Biology subjects

Garcia, M.

Publications and source records attributed to Garcia, M..

60 records · Page 4Linked to original sources

bioRxiv2020

Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance

Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance 1,2. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy 2-4. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways 5-9. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5-untranslated region. As a result, we found that sustained translation of IGF-1R mRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance.

cancer biology↗

bioRxiv2020

Expansion of SARS-CoV-2-specific Antibody-secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19, and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers, suggesting that SARS-CoV-2-specific antibody levels may reflect the titers of neutralizing antibodies in COVID-19 patients during the acute phase of infection. Lastly, we showed that interleukin 6 (IL-6) and C-reactive protein (CRP) concentrations were higher in serum of patients who were hospitalized for longer, supporting the recent observations that IL-6 and CRP could be used to predict COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in twenty COVID-19 patients, with a focus on B cell and antibody responses, and provides tools to study immune responses to SARS-CoV-2 infection and vaccination.

immunology↗

bioRxiv2019

Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish

The establishment of reproductive barriers between populations is the key process that fuels the evolution of new species. A genetic framework for this process was proposed over 80 years ago, which posits "incompatible" interactions between genes that result in reduced survival or reproduction in hybrids. Despite this foundational work, progress has been slow in identifying individual genes that underlie hybrid incompatibilities, with only a handful known to date. Here, we use a combination of approaches to precisely map the genes that drive the development of a melanoma incompatibility in swordtail fish hybrids. We find that one of the genes involved in this incompatibility also causes melanoma in hybrids between distantly related species. Moreover, we show that this melanoma reduces survival in the wild, likely due to progressive degradation of the fin. Together, this work represents only the second case where the genes underlying a vertebrate hybrid incompatibility have been identified and provides the first glimpse into the action of these genes in natural hybrid populations. One sentence summaryUsing a combination of mapping approaches, we identify interacting genes that lead to melanoma in hybrids and characterize their effects in natural hybrid populations.

evolutionary biology↗

bioRxiv2019

nf-core: Community curated bioinformatics pipelines

The standardization, portability, and reproducibility of analysis pipelines is a renowned problem within the bioinformatics community. Most pipelines are designed for execution on-premise, and the associated software dependencies are tightly coupled with the local compute environment. This leads to poor pipeline portability and reproducibility of the ensuing results - both of which are fundamental requirements for the validation of scientific findings. Here, we introduce nf-core: a framework that provides a community-driven, peer-reviewed platform for the development of best practice analysis pipelines written in Nextflow. Key obstacles in pipeline development such as portability, reproducibility, scalability and unified parallelism are inherently addressed by all nf-core pipelines. We are also continually developing a suite of tools that assist in the creation and development of both new and existing pipelines. Our primary goal is to provide a platform for high-quality, reproducible bioinformatics pipelines that can be utilized across various institutions and research facilities.

bioinformatics↗

bioRxiv2018

Sarek: A portable workflow for whole-genome sequencing analysis of germline and somatic variants

SummaryWhole-genome sequencing (WGS) is a cornerstone of precision medicine, but portable and reproducible open-source workflows for WGS analyses of germline and somatic variants are lacking. We present Sarek, a modular, comprehensive, and easy-to-install workflow, combining a range of software for the identification and annotation of single-nucleotide variants (SNVs), insertion and deletion variants (indels), structural variants, tumor sample heterogeneity, and karyotyping from germline or paired tumor/normal samples. Sarek is implemented in a bioinformatics workflow language (Nextflow) with Docker and Singularity compatible containers, ensuring easy deployment and full reproducibility at any Linux based compute cluster or cloud computing environment. Sarek supports the human reference genomes GRCh37 and GRCh38, and can readily be used both as a core production workflow at sequencing facilities and as a powerful stand-alone tool for individual research groups.\n\nAvailabilitySource code and instructions for local installation are available at GitHub (https://github.com/SciLifeLab/Sarek) under the MIT open-source license, and we invite the research community to contribute additional functionality as a collaborative open-source development project.

bioinformatics↗

bioRxiv2017

Non-canonical aberrant DNA hypermethylation in glioma

Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC in primary samples from 54 gliomas and 72 colorectal cancer patients. Levels of 5hmC in colorectal cancer were very low and no consistent changes were detected between control tissues and tumors. As expected, levels of 5hmC in non-tumoral brain samples were high and significantly reduced at the 49,601 CpG sites in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) of these CpG sites was associated with aberrant DNA hypermethylation. The DNA regions containing these CpG sites were enriched in H3K4me2, and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. We conclude that this data identifies a novel 5hmC-dependent non-canonical class of aberrant DNA hypermethylation in glioma.

cancer biology↗