendly software Network Calculator (https://github.com/Haoxiang-Qi/Network-Calculator.git). By using Network Calculator, we identified a network composed of 13 risk genes and 28 SARS-CoV-2 interacted host genes that had the highest network proximity with each other, with a hub gene HNRNPK identified. Among these genes, 14 of them were identified to be differentially expressed in RNA-seq data from severe COVID-19 cases. Besides, by expression enrichment analysis in single-cell RNA-seq data, compared with mild COVID-19, these genes were significantly enriched in macrophage, T cell and epithelial cell for severe COVID-19. Meanwhile, 74 pathways were significantly enriched. Our analysis provided insights for the underlying genetic etiology of severe COVID-19 from the perspective of network biology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Bipolar disorder (BD) is a highly heritable psychiatric illness exhibiting substantial correlation with intelligence. Methods To investigate the shared genetic signatures between BD and ...intelligence, we utilized the summary statistics from genome-wide association studies (GWAS) to conduct the bivariate causal mixture model (MiXeR) and conjunctional false discovery rate (conjFDR) analyses. Subsequent expression quantitative trait loci (eQTL) mapping in human brain and enrichment analyses were also performed. Results Analysis with MiXeR suggested that approximately 10.3K variants could influence intelligence, among which 7.6K variants were correlated with the risk of BD (Dice: 0.80), and 47% of these variants predicted BD risk and intelligence in consistent allelic directions. The conjFDR analysis identified 37 distinct genomic loci that were jointly associated with BD and intelligence with a conjFDR < 0.01, and 16 loci (43%) had the same directions of allelic effects in both phenotypes. Brain eQTL analyses found that genes affected by the "concordant loci" were distinct from those modulated by the "discordant loci". Enrichment analyses suggested that genes related to the "concordant loci" were significantly enriched in pathways/phenotypes related with synapses and sleep quality, whereas genes associated with the "discordant loci" were enriched in pathways related to cell adhesion, calcium ion binding, and abnormal emotional phenotypes. Conclusions We confirmed the polygenic overlap with mixed directions of allelic effects between BD and intelligence and identified multiple genomic loci and risk genes. This study provides hints for the mesoscopic phenotypes of BD and relevant biological mechanisms, promoting the knowledge of the genetic and phenotypic heterogeneity of BD. The essential value of leveraging intelligence in BD investigations is also highlighted. Keywords: Bipolar disorder, Intelligence, Genome-wide association study, Polygenic overlap, Shared loci
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A series of nickel halides bearing 2,4-di-t-butyl-6-（quinolin-8-yliminomethyl） phenolate ligands was synthesized and characterized by IR spectroscopy and elemental analysis. Molecular structures of ...C1 （R = H, X = Br） and C2 （R = H, X = C1） were further confirmed by single-crystal X-ray crystallographic studies, and revealed a distorted square planar geometry at nickel. Upon activation with diethylaluminum chloride （Et2AlCl）, all nickel pre-catalysts displayed good catalytic activity up to 9.3 × 10^5 g mol-1（Ni） h-1 for ethylene oligomerization with major dimerization. In the presence of methylaluminoxane （MAO）, the nickel complex C1 was capable of ethylene polymerization under 3 MPa, and produced polyethylene products with narrow polydispersity （1.16-1.73） and molecular weights in the range of 2.6-4.95 kg/mol.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cyberspace is the fifth sovereignty space after the sea,land,sky and space.The security of cyberspace is closely relative to national security.How to discover threat in time,how to defense network ...attack,how to trace attackers were the problems to be selved.Facing the polyphyletic,isomeric,disconnected properties in the cyberspace,bases on a credible IaaS,a cyberspace security situation awareness was constructed by ontology,semantic Web and linked data theory.While guarantee the access security of integrating data,the model could make a comprehensive analysis on the properties in the cyberspace,which contributes to cyberspace governance.
