Biology subjects

Lao, J.

Publications and source records attributed to Lao, J..

8 recordsLinked to original sources

bioRxiv2023

Inter-phylum circulation of a beta-lactamase - encoding gene: a rare but observable event

Beta-lactam degradation by beta-lactamases is the most common mechanism of beta-lactam resistance in Gram-negative bacteria. Beta-lactamase encoding genes can be transferred between closely-related bacteria, but spontaneous inter-phylum transfers (between distantly related bacteria) has never been reported. Here, we describe an extended-spectrum beta-lactamase (ESBL)-encoding gene (blaMUN-1) shared between the Peudomonadota and Bacteroidota phyla. An Escherichia coli strain was isolated from a patient in Munster (Germany). Its genome was sequenced (Illumina and Nanopore). The ESBL encoding gene was cloned and the corresponding enzyme was characterised. Distribution of the gene among bacteria was studied with BLASTN using RefSeq Genomes databases. Frequency of its closest homolog in the Global Microbial Gene Catalog (GMGC) was also analysed. The blaMUN-1 gene found in the E. coli strain, encoded for an Ambler subclass A2 beta-lactamase with 82.2% amino acid identity to TLA-1 and it was found to confer an ESBL phenotype. blaMUN-1 was found in four copies, two chromosomal copies and two located on a phage-plasmid p0111. Each copy was found on a 7.6kb genomic island associated with mobility. blaMUN-1 was found distributed among the Bacteroidales order and in Sutterella wardsworthensis (Pseudomonadota). Its closest homolog in the GMGC was found predominantly and frequently in the Human gut sub-catalog (found in 26.8% of the samples). This is the first reported case of inter-phylum transfer of an ESBL-encoding gene, between the Bacteroidota and Pseudomonadota phyla. While the gene was frequently found in the human gut, inter-phylum transfer was rare, suggesting that inter-phylum barriers are strong but not impassable.

microbiology↗

bioRxiv2022

Comparative genome analysis of Enterococcus cecorum reveals intercontinental spread of a lineage of clinical poultry isolates.

Enterococcus cecorum is an emerging pathogen responsible for osteomyelitis, spondylitis, and femoral head necrosis causing animal suffering, mortality, and requiring antimicrobial use in poultry. Paradoxically, E. cecorum is a common inhabitant of the intestinal microbiota of adult chickens. Despite evidence suggesting the existence of clones with pathogenic potential, the genetic and phenotypic relatedness of disease-associated isolates remains little investigated. Here, we sequenced and analyzed the genomes and characterized the phenotypes of more than 100 isolates, the majority of which were collected over the last ten years in 16 French broiler farms. Comparative genomics, genome-wide association study, and measured susceptibility to serum, biofilm forming capacity, and adhesion to chicken type II collagen were used to identify features associated with clinical isolates. We found that none of the tested phenotypes could discriminate origin of the isolates or phylogenetic group. Instead, we found that most clinical isolates are grouped phylogenetically and our analyses selected six genes that discriminate 94% of isolates associated with disease from those that are not. Analysis of the resistome and the mobilome revealed that multidrug-resistant clones of E. cecorum cluster in few clades and that integrative conjugative elements and genomic islands are the main carriers of antimicrobial resistance. This comprehensive genomic analysis shows that disease-associated clones of E. cecorum belong mainly to one phylogenetic clade. IMPORTANCEEnterococcus cecorum is an important pathogen in poultry worldwide. It causes a number of locomotor disorders and septicemia, particularly in fast-growing broilers. Animal suffering, antimicrobial use, and associated economic losses require a better understanding of disease-associated E. cecorum isolates. To address this need, we performed whole genome sequencing and analysis of a large collection of isolates responsible for outbreaks in France. By providing the first dataset on the genetic diversity and resistome of E. cecorum strains circulating in France, we pinpoint an epidemic lineage probably also circulating elsewhere and which should be targeted preferentially by preventive strategies in order to reduce the burden of E. cecorum-related diseases.

genomics↗

bioRxiv2022

ResFinderFG v2.0: a database of antibiotic resistance genes obtained by functional metagenomics

Metagenomics can be used to monitor the spread of antibiotic resistance genes (ARGs). ARGs found in databases such as ResFinder and CARD primarily originate from culturable and pathogenic bacteria, while ARGs from non-culturable and non-pathogenic bacteria remain understudied. Functional metagenomics is based on phenotypic gene selection and can identify ARGs from non-culturable bacteria with a potentially low identity shared with known ARGs. In 2016, the ResFinderFG v1.0 database was created to collect ARGs from functional metagenomics studies. Here, we present the second version of the database, ResFinderFG v2.0, which is available on the Center of Genomic Epidemiology web server (https://cge.food.dtu.dk/services/ResFinderFG/). It comprises 3,913 ARGs identified by functional metagenomics from 50 carefully curated datasets. We assessed its potential to detect ARGs in comparison to other popular databases in gut, soil and water (marine + freshwater) Global Microbial Gene Catalogues (https://gmgc.embl.de). ResFinderFG v2.0 allowed for the detection of ARGs that were not detected using other databases. These included ARGs conferring resistance to beta-lactams, cycline, phenicol, glycopeptide/cycloserine and trimethoprim/sulfonamide. Thus, ResFinderFG v2.0 can be used to identify ARGs differing from those found in conventional databases and therefore improve the description of resistomes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/512667v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a16f6dorg.highwire.dtl.DTLVardef@19a7589org.highwire.dtl.DTLVardef@19a7d5forg.highwire.dtl.DTLVardef@19d1c16_HPS_FORMAT_FIGEXP M_FIG C_FIG Caption: Additional use of ResFinderFG v2.0 database (composed of antibiotic resistance genes obtained with functional metagenomics) on the Center of Genomic Epidemiology webserver (https://cge.food.dtu.dk/services/ResFinderFG/), allows for more exhaustive resistome descriptions.

