Biology subjects

Luo, J.

Publications and source records attributed to Luo, J..

At least 253 records · Page 14Linked to original sources

bioRxiv2021

High-throughput variant detection using a color-mixing strategy in real-time PCR reactions

Many diseases are related to multiple genetic alterations along a single gene. Probing for highly multiple (>10) variants in a single qPCR tube is not possible due to a limited number of fluorescence channels and one variant per channel, so many more tubes are needed. Here, we experimentally validate our novel color-mixing strategy that uses fluorescence combinations as digital color codes to probe multiple variants simultaneously. The color-mixing strategy relies on a simple intra-tube assay that can probe for 15 variants as part of an inter-tube assay that can probe for an exponentially increased number of variants. The color-mixing strategy is achieved using multiplex double-stranded toehold probes modified with fluorophores and quenchers; the probes are designed to be quenched or luminous after binding to wildtype or variant templates. We used the color-mixing strategy to probe for 21 pathogenic mutations in thalassemia and to distinguish between heterozygous and homozygous variants in 6 tubes, with a specificity of 99% and a sensitivity of 94%. To support tuberculosis diagnosis, we used the same strategy to simultaneously probe in Mycobacterium tuberculosis for rifampicin-resistance mutations occurring within one 81-bp region and one 48-bp region in rpoB gene, plus five isoniazid-resistance mutations in inhA and katG genes.

genetics↗

bioRxiv2021

Haemosporidian Blood Parasites in nestling birds of prey in Mongolia

Haemosporidians are vector-transmitted intracellular parasites that happen in numerous bird species worldwide and may possibly have important effects for wild bird populations. Studies of haemosporidians most dedicated on Europe and North America, and only newly some study in the Neotropics has been done, where the occurrence and influences of the disease have been less considered and are not understood well. In this study we designed a study in the nestling birds of prey in Mongolia. We sampled blood from 72 raptors at 2 different species and evaluated avian haemosporidian infection by two nested PCR protocol and one Real time PCR protocol. Sequencing a portion of the cytochrome b (cyt b) gene of the parasite. From the sampled birds, 10 % were infected by Plasmodium. Inclusive, our findings advocate a high haemosporidian species richness in the bird community of Mongolia. In view of the frequency of local habitat loss that in this area is living, recognize how avian haemosporidians affect bird populations it is very important; in addition, more exhaustive sampling is required to fully understand the range of avian haemosporidian infection in this area.

microbiology↗

bioRxiv2021

The Human Tumor Atlas Network (HTAN) Breast PreCancer Atlas: A multi-omic integrative analysis of ductal carcinoma in situ with clinical outcomes

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We identified 812 genes associated with ipsilateral recurrence within 5 years from treatment and developed a classifier that was predictive of DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions were identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome. HIGHLIGHTS Development of a new classifier for DCIS recurrence or progression Outcome associated pathways identified across multiple data types and compartments Four stroma-specific signatures identified CNAs characterize DCIS subgroups associated with high risk invasive cancers

cancer biology↗

bioRxiv2021

Induce Pluripotency via Specific distal enhancer-promoter associations

Induced pluripotent stem cell (iPSC) technology promises to be an inexhaustible source of any type of cell needed for therapeutic and research purposes. It is unclear that how distal enhancer-promoter associations/ 3D chromatin conformation involving in the capacity of self-renewal and pluripotency maintenance. In this study, we have selected a few defined enhancer-promoter associations. After screening of enhancer specificity and activity individually, we design the different combinations and transfect these enhancers into the MEF cells. We simultaneously transfect 7 determined enhancers which represents various specific distal chromatin associations into a GFP tracing MEF cell line. We observe that the MEF cells start generating iPS-like clones at day 22. Importantly, our validations with three germ layer marker genes and in vitro experiments have further confirmed the pluripotency of these clones. Here, our study proposes a potential de novo method of a low-genetic risk iPS generation by introducing spatiotemporal distal chromatin associations. This result also paves out the way on utilizing 3D genomic information to alter cell identity and reprogramming for potential therapeutic strategy.

