Biology subjects

Acosta, A.

Publications and source records attributed to Acosta, A..

14 recordsLinked to original sources

bioRxiv2026

Context-specific genetic interaction mapping reveals combinatorial KRAS/FGFR dependence in pancreatic cancer

Oncogenic KRAS drives >90% of pancreatic ductal adenocarcinoma (PDAC), and the pan-RAS inhibitor daraxonrasib doubles overall survival, but adaptive and acquired resistance limit the depth and duration of responses. To systematically map combination vulnerabilities, we developed RAS+, a digenic CRISPR knockout library testing 10,296 pairwise perturbations across oncogenic signaling pathways, and screened 12 cell lines, revealing genotype- and lineage-specific interactions. In KRASmut PDAC, the most differentially effective gene pair was KRAS and FRS2, an adapter coupling FGFR signaling to RAS. Combined KRAS/pan-FGFR inhibition was synergistic and cytotoxic, eradicating tumor cells and overcoming resistance in vitro and deepening and prolonging regressions in vivo. Single-cell analysis identified cancer-associated fibroblasts (CAFs) as a primary source of FGF ligands in PDAC, and CAF conditioned media or individual FGFs promoted resistance. These findings define a stroma-to-tumor adaptive FGFR circuit limiting the effects of KRAS inhibition. Thus, combined KRAS/FGFR blockade may be a strategy to improve responses.

cancer biology↗

bioRxiv2025

Preparatory encoding of diverse features of intended movement in the human motor cortex

Over the course of a voluntary movement, motor cortical activity exhibits a transition from preparation to execution, with markedly different activity across these phases. Preparatory activity in particular might be used to improve brain-computer interfaces (BCIs) that harness brain activity to control external assistive devices, for example by anticipating a users intended movement trajectory for quick and fluid performance. However, to leverage preparatory activity for clinical BCIs, we must first understand which features of upcoming movements are encoded by preparatory activity in humans. In this work, we collected intracortical recordings from 3 research participants in the BrainGate2 clinical trial to investigate whether diverse features of movement, such as direction, curvature, and distance, are encoded by preparatory activity in the human motor cortex. We first show that preparatory activity is tuned to the direction of upcoming movements, and this tuning is largely preserved across movements with different effectors. Further investigation demonstrated this preparatory activity is also informative of initial and endpoint directions of curved movement trajectories, and encodes movement distance and speed independently. Finally, we present an online control paradigm that leverages preparatory activity to predict movements towards intended directions in advance, yielding rapid, self-paced control of a computer cursor by human participants. Altogether, these results demonstrate that preparatory activity in the human motor cortex encodes rich features of upcoming movement, highlighting its potential use for high performance brain-computer interface applications.

neuroscience↗

bioRxiv2025

At the Southern Limit: The Arenal Central Site and the Guarani Occupation of the Parana Delta (Argentina)

This study analyzes the archaeological record of the Arenal Central site, a Guarani residential base located on Martin Garcia Island, within the Rio de la Plata estuary--marking the southernmost extent of this population originating from the tropical forests of South America. The results significantly advance our understanding of these Amazonian forager-horticulturalists in the region, allowing us to explore a range of strategies and material culture expressions developed in an environment suboptimal for canoe-based populations. The study also presents a new set of chronological data, substantially increasing the number of radiocarbon dates available for these groups in the area. Findings indicate that Arenal Central was occupied around 1400 CE, during the final phase of the Guarani expansion across the La Plata Basin. From this location, a vast catchment area was incorporated, including the lower Uruguay River, the Parana Delta islands, and the adjacent Uruguayan steppe. The extensive use of territory appears to have been a strategic response to the islands limited carrying capacity and the scarcity of key resources required to sustain the Guarani ecological niche. While the recovered assemblage preserves the core features of Guarani material culture, a marked decline is observed in the complexity of pictorial expressions--particularly in painted ceramics. This simplification may reflect reduced intra-ethnic interaction, likely due to the low density of Guarani populations in the surrounding area, as well as the challenges imposed by a constrained insular setting. We also compare subsistence strategies and ceramic assemblages from other sites that have been excavated and analyzed following comparable standards. Finally, the results are contextualized within the broader process of Guarani occupation of the Parana Delta and the Rio de la Plata estuary.

