Biology subjects

Gonzalez, J.

Publications and source records attributed to Gonzalez, J..

85 records · Page 5Linked to original sources

bioRxiv2019

Novel computational deep learning strategy for neuroprotection identification reveals unique set of nicotine analogs as potential therapeutic compounds against Parkinsons disease

Dopaminergic replacement has been used for Parkinsons Disease (PD) treatment with positive effects on motor symptomatology but with low effects over disease progression and prevention. Different epidemiological studies have shown that nicotine consumption decreases PD prevalence through the activation of neuroprotective mechanisms. Nicotine-induced neuroprotection has been associated with the overstimulation of intracellular signaling pathways (SP) such as Phosphatidyl Inositol 3-kinase/Protein kinase-B (PI3K/AKT) through nicotinic acetylcholine receptors (e.g 7 nAChRs) and the over-expression of the anti-apoptotic gene Bcl-2. Considering its harmful effects (toxicity and dependency), the search for nicotine analogs with decreased secondary effects, but similar neuroprotective activity, remains a promissory field of study. In this work, a computational strategy integrating structural bioinformatics, signaling pathway (SP) manual reconstruction, and deep learning was performed to predict the potential neuroprotective activity of a series of 8 novel nicotine analogs over the behavior of PI3K/AKT. We performed a protein-ligand analysis between nicotine analogs and 7 nAChRs receptor using geometrical conformers, physicochemical characterization of the analogs and developed a manually curated neuroprotective dataset to analyze their potential activity. Additionally, we developed a predictive machine-learning model for neuroprotection in PD through the integration of Markov Chain Monte-Carlo transition matrix for the SP with synthetic training datasets of the physicochemical properties and structural dataset. Our model was able to predict the potential neuroprotective activity of seven new nicotine analogs based on the binomial Bcl-2 response regulated by the activation of PI3K/AKT. We present a new computational strategy to predict the pharmacological neuroprotective potential of nicotine analogs based on SP architecture, using deep learning and structural data. Our theoretical strategy can be further applied to the study new treatments related with SP deregulation and may ultimately offer new opportunities for therapeutic interventions in neurodegenerative diseases.\n\nAuthor SummaryParkinsons disease is one of the most prevalent neurodegenerative diseases across population over age 50. Affecting controlled movements and non-motor symptoms, treatments for Parkinson prevention are indispensable to reduce patients population in the future. Epidemiological data provide evidence that nicotine have a neuroprotective effect decreasing Parkinson prevalence. By interacting with nicotine receptors in neurons and modulating signaling pathways expressing anti-apoptotic genes nicotine arise as a putative neuroprotective therapy. Nevertheless, toxicity and dependency prevent the use of nicotine as a suitable drug. Nicotine analogs, structurally similar compounds emerge as an alternative for Parkinson preventive treatment. In this sense we developed a quantitative strategy to predict the potential neuroprotective activity of nicotine analogs. Our model is the first approach to predict neuroprotection in the context of Parkinson and signaling pathways using machine learning and computational chemistry.

bioinformatics↗

bioRxiv2019

Decreased electrocortical temporal complexity distinguishes sleep from wakefulness

In most mammals, the sleep-wake cycle is constituted by three behavioral states: wakefulness (W), non-NREM (NREM) sleep, and REM sleep. These states are associated with drastic changes in cognitive capacities, mostly determined by the function of the thalamo-cortical system. The intra-cranial electroencephalogram or electocorticogram (ECoG), is an important tool for measuring the changes in the thalamo-cortical activity during W and sleep. In the present study we analyzed broad-band ECoG recordings of the rat by means of a time-series complexity measure that is easy to implement and robust to noise: the Permutation Entropy (PeEn). We found that PeEn is maximal during W and decreases during sleep. These results bring to light the different thalamo-cortical dynamics emerging during sleep-wake states, which are associated with the well-known spectral changes that occur when passing from W to sleep. Moreover, the PeEn analysis allows to determine behavioral states independently of the electrodes cortical location, which points to an underlying global pattern in the signal that differs among the cycle states that is missed by classical methods. Consequently, our data suggest that PeEn analysis of a single EEG channel could allow for cheap, easy, and efficient sleep monitoring.

