Miracle-dz/UniFAR-FTUs huggingface dataset:
A tissue-specific collaborative mixed model for jointly analyzing multiple tissues in transcriptome-wide association studies

Transcriptome-wide association studies (TWAS) integrate expression quantitative trait loci (eQTLs) studies with genome-wide association studies (GWASs) to prioritize candidate target genes for complex traits. Several statistical methods have been recently proposed to improve the performance of TWAS in gene prioritization by integrating transcriptome information imputed from multiple tissues, and made significant achievements in improving the ability to detect gene-trait associations. The major limitation of these methods is that they cannot be used to elucidate the specific functional effects of candidate genes across different tissues. Here, we propose a tissue-specific collaborative mixed model (TisCoMM) for TWAS, using a computational framework that integrates multi-tissue eQTL analysis. TisCoMM leverages the co-regulation of genetic variations across different tissues explicitly via a unified collaborative mixed model. With the probabilistic framework, TisCoMM not only performs hypothesis testing to prioritize gene-trait associations but also ascertains the tissue-specific role of candidate target genes in complex traits. To make use of widely available GWAS summary statistics, we extend TisCoMM to use summary-level data, namely, TisCoMM-S2. Using extensive simulation studies, we demonstrate both the type I error control and the improved statistical power for the proposed methods. We further illustrate the benefits of our methods in applications to summary-level GWAS data for 35 traits. Notably, apart from better identifying potential trait-associated genes, we can elucidate the tissue-specific role of candidate target genes. The follow-up pathway analysis from tissue-specific genes for asthma shows that the immune system plays an essential function for asthma development in both thyroid and lung tissues.
Genomic profiling of plasma circulating tumor DNA reveals genetics and residual disease in extranodal NK/T-cell lymphoma

Extranodal NK/T-cell lymphoma, nasal type (ENTKL), is an aggressive hematological malignancy with poor prognosis. Early detection of tumors at initial diagnosis or during routine surveillance is important for improving survival outcomes. Molecular profiling of circulating tumor DNA (ctDNA) is a promising noninvasive tool for monitoring disease status. Here, we assessed the gene mutation spectrum of plasma ctDNA in ENKTL by cancer personalized profiling sequencing (CAPP-Seq). We found that the most frequently mutated genes were MGA (33.3%), TP53 (30%), ASXL3 (28.3%), DDX3X (25%), BCORL1 (25%), TRAF3 (21.7%), NOTCH3 (21.7%), STAT5B (21.7%), EP300 (21.7%), APC (20%), ATM (18.3%), TNFRSF14 (16.7%), KMT2D (16.7%), EZH2 (16.7%) and SETD2 (16.7%). The mutation frequencies of MGA and TP53 were significantly higher in stage III-IV, and mutations in MGA, TP53, and NOTCH3, et al were significantly correlated with the metabolic tumor burden of the patients. Compared with tumor tissue DNA, ctDNA profiling showed good concordance. Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequency of genes. Compared with PET/CT, ctDNA has more advantages for tracking residual disease in patients. In addition, we also found that mutated MGA, TP53, SETD2, and APC predicted poor prognosis in patients. Collectively, our results provide evidence that ctDNA may serve as a novel precision medicine biomarker in ENKTL.
The usage of human IGHJ genes follows a particular nonrandom selection: The recombination signal sequence affects the usage of human IGHJ genes

The formation of the B cell receptor (BCR) heavy chain variable region is derived from the germline V(D)J gene rearrangement according to the “12/23” rule and the “beyond 12/23” rule. The usage frequency of each V(D)J gene in the peripheral BCR repertoires is related to the initial recombination, self-tolerance selection, and the clonal proliferative response. However, their specific differences and possible mechanisms are still unknown. We analyzed in-frame and out-of-frame BCR-H repertoires from human samples with physiological and various pathological conditions by high-throughput sequencing. Our results showed that IGHJ gene frequency follows a similar pattern where IGHJ4 is used at high frequency (>40%), IGHJ6/IGHJ3/IGHJ5 is used at medium frequencies (10%∼20%), and IGH2/IGHJ1 is used at low frequency (<4%) under whether physiological or various pathological conditions. Furthermore, analysis of the recombination signal sequences suggested that the conserved nonamer and heptamer and certain 23 bp spacer length may affect the initial IGHD-IGHJ recombination, which results in different frequencies of IGHJ genes among the initial BCR-H repertoire. Based on this “background repertoire”, we recommend that re-evaluation and further investigation are needed when analyzing the significance and mechanism of IGHJ gene frequency in self-tolerance selection and the clonal proliferative response.
Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Significance Human genes homozygous for apparent loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. These putatively dispensable genes showed relaxation of selective constraints, suggesting that a considerable proportion of these genes may be undergoing pseudogenization. Eight of these LoF variants displayed robust signals of positive selection, including two variants in genes involved in resistance to infectious diseases. The identification of dispensable genes will facilitate the identification of functions that are now redundant, or possibly even advantageous, for human survival. Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.
Bonga shad (
 Ethmalosa fimbriata
 ) spawning tactics in an upwelling environment