zoology↗

bioRxiv2024

A multidisciplinary investigation into whether Andean caravans reached the southern lowlands of the Parana-Plata basin during pre-Columbian times

The expansion of llama caravans and the dispersal of domesticated camelids to extra-Andean regions is one of the key topics in South American archaeology, as it reflects the degree of connection between Andean societies and the surrounding lowland societies, as well as the extent of pre-Columbian pastoralism. One of the primary indicators of both processes is the presence of domesticated camelids in the archaeological record, particularly the llama (Lama glama). Based on somewhat ambiguous historical evidence, it has been suggested that llama caravanning may have reached the northern Pampean region and the southern Parana River valley from an unspecified time until historical times. While the archaeological sites in these two regions have abundant camelid remains that have thus far been identified as guanaco (Lama guanicoe), the possibility of misidentification due to the osteometric similarity between the domestic and wild camelids could mask the presence of llamas in the record, undermining evidence of this potential major expansion of llama caravans. To clarify this issue, we applied a multidisciplinary approach combining archaeological, isotopic, and paleogenomic analyses to determine the taxonomic status of camelids recovered from archaeological sites in both areas. Our findings demonstrate that all the individuals analyzed correspond to guanacos, whose survival extended into early historical times. There is no regional evidence to support the presence of llama caravanning or domesticated camelids in the northern Pampean region or the lower Parana River valley.

genomics↗

bioRxiv2024

A mosaic of whole-body representations in human motor cortex

Understanding how the body is represented in motor cortex is key to understanding how the brain controls movement. The precentral gyrus (PCG) has long been thought to contain largely distinct regions for the arm, leg and face (represented by the "motor homunculus"). However, mounting evidence has begun to reveal a more intermixed, interrelated and broadly tuned motor map. Here, we revisit the motor homunculus using microelectrode array recordings from 20 arrays that broadly sample PCG across 8 individuals, creating a comprehensive map of human motor cortex at single neuron resolution. We found whole-body representations throughout all sampled points of PCG, contradicting traditional leg/arm/face boundaries. We also found two speech-preferential areas with a broadly tuned, orofacial-dominant area in between them, previously unaccounted for by the homunculus. Throughout PCG, movement representations of the four limbs were interlinked, with homologous movements of different limbs (e.g., toe curl and hand close) having correlated representations. Our findings indicate that, while the classic homunculus aligns with each areas preferred body region at a coarse level, at a finer scale, PCG may be better described as a mosaic of functional zones, each with its own whole-body representation.

neuroscience↗

bioRxiv2024

The global fish and invertebrate abundance value of mangroves

Mangroves are a critical coastal habitat that provides a suite of ecosystem services and supports livelihoods. We undertake the first global analysis to estimate density and abundance of 37 commercially important fish and invertebrates that are known to extensively use mangroves. Geomorphic mangrove type, sea surface salinity and temperature, and length of mangrove forest edge were important in predicting the density of commercial fish and invertebrates, with deltaic systems supporting the highest densities. The model predicted high densities throughout parts of southeast Asia, the northern coast of South America, the Red Sea, and the Caribbean and Central America. Application of our model onto the global mangrove extent, estimates that mangroves support the annual abundance of nearly 800 billion young-of-year fish and invertebrates contained in our model. Our results confirm the critical role of mangroves globally in supporting fish and fisheries, and further builds the case for their conservation and restoration.

ecology↗

bioRxiv2023

REM Sleep Measures and REM Vagal Activity Predict Extinction Recall in Trauma-Exposed Individuals

