Biology subjects

Park, S.

Publications and source records attributed to Park, S..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

Sequential development of task representation from hippocampus to prefrontal cortex supports goal-directed spatial navigation

Successful goal-directed navigation requires the coordination between the hippocampus and medial prefrontal cortex. However, it is not fully confirmed that the medial prefrontal cortex learns its spatial code from the hippocampus. To test this, we examined spatial representations of the intermediate hippocampus and medial prefrontal cortex while rats learned a spatial navigation task. Rats performed a goal-directed spatial navigation task in 2D VR to find an unmarked goal zone, and we discovered robust directional tuning of single neurons in both regions. Neural manifold analysis further confirmed population-level directional tuning in both regions, with manifolds having ring-like geometry. We found that this ring-like structure evolved after learning, in a way that the hippocampal-prefrontal manifolds converged to a shared geometry. Furthermore, this evolution of ring-like structure was preceded by the hippocampus at the trial level. It was further verified that the evolution of the ring-like structure is linked to phase locking to the hippocampal theta rhythm, particularly in the prefrontal manifolds. Our findings provide compelling evidence that spatial representations of the hippocampal-prefrontal network become aligned after learning, and also highlight the information flow from the hippocampus to the medial prefrontal cortex during this geometry synchronization.

neuroscience↗

bioRxiv2025

Redefining Parkinson's Disease by Dysregulated Genetic Networks in Distinct Cell Types

Parkinsons disease (PD) is classically linked to dopaminergic neuron loss, but emerging evidence suggests broader cellular involvement. Here we show that PD risk variants converge on distinct molecular networks across specific brain cell types, enabling stratification of patients into six subgroups: dopaminergic, oligodendrocyte progenitor cells (O), excitatory (E), dopaminergic/excitatory, dopaminergic/oligodendrocyte and other. While all subgroups exhibit motor symptoms, the E-group individuals also display more severe non-motor symptoms, including dementia, hyposmia, and REM sleep behavior disorder. The O-group individuals exhibit reduced myelin integrity, as demonstrated by diffusion tensor imaging, implicating NRG6 (formerly C1orf56), a previously uncharacterized high-risk PD gene. We show that NRG6 encodes a conserved epidermal growth factor-like domain structurally and functionally analogous to neuregulin-1, which is critical for oligodendrocyte development and myelination. These findings redefine the cellular architecture of PD vulnerability and identify neuregulin-like signaling in oligodendrocytes as a potential contributor to non-motor symptoms.

neuroscience↗

bioRxiv2025

Human-specific features of the cerebellum and ZP2-regulated synapse development

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

neuroscience↗

bioRxiv2025

Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1, enhances autophagy and counteracts TDP-43 toxicity

Cytoplasmic aggregation of nuclear proteins such as TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) is associated with several neurodegenerative diseases. Studies in higher cells suggest that these aggregates of TDP-43 and FUS sequester polysomes by binding RACK1 (receptor for activated C kinase 1), a ribosomal protein, thereby inhibiting global translation and contributing to toxicity. But RACK1 is also a scaffold protein with many other roles including a role in autophagy. Using yeast we find that deletion of the RACK1 ortholog, ASC1, reduces TDP-43 toxicity, but not FUS toxicity. TDP-43 foci remain liquid like in the presence asc1{Delta} but they become smaller. This is consistent with the findings in cell culture. However, using double label tags we establish that ASC1 does not co-localize with TDP-43 foci, arguing against the sequestration hypothesis. Instead, ASC1 appears to influence toxicity through autophagy. We previously showed that expression of TDP-43 inhibits autophagy and TOROID (TORC1 Organized in Inhibited Domains) formation and that modifiers that rescue yeast from TDP-43 toxicity reverse these inhibitions. Here we show that FUS does not inhibit autophagy. This autophagy enhanced by asc1{Delta} is non-canonical, marked by reduced TOROID formation, and effectively counteracts the autophagy inhibition caused by TDP-43. Our findings suggest that ASC1 influences TDP-43 toxicity through autophagy regulation rather than polysome sequestration, highlighting autophagy as a key therapeutic target. SummaryTDP-43 and FUS aggregates are linked to neurodegenerative diseases. RACK1, a ribosomal protein, was previously thought to contribute to toxicity by co-localizing with these aggregates and sequestering polysomes. In yeast, deletion of ASC1--the RACK1 homolog--reduces TDP-43 toxicity but not FUS toxicity. TDP-43 foci remain liquid-like, but ASC1 does not co-localize with them, challenging the sequestration hypothesis. Instead, asc1{Delta} enhances autophagy, rescuing cells from the autophagy inhibition caused by TDP-43. Unlike TDP-43, FUS does not inhibit autophagy. These findings highlight autophagy, rather than polysome sequestration, as the key mechanism of TDP-43 toxicity and its mitigation via ASC1/RACK1 reduction.

