Biology subjects

Ruiz Carmona, S.

Publications and source records attributed to Ruiz Carmona, S..

3 recordsLinked to original sources

bioRxiv2024

Skeletal Muscle Specific PolG Dysfunction Activates the Integrated Stress Response and Promotes a Cachexia like Phenotype

During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is specifically activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for this activation remain elusive. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase {gamma} (PolG). Here, we describe what is to our knowledge the first conditional muscle specific model of PolG mutation, and demonstrate a rapid development of mitochondrial dysfunction and cachexia in these animals from [~]5 months of age. Detailed molecular profiling of muscles demonstrated robust activation of the mtISR, likely mediated upstream by the HRI/DELE1 stress pathway. This was accompanied by striking alterations to the mitochondrial folate cycle and its metabolites, strongly implying imbalanced folate intermediates as a previously unrecognised pathology driving the mtISR in mitochondrial disease.

physiology↗

bioRxiv2021

The carbon footprint of bioinformatics

Bioinformatic research relies on large-scale computational infrastructures which have a non-zero carbon footprint. So far, no study has quantified the environmental costs of bioinformatic tools and commonly run analyses. In this study, we estimate the bioinformatic carbon footprint (in kilograms of CO2 equivalent units, kgCO2e) using the freely available Green Algorithms calculator (www.green-algorithms.org). We assess (i) bioinformatic approaches in genome-wide association studies (GWAS), RNA sequencing, genome assembly, metagenomics, phylogenetics and molecular simulations, as well as (ii) computation strategies, such as parallelisation, CPU (central processing unit) vs GPU (graphics processing unit), cloud vs. local computing infrastructure and geography. In particular, for GWAS, we found that biobank-scale analyses emitted substantial kgCO2e and simple software upgrades could make GWAS greener, e.g. upgrading from BOLT-LMM v1 to v2.3 reduced carbon footprint by 73%. Switching from the average data centre to a more efficient data centres can reduce carbon footprint by ~34%. Memory over-allocation can be a substantial contributor to an algorithms carbon footprint. The use of faster processors or greater parallelisation reduces run time but can lead to, sometimes substantially, greater carbon footprint. Finally, we provide guidance on how researchers can reduce power consumption and minimise kgCO2e. Overall, this work elucidates the carbon footprint of common analyses in bioinformatics and provides solutions which empower a move toward greener research.

bioinformatics↗

bioRxiv2018

Are protein-ligand complexes robust structures?

The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. While this is convenient from a design perspective, it ignores the fact that structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, any potential benefit of a rigid binding mode will have to be balanced against the entropic penalty that it entails. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Here we investigate two diverse sets of structures, comprising 79 drug-like and 27 fragment ligands, respectively. We focus on hydrogen bond interactions (469 in total), as they have been described as essential for structural stability. We find that 75% of complexes are anchored by at least one robust hydrogen bond, the remaining 25% either form loose complexes or are constrained by other interactions types. The first type of complexes generally combine a single anchoring point with looser regions, thus balancing order and disorder. Completely constricted protein-ligand complexes are rare and seem to fulfil a functional necessity. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.

biophysics↗