Biology subjects

Yu, S.

Publications and source records attributed to Yu, S..

At least 217 records · Page 12Linked to original sources

bioRxiv2019

EPS8 facilitates uncoating of influenza A virus

All viruses balance interactions between cellular machinery co-opted to support replication and host factors deployed to halt the infection. We used gene correlation analysis to perform an unbiased screen for host factors involved in influenza A virus (FLUAV) infection. Our screen identified the cellular factor epidermal growth factor receptor pathway substrate 8 (EPS8) as the highest confidence pro-viral candidate. Knockout and overexpression of EPS8 confirmed its importance in enhancing FLUAV infection and titers. Loss of EPS8 did not affect virion attachment, uptake, or fusion. Rather, our data show that EPS8 specifically functions during virion uncoating. EPS8 physically associated with incoming virion components, and subsequent nuclear import of released ribonucleoprotein complexes was significantly delayed in the absence of EPS8. Our study identified EPS8 as a host factor important for uncoating, a crucial step of FLUAV infection during which the interface between the virus and host is still being discovered.

microbiology↗

bioRxiv2019

High-throughput Multimodal Automated Phenotyping (MAP) with Application to PheWAS

ObjectiveElectronic health records (EHR) linked with biorepositories are a powerful platform for translational studies. A major bottleneck exists in the ability to phenotype patients accurately and efficiently. The objective of this study was to develop an automated high-throughput phenotyping method integrating International Classification of Diseases (ICD) codes and narrative data extracted using natural language processing (NLP).\n\nMethodWe developed a mapping method for automatically identifying relevant ICD and NLP concepts for a specific phenotype leveraging the UMLS. Aggregated ICD and NLP counts along with healthcare utilization were jointly analyzed by fitting an ensemble of latent mixture models. The MAP algorithm yields a predicted probability of phenotype for each patient and a threshold for classifying subjects with phenotype yes/no. The algorithm was validated using labeled data for 16 phenotypes from a biorepository and further tested in an independent cohort PheWAS for two SNPs with known associations.\n\nResultsThe MAP algorithm achieved higher or similar AUC and F-scores compared to the ICD code across all 16 phenotypes. The features assembled via the automated approach had comparable accuracy to those assembled via manual curation (AUCMAP 0.943, AUCmanual 0.941). The PheWAS results suggest that the MAP approach detected previously validated associations with higher power when compared to the standard PheWAS method based on ICD codes.\n\nConclusionThe MAP approach increased the accuracy of phenotype definition while maintaining scalability, facilitating use in studies requiring large scale phenotyping, such as PheWAS.

bioinformatics↗

bioRxiv2019

Characterization of pyruvate dehydrogenase complex E1 alpha and beta subunits of Mycoplasma synoviae

Mycoplasma synoviae (MS) is an important pathogen, causing enormous economic losses to the poultry industry worldwide every year. Therefore, the studies on MS will lay the foundation for diagnosis, prevention and treatment of MS infection. In this study, primers designed based on the sequences of pyruvate dehydrogenase complex (PDC) E1 alpha and beta subunit genes (pdhA and pdhB, respectively) of MS WVU1853 strain in GenBank were used to amplify the pdhA and pdhB genes of MS WVU1853 strain through PCR. Then the prokaryotic expression vectors pET-pdhA and pET-pdhB were constructed and were expressed in Escherichia coli BL21(DE3) cells. Subsequently, the recombinant proteins rMSPDHA and rMSPDHB were purified and anti-rMSPDHA and anti-rMSPDHB sera were prepared by immunizing rabbits, respectively. Finally, the subcellular localization of PDHA and PDHB in MS, binding activity of rMSPDHA and rMSPDHB to chicken plasminogen (Plg) and human fibronectin (Fn), complement-dependent mycoplasmacidal assays, and adherence and adherence inhibition assays were accomplished. The results showed that PDHA and PDHB were distributed both on the surface membrane and within soluble cytosolic fractions of MS cells. The rMSPDHA and rMSPDHB presented binding activity with chicken Plg and human Fn. The rabbit anti-rMSPDHA and anti-rMSPDHB sera had distinct mycoplasmacidal efficacy in the presence of guinea pig complement, and the adherence of MS to DF-1 cells pretreated with Plg was effectively inhibited by treatment with anti-rMSPDHA or anti-rMSPDHB sera. Hence, the study indicates that the surface-associated MSPDHA and MSPDHB are the adhesion-related factors of MS that contributes to bind to Plg/Fn and adhesion to DF-1 cells.

