Biology subjects

Wang, C.

Publications and source records attributed to Wang, C..

At least 1,045 records · Page 58Linked to original sources

bioRxiv2019

A hierarchical Bayesian latent class mixture model with censorship for detection of linear temporal changes in antibiotic resistance

Identifying and controlling the emergence of antimicrobial resistance (AMR) is a high priority for researchers and public health officials. One critical component of this control effort is timely detection of emerging or increasing resistance using surveillance programs. Currently, detection of temporal changes in AMR relies mainly on analysis of the proportion of resistant isolates based on the dichotomization of minimum inhibitory concentration (MIC) values. In our work, we developed a hierarchical Bayesian latent class mixture model that incorporates a linear trend for the mean log2MIC of the non-resistant population. By introducing latent variables, our model addressed the challenges associated with the AMR MIC values, compensating for the censored nature of the MIC observations as well as the mixed components indicated by the censored MIC distributions. Inclusion of linear regression with time as a covariate in the hierarchical structure allowed modelling of the linear creep of the mean log2MIC in the non-resistant population. The hierarchical Bayesian model was accurate and robust as assessed in simulation studies. The proposed approach was illustrated using Salmonella enterica I,4,[5],12:i:- treated with chloramphenicol and ceftiofur in human and veterinary samples, revealing some significant linearly increasing patterns from the applications. Implementation of our approach to the analysis of an AMR MIC dataset would provide surveillance programs with a more complete picture of the changes in AMR over years by exploring the patterns of the mean resistance level in the non-resistant population. Our model could therefore serve as a timely indicator of a need for antibiotic intervention before an outbreak of resistance, highlighting the relevance of this work for public health. Currently, however, due to extreme right censoring on the MIC data, this approach has limited utility for tracking changes in the resistant population.

microbiology↗

bioRxiv2019

Estimating and testing the microbial causal mediation effect with high-dimensional and compositional microbiome data

MotivationRecent microbiome association studies have revealed important associations between microbiome and disease/health status. Such findings encourage scientists to dive deeper to uncover the causal role of microbiome in the underlying biological mechanism, and have led to applying statistical models to quantify causal microbiome effects and to identify the specific microbial agents. However, there are no existing causal mediation methods specifically designed to handle high dimensional and compositional microbiome data.\n\nResultsWe propose a rigorous Sparse Microbial Causal Mediation Model (SparseMCMM) specifically designed for the high dimensional and compositional microbiome data in a typical three-factor (treatment, microbiome and outcome) causal study design. In particular, linear log-contrast regression model and Dirichlet regression model are proposed to estimate the causal direct effect of treatment and the causal mediation effects of microbiome at both the community and individual taxon levels. Regularization techniques are used to perform the variable selection in the proposed model framework to identify signature causal microbes. Two hypothesis tests on the overall mediation effect are proposed and their statistical significance is estimated by permutation procedures. Extensive simulated scenarios show that SparseMCMM has excellent performance in estimation and hypothesis testing. Finally, we showcase the utility of the proposed SparseMCMM method in a study which the murine microbiome has been manipulated by providing a clear and sensible causal path among antibiotic treatment, microbiome composition and mouse weight.

bioinformatics↗

bioRxiv2019

Recombinant Expression of Aldehyde Dehydrogenase 2 (ALDH2) in Escherichia coli Nissle 1917 for Oral Delivery in ALDH2-Deficient Individuals

Turning red after consuming alcohol may seem like a mere social inconvenience. Yet, this flushing response is caused by an accumulation of acetaldehyde, a carcinogenic intermediate of alcohol metabolism. Aldehyde dehydrogenase 2 (ALDH2) deficiency, the result of a point mutation, produces a less efficient ALDH2. The resulting accumulation of acetaldehyde greatly increases the risk of developing esophageal and head and neck cancers. In this study, we produced recombinant ALDH2 in the probiotic E. coli Nissle 1917, which successfully reduces acetaldehyde levels in simulated oral conditions. Packaged in a hard candy, the ALDH2-probiotic would remain in the mouth to specifically target salivary acetaldehyde. Using mathematical modeling, we also determined how much recombinant ALDH2 is needed to reduce elevated acetaldehyde levels.\n\nFinancial DisclosureThis work was funded by Taipei American School. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting InterestsThe authors have declared that no competing interests exist.\n\nEthics StatementN/A\n\nData AvailabilityYes - all data are fully available without restriction. Sequences for the plasmids used in this study are available through the Registry of Standard Biological Parts. Links to raw data are included in Supplementary Information.

