Taking a color photo: A homozygous 25-bp deletion in Bace2 may cause brown-and-white coat color in giant pandas.

Brown-and-white giant pandas (hereafter brown pandas) are distinct coat color mutants found exclusively in the Qinling Mountains, Shaanxi, China. However, its genetic mechanism has remained unclear since their discovery in 1985. Here, we identified the genetic basis for this coat color variation using a combination of field ecological data, population genomic data, and a CRISPR-Cas9 knockout mouse model. We de novo assembled a long-read-based giant panda genome and resequenced the genomes of 35 giant pandas, including two brown pandas and two family trios associated with a brown panda. We identified a homozygous 25-bp deletion in the first exon of Bace2, a gene encoding amyloid precursor protein cleaving enzyme, as the most likely genetic basis for brown-and-white coat color. This deletion was further validated using PCR and Sanger sequencing of another 192 black giant pandas and CRISPR-Cas9 edited knockout mice. Our investigation revealed that this mutation reduced the number and size of melanosomes of the hairs in knockout mice and possibly in the brown panda, further leading to the hypopigmentation. These findings provide unique insights into the genetic basis of coat color variation in wild animals.

Epstein-Barr virus induces germinal center light zone chromatin architecture and promotes survival through enhancer looping at the BCL2A1 locus.

IMPORTANCE: Epstein-Barr virus has evolved with its human host leading to an intimate relationship where infection of antibody-producing B cells mimics the process by which these cells normally recognize foreign antigens and become activated. Virtually everyone in the world is infected by adulthood and controls this virus pushing it into life-long latency. However, immune-suppressed individuals are at high risk for EBV+ cancers. Here, we isolated B cells from tonsils and compare the underlying molecular genetic differences between these cells and those infected with EBV. We find similar regulatory mechanism for expression of an important cellular protein that enables B cells to survive in lymphoid tissue. These findings link an underlying relationship at the molecular level between EBV-infected B cells in vitro with normally activated B cells in vivo. Our studies also characterize the role of a key viral control mechanism for B cell survival involved in long-term infection.

Enhancing Enterprise Credit Risk Assessment with Cascaded Multi-level Graph Representation Learning.

The assessment of Enterprise Credit Risk (ECR) is a critical technique for investment decisions and financial regulation. Previous methods usually construct enterprise representations by credit-related indicators, such as liquidity and staff quality. However, indicators of many enterprises are not accessible, especially for the small- and medium-sized enterprises. To alleviate the indicator deficiency, graph learning based methods are proposed to enhance enterprise representation learning by the neighbor structure of enterprise graphs. However, existing methods usually only focus on pairwise relationships, and overlook the ubiquitous high-order relationships among enterprises, e.g., supply chain connecting multiple enterprises. To resolve this issue, we propose a Multi-Structure Cascaded Graph Neural Network framework (MS-CGNN) for ECR assessment. It enhances enterprise representation learning based on enterprise graph structures of different granularity, including knowledge graphs of pairwise relationships, homogeneous and heterogeneous hypergraphs of high-order relationships. To distinguish influences of different types of hyperedges, MS-CGNN redefine new type-dependent hyperedge weight matrices for heterogeneous hypergraph convolutions. Experimental results show that MS-CGNN achieves state-of-the-art performance on real-world ECR datasets.

Evolutionary genomics of camouflage innovation in the orchid mantis.

The orchid mantises achieve camouflage with morphological modifications in body color and pattern, providing an interesting model for understanding phenotypic innovation. However, a reference genome is lacking for the order Mantodea. To unveil the mechanisms of plant-mimicking body coloration and patterns, we performed de novo assembly of two chromosome-level genomes of the orchid mantis and its close relative, the dead leaf mantis. Comparative genomic analysis revealed that the Scarlet gene plays an important role in the synthesis of xanthommatin, an important pigment for mantis camouflage coloration. Combining developmental transcriptomic analysis and genetic engineering experiments, we found that the cuticle was an essential component of the 'petal-like' enlargement, and specific expression in the ventral femur was controlled by Wnt signaling. The prolonged expression of Ultrabithorax (Ubx) accompanied by femoral expansion suggested that Ubx determines leg remodeling in the early developmental stage. We also found evidence of evolution of the Trypsin gene family for insectivory adaptation and ecdysone-dependent sexual dimorphism in body size. Overall, our study presents new genome catalogs and reveals the genetic and evolutionary mechanisms underlying the unique camouflage of the praying mantis, providing evolutionary developmental insights into phenotypic innovation and adaptation.

Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial.

BACKGROUND: Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs. METHODS: ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages. DISCUSSION: This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

A right ventricular diverticulum with a very special cardiac anomaly.

