Biology subjects

Garcia, V.

Publications and source records attributed to Garcia, V..

28 records · Page 2Linked to original sources

bioRxiv2021

First description of two immune escape indian B.1.1.420 and B.1.617.1 SARS-CoV2 variants in France

Following the outbreak of the SARS-CoV2 virus worldwide in 2019, the rapid widespread overtime of variants suggests today an undergoing positive selection of variants which could potentially provide advantageous genetic property of the virus. Numerous variants have already been described across different countries including N501Y, E484K or L452R mutations on gene coding to spike protein. Most recently, 2 new Indian variants with N440K and E484Q and L452R mutations associated with impaired antibody response and immune reactions were identified in India. The potential consequences of emerging variants are increased transmissibility, increased pathogenicity and the ability to escape natural or vaccine-induced immunity. We described for the first time in France both variants: the N440K immune escape variant within a new strain detected in France in a couple of patients who did not have any history of travel abroad and the new E484Q and L452R Indian variant from a patient travelling from Indian to Marseille to embark on a ship as a crew member. Such study of the circulating viral strains and their variants within the increasing number of infected people worldwide will provide further insights into the viral dissemination. Hence, real time close monitoring variant could help the scientific community to prevent fast-spreading and raise alarms towards potentially harmful variants.

molecular biology↗

bioRxiv2021

Activation of proneuronal transcription factor Ascl1 in maternal liver ensures a healthy pregnancy

Background & AimsMaternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice. MethodsTo investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from mid-gestation until term. ResultsAs a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 exhibited aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and elevated release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta displayed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 exhibited robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments. ConclusionIn summary, we demonstrate that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies reveal Ascl1 as a novel and critical regulator of the physiology of pregnancy. SynopsisHow the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression of Ascl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

physiology↗

bioRxiv2021

The Lack of Nrf2 Causes Hepatocyte Dedifferentiation and Reduced Albumin Production in an Experimental Extrahepatic Cholestasis Model

The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. The aim of this study was to evaluate whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. Various assessments were performed at different days after surgery. Significant genotype-dependent changes in liver size, biliary ductular reaction, hepatocyte proliferation, and fibrotic response were not observed. However, as cholestasis progressed to Day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and fibroblast growth factor-inducible 14 (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. Collectively, our studies revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis. These findings enable us to gain novel insight into how hepatocytes respond to cholestasis. New and NoteworthyWe found that, when hepatocytes are exposed to cholestasis, they exhibit a tendency of dedifferentiation. In this case, Nrf2 is highly activated to markedly up-regulate the expression of epithelial differentiation gene DMBT1, which potentially prevent hepatocytes from dedifferentiation. Our findings revealed a plastic property of hepatocytes in response to cholestasis and demonstrated a novel Nrf2/DMBT1 pathway likely controlling this property of hepatocytes.

pathology↗

bioRxiv2019

Concerted cutting by Spo11 illuminates DNA break mechanisms and initiates gap repair during meiosis

Genetic variation arises during meiosis via repair of DNA double-strand breaks (DSBs) created by the topoisomerase-like Spo11 protein. These DSBs are thought to always occur sparsely across the genome, with isolated DSBs generating discrete recombination events. We challenge this view, demonstrating that hyper-localised coincident DSBs frequently form within hotspots in both S. cerevisiae and mouse--a process suppressed by the DNA damage response kinase Tel1/ATM. Remarkably, the distances separating coincident DSBs vary with [~]10.5 bp periodicity, invoking a model where adjacent Spo11 molecules have a fixed orientation relative to the DNA helix. Deep sequencing of meiotic progeny identifies recombination scars consistent with gap repair initiated by adjacent DSBs. Our results revise current thinking about how genetic recombination initiates, reviving original concepts of meiotic recombination as double-strand gap repair.

molecular biology↗

bioRxiv2019

Bacterially produced GABA protects neurons from degeneration

Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the MEC-4(d) DEG/ENaC channel which causes the progressive degeneration of the touch receptor neurons (TRNs). Using such model, this study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. While degeneration of TRNs was steadily carried and completed at adulthood in the strain routinely used for C. elegans maintenance Escherichia coli OP50, it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of the DAF-16/FOXO transcription factor, a phenomenon previously reported to underlie neuroprotection caused by downregulation of the insulin receptor in this system. Moreover, a daf-16 loss of function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics and metabolomics approaches pinpointed the neurotransmitter {gamma}-aminobutyric acid (GABA) as a metabolite differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Together, these results demonstrate that bacterially produced GABA exerts an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.

microbiology↗

bioRxiv2018

Cancer-Induced Immunosuppression can enable Effectiveness of Immunotherapy through Bistability Generation: a mathematical and computational Examination

Cancer immunotherapies rely on how interactions between cancer and immune system cells are constituted. The more essential to the emergence of the dynamical behavior of cancer growth these are, the more effectively they may be used as mechanisms for interventions. Mathematical modeling can help unearth such connections, and help explain how they shape the dynamics of cancer growth. Here, we explored whether there exist simple, consistent properties of cancer-immune system interaction (CISI) models that might be harnessed to devise effective immunotherapy approaches. We did this for a family of three related models of increasing complexity. To this end, we developed a base model of CISI, which captures some essential features of the more complex models built on it. We find that the base model and its derivates can plausibly reproduce biological behavior that is consistent with the notion of an immunological barrier. This behavior is also in accord with situations in which the suppressive effects exerted by cancer cells on immune cells dominate their proliferative effects. Under these circumstances, the model family may display a pattern of bistability, where two distinct, stable states (a cancer-free, and a full-grown cancer state) are possible. Increasing the effectiveness of immune-caused cancer cell killing may remove the basis for bistability, and abruptly tip the dynamics of the system into a cancer-free state. Additionally, in combination with the administration of immune effector cells, modifications in cancer cell killing may be harnessed for immunotherapy without the need for resolving the bistability. We use these ideas to test immunotherapeutic interventions in silico in a stochastic version of the base model. This bistability-reliant approach to cancer interventions might offer advantages over those that comprise gradual declines in cancer cell numbers.