synthetic biology↗

bioRxiv2019

Metagenomic Next-generation Sequencing of Cerebrospinal Fluid for the Diagnosis of Central Nervous System Infections: A Multicentre Prospective Study

BackgroundInfectious encephalitis and meningitis are often treated empirically without identification of the causative pathogen. Metagenomic next-generation sequencing (mNGS) is a high throughput technology that enables the detection of pathogens independent of prior clinical or laboratory information.\n\nMethodsThe present study was a multicentre prospective evaluation of mNGS of cerebrospinal fluid (CSF) for the diagnosis of suspected central nervous system infections.\n\nResultsA total of 276 patients were enrolled in this study between Jan 1, 2017 and Jan 1, 2018. Identification of an etiologic pathogen in CSF by mNGS was achieved in 101 patients (36.6%). mNGS detected 11 bacterial species, 7 viral species, 2 fungal species, and 2 parasitic species. The five leading positive detections were varicella-zoster virus (17), Mycobacterium tuberculosis (14), herpes simplex virus 1 (12), Epstein-Barr virus (12), and Cryptococcus neoformans (7). False positives occurred in 12 (4.3%) patients with bacterial infections known to be widespread in hospital environments. False negatives occurred in 16 (5.8%) patients and included bacterial, viral and fungal aetiologies.\n\nConclusionsmNGS of CSF is a powerful diagnostic method to identify the pathogen for many central nervous system infections.

genomics↗

bioRxiv2019

Screening and functional analysis of differentially expressed genes in an animal model of EBV-associated lymphomas

Epstein-Barr virus (EBV) is an important human oncogenic virus. This paper is to explore how EBV induce malignant transformation of human lymphocytes and the related mechanism of lymphomagenesis. We have constructed hu-PBL/SCID chimeric mice and established a model of EBV-associated human-derived lymphomas. By using Agilent human whole genome microarray and a series of bioinformatic analyses, a total of 202 differentially expressed genes were screened from the EBV-induced lymphomas in hu-PBL/SCID mice, including 44 up-regulated and 158 down-regulated genes. Calculation of the rank score (RS) values of these genes in the HIPPIE protein interaction networks showed that topoisomerase II alpha (TOP2A), ubiquitin like with PHD and ring finger domains 1 (UHRF1), histone cluster 2 H2B family member E (HIST2H2BE), phosphoglycerate dehydrogenase (PHGDH), vinculin (VCL), insulin-like growth factor 1 receptor (IGF1R), Fos proto-oncogene (FOS), snail family transcriptional repressor 1 (SNAI1), PDZ binding kinase (PBK), and ring finger protein 144B (RNF144B) were the top 10 key node genes of EBV-induced lymphoma. In which, PBK, an up-regulated genes with the highest number of GO annotations, was verified by cellular function experiments and clinical lymphoma samples.\n\nAuthor summaryEB virus is closely associated with human lymphoma and nasopharyngeal carcinoma. Since the susceptible hosts of EBV limit to human and cottontop tammarins, there are no appropriate animal models so far to study the EBV-associated oncogenesis. In our previous experiments, the EBV-associated lymphomas were induced in hu-PBL/SCID chimera (a new humanized mouse model). However, the cellular and molecular mechanisms of malignant transformation of normal human cells and tumor formation induced by EBV remain unclear. In this study, we examined and compared the gene expression profiles of EBV-induced lymphomas and normal human lymphocytes of the same origin in SCID mice. By constructing the gene-function relationship network, we preliminarily found that TOP2A, UHRF1, HIST2H2BE, PHGDH, VCL, IGF1R, FOS, SNAI1, PBK, and RNF144B may be the key genes in EBV-induced lymphomas. These findings suggest that the induction of lymphoma by EBV is a complex process that involves multiple genes and pathways.

