Biology subjects

Hsu, T.

Publications and source records attributed to Hsu, T..

9 recordsLinked to original sources

bioRxiv2026

Single-cell spatial multi-omic characterization of the tumour microenvironment in transformed follicular lymphoma

Histological examination of follicular lymphoma (FL) biopsies remains the cornerstone for diagnostic grading of FL. Single-cell sequencing approaches, while transcriptomically rich, require tissue dissociation and lose the native spatial context that underpins FL transformation to diffuse large B-cell lymphoma (DLBCL). To investigate the spatial interplay between malignant B-cells and the tumour microenvironment (TME) across disease states, we performed subcellular single-cell spatial transcriptomics and spatial proteomics on 12 paired pre/post-transformation samples and 10 non-transforming FL controls, integrated with matched single-cell whole genome sequencing (scWGS). Our analysis reveals that transformation is accompanied by a shift toward B-cell-predominant stromal and immunosuppressive cellular neighbourhoods, where the magnitude of expansion correlates with time to transformation. Prior to transformation, immunomodulatory Galectin-9 interactions move from the intra-follicular core to the extra-follicular space. Integration with scWGS demonstrates that high copy-number instability in malignant B-cells is associated with reduced supportive T-cell niches and intensified immunoregulatory crosstalk at the transformed state. Collectively, our multi-omic analysis characterizes TME remodeling during FL transformation, contributing to a refined disease evolution model.

bioinformatics↗

bioRxiv2025

Cell-type specific sensory and motor activity in the cuneiform nucleus and pedunculopontine nucleus in mice

The activity of neurotransmitter-based cell types in the cuneiform and pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation is not fully understood. Using fiber photometry in mice, we found cell-type specific responses to sensory stimuli. Glutamatergic and GABAergic cells responded to sound, visual looming, and air puffs, except for pedunculopontine GABAergic cells, which did not respond to visual looming. Cholinergic cells responded to air puffs. When a stimulus triggered high-speed locomotion, activity increased in cuneiform glutamatergic neurons. Conversely, when low-speed locomotion was triggered, activity increased in pedunculopontine glutamatergic neurons. During spontaneous low-speed locomotion, activity increased in pedunculopontine glutamatergic cells. Activity also increased in a cell type-specific manner during grooming or rearing. Our study shows cell type-specific activity in the cuneiform or pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation. Sensory responsiveness likely has relevance in Parkinsons disease, where sensory circuits are increasingly targeted to improve walking.

neuroscience↗

bioRxiv2024

Deep Learning Unravels Potential Antibiotic-Resistance Drugs against Klebsiella Pneumoniae

BackgroundKlebsiella pneumoniae (KP) is a critical pathogen recognized by the World Health Organization due to its high mortality rates and resistance to antibiotics. Developing effective treatments for KP is essential to mitigate the growing threat of multidrug-resistant infections. This study leverages deep learning techniques to identify and validate potential drug candidates against KP, accelerating the drug discovery process and reducing associated risks. ResultsA comprehensive dataset was constructed, comprising 3,475 drugs selected from the DrugBank database, filtered for their potential efficacy and safety. Using convolutional neural networks (CNNs) for drug-drug interaction analysis, a prediction accuracy of 72% was achieved. Evolutionary Scale Modeling (ESM) was employed to calculate molecular similarities between drugs and KP strains, identifying five promising candidates with structural similarities exceeding 85% to known KP targets. A drug repurposing knowledge graph (DRKG) further validated these findings, with the PairRE model outperforming other approaches in ranking potential drug candidates. ConclusionsThis study presents a scalable and efficient framework for identifying and validating drug candidates to combat antibiotic-resistant KP. By integrating deep learning models, molecular similarity analysis, and knowledge graph techniques, this approach shortens the drug discovery timeline from years to months. The identified candidates hold significant promise for preclinical and clinical testing, offering a pathway to effective therapies against KP and other multidrug-resistant pathogens.

bioinformatics↗

bioRxiv2024

Deep Learning with Evolutionary Scale Modeling to discover Antibiotic-Resistance Drug against Klebsiella Pneumoniae

