Biology subjects

Fan, H.

Publications and source records attributed to Fan, H..

9 recordsLinked to original sources

bioRxiv2018

A Whole-Genome Association Approach for Large-scaled Inter-species Trait

Genome wide association studies (GWAS) have provided an avenue for the association between common genetic variants and complex traits. However, using SNP as a genetic marker, GWAS has been confined to detect genetic basis traits only for within species but not for the large-scale inter-species traits. Here, we propose a practical statistical approach that is using kmer frequencies as the genetic markers to associate genetic variants with large scale inter-species traits. We applied this new approach to the trait of chromosome number in 96 mammalian proteomes, and we prioritized 130 genes including TP53 and BAD, of which 6 were candidate genes. These genes were proved to be associated with cellular reaction of DNA double-strand breaks caused by chromosome fission/fusion. Our study provides a new effective genomic strategy to perform association studies for large-scaled inter-species traits, using the chromosome number as a case. We hope this approach could provide exploration for broadly widely traits.

genomics↗

bioRxiv2018

GrgA as a potential target of selective antichlamydials

Chlamydia is a common pathogen that can causes serious complications in the reproductive system and eyes. Lack of vaccine and other effective prophylactic measures coupled with the largely asymptomatic nature and unrare clinical treatment failure calls for development of new antichlamydials, particularly selective antichlamydials without adverse effects on humans and the beneficial microbiota. We previously reported that benzal-N-acylhydrazones (BAH) can inhibit chlamydiae without detectable adverse effects on host cells and beneficial lactobacilli that dominate the human vaginal microbiota among reproductive-age women. However, the antichlamydial mechanism of BAH is not known. Whereas 4 single nucleotide polymorphisms (i.e., SNP1-4) were identified in a rare Chlamydia variant with a low level of BAH resistance, termed MCR, previous studies failed to establish a causal effect of any particular SNP(s). In the present work, we performed recombination to segregate the four SNPs. Susceptibility tests indicate that the R51G GrgA allele is both necessary and sufficient for the low level of BAH resistance. Thus, the Chlamydia-specific transcription factor GrgA either is a direct target of BAH or regulates BAH susceptibility. We further confirm an extremely low rate of BAH resistance in Chlamydia. Our findings warrant exploration of GrgA as a therapeutic and prophylactic target for chlamydial infections.

microbiology↗

bioRxiv2018

Active information maintenance in working memory by a sensory cortex

Working memory is a critical function of the brain to maintain and manipulate information over delay periods of seconds. Sensory areas have been implicated in working memory; however, it is debated whether the delay-period activity of sensory regions is actively maintaining information or passively reflecting top-down inputs. We hereby examined the anterior piriform cortex, an olfactory cortex, in head-fixed mice performing a series of olfactory working memory tasks. Information maintenance is necessary in these tasks, especially in a dual-task paradigm in which mice are required to perform another distracting task while actively maintaining information during the delay period. Optogenetic suppression of the piriform cortex activity during the delay period impaired performance in all the tasks.Furthermore, electrophysiological recordings revealed that the delay-period activity of the anterior piriform cortex encoded odor information with or without the distracting task.Thus, this sensory cortex is critical for active information maintenance in working memory.

neuroscience↗

bioRxiv2018

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

The regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed five compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that four out of the five drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 M. Structural analysis of the docking poses show the four compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of four novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

bioinformatics↗

bioRxiv2018

A role for GrgA in regulation of σ28-dependent transcription in the obligate intracellular bacterial pathogen Chlamydia trachomatis

The sexually transmitted obligate intracellular bacterial pathogen Chlamydia trachomatis has a unique developmental cycle consisting of two contrasting cellular forms. Whereas the primary Chlamydia sigma factor, {sigma}66, is involved in the expression of the majority of chlamydial genes throughout the developmental cycle, expression of several late genes requires the alternative sigma factor {sigma}28. In prior work we identified GrgA as a Chlamydia-specific transcription factor that activates {sigma}66-dependent transcription by binding DNA and interacting with a non-conserved region (NCR) of {sigma}66. Here, we extend these findings by showing GrgA can also activate {sigma}28-dependent transcription through direct interaction with {sigma}28. We measure the binding affinity of GrgA for both {sigma}66and {sigma}28, and we identify regions of GrgA important for {sigma}28-dependent transcription. Similar to results obtained with {sigma}66, we find that GrgAs interaction with {sigma}28 involves a NCR located upstream of conserved region 2 of {sigma}28. Our findings suggest GrgA is an important regulator of both {sigma}66- and {sigma}28-dependent transcription in C. trachomatis and further highlight NCRs of bacterial RNA polymerase as targets for regulatory factors unique to particular organisms.

microbiology↗

bioRxiv2018

Deciphering the metabolic perturbation in hepatic alveolar echinococcosis: a 1H NMR-based metabolomics study