cancer biology↗

bioRxiv2019

Analysis of meiosis in Pristionchus pacificus reveals plasticity in homolog pairing and synapsis within the nematode lineage

Meiosis is conserved across eukaryotes yet varies in the details of its execution. Here we describe a new comparative model system for molecular analysis of meiosis, the nematode Pristionchus pacificus, a distant relative of the widely studied model organism Caenorhabditis elegans. P. pacificus shares many anatomical and other features that facilitate analysis of meiosis in C. elegans. However, while C. elegans has lost the meiosis-specific recombinase Dmc1 and evolved a recombination-independent mechanism to synapse its chromosomes, P. pacificus expresses both DMC-1 and RAD-51. We find that SPO-11 and DMC-1 are required for stable homolog pairing, synapsis, and crossover formation, while RAD-51 is dispensable for these key meiotic processes. RAD-51 and DMC-1 localize sequentially to chromosomes during meiotic prophase and show nonoverlapping functions. We also present a new genetic map for P. pacificus that reveals a crossover landscape very similar to that of C. elegans, despite marked divergence in the regulation of synapsis and crossing-over between these lineages.

cell biology↗

bioRxiv2019

Clonal replacement of tumor-specific T cells following PD-1 blockade

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) pre- and post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

immunology↗

bioRxiv2019

Dynamic Changes of G-CSF etc. Nine Cytokines in Mouse Bloodstream Infection Models of Staphylococcus aureus and Klebsiella pneumoniae and their Clinical Performances

Blood culture has been considered as the gold standard to diagnose the bacterial bloodstream infection, but its long turnaround time gravely obstructed the clinical medication by physicians. Cytokines play an important role in bacterial infection. The purpose of this study was to monitor the kinetic changes of nine cytokines in mouse infection models and to infer their diagnostic value in early infection.\n\nMethodsThe mouse bloodstream infection model of Staphylococcus aureus and the other model of Staphylococcus aureus and Klebsiella pneumoniae were constructed respectively, and the dynamic changes of nine cytokines were monitored within 48 hours after infected with 1/2 LD50 bacterial concentration. Cytokines with significant differences between the two groups and PBS control group from 0 to 6 hours after infection were selected for theoretical proof in patient sera that were clearly diagnosed as bloodstream infection. Receiver operating characteristic (ROC) curve analysis was conducted to determine the clinical differentiation of different cytokines.\n\nResultsTwo models of S.aureus and K. pneumoniae bloodstream infection in mice were constructed successfully. In the two mouse models, six of the nine cytokines monitored were different (P<0.05) in each experimental group. In the 121 patient sera samples, three cytokines, IL-6, IL-12p70 and G-CSF in the infection groups and control group had showed differences. In particular, AUC of G-CSF was 0.9051, the accuracy is better than IL-6 for diagnosing the infection. In addition, only G-CSF was significantly different between the two infection groups and in the analysis of ROC curve, AUC is equal to 0.735.\n\nConclusionsG-CSF can not only judge the bacterial infection and non-infection, but also distinguish the infection of S.aureus from K. pneumoniae.

microbiology↗

bioRxiv2019

Carbon starvation induces the expression of PprB-regulated genes in Pesudomonas aeruginosa