Cardiac diverticula are rare congenital anomalies. Among them, right ventricular diverticula are far fewer than left ventricular diverticula. Herein, we write to share an exceedingly rare case of a special right ventricular diverticulum connecting to left ventricle through a tunnel-like structure originating from the membranous ventricular septum. Surgical closure of the origin of the connecting tunnel was performed, while the right ventricular diverticulum was preserved. Postoperative recovering was uneventful.

Meta-HGT: Metapath-aware HyperGraph Transformer for heterogeneous information network embedding.

Heterogeneous information network embedding aims to learn low-dimensional node vectors in heterogeneous information networks (HINs), concerning not only structural information but also heterogeneity of diverse node and relation types. Most existing HIN embedding models mainly rely on metapath to define composite relations between node pairs and thus extract substructures from the original HIN. However, due to the pairwise structure of metapath, these models fail to capture the high-order relations (such as "Multiple authors co-authoring a paper") implicitly contained in HINs. To tackle the limitation, this paper proposes a Metapath-aware HyperGraph Transformer (Meta-HGT) for node embedding in HINs. Meta-HGT first extends metapath to guide the high-order relation extraction from original HIN and constructs multiple metapath based hypergraphs with diverse composite semantics. Then, Meta-HGT learns the latent node and hyperedge embeddings in each metapath based hypergraph through Meta-HGT layers. Each layer consists of two types of components, i.e., intra-hyperedge aggregation and inter-hyperedge aggregation, in which a novel type-dependent attention mechanism is proposed for node and hyperedge feature aggregation. Finally, it fuses multiple node embeddings learned from different metapath based hypergraphs via a semantic attention layer and generates the final node embeddings. Extensive experiments have been conducted on three HIN benchmarks for node classification. The results demonstrate that Meta-HGT achieves state-of-the-art performance on all three datasets.

Profiling the quantitative occupancy of myriad transcription factors across conditions by modeling chromatin accessibility data.

Over a thousand different transcription factors (TFs) bind with varying occupancy across the human genome. Chromatin immunoprecipitation (ChIP) can assay occupancy genome-wide, but only one TF at a time, limiting our ability to comprehensively observe the TF occupancy landscape, let alone quantify how it changes across conditions. We developed TF occupancy profiler (TOP), a Bayesian hierarchical regression framework, to profile genome-wide quantitative occupancy of numerous TFs using data from a single chromatin accessibility experiment (DNase- or ATAC-seq). TOP is supervised, and its hierarchical structure allows it to predict the occupancy of any sequence-specific TF, even those never assayed with ChIP. We used TOP to profile the quantitative occupancy of hundreds of sequence-specific TFs at sites throughout the genome and examined how their occupancies changed in multiple contexts: in approximately 200 human cell types, through 12 h of exposure to different hormones, and across the genetic backgrounds of 70 individuals. TOP enables cost-effective exploration of quantitative changes in the landscape of TF binding.

Enhancer selection dictates gene expression responses in remote organs during tissue regeneration.

Acute trauma stimulates local repair mechanisms but can also impact structures distant from the injury, for example through the activity of circulating factors. To study the responses of remote tissues during tissue regeneration, we profiled transcriptomes of zebrafish brains after experimental cardiac damage. We found that the transcription factor gene cebpd was upregulated remotely in brain ependymal cells as well as kidney tubular cells, in addition to its local induction in epicardial cells. cebpd mutations altered both local and distant cardiac injury responses, altering the cycling of epicardial cells as well as exchange between distant fluid compartments. Genome-wide profiling and transgenesis identified a hormone-responsive enhancer near cebpd that exists in a permissive state, enabling rapid gene expression in heart, brain and kidney after cardiac injury. Deletion of this sequence selectively abolished cebpd induction in remote tissues and disrupted fluid regulation after injury, without affecting its local cardiac expression response. Our findings suggest a model to broaden gene function during regeneration in which enhancer regulatory elements define short- and long-range expression responses to injury.

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration.

The epicardium is a mesothelial tissue layer that envelops the heart. Cardiac injury activates dynamic gene expression programs in epicardial tissue, which in zebrafish enables subsequent regeneration through paracrine and vascularizing effects. To identify tissue regeneration enhancer elements (TREEs) that control injury-induced epicardial gene expression during heart regeneration, we profiled transcriptomes and chromatin accessibility in epicardial cells purified from regenerating zebrafish hearts. We identified hundreds of candidate TREEs, which are defined by increased chromatin accessibility of non-coding elements near genes with increased expression during regeneration. Several of these candidate TREEs were incorporated into stable transgenic lines, with five out of six elements directing injury-induced epicardial expression but not ontogenetic epicardial expression in larval hearts. Whereas two independent TREEs linked to the gene gnai3 showed similar functional features of gene regulation in transgenic lines, two independent ncam1a-linked TREEs directed distinct spatiotemporal domains of epicardial gene expression. Thus, multiple TREEs linked to a regeneration gene can possess either matching or complementary regulatory controls. Our study provides a new resource and principles for understanding the regulation of epicardial genetic programs during heart regeneration. This article has an associated 'The people behind the papers' interview.