genomics↗

bioRxiv2021

African swine fever virus structural protein p17 inhibits cGAS-STING signaling pathway through interacting with STING

African swine fever (ASF) is highly contagious, causes high mortality in domestic and feral swine, and has a significant economic impact on the global swine industry due to the lack of a vaccine or an effective treatment. African swine fever virus (ASFV) encodes more than 150 polypeptides, which may have intricate and delicate interactions with the host for the benefit of the virus to evade the hosts defenses. However, currently, there is still a lack of information regarding the roles of the viral proteins in host cells. Here, our data demonstrated that the p17, encoded by D117L gene could suppress porcine cGAS-STING signaling pathway, exhibiting the inhibitions of TBK1 and IRF3 phosphorylations, downstream promoter activities, cellular mRNA transcriptions and ISG56 induction, and antiviral responses. Further, we found that p17 was located in endoplasmic reticulum (ER) and Golgi apparatus, and interacted with STING, perturbing it in the recruitment of TBK1 and IKK{varepsilon}. Additionally, it appeared that the transmembrane domain (amino acids 39-59) of p17 could be required for interacting with STING and inhibiting cGAS-STING pathway. Taken together, p17 could inhibit the cGAS-STING pathway through its interaction with STING and interference with STING in the recruitment of TBK1 and IKK{varepsilon}. ImportanceAfrican swine fever (ASF) is a highly contagious disease in domestic and feral swine, posing significant economic impacts on the global swine industry, and the pathogen ASFV is a large icosahedral DNA virus. The innate immune cGAS-STING DNA sensing pathway plays a critical role in sensing invading ASFV and triggering antiviral responses. However, there is still a lack of information regarding the molecular mechanisms of ASFV evasion of the cGAS-STING pathway. We have analyzed the effects of whole genomic open reading frames (ORFs) of ASFV China 2018/1 on the activation of cGAS-STING pathway, and found that p17 was able to inhibit cGAS-STING mediated type I IFN production by targeting STING, altering its capacity to recruit both TBK1 and IKK{varepsilon}. Findings presented here will expand our knowledge on the molecular mechanisms by which ASFV counteracts the antiviral innate immunity and provide deep insights into ASF pathogenesis.

immunology↗

bioRxiv2021

The African swine fever virus protease pS273R inhibits DNA sensing cGAS-STING pathway by targeting IKKε

African swine fever virus (ASFV), a large and complex cytoplasmic double-stranded DNA virus, has developed multiple strategies to evade the antiviral innate immune responses. Cytosolic DNA arising from invading ASFV is mainly detected by the cyclic GMP-AMP synthase (cGAS) and then triggers a series of innate immune responses to prevent virus invasion. However, the immune escape mechanism of ASFV remains to be fully clarified. The pS273R of ASFV is a member of the SUMO-1-specific protease family and is crucial for valid virus replication. In this study, we identified pS273R as a suppressor of cGAS-STING pathway mediated type I interferon (IFN) production by ASFV genomic open reading frame screening. The pS273R was further confirmed as an inhibitor of IFN production as well as its downstream antiviral genes in cGAS-STING pathway. Mechanistically, pS273R greatly decreased the cGAS-STING signaling by targeting IKK{varepsilon} but not TBK1 and pS273R was found to disturb the interaction between IKK{varepsilon} and STING through its interaction with IKK{varepsilon}. Further, mutational analyses revealed that pS273R antagonized the cGAS-STING pathway by enzyme catalytic activity, which may affect the IKK{varepsilon} sumoylation state required for the interaction with STING. In summary, our results revealed for the first time that pS273R acts as an obvious negative regulator of cGAS-STING pathway by targeting IKK{varepsilon} via its enzymatic activity, which shows a new immune evasion mechanism of ASFV. ImportanceAfrican swine fever (ASF) is a devastating disease for domestic pigs and wild boar and the pathogen ASFV is a cytoplasmic double-stranded DNA virus. The innate immune cGAS-STING-IFN signaling pathway exerts a critical role in sensing ASFV infection. However, the functions of half ASFV encoded 150 plus proteins are still unknown and the evasion against the cGAS-STING pathway is not resolved. In our study, via ASFV genomic open reading frame (ORF) screening, we found that 29 ASFV proteins could inhibit cGAS-STING signaling pathway, with pS273R showing the most obvious inhibitory effect. Surprisingly, pS273R was found to antagonize the cGAS-STING signaling by targeting IKK{varepsilon}. Moreover, the pS273R enzyme activity is required for its ability to inhibit the cGAS-STING pathway. Our findings deepen the understanding of the immune evasion mechanism of ASFV, which will provide a support for the development of safe and effective ASFV vaccines.

