Biology subjects

Yu, S.

Publications and source records attributed to Yu, S..

18 recordsLinked to original sources

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↗

bioRxiv2018

The plasma miR-122 basal levels respond to circulating catecholamine in rats

miR-122 in circulation is a promising non-invasive biomarker as a replacement or supplement of current serum biomarkers for liver injuries. But the concept was questioned by recent studies, mainly due to its release from hepatocytes in absence of overt cellular injuries. In this study, we reported that the hepatic metabolism of circulating catecholamines resulted in the release of hepatocyte-specific miR-122. Acute stress-induced hepatocellular deformation was histopathologically different from drug-induced liver injury with significant increases of plasma miR-122 levels. The basal levels of human plasma miR-122 could be significantly altered by emotional responses. Interday variances of plasma miR-122 measurements were reduced effectively by stress-relief measures. The metabolism of basal circulating norepinephrine and epinephrine in liver might contribute to the basal levels of plasma miRNAs expressed in hepatocytes.

molecular biology↗

bioRxiv2018

Data-mining of Antibiotic Resistance Genes Provides Insight into the Community Structure of Ocean Microbiome

BackgroundAntibiotics have been spread widely in environments, asserting profound effects on environmental microbes as well as antibiotic resistance genes (ARGs) within these microbes. Therefore, investigating the associations between ARGs and bacterial communities become an important issue for environment protection. Ocean microbiomes are potentially large ARG reservoirs, but the marine ARG distribution and its associations with bacterial communities remain unclear.\n\nMethodswe have utilized the big-data mining techniques on ocean microbiome data to analysis the marine ARGs and bacterial distribution on a global scale, and applied comprehensive statistical analysis to unveil the associations between ARG contents, ocean microbial community structures, and environmental factors by reanalyzing 132 metagenomic samples from the Tara Oceans project.\n\nResultsWe identified in total 1,926 unique ARGs and found that: firstly, ARGs are more abundant and diverse in the mesopelagic zone than other water layers. Additionally, ARG-enriched genera are closely connected in co-occurrence network. We also found that ARG-enriched genera are often more abundant than their ARG-less neighbors. Furthermore, we found that samples from the Mediterranean that is surrounded by human activities often contain more ARGs.\n\nConclusionOur research for investigating the marine ARG distribution and revealing the association between ARG and bacterial communities provide a deeper insight into the marine bacterial communities. We found that ARG-enriched genera were often more abundant than their ARG-less neighbors in the same environment, indicating that genera enriched with ARGs might possess an advantage over others in the competition for survival in the oceanic microbial communities.

microbiology↗

bioRxiv2017

Verbalizing phylogenomic conflict: Representation of node congruence across competing reconstructions of the neoavian explosion

Phylogenomic research is accelerating the publication of landmark studies that aim to resolve deep divergences of major organismal groups. Meanwhile, systems for identifying and integrating the novel products of phylogenomic inference - such as newly supported clade concepts - have not kept pace. However, the ability to verbalize both node concept congruence and conflict across multiple, (in effect) simultaneously endorsed phylogenomic hypotheses, is a critical prerequisite for building synthetic data environments for biological systematics, thereby also benefitting other domains impacted by these (conflicting) inferences. Here we develop a novel solution to the conflict verbalization challenge, based on a logic representation and reasoning approach that utilizes the language of Region Connection Calculus (RCC-5) to produce consistent alignments of node concepts endorsed by incongruent phylogenomic studies. The approach employs clade concept labels to individuate concepts used by each source, even if these carry identical names. Indirect RCC-5 modeling of intensional (property-based) node concept definitions, facilitated by the local relaxation of coverage constraints, allows parent concepts to attain congruence in spite of their differentially sampled children. To demonstrate the feasibility of this approach, we align two recently published phylogenomic reconstructions of higher-level avian groups that entail strong conflict in the \"neoavian explosion\" region. According to our representations, this conflict is constituted by 26 instances of input \"whole concept\" overlap. These instances are further resolvable in the output labeling schemes and visualizations as \"split concepts\", thereby providing the provenance services needed to build truly synthetic phylogenomic data environments. Because the RCC-5 alignments fundamentally reflect the trained, logic-enabled judgments of systematic experts, future designs for such environments need to promote a culture where experts routinely assess the intensionalities of node concepts published by our peers - even and especially when we are not in agreement with each other.

evolutionary biology↗

bioRxiv2017

The fruitENCODE project sheds light on the genetic and epigenetic basis of convergent evolution of climacteric fruit ripening

Fleshy fruit evolved independently multiple times during angiosperm history. Many climacteric fruits utilize the hormone ethylene to regulate ripening. The fruitENCODE project shows there are multiple evolutionary origins of the regulatory circuits that govern climacteric fruit ripening. Eudicot climacteric fruits with recent whole-genome duplications (WGDs) evolved their ripening regulatory systems using the duplicated floral identity genes, while others without WGD utilised carpel senescence genes. The monocot banana uses both leaf senescence and duplicated floral-identity genes, forming two interconnected regulatory circuits. H3K27me3 plays a conserved role in restricting the expression of key ripening regulators and their direct orthologs in both the ancestral dry fruit and non-climacteric fleshy fruit species. Our findings suggest that evolution of climacteric ripening was constrained by limited availability of signalling molecules and genetic and epigenetic materials, and WGD provided new resources for plants to circumvent this limit. Understanding these different ripening mechanisms makes it possible to design tailor-made ripening traits to improve quality, yield and minimize postharvest losses.\n\nOne Sentence SummaryThe fruitENCODE project discovered three evolutionary origins of the regulatory circuits that govern climacteric fruit ripening.