neuroscience↗

bioRxiv2019

A DNA Methylation Fingerprint of Cellular Senescence

Recent years have witnessed an influx of therapies aimed at targeting the biological aging process. While many hold promise for potentially delaying the simultaneous onset of multiple chronic conditions, a major hurdle in developing interventions to slow human aging is the lack of reliable and valid endpoints from which to evaluate potential candidates. The aim of this study was to develop a biomarker that could serve as a potential endophenotype in evaluation of one of the most promising and exciting aging therapeutics being developed--senolytics. Senolytics are compounds which selectively clear senescent cells by targeting anti-apoptotic pathways. Using DNAm data from fibroblasts and mesenchymal stromal cells (MSC) in culture, we developed a predictor of cellular senescence that related to three distinct senescence inducers (replicative, oncogene induced (OIS), and ionizing radiation (IR)). Our measure, termed DNAmSen, showed expected classification of validation data from embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), and near senescent cells in culture. Further, using bulk data from whole blood, peripheral tissue samples, and postmortem tissue, we observed robust correlations between age and DNAmSen. We also observed age adjusted associations between DNAmSen and idiopathic pulmonary fibrosis (IPS), COPD, lung cancer, and Werner syndrome compared to controls. When characterizing the 88 CpGs in the DNAmSen measure, we observed a enrichment for those located in enhancer regions and regulatory regions marked by DNase I hypersensitive sites (DHSs). Interestingly most of the CpGs were observed to be moderately hypomethyled in early passage cells, yet exhibited further hypomethylation upon induction of cellular senescence, suggesting senescence is accompanied by programmatic alterations to the epigenome, rather than entropic drift.

systems biology↗

bioRxiv2019

Natural transposable element insertions drive expression changes in genes underlying Drosophila immune response

BackgroundVariation in gene expression underlies interindividual variability in relevant traits including immune response. However, the genetic variation responsible for these gene expression changes remain largely unknown. Among the non-coding variants that could be relevant, transposable element insertions are promising candidates as they have been shown to be a rich and diverse source of cis-regulatory elements. ResultsIn this work, we used a population genetics approach to identify transposable element insertions likely to increase the tolerance of Drosophila melanogaster to bacterial infection by affecting the expression of immune-related genes. We identified 12 insertions associated with allele-specific expression changes in immune-related genes. We experimentally validated three of these insertions including one likely to be acting as a silencer, one as an enhancer, and one with a dual role as enhancer and promoter. The direction in the change of gene expression associated with the presence of several of these insertions was consistent with an increased survival to infection. Indeed, for one of the insertions, we showed that this is the case by analyzing both natural populations and CRISPR/Cas9 mutants in which the insertion was deleted from its native genomic context. ConclusionsWe showed that transposable elements contribute to gene expression variation in response to infection in D. melanogaster and that this variation is likely to affect their survival capacity. Because the role of transposable elements as regulatory elements is not restricted to Drosophila, TEs are likely to play a role in immune response in other organisms as well.

evolutionary biology↗

bioRxiv2019

Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer’s disease in large cohort

Alzheimers disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the Transferrin (TF) gene and rs1800562 in the Homeostatic Iron Regulator (HFE) gene, commonly known as \"the hemochromatosis gene\", is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger dataset from the Alzheimers Disease Genetics Consortium (ADGC), we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p=0.38 and HFE rs1800562 p=0.40). In addition, logistic regression with an interaction term and a Synergy Factor Analysis (SFA) both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF=0.94; p=0.48) in AD cases. Each of these analyses had sufficient statistical power (Power>0.99), suggesting that previously-reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or were false-positive associations due to limited sample sizes.

genetics↗

bioRxiv2019

Strategies based on sum of peak intensities may better reflect protein expression than peak area integration in iTRAQ protein expression measurement by LC-MS/MS using a TripleTOF 5600+ platform

In the field of quantitative proteomics, the Isobaric Tags for Relative & Absolute Quantitation (iTRAQ) technology has demonstrated efficacy for proteome monitoring despite its lack of a consensus for data handling. In this study, after peptide and protein identification, we compared the widespread quantitation method based on the calculation of MS/MS reporter ion peaks areas ratios (ProteinPilot) to the alternative method based on the calculation of ratios of the sum of peak intensities (jTRAQx (Quant)) and we processed output data with the in-house Customizable iTRAQ Ratios Calculator (CiR-C) algorithm. Quantitation based on peak area ratios displayed no significant linear correlation with Western blot quantitation. In contrast, quantitation based on the sum of peak intensities displayed a significant linear association with Western blot quantitation (non-zero slope; Pearson correlation coefficient test, r = 0.2962, p = 0.0099 **) with an average bias of 0.08747 {+/-} 0.5004 and 95% Limits of Agreement from - 0.8932 to 1.068. We proposed the Mascot-jTRAQx-CiR-C strategy as a simple yet powerful data processing adjunct to the iTRAQ technology.