cell biology↗

bioRxiv2025

Update on the reproduction and interpretation of DIANA fMRI

Three years ago, our group reported direct imaging of neuronal activity (DIANA) with high spatiotemporal resolution, but its reproducibility and signal origin remain controversial. Here, we report the results of our reproduction experiments of DIANA fMRI performed to date using forelimb electrical stimulation at various magnetic field strengths in anesthetized mice, along with the characteristics of DIANA signal, called the pseudo-steady state (PSS). Theoretical analysis and Bloch simulations demonstrated that the spatial location and temporal phase of PSS oscillations are primarily determined by frequency-offset, and that their spatiotemporal superposition can generate peak signals in specific regions at specific timing that closely resemble DIANA signals. These findings suggest that if PSS oscillations are the primary source of DIANA signals, it may be premature to interpret them as neuronal responses to sensory stimulation. Further studies are needed to clarify the relationship between DIANA signals and brain activation.

neuroscience↗

bioRxiv2025

Linking Kinetochore Attachment to Checkpoint Control: The Role of Aurora B in BubR1 Acetylation

We report here that Aurora B kinase is critical in BubR1 acetylation at K250, transducing kinetochore attachment status to spindle assembly checkpoint (SAC) activity. Aurora B phosphorylates BubR1 at serines 16 and 39 in an unattachment-dependent manner, which is a prerequisite for BubR1 acetylation at lysine 250 (K250). Utilizing a novel anti-AcK250 monoclonal antibody in structured illumination microscopy (SIM), we reveal that BubR1 acetylation is associated with kinetochore expansion, evidenced by crescent-shaped volume increase of ZW10 and Mad2 surrounding the kinetochore. Furthermore, K250-BubR1 acetylation enhances its interaction with CENP-E, a kinesin crucial for chromosome alignment through facilitating end-on attachment. Disrupting Aurora B-mediated phosphorylation of Ser16/39 impaired K250 acetylation, compromising both fibrous corona polymerization and mitotic checkpoint complex (MCC) maintenance. Conversely, introducing K250 acetylation mimetic form rescued MCC and fibrous corona in cells expressing phosphorylation-deficient S16A/S39A mutants. Our findings reveal Aurora B-BubR1 acetylation axis as a critical SAC signaling pathway, interlinking unattachment sensing with kinetochore expansion and SAC activity. We propose that this stepwise phosphorylation-acetylation on BubR1 constitutes a crucial part of SAC signaling code, transducing unattachment signal to fibrous corona polymerization and SAC activity. This phosphorylation-acetylation cascade in BubR1 offers potential therapeutic targets in treating cancers of chromosome instability.

cell biology↗

bioRxiv2025

Intron retention regulates STAT2 function and predicts immunotherapy response in lung cancer