microbiology↗

bioRxiv2019

Dual forms of aging-related NADPH diaphorase neurodegeneration in the sacral spinal cord of aged non-human primates

We discovered two different anomalous NADPH diaphorase (NADPH-d) positive alterations, which were expressed as aging-related NADPH-d positive spheroidal bodies and megaloneurites specially distributed in the superficial dorsal horn, dorsal gray commissure (DGC), lateral collateral pathway (LCP) and sacral parasympathetic nucleus (SPN) in the aged monkeys sacral spinal cord, compared with the cervical, thoracic and lumbar segments. In the gracile nucleus of aged monkeys, only aging-related spheroidal bodies were observed and no megaloneurites occurred. The dense, abnormal NADPH-d positive megaloneurites, extremely different from regular NADPH-d positive fibers, were prominent in the sacral segments and occurred in extending from Lissauers tract (LT) through lamina I along the lateral boundary of the dorsal horn to the region of the SPN. Meanwhile, large diameter punctate NADPH-d activity occurred and scattered in the lateral white matter of the LCP and dorsal root entry zone (DREZ) at the same level of NADPH-d abnormality in the gray matters. Those dot-like NADPH-d alterations were examined by horizontal sectioning and indicated ascending or descending oriental fibers. These NADPH-d megaloneurites had the same composition as the punctate NADPH-d alterations and were co-localized with the VIP immunoreaction, while the ANBs did not coexist with the VIP immunoreaction. Both ANBs and megaloneurites provide consistent evidence that the anomalous neuritic alterations in the aged sacral spinal cord are referred to as a specialized aging marker in the pelvic visceral organs in non-human primates.

neuroscience↗

bioRxiv2018

Human, Nonhuman Primate, and Bat Cells Are Broadly Susceptible to Tibrovirus Particle Cell Entry

In 2012, the genome of a novel rhabdovirus, Bas-Congo virus, was discovered in the acute-phase serum of a Congolese patient with presumed viral hemorrhagic fever. In the absence of a replicating virus isolate, fulfilling Kochs postulates to determine whether Bas-Congo virus is indeed a human virus and/or pathogen has been impossible. However, experiments with vesiculoviral particles pseudotyped with Bas-Congo glycoprotein suggested that Bas-Congo virus particles can enter cells from multiple animals, including humans. In 2015, genomes of two related viruses, Ekpoma virus 1 and Ekpoma virus 2, were detected in human sera in Nigeria. Isolates could not be obtained. Phylogenetic analyses led to the classification of Bas-Congo virus, Ekpoma virus 1, and Ekpoma virus 2 in the same genus, Tibrovirus, together with five biting midge-borne rhabdoviruses (i.e., Beatrice Hill virus, Bivens Arm virus, Coastal Plains virus, Sweetwater Branch virus, and Tibrogargan virus) not known to infect humans. Using individual recombinant vesiculoviruses expressing the glycoproteins of all eight known tibroviruses and more than 75 cell lines representing different animal species, we demonstrate that the glycoproteins of all tibroviruses can mediate vesiculovirus particle entry into human, bat, nonhuman primate, cotton rat, boa constrictor, and Asian tiger mosquito cells. Using four of five isolated authentic tibroviruses (i.e., Bivens Arm virus, Coastal Plains virus, Sweetwater Branch virus, and Tibrogargan virus), our experiments indicate that many cell types may be partially resistant to tibrovirus replication after virion cell entry. Consequently, experimental data solely obtained from experiments using tibrovirus surrogate systems (e.g., vesiculoviral pseudotypes, recombinant vesiculoviruses) cannot be used to predict whether Bas-Congo virus, or any other tibrovirus, infects humans.