Pseudomonas aeruginosa can cause severe infections in humans. This bacteria often adopt a biofilm lifestyle that is hard to treat. In several previous studies, the PprA-PprB two-component system (TCS), which controls the expression of type IVb pili, BapA adhesin, and CupE fimbriae, was shown to be involved in biofilm formation. However, signals or environmental conditions that can trigger the PprA-PprB TCS are still unknown, and the molecular mechanisms of PprB-mediated biofilm formation are poorly characterized. Here we report that carbon starvation stress (CCS) can induce the expression of pprB and genes in the PprB regulon. The stress response sigma factor RpoS, rather than the two-component sensor PprA, was determined to mediate the induction of pprB transcription. We also observed a strong negative regulation of PprB to the transcription of itself. Further experiments showed that PprB overexpression greatly enhanced cell-cell adhesion (CCA) and cell-surface adhesion (CSA) in P. aeruginosa. Specially, under the background of PprB overexpression, both of the BapA adhesin and CupE fimbriae displayed positive effect on CCA and CSA, while the type IVb pili showed an unexpected negative effect on CCA and no effect on CSA. In addition, expression of the PprB regulon genes displayed significant increases in 3-day colony biofilms, indicating a possible carbon limitation state in these biofilms. The CSS-RpoS-PprB-Bap/Flp/CupE/Tad pathway identified in this study provides a new perspective on the process of biofilm formation under carbon-limited environments.\n\nIMPORTANCETypically, determining the external signals that can trigger a regulatory system is crucial to understand the regulatory logic and inward function of that system. The PprA-PprB two-component system was reported to be involved in biofilm formation in Pseudomonas aeruginosa, but the signals that can trigger this system are unknown. In this study, we found that carbon starvation stress (CSS) can induce the transcription of pprB and genes in PprB regulon, through an RpoS dependent pathway. Increase of PprB expression leads to enhanced cell-cell and cell-surface adhesions in P. aeruginosa, both of which are dependent mainly on the Bap adhesin secretion system and partially on the CupE fimbriae. Our findings suggest that PprB reinforces the structure of biofilms under carbon-limited conditions, and the Bap secretion system and CupE fimbriae are two potential targets for biofilm treatment.

microbiology↗

bioRxiv2019

Title: Risk factors for postoperative meningitis after microsurgery for vestibular schwannoma

OBJECTIVEMeningitis after microsurgery for vestibular schwannoma (VS) is a severe complication and result in high morbidity. But few studies have focused on meningitis after VS surgery alone. The purpose of this study was to identify the risk factors for meningitis after VS surgery.\n\nMETHODSWe undertook a retrospective analysis of all VS patients, who underwent microsurgery of VS and at least live for 7 days after surgery, between 1st June 2015 and 30st November 2018 at West China Hospital of Sichuan University. Univariate and multivariate analyses were performed to identify the risk factors for postoperative meningitis (POM).\n\nRESULTSWe collected 410 patients, 27 of whom had POM. Through univariate analysis, hydrocephalus (p=0. 018), Koos grade IV (p=0.04), The operative duration (> 3 hours p=0.03) and intraoperative bleeding volume ([≥] 400ml p=0. 02) were significantly correlated to POM. Multivariate analysis showed that Koos grade IV (p=0.04; OR=3.19; 95% CI 1.032-3.190), operation duration (> 3 hours p=0.03 OR= 7.927; 95% CI 1.043-60.265), and intraoperative bleeding volume ([≥] 400ml p=0.02; OR=2.551; 95% CI 1.112-5.850) are the independent influencing factors of POM.\n\nCONCLUSIONSKoos grade IV, the duration of operation, and the amount of bleeding were identified as independent risk factors for POM after microsurgery of VS. POM caused a prolonged hospital stay.

neuroscience↗

bioRxiv2019

Discovery of an essential mycobacterial polar growth factor involved in cell envelope integrity and LM/LAM transport