Immunotherapy benefits only a subset of lung cancer patients, and the molecular determinants of variable outcomes remain unclear. Using long-read RNA-sequencing we mapped the landscape of alternative RNA splicing in human primary lung adenocarcinomas. We identified over 180,000 full-length mRNA isoforms, more than half of which were novel and many of which occurred in immune-related genes, particularly within the type I interferon response pathway. We discovered retained introns in the STAT2 gene that produce altered protein isoforms that regulate immune signaling and interferon responses. Furthermore, STAT2 intron retention levels predicted patient responses to checkpoint inhibitors. These findings position alternative splicing as a key regulator of tumor immune responses and reveal mRNA splicing alterations as potential biomarkers to identify patients who might respond to cancer immunotherapy.

immunology↗

bioRxiv2025

Rapid Liquid Chromatography-Mass Spectrometry (rLC-MS) for Deep Metabolomics Analysis of Population Scale Studies

Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies of human populations, limiting power to discover physiological roles of metabolites. Here, we introduce a fully automated rapid liquid chromatography-mass spectrometry (rLC-MS) system coupled to an AI-enabled computational pipeline that enables high-throughput, reproducible, non-targeted metabolite measurements across tens of thousands of samples. This system captures thousands of polar, amphipathic and nonpolar (lipid) metabolites in a human plasma sample in 53 seconds of analytical time, enabling analysis of greater than 1,000 samples per day per instrument. To demonstrate the discovery power of the rLC-MS platform, a subset of samples from Sapients DynamiQ biorepository - comprised of 62,039 total plasma samples collected longitudinally from 11,045 individuals - were selected for deep analysis by rLC-MS to capture a rich, dynamic landscape of chemical variation that reflects both physiological processes and environmental influences. 26,042 plasma samples with matched real-world data (RWD) were chosen for the study, representing 6,935 individuals with diverse demographic backgrounds and disease profiles. Unbiased exploratory analysis revealed human metabotypes that correlate with heterogenous disease phenotypes, including key sub-populations of cardiometabolic and other human diseases. Moreover, a metabolic aging clock machine learning model trained on healthy individuals in this dataset accurately predicted accelerated aging in various chronic diseases, with dynamic reversal of metabolic aging following definitive therapy. These data demonstrate that the rLC-MS platform enables prediction of clinically relevant physiological states from plasma metabolomics at scale in human populations.

biochemistry↗

bioRxiv2025

Omicron Subvariants Infection Kinetics and Nirmatrelvir Efficacy in Transgenic K18-hACE2 Mice

The persistent evolution of SARS-CoV-2 has led to the emergence of antigenically distinct Omicron subvariants exhibiting increased transmissibility, immune evasion, and altered pathogenicity. Among these, recent subvariants like JN.1, KP.3.1.1, and LB.1 possess unique antigenic and virological features, underscoring the need for continued surveillance and therapeutic evaluation. As vaccines and commercial monoclonal antibodies show reduced effectiveness against these variants, the role of direct-acting antivirals, such as Nirmatrelvir, targeting conserved viral elements like the main protease inhibitor, becomes increasingly crucial. In this study, we investigated the replication kinetics, host immune responses, and therapeutic susceptibility of three recently circulating Omicron subvariants in the K18-hACE2 transgenic mouse model, using the SARS-CoV-2 parent WA1/2020 strain as a reference. Omicron subvariants exhibited a marked temporal shift in viral infection kinetics characterized by an early lung viral titer peak ([~]7-8 Log PFU) at 2 days post-infection (dpi), followed by a decline (1-3 Log PFU) by 4 dpi. Pulmonary cytokine and chemokine responses (GM-CSF, TNF-, IL-1{beta}, IL-6) showed an earlier increase in subvariant-infected mice compared to a gradual response in WA1/2020 infection. Notably, Nirmatrelvir treatment led to significant reduction in lung viral titers in subvariant-infected mice than in WA1/2020, surpassing its efficacy against the parent strain. These findings highlight that Omicron subvariants infection yields a broad dynamic range in viral burden with minimum variability, while retaining a prominent therapeutic response to Nirmatrelvir. This study provides insights to the emerging subvariants pathogenesis and therapeutic responsiveness, reinforcing the importance of continued variant monitoring and the development of effective countermeasures. ImportanceThe emergence of SARS-CoV-2 Omicron subvariants still poses a significant public health challenge due to their antigenic drift, altered pathogenesis, and immune evasion capabilities. This study comprehensively highlights the distinct replication kinetics, immune responses, and therapeutic susceptibility of the recently circulating Omicron subvariants JN.1, KP.3.1.1, and LB.1 using the K18-hACE2 mouse model. We demonstrate that while these subvariants exhibit altered virological profiles and immune activation patterns compared to the parent WA1/2020 strain, they remain susceptible to Nirmatrelvir which is a direct-acting main protease inhibitor. Notably, Nirmatrelvir demonstrated greater in vivo antiviral efficacy in Omicron subvariant infections than in the ancestral WA1/2020 strain. These findings underscore the enduring therapeutic value of protease-targeting antivirals and emphasize the critical need for ongoing variant-specific preclinical assessments.