microbiology↗

bioRxiv2018

Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

How pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood. We used Nur77--a marker of T cell antigen receptor (TCR) signaling--to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. Moreover, the enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery. As a result, the more autoreactive GFPhi CD4 T cells from SKGNur mice were hyper-responsive to IL-6. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA. Additionally, endogenous Nur77 protein expression was enriched in a subset of synovial CD4 T cells from arthritic joints in SKG mice, consistent with antigen-activated T cells. This was was extended to patients with seropositive RA, suggesting that pathogenic CD4 T cells are enriched in RA joints and are likely recognizing an intra-articular auto-antigen(s).

immunology↗

bioRxiv2018

Effects of Biogas Slurry on Fruit Economic Traits and Soil Nutrient of Camellia oleifera Abel

Soil nutrients play a principal role in Camellia oleifera Abel (oil-seed camellia) production. Camellia oleifera absorbs nutrients from surrounding soils and its production is highly influenced by nutrients or fertilization. In this study, we investigated the effects of biogas slurry applications on soil nutrients and economic traits of C. oleifera fruits. Five different amounts of fertilizing biogas slurry (0, 10, 20, 30, or 40 kg/plant/year from three applications per year) were applied to C. oleifera plants in 2015 and 2016. Rhizosphere soil nutrients and C. oleifera fruit economic traits (yield, seed rate, and oil yield)were measured. Fertilization with biogas slurryincreasedsoil organic matter, available nitrogen (N), phosphorus (P), and potassium (K) in both 2015 and 2016. Increases in soil available N, P, and Kwere largest at the highest slurry application rate and second largest at the second highest application rate. Fruit economic traits were maximized at the two highest application rates. Oil yield was correlated withsoil available P in 2015 and 2016, and soil organic matter in 2015. Fertilization with biogas slurry decreased saturated fatty acid content in fruit but had no effect on unsaturated fatty acid content. In conclusion, fertilization with biogas slurry increases rhizosphere soil nutrients and fruit economic traits of C. oleifera with the rates of at least 30 kg/plant/year having the most positive effects.

plant biology↗

bioRxiv2018

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

Liver-specific knockout of Nrf1 in mice leads to non-alcoholic steatohepatitis with dyslipidemia, and its deterioration results in spontaneous hepatoma, but the underlying mechanism remains elusive. A similar pathological model is herein reconstructed by using human Nrf1-specific knockout cell lines. We demonstrated that a marked increase of the inflammation marker COX2 in Nrf1-/- cells. Loss of Nrf1 leads to hyperactivation of Nrf2, which results from substantial decreases in both Keap1 and PTEN in Nrf1-/- cells. Further investigation of xenograft mice showed that malignant growth of Nrf1-/--derived tumor is almost abolished by silencing Nrf2, while Nrf1+/+-tumor is markedly repressed by inactive Nrf2-/-{Delta}TA, but unaffected by a priori constitutive activator of caNrf2{Delta}N. Mechanistic studies unraveled there exist opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2. Collectively, Nrf1 manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity, while Nrf2 can directly activate the transcriptional expression of Nrf1 to form a negative feedback loop.\n\nHIGHLIGHTSO_LIOpposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2\nC_LIO_LIMalignant growth of Nrf1-/--derived tumor is prevented by silencing Nrf2\nC_LIO_LIHyper-activation of Nrf2 by Nrf1-/- results from decreased Keap1 and PTEN\nC_LIO_LINrf1+/+-tumor is repressed by Nrf2-/-{Delta}TA, but unaltered by its active caNrf2{Delta}N\nC_LI

molecular biology↗

bioRxiv2018

Population based hospitalization burden of laboratory-confirmed hand, foot and mouth disease caused by multiple enterovirus serotypes in southern China