Mycobacteria, including the human pathogen Mycobacterium tuberculosis, grow by inserting new cell wall material at their poles. This process and that of division are asymmetric, producing a phenotypically heterogeneous population of cells that respond non-uniformly to stress (Aldridge et al., 2012; Rego et al., 2017; Richardson et al., 2016). Surprisingly, deletion of a single gene - lamA - leads to more symmetry, and to a population of cells that is more uniformly killed by antibiotics (Rego et al., 2017). How does LamA create asymmetry? Here, using a combination of quantitative time-lapse imaging, bacterial genetics, and lipid profiling, we find that LamA recruits essential proteins involved in cell wall synthesis to one side of the cell - the old pole. One of these proteins, MSMEG_0317, here renamed PgfA, was of unknown function. We show that PgfA is a periplasmic protein that interacts with MmpL3, an essential transporter that flips mycolic acids in the form of trehalose monomycolate (TMM), across the plasma membrane. PgfA interacts with a TMM analog suggesting a direct role in TMM transport. Yet our data point to a broader function as well, as cells with altered PgfA levels have differences in the abundance of other lipids and are differentially reliant on those lipids for survival. Overexpression of PgfA, but not MmpL3, restores growth at the old poles in cells missing lamA. Together, our results suggest that PgfA is a key regulator of polar growth and cell envelope composition in mycobacteria, and that the LamA-mediated recruitment of this protein to one side of the cell is a required step in the establishment of cellular asymmetry.

microbiology↗

bioRxiv2019

JASPer controls interphase histone H3S10 phosphorylation by chromosomal kinase JIL-1 in Drosophila

In flies, the chromosomal kinase JIL-1 is responsible for most interphase histone H3S10 phosphorylation and has been proposed to protect active chromatin from acquiring heterochromatic marks, like dimethylated histone H3K9 (H3K9me2) and HP1. Here, we show that JIL-1s targeting to chromatin depends on a new PWWP domain-containing protein JASPer (JIL-1 Anchoring and Stabilizing Protein). The JASPer-JIL-1 (JJ)-complex is the major form of the kinase in vivo and is targeted to active genes and telomeric transposons via binding of the PWWP domain of JASPer to H3K36me3 nucleosomes. Put in place, the complex modulates the transcriptional output. JIL-1 and JJ-complex depletion in cycling cells lead to small changes in H3K9me2 distribution at active genes and telomeric transposons. Finally, we identified many new interactors of the endogenous JJ-complex and propose that JIL-1 not only prevents heterochromatin formation, but also coordinates chromatin-based regulation in the transcribed part of the genome.

molecular biology↗

bioRxiv2019

Leveraging Endogenous ADAR for Programmable Editing on RNA

Nucleic acid editing carries enormous potential for biological research and the development of therapeutics. Current tools for DNA or RNA editing rely on introducing exogenous proteins into living organisms, which is subject to potential risks or technical barriers due to possible aberrant effector activity, delivery limits and immunogenicity. Here, we report a programmable approach that employs a short RNA to leverage endogenous ADAR (Adenosine Deaminase Acting on RNA) proteins for targeted RNA editing. We engineered an RNA that is partially complementary to the target transcript to recruit native ADAR1 or ADAR2 to change adenosine to inosine at a specific site. We designated this new method as LEAPER (Leveraging Endogenous ADAR for Programmable Editing on RNA) and the ADAR-recruiting RNA as arRNA. arRNA, either expressed from plasmid or viral vector, or synthesized as an oligonucleotide, could achieve desirable editing. LEAPER has a manageable off-target rate on the targeted transcripts and rare global off-targets. We demonstrated that LEAPER could restore p53 function by repairing a specific cancer-relevant point mutation. Moreover, LEAPER could apply to a broad spectrum of cell types including multiple human primary cells, and it restored the -L-iduronidase catalytic activity in Hurler syndrome patient-derived primary fibroblasts without evoking innate immune responses. As a single molecule system akin to RNAi, LEAPER enables precise and efficient RNA editing, offering the transformative potential for basic research and therapeutics.

genomics↗

bioRxiv2019

Meiosis related cancer-testis genes correlate with tumor aneuploidy and immune infiltration in 21 cancer types

