Biology subjects

Baca, M.

Publications and source records attributed to Baca, M..

7 recordsLinked to original sources

bioRxiv2026

CAR-T Targeting of Mutant Calreticulin Establishes a Potentially Curative Stem Cell-Directed Therapy for Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are sustained by mutated hematopoietic stem cells (HSCs). Existing therapies fail to eliminate this compartment, leaving allogeneic HSC transplantation as the only curative option. Recurrent MPN driver mutations in calreticulin (CALRmut) generate a C-terminal neopeptide that requires cell-surface expression for oncogenic signaling, making it an attractive immunologic target. However, it remains unknown if CALRmut is uniformly displayed on all MPN HSCs within hematopoietic microenvironments. We generated huAB2, a high-affinity CALRmut-specific humanized antibody, to use as the targeting domain for chimeric antigen receptor (CAR)-T cells. We show that CALRmut is consistently displayed on functional MPN HSCs and accessible in vivo. huAB2 CAR-T cells eradicate MPN-propagating CALRmut HSCs in patient-derived tumor xenograft models without antigen escape while preserving coexisting normal human and host hematopoiesis. These findings establish CALRmut display as an obligate feature of MPN HSC fitness and support the feasibility of curative, non-transplant immunotherapy for CALRmut MPNs. SignificanceTherapies that eradicate cancer stem cells enable cure, but their feasibility is unknown. We establish an approach to potentially cure MPNs by proving mutant calreticulin to be a MPN stem cell marker that can be targeted by CAR-T cells to selectively wipe out disease in preclinical models of human MPNs.

cancer biology↗

bioRxiv2025

Evaluating Flavoprotein Fluorescence Imaging as a Biomarker of Early Retinal Ganglion Cell Mitochondrial Stress

PurposeRetinal neurodegeneration is difficult to monitor due to insensitive disease endpoints. Mitochondrial dysfunction and oxidative stress are promising early biomarkers of retinal ganglion cell (RGC) degeneration. This study investigates dynamics of flavoprotein fluorescence (FPF), a non-invasive mitochondrial oxidative stress measure, and sensitivity to early neurodegeneration and neuroprotection in vitro and in vivo. MethodsFPF activity in response to neurodegeneration and neuroprotection were characterized in vitro in wild-type (WT) and SARM1 knockout (SARMKO) human embryonic stem cell-derived RGCs with and without Vacor treatment over 24 hours and confirmed with mitochondrial reactive oxygen species (ROS) measures. Further FPF evaluation was explored in vivo using the optic nerve crush (ONC) model in WT and SARMKO mice to compare early RGC stress detection within rodent retinas. ResultsIn vitro FPF intensities in WT RGCs increased within 8 hours of degeneration induction, preceding significant mitochondrial ROS production. Neuroprotective SARMKO RGCs maintained comparable FPF and ROS levels following insult. In vivo FPF changes were not observed in WT and SARMKO mice over 4 days following ONC, while only early retinal thickening was observed from OCT. Early FPF and OCT changes were not reflective of late RGC survival observed from ex vivo RGC soma and axon counts. ConclusionsThese findings highlight differences in FPF sensitivity to mitochondrial stress between simplified in vitro systems and complex in vivo rodent retinas. This study demonstrates the potential of FPF as an early neurodegeneration and neuroprotection endpoint in vitro while identifying limitations and areas of development for its translatability to preclinical in vivo assessment.

bioengineering↗

bioRxiv2022

Ancient DNA reveals interstadials as a driver of the common vole population dynamics during the last glacial period

1AimThe common vole is a temperate rodent widespread across Europe. It was also one of the most abundant small mammal species throughout the Late Pleistocene. Phylogeographic studies of its extant populations suggested the Last Glacial Maximum (LGM, 26.5-19 ka ago) as one of the main drivers of the species population dynamics. However, analyses based solely on extant genetic diversity may not recover the full complexity of past population history. The main aim of this study was to investigate the evolutionary history and identify the main drivers of the common vole population dynamics during the Late Pleistocene. LocationEurope TaxonCommon vole (Microtus arvalis) MethodsWe generated a dataset comprising 4.2 kb-long fragment of mitochondrial DNA from 148 ancient and 51 modern specimens sampled from multiple localities across Europe and covering the last 60 thousand years (ka). We used Bayesian inference to reconstruct their phylogenetic relationships and to estimate the age of specimens that were not directly dated. ResultsWe estimate the time to the most recent common ancestor of all Last Glacial and extant common vole lineages to 90 ka ago and the divergence of the main mtDNA lineages present in extant populations to between 55 and 40 ka ago, earlier than previous estimates. We find multiple lineage turnovers in Europe in the period of high climate variability at the end of Marine Isotope Stage 3 (MIS 3; 57-29 ka ago) in addition to those found previously around the Pleistocene/Holocene transition. Conversely, data from the Western Carpathians suggest continuity throughout the LGM even at high latitudes. Main conclusionsOur results suggest that the main factor affecting the common vole populations during the last glacial period was the reduction of open habitats during the interstadial periods while the climate deterioration during the LGM had little impact on species population dynamics.