microbiology↗

bioRxiv2025

Precision functional mapping reveals less inter-individual variability in the child vs. adult human brain

Human brain organization shares a common underlying structure, though recent studies have shown that features of this organization also differ significantly across individual adults. Understanding the developmental pathways that lead to individually unique brains is important for advancing models of cognitive development and neurodevelopmental disorders. Here we use highly personalized precision neuroimaging methods to map brain networks within 12 individual children, ages 8-12 years. We demonstrate fMRI functional connectivity maps that substantially exceed the reliability of traditional techniques, allowing us to measure individual differences after overcoming biases from measurement noise. Children share core functional network topography, with greatest inter-individual variability in association regions, consistent with adult findings. However, children show less between-subject variability than adults, suggesting increasing individual differentiation in brain networks with development. This pediatric precision neuroimaging dataset is publicly available to support future brain development research and provides a high-fidelity foundation for studying individual variation in atypical development.

neuroscience↗

bioRxiv2025

Estimating Actual Striking Forces Using Attenuation Properties of Taekwondo Protectors

BackgroundProtectors attenuate impact forces significantly, however, their quantitative attenuation characteristics under varying conditions remain poorly understood. Accurate measurement of striking forces is essential for evaluation. However, direct measurement of athletes striking forces presents significant practical and safety challenges, necessitating the development of indirect estimation approaches. MethodA controllable pendulum-based impact testing apparatus was developed to evaluate force attenuation characteristics of Taekwondo body protectors. The system delivered repeatable impacts across varying magnitudes and contact durations to a mannequin equipped with a protector. Simultaneous measurements of input and transmitted forces through the protector enabled direct quantification of attenuation ratios under controlled conditions. To demonstrate practical application, five Taekwondo athletes performed standardized kicks on the instrumented protector setup, allowing estimation of their actual striking forces using the derived attenuation factor. ResultsForce attenuation ratios demonstrated high consistency across impact magnitudes ranging from 300 to 5800 Newtons, with impact duration variations showing minimal influence on attenuation performance. Linear attenuation relationships were established between input and transmitted forces (R2[≥] 0.987), enabling derivation of a predictive attenuation factor. Validation testing with the pendulum system showed that the estimated input force trajectories achieved an nRMSE of 3.5%. Averaged across the entire force range, the MAPE was 4.7% for maximum force, 1.4% for impact duration, and 3.5% for impulse. Applying the attenuation factor to standardized kicks performed by five Taekwondo athletes yielded estimated maximum striking forces ranging from approximately 1300 to 1800 Newtons, demonstrating the methods capability to quantify actual forces that would otherwise be difficult to measure directly. DiscussionThis study establishes the first quantitative characterization of impact attenuation in Taekwondo body protectors, providing a validated attenuation factor for estimating striking forces from transmitted forces. These findings demonstrate a practical methodology for quantifying striking forces that are otherwise difficult to measure directly. Author summary

bioengineering↗

bioRxiv2025

Interhelical distance measurements support a hairpin conformation for Caveolin-1 in phospholipid bicelles

