Biology subjects

Cisneros, E.

Publications and source records attributed to Cisneros, E..

6 recordsLinked to original sources

bioRxiv2026

Understanding Strategic Motor Learning as a Process of Hypothesis Testing

Multiple learning processes contribute to successful goal-directed actions under changing physiological states, biomechanical constraints, and environmental contexts. Among these, explicit strategies enable us to discover new movement patterns when existing ones no longer achieve the desired outcome. Yet, how strategies are discovered during motor learning remains unknown. To address this, we developed a novel behavioral paradigm that isolates strategy discovery in response to a range of visuomotor perturbations. This approach revealed that strategy discovery unfolds through an initial period of systematic exploration across multiple candidate strategies, followed by an 'aha' moment in which behavior converges on a stable solution. To account for these dynamics, we developed a computational model based on hypothesis testing in which learners generate and evaluate visuomotor rules to counteract the perturbation. This hypothesis testing model outperformed a range of alternative accounts, including gradual error reduction, win-stay lose-shift learning, and sudden one-shot insight. Together, these findings identify hypothesis testing as a computational mechanism by which humans discover new strategies during motor learning.

neuroscience↗

bioRxiv2025

Bioreactor-Enabled Extracellular Vesicle Production for Downstream Functional Engineering

Extracellular vesicles (EVs) hold significant therapeutic potential, yet clinical translation is hindered by production yield and low-efficiency post-isolation engineering methods, highlighting the need for high-density bioreactor systems that support both reliable production and downstream modification. Here, we systematically compare EV output from standard flask cultures, a membrane-based two-chamber bioreactor, and a hollow-fiber bioreactor. Across culture conditions, hollow-fiber bioreactors produced markedly higher EV concentrations while requiring significantly less culture medium, demonstrating major advantages in scalability and resource efficiency. EV production was assessed with nanoparticle tracking analysis, immunoblotting, and transmission electron microscopy. Additionally, proteomic analysis revealed that bioreactor-derived EVs maintained canonical phenotypes and translational feasibility in the context of post-isolation EV engineering. Engineering feasibility was assessed with the first known reported instance of cargo-loading through EV-micelle hybridization, surface-modification through post-insertion of molecules carried by micelles (MCs), and exploitation of Nanoparticle Tracking Analysis (NTA) detection limits. Bioreactor-derived EVs remained readily engineerable, and all engineering experiments required only a small fraction of total EVs produced. Together, these findings demonstrate that bioreactor platforms overcome critical throughput limitations of conventional cultures while producing engineerable EVs. This integrated assessment establishes hollow-fiber and membrane-based bioreactors as scalable, translation-oriented systems for improved EV production and drug delivery potential via post-production engineering.

bioengineering↗

bioRxiv2025

Biophysical modeling for accurate T cell specificity prediction of viral and tumor antigens

Accurate predictions of T cell receptor (TCR) specificity remain an important open problem in immunology, with broad implications for vaccine design, optimal immunotherapy, and improved management of autoimmune diseases. However, diversity in peptide antigens and TCR sequences at the level of individual patient repertoires remains a formidable computational challenge. Here, we develop a joint experimental and computational approach for predicting the antigen specificity of clinically-derived TCR sequences. Our model is trained on a combination of experimentally pre-identified and in silico-predicted TCR-pMHC structures using AlphaFold3. We apply our structural model in the clinical setting of hematopoietic stem cell transplant (HSCT) and demonstrate that our model is able to effectively discern the specificity of previously unseen donor and patient-derived TCR sequences against tumor associated and viral antigens. Model performance was further enhanced through the integration of sequence-based clustering and structurally diverse training templates. Our results highlight the predictive capabilities of structurally guided machine learning frameworks, trained on a minority test dataset, for antigen specificity prediction on unseen TCR sequences and their potential impact on a wide range of immunological applications.

immunology↗

bioRxiv2024

Differential Aging Effects on Implicit and Explicit Sensorimotor Learning

Deterioration in motor control is a hallmark of aging, significantly contributing to a decline in quality of life. More controversial is the question of whether and how aging impacts sensorimotor learning. We hypothesized that the inconsistent picture observed in the current literature can be attributed to at least two factors. First, aging studies tend to be underpowered. Second, the learning assays used in these experiments tend to reflect, to varying degrees, the operation of multiple learning processes, making it difficult to make inferences across studies. We took a two-pronged approach to address these issues. We first performed a meta-analysis of the sensorimotor adaptation literature focusing on outcome measures that provide estimates of explicit and implicit components of adaptation. We then conducted two well-powered experiments to re-examine the effect of aging on sensorimotor adaptation, using behavioral tasks designed to isolate explicit and implicit processes. Convergently, both approaches revealed a striking dissociation: Older individuals exhibited a marked impairment in their ability to discover an explicit strategy to counteract a visuomotor perturbation. However, they exhibited enhanced implicit recalibration. We hypothesize that the effect of aging on explicit learning reflects an age-related decline in reasoning and problem solving, and the effect of aging on implicit learning reflects age-related changes in multisensory integration. Taken together, these findings deepen our understanding of the impact of aging on sensorimotor learning.

neuroscience↗

bioRxiv2023

Identification of a pharmaceutical biostasis inducer that slows metabolism in multiple vertebrates that do not hibernate

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1,000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations.

bioengineering↗

bioRxiv2019

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

Millions of individuals worldwide suffer from impaired vision, a condition with multiple origins that often impinge upon the light sensing cells of the retina, the photoreceptors, affecting their integrity. The molecular components contributing to this integrity are however not yet fully understood. Here we have asked whether Secreted Frizzled Related Protein 1 (SFRP1) may be one of such factors. SFRP1 has a context-dependent function as modulator of Wnt signalling or of the proteolytic activity of A Disintegrin And Metalloproteases (ADAM) 10, a main regulator of neural cell-cell communication. We report that in Sfrp1-/- mice, the outer limiting membrane (OLM) is discontinuous and the photoreceptors disorganized and more prone to light-induced damage. Sfrp1 loss significantly enhances the effect of the Rpe65Leu450Leu genetic variant -present in the mouse genetic background- which confers sensitivity to light-induced stress. These alterations worsen with age, affect visual function and are associated to an increased proteolysis of Protocadherin 21 (PCDH21), localized at the photoreceptor outer segment, and N-cadherin, an OLM component. We thus propose that SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in view of the broader implication of SFRP1 in neurodegeneration and aging.

neuroscience↗