evolutionary biology↗

bioRxiv2022

High-resolution cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function

Sensory neurons of the dorsal root ganglion (DRG) play a crucial role in maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies of DRGs are conducted in rodents, much less is known about the mechanisms of sensory perception in primates. We generated a transcriptome atlas of mouse, guinea pig, cynomolgus monkey, and human DRGs using a framework that implements a common laboratory workflow and multiple data-integration approaches to generate high-resolution cross-species mappings of sensory neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related to inflammatory response. We also identified divergent expression of key genes involved in DRG function, suggesting species-specific adaptations. Among these, we validated that Tafa4, a member of the druggable genome, was expressed in distinct populations of DRG neurons across species, highlighting species-specific programs that are critical for therapeutic development.

neuroscience↗

bioRxiv2021

Ancient genomes reveal long range influence of the site and culture of Tiwanaku

Tiwanaku was a civilization that flourished in the Lake Titicaca Basin (present-day Bolivia) between 500 and 1000 CE. At its apogee, Tiwanaku controlled the lakes southern shores and influenced certain areas of the Southern Andes. There is a considerable amount of archaeological and anthropological data concerning the Tiwanaku culture; however, our understanding of the population of the site of Tiwanaku is limited. To understand the population dynamics at different stages of the Tiwanaku cultural development, we analyzed 17 low-coverage genomes from individuals dated between 300 and 1500 CE. We found that the population from the Lake Titicaca Basin remained genetically unchanged throughout more than 1200 years, indicating that significant cultural and political changes were not associated with large scale population movements. In contrast, individuals excavated from Tiwanakus ritual core were highly heterogeneous, some with genetic ancestry from as far away as the Amazon, supporting the proposition of foreign presence at the site. However, mixed-ancestry individuals presence suggests they were local descendants of incomers from afar rather than captives or visiting pilgrims. A number of human offerings from the Akapana Platform dating to ca. 950 CE mark the end of active construction and maintenance of the monumental core and the wane of Tiwanaku culture. Significance StatementTiwanaku was an important pre-Inca polity in South America and an example of primary social complexity on par with civilizations in the Indus and Nile river valley. Flourishing between 500 and 1000 CE, Tiwanaku exercised control in the south Titicaca basin and influenced a vast area in southern Peru, Bolivia, and northern Chile. Comprehensive archeological studies provided information about the rise, expansion, and fall of the Tiwanaku culture, but little is known about the monumental sites population. To address this lacuna, we generated low coverage genomes for 17 individuals, revealing that while the Titicaca basins residential population was homogenous, the individuals excavated from the ritual core of Tiwanaku drew their ancestry from distant regions.

genomics↗

bioRxiv2018

Human mediated dispersal of cats in the Neolithic Central Europe

Archaeological and genetic evidence suggest that all domestic cats derive from the Near Eastern wildcat (Felis silvestris lybica) and were domesticated twice, first in the Near East around 10 000 years ago and for the second time in Ancient Egypt ca. 3 500 years ago. The spread of the domesticated form in Europe occurred much later, primarily mediated by Greek and Phoenician traders and afterwards by Romans who introduced cats to Western and Central Europe around 2 000 years ago. We investigated mtDNA of Holocene Felis remains and provide evidence of an unexpectedly early presence of cats bearing the Near Eastern wildcat mtDNA haplotypes in Central Europe, being ahead of Roman Period by over 2 000 years. The appearance of the Near Eastern wildcats in Central Europe coincide with the peak of Neolithic settlement density, moreover most of those cats belonged to the same mtDNA lineages as those domesticated in the Near East. Thus, although we cannot fully exclude that the Near Eastern wildcats appeared in Central Europe as a result of introgression with European wildcat, our findings strongly support the hypothesis that the Near Eastern wildcats spread across Europe together with the first farmers, perhaps as commensal animals. We also found that cats dated to the Neolithic period belonged to different mtDNA lineages than those brought to Central Europe in Roman times, this supports the hypothesis that the gene pool of contemporary European domestic cats might have been established from two different source populations that contributed in different periods.

ecology↗

bioRxiv2016

Impact of climatic changes in the Late Pleistocene on migrations and extinctions of mammals in Europe: four case studies

Climate changes that occurred during the Late Pleistocene have profound effects on the distribution of many plant and animal species and influenced the formation of contemporary faunas and floras of Europe. The course and mechanisms of responses of species to the past climate changes are now being intensively studied by the use of direct radiocarbon dating and genetic analyses of fossil remains. Here, we review the advances in understanding these processes by the example of four mammal species: woolly mammoth (Mammuthus primigenius), cave bear (Ursus spelaeus s. l.), saiga antelope (Saiga tatarica) and collared lemmings (Dicrostonyx ssp.). The cases discussed here as well as others show that the migrations, range shifts and local extinctions were the main responses to climate changes and that the dynamics of these climate driven processes were much more profound than it was previously thought. Each species reacted by its individual manner, which depended on its biology and adaptation abilities to the changing environment and climate conditions. The most severe changes in European ecosystems that affected the largest number of species took place around 33-31 ka BP, during the Last Glacial Maximum 22-19 ka BP and the Late Glacial warming 15-13 ka BP.

evolutionary biology↗