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Biology subjects

Aviles, S.

Publications and source records attributed to Aviles, S..

4 recordsLinked to original sources

Autobehaver: An AI-Based Pipeline for Animal Behavior Analysis

Behavior arises from the complex interplay between an organisms nervous system, its genetic makeup, and the environment. High-resolution, high-throughput behavioral quantification is essential for dissecting biological function and the effects of genetic perturbation, but automated analysis remains challenging. Here, we present Autobehaver, an automated behavioral analysis pipeline based on a low-cost, high-throughput recording platform that captures videos of individual Drosophila. From each video, we extracted keypoints and used a custom Transformer to assign frame-wise behavior and orientation labels. We then converted these predictions into high-dimensional per-animal feature vectors and trained XGBoost ensembles to classify animals and identify the features that separated groups. By applying SHAP analysis to the classifier ensemble, we identified the behavioral features most informative for distinguishing groups of flies. We demonstrated the approach in several ways. First, we recovered known behavioral changes associated with heat-activated dTrpA1 activity in specific neural circuits. Second, we detected age-associated behavioral changes consistent with gradual impairment of locomotor and climbing ability. Finally, we used Autobehavers classifier ensemble to place animals with intermediate phenotypes along a behavioral axis and used feature-importance analysis to reveal the behavioral features underlying those intermediate states. Together, Autobehaver provides an interpretable framework for quantitative behavioral phenotyping and comparative analysis of complex genotypes.

animal behavior and cognition↗

A Druggable G Protein Checkpoint in Cholesterol Efflux

Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to resolve lipid overload via reverse cholesterol transport (RCT), the bodys sole pathway for lipid disposal. How RCT is restrained in disease remains unknown. Integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations associated with plaque progression and uncover CCDC88A (GIV) as a macrophage-intrinsic checkpoint on RCT. Myeloid-specific GIV deletion in mice reduces aortic plaque burden, mobilizes hepatic and adipose lipid stores and promotes fecal sterol disposal. Mechanistically, GIV sequesters the cholesterol transporter ABCA1 within endomembranes and activates Gi[bullet]{beta}{gamma} signaling to suppress cAMP/PKA-CREB-dependent efflux programs. Pharmacogenomic disruption of this checkpoint reactivates efflux programs. In human plaque-in-a-dish models targeting this pathway restored efflux where statins and {beta}-blockers failed, translating to an estimated [~]98% reduction in plaque-progression risk in outcome modeling. Thus, RCT-restoration represents a macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/705962v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@50dd10org.highwire.dtl.DTLVardef@e16d9borg.highwire.dtl.DTLVardef@1e2eaf3org.highwire.dtl.DTLVardef@af29b9_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbLipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis. HighlightsO_LIStatins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction C_LIO_LIGIV (CCDC88A) non-canonically modulates Gi to suppress macrophage cholesterol efflux C_LIO_LIGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control C_LIO_LIBlocking GIV[bullet]Gi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload C_LIO_LISIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease C_LI

immunology↗

Intracortical transplantation of human induced pluripotent stem cell-derived progenitors ameliorates delayed thalamic degeneration following cortical stroke

Cortical ischemic stroke can trigger secondary neurodegeneration in remote brain regions connected to the primary lesion, particularly the thalamus. Although secondary thalamic degeneration is well established, the temporal relationship among early disruption of the thalamocortical pathway, neuronal degeneration, neuroinflammation, and delayed thalamic atrophy remains incompletely defined. Here, we investigated the longitudinal progression of secondary thalamic degeneration after cortical stroke, with particular emphasis on diffusion MRI tractography to monitor changes in anatomically defined thalamocortical pathways. We further determined whether early intracortical transplantation of human induced pluripotent stem cell (hiPSC)-derived neuronal progenitors could protect the remote thalamus and preserve thalamocortical connectivity.Cortical ischemic stroke was induced by distal middle cerebral artery occlusion in rats, and animals were assessed at multiple time points up to 6 months after stroke using longitudinal volumetric MRI and diffusion MRI tractography, combined with histological analyses of neuronal degeneration and microglial activation. The cortical infarct was established within 3-4 days, whereas alterations in diffusion metrics of thalamocortical pathways were detected within the first days after stroke. Neuronal degeneration in the ipsilateral ventral posterior nucleus (VPN) was evident at 2 weeks and preceded measurable VPN atrophy, which began at 3 months. Microglial activation also peaked at 2 weeks, coinciding with the onset of neuronal degeneration. Early intracortical transplantation of cortically primed hiPSC-derived neuronal progenitors 48 h after stroke did not alter cortical infarct volume but preserved VPN neurons, reduced subsequent thalamic atrophy, and maintained diffusion properties of affected thalamocortical pathways.These findings define secondary thalamic degeneration as a temporally ordered process in which early alterations in the thalamocortical pathway precede neuronal loss and delayed structural atrophy. Importantly, longitudinal tractography monitored both cortical stroke-induced thalamocortical degeneration and its modification by hiPSC-derived neuronal transplantation, establishing an in vivo approach to assess remote circuit degeneration and transplantation-dependent neuroprotection after cortical stroke.

neuroscience↗

Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity.

Retinoic Acid-Related Orphan Receptor Beta (ROR{beta}) is a transcription factor (TF) and marker of layer 4 (L4) neurons, which are distinctive both in transcriptional identity and the ability to form aggregates such as barrels in rodent somatosensory cortex. However, the relationship between transcriptional identity and L4 cytoarchitecture is largely unknown. We find ROR{beta} is required in the cortex for L4 aggregation into barrels and thalamocortical afferent (TCA) segregation. Interestingly, barrel organization also degrades with age. Loss of ROR{beta} delays excitatory input and disrupts gene expression and chromatin accessibility, with downregulation of L4 and upregulation of L5 genes, suggesting a shift in cellular identity. Expression and binding site accessibility change for many other TFs, including closure of neurodevelopmental TF binding sites and increased expression and binding capacity of activity-regulated TFs. Lastly, a putative target of ROR{beta}, Thsd7a, is downregulated without ROR{beta}, and Thsd7a knockout alone disrupts TCA organization in adult barrels.

neuroscience↗