Biology subjects

Nagy, M.

Publications and source records attributed to Nagy, M..

12 recordsLinked to original sources

bioRxiv2026

Neuronal overexpression of mouse potassium channel subunit Kcnn1 in A53T α-synuclein mice more than doubles median survival time, associated with suppression of phospho-S129 α-synuclein formation

Synucleinopathies, including idiopathic Parkinsons Disease, are driven by misfolding and aggregation of the 140 residue -synuclein protein that plays a role in presynaptic vesicle regulation. We describe effects of a modifier, neuronal overexpression of the mouse calcium-activated potassium channel subunit Kcnn1, on a mouse model in which transgenic Thy1.2-driven A53T -synuclein directs fully penetrant lethal motor disease. Kcnn1 overexpression increased median survival of these mice from 8.5 months to 18 months, associated with an altered clinical presentation from a rapidly progressive dystonic-like behavior of the limbs to a later-onset (12-16 mo) and slowly progressive lower limb clasping when lifted by the tail. At the tissue level, accretion of disease-associated phospho-serine 129 -synuclein was prevented by overexpression of Thy1.2-driven Kcnn1, which was observed in many brain regions, including the ones where phospho-serine 129 -synuclein was copiously accreted in A53T mice at endstage. The action of blocking production of phospho-serine 129 -synuclein was also observed in adult presymptomatic A53T mice injected with an AAV9 scCMV-Kcnn1 virus into the right superior colliculus. At endstage [~]2 months later, the right superior colliculus exhibited overexpression of Kcnn1 and showed essentially no phospho-serine 129 -synuclein, whereas the uninjected left superior colliculus exhibited copious phospho-serine 129 -synuclein. The neuroprotective action of Kcnn1 overexpression remains to be fully resolved, but the channel protein subunit, targeted to the ER membrane, has been shown to induce an ER stress response. This response, which may activate autophagy, along with potential channel formation, may diminish the rate of formation or lifetime of neurotoxic forms of A53T -synuclein.

neuroscience↗

bioRxiv2025

RAPID: Real-time Animal Pattern re-Identification on edge Devices

Automatic re-identification of animals has significant potential for addressing pressing challenges of our times via population monitoring, individual health assessment or detailed behavior analysis. Although numerous computer vision based solutions have been proposed and many achieve high accuracy, those still remain unsuitable for real-time analysis and deployment on edge devices. Here, we introduce RAPID, an open-source1 algorithm for re-identifying patterned animal images at a rate exceeding 40-60 queries per second on standard PC or Laptop and over 10 queries per second on an inexpensive off-the-shelf edge device. RAPID operates efficiently in computationally restricted environments, relying solely on CPU, leaving GPU resources available for other tasks, all while maintaining state-ofthe-art accuracy. Our approach leverages SIFT descriptors, which continue to demonstrate competitive robustness and accuracy against recent traditional and deep-learning based methods. To counterpoise SIFTs primary limitations its high-dimensional feature vectors and the associated computational costs - we incorporate recent advancements in vector similarity search and construct a database of feature vectors rather than database images, further accelerating the search process. We evaluate our method, RAPID, on public re-identification datasets; additionally propose a RAPID-based tool, FalseTagFinder, for cleaning benchmark dataset labels and as a demonstration, provide corrections for the StripeSpotter dataset.

ecology↗

bioRxiv2024

Neuronal overexpression of potassium channel subunit Kcnn1 prolongs survival of SOD1-linked ALS and A53T alpha-synuclein mouse models