Previous molecular dynamics (MD) simulations of caveolin-1 (Cav1) in our labs revealed the possibility of two stable conformations of its intramembrane helices (H1 and H2). To distinguish between these two conformations, experimental intramolecular distances obtained using FRET (Forster resonance energy transfer) were integrated into the MD simulations to better define the position of these helices. Two mutants of Cav1 were generated where an acceptor fluorophore, dansyl, was positioned at the N-terminal end and center of H1 (A87C, F99C respectively), while a donor fluorophore, a native tryptophan, was positioned at the C-terminal end of H2 (W128). For the A87C W128 mutant, a distance of 22.5 {+/-} 0.3 [A] was observed while a distance of 24.4 {+/-} 0.2 [A] was observed for the F99C W128 mutant in phospholipid bicelles. These experimental FRET distances were compared to distances in MD simulations of over 100 Cav1 structures. Together these studies support that H1 and H2 adopt a hairpin conformation in bicelles.

biochemistry↗

bioRxiv2025

Proteomics of Transglutaminase 2 polyaminated proteins

Post-translational modification of proteins by polyamines (putrescine, spermine and spermidine) is poorly studied due to technical challenges in identification. Polyamination is mainly performed by transglutaminases via transamidation of a polyamine to an acceptor glutamine-residue on the target protein. We performed polyamination reactions on whole cell lysates using 2 different polyamine probes (Biotin-pentylamine and DNP-pentylamine) and identified modified peptides by mass spectrometry. 51 protein targets modified on 66 different sites were identified, with an overlap between hits tagged with the different probes. Many of the targets are involved in translation, cytoskeletal organization or have roles in cancer.

molecular biology↗

bioRxiv2025

An intermediate activation state primes Langerhans cell migration from the epidermis

Langerhans cells (LC) are antigen-presenting cells that form dense epidermal networks for immune surveillance. Upon antigen uptake, LCs are activated and subsequently orchestrate immune responses by migrating into the lymphatic system. However, the regulation of transcriptional programs during activation and the behavior of LCs in vivo during this transition remain poorly understood. Therefore, this study combines single-cell transcriptomic analysis with intravital imaging to reconstruct the activation trajectory of epidermal LCs. In particular, the study generates a high-resolution single-cell transcriptomic dataset comprising over 22,000 high-quality epidermal LCs under both homeostatic and injury conditions. Notably, a distinct intermediate activated state that precedes LC migration was identified and characterized at the level of signaling pathways and transcription factors. The integration of this dataset with external datasets from homeostatic and injured skin reveals wound-specific fibroblasts as the major source of C3, which is the central component of the complement cascade. Moreover, intravital imaging of C3-deficient mice and pegcetacoplan treatment demonstrates that C3 contributes to LC accumulation adjacent to wound sites. Collectively, the study findings identify an activated epidermal LC population and implicate complement signaling in the regulation of LC behavior during skin injury.

cell biology↗

bioRxiv2025

Physics-Informed Digital Twin Can Predict Cerebral Blood Flow and Cerebral Vascular Regulation Mechanisms in Neurocritical Care Patients

1Cerebral blood flow is vital for brain function and is acutely controlled through a set of physiological mechanisms known as cerebral vascular regulation (CVR)[1-3]. It remains challenging to directly measure the dynamics and function of individual CVR mechanisms[4], limiting our ability to understand and optimize brain perfusion, particularly for neurologically injured patients. Digital twins offer an ideal tool for overcoming this gap because they enable estimation, tracking, and forecasting of unmeasured physiological states[5, 6]. Here, we introduce CereBRLSIM (Cerebral Blood Regulation Latent State Inference and Modeling), a digital twin that integrates physiological knowledge and patient data to infer CVR function and predict cerebral dynamics. Using both in vivo experiments and simulated data, CereBRLSIM predicted cerebral hemodynamics with high accuracy and estimated the dynamics of myogenic, endothelial, and metabolic mechanisms underlying CVR. When personalized to neurocritical care patient data, CereBRLSIM differentiated cerebral hemodynamic phenotypes, predicted patient outcomes, and forecasted blood flow with significantly higher accuracy than machine learning models. This work provides a novel, interpretable, and clinically compatible approach for quantifying CVR function and forecasting cerebral blood flow, enabling new opportunities in precision diagnostics and foundational understanding of cerebral hemodynamics.

bioengineering↗

bioRxiv2025

Unveiling differential responses to UVB (305 nm) and UVC (275 nm) in cacao-infecting Colletotrichum gloeosporioides and Pestalotiopsis sp.