BackgroundHand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is as yet not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China.\n\nMethodsWe enrolled pediatric patients admitted to 3/3 county-level hospitals and 3/23 township level hospitals in Anhua county, Hunan (CN) with HFMD, and collected samples to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. The information of other eligible but un-enrolled patients were retrospectively collected from the same six hospitals. Monthly number of hospitalizations for all causes was collected from each of 23 township level hospitals to extrapolate hospitalizations associated with HFMD among these.\n\nResultsDuring the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one patient was severe. The mean hospitalization rates were 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enteroviruses associated HFMD (134, 39 and 66 per 100,000 person-years, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages.\n\nConclusionsOur study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD.

epidemiology↗

bioRxiv2018

Regulation by HSP70/90 in the different tissues and testis development of male cattle (Cattle-yak and Yak)

HSP70/90 play important role in testis develop and spermatozoa regulation, but the contact of HSP70/90 with infertility in cattle is unclear. Here, we focus on male cattle-yak and yak, which to investigate the expression and localization of HSP70/90 in different tissues, and explore the influence of HSP70/90 to infertility. In our study, a total of 54 cattle (24 cattle-yak and 30 yak) were examined. The HSP90 mRNA of cattle-yak was cloned first and found amino acid variation in HSP90, which led to difference at protein spatial structure compare with yak. To investigate whether the expression of HSP70/90 mRNA and protein are different in cattle-yak and yak, we used real-time quantitative PCR (qRT-PCR) and Western blot (WB) to examine them. We found that the expression level of HSP70/90 mRNA and protein are disparity in different tissues and testis development stages, and obviously high expression was observed in testicle during juvenile and adult, Moreover, it s interestingly in which the HSP70 expression is significant high in yak whereas HSP90 in cattle-yak (P<0.01). On this bases, we detect the location of HSP70/90 in testis by immunohistochemical (IHC) and immunofluorescence (IF), the results demonstrate that HSP70/90 were located in the epithelial cells, spermatogenic cells and mesenchymal cells. In summary, our study proved the expression of HSP70/90 are different in tissues, and the expression of HSP90 is obviously high in testis of cattle-yak, which propose that the infertility of cattle-yak may cause from up-regulating of HSP90.

biochemistry↗

bioRxiv2018

Identification, Genotyping, and Pathogenicity of Trichosporon spp. Isolated from Giant Pandas

Trichosporon is the dominant genus of epidermal fungi in giant pandas and causes local and deep infections. To provide the information needed for the diagnosis and treatment of trichosporosis in giant pandas, the sequence of ITS, D1/D2, and IGS1 loci in 29 isolates of Trichosporon spp. which isolated from the body surface of giant pandas were combination to investigate interspecies identification and genotype. Morphological development was examined via slide culture. Additionally, mice were infected by skin inunction, intraperitoneal injection, and subcutaneous injection for evaluation of pathogenicity. The twenty-nine isolates of Trichosporon spp. were identified as belonging to 11 species, and Trichosporon jirovecii and T. asteroides were the commonest species. Four strains of T. laibachii and one strain of T. moniliiforme were found to be of novel genotypes, and T. jirovecii was identified to be genotype 1. T. asteroides had the same genotype which involved in disseminated trichosporosis. The morphological development processes of the Trichosporon spp. were clearly different, especially in the processes of single-spore development. Pathogenicity studies showed that 7 species damaged the liver and skin in mice, and their pathogenicity was stronger than other 4 species. T. asteroides had the strongest pathogenicity and might provoke invasive infection. The pathological characteristics of liver and skin infections caused by different Trichosporon spp. were similar. So it is necessary to identify the species of Trichosporon on the surface of giant panda. Combination of ITS, D1/D2, and IGS1 loci analysis, and morphological development process can effectively identify the genotype of Trichosporon spp.

microbiology↗

bioRxiv2018

Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1. However, patients with the same genetic defect can have different clinical presentation 2-4, and some individuals carrying known disease-causing variants can appear unaffected 5. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.

genetics↗

bioRxiv2018

Molecular mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct proteoforms within the coupled positive and negative feedback circuits

