Biology subjects

Rodriguez, F.

Publications and source records attributed to Rodriguez, F..

25 records · Page 2Linked to original sources

bioRxiv2020

Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

Host resistance to Toxoplasma gondii relies on CD8 T cell IFN{gamma} responses, which if modulated by the host or parasite could influence chronic infection and parasite transmission between hosts. Since host-parasite interactions that govern this response are not fully elucidated, we investigated requirements for eliciting naive CD8 T cell IFN{gamma} responses to a vacuolar resident antigen of T. gondii, TGD057. Naive TGD057 antigen-specific CD8 T cells (T57) were isolated from transnuclear mice and responded to parasite-infected bone marrow-derived macrophages (BMDMs) in an antigen-dependent manner, first by producing IL-2 and then IFN{gamma}. T57 IFN{gamma} responses to TGD057 were independent of the parasites protein export machinery ASP5 and MYR1. Instead, host immunity pathways downstream of the regulatory Immunity-Related GTPases (IRG), including partial dependence on Guanylate-Binding Proteins, are required. Multiple T. gondii ROP5 isoforms and allele types, including avirulent ROP5A from clade A and D parasite strains, were able to suppress CD8 T cell IFN{gamma} responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFN{gamma} differentiation occurs independently of parasite virulence or any known IRG-ROP5 interaction. Consistent with this, removal of ROP5 is not enough to elicit maximal CD8 T cell IFN{gamma} production to parasite-infected cells. Instead, macrophage expression of the pathogen sensors, NLRP3 and to a large extent NLRP1, were absolute requirements. Other members of the conventional inflammasome cascade are only partially required, as revealed by decreased but not abrogated T57 IFN{gamma} responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFN{gamma} production was only partially reduced in the absence of IL-12, IL-18 or IL-1R signaling. In summary, T. gondii effectors and host machinery that modulate parasitophorous vacuolar membranes, as well as NLR-dependent but inflammasome-independent pathways, determine the full commitment of CD8 T cells IFN{gamma} responses to a vacuolar antigen. AUTHOR SUMMARYParasites are excellent "students" of our immune system as they can deflect, antagonize and confuse the immune response making it difficult to vaccinate against these pathogens. In this report, we analyzed how a widespread parasite of mammals, Toxoplasma gondii, manipulates an immune cell needed for immunity to many intracellular pathogens, the CD8 T cell. Host pathways that govern CD8 T cell production of the immune protective cytokine, IFN{gamma}, were also explored. We hypothesized the secreted Toxoplasma virulence factor, ROP5, work to inhibit the MHC 1 antigen presentation pathway therefore making it difficult for CD8 T cells to see T. gondii antigens sequestered inside a parasitophorous vacuole. However, manipulation through T. gondii ROP5 does not fully explain how CD8 T cells commit to making IFN{gamma} in response to infection. Importantly, CD8 T cell IFN{gamma} responses to T. gondii require the pathogen sensor NLRP3 to be expressed in the infected cell. Other proteins associated with NLRP3 activation, including members of the conventional inflammasome activation cascade pathway, are only partially involved. Our results identify a novel pathway by which NLRP3 regulates T cell function and underscore the need for inflammasome-activating adjuvants in vaccines aimed at inducing CD8 T cell IFN{gamma} responses to parasites.

immunology↗

bioRxiv2019

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.

cancer biology↗

bioRxiv2019

Sex-specific genetic effects across biomarkers

Sex differences have been shown in laboratory biomarkers; however, the extent to which this is due to genetics is unknown. In this study, we infer sex-specific genetic parameters (heritability and genetic correlation) across 33 quantitative biomarker traits in 181,064 females and 156,135 males from the UK Biobank study. We apply a Bayesian mixture model, Sex Effects Mixture Model, to Genome-wide Association Study summary statistics in order to (1) estimate the contributions of sex to the genetic variance of these biomarkers and (2) identify variants whose statistical association with these traits is sex-specific. We find that the genetics of most biomarker traits are shared between males and females, with the notable exception of testosterone, where we identify 119 female and 444 male-specific variants. These include protein-altering variants in steroid hormone production genes (POR, CYP3A43, UGT2B7). Using the sex-specific variants as genetic instruments for Mendelian Randomization, we find evidence for causal links between testosterone levels and height, body mass index, waist circumference, and type 2 diabetes. We also show that sex-specific polygenic risk score models for testosterone outperform a combined model. Overall, these results demonstrate that while sex has a limited role in the genetics of most biomarker traits, sex plays an important role in testosterone genetics.

genetics↗

bioRxiv2019

Genetics of 38 blood and urine biomarkers in the UK Biobank

Clinical laboratory tests are a critical component of the continuum of care and provide a means for rapid diagnosis and monitoring of chronic disease. In this study, we systematically evaluated the genetic basis of 38 blood and urine laboratory tests measured in 358,072 participants in the UK Biobank and identified 1,857 independent loci associated with at least one laboratory test, including 488 large-effect protein truncating, missense, and copy-number variants. We tested these loci for enrichment in specific single cell types in kidney, liver, and pancreas relevant to disease aetiology. We then causally linked the biomarkers to medically relevant phenotypes through genetic correlation and Mendelian randomization. Finally, we developed polygenic risk scores (PRS) for each biomarker and built multi-PRS models using all 38 PRSs simultaneously. We found substantially improved prediction of incidence in FinnGen (n=135,500) with the multi-PRS relative to single-disease PRSs for renal failure, myocardial infarction, liver fat percentage, and alcoholic cirrhosis. Together, our results show the genetic basis of these biomarkers, which tissues contribute to the biomarker function, the causal influences of the biomarkers, and how we can use this to predict disease.

