Biology subjects

Davila, S.

Publications and source records attributed to Davila, S..

6 recordsLinked to original sources

bioRxiv2026

Individual differences in novelty-seeking behavior are modulated by GRK2/3 inhibition in rats

Background and Purpose High novelty-seeking is an endophenotype associated with greater vulnerability to drug addiction, marked by a hyperdopaminergic state and reduced dopamine D2 receptor (D2R) levels in the dorsal striatum (DS). G protein-coupled receptor kinases (GRKs) regulate desensitization, internalization, and recycling of these receptors, including the D2R. This study investigated the relevance of GRK2 and 3 (GRK2/3) in novelty-seeking behavior and striatal dopamine dynamics. Experimental Approach Individual novelty-seeking trait was assessed in Sprague Dawley rats using an open-field test. D2R, GRK2, and GRK5 protein levels were measured in synaptosomal DS samples using Western Blot. Pharmacological inhibition of GRK2/3 was assessed using Cmpd101. We tested the effect of systemic Cmpd101 administration on contextual novelty discrimination and local Cmpd101 perfusion on baseline and stimulus-evoked extracellular dopamine (DA) levels in the DS. Key Results Locomotor activity in a novel environment inversely correlated with the synaptosomal GRK2 and D2R protein levels in the DS. Systemic Cmpd101 treatment modulated the locomotor discrimination index in a novelty phenotype-dependent manner. Moreover, local Cmpd101 perfusion in the DS elicited a sustained elevation in basal extracellular dopamine levels and significantly blunted subsequent stimulus-evoked DA release, both effects independent of novelty-seeking phenotype. Conclusion and Implications Together, our findings link GRK2/3 signaling to individual differences in novelty-seeking and striatal dopaminergic function. These results suggest a potential relevance to drug addiction vulnerability.

neuroscience↗

bioRxiv2022

RAPTOR: A Five-Safes approach to a secure, cloud native and serverless genomics data repository

Genomic researchers are increasingly utilizing commercial cloud platforms (CCPs) to manage their data and analytics needs. Commercial clouds allow researchers to grow their storage and analytics capacity on demand, keeping pace with expanding project data footprints and enabling researchers to avoid large capital expenditures while paying only for IT capacity consumed by their project. Cloud computing also allows researchers to overcome common network and storage bottlenecks encountered when combining or re-analysing large datasets. However, cloud computing presents a new set of challenges. Without adequate security controls, the risk of unauthorised access may be higher for data stored on the cloud. In addition, regulators are increasingly mandating data access patterns and specific security protocols on the storage and use of genomic data to safeguard rights of the study participants. While CCPs provide tools for security and regulatory compliance, utilising these tools to build the necessary controls required for cloud solutions is not trivial as such skill sets are not commonly found in a genomics lab. The Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud native genomics data repository and analytics platform focusing on security and regulatory compliance. Using a "five-safes" framework (Safe Purpose, Safe People, Safe Settings, Safe Data and Safe Output), RAPTOR provides security and governance controls to data contributors and users leveraging cloud computing for sharing and analysis of large genomic datasets without the risk of security breaches or running afoul of regulations. RAPTOR can also enable data federation with other genomic data repositories using GA4GH community-defined standards, allowing researchers to boost the statistical power of their work and overcome geographic and ancestry limitations of data sets

genomics↗

bioRxiv2022

Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tuberculosis and provide novel drug targets. Single sentence summaryRNA released from Mycobacterium tuberculosis in the macrophage phagosome is sensed by the pattern recognition receptor TLR8 controlling host susceptibility to tuberculosis and revealing a druggable pathway for host-directed therapy.

immunology↗

bioRxiv2020

Family History Assessment Significantly Enhances Delivery of Precision Medicine in the Genomics Era

BackgroundFamily history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs, with less emphasis on family history assessment. We evaluated the utility of family history for genomic sequencing selection. MethodsWe analysed whole genome sequences of 1750 healthy research participants, with and without preselection based on standardised family history collection, screening 95 cancer genes. ResultsThe frequency of likely pathogenic/ pathogenic (LP/P) variants in 884 participants with no family history available (FH not available group) (2%) versus 866 participants with family history available (FH available group) (3.1%) was not significant (p=0.158). However, within the FH available group, amongst 73 participants with an increased family history cancer risk (increased FH risk), 1 in 7 participants carried a LP/P variant inferring a six-fold increase compared with 1 in 47 participants assessed at average family history cancer risk (average FH risk) and a seven-fold increase compared to the FH not available group. The enrichment was further pronounced (up to 18-fold) when assessing the 25 cancer genes in the ACMG 59-gene panel. Furthermore, 63 participants had an increased family history cancer risk in absence of an apparent LP/P variant. ConclusionOur findings show that systematic family history collection remains critical for health risk assessment, providing important actionable data and augmenting the yield from genomic data. Family history also highlights the potential impact of additional hereditary, environmental and behavioural influences not reflected by genomic sequencing.

genomics↗

bioRxiv2019

Digital phenotyping by consumer wearables identifies sleep-associated markers of cardiovascular disease risk and biological aging

Despite growing adoption of consumer wearables, the potential for sleep metrics from these devices to contribute to sleep-related biomedical research remains largely uncharacterized. Here we analyze sleep tracking data, along with questionnaire responses and multi-modal phenotypic data, generated from 482 normal volunteers. First, we provide a detailed comparison of wearable-derived and self-reported sleep metrics, particularly total sleep time (TST) and sleep efficiency (SE). We then identified demographic, socioeconomic and lifestyle factors associated with wearable-derived sleep duration. We also analyzed our multi-modal phenotypic data and showed that wearable-derived TST and SE are associated with various cardiovascular disease risk markers, whereas self-reported measures were not. Using whole-genome sequencing data, we estimated leukocyte telomere length and showed that volunteers with insufficient sleep also exhibit premature telomere attrition. Our study highlights the potential for sleep metrics generated by consumer wearables to provide novel insights into data generated from population cohort studies.

epidemiology↗

bioRxiv2018

Variation in Genome-wide NF-kappaB RELA Binding Sites upon Microbial Stimuli and Identification of a Virus Response Profile

NF-kB transcription factors are master regulators of the innate immune response. Activated downstream of pathogen recognition receptors, they regulate the expression of genes to help fighting infections as well as recruiting the adaptive immune system. NF-kB responds to a wide variety of signals, but the processes by which stimulus-specificity is attained remain unclear. Here, we characterized the response of one NF-kB member, RELA, to four stimuli mimicking infection in human nasopharyngeal epithelial cells. Comparing genome-wide RELA binding, we observed stimulus-specific sites, although most sites overlapped across stimuli. Specifically, the response to Poly I:C - mimicking viral dsRNA and signalling through TLR3 - induced a distinct RELA profile, binding in the vicinity of antiviral genes and correlating with corresponding gene expression. This group of binding sites was also enriched in Interferon Regulatory Factor (IRF) motifs and showed overlapping with IRFs binding sites. A novel NF-kB target, OASL was further validated and showed TLR3-specific activation. This work showed that some RELA DNA binding sites varied in activation response following different stimulations and that interaction with more specialized factors could help achieve this stimulus-specific activity. Our data provide a genomic view of regulated host response to different pathogen stimuli.

genomics↗