microbiology↗

bioRxiv2022

Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification

Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 12 homeobox genes in 20 distinct neuron classes that are mostly unrelated by location, function and lineage history. 10 of these 20 neuron classes had no homeobox gene function ascribed to them before, while in the other 10 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analysis, 111 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.

neuroscience↗

bioRxiv2021

Microarray Analysis of Potential Biomarkers for brachial plexus avulsion caused neuropathic pain

Nerve injury-induced neuropathic pain remains a challenging clinical problem due to a lack of satisfactory treatment. Pain after BPA (Brachial Plexus Avulsion) is resistant to most traditional pain relief treatments due to the lack of understanding of the cellular or molecular mechanism of pain development. The present study aimed to investigate the expression of mRNA in the brachial plexus avulsion neuropathic pain model and analyze biological functions. Sprague-Dawley rats were treated with complete brachial plexus avulsion. An animal behavior test was carried out to distinguish the pain group from the control group. In this study, a microarray mRNA assay and reverse transcriptase quantitative polymerase chain reaction (RT-PCR) was conducted. The whole blood was collected from two groups for Microarray mRNA analysis. The predicted mRNA targets were studied by gene ontology analysis and pathway analysis. The PIK3CB, HRAS, and JUN genes were verified by RT-PCR. In total, differentially expressed genes(DEGs) were identified between individuals with or without neuropathic pain (case and control), and A biological processes were enriched. We identified 3 targeted mRNAs, including PIK3CB, HRAS, and JUN, which may be potential biomarkers for BPA-caused NP. The results showed that PIK3CB, HRAS, and JUN gene expression was increased in the control group but decreased in the neuropathic pain group. The PIK3CB gene was part of the Neurotrophin signaling pathway. The function of the HRAS gene was synergetic in the aspect of axon guidance and the Neurotrophin signaling pathway. The JUN gene participates in axon regeneration. These results suggest that PIK3CB, HRAS, and JUN genes might become potential biomarkers for the prediction of and new targets for the prevention and treatment of neuropathic pain after BPA. These findings indicate that mRNA expression changes in the blood may play an important role in the development of NP after BPA, which is of theoretical and clinical importance for future research and clinical-treatment strategies.

neuroscience↗

bioRxiv2019

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG

Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation affecting over 1,000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. In order to identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multi-species drug repurposing screen using a first-ever worm model of PMM2-CDG followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 are plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains range from 30% to 400% over baseline depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.

pharmacology and toxicology↗

bioRxiv2018

Neural representations of faces are tuned to eye movements

Eye movements provide a functional signature of how human vision is achieved. Many recent studies have reported idiosyncratic visual sampling strategies during face recognition. Whether these inter-individual differences are mirrored by idiosyncratic neural responses has not been investigated yet. Here, we tracked observers eye movements during face recognition; additionally, we obtained an objective index of neural face discrimination through EEG that was recorded while subjects fixated different facial information.\n\nAcross all observers, we found that those facial features that were fixated longer during face recognition elicited stronger neural face discrimination responses. This relationship occurred independently of inter-individual differences in fixation biases. Our data show that eye movements play a functional role during face processing by providing the neural system with information that is diagnostic to a specific observer. The effective processing of face identity involves idiosyncratic, rather than universal representations.

neuroscience↗

bioRxiv2018

Temporal Multivariate Pattern Analysis (tMVPA): a single trial approach exploring the temporal dynamics of the BOLD signal

BackgroundfMRI provides spatial resolution that is unmatched by any non-invasive neuroimaging technique. Its temporal dynamics however are typically neglected due to the sluggishness of the hemodynamic based fMRI signal.\n\nNew MethodsWe present temporal multivariate pattern analysis (tMVPA), a method for investigating the temporal evolution of neural representations in fMRI data, computed using pairs of single-trial BOLD time-courses, leveraging both spatial and temporal components of the fMRI signal. We implemented an expanding sliding window approach that allows identifying the time-window of an effect.\n\nResultsWe demonstrate that tMVPA can successfully detect condition-specific multivariate modulations over time, in the absence of univariate differences. Using Monte Carlo simulations and synthetic data, we quantified family-wise error rate (FWER) and statistical power. Both at the group and at the single subject level, FWER was either at or significantly below 5%. For the group level, we reached the desired power with 18 subjects and 12 trials; for the single subject scenario, 14 trials were required to achieve comparable power.\n\nComparison with existing methodstMVPA adds a temporal multivariate dimension to the tools available for fMRI analysis, enabling investigations of the evolution of neural representations over time. Moreover, tMVPA permits performing single subject inferential statistics by considering single-trial distribution.\n\nConclusionThe growing interest in fMRI temporal dynamics, motivated by recent evidence suggesting that the BOLD signal carries temporal information at a finer scale than previously thought, advocates the need for analytical tools, such as the tMVPA approach proposed here, tailored to investigating BOLD temporal information.

neuroscience↗