Biology subjects

Lima, I.

Publications and source records attributed to Lima, I..

3 recordsLinked to original sources

bioRxiv2020

Genome-wide association of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) plasma levels in the ELSA-Brasil study

Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genome-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the ELSA-Brasil cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array and imputation used the TOPMED multi-ancestry sample panel. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined p value threshold of 1 x 10-6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variation in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identifying new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

genetics↗

bioRxiv2020

SS3D: Sequence similarity in 3D for comparison of protein families

Homologous proteins are often compared by pairwise sequence alignment, and structure superposition if the atomic coordinates are available. Unification of sequence and structure data is an important task in structural biology. Here, we present Sequence Similarity 3D (SS3D), a new method for integrating sequence and structure information for comparison of homologous proteins. SS3D quantifies the spatial similarity of residues within a given radius of homologous through-space contacts. The spatial alignments are scored using native BLOSUM and PAM substitution matrices. This work details the SS3D approach and demonstrates its utility through case studies comparing members of several protein families: GPCR, p53, kelch, SUMO, and SARS coronavirus spike protein. We show that SS3D can more clearly highlight biologically important regions of similarity and dissimilarity compared to pairwise sequence alignments or structure superposition alone. SS3D is written in C++, and is available with a manual and tutorial at https://github.com/0x462e41/SS3D/.

bioinformatics↗

bioRxiv2018

Generation Of iPSC-Derived Human Peripheral Sensory Neurons Releasing Substance P Elicited By TRPV1 Agonists

Neural crest stem cells (NCPCs) have been shown to differentiate into various cell types and tissues during embryonic development, including sensory neurons. The few studies addressing the generation of NCPCs and peripheral sensory neurons (PSNs) from human induced Pluripotent Stem Cells (hiPSCs), generated sensory cells without displaying robust activity. Here, we describe an efficient strategy for hiPSCs differentiation into NCPCs and functional PSNs using chemically defined media and factors to achieve efficient differentiation, confirmed by the expression of specific markers. After 10 days hiPSCs differentiated into NCPCs, cells were then maintained in neural induction medium containing defined growth factors for PSNs differentiation, followed by 10 days in neonatal human epidermal keratinocytes-(HEKn-) conditioned medium. We observed a further increase in PSN markers expression and neurites length after conditioned medium treatment. The resulting neurons released substance P (SP) in response to nociceptive agents such as anandamide and resiniferatoxin. Anandamide induced substance P release via activation of TRPV1 and not CB1. Transcriptomic analysis of the PSNs revealed the main dorsal root ganglia (DRG) neuronal markers and a transcriptional profile compatible with C-LTMR. TRPV1 was detected by immunofluorescence and RNA-Seq in multiple experiments. In conclusion, the developed strategy generated PSNs useful for drug screening that could be applied to patient-derived hiPSCs, consisting in a powerful tool to model human diseases in vitro.

neuroscience↗