The development of effective antibiotics is crucial in combating antibiotic-resistant pathogens such as Klebsiella pneumoniae (KP). This study utilizes deep learning, specifically Evolutionary Scale Modeling (ESM), to identify potential drug candidates. By analyzing molecular similarities between known drugs and KP strains, we aim to accelerate the discovery of new treatments and reduce the risks associated with clinical trials. This approach may shed new lights in the field of drug repositioning.

bioinformatics↗

bioRxiv2024

Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (mROS) and peroxynitrite, blocking of which abrogated IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.

immunology↗

bioRxiv2022

MicroRNA-27a is essential for bone remodeling by modulating p62-mediated osteoclast signaling

The ability to simultaneously modulate a set of genes for lineage-specific development has made microRNA an ideal master regulator for organogenesis. However, most microRNA deletions do not exhibit obvious phenotypic defects possibly due to functional redundancy. MicroRNAs are known to regulate skeletal lineages as the loss of their maturation enzyme Dicer impairs bone remodeling processes. Therefore, it is important to identify specific microRNA essential for bone homeostasis. We report the loss of miR-27a causing severe osteoporosis in mice. MiR-27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Gene profiling and bioinformatics further identify the specific targets of miR-27a in osteoclast cells. MiR-27a exerts its effects on osteoclast differentiation through modulation of Squstm1/p62 whose mutations have been linked to Pagets disease of bone. Our findings reveal a new miR-27a-p62 axis necessary and sufficient to mediate osteoclast differentiation and highlight a therapeutic implication for osteoporosis.

developmental biology↗

bioRxiv2021

Abolishing the prelamin A ZMPSTE24 cleavage site leads to progeroid phenotypes with near-normal longevity in mice

Prelamin A is a farnesylated precursor of lamin A, a nuclear lamina protein. Accumulation of the farnesylated prelamin A variant progerin, with an internal deletion including its processing site, causes Hutchinson-Gilford progeria syndrome. Loss of function mutations in ZMPSTE24, which encodes the prelamin A processing enzyme, lead to accumulation of full-length farnesylated prelamin A and cause related progeroid disorders. Some data suggest that prelamin A also accumulates with physiological aging. Zmpste24-/- mice die young, at ~20 weeks. Because ZMPSTE24 has functions in addition to prelamin A processing, we generated a mouse model to examine effects solely due to the presence of permanently farnesylated prelamin A. These mice have an L648R amino acid substitution in prelamin A that blocks ZMPSTE24-catalyzed processing to lamin A. The LmnaL648R/L648R mice express only prelamin and no mature protein. Notably, nearly all survive to 65-70 weeks, with approximately 40% of male and 75% of female LmnaL648R/L648R mice having near-normal lifespans of 90 weeks (almost 2 years). Starting at ~10 weeks of age, LmnaL648R/L648R mice of both sexes have lower body masses and body fat than controls. By ~20-30 weeks of age, they exhibit detectable cranial, mandibular and dental defects similar to those observed in Zmpste24-/- mice, and have decreased vertebral bone density compared to age- and sex-matched controls. Cultured embryonic fibroblasts from LmnaL648R/L648R mice have aberrant nuclear morphology that is reversible by treatment with a protein farnesyltransferase inhibitor. These novel mice provide a robust model to study the effects of farnesylated prelamin A during physiological aging.

cell biology↗

bioRxiv2020

Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses

Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human {gamma}-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a novel approach to effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.

microbiology↗

bioRxiv2018

Mitochondrial cristae biogenesis coordinates with ETC complex IV assembly during Drosophila maturation

Mitochondrial cristae contain electron transport chain (ETC) complexes and are distinct from the inner boundary membrane (IBM) in both protein composition and function. While many details of mitochondrial membrane structure are known, the processes governing cristae biogenesis, including the organization of lipid membranes and assembly of proteins encoded by both nuclear and mitochondrial DNA, remain obscure. We followed cristae biogenesis in situ upon Drosophila eclosion using serial-section electron tomography and revealed that the morphogenesis of lamellar cristae coordinates with ETC complex IV assembly. The membrane morphogenesis and gain-of-function were intricately co-evolved during cristae biogenesis. Marf-knockdown flies formed lamellar cristae containing ATP synthase and functional COX. However, OPA1-knockdown flies showed impaired cristae biogenesis. Overall, this study revealed the multilevel coordination of protein-coupled membrane morphogenesis in building functional cristae.

cell biology↗