Hepatic alveolar echinococcosis (HAE) is a chronic and potentially lethal parasitic disease. It is caused by growth of Echinococcus multilocularis larvae in liver. To date, early-stage diagnosis for the disease is not mature due to its long asymptomatic incubation period. In this study, a proton nuclear magnetic resonance (1H NMR) -based metabolomics approach was applied in conjunction with multivariate statistical analysis to investigate the altered metabolic profiles in blood serum and urine samples from HAE patients and to identify characteristic metabolic markers associated with HAE. The current results identified 21 distinctive metabolic difference between the HAE patients and healthy individuals, which can be associated with perturbations in energy metabolism, amino acid metabolism, oxidative stress, and neurotransmitter imbalance. In addition, the Fischer ratio, which is the molar ratio of branched-chain amino acids to aromatic amino acids was found significantly lower (p<0.001) in blood serum from HAE patients. The ratio, together with changes in other metabolic pathways may provide new insight into mechanistic understanding of HAE pathogenesis, and may be useful for early-stage HAE diagnosis.\n\nAuthor SummaryHepatic alveolar echinococcosis (HAE) is a life-threatening disease caused by Echinococcus multilocularis infection. The disease has a long asymptomatic early stage (5~15 years), which complicates effective diagnosis of early-stage HAE even with advanced imaging techniques. Metabolomics is an emerging analytical platform that comprises of analysis of all small molecule metabolites that are present within an organism. The applications of metabolomics method on HAE may help to reveal the molecular biology mechanisms of HAE. In the current study, we had used 1H NMR-based metabolomics technique to investigate blood serum and urine samples from HAE patients. Altered metabolic responses and characteristic differential metabolites for HAE were identified. The metabolic profiling of human biofluids provided valuable information for early-stage HAE diagnosis and for therapeutic interventions, without having to extract HAE vesicles from patients. By featuring global and comprehensive metabolic status, the metabolomics approach holds considerable promise as a noninvasive, dynamic, and effective tool for probing the underlying mechanism of HAE.

systems biology↗

bioRxiv2018

A benchmarking study on virtual ligand screening against homology models of human GPCRs

G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening. For a small subset of GPCRs, we also explored how certain methods like consensus enrichment and sidechain perturbation affect the utility of homology models in virtual screening, as well as the selectivity between agonists and antagonists. Most notably, consensus enrichment across multiple homology models often yields results comparable to the best performing model, suggesting that ligand candidates predicted with consensus scores from multiple models can be the optimal option in practical applications where the performance of each model cannot be estimated.

bioinformatics↗

bioRxiv2018

Metagenomics reveals diet-specific specialization in fungus gardens of grass- and dicot-cutter ants

Leaf-cutter ants in the genus Atta are dominant herbivores in the Neotropics. While most species of Atta cut dicots to incorporate into their fungus gardens, some species specialize on grasses. Here we examine the bacterial community associated with the fungus gardens of grass- and dicot-cutter ants to examine how changes in substrate input affect the bacterial community. We sequenced the metagenomes of 12 Atta fungus gardens, across four species of ants, with a total of 5.316 Gbp of sequence data. We show significant differences in the fungus garden bacterial community composition between dicot- and grass-cutter ants, with grass-cutter ants having lower diversity. Reflecting this difference in community composition, the bacterial functional profiles between the fungus gardens are significantly different. Specifically, grass-cutter ant fungus garden metagenomes are particularly enriched for genes responsible for amino acid, siderophore, and terpenoid biosynthesis while dicot-cutter ant fungus gardens metagenomes are enriched in genes involved in membrane transport. These differences in bacterial community composition and functional capacity show that different substrate inputs matter for fungus garden bacteria, and sheds light on the potential role of bacteria in mediating the ants transition to the use of a novel substrate.

microbiology↗

bioRxiv2017

Reconstructing phylogeny from reduced-representation genome sequencing data without assembly or alignment

Although genome sequencing is becoming cheaper and faster, reducing the quantity of data by only sequencing part of the genome lowers both sequencing costs and computational burdens. One popular genome-reduction approach is restriction site associated DNA sequencing, or RADseq. RADseq was initially designed for studying genetic variation across genomes usually at the population level, and it has also proved to be suitable for interspecific phylogeny reconstruction. RADseq data pose challenges for standard phylogenomic methods, however, due to incomplete coverage of the genome and large amounts of missing data. Alignment-free methods are both efficient and accurate for phylogenetic reconstructions with whole genomes and are especially practical for non-model organisms; nonetheless, alignment-free methods have only been applied with whole genome sequences. Here, we test a full-genome assembly and alignment-free method, AAF, in application to RADseq data and propose two procedures for reads selection to remove missing data. We validate these methods using both simulations and a real dataset. Reads selection improved the accuracy of phylogenetic construction in every simulated scenario and the real dataset, making AAF comparable to or better than alignment-based method with much lower computation burdens. We also investigated the sources of missing data in RADseq and their effects on phylogeny reconstruction using AAF. The AAF pipeline modified for RADseq data, phyloRAD, is available on github (https://github.com/fanhuan/phyloRAD).

bioinformatics↗