cell biology↗

bioRxiv2018

Consensify: a method for generating pseudohaploid genome sequences from palaeogenomic datasets with reduced error rates

A standard practise in palaeogenome analysis is the conversion of mapped short read data into pseudohaploid sequences, typically by selecting a single high quality nucleotide at random from the stack of mapped reads. This controls for biases due to differential sequencing coverage but it does not control for differential rates and types of sequencing error, which are frequently large and variable in datasets obtained from ancient samples. These errors have the potential to distort phylogenetic and population clustering analyses, and to mislead tests of admixture using D statistics. We introduce Consensify, a method for generating pseudohaploid sequences which controls for biases resulting from differential sequencing coverage while greatly reducing error rates. The error correction is derived directly from the data itself, without the requirement for additional genomic resources or simplifying assumptions such as contemporaneous sampling. For phylogenetic analysis, we find that Consensify is less affected by branch length artefacts than methods based on standard pseudohaploidisation, and it performs similarly for population clustering analysis based on genetic distances. For D statistics, Consensify is more resistant to false positives and appears to be less affected by biases resulting from different laboratory protocols than other available methods. Although Consensify is developed with palaeogenomic data in mind, it is applicable for any low to medium coverage short read datasets. We predict that Consenify will be a useful tool for future studies of palaeogenomes.

genomics↗

bioRxiv2018

A new species in the Anopheles gambiae complex reveals new evolutionary relationships between vector and non-vector species

Complexes of closely related species provide key insights about the rapid and independent evolution of adaptive traits. Here, we described and studied a presumably new species in the Anopheles gambiae complex, Anopheles fontenillei, recently discovered in the forested areas of Gabon, Central Africa. Our analysis placed the new taxon in the phylogenetic tree of the An. gambiae complex, revealing important introgression events with other members of the complex. In particular, we detected recent introgression with An. gambiae and An. coluzzii of genes directly involved in vectorial capacity. Moreover, genome analysis of the new species also allowed us to resolve the evolutionary history of inversion 3La. Overall, Anopheles fontenillei has implemented our understanding about the relationship of species within the gambiaecomplex and provides insight into the evolution of vectorial capacity traits, relevant for the successful control of malaria in Africa.

evolutionary biology↗

bioRxiv2018

Nasal respiration entrains neocortical long-range gamma coherence during wakefulness

Recent studies have shown that slow cortical potentials in archi-, paleo- and neocortex, can phase-lock with nasal respiration. In some of these areas, gamma activity ({gamma}: 30-100 Hz) is also coupled to the animals respiration. It has been hypothesized that this interaction plays a role in coordinating distributed neural activity. In a similar way, inter-cortical interactions at {gamma} frequency has been also associated as a binding mechanism by which the brain generates temporary opportunities necessary for implementing cognitive functions. The aim of the present study is to explore if nasal respiration entrains inter-cortical interactions at {gamma} frequency.\n\nSix adult cats chronically prepared for electrographic recordings were employed in this study. Our results show that slow cortical respiratory potentials are present in several areas of the neocortex and olfactory bulb during wakefulness. Also, we found cross-frequency coupling between the respiratory phase and the amplitude of {gamma} activity in all recorded areas. These oscillatory entrainments are independent of muscular activity, because are maintained during cataplexy induced by carbachol microinjection into the nucleus pontis oralis. Importantly, we observed that respiratory phase modulates the inter-cortical gamma coherence between neocortical pairs of electrodes during wakefulness. However, during NREM and REM sleep, breathing was unable to entrain the oscillatory activity, neither in the olfactory bulb nor in the neocortex. These results suggest a single unified phenomenon involving cross frequency coupling and long-range {gamma} coherence across the neocortex. This fact could be related to a temporal binding process necessary for cognitive functions during wakefulness.

neuroscience↗

bioRxiv2018

Stress response, behavior, and development are shaped by transposable element-induced mutations in Drosophila

