Biology subjects

Lin, T.-H.

Publications and source records attributed to Lin, T.-H..

9 recordsLinked to original sources

bioRxiv2026

Protein tyrosine phosphatase receptor type kappa (PTPRκ) regulates Superior ON-Direction Selective Ganglion Cell development, facilitating image stabilization

In vertebrates, gaze stabilization during global visual motion requires ON direction-selective ganglion cells (oDSGCs) in the Accessory Optic System (AOS) to drive the optokinetic reflex (OKR). Three types of oDSGCs form independent mosaics; however, the mechanisms that specify and maintain their numbers to create these mosaics during development remain unknown. Here, we identify protein tyrosine phosphatase receptor type kappa (Ptprk) as a key regulator of Superior oDSGC density, the subtype tuned to upward motion. High-depth single-cell RNA sequencing (scRNAseq) reveals that Ptprk is selectively enriched in Superior oDSGCs compared to Inferior oDSGCs, which detect downward motion. Genetic deletion of Ptprk selectively halves the number of Superior oDSGCs while preserving the number of Inferior oDSGCs. Anatomically, Superior oDSGCs in Ptprk mutants exhibit compensatory neurite remodeling to preserve mosaics. Physiologically, oDSGCs have broader tuning curves, and a subset of Superior oDSGCS have aberrant preferred directions in Ptprk mutants. Postsynaptically, loss of Ptprk reduces oDSGC connectivity to central targets. Behaviorally, the OKR responses to upward motion are attenuated in both global and pan-retinal Ptprk mutants, confirming a retinal role for Ptprk in upward image stabilization. Together, these findings demonstrate that the density of a retinal ganglion cell type is under molecular control, and that reducing density drives neurite remodeling, alters circuit computation, and ultimately impairs visually-guided behavior.

neuroscience↗

bioRxiv2025

The receptor binding properties of H5Nx influenza A viruses have evolved to promiscuously bind to avian-type mucin-like O-glycans

Highly pathogenic H5Nx influenza A viruses are causing unprecedented, season-independent outbreaks across avian and mammalian species, including dairy cattle, a novel reservoir. The sialoside-binding properties of influenza A hemagglutinin (HA) are strongly related to its ability to infect and transmit between hosts. Mucin-like O-glycans, omnipresent in respiratory tracts, have been understudied as viral receptors due to their complexity. To address this, we synthesized 25 O-linked glycans with diverse sialosides, including modifications by fucosides and sulfates. Our findings reveal that H5Nx 2.3.4.4b viruses uniquely bind core 3 sialyl-Lewisx and Sia-Gal-{beta}3GalNAc, glycans not recognized by classical H5 or other avian viruses. By determining its crystal structure, we resolved the structural features of both structures in an H5 hemagglutinin (HA) from a 2016 2.3.4.4b virus. While these viruses do not bind human-type receptors, their promiscuous receptor specificity enhances binding to human tracheal tissues, suggesting that O-glycan recognition contributes to their zoonotic potential.

microbiology↗

bioRxiv2025

The Q226L mutation can convert a highly pathogenic H5 2.3.4.4e virus to bind human-type receptors

AbstractH5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naive to H5 viruses. A significant determinant of transmission to and between humans is the ability of the influenza A virus hemagglutinin (HA) protein to shift from an avian-type to a human-type receptor specificity. Here, we demonstrate that a 2016 2.3.4.4e virus HA can convert to human-type receptor binding via a single Q226L mutation, in contrast to a cleavage-modified 2016 2.3.4.4b virus HA. Using glycan arrays, x-ray structural analyses, tissue- and direct glycan binding, we show that L133a{Delta} and 227Q are vital for this phenotype. Thus, whereas the 2.3.4.4e virus HA only needs a single amino acid mutation, the modified 2.3.4.4b HA was not easily converted to human-type receptor specificity.

microbiology↗

bioRxiv2024

Predation by nematode-trapping fungus triggers mechanosensory-dependent quiescence in C. elegans