Eye muscles and the motor neurons in the innervating cranial nerve nuclei are relatively spared in human ALS, and likewise, these cranial motor neurons are spared of SOD1YFP aggregation in a transgenic mouse model of SOD1-linked ALS, G85R SOD1YFP. RNA profiling of mouse oculomotor (CN3) neurons (resistant) vs hypoglossal (CN12) and spinal cord motor neurons (susceptible) from nontransgenic mice identified differentially expressed channel and receptor genes. A number were evaluated for effects on survival of the ALS strain by transgenesis or knockout to emulate the relative RNA level in oculomotor neurons. Transgenesis of Thy1.2-driven cDNA for mouse Kcnn1, a potassium channel subunit, extended the median days of survival time to paralysis of mutant G85R SOD1YFP mice by up to 100%, associated with absence of fluorescent aggregates; extended the median time to paralysis of G93A SOD1 mice by up to 55%; and extended the median time to endstage motor disease of a Thy1.2-driven alpha-synuclein transgenic strain by up to greater than 100%. The overexpressed Kcnn1 subunit was diffusely cytoplasmic in motor neurons and found to induce a multifaceted stress response as judged by RNAseq and immunostaining, including ER stress response, mitochondrial stress response, and an integrated stress response. Like other potassium channel subunits, Kcnn1 subunit is likely targeted to the ER, but as reported earlier in rodent Kcnn1-transfected cultured cells, in the absence of Kcnn2 with which to co-assemble, Kcnn1 is channel-inactive and is diffusely cytoplasmic. Thus, a nonassembled and potentially misfolded state of overexpressed Kcnn1 targeted to the ER of neurons may explain the stress responses, which in the mutant SOD1 and A53T alpha-synuclein mice, protect against the pathogenic proteins. Major neurodegenerative diseases, including Alzheimers Disease and Parkinsons Disease, are associated with the accumulation of characteristic proteins, Abeta/Tau and alpha-synuclein in AD and PD, respectively, that misfold, aggregate, and in many cases form amyloid fibrils (e.g. Long and Holtzman, 2019; Sierksma et al, 2020; Tanner et al, 2024). Such pathogenic behavior is associated with malfunction/death of specific neuronal populations, producing consequent clinical symptoms. It seems counterintuitive to observe proteinopathy as a major facet of these diseases considering that there is generally a quality control machinery in all cells, consisting of effectors - molecular chaperones, ubiquitin/proteasomal components, and autophagy/lysosome components - governed by a "sensor" circuitry - e.g. UPR, ISR, HSF - that can detect such misbehavior and induce protective responses. While neurons may be particularly susceptible because they are postmitotic and unable to distribute damaging protein species to daughter cells as a protective means, it has remained unclear whether the endogenous sensor/effector pathways can be induced sufficiently in vivo so as to mediate protection. Here, we report that neuronal overexpression of a potassium channel subunit, mouse Kcnn1, in two different transgenic mouse neurodegenerative models, protects against aggregation and cell loss by apparent induction of multiple stress response pathways, substantially extending survival of the mice.

neuroscience↗

bioRxiv2024

Optimizing transcriptome-based synthetic lethality predictions to improve precision oncology in early-stage breast cancer: BC-SELECT

BackgroundPatients with non-metastatic triple-negative (TNBC) or HER2-positive (HER2+) breast cancer do not have tools to predict treatment response or prioritize options prior to starting therapy. Pathologic complete response (pCR) is a proxy that requires neoadjuvant treatment. BC-SELECT leverages genetic interactions (e.g. synthetic lethality (SL)/rescue (SR)) to predict treatment response via pCR from breast cancer gene expression data. BC-SELECT involves (1) "gene-pair identification" that identifies clinically relevant partner genes from large-scale datasets for a given targeted therapy or immunotherapy target, and (2) "training / parameter tuning" using clinical trials to predict treatment response. We evaluated BC-SELECTs ability to predict pCR for trastuzumab, poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy, with tuning supported by three trials (n=86) and validation on nine unseen trials (n=722). ResultsBC-SELECT significantly predicted pCR in 6/9 trials, including all PARP inhibitors (ROC-AUCs 0.6-0.8; Odds Ratio (OR): 1.9-3.5) and immunotherapy (ROC-AUCs 0.7-0.8; OR: 3.2-7.1). BC-SELECT significantly distinguished between pCR and residual disease in 8/9 trials. ConclusionsNo current standard-of-care, pre-treatment approaches predict benefit in non-metastatic TNBC and HER2+ breast cancer. BC-SELECT leverages genetic interactions to predict treatment response from gene expression data. Our findings support development of BC-SELECT towards prioritizing PARP inhibitors and immunotherapy in non-metastatic breast cancer.

bioinformatics↗

bioRxiv2023

Functional Tissue Units in the Human Reference Atlas.