Mapping genotype to phenotype is challenging because of the difficulties in identifying both the traits under selection and the specific genetic variants underlying these traits. Most of the current knowledge of the genetic basis of adaptive evolution is based on the analysis of single nucleotide polymorphisms (SNPs). Despite increasing evidence for their causal role, the contribution of structural variants to adaptive evolution remains largely unexplored. In this work, we analyzed the population frequencies of 1,615 Transposable Element (TE) insertions in 91 samples from 60 worldwide natural populations of Drosophila melanogaster. We identified a set of 300 TEs that are present at high population frequencies, and located in genomic regions with high recombination rate, where the efficiency of natural selection is high. The age and the length of these 300 TEs are consistent with relatively young and long insertions reaching high frequencies due to the action of positive selection. Indeed, we, and others, found evidence of selective sweeps and/or population differentiation for 65 of them. The analysis of the genes located nearby these 65 candidate adaptive insertions suggested that the functional response to selection is related with the GO categories of response to stimulus, behavior, and development. We further showed that a subset of the candidate adaptive TEs affect expression of nearby genes, and five of them have already been linked to an ecologically relevant phenotypic effect. Our results provide a more complete understanding of the genetic variation and the fitness-related traits relevant for adaptive evolution. Similar studies should help uncover the importance of TE-induced adaptive mutations in other species as well.

evolutionary biology↗

bioRxiv2018

Broad geographic sampling reveals predictable and pervasive seasonal adaptation in Drosophila

To advance our understanding of adaptation to temporally varying selection pressures, we identified signatures of seasonal adaptation occurring in parallel among Drosophila melanogaster populations. Specifically, we estimated allele frequencies genome-wide from flies sampled early and late in the growing season from 20 widely dispersed populations. We identified parallel seasonal allele frequency shifts across North America and Europe, demonstrating that seasonal adaptation is a general phenomenon of temperate fly populations. Seasonally fluctuating polymorphisms are enriched in large chromosomal inversions and we find a broad concordance between seasonal and spatial allele frequency change. The direction of allele frequency change at seasonally variable polymorphisms can be predicted by weather conditions in the weeks prior to sampling, linking the environment and the genomic response to selection. Our results suggest that fluctuating selection is an important evolutionary force affecting patterns of genetic variation in Drosophila.

evolutionary biology↗

bioRxiv2018

Genomic analysis of European Drosophila melanogaster populations on a dense spatial scale reveals longitudinal population structure and continent-wide selection

Genetic variation is the fuel of evolution, with standing genetic variation especially important for short-term evolution and local adaptation. To date, studies of spatio-temporal patterns of genetic variation in natural populations have been challenging, as comprehensive sampling is logistically difficult, and sequencing of entire populations costly. Here, we address these issues using a collaborative approach, sequencing 48 pooled population samples from 32 locations, and perform the first continent-wide genomic analysis of genetic variation in European Drosophila melanogaster. Our analyses uncover longitudinal population structure, provide evidence for continent-wide selective sweeps, identify candidate genes for local climate adaptation, and document clines in chromosomal inversion and transposable element frequencies. We also characterise variation among populations in the composition of the fly microbiome, and identify five new DNA viruses in our samples.

evolutionary biology↗

bioRxiv2018

Genome-wide patterns of local adaptation in Drosophila melanogaster: adding intra European variability to the map

Signatures of spatially varying selection have been investigated both at the genomic and transcriptomic level in several organisms. In Drosophila melanogaster, the majority of these studies have analyzed North American and Australian populations, leading to the identification of several loci and traits under selection. However, populations in these two continents showed evidence of admixture that likely contributed to the observed population differentiation patterns. Thus, disentangling demography from selection is challenging when analyzing these populations. European populations could be a suitable system to identify loci under spatially varying selection provided that no recent admixture from African populations would have occurred. In this work, we individually sequence the genome of 42 European strains collected in populations from contrasting environments: Stockholm (Sweden), and Castellana Grotte, (Southern Italy). We found low levels of population structure and no evidence of recent African admixture in these two populations. We thus look for patterns of spatially varying selection affecting individual genes and gene sets. Besides single nucleotide polymorphisms, we also investigate the role of transposable elements in local adaptation. We concluded that European populations are a good dataset to identify loci under spatially varying selection. The analysis of the two populations sequenced in this work in the context of all the available D. melanogaster data allowed us to pinpoint genes and biological processes relevant for local adaptation. Identifying and analyzing populations with low levels of population structure and admixture should help to disentangle selective from non-selective forces underlying patterns of population differentiation in other species as well.

evolutionary biology↗