Successful recruitment in small pelagic fish populations inhabiting upwelling zones is subject to variation in fecundity and is driven by spatial and temporal fluctuations in environmental conditions, that is, mainly sea surface temperature, salinity and food availability. These fluctuations in abiotic factors have stimulated small pelagic fish populations to exhibit specifically adapted spawning tactics. To better understand to what extent a short-lived exploited fish species such as bonga shad Ethmalosa fimbriata has adapted to an upwelling environment, we have investigated the interrelationship between upwelling intensity as a proxy for productivity and population fecundity by means of a virtual population analysis. We found that females of intermediate size contributed significantly more eggs to the population's fecundity than smaller or larger ones. Our model results further indicate that E. fimbriata exhibits a spawning preference at water temperatures of around 25 degrees C and upwelling intensities of around 2.5 m(3) s(-1) m(-1). Hence, we hypothesize that climate change-driven increases in sea temperatures and modifications of upwelling-favourable winds could significantly impact the species' reproductive biology. To understand how climate change might impact fisheries, spawning tactics of small pelagic fishes are important to assess as well as their recruitment success. Such information is particularly relevant in countries where the fishery is critical at socio-economic level, to better implement fisheries management addressing multiple stressors.
Ecological niche modelling and genetic diversity of Anomochloa marantoidea (Poaceae): filling the gaps for conservation in the earliest-diverging grass subfamily

Anomochlooideae (Poaceae) represent the earliest-diverging extant lineage of grasses. One of the two genera is the monotypic Anomochloa, which is extremely rare and restricted to the Atlantic Forest of southern Bahia state in Brazil, where only two natural populations have been recorded to date. Knowledge of A. marantoidea is considered crucial to understanding evolutionary and diversification patterns in Poaceae. Despite this, knowledge of the biology and distribution of A. marantoidea remain incomplete, and thus the conservation of this poorly known species is problematic. We used niche modelling to estimate its current distribution and assess potential ranges in situ to explore new occurrences. In addition, genetic diversity and the factors that disrupt gene flow between populations of this species were estimated using molecular markers. Two new populations were documented; the modelled ecological niche indicates high climatic restriction, but also revealed suitable sites for the establishment of new populations. Genetic diversity is correlated to population size, and genetic structure analysis suggests recent fragmentation and low gene flow among the remaining populations, which exhibit high levels of inbreeding. These levels also indicate the capacity of A. marantoidea to respond favourably to selection and, thus, that a conservation plan could be designed to maintain the current genetic diversity.
Adverse events associated with bidirectional endoscopy with midazolam and pethidine

Same-day bidirectional endoscopy has been reported to reduce recovery time, and procedure-related cost. The safety of bidirectional endoscopy vs colonoscopy only, while using midazolam and pethidine, has never been evaluated. We reviewed 1,202 consecutive patients who underwent bidirectional endoscopy or colonoscopy only with administration of midazolam and pethidine in Toyoshima Ensdoscopy Clinic. We compared the clinical characteristics and adverse events associated with method of endoscopy (colonoscopy only vs bidirectional endoscopy). Furthermore, multivariate logistic regression analyses were conducted to study the role of age, sex, use of sedative, polypectomy, and bidirectional endoscopy in adverse events. In the bidirectional endoscopy group, the doses of pethidine and midazolam, and the incidence rates of hypoxia and posto-endoscopic nausea were significantly higher. On multivariate analysis, age (odds ratio = 1.061, p<0.001), use of pethidine (odds ratio = 4.311, p = 0.003), and bidirectional endoscopy (odds ratio = 3.658, p<0.001) were independently associated with hypoxia. On multivariate analysis, female sex (odds ratio = 10.25, p = 0.027) and bidirectional endoscopy (odds ratio = 6.051, p = 0.022) were independently associated with post-endoscopic nausea. In conclusion, bidirectional endoscopy could increase hypoxia in elderly patients using pethidine and post-endoscopic nausea in female patients.
Developing Symbiotic Clinical Educators: Using Program Logic to Evaluate a Clinical Education Course

Developing health professional clinical educators able to meet the shifting health care requirements of this century is a current government priority. To change practices in the clinic, those who teach need to change and that is best achieved by specific curricula designed for faculty development. Principles revealed during an investigation of a successful community-based medical education program underpin the Master of Clinical Education (MCE) course, a new faculty development curriculum. After six years, it is timely to evaluate whether the educational goals of the MCE course are being met. The MCE faculty employed an independent research officer to conduct the study. A two-phase approach used semi-structured interviews and content analysis to develop and assess outcomes against an outcomes logic model. The program achieved all short-term goals: understanding the symbiotic model; commitment to self as teacher; and changes in the way to give feedback. It achieved two of three medium-term goals: belief of transformation; and relationship development. One medium-term goal was not met: developing a sense of community. This evaluation of the MCE course shows the program develops clinicians as committed educators and also as change agents who see building relationships as the key to operating effectively within complex health services and systems.
The Mechanism of Caspase-8-Mediated Gene Expression and Its Integral Role in Host Defense