genomics↗

bioRxiv2017

Exchange protein directly activated by cAMP plays a critical role in regulation of vascular fibrinolysis

RationaleTo maintain vascular patency, endothelial cells (ECs) actively regulate hemostasis. Among the myriad of pathways by which they control both fibrin formation and fibrinolysis is EC expression of annexin A2 (ANXA2) in a heterotetrameric complex with S100A10 [(ANXA2-S100A10)2]. This complex is a well-recognized endothelial surface platform for the activation of plasminogen by tissue plasminogen activator. A noteworthy advance in this field came about when it was shown that the cAMP pathway is linked to the regulation of (ANXA2-S100A10)2 in ECs.\n\nObjectiveThese findings prompted us to determine whether a druggable target, namely the exchange protein directly activated by cAMP (EPAC) pathway, plays a role in vascular luminal fibrinolysis.\n\nMethods and ResultsTaking advantage of our Epac1-null mouse model, we found that depletion of Epac1 results in fibrin deposition, fibrinolytic dysfunction, and decreased endothelial surface ANXA2 in mice, which are similar to phenomena discovered in ANXA2-null and S100A10-null mice. We observed upregulation of EPAC1 and downregulation of fibrin in endocardial tissues beneath atrial mural thrombi in humans. Of note, our thrombosis model revealed that dysfunction of fibrinolysis in EPAC1-null mice can be ameliorated by recombinant ANXA2. Furthermore, we demonstrated that suppression of EPAC1 using a small-molecule inhibitor (ESI09) reduces the expression of ANXA2 in lipid rafts and impedes ANXA2 association with S100A10. Endothelial apical surface expression of both ANXA2 and S100A10 were markedly decreased in ESI09-treated ECs, which was corroborated by results from a nanoforce spectroscopy study. Moreover, inactivation of EPAC1 decreases tyrosine 23 phosphorylation of ANXA2 in the cell membrane compartment.\n\nConclusionsOur data reveal a novel role for EPAC1 in vascular fibrinolysis, by showing that EPAC1 is responsible for the translocation of ANXA2 to the EC surface. This process promotes conversion of plasminogen to plasmin, thereby enhancing local fibrinolytic activity.

cell biology↗

bioRxiv2017

RhlR, but not RhlI, allows P. aeruginosa bacteria to evade Drosophila Tep4- mediated opsonization

When Drosophila flies feed on Pseudomonas aeruginosa strain PA14, some bacteria cross the intestinal barrier and start proliferating inside the hemocoel. This process is limited by hemocytes through phagocytosis. We have previously shown that the PA14 quorum-sensing regulator RhlR is required for these bacteria to elude the cellular immune response. RhlI synthesizes the auto-inducer signal that activates RhlR. Here, we compare the null mutant phenotypes of rhlR and rhlI in a variety of infection assays in Drosophila and in the nematode Caenorhabditis elegans. Surprisingly, in Drosophila, unlike{Delta} rhlR mutants,{Delta} rhlI mutants are only modestly attenuated for virulence and are poorly phagocytosed and opsonized in a Thioester-containing Protein4-dependent manner. Likewise, {Delta}rhlI but not {Delta}rhlR mutants colonize the digestive tract of C. elegans and kill it as efficiently as wild-type PA14. Thus, RhlR has an RhlI-independent function in eluding detection or counter-acting the action of the immune system. In contrast to the intestinal infection model, Tep4 mutant flies are more resistant to PA14 in a septic injury model, which also depends on rhlR. Thus, the Tep4 putative opsonin can either be protective or detrimental to host defense depending on the infection route.

immunology↗

bioRxiv2017

DNA 5-Hydroxymethylcytosines from Cell-free Circulating DNA as Diagnostic Biomarkers for Human Cancers

DNA modifications such as 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) are epigenetic marks known to affect global gene expression in mammals(1, 2). Given their prevalence in the human genome, close correlation with gene expression, and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology(3), we report here genome-wide 5hmC profiling in circulating cell-free DNA (cfDNA) and in genomic DNA of paired tumor/adjacent tissues collected from a cohort of 90 healthy individuals and 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver, or thyroid cancer. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures in cfDNA were identified with specificity for different cancers. 5hmC-based biomarkers of circulating cfDNA demonstrated highly accurate predictive value for patients with colorectal and gastric cancers versus healthy controls, superior to conventional biomarkers, and comparable to 5hmC biomarkers from tissue biopsies. This new strategy could lead to the development of effective blood-based, minimally-invasive cancer diagnosis and prognosis approaches.

cancer biology↗