cancer biology↗

bioRxiv2018

De novo mutations drive the spread of macrolide resistant Mycoplasma genitalium: mathematical modelling study

BackgroundThe rapid spread of azithromycin resistance in sexually transmitted Mycoplasma genitalium infections is a growing concern. It is not yet clear to what degree macrolide resistance in M. genitalium results from the emergence of de novo mutations or the transmission of resistant strains.\n\nMethodsWe analyzed epidemiological data and developed a compartmental model to investigate the contribution of de novo macrolide resistance mutations to the spread of antimicrobial-resistant M. genitalium. We fitted the model to data from France, Denmark and Sweden and estimated treatment rates of infected individuals and the time point of azithromycin introduction.\n\nResultsWe found a high probability of de novo resistance (12%, 95% CI 8-17%), which is responsible for the observed rapid spread of antimicrobial resistant M. genitalium. The estimated per capita treatment rate in France was lower than in Denmark and Sweden but confidence intervals for the three estimates overlap. The estimated dates of introduction of azithromycin in each country are consistent with published reports.\n\nConclusionsSince de novo resistance is the main driver of macrolide resistance in M. genitalium, blind treatment of urethritis with azithromycin is not recommended. Clinical management strategies for M. genitalium should limit the unnecessary use of macrolides.

microbiology↗

bioRxiv2018

Accounting for programmed ribosomal frameshifting in the computation of codon usage bias indices

Experimental evidence shows that synonymous mutations can have important consequences on genetic fitness. Many organisms display codon usage bias (CUB), where synonymous codons that are translated into the same amino acid appear with distinct frequency. CUB is thought to arise from selection for translational efficiency and accuracy, termed the translational efficiency hypothesis (TEH). Indeed, CUB indices correlate with protein expression levels, which is widely interpreted as evidence for translational selection. However, these tests neglect -1 programmed ribosomal frameshifting (-1 PRF), an important translational disruption effect found across all organisms of the tree of life. Genes that contain -1 PRF signals should cost more to express than genes without. Thus, CUB indices that do not consider -1 PRF may overestimate genes true adaptation to translational efficiency and accuracy constraints. Here, we first investigate whether -1 PRF signals do indeed carry such translational cost. We then propose two corrections for CUB indices for genes containing -1 PRF signals. We retest the TEH under these corrections. We find that the correlation between corrected CUB index and protein expression remains intact for most levels of uniform -1 PRF efficiencies, and tends to increase when these efficiencies decline with protein expression. We conclude that the TEH is strengthened and that -1 PRF events constitute a promising and useful tool to examine the relationships between CUB and selection for translation efficiency and accuracy.

genetics↗

bioRxiv2017

Modeling the consequences of regional heterogeneity in human papillomavirus (HPV) vaccination uptake on transmission in Switzerland

BackgroundCompleted human papillomavirus (HPV) vaccination by age 16 years among women in Switzerland ranges from 17 to 75% across 26 cantons. The consequences of regional heterogeneity in vaccination coverage on transmission and prevalence of HPV-16 are unclear.\n\nMethodsWe developed a deterministic, population-based model that describes HPV-16 transmission among young adults within and between the 26 cantons of Switzerland. We parameterized the model using sexual behavior data from Switzerland and data from the Swiss National Vaccination Coverage Survey. First, we investigated the general consequences of heterogeneity in vaccination uptake between two sub-populations. We then compared the predicted prevalence of HPV-16 after the introduction of heterogeneous HPV vaccination uptake in all of Switzerland with homogeneous vaccination at an uptake that is identical to the national average (52%).\n\nResultsHPV-16 prevalence in women is 3.34% when vaccination is introduced and begins to diverge across cantons, ranging from 0.14 to 1.09% after 15 years of vaccination. After the same time period, overall prevalence of HPV-16 in Switzerland is only marginally higher (0.55 %) with heterogeneous vaccination uptake than with homogeneous uptake (0.49%). Assuming inter-cantonal sexual mixing, cantons with low vaccination uptake benefit from a reduction in prevalence at the expense of cantons with high vaccination uptake.\n\nConclusionsRegional variations in uptake diminish the overall effect of vaccination on HPV-16 prevalence in Switzerland, although the effect size is small. Cantonal efforts towards HPV-prevalence reduction by increasing vaccination uptake are impaired by cantons with low vaccination uptake. Harmonization of cantonal vaccination programs would reduce inter-cantonal differences in HPV-16 prevalence.

epidemiology↗

bioRxiv2016

Finite-sites multiple mutations interference gives rise to wavelet-like oscillations of multilocus linkage disequilibrium

Within-host adaptation of pathogens such as human immunodeficiency virus (HIV) often occurs at more than two loci. Multiple beneficial mutations may arise simultaneously on different genetic backgrounds and interfere, affecting each other's fixation trajectories. Here, we explore how these adaptive dynamics are mirrored in multilocus linkage disequilibrium (MLD), a measure of multi-way associations between alleles. In the parameter regime corresponding to HIV, we show that deterministic early infection models induce MLD to oscillate over time in a wavelet-like fashion. We find that the frequency of these oscillations is proportional to the rate of adaptation. This signature is robust to drift, but can be eroded by high variation in fitness effects of beneficial mutations. Our findings suggest that MLD oscillations could be used as a signature of interference among multiple equally advantageous mutations and may aid the interpretation of MLD in data.

genetics↗