The meiosis stage of spermatogenesis and the aneuploidy generation in tumorigenesis are highly linked. Cancer-testis genes (CT genes) were specifically expressed in testis and cancers and may serve as the molecular basis of the shared features between spermatogenesis and tumorigenesis. In the present study, we integrated multi-omics data from bulk samples and cell lines, and single cell RNA-Seq data from testis and two tumors to systematically investigate the association between CT genes and aneuploidy. After ranking genes according to their association with aneuploidy level, we found that CT genes, especially CT genes specifically expressed in meiosis, showed a consistently positive correlation with aneuploidy and homologous recombination deficiency (HRD) level. Similar results were also found in the CT non-coding genes. Then, we constructed a regulatory network based on the single cell RNA-seq data and revealed that the gain of accelerator transcriptional factors (TFs) E2F7 and E2F8 and the loss of the stabilizer TFs RFX2 and NFYA aberrantly activated CT genes in the cancers and were associated with the increase of HRD level. Finally, we found that the association between CT genes and cytotoxic infiltrating lymphocytes can be influenced by the HRD level. In sum, our results revealed the evidence of pseudomeiotic functions of CT genes in the aneuploidy generation process in the cancer cells. The results may help illuminate the origin of aneuploidy in cancers and guide future immunotherapy targeting CT antigens.

genomics↗

bioRxiv2019

In Vitro Potent Activity of ε-poly-L-lysine against Candida albicans and the Underlying Mechanisms

ObjectiveThis study aimed to examine the antifungal activity of {varepsilon}-poly-L-lysine ({varepsilon}-PL) against the planktonic cells or biofilms of Candida albicans and explore the underlying mechanism.\n\nMethodsThe minimal inhibitory concentration, minimum fungal concentration, and sessile minimal inhibitory concentration were estimated. The germ tube formation and yeast-to-hypha transformation of C. albicans in different media that induced mycelial growth were recorded. The effect of different concentrations of {varepsilon}-PL on the biofilm formation process and mature biofilm of C. albicans was determined. The reactive oxygen species (ROS) and malondialdehyde (MDA) contents of C. albicans after {varepsilon}-PL treatment were measured. The changes in major virulence genes and proteins of C. albicans were detected.\n\nResults{varepsilon}-PL (512 g/mL) exerted a strong inhibitory effect on C. albicans and biofilms. It blocked the yeast-to-hypha transition and reduced the germ tube formation and germ tube length of C. albicans. The MDA and ROS contents showed an upward trend, indicating a positive correlation with the concentration. Further, {varepsilon}-PL inhibited the high expression of virulence genes in oxidative stress induced by C. albicans. The main peak in the mass spectrum of C. albicans was found to be clear.\n\nConclusions{varepsilon}-PL exerted a significant antifungal effect on the phytoplankton and biofilm of C. albicans. High concentrations of {varepsilon}-PL significantly inhibited the main mycelium of C. albicans. {varepsilon}-PL induced ROS, released cytochrome C, attacked the C. albicans cell membrane to aggravate its lipid oxidation, and inhibited the expression of C. albicans-associated virulence genes and proteins, thereby exerting a bacteriostatic effect.\n\nImportanceThe last two decades have seen a growing trend toward the failure of current antifungal drugs attributed to Candida biofilms. Under appropriate conditions, adherence and colonization of planktonic cells on host tissues and medical devices initiate multicellular organization called biofilm, which is an organized heterogeneous mixture of yeast, hyphae, and pseudohyphal forms embedded in a complex extracellular matrix. Compared with the planktonic cells, biofilms show high resistance to a wide variety of antifungal agents and tolerance to harsh environments and host immune system. Moreover, the development of antifungal drugs is costly, long-term, and difficult. Thus, researchers turned their attention to natural antibacterial peptides, hoping to find an effective antifungal substance or enhance the sensitivity of the existing antifungal drugs to C. albicans.

microbiology↗

bioRxiv2019

Dynamic chromosome rearrangements of the white-spotted bamboo shark shed light on cartilaginous fish diversification mechanisms