Functional tissue units (FTUs) form the basic building blocks of organs and are important for understanding and modeling the healthy physiological function of the organ and changes during disease states. In this first comprehensive catalog of FTUs, we document the definition, physical dimensions, vasculature, and cellular composition of 22 anatomically correct, nested functional tissue units (FTUs) in 10 healthy human organs. The catalog includes datasets, illustrations, an interactive online FTU explorer, and a large printable poster. All data and code are freely available. This is part of a larger ongoing international effort to construct a Human Reference Atlas (HRA) of all cells in the human body.

bioinformatics↗

bioRxiv2023

Deactivation of ligand-receptor interactions enhancing lymphocyte infiltration drives melanoma resistance to Immune Checkpoint Blockade

Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (Immunotherapy Resistance cell-cell Interaction Scanner), a machine learning model aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to mediate ICB resistance in the tumor microenvironment (TME). We developed and applied IRIS to identify resistance-mediating cell-type-specific ligand-receptor interactions by analyzing deconvolved transcriptomics data of the five largest melanoma ICB therapy cohorts. This analysis identifies a set of specific ligand-receptor pairs that are deactivated as tumors develop resistance, which we refer to as resistance deactivated interactions (RDI). Quite strikingly, the activity of these RDIs in pre-treatment samples offers a markedly stronger predictive signal for ICB therapy response compared to those that are activated as tumors develop resistance. Their predictive accuracy surpasses the state-of-the-art published transcriptomics biomarker signatures across an array of melanoma ICB datasets. Many of these RDIs are involved in chemokine signaling. Indeed, we further validate on an independent large melanoma patient cohort that their activity is associated with CD8+ T cell infiltration and enriched in hot/brisk tumors. Taken together, this study presents a new strongly predictive ICB response biomarker signature, showing that following ICB treatment resistant tumors turn inhibit lymphocyte infiltration by deactivating specific key ligand-receptor interactions.

bioinformatics↗

bioRxiv2023

Unlocking Predictive Power: A Machine Learning Tool Derived from In-Depth Analysis to Forecast the Impact of Missense Variants in Human Filamin C

Cardiomyopathies, diseases of the heart muscle, are a leading cause of heart failure. An increasing proportion of cardiomyopathies have been associated with specific genetic changes, such as mutations in FLNC, the gene that codes for filamin C. Altogether, more than 300 variants of FLNC have been identified in patients, including a number of single point mutations. However, the role of a significant number of these mutations remains unknown. Here, we conducted a comprehensive analysis, starting from clinical data that led to identification of new pathogenic and non-pathogenic FLNC variants. We selected some of these variants for further characterization that included studies of in vivo effects on the morphology of neonatal cardiomyocytes to establish links to phenotype, and the in vitro thermal stability and structure determination to understand biophysical factors impacting function. We used these findings to compile vast datasets of pathogenic and non-pathogenic variant structures and developed a machine-learning-based neural network (AMIVA-F) to predict the impact of single point mutations. AMIVA-F outperformed most commonly used predictors both in disease related as well as neutral variants, approaching [~]80% accuracy. Taken together, our study documents additional FLNC variants, their biophysical and structural properties, and their link to the disease phenotype. Furthermore, we developed a state-of-the-art web-based server AMIVA-F that can be used for accurate predictions regarding the effect of single point mutations in human filamin C, with broad implications for basic and clinical research.

biophysics↗

bioRxiv2023

Social structure and individuals' behavior shaped by group composition in long-term tracking of rats

Rodents serve as an important model for examining both individual and collective behavior. Dominance within rodent social structures can determine access to critical resources, such as food and mating opportunities. Yet, many aspects of the intricate interplay between individual behaviors and the resulting group social hierarchy, especially its evolution over time, remain unexplored. In this study, we utilized an automated tracking system that continuously monitored groups of male rats for over 250 days to enable an in-depth analysis of individual behavior and the overarching group dynamic. We describe the evolution of social structures within a group and additionally investigate how past behaviors influence the emergence of new social hierarchies when group composition and experimental area changes. Notably, we find that conventional individual and pairwise tests exhibit a weak correlation with group behavior, highlighting their limited accuracy in predicting behavioral outcomes in a collective context. These results emphasize the context-dependence of social behavior as an emergent property of interactions within a group and highlight the need to measure and quantify social behavior in more naturalistic environments.

