Biology subjects

Tran, A. T.

Publications and source records attributed to Tran, A. T..

4 recordsLinked to original sources

bioRxiv2025

Neuroanatomical Basis of Coma in Acute Ischemic Stroke

BackgroundAcute ischemic stroke (AIS) can lead to profound disturbances in consciousness, including coma, which is associated with poor prognosis and increased mortality. Clarifying the lesion patterns that precipitate loss of consciousness can refine pathophysiological models and guide prognosis. ObjectivesIn this study, we aim to identify the brain regions most commonly affected in comatose AIS and determine whether specific combinations of lesions are necessary and sufficient to produce coma. MethodsWe retrospectively analyzed 476 AIS patients (52 comatose) using diffusion-weighted imaging. Infarcts were automatically segmented, manually verified, and normalized to MNI space. Support vector regression lesion-symptom mapping (SVR-LSM) quantified voxel-wise associations with coma, controlling for lesion volume. To assess the necessity and sufficiency of lesion combinations, we employed permutation-based nested logistic regression models comparing all subsets of four anatomical predictors: brainstem, thalamus, cerebellum, and the rest of brain lesions. ResultsSVR-LSM revealed that coma was strongly associated with lesions involving the brainstem, thalamus, and cerebellum, whereas non-comatose patients exhibited predominantly cortical infarcts. Nested model comparisons showed that concurrent lesions to both the brainstem and thalamus were necessary and sufficient for coma. Additional involvement of the cerebellum or cerebral cortex did not improve predictive performance. ConclusionsComa after AIS results from a dual-node subcortical lesion pattern involving both the brainstem and thalamus. Cerebellar and cortical lesions, even when extensive, did not induce coma in the absence of the dual-brainstem and thalamic lesions. These observations emphasize the predominant role of lesion location over lesion volume in the pathogenesis of coma. They also support mechanistic models that position the brainstem and thalamic hubs as central to the neural circuitry underlying arousal. Furthermore, these findings delineate a specific anatomical substrate that may serve as a strategic target for circuit-based neuroprotective and neuromodulatory therapies.

neuroscience↗

bioRxiv2025

Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of Fragile X mice and identifies EPAC2 as a therapeutic target.

Symptoms of Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell type specific mRNA sequencing to profile molecular alterations of cortical excitatory and inhibitory neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. Differentially expressed genes (DEG) were largely upregulated in Camk2a expressing excitatory neurons but downregulated in Pvalb-expressing inhibitory neurons, and the underlying signaling pathways were often altered in opposite directions. Among the 184 DEGs that were concordantly dysregulated across both cell types, only Rapgef4 (Epac2) was also an FMRP target, an ASD risk gene and brain enriched. EPAC2 has been implicated in synaptic maturation and plasticity. Systemic administration of an EPAC2 antagonist restored cortical circuit function in Fmr1 KO mice and ameliorated sensory behavioral phenotypes. EPAC2 is a potential target for therapy in FXS.

neuroscience↗

bioRxiv2024

LYMTACs: Chimeric Small Molecules Repurpose Lysosomal Membrane Proteins for Target Protein Relocalization and Degradation

Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a novel small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. To extend these findings, we show that oncogenic, membrane-associated KRASG12D protein can be tethered to RNF152, inducing KRAS relocalization to the lysosomal membrane, inhibiting downstream phospho-ERK signaling, and leading to lysosomal degradation of KRASG12D in a LYMTAC-dependent manner. Notably, potent cell killing could be attributed to the multi-pharmacology displayed by LYMTACs, which differentiates the LYMTAC technology from existing modalities. Thus, LYMTACs represent a proximity-based therapeutic approach that promises to expand the target space for challenging membrane proteins through targeted protein relocalization and degradation.

cancer biology↗

bioRxiv2024

A novel GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE 13 is involved in the Phosphate starvation-induced lipid remodeling in rice

Phosphorus (P) is one of the most vital macronutrient determinants in plant development and productivity. However, the bioavailability of inorganic phosphate (Pi), the only form that plants can assimilate, is limited in the soil, thus significantly affecting plant development. Plants have adopted various specialized strategies to modify their morphological, physiological, and biochemical properties for better adaptation to Pi deficiency conditions. GLYCEROPHOSPHODIESTER PHOSPHODIESTERASES (GDPDs), generally known as phospholipid remodeling proteins, have been suggested to play essential roles in maintaining phosphate homeostasis. The previous genome-wide association studies (GWAS) in a Vietnamese rice collection led to the discovery of a robust QTL named qRST9.14 associating with the phosphate adaption in rice, in which OsGDPD13 is located within this locus. Interestingly, we discovered an absence of OsGDPD13 from the Indica reference genome. A subcellular localization study showed that the GDPD13 protein localizes to the plasma membrane, cytoplasmic speckles, and plasmodesmata. The osgdpd13 knockout mutant was generated in the Japonica cv Kitaake background to characterize its function. Phenotypic analysis indicated that mutation of OsGDPD13 significantly lowered crown root number and reduced the plant height under Pi deficient condition. Moreover, osgdpd13 lines reduce the capability to degrade total phospholipids compared to the wild type under Pi starvation conditions. This finding suggests the involvement of the OsGDPD13 gene in rice growth and the Phosphate starvation-induced lipid remodeling under P deficiency. This work will provide valuable information for developing crop plants with higher Phosphate use efficiency.

plant biology↗