Accumulating evidence suggests that rapid eye movement sleep (REM) supports the consolidation of extinction memory. REM is disrupted in PTSD, and REM abnormalities after traumatic events increase the risk of developing PTSD. Therefore, it was hypothesized that abnormal REM in trauma-exposed individuals may pave the way for PTSD by interfering with the processing of extinction memory. In addition, PTSD patients display reduced vagal activity. Vagal activity contributes to the strengthening of memories, including fear extinction memory, and recent studies show that the role of vagus in memory processing extends to memory consolidation during sleep. Therefore, it is plausible that reduced vagal activity during sleep in trauma-exposed individuals may be an additional mechanism that impairs extinction memory consolidation. However, to date, the contribution of sleep vagal activity to the consolidation of extinction memory or any emotional memory has not been investigated. To test these hypotheses, we examined the association of extinction memory with REM characteristics and REM vagal activity (indexed as heart rate variability) in a large sample of trauma-exposed individuals (n=113). Consistent with our hypotheses, REM disruption was associated with poorer physiological and explicit extinction memory. Furthermore, higher vagal activity during REM was associated with better explicit extinction memory, and physiological extinction memory in males. These findings support the notion that abnormal REM may contribute to PTSD by impairing the consolidation of extinction memory and indicate the potential utility of interventions that target REM sleep characteristics and REM vagal activity in fear-related disorders.

neuroscience↗

bioRxiv2023

The CB1 Negative Allosteric Modulator PSNCBAM-1 Reduces Ethanol Self-Administration via a Nonspecific Hypophagic Effect

Alcohol use disorder (AUD) affects more than 15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. The cannabinoid receptor type 1 (CB1) has been a target of interest for the development of medications for substance use disorders and other compulsive disorders. However, CB1 antagonists/inverse agonists (e.g., rimonabant) have severe side effects that limit their clinical utility, including anxiety, depression, and suicide. Recent development of CB1 negative allosteric modulators (NAMs), including PSNCBAM-1, may provide an alternative mechanism of attenuating CB1 signaling with reduced side effects. PSNCBAM-1 has not yet been evaluated for effects in models of AUD. In this study, we investigated the effects of the CB1 NAM, PSNCBAM-1, in rodent models of AUD using adult male mice. PSNCBAM-1 dose-dependently attenuated oral ethanol self-administration (8% w/v ethanol in water), significantly reducing ethanol rewards at a dose of 30 mg/kg, but not at 10 or 18 mg/kg. PSNCBAM-1 also dose-dependently attenuated palatable food self-administration (diluted vanilla Ensure), significantly reducing food rewards at 18 and 30 mg/kg PSNCBAM-1. PSNCBAM-1 did not affect conditioned place preference for 2 g/kg ethanol. These results suggest PSNCBAM-1 reduces ethanol-taking behavior via a nonspecific hypophagic effect and does not reduce the rewarding effects of ethanol.

pharmacology and toxicology↗

bioRxiv2023

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function

Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. ADA-OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA-OE increases proliferation and decreases exhaustion in -CD19 and -HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by -HER2 CAR-T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy. SynopsisThe authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in -CD19 and -HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE -HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumors in vivo.

cancer biology↗

bioRxiv2022

Risk factors and spatiotemporal analysis of classical swine fever in Ecuador

1.Classical swine fever (CSF) is one of the most important re-emergent swine diseases worldwide. Despite concerted control efforts in the Andean countries, the disease remains endemic in several areas, limiting production and trade opportunities. In this study, we aim to determine herd-level risk factors and spatiotemporal implications associated with CSF. We analysed passive surveillance datasets and vaccination programmes from 2014 to 2020; Then, structured a herd-level case-control study using a multivariable logistic model containing 339 cases, and a spatiotemporal Bayesian model, considering 115 thousand premises, 2.3 million annual vaccine doses and a population of 1.6 million pigs distributed in 1,006 parishes. Our results showed that the risk factors that increased the odds of CSF occurrence were swill feeding (OR 9.28), time of notification (OR 2.18), animal entry in the last 30 days (OR 2.08), lack of CSF vaccination (OR 1.88), age of animals between 3-6 months (OR 1.58) and being in the coastal region (OR 1.87). Spatiotemporal models showed that the vaccination campaign reduced the risk by 33% while temperature increased the risk by 17%. The calculated priority index aims to facilitate the intervention process that should be focused on a couple of provinces, mainly in Morona Santiago and Los Rios as well as in specific parishes around the country. Our findings provide insight and understanding of the risk factors associated with CSF in Ecuador, which stands for the Andean region; even though the results are specific for the implementation of risk-based surveillance for CSF, data and methods could be valuable for the prevention and control of diseases such as African swine fever, or porcine reproductive and respiratory syndrome. In conclusion, the results highlight the complexity of the CSF control programme, the need to inform decision-makers, involve stakeholders and implement better strategies to update continental health policies to eradicate swine diseases.