Sustainable control of microbial pathogens requires alternatives to chemicals, but physical methods like Ultraviolet-C (UVC) show variable efficacy linked to poorly understood pathogen-specific responses. Here, we investigate differential UVB/UVC responses in plant pathogenic fungi (Colletotrichum gloeosporioides, Pestalotiopsis sp.). Using hyperspectral imaging and machine learning, we dissect the physiological underpinnings of UV sensitivity. UVC proves more potent than UVB, with Pestalotiopsis sp. showing significantly higher resistance than C. gloeosporioides isolates. Crucially, hyperspectral signatures correlated with resistance, revealing UVC-induced photopigment changes, biochemical disruption, and oxidative stress markers in sensitive isolates, contrasting with minimal perturbation in the resistant isolate. Machine learning accurately decoded these complex phenotypes for classification. This understanding enabled enhanced inactivation via optimized pulsed UVC and synergistic sonication. We link distinct physiological states, non-invasively detected via hyperspectral imaging, to fungal UV resistance, demonstrating how integrating advanced phenotyping and machine learning provides a mechanistic basis for optimizing physical pathogen controls.

microbiology↗

bioRxiv2025

Design, Structure, and Immunogenicity of a Soluble Prefusion-stabilized EBV gB Antigen

Epstein-Barr virus (EBV), the causative agent of mononucleosis, is linked to over 140,000 annual cancer-related deaths globally and increases the risk of multiple sclerosis by up to 32-fold. As a herpesvirus, EBV establishes lifelong infection, and over 90% of U.S. adults are EBV-seropositive. Despite its significant disease burden, no approved EBV vaccines or therapeutics exist. Among EBV envelope glycoproteins, the fusion protein (gB) is strictly required for epithelial and B cell infection. Using a combination of AlphaFold-guided modeling, rational design, and ThermoMPNN-informed optimization, we engineered a stabilized prefusion gB variant, D2C3. This construct incorporates two inter-protomeric disulfide bonds and three cavity-filling substitutions, resulting in a melting temperature of 54 {degrees}C. Cryo-EM analysis of this construct allowed us to determine the prefusion structure of EBV gB, providing insights into the structural transitions required to adopt the postfusion conformation. Murine immunizations and depletion studies with human sera suggested a trend toward improved functional immunogenicity of D2C3 compared to postfusion gB. Collectively, these studies define engineering principles to stabilize class III fusion proteins, provide reagents to interrogate the human antibody response to EBV gB, and lay a foundation for further studies to develop EBV gB-based vaccine candidates.

biochemistry↗

bioRxiv2025

SoftAlign: End-to-end protein structures alignment

With the recent breakthrough of highly accurate structure prediction methods, there has been a rapid growth of available protein structures. Efficient methods are needed to infer structural similarity within these datasets. We present an end-to-end alignment method, called SoftAlign, which takes as input the 3D coordinates of a protein pair and outputs a structural alignment. In addition to the traditional Smith-Waterman alignment method, we introduce a modified softmax alignment that shows very promising results for structure similarity detection. We demonstrate that the SoftAlign model is able to recapitulate TM-align alignments while running faster, and it is more accurate than Foldseek on alignment and classification tasks. Although SoftAlign is not the fastest method available, it is highly precise and can be used effectively with other prefilters. In addition to developing an end-to-end structural aligner, our main contribution is the introduction and analysis of a pseudo-alignment method based on softmax, which can be used with other architectures, even those not based on structural information. The code for SoftAlign is available at https://github.com/jtrinquier/SoftAlign.

bioinformatics↗