immunology↗

bioRxiv2021

Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in both wildtype and transformed murine astrocytes and patient-derived GBM cell lines. Using a novel Four Core Genotypes model of GBM, we further show that sex differences in p21-induced senescence are patterned by gonadal sex. These data suggest that sex differences in p21 induced senescence contribute to the female survival advantage in GBM.

cancer biology↗

bioRxiv2021

Flexibility-aware graph-based algorithm improves antigen epitopes identification

Epitopes of an antigen are the surface residues in the spatial proximity that can be recognized by antibodies. Identifying such residues has shown promising potentiality in vaccine design, drug development and chemotherapy, thus attracting extensive endeavors. Although great efforts have been made, the epitope prediction performance is still unsatisfactory. One possible issue accounting to this poor performance could be the ignorance of structural flexibility of antigens. Flexibility is a natural characteristic of antigens, which has been widely reported. However, this property has never been used by existing models. To this end, we propose a novel flexibility-aware graph-based computational model to identify epitopes. Unlike existing graph-based approaches that take the static structures of antigens as input, we consider all possible variations of the side chains in graph construction. These flexibility-aware graphs, of which the edges are highly enriched, are further partitioned into subgraphs by using a graph clustering algorithm. These clusters are subsequently expanded into larger graphs for detecting overlapping residues between epitopes if exist. Finally, the expanded graphs are classified as epitopes or non-epitopes via a newly designed graph convolutional network. Experimental results show that our flexibility-aware model markedly outperforms existing approaches and promotes the F1-score to 0.656. Comparing to the state-of-the-art, our approach makes an increment of F1-score by 16.3%. Further in-depth analysis demonstrates that the flexibility-aware strategy contributes the most to the improvement. The source codes of the proposed model is freely available at https://github.com/lzhlab/epitope. Author summaryEpitope prediction is helpful to many biomedical applications so that dozens of models have been proposed aiming at improving prediction efficiency and accuracy. However, the performances are still unsatisfactory due to its complicated nature, particularly the noteworthy flexible structures, which makes the precise prediction even more challenging. The existing approaches have overlooked the flexibility during model construction. To this end, we propose a graph model with flexibility heavily involved. Our model is mainly composed of three parts: i) flexibility-aware graph construction; ii) overlapping subgraph clustering; iii) graph convolutional network-based subgraph classification. Experimental results show that our newly proposed model markedly outperforms the existing best ones, making an increment of F1-score by 16.3%.

bioinformatics↗

bioRxiv2021

Long-term stress and trait anxiety alter brain network balance in dynamic decisions during working memory