ecology↗

bioRxiv2022

A study of thermally-induced sex reversal in casque-headed lizards

Non-avian reptiles, unlike mammals and birds, have undergone numerous sex determination turnovers. For example, casque-headed lizards replaced the ancestral XY system shared across pleurodonts with a new pair of XY chromosomes. However, the evolutionary forces that triggered this transition have remained unclear. An interesting evolutionary hypothesis suggests that species with intermediate states, with sex chromosomes but also thermal-induced sex reversal at specific incubation temperatures, could be more susceptible to sex determination turnovers. We contrasted genotypic data (presence/absence of the Y chromosome) against the histology of gonads of embryos from stages 35-37 incubated at various temperatures, including typical male-producing (26{degrees}C) and female-producing (32{degrees}C) temperatures. We observed perfect concordance between genotype and phenotype at all temperatures. However, analysis of transcriptomic data from embryos incubated at 26{degrees}C and 32{degrees}C identified transcript variants of the chromatin modifiers JARID2 and KDM6B that have been linked to temperature-dependent sex determination in other reptiles. Besides, our work reports for the first time to our knowledge the histology of gonads, including morphological changes, from stages 35-37 of development in the Corytophanidae family. We also observed that all embryos developed hemipenes, suggesting sex-linked developmental heterochrony.Our work tested the validity of a mixed sex determination system in the Corytophanidae family. We showed that XY chromosomes are dominant, however, our work supports the hypothesis of a conserved transcriptional response to incubation temperatures across non-avian reptiles that could be the reminiscence of an ancestral sex determination system.

developmental biology↗

bioRxiv2021

Survey of extracellular communication of systemic and organ-specific inflammatory responses through cell free messenger RNA profiling in mice

Inflammatory and immune responses are essential and dynamic biological processes that protect the body against acute and chronic adverse stimuli. While conventional protein markers have been used to evaluate systemic inflammatory response, the immunological response to stimulation is complex and involves modulation of a large set of genes and interacting signaling pathways of innate and adaptive immune systems. Therefore, there is a need for a non-invasive tool that can comprehensively evaluate and monitor molecular dysregulations associated with inflammatory and immune responses. Here we utilized cell-free messenger RNA (cf-mRNA) RNA-Seq whole transcriptome profiling to assess lipopolysaccharide (LPS) induced and JAK inhibitor modulated inflammatory and immune responses in mouse plasma samples. Considering that, both organspecific recruitment of immune cells and organ resident bespoke immune cells contributes to restoration of organ homeostasis, we also examined LPS-induced gene-expression dysregulation of multiple organs to shed light on organ crosstalk. Cf-mRNA profiling displayed a pattern of systemic immune responses elicited by LPS and dysregulation of associated pathways. Moreover, attenuation of several inflammatory pathways, including STAT and interferon pathways, were observed following the treatment of JAK inhibitor. Lastly, we identified the dysregulation of liverspecific transcripts in cf-mRNA which reflected changes in the gene-expression pattern in this biological compartment. Collectively, using a preclinical model, we demonstrated the potential of plasma cf-mRNA profiling for systemic and organ-specific characterization of drug-induced molecular alterations that are associated with inflammatory and immune responses. O_FIG O_LINKSMALLFIG WIDTH=149 HEIGHT=200 SRC="FIGDIR/small/472685v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@14603f0org.highwire.dtl.DTLVardef@1acb99corg.highwire.dtl.DTLVardef@cdb8ceorg.highwire.dtl.DTLVardef@1fe70d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Amblyomma mixtum free-living stages: Summer and winter use, preference, and niche width in an agroecosystem (Yopal, Casanare, Colombia)