The role of StAR2 gene in testicular differentiation and spermatogenesis in Nile tilapia (Oreochromis niloticus).

Sex steroids play critical roles in sex differentiation and gonadal development in teleosts. Steroidogenic acute regulatory protein (StAR), transporting cholesterol (the substrate for steroidogenesis) from the outer mitochondrial membrane to the inner membrane, is the first rate-limiting factor of steroidogenesis. Interestingly, two StAR genes (named as StAR1 and StAR2) have been isolated from non-mammalian vertebrates. To characterize the functions of the novel StAR2 gene in the gonadal differentiation and fertility, we generated a StAR2 homozygous mutant line in Nile tilapia (Oreochromis niloticus). StAR2 gene knockout in male tilapia impeded meiotic initiation, associate with the down-regulation of meiosis related gene expressions of vasa, sycp3 and dazl at 90 days after hatching (dah). Meanwhile, cyp11b2 expression and serum 11-KT production significantly declined in StAR2-/- XY fish at 90 dah. From 120-300 dah, spermatogenesis gradually recovered, and so did the expressions of vasa, sycp3 and dazl in StAR2-/- XY fish testes. However, seminiferous lobules arranged disorderly in StAR2-/- XY fish testes at 300 dah. The number of Leydig cells and expressions of downstream steroidogenesis enzymes including cyp11a1, 3ß-HSD-I, 3ß-HSD-II, cyp17a1 and cyp17a2 decreased in StAR2-/- XY fish testes at 300 dah. Serum testosterone and 11-KT levels were significantly lower in StAR2-/- XY fish than that of their control counterparts. Furthermore, significantly elevated ar, fsh and lh expressions in StAR2-deficient XY fish testes and pituitaries were found when compared with the control XY fish. Testes degeneration and spermatogenic cell apoptosis were observed, while no sperm were squeezed out in StAR2-/- XY fish testes at 540 dah. Taken together, our results suggest that StAR2 has a role in testicular development, spermatogenesis and spermiation by regulating androgen production in tilapia, but may not be essential and could be compensated.

Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.

BACKGROUND: In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer's disease (LOAD) and translate the associations to causation. METHODS: We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. RESULTS: We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets. CONCLUSIONS: Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.

Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance.

Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.

Electrochemical decarboxylative C3 alkylation of quinoxalin-2(1H)-ones with N-hydroxyphthalimide esters.

We have developed a protocol for electrochemical decarboxylative C3 alkylation of a wide range of quinoxalin-2(1H)-ones under metal- and additive-free conditions. N-Hydroxyphthalimide esters derived from chain, cyclic, primary, secondary, and tertiary carboxylic acids with a broad scope proved to be suitable substrates. This operationally simple protocol performed in an undivided cell under constant-current conditions is suitable for late-stage functionalization of quinoxalin-2(1H)-ones. The reactions can even be carried out with a 3 V battery as a power source, which demonstrates that organic electrosynthesis can be accomplished without the need for specialized equipment.

Identification and requirements of enhancers that direct gene expression during zebrafish fin regeneration.

To identify candidate tissue regeneration enhancer elements (TREEs) important for zebrafish fin regeneration, we performed ATAC-seq from bulk tissue or purified fibroblasts of uninjured and regenerating caudal fins. We identified tens of thousands of DNA regions from each sample type with dynamic accessibility during regeneration, and assigned these regions to proximal genes with corresponding expression changes by RNA-seq. To determine whether these profiles reveal bona fide TREEs, we tested the sufficiency and requirements of several sequences in stable transgenic lines and mutant lines with homozygous deletions. These experiments validated new non-coding regulatory sequences near induced and/or essential genes during fin regeneration, including fgf20a, mdka and cx43, identifying distinct domains of directed expression for each confirmed TREE. Whereas deletion of the previously identified LEN enhancer abolished detectable induction of the nearby leptin b gene during regeneration, deletions of enhancers linked to fgf20a, mdka and cx43 had no effect or partially reduced gene expression. Our study generates a new resource for dissecting the regulatory mechanisms of appendage generation and reveals a range of requirements for individual TREEs in control of regeneration programs.

CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .

Effects of long term antiprogestine mifepristone (RU486) exposure on sexually dimorphic lncRNA expression and gonadal masculinization in Nile tilapia (Oreochromis niloticus).