Predation can induce behavioral changes in prey, yet the molecular and neuronal mechanisms underlying prey responses remain poorly understood. Here, we investigated how the nematode Caenorhabditis elegans responds to predation by the nematode-trapping fungus, Arthrobotrys oligospora. We found that A. oligospora predation induced quiescence in C. elegans showing rapid cessation of pharyngeal pumping and movement. Calcium imaging revealed that this quiescence was regulated by the activation of sleep-promoting neurons, ALA and RIS. Genetic analyses demonstrated that ALA were essential for pharyngeal pumping inhibition, whereas both ALA and RIS contributed to movement cessation. Transcriptomic analysis in C. elegans showed the upregulation of immune defense genes in response to A. oligospora predation. We demonstrated that mechanosensation was required for pumping inhibition and transcriptomic regulation upon A. oligospora trapping. These findings suggest that physical constraints imposed by fungal traps trigger a stress-induced quiescence and the upregulation of defense genes in C. elegans. We suggest that trapping-induced quiescence might be a predation strategy used by sessile predators to prevail in the evolutionary arms race.

microbiology↗

bioRxiv2024

Worldwide soundscape ecology patterns across realms

Abstract and keywordsO_ST_ABSAimC_ST_ABSThe urgency for remote, reliable, and scalable biodiversity monitoring amidst mounting human pressures on ecosystems has sparked worldwide interest in Passive Acoustic Monitoring (PAM), which can track life underwater and on land. However, we lack a unified methodology to report this sampling effort and a comprehensive overview of PAM coverage to gauge its potential as a global research and monitoring tool. To remediate this, we created the Worldwide Soundscapes project, a collaborative network and growing database comprising metadata from 409 datasets across all realms (terrestrial, marine, freshwater, and subterranean). LocationWorldwide, 12 200 sites, all ecosystems. Time period1991 to present. Major taxa studiedAll soniferous taxa. MethodsWe synthesise sampling coverage across spatial, temporal, and ecological scales using metadata describing sampling locations, deployment schedules, focal taxa, and recording parameters. We explore global trends in biological, anthropogenic, and geophysical sounds based on 168 recordings from twelve ecosystems across all realms. ResultsTerrestrial sampling is spatially denser (45 sites/Mkm2) than aquatic sampling (0.3 and 1.8 sites/Mkm2 in oceans and fresh water) with only two subterranean datasets. Although diel and lunar cycles are well-covered in all realms, only marine datasets (56%) comprehensively sample all seasons. Across twelve ecosystems, biological sounds show contrasting diel patterns, decline with distance from the equator and negatively correlate with anthropogenic sounds. Main conclusionsPAM can inform macroecology studies as well as global conservation and phenology syntheses, but representation can be improved by expanding terrestrial taxonomic scope, sampling coverage in the high seas and subterranean ecosystems, and spatio-temporal replication in freshwater habitats. Overall, this global PAM network holds promise to support global biodiversity research and monitoring efforts.

ecology↗

bioRxiv2023

The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway

Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.

neuroscience↗

bioRxiv2022

Broadly neutralizing antibodies target the coronavirus fusion peptide

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2 cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2 cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence SummaryRare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

immunology↗

bioRxiv2020

Forecasting symptomatic influenza A infection based on pre-exposure gene expression using a Deep Learning approach

Background and ObjectiveNot everyone gets sick after an exposure to influenza A viruses (IAV). Although KLRD1 has been identified as a potential biomarker for influenza susceptibility, it remains unclear whether forecasting symptomatic flu infection based on pre-exposure host gene expression might be possible. MethodTo examine this hypothesis, we developed DeepFlu using the state-of-the-art deep learning approach on the human gene expression data infected with IAV subtype H1N1 or H3N2 viruses to forecast who would catch the flu prior to an exposure to IAV. ResultsThe results indicated that such forecast is possible and, in other words, gene expression could reflect the strength of host immunity. In the leave-one-person-out cross-validation, DeepFlu based on deep neural network outperformed the models using convolutional neural network, random forest, or support vector machine, achieving 70.0% accuracy, 0.787 AUROC, and 0.758 AUPR for H1N1 and 73.8% accuracy, 0.847 AUROC, and 0.901 AUPR for H3N2. In the external validation, DeepFlu also reached 71.4% accuracy, 0.700 AUROC, and 0.723 AUPR for H1N1 and 73.5% accuracy, 0.732 AUROC, and 0.749 AUPR for H3N2, surpassing the KLRD1 biomarker. In addition, DeepFlu which was trained only by pre-exposure data worked the best than by other time spans and mixed training data of H1N1 and H3N2 did not necessarily enhance prediction. DeepFlu is available at https://github.com/ntou-compbio/DeepFlu. ConclusionsDeepFlu is a prognostic tool that can moderately recognize individuals susceptible to the flu and may help prevent the spread of IAV.

bioinformatics↗

bioRxiv2018

Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

Lung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

cancer biology↗