Cartilaginous fishes have a very high phenotypical diversity, a phenomenon for which the mechanisms have been largely unexplored. Here, we report the genome of the white-spotted bamboo shark as the first chromosome-level genome assembly of cartilaginous fish. Using this genome, we illustrated a dynamic chromosome rearrangement process in the bamboo shark, which resulted in the formation of 13 chromosomes, all of which were sparsely distributed with conserved genes and fast-evolving. We found the fast-evolving chromosomes to be enriched in immune-related genes with two chromosomes harboring the major genes for developing the single-chain antibody. We also found chromosome rearrangements to have resulted in the loss of two genes (p2rx3 and p2rx5) which we also showed were involved in cartilage development using a CRISPR/Cas9 approach in zebrafish. Our study highlighted the significance of chromosome rearrangements in the phenotypical evolution of cartilaginous fishes, providing clues to inform further studies on mechanisms for fish diversification.

genomics↗

bioRxiv2019

Effect of progesterone on Candida albicans biofilm formation under acidic conditions: a transcriptomic analysis

Vulvovaginal candidiasis (VVC) caused by Candida albicans is a common disease worldwide. A very important C. albicans virulence factor is its ability to form biofilms on epithelium and/or on intrauterine devices promoting VVC. It has been shown that VVC has a hormonal dependency and that progesterone affects virulence traits of C. albicans cells. To understand how the acidic environment (pH 4) and progesterone (either alone and in combination) modulate C. albicans response during formation of biofilm, a transcriptomic analysis was performed together with characterization of the biofilm properties. Compared to planktonic cells, acidic biofilm-cells exhibited major changes in their transcriptome, including modifications in the expression of 286 genes that were not previously associated with biofilm formation in C. albicans. The vast majority of the genes up-regulated in the acidic biofilm cells (including those uniquely identified here) are known targets of Sfl1, and the expression of this regulator impaired formation of the acidic biofilm. Under the acidic conditions used, progesterone treatment reduced C. albicans biofilm biomass, structural cohesion, matrix quantity and susceptibility to fluconazole. Transcriptomic analysis of progesterone-exposed biofilms led to the identification of 65 down-regulated genes including, among others, the regulator Tec1 and several of its target genes suggesting that the function of this transcription factor is inhibited by the presence of the hormone. Overall, the results of this study show that progesterone modulates C. albicans biofilm formation and genomic expression under acidic conditions, which may have implications for C. albicans pathogenicity in the vaginal environment.\n\nAuthor summaryVulvovaginal candidiasis (VVC) is an infection of the vaginal tract that affects millions of women every year. It is caused by fungi of the genus Candida, mainly Candida albicans. Several C. albicans virulence factors contribute to the establishment of this infection, including the ability to form biofilms on vaginal walls and intrauterine devices. Candida species belong to vaginal microflora, however under certain conditions they can cause infection. It has been shown that conditions that prompt VVC include those leading to high progesterone levels, as pregnancy. Here we show that progesterone impairs the ability of C. albicans cells to form biofilms but causes a potential protective stress response. Indeed, we reveal an increased fluconazole resistance of biofilm cells grown in the presence of the hormone. Additionally, our results suggest that biofilm cells have a specific response to acidic conditions, as those established in the vaginal environment. Deepening the knowledge on the modulation of C. albicans virulence by vaginal conditions is essential for a full understanding of the pathogenesis of this species in the vaginal tract and contribute to the disclosure of new targets to treat VVC.

microbiology↗

bioRxiv2019

Treatment of Murine Lupus with TIGIT-Ig

The TIGIT (T cell immunoreceptor with Ig and ITIM domains) protein is a co-inhibitory receptor that has been reported to suppress autoreactive T and B cells to trigger immunological tolerance. We generated a new recombinant protein by connecting the extracellular domain of murine TIGIT to the Fc region of the rat immunoglobulin IgG2a. The fusion protein was then characterized. The results suggested that among mice with lupus that were treated with the TIGIT-Ig fusion protein, the onset of proteinuria was delayed, serum concentrations of autoantibodies, such as antinuclear antibodies, were reduced without a decrease in the total IgG concentrations, and the survival rate was significantly increased compared to those of the controls. In conclusion, TIGIT-Ig administration showed promising results for both the prevention and treatment of autoimmune diseases in mice. This indicates that treatment with recombinant human TIGIT-Ig shows promise as an effective way to treat human autoimmune diseases.

immunology↗