Mifepristone (RU486), a clinical abortion agent and potential endocrine disruptor, binds to progestin and glucocorticoid receptors and has multiple functional importance in reproductive physiology. A long-term exposure of RU486 resulted in masculinization of female fish, however, the epigenetic landscape remains elusive. Recent studies demonstrated that long non-coding RNAs (lncRNAs) might play potential roles in epigenetic modulation of sex differentiation, ovarian cancer and germline stem cell survival. To further understand the influence of RU486 exposure on epigenetic regulation, we performed a comparative investigation on sex-biased gonadal lncRNAs profiles using control XX/XY and RU486-induced sex reversed XX Nile tilapia (Oreochromis niloticus) by RNA-seq. In total, 962 sexually differentially expressed lncRNAs and their target genes were screened from the gonads of control and sex reversed fish. In comparison with the control XX group, sex reversal induced by RU486 treatment led to significant up-regulation of 757 lncRNAs and down-regulation of 221 lncRNAs. Hierarchical clustering analysis revealed that global lncRNA expression profiles in RU486-treated XX group clustered into the same branch with the control XY, whereas XX control group formed a separate branch. The KEGG pathway enrichment analysis showed that the cis-target genes between RU486-XX and control-XX were concentrated in NOD - like receptor signaling pathway, Cell adhesion molecules (CAMs) and Biosynthesis of amino acids. Real-time PCR and in situ hybridization experiments demonstrate that lncRNAs showing intense fluctuation during RU486 treatment are also sexually dimorphic during early sex differentiation, which further proves the intimate relationship between lncRNAs and sex differentiation and sexual transdifferentiation. Taken together, our data strongly indicates that a long-term exposure of RU486 resulted in sex reversal of XX female fish and the altered expression of sexually dimorphic lncRNAs might partially account for the sex reversal via epigenetic modification.

Repair of partial atrioventricular canal defect in adult patients: two-year follow-up outcomes of a retrospective study.

BACKGROUND: Partial atrioventricular canal defects (PAVC) are preferred to be repaired when diagnosed and before an operation would interfere with school. There were rare previous studies about partial atrioventricular canal defect operations in adult patients. In this single-center retrospective study, we mean to review the mid-term follow-up outcomes of late diagnosed and repaired partial atrioventricular canal defects in adult patients. METHODS: 46 adult partial atrioventricular canal defect patients who underwent operation in West China Medical Center from 2009 to 2017 were included. Required data were obtained from operation notes, patient charts and the outpatient records. RESULTS: Among 46 patients, 10(21.7%)were male and mean age at operation was 37.6 ± 12.4 years. 11 patients had prior arrythmia, including 8 atrial fibrillations, 2 atrioventricular blocks and 1 left bundle branch block. There were 41 patients with tricuspid valve regurgitation and 22 underwent tricuspid valvuloplasty. All the patients had mitral regurgitation. 6 patients with valve incrassation and shrinkage underwent mitral valve replacement, and the rest underwent mitral repair surgery. There was one early death post operation and no more mortalities in the following follow-up years. According to the follow-up outcomes, heart function of the patients recovered significantly, dilation of atriums and ventricles, except for left atriums, were reversed to a large extent and all but one patients' tricuspid valve regurgitations were reduced to mild and below. 4(8.7%) patients underwent reoperation and the main reasons were arrythmia and recurrent severe mitral valve regurgitation. CONCLUSION: Partial atrioventricular canal defect repair in adult patients can achieve good results. Compared with the results of patients underwent operations in preschool years, though delayed surgery timing seems to bring more preoperative complications and influences heart function, the mortality and reoperation rate are excellent.

Open Chromatin Profiling in Adipose Tissue Marks Genomic Regions with Functional Roles in Cardiometabolic Traits.

Identifying the regulatory mechanisms of genome-wide association study (GWAS) loci affecting adipose tissue has been restricted due to limited characterization of adipose transcriptional regulatory elements. We profiled chromatin accessibility in three frozen human subcutaneous adipose tissue needle biopsies and preadipocytes and adipocytes from the Simpson Golabi-Behmel Syndrome (SGBS) cell strain using an assay for transposase-accessible chromatin (ATAC-seq). We identified 68,571 representative accessible chromatin regions (peaks) across adipose tissue samples (FDR < 5%). GWAS loci for eight cardiometabolic traits were enriched in these peaks (P < 0.005), with the strongest enrichment for waist-hip ratio. Of 110 recently described cardiometabolic GWAS loci colocalized with adipose tissue eQTLs, 59 loci had one or more variants overlapping an adipose tissue peak. Annotated variants at the SNX10 waist-hip ratio locus and the ATP2A1-SH2B1 body mass index locus showed allelic differences in regulatory assays. These adipose tissue accessible chromatin regions elucidate genetic variants that may alter adipose tissue function to impact cardiometabolic traits.

Transcriptome and epigenome landscape of human cortical development modeled in organoids.

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.