animal behavior and cognition↗

bioRxiv2021

The geometry of decision-making

Choosing among spatially-distributed options is a central challenge for animals, from deciding among alternative potential food sources or refuges, to choosing with whom to associate. Using an integrated theoretical and experimental approach (employing immersive virtual reality), we consider the interplay between movement and vectorial integration during decision-making regarding two, or more, options in space. In computational models of this process we reveal the occurrence of spontaneous and abrupt "critical" transitions (associated with specific geometrical relationships) whereby organisms spontaneously switch from averaging vectorial information among, to suddenly excluding one, among the remaining options. This bifurcation process repeats until only one option--the one ultimately selected--remains. Thus we predict that the brain repeatedly breaks multi-choice decisions into a series of binary decisions in space-time. Experiments with fruit flies, desert locusts, and larval zebrafish reveal that they exhibit these same bifurcations, demonstrating that across taxa and ecological context, there exist fundamental geometric principles that are essential to explain how, and why, animals move the way they do.

animal behavior and cognition↗

bioRxiv2020

Genome Methylation Predicts Age and Longevity of Bats

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.

genomics↗

bioRxiv2018

Motor nuclei innervating eye muscles spared in mouse model of SOD1-linked ALS

The eye muscles of humans with either inherited or sporadic forms of ALS are relatively unaffected during disease progression, a function of sparing of the cranial nerve motor neurons supplying them. Here we observe that cranial nerve nuclei are also spared in a mouse model of inherited SOD1-linked ALS. We examined the cranial nerve motor nuclei in a mouse strain, G85R SOD1YFP, which carries a high copy transgene encoding a mutant human SOD1-YFP fusion protein, that exhibits florid YFP-fluorescent aggregates in spinal cord motor neurons and paralyzes by 6 months of age. We observed in the cranial nerve nuclei that innervate the eye, 3N (oculomotor), 4N (trochlear), and 6N (abducens), that there was little (4N, 6N) or no (3N) aggregation, in comparison with other motor nuclei, 5N (trigeminal), 7N (facial), and 12N (hypoglossal), in the latter two of which florid aggregation was observed. Correspondingly, the number of ChAT positive motor neurons in 3N of G85R SOD1YFP relative to that in 3N of ChAT-EGFP mice showed that there was no loss of motor neurons over time, whereas in 12N there was progressive loss of motor neurons, amounting to a loss of [~]30% from G85R SOD1YFP by end-stage. Thus, the sparing of extraocular motor neurons as occurs in humans with ALS appears to be replicated in our SOD1-linked ALS mouse strain, supporting the validity of the mouse model for studying this aspect of selective motor system loss in ALS. Comparisons of extraocular motor neurons (e.g., from 3N), resistant to ALS pathology, with other cranial motor neurons (e.g., from 12N), sensitive to such pathology, may thus be of value in understanding mechanisms of protection vs. susceptibility of motor neurons.

neuroscience↗

bioRxiv2017

Integrated growth factor signaling promotes lung epithelial progenitor cell expansion and maintenance in mice and humans

The bud tip epithelium of the branching mouse and human lung contains multipotent progenitors that are able to self-renew and give rise to all mature lung epithelial cell types. The current study aimed to understand the developmental signaling cues that regulate bud tip progenitor cells in the human fetal lung, which are present during branching morphogenesis, and to use this information to induce a bud tip progenitor-like population from human pluripotent stem cells (hPSCs) in vitro. We identified that FGF7, CHIR-99021 and RA maintained isolated human fetal lung epithelial bud tip progenitor cells in an undifferentiated state in vitro, and led to the induction of a 3-dimensional lung-like epithelium from hPSCs. 3-dimensional hPSC-derived lung tissue was initially patterned, with airway-like interior domains and bud tip-like progenitor domains at the periphery. Epithelial bud tip-like domains could be isolated, expanded and maintained as a nearly homogeneous population by serial passaging. Comparisons between human fetal lung epithelial bud tip cells and hPSC-derived bud tip-like cells were carried out using immunostaining, in situ hybridization and transcriptome-wide analysis, and revealed that in vitro derived tissue was highly similar to native lung. hPSC-derived epithelial bud tip-like structures survived in vitro for over 16 weeks, could be easily frozen and thawed and maintained multi-lineage potential. Furthermore, hPSC-derived epithelial bud tip progenitors successfully engrafted in the proximal airways of injured immunocompromised NSG mouse lungs, where they persisted for up to 6 weeks and gave rise to several lung epithelial lineages.

developmental biology↗