In an attempt to terminate the chaotic state of the literature on Nrf1/TCF11 with various confused molecular masses, we herein establish a generally acceptable criterion required for identification of its endogenous full-length proteins and derivative isoforms expressed differentially in distinct experimental cell lines. Further work has been focused on the molecular mechanisms that dictate the successive multistate post-translational modifications (i.e. glycosylation by OST, deglycosylation by NGLY, and ubiquitination by Hrd1) of this CNC-bZIP protein and its proteolytic processing to yield multiple isoforms. Several lines of experimental evidence have demonstrated that the nascent Nrf1/TCF11 polypeptide (non-glycosylated) is transiently translocated into the endoplasmic reticulum (ER), in which it becomes an inactive glycoprotein-A, and also folded in a proper topology within and around membranes. Thereafter, dynamic repositioning of the ER-resident domains in Nrf1 glycoprotein is driven by p97-fueled retrotranslocation into extra-ER compartments. Therein, glycoprotein of Nrf1 is allowed for digestion into a deglycoprotein-B and then its progressive proteolytic processing by cytosolic DDI-1/2 and proteasomes to yield distinct proteoforms (i.e. protein-C/D). The processing is accompanied by removal of a major N-terminal ~12.5-kDa polypeptide from Nrf1. Interestingly, our present study has further unraveled that coupled positive and negative feedback circuits exist between Nrf1 and its cognate target genes, including those encoding its regulators p97, Hrd1, DDI-1 and proteasomes. These key players are differentially or even oppositely involved in diverse cellular signalling responses to distinct extents of ER-derived proteotoxic and oxidative stresses induced by different concentrations of proteasomal inhibitors.

biochemistry↗

bioRxiv2018

Catalysis of cataract-associated human γD crystallin aggregation via dynamic disulfide exchange

Several mutations in human {gamma}D-crystallin (H{gamma}D), a long-lived eye lens protein, cause misfolding and aggregation, leading to cataract. Surprisingly, wild-type H{gamma}D catalyzes aggregation of its cataract related W42Q variant while itself remaining soluble - the inverse of the classical prion-like scenario whereby misfolded polypeptides catalyze aggregation of natively folded ones. The search for a biochemical mechanism of catalysis of W42Q aggregation by WT has revealed that WT H{gamma}D can transfer a disulfide bond to the W42Q variant. The transferred disulfide kinetically traps an aggregation-prone intermediate made accessible by the W42Q mutation, facilitating light-scattering aggregation of the W42Q variant. The aggregating variant thus becomes a disulfide sink, removing the disulfides from solution. Such redox \"hot potato\" competitions among wild-type and mutant or modified polypeptides may be relevant for many long-lived proteins that function in oxidizing environments. In these cases aggregation may be forestalled by inhibiting disulfide flow toward damaged polypeptides.

biochemistry↗

bioRxiv2018

Nucleosome remodelling at origins of Global Genome-Nucleotide Excision Repair occurs at the boundaries of higher-order chromatin structure

Repair of UV-induced DNA damage requires chromatin remodeling. How repair is initiated in chromatin remains largely unknown. We recently demonstrated that Global Genome Nucleotide Excision Repair (GG-NER) in chromatin is organized into domains around open reading frames. Here, we identify these domains, and by examining DNA damage-induced changes in the linear structure of nucleosomes, we demonstrate how chromatin remodeling is initiated during repair. In undamaged cells, we show that the GG-NER complex occupies chromatin at nucleosome free regions of specific gene promoters. This establishes the nucleosome structure at these genomic locations, which we refer to as GG-NER complex binding sites (GCBSs). We demonstrate that these sites are frequently located at genomic boundaries that delineate chromasomally interacting domains (CIDs). These boundaries define domains of higher-order nucleosome-nucleosome interaction. We show that efficient repair of DNA damage in chromatin is initiated following disruption of H2A.Z-containing nucleosomes adjacent to GCBSs by the GG-NER complex.

genomics↗

bioRxiv2018

Hedgehog signaling controls progenitor differentiation timing during heart development