Long-term stress has a profound impact on the human brain and cognition, and trait anxiety influences stress-induced adaptive and maladaptive effects. However, the neurocognitive mechanisms underlying long-term stress and trait anxiety interactions remain elusive. Here we investigated how long-term stress and trait anxiety interact to affect dynamic decisions during working-memory (WM) by altering functional brain network balance. In comparison to controls, male participants under long-term stress experienced higher psychological distress and exhibited faster evidence accumulation but had a lower decision-threshold during WM. This corresponded with hyper-activation in the anterior insula, less WM-related deactivation in the default-mode network, and stronger default-mode network decoupling with the frontoparietal network. Critically, high trait anxiety under long-term stress led to slower evidence accumulation through higher WM-related frontoparietal activity, and increased decoupling between the default-mode and frontoparietal networks. Our findings provide neurocognitive evidence for long-term stress and trait anxiety interactions on executive functions with (mal)adaptive changes.

neuroscience↗

bioRxiv2021

A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk

The human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms--the blood-brain barrier--impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimers disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmed in situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.

neuroscience↗

bioRxiv2021

A bacterial "shield and sword": A previously uncharacterized two-component system protects uropathogenic Escherichia coli from host-derived oxidative insults and promotes hemolysin-mediated host cell pyroptosis

Uropathogenic Escherichia coli (UPEC) deploys an array of virulence factors to successfully establish urinary tract infections. Coordinated expression of these various virulence factors is critical for UPECs overall fitness in the host. Two-component signaling systems (TCSs) are a major mechanism by which bacteria sense environmental cues and initiate adaptive responses. Here, we report a previously uncharacterized TCS encoded on a pathogenicity island in UPEC that directly activates the expression of a putative methionine sulfoxide reductase system (C3566/C3567) and a pore-forming -hemolysin in response to host-derived hydrogen peroxide (H2O2) exposure. The TCS increases UPEC resistance to H2O2 in vitro and survival in macrophages in tissue culture via C3566/C3567. Additionally, the TCS mediates -hemolysin-induced renal epithelial cell and macrophage death via a pyroptosis pathway. Taken together, our data suggest a paradigm in which this signal transduction system coordinates both bacterial pathogen defensive and offensive traits in the presence of host-derived signals.

microbiology↗

bioRxiv2021

Comprehensive epigenomic profiling of human alveolar epithelial differentiation identifies key epigenetic states and transcription factor co-regulatory networks for maintenance of distal lung identity

Disruption of alveolar epithelial cell (AEC) differentiation is implicated in peripheral lung diseases strongly impacting morbidity and mortality worldwide, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma. Elucidating underlying disease pathogenesis requires a mechanistic molecular understanding of AEC differentiation. However, to date no study has comprehensively characterized the dynamic epigenomic alterations that facilitate this critical process in humans. We comprehensively profiled the epigenomic states of human AECs during type 2 to type 1-like cell differentiation, including the methylome and chromatin functional domains, and integrated this with transcriptome-wide RNA expression. Enhancer regions were drastically altered during AEC differentiation. Transcription factor binding analysis within enhancer regions revealed diverse interactive networks with enrichment for dozens of transcription factors, including NKX2-1 and FOXA family members, as well as transcription factors with previously uncharacterized roles in lung differentiation, such as members of the MEF2, TEAD, and AP1 families. Additionally, associations between transcription factors changed during differentiation, implicating a complex network of heterotrimeric complex switching may be involved in facilitating differentiation. Integration of AEC enhancer states with the catalog of enhancer elements in the Roadmap Epigenomics Mapping Consortium and Encyclopedia of DNA Elements (ENCODE) revealed that human mammary epithelial cells (HMEC) have a similar epigenomic structure to alveolar epithelium, with NKX2-1 serving as a distinguishing feature of distal lung differentiation. Taken together, our results suggest that enhancer regions with dynamic transcription factor interactions are hotspots of epigenomic alteration that help to facilitate AEC differentiation. Author SummaryHuman health and disease states are heavily influenced by the critical cellular processes that regulate and protect our genomes. One of these safeguards is the epigenome; the coordinated set of signals overlaid on top of our DNA that controls what can happen to a given stretch DNA. Hence, epigenomic signatures play a critical role in the development and maintenance of cellular fate and function. To determine the relationship between epigenomic alterations and cellular fates of distal lung cells in humans during the process that regenerates the human lung epithelial layer after injury, we performed comprehensive genome-wide profiling of many epigenetic modifications that have roles in regulating the function of the underlying DNA. We found that changes to enhancer regions, which act to turn on associated gene expression, were the major alterations to the epigenome during distal lung differentiation, and that within those regions dynamic changes in transcription factor associations were occurring to facilitate this process. We then characterize what was similar and distinct to the enhancers of distal lung from among other epithelial tissues and describe a novel role for specific transcription factors in this process that previously had no known role in normal lung repair.

