Biology subjects

Camacho, C.

Publications and source records attributed to Camacho, C..

6 recordsLinked to original sources

bioRxiv2025

Multilayered human activities shape the microbial communities of groundwater-dependent ecosystems in an arid oceanic island

Island coastal aquifers, though physically small compared to continental groundwater systems, are of huge ecological and societal importance, sustaining functions that connect to locally crucial provision, maintenance and culture ecosystem services. Those functions are largely dependent on the presence of highly adapted biological communities, for which, their microbial communities remain understudied. Our goal is to describe the bacterial communities across the groundwater-dependent ecosystems on Lanzarote, spanning a gradient of anthropogenic pollution using 16SrRNA amplicon sequencing. We sampled coastal caves and pools, wells and water galleries, springs, saltworks and marine bays affected by submarine groundwater discharge. Ecological analyses highlight that richness and composition of bacterial communities strongly depend on the type of habitats. Pathogens and human-derived species were ubiquitous in our samples, but, strikingly, caves and wells were strongly enriched with them compared to other habitats. We propose that our results highlight the susceptibility of groundwater environments to pollution and indicate that aquifers act as reservoirs of biological contamination in addition to natural diversity--regardless of their salinity. Since this enrichment might compromise some of the functions and services that groundwater-dependent ecosystems provide in oceanic islands, we call for integrative conservation strategies that include hydrological and biological perspectives into the decision making.

microbiology↗

bioRxiv2025

Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition

Immune checkpoint inhibition (ICI) has fundamentally changed cancer treatment. However, only a minority of patients with metastatic triple negative breast cancer (TNBC) benefit from ICI, and the determinants of response remain largely unknown. To better understand the factors influencing patient outcome, we assembled a longitudinal cohort with tissue from multiple timepoints, including primary tumor, pre-treatment metastatic tumor, and on-treatment metastatic tumor from 117 patients treated with ICI (nivolumab) in the phase II TONIC trial. We used highly multiplexed imaging to quantify the subcellular localization of 37 proteins in each tumor. To extract meaningful information from the imaging data, we developed SpaceCat, a computational pipeline that quantifies features from imaging data such as cell density, cell diversity, spatial structure, and functional marker expression. We applied SpaceCat to 678 images from 294 tumors, generating more than 800 distinct features per tumor. Spatial features were more predictive of patient outcome, including features like the degree of mixing between cancer and immune cells, the diversity of the neighboring immune cells surrounding cancer cells, and the degree of T cell infiltration at the tumor border. Non-spatial features, including the ratio between T cell subsets and cancer cells and PD-L1 levels on myeloid cells, were also associated with patient outcome. Surprisingly, we did not identify robust predictors of response in the primary tumors. In contrast, the metastatic tumors had numerous features which predicted response. Some of these features, such as the cellular diversity at the tumor border, were shared across timepoints, but many of the features, such as T cell infiltration at the tumor border, were predictive of response at only a single timepoint. We trained multivariate models on all of the features in the dataset, finding that we could accurately predict patient outcome from the pre-treatment metastatic tumors, with improved performance using the on-treatment tumors. We validated our findings in matched bulk RNA-seq data, finding the most informative features from the on-treatment samples. Our study highlights the importance of profiling sequential tumor biopsies to understand the evolution of the tumor microenvironment, elucidating the temporal and spatial dynamics underlying patient responses and underscoring the need for further research on the prognostic role of metastatic tissue and its utility in stratifying patients for ICI.

cancer biology↗

bioRxiv2024

An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck

While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using 1H-15N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuterium exchange mass spectrometry, with PDA1 stabilizing and PDA2 disrupting the overall kinase conformation. Kinase activity assays were consistent with these observations, with PDA2 enhancing kinase activity while PDA1 was without effect. Molecular dynamics simulations predicted selective bridging of the kinase domain N-lobe and SH3 domain by PDA1, a mechanism of allosteric stabilization supported by site-directed mutagenesis of N-lobe contact sites. Cellular thermal shift assays confirmed SH3 domaindependent interaction of PDA1 with wild-type Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.

pharmacology and toxicology↗

bioRxiv2024

Epigenetic potential and dispersal propensity in a free-living songbird: a spatial and temporal approach

Natal dispersal is a key life-history trait determining fitness and driving population dynamics, genetic structure and species distributions. Despite existing evidence that not all phenotypes are equally likely to successfully establish in new areas, the mechanistic underpinnings of natal dispersal remain poorly understood. The propensity to disperse into a new environment can be favored by a high degree of phenotypic plasticity which facilitates local adaptation and may be achieved via epigenetic mechanisms, which modify gene expression and enable rapid phenotypic changes. Epigenetic processes occur in particular genomic regions - DNA methylation on CpG sites in vertebrates -, and thus individual genomes may differ in their capacity to be modified epigenetically. This "Epigenetic potential" (EP) may represent the range of phenotypic plasticity attainable by an individual, and be a key determinant of successful settlement in novel areas. We investigated the association between EP - quantified as the number of genome-wide CpG variants - and natal dispersal propensity in a long-term study population of Pied flycatchers (Ficedula hypoleuca) monitored since colonization of a new habitat 35 years ago. We tested this association at three levels, comparing EP between: i) individuals dispersing between and within habitat patches; ii) immigrants to the population and locally-born individuals; and iii) individuals from first (comprising colonizers or their direct descendants) and later generations of the population (consisting of locally-born individuals, which did not show natal dispersal). Results show a significant, positive association between EP and dispersal propensity in comparisons i) and iii), but not ii). Furthermore, CpG variants were non-randomly distributed across the genome, suggesting species- and/or population-specific CpGs being more frequent in promoters and exons. Our findings point to EP playing a role in dispersal propensity at spatial and temporal scales, supporting the idea that epigenetically-driven phenotypic plasticity facilitates dispersal and environmental coping in free-living birds.

ecology↗

bioRxiv2023

ElasticBLAST: Accelerating Sequence Search via Cloud Computing

BackgroundBiomedical researchers use alignments produced by BLAST (Basic Local Alignment Search Tool) to categorize their query sequences. Producing such alignments is an essential bioinformatics task that is well suited for the cloud. The cloud can perform many calculations quickly as well as store and access large volumes of data. Bioinformaticians can also use it to collaborate with other researchers, sharing their results, datasets and even their pipelines on a common platform. ResultsWe present ElasticBLAST, a cloud native application to perform BLAST alignments in the cloud. ElasticBLAST can handle anywhere from a few to many thousands of queries and run the searches on thousands of virtual CPUs (if desired), deleting resources when it is done. It uses cloud native tools for orchestration and can request discounted instances, lowering cloud costs for users. It is supported on Amazon Web Services and Google Cloud Platform. It can search BLAST databases that are user provided or from the National Center for Biotechnology Information. ConclusionWe show that ElasticBLAST is a useful application that can efficiently perform BLAST searches for the user in the cloud, demonstrating that with two examples. At the same time, it hides much of the complexity of working in the cloud, lowering the threshold to move work to the cloud.

bioinformatics↗

bioRxiv2019

MAP2 is Hyperphosphorylated in Schizophrenia and Alters its Function

Schizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of Microtubule-associated Protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into 3 modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wildtype and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz - that a large proportion of individuals have a "MAP2opathy" - in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

neuroscience↗