Caspase-8 is a key integrator of cell survival and cell death decisions during infection and inflammation. Additionally, caspase-8 has an important, but less understood, role in cell-intrinsic inflammatory gene expression. Macrophages lacking caspase-8 have defective inflammatory cytokine expression in response to bacterial infection or TLR stimulation. How caspase-8 regulates cytokine gene expression, and whether caspase-8-mediated gene regulation has a physiological role during infection remains poorly defined. In this thesis we demonstrate that both caspase-8 enzymatic activity and scaffolding functions play a role in control of inflammatory cytokine gene expression. Caspase-8 enzymatic activity mediates IKK phosphorylation and nuclear translocation of the NF-κB family member c-Rel to promote maximal expression of Il1b and Il12b. Overexpression of c-Rel was sufficient to restore expression of IL-12 and IL-1β in caspase-8-deficient cells. Moreover, the cytokine regulatory function of caspase-8 promoted host survival during infection by the intracellular parasite Toxoplasma gondii. Caspase-8-deficient mice displayed acute mortality during T. gondii infection and a defect in intracellular IL-12 production by DCs. Exogenous IL-12 promoted complete survival of caspase-8-deficient mice during acute toxoplasmosis. Our findings provide new insight into how caspase-8 controls inflammatory gene expression and, for the first time, identify a critical role for caspase-8 in host defense against a eukaryotic pathogen. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Igor E. Brodsky
Widespread dysregulation of long non-coding genes associated with fatty acid metabolism, cell division, and immune response gene networks in xenobiotic-exposed rat liver

Xenobiotic exposure activates or inhibits transcription of hundreds of protein-coding genes in mammalian liver, impacting many physiological processes and inducing diverse toxicological responses. Little is known about the effects of xenobiotic exposure on long noncoding RNAs (lncRNAs), many of which play critical roles in regulating gene expression. Objective: to develop a computational framework to discover liver-expressed, xenobiotic-responsive lncRNAs (xeno-lncs) with strong functional, gene regulatory potential and elucidate the impact of xenobiotic exposure on their gene regulatory networks. We analyzed 115 liver RNA-seq data sets from male rats treated with 27 individual chemicals representing seven mechanisms of action (MOAs) to assemble the long non-coding transcriptome of xenobiotic-exposed rat liver. Ortholog analysis was combined with co-expression data and causal inference methods to infer lncRNA function and deduce gene regulatory networks, including causal effects of lncRNAs on protein-coding gene expression and biological pathways. We discovered >1,400 liver-expressed xeno-lncs, many with human and/or mouse orthologs. Xenobiotics representing different MOAs were often regulated common xeno-lnc targets: 123 xeno-lncs were dysregulated by at least 10 chemicals, and 5 xeno-lncs responded to at least 20 of the 27 chemicals investigated. 81 other xeno-lncs served as MOA-selective markers of xenobiotic exposure. Xeno-lnc–protein-coding gene co-expression regulatory network analysis identified xeno-lncs closely associated with exposure-induced perturbations of hepatic fatty acid metabolism, cell division, and immune response pathways. We also identified hub and bottleneck lncRNAs, which are expected to be key regulators of gene expression in cis or in trans. This work elucidates extensive networks of xeno-lnc–protein-coding gene interactions and provides a framework for understanding the extensive transcriptome-altering actions of diverse foreign chemicals in a key responsive mammalian tissue.
Genomic features of BRDT binding sites in gene units suggest transcriptional partners and specific epigenetic landscapes to regulate transcriptional activity during spermatogenesis

BRDT, a member of the BET family of double bromodomain-containing proteins, is expressed uniquely in the male germ line, is essential for spermatogenesis in the mouse, and binds to acetylated transcription start sites of genes expressed in meiosis and spermiogenesis. It has thus been postulated to be a key regulator of transcription in meiotic and post-meiotic cells. To understand the function of BRDT in regulating gene expression, we characterized its genome-wide distribution, in particular the features of the BRDT binding sites within gene units, by ChIP-Seq analysis of enriched fractions of spermatocytes and spermatids. In both cell types, BRDT binding sites were mainly located in promoters, first exon, and introns of genes that are highly transcribed during meiosis and spermiogenesis. Furthermore, in promoters, BRDT binding sites overlapped with several histone modifications and histone variants associated with active transcription, and were also enriched for consensus sequences for specific transcription factors, including MYB, RFX, ETS and ELF1 in pachytene spermatocytes, and JunD, c-Jun, CRE and RFX in round spermatids. Our analysis further revealed that BRDT-bound genes play key roles in diverse biological processes that are essential for proper spermatogenesis. Taken together, our data suggest that BRDT is involved in the recruitment of different transcription factors to distinctive chromatin regions within gene units to regulate diverse downstream target genes that function in male meiosis and spermiogenesis.
Two Brain Pathways Initiate Distinct Forward Walking Programs in Drosophila