Heterochrony, defined as differences in the timing of developmental processes, impacts organ development, homeostasis, and regeneration. The molecular basis of heterochrony in mammalian tissues is poorly understood. We report that Hedgehog signaling activates a heterochronic pathway that controls differentiation timing in multiple lineages. A differentiation trajectory from second heart field cardiac progenitors to first heart field cardiomyocytes was identified by single-cell transcriptional profiling in mouse embryos. A survey of developmental signaling pathways revealed specific enrichment for Hedgehog signaling targets in cardiac progenitors. Removal of Hh signaling caused loss of progenitor and precocious cardiomyocyte differentiation gene expression in the second heart field in vivo. Introduction of active Hh signaling to mESC-derived progenitors, modelled by transient expression of the Hh-dependent transcription factor GLI1, delayed differentiation in cardiac and neural lineages in vitro. A shared GLI1-dependent network in both cardiac and neural progenitors was enriched with FOX family transcription factors. FOXF1, a GLI1 target, was sufficient to delay onset of the cardiomyocyte differentiation program in progenitors, by epigenetic repression of cardiomyocyte-specific enhancers. Removal of active Hh signaling or Foxf1 expression from second heart field progenitors caused precocious cardiac differentiation in vivo, establishing a mechanism for resultant Congenital Heart Disease. Together, these studies suggest that Hedgehog signaling directly activates a gene regulatory network that functions as a heterochronic switch to control differentiation timing across developmental lineages.

developmental biology↗

bioRxiv2018

Holmes-ITS2: Consolidated ITS2 resources and search engines for plant DNA-based marker analyses

Plants are valuable resources for a variety of products in modern societies. Plant species identification is an integral part of research and practical application on plants. In parallel with high-throughput sequencing technology, the high-throughput screening of species is in high demand. Highly accurate and efficient DNA-based marker identification is essential for the effective analysis of plant species or biological constituents of a mixture of plants as well. Therefore, it is of general interests and significance to generate a comprehensive and accurate DNA-based marker sequence resource, as well as to build efficient sequence search engines, for the accurate and fast identification of plant species.\n\nIn this work, we have firstly established a high-quality ITS2 sequence database of plant species containing more than 150,000 entries, through the systematical collection and manually collation of the published ITS2 sequencing data of plant species, data quality control, as well as representative sequence refinement based on clustering method. Secondly, an accurate and efficient plant species identification system based on ITS2 sequence was constructed, which is the proper combination of sequence search algorithms including BLAST and Kraken. Through the deployment of high-performance and frequently updated web service, its expected to serve for a wide range of researchers involving the taxonomy classification of plant species, as well as for deciphering of plant mixed systems including herbal materials in TCM preparations.\n\nThe Holmes-ITS2 web service is freely accessible at: http://its2.tcm.microbioinformatics.org/. The input of this web service could be multiple sequences in a single fasta format, to search for matching ITS2 biomarker sequences already annotated in the database. This sequence-based search is based on two engines: BLAST, and k-mer based Kraken. Alternatively, users can directly search for species name for the corresponding ITS2 biomarker sequences. The web service has been put to the test by more than 50 experts from China, Denmark and US, and the average running time for the search ranges from 3-30 seconds for up to 100 sequences as a batch query.

bioinformatics↗

bioRxiv2018

Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP pathways in macrophages

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of SREBP1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here, we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in liver that lead to hypertriglyceridemia.\n\nSIGNIFICANCE STATEMENTThe beneficial effects of LXR pathway activation in the prevention of atherosclerotic heart disease have long been appreciated. However, efforts to translate those effects in humans with synthetic LXR ligands has been met with the unintended consequence of hypertriglyceridemia, a product of co-activation of SREBP1c. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here, we demonstrate that synthetic desmosterol mimetics activate LXR pathways macrophages both in vitro and in vivo without co-stimulation of SREBP1c. Unexpectedly, desmosterol and synthetic desmosterol mimetics almost no effect on LXR activity in hepatocytes in comparison to conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development.

cell biology↗