The La2/3Cal/3Mn03_σ film has been deposited on the （001） SrTiO3 substrate and its temper- ature-dependent photoconductive properties have been investigated from 80 to 300 K. The La2/3Cal/3MnO3-σ ...film has a novel photoelectric property due to its oxygen-deficient structure. We observed laser-induced giant negative photoresistance of the sample in a wide temperature range. The change rate of negative photoresistance was nearly 100% at the low temperature when the sample was irradiated by 532 nm laser. In addition, this effect was sensitive to the power of laser irradiation. The oxygen-deficiency of La2/3Cal/3Mn03-σ film seems to have an impact on the laser-induced resistance variation. The experimental results made the La2/3Cal/3MnO3_σ film a promising application as a photoswitch device.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The electrocardiogram （ECG） has broad applications in clinical diagnosis and prognosis of cardiovascular disease. Many researchers have contributed to its progressive development. To commemorate ...those pioneers, and to better study and promote the use of ECG, we reviewed and present here a systematic introduction about the history, hotspots, and trends of ECG. In the historical part, information including the invention, improvement, and extensive applications of ECG, such as in long QT syndrome （LQTS）, angina, and myocardial infarction （MI）, are chronologi- cally presented. New technologies and applications from the 1990s are also introduced. In the second part, we use the bibliometric analysis me- thod to analyze the hotspots in the field of ECG-related research. By using total citations and year-specific total citations as our main criteria, four key hotspots in ECG-related research were identified from 11 articles, including atrial fibrillation, LQTS, angina and MI, and heart rate variability. Recent studies in those four areas are also reported. In the final part, we discuss the future trends concerning ECG-related research. The authors believe that improvement of the ECG instrumentation, big data mining for ECG, and the accuracy of diagnosis and application will be areas of continuous concern.
Background Clinical practice guidelines （CPGs） play an important role in healthcare in China as well as in the world. However, the current status and trends of Chinese CPGs are unknown. The aim of ...this study was to systematically review the present situation and the quality of Chinese CPGs published in the peer-reviewed medical literature. Methods To identify Chinese CPGs, a systematic search of relevant literature databases （CBM, WANFANG, VIP, and CNKI） was performed for the period January 1978 to December 2010. We used the AGREE II instrument to assess the quality of the included guidelines. Results We evaluated 269 guidelines published in 115 medical journals from 1993 to 2010 and produced by 256 different developers. Only four guidelines （1%） described the systematic methods for searching and selecting the evidence, 14 （5%） guidelines indicated an explicit link between the supporting evidence and the recommendations, only one guideline used the Grading of Recommendations Assessment, Development and Evaluation （GRADE） system. Thirty-one guidelines （12%） mentioned updates and the average frequency of update was 5.5 years; none described a procedure for updating the guideline. From the assessment with the Appraisal of Guidelines for Research and Ecaluation II （AGREE II）, the mean scores were low for the domains ＂scope and purpose＂ （19%） and ＂clarity of presentation＂ （26%） and very low for the other domains （＂rigour of development＂ 7%, ＂stakeholder involvement＂ 8%, ＂applicability＂ 6% and ＂editorial independence＂ 2%）. Conclusions Compared with other studies on the quality of guidelines assessed with the AGREE instrument in other countries, Chinese CPGs received lower scores, which indicates a relatively poor quality of the guidelines. However, there was some increase over time.
Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI ...resistance, but direct clinical evidence is lacking.
Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets.
Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets.
We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Precise methods for postoperative risk stratification to guide the administration of adjuvant chemotherapy (ACT) in localized colorectal cancer (CRC) are still lacking. Here, we conducted a ...prospective, observational, and multicenter study to investigate the utility of circulating tumor DNA (ctDNA) in predicting the recurrence risk.
From September 2017 to March 2020, 276 patients with stage II/III CRC were prospectively recruited in this study and 240 evaluable patients were retained for analysis, of which 1290 serial plasma samples were collected. Somatic variants in both the primary tumor and plasma were detected via a targeted sequencing panel of 425 cancer-related genes. Patients were treated and followed up per standard of care.
Preoperatively, ctDNA was detectable in 154 of 240 patients (64.2%). At day 3-7 postoperation, ctDNA positivity was associated with remarkably high recurrence risk (hazard ratio HR, 10.98; 95%CI, 5.31-22.72; P < 0.001). ctDNA clearance and recurrence-free status was achieved in 5 out of 17 ctDNA-positive patients who were subjected to ACT. Likewise, at the first sampling point after ACT, ctDNA-positive patients were 12 times more likely to experience recurrence (HR, 12.76; 95%CI, 5.39-30.19; P < 0.001). During surveillance after definitive therapy, ctDNA positivity was also associated with extremely high recurrence risk (HR, 32.02; 95%CI, 10.79-95.08; P < 0.001). In all multivariate analyses, ctDNA positivity remained the most significant and independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors. Serial ctDNA analyses identified recurrence with an overall accuracy of 92.0% and could detect disease recurrence ahead of radiological imaging with a mean lead time of 5.01 months.
Postoperative serial ctDNA detection predicted high relapse risk and identified disease recurrence ahead of radiological imaging in patients with stage II/III CRC. ctDNA may be used to guide the decision-making in postsurgical management.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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