An animal at rest or engaged in stationary behaviors can instantaneously initiate goal-directed walking. How descending brain inputs trigger rapid transitions from a non-walking state to an appropriate walking state is unclear. Here, we identify two specific neuronal classes in the Drosophila brain that drive two distinct forward walking programs in a context-specific manner. The first class, named P9, consists of descending neurons that drive forward walking with ipsilateral turning. P9 receives inputs from central courtship-promoting neurons and visual projection neurons and is necessary for a male to track a female during courtship. The second class comprises novel, higher order neurons, named BPN, that drives straight, forward walking. BPN is required for high velocity walking and is active during long, fast, straight walking bouts. Thus, this study reveals separate brain pathways for object-directed steering and fast straight walking, providing insight into how the brain initiates different walking programs.
The complete chloroplast genome sequence of Vitis pseudoreticulata

Abstract Vitis pseudoreticulata is a wild Vitis species distributed in Southern China and wildly used to crossbreeding based on its resistance to moisture. In this study, the complete chloroplast genome of V. pseudoreticulata was assembled for the first time. The chloroplast genome was 161,065 bp in length, including two single-copy regions (19,083 and 89,276), which separated by a pair of inverted repeat regions. In totally, 132 genes were predicted, including 87 CDSs, 8 rRNA genes and 37 tRNA genes. The phylogenetic tree analysis showed that V. pseudoreticulata was the closest related to Vitis amurensis.
On the systematics and ecology of two new species of Provanna (Gastropoda: Provannidae) from deep-sea hydrothermal vents in the Caribbean Sea and Southern Ocean

The recent discovery and exploration of deep-sea hydrothermal vent fields in the Mid-Cayman Spreading Centre, Caribbean Sea (Beebe Vent Field, 4956–4972 m depth) and the East Scotia Ridge, Southern Ocean (E2 and E9 vent fields, 2394–2641 m depth) have yielded extensive collections of two new provannid species, Provanna beebei n. sp. and P. cooki n. sp. Morphological and molecular taxonomy (530 bp of the mitochondrial cytochrome c oxidase subunit I gene) confirm P. beebei n. sp. and P. cooki n. sp. as distinct species; these species are formally described, and details are provided of their distribution, habitat and species associations. Bayesian and maximum likelihood analyses support the placement of P. beebei n. sp. and P. cooki n. sp within the genus Provanna and show that these two new deep-sea species form a well-supported clade with the abyssal West Pacific P. cingulata. Provanna beebei n. sp. and P. cooki n. sp. represent the first records of Provanna from hydrothermal vents in the Caribbean Sea and Southern Ocean, respectively, and extend the known geographic range of the genus. For the first time, intraspecific phenotypic variation in size and sculpture has been reported for Provanna. At the East Scotia Ridge, shell-size frequency distributions and median shell size of P. cooki n. sp. varied significantly between the E2 and E9 vent fields, as well as between diffuse flow and high-temperature venting habitats within each field. The variation in shell sculpture in relation to habitat was also observed in P. cooki n. sp.
First pollen record for Ancyloscelis apiformes (Apidae: Emphorini) in Central Amazon

Abstract The first pollen study for the solitary bee Ancyloscelis apiformes (Emphorini) in a nest aggregation in the Central Amazon was made in October 2012 at the Sucupira apiary in east Manaus, Amazonas, at 03° 00ʹ 05″ S, 59° 51ʹ 05″ W. A total of 15 samples/nests (N1–N15) were analysed, including intact pollen loads (stored inside the nest) and post-emergence residues, which were acetolysed and mounted in glycerine gelatin. From each sample, 500 pollen grains were counted to determine the pollen frequencies and diversity (H′) and evenness (J′) indices. The most representative pollen types were Bonamia ferruginea (N1 = 95.6% and N2 = 96.00%) and the Ipomoea (N3 = 96.40%), both of which belong to the Convolvulaceae. In addition, Byrsonima crispa (N10 = 93.40%) and Malpighia glabra (N7 = 90.20% and N9 = 97.60%), representatives of the Malpighiaceae, were classified as temporary specialisation events with frequencies above 90%. In this study, A. apiformes, which is considered an oligolectic bee species, presented a polylectic tendency since it collected large percentages of pollen types from plants in distinct families that were not phylogenetically related.