genomics↗

bioRxiv2021

Portrait of a genus: the genetic diversity of Zea

Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in the wild relatives of maize. Here, we characterize a high-density genomic variation map from ~700 genomes encompassing maize and all wild taxa of the genus Zea, identifying over 65 million single nucleotide polymorphisms (SNPs), 8 million Insertion/Deletion (InDel) polymorphisms, and over one thousand novel inversions. The variation map reveals evidence of selection within taxa displaying novel adaptations such as perenniality and regrowth. We focus in detail on evidence of convergent adaptation in highland teosinte and temperate maize. This study not only indicates the key role of hormone related pathways in highland adaptation and flowering time related pathways in high latitude adaptation, but also identifies significant overlap in the genes underlying adaptations to both environments. To show how this data can identify useful genetic variants, we generated and characterized novel mutant alleles for two flowering time candidate genes. This work provides the most extensive sampling to date of the genetic diversity inherent in the genus Zea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.

evolutionary biology↗

bioRxiv2021

Sex-specific, pdfr-1-dependent modulation of pheromone avoidance by food abundance enables flexibility in C. elegans foraging behavior

To make adaptive feeding and foraging decisions, animals must integrate diverse sensory streams with multiple dimensions of internal state. In C. elegans, foraging and dispersal behaviors are influenced by food abundance, population density, and biological sex, but the neural and genetic mechanisms that integrate these signals are poorly understood. Here, by systematically varying food abundance, we find that chronic avoidance of the population-density pheromone ascr#3 is modulated by food thickness, such that hermaphrodites avoid ascr#3 only when food is scarce. The integration of food and pheromone signals requires the conserved neuropeptide receptor PDFR-1, as pdfr-1 mutant hermaphrodites display strong ascr#3 avoidance even when food is abundant. Conversely, increasing PDFR-1 signaling inhibits ascr#3 aversion when food is sparse, indicating that this signal encodes information about food abundance. In both wild-type and pdfr-1 hermaphrodites, chronic ascr#3 avoidance requires the ASI sensory neurons. In contrast, PDFR-1 acts in interneurons, suggesting that it modulates processing of the ascr#3 signal. Although a sex-shared mechanism mediates ascr#3 avoidance, food thickness modulates this behavior only in hermaphrodites, indicating that PDFR-1 signaling has distinct functions in the two sexes. Supporting the idea that this mechanism modulates foraging behavior, ascr#3 promotes ASI-dependent dispersal of hermaphrodites from food, an effect that is markedly enhanced when food is scarce. Together, these findings identify a neurogenetic mechanism that sex-specifically integrates population and food abundance, two important dimensions of environmental quality, to optimize foraging decisions. Further, they suggest that modulation of attention to sensory signals could be an ancient, conserved function of pdfr-1.

neuroscience↗

bioRxiv2021

Epigallocatechin Gallate from Green Tea Effectively Blocks Infection of SARS-CoV-2 and New Variants by Inhibiting Spike Binding to ACE2 Receptor

As the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Here, we demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.

microbiology↗

bioRxiv2021

A H3K9me2-Binding Protein AGDP3 Limits DNA Methylation and Transcriptional Gene Silencing in Arabidopsis