Studying a species tolerance to an ecosystems environmental conditions and its selection of available resources is relevant in ecological and evolutionary terms. Moreover, formulation of effective control strategies implicitly includes the study of habitat use and preference and niche width in anthropogenically transformed natural landscapes. Here, we evaluated whether the use, habitat preference, and niche range of the Amblyomma mixtum tick changed between stages, habitats, and seasons (summer-winter 2019) on a farm in Yopal (Casanare, Colombia). To this end, the presence and relative abundance of larvae, nymphs, and free-living adults was quantified in four different habitats according to the type of vegetation cover (Riparian Forest, Cocoa Crop, King Grass Crop, and Star Grass Paddock). Habitat availability was calculated, environmental variables were analyzed, and various indices of habitat use and preference and niche width were calculated. A. mixtums habitat use and preference and niche width changed between stages, habitat types, and time of the year. The total abundance of A. mixtum was an order of magnitude greater in summer than winter. Nymphs and larvae dominated it in the summer and adults in the winter. In summer, all the stages used the four habitats. In winter, the larvae did not use two habitats (Riparian Forest and Cocoa Crop); nymphs did not use the cocoa crop. A. mixtum adults used all the habitats in both seasons. In summer, the nymphs and larvae preferred three of the four habitats (King Grass Crop, Star Grass Paddock, and Cocoa Crops), while adults preferred the King Grass Crop. In winter, the nymphs and larvae preferred the King Grass Crop and Star Grass Paddock, while the adults preferred the King Grass Crop. The value of the niche width index was high for larvae, nymphs, and adults in summer, while it was high only for adults in winter. A. mixtum is exposed to significant daily, seasonal, and multiannual variations in relative humidity (minimum 30%), ambient temperature (minimum 18{degrees}C), solar radiation (maximum 800 W/m2), and precipitation (maximum 481 mm/month). Thus, the local A. mixtum population could rapidly acclimatize to changing habitats (unstable or temporary) under fluctuating environmental conditions (e.g., King Grass Crop). However, the winter flood season in Yopal could exceed A. mixtums adaptive capacity during its most vulnerable stages. Mathematically, a low number of female A. mixtum, surviving the most demanding environmental conditions, could sufficiently ensure the populations persistence, which, coupled with the vast host range, could facilitate the ticks stages dispersal among habitats to complete their life cycle. A. mixtums population control should be carried out during its season of greater vulnerability (winter), when the population is low, particularly the females.

ecology↗

bioRxiv2019

Non-invasive characterization of human bone marrow by cell free messenger-RNA reveals response to growth factor stimulation and hematopoietic reconstitution after transplantation

Circulating cell free mRNA (cf-mRNA) holds great promise as a non-invasive diagnostic biomarker. However, the biological origin of cf-mRNA is still not well understood, limiting the clinical applications of this technology. Here, we use the bone marrow (BM) and pharmacologic manipulation of its resident cells as a window to study the origin of cf-mRNA. Using NGS-based profiling, we show that cf-mRNA is enriched in transcripts derived from the BM compared to circulating cells. Further, BM ablation experiments followed by hematopoietic stem cell transplants in cancer patients show that cf-mRNA levels reflect the transcriptional activity of BM resident hematopoietic lineages during marrow reconstitution. Finally, by stimulating specific BM cell populations in vivo using growth factor therapeutics (i.e. EPO, G-CSF), we show that cf-mRNA reveals dynamic functional changes in growing cell types, suggesting that, unlike other cell-free nucleic acids, cf-mRNA is secreted from living cells, rather than exclusively from apoptotic cells. Our results shed new light on the biology of cf-mRNA and demonstrate its potential applications in clinical practice.

molecular biology↗