genetics↗

bioRxiv2019

Emerging arbovirosis (Dengue, Chikungunya, Zika) in the Southeastern Mexico: influence of social and environmental determinants on knowledge and practices. A mixed method study

BackgroundThe incidence and geographical distribution of arboviruses is constantly increasing. The epidemiological patterns of the proliferation of viruses and their vectors (Aedes aegypti and Aedes albopictus) are associated with socio-environmental determinants, and are closely related to human habits, especially at the household level. The aim of this work is to analyze the influence of socio-environmental determinants on the knowledge and practices related to arboviruses and their transmission, among the residents of three communities on the southern border of Mexico.\n\nMethodologyBetween June 2017 and August 2018, our investigation covered a set of 149 households from three communities of Tapachula (Chiapas) and Villahermosa (Tabasco). We first conducted household surveys about knowledge and practices on arbovirosis. Then, we carried out direct observations of risk factors for vector proliferation at the domestic level, before and after exposing a part of the population to a cycle of community engagement prevention activities. Through semi-structured interviews, we also focused on the detection of environmental risk situations for vector breeding at the community level.\n\nKey resultsWe found that most dwellings had an adequate knowledge about the origin and transmission of arboviruses, but only a minority of them also implemented appropriate practices. Higher education levels were associated with better prevention scores. The observations made after the cycle of community activities in Chiapas revealed a decrease in the accumulation of unprotected water deposits. A higher percentage of domestic risk practices were detected in association with significant deficiencies in sanitation and water supply services. Furthermore, the perception of greater risk and difficulty in complying with preventive measures was detected among the population.\n\nDiscussionKnowledge does not necessarily lead to adequate prevention practices. A better understanding of all these dimensions and their interactions is required. In addition to the educational level, intermediate social determinants (such as water supply and environmental sanitation) influence the persistence of behaviors that are risk factors for the proliferation of arbovirosis. The achievement of an effective and sustainable vector management is required to address these related aspects.\n\nAuthor summaryDengue, Chikungunya and Zika are arboviral diseases, transmitted by Aedes mosquitoes. As a result of a continuous increase in the geographical spread and burden of disease, arbovirosis have become a priority issue for global health.\n\nThe proliferation of viruses and their vectors are influenced by a complex interaction of environmental and social determinants. Thus, the design of effective and sustainable prevention and control measures requires an understanding of all these different aspects.\n\nThe aim of our work is to explore the effects of social and environmental factors on the knowledge and practices related to Dengue, Chikungunya and Zika and their transmission, among the residents of three communities on the southern border of Mexico, currently an endemic area. Our study draws on the application of a program combining the implementation of new technologies for vector management with a participatory and holistic multidisciplinary approach.\n\nBetween June 2017 and August 2018, we used different surveys and methodological approaches to explore knowledge and practices on arbovirosis, as well as to identify risk factors for vector proliferation. We found that intermediate social determinants (such as occasional water supply and infrequent waste collections) influence the persistence of behaviors that are risk factors for the proliferation of arbovirosis.\n\nPublic health interventions for arbovirosis prevention must be accompanied by intersectoral work that includes the improvement of these related aspects, according to the multifactorial etiology of arboviruses.

epidemiology↗

bioRxiv2019

A draft genome sequence of the miniature parasitoid wasp, Megaphragma amalphitanum

Body size reduction, also known as miniaturization, is an important evolutionary process that affects a number of physiological and phenotypic traits and helps animals to conquer new ecological niches. However, this process is poorly understood at the molecular level. Here, we report genomic and transcriptomic features of arguably the smallest known insect - the parasitoid wasp, Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae). In contrast to expectations, we find that the genome and transcriptome sizes of this parasitoid wasp are comparable to other members of the Chalcidoidea superfamily. Moreover, the gene content of M. amalphitanum compared to other chalcid wasps is remarkably conserved. Among the very rare cases of apparent gene loss is centrosomin, which encodes an important centrosome component; the absence of this protein might be related to the large number of anucleate neurons in M. amalphitanum. Intriguingly, we also observed significant changes in M. amalphitanum transposable element dynamics over time, whereby an initial burst was followed by suppression of activity, possibly due to a recent reinforcement of the genome defense machinery. Thus, while the M. amalphitanum genomic data reveal certain features that may be linked to the unusual biological properties of this organism, miniaturization is not associated with a large decrease in genome complexity.

genomics↗

bioRxiv2018

NetPyNE: a tool for data-driven multiscale modeling of brain circuits

Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The NetPyNE tool (www.netpyne.org) provides both programmatic and graphical interfaces to develop data-driven multiscale network models in NEURON. NetPyNE clearly separates model parameters from implementation code. Users provide specifications at a high level via a standardized declarative language, e.g., a connectivity rule, instead of tens of loops to create millions of cell-to-cell connections. Users can then generate the NEURON network, run efficiently parallelized simulations, optimize and explore network parameters through automated batch runs, and use built-in functions for visualization and analysis - connectivity matrices, voltage traces, raster plots, local field potentials, and information theoretic measures. NetPyNE also facilitates model sharing by exporting and importing using NeuroML and SONATA standardized formats. NetPyNE is already being used to teach computational neuroscience students and by modelers to investigate different brain regions and phenomena.

neuroscience↗