DNA methylation is critical for tuning gene expression to prevent potentially deleterious gene-silencing. The Arabidopsis DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1) initiates active DNA demethylation and is required for the prevention of DNA hypermethylation at thousands of genomic loci. However, the mechanism recruiting ROS1 to specific loci is not well understood. Here, we report the discovery of Arabidopsis AGENET Domain Containing Protein 3 (AGDP3) as a cellular factor required for ROS1-mediated DNA demethylation, and targets ROS1 to specific loci. We found that AGDP3 could bind to the H3K9me2 mark by its AGD12 cassette. The crystal structure of the AGDP3 AGD12 in complex with an H3K9me2 peptide reveals the molecular basis for the specific recognition, that the dimethylated H3K9 and unmodified H3K4 are specifically anchored into two different surface pockets. Interestingly, a histidine residue located in the methylysine binding aromatic cage enables AGDP3 pH-dependent H3K9me2 binding capacity. Considering the intracellular pH correlates with the histone acetylation status, our results provide the molecular mechanism for the regulation of ROS1 DNA demethylase by the gene silencing H3K9me2 mark and the potential crosstalk with active histone acetylation mark.

plant biology↗

bioRxiv2021

Graph Contextualized Attention Network for Predicting Synthetic Lethality in Human Cancers

MotivationSynthetic Lethality (SL) plays an increasingly critical role in the targeted anticancer therapeutics. In addition, identifying SL interactions can create opportunities to selectively kill cancer cells without harming normal cells. Given the high cost of wet-lab experiments, in silico prediction of SL interactions as an alternative can be a rapid and cost-effective way to guide the experimental screening of candidate SL pairs. Several matrix factorization-based methods have recently been proposed for human SL prediction. However, they are limited in capturing the dependencies of neighbors. In addition, it is also highly challenging to make accurate predictions for new genes without any known SL partners. ResultsIn this work, we propose a novel graph contextualized attention network named GCATSL to learn gene representations for SL prediction. First, we leverage different data sources to construct multiple feature graphs for genes, which serve as the feature inputs for our GCATSL method. Second, for each feature graph, we design node-level attention mechanism to effectively capture the importance of local and global neighbors and learn local and global representations for the nodes, respectively. We further exploit multi-layer perceptron (MLP) to aggregate the original features with the local and global representations and then derive the feature-specific representations. Third, to derive the final representations, we design feature-level attention to integrate feature-specific representations by taking the importance of different feature graphs into account. Extensive experimental results on three datasets under different settings demonstrate that our GCATSL model outperforms 14 state-of-the-art methods consistently. In addition, case studies further validate the effectiveness of our proposed model in identifying novel SL pairs. AvailabilityPython codes and dataset are available at: Contactluojiawei@hnu.edu.cn and xlli@i2r.a-star.edu.sg

bioinformatics↗

bioRxiv2020

Super-dosed butyrate induces a revisable metabolic paralysis through transient mitochondrial reprogramming in the gut-brain axis

Background and purposeSodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. However, the toxic effect of SB remains largely unknown. This issue is addressed in current study. Experimental approachSB (0.3 - 2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brain hypothalamus were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect. Key resultsThe temperature was reduced by SB (1.2 -2.5 g/kg) in a dose-dependent manner in mice for 2-4 hr. In the brain, the effect was associated with SB elevation and neurotransmitter (Glutamate and GABA) reduction. The mitochondria exhibited a transient volume expansion and crista loss in the hypothalamic neurons. ADP/ATP ratio was increased with accumulation of intermediate metabolites in the glycolysis, TCA cycle and pentose phosphate pathways. The mitochondrial protein, adenine nucleotide transporter (ANT), was activated for proton transportation leading to a transient potential collapse by proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. The temperature drop was attenuated by i.p. injection of norepinephrine. The HDAC inhibitors, such as SAHA and pyruvate, did not exhibit the same effect. Conclusion and implicationsSuper-dosed SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial reprogramming in the brain. The mechanism was quick activation of ANT proteins for the proton leak in mitochondria.

pharmacology and toxicology↗