Biology subjects

Kuo, Y.

Publications and source records attributed to Kuo, Y..

5 recordsLinked to original sources

bioRxiv2026

Meningeal neutrophil infiltration drives inflammation-exacerbated pediatric stroke through IL-36γ signaling

Infection and systemic inflammation have been identified as major risk factors for pediatric stroke; however, the immune mechanisms underlying these clinical observations remain poorly understood. Here, we utilized an LPS-sensitized photothrombotic stroke model (LPS/PT) to investigate the contribution of immune cell infiltration to pediatric stroke pathogenesis and identified a previously unrecognized route of neutrophil entry into the injured brain. Compared with photothrombotic stroke alone (PT), LPS/PT mice exhibited markedly increased neutrophil infiltration accompanied by a hyperactivated phenotype. Depletion of neutrophils, but not monocytes, significantly reduced infarct size in LPS/PT animals, indicating a central role for neutrophils in inflammation-exacerbated pediatric stroke. Notably, we observed that neutrophils first accumulated within the leptomeningeal space before entering the brain parenchyma during the early phase of stroke, suggesting that the meninges may serve as an initial staging site for neutrophil recruitment. Using KikGR photoconvertible reporter mice combined with two-photon imaging, we further demonstrated that neutrophils infiltrate the ischemic brain through a compromised meningeal barrier following stroke. Transcriptomic analysis of infiltrating neutrophils revealed distinct gene expression signatures between meningeal neutrophils and circulating blood-derived neutrophils. Among these, IL-36{gamma} was highly enriched in meninges-associated neutrophils during pediatric stroke. Consistently, single-cell RNA sequencing of meningeal immune cells confirmed elevated IL-36{gamma} expression within the neutrophil cluster in LPS/PT animals. Importantly, intracisternal administration of IL-36 receptor antagonist (IL-36Ra) or anti-ICAM-1 antibody significantly reduced infarct volume in this pediatric stroke model. Together, our findings identify the meningeal barrier as a critical gateway for neutrophil infiltration and reveal IL-36{gamma} as a key inflammatory mediator regulating neuroinflammation in pediatric stroke, highlighting a potential therapeutic target for limiting immune-mediated brain injury.

neuroscience↗

bioRxiv2025

Single oocyte full-length isoform sequencing unveils the impact of transposable elements on RNA diversity and stability during oocyte maturation

The oocyte-specific isoforms play crucial roles in oocyte maturation, while current understanding of the oocyte transcriptome is mainly focused on gene level. Here, we utilized single cell full-length isoform sequencing based on third generation sequencing to detect entire transcripts in human and mouse oocytes. Isoform diversity during oocyte maturation was systematically profiled, including 6,736 and 4,902 putative novel human and mouse transcripts, respectively. More than half of novel isoforms were categorized as the novel-not-in-catalog (NNC) and may serve specific functions in oocytes, including novel isoforms of ARHGAP18, colocalized with microtubules and targeted knockdown disrupting oocyte maturation. Moreover, over 25% of NNC isoforms were derived from transposable elements (TEs), and their incorporation within transcripts could enhance isoform stability during oocyte maturation. Altogether, our findings represent a valuable resource showcasing the complexity and diversity of RNA isoforms in oocytes, as well as TE co-option for novel isoform generation and isoform stability enhancement.

developmental biology↗

bioRxiv2024

The Taiwan Precision Medicine Initiative: A Cohort for Large-Scale Studies

The Taiwan Precision Medicine Initiative (TPMI), a project initiated by the Academia Sinica in collaboration with 16 major medical centers around Taiwan, has recruited 565,390 participants who consented to provide DNA samples for genetic profiling and grant access to their electronic medical records (EMR) for studies to develop precision medicine. Access to the EMR is both retrospective and prospective, allowing researchers to conduct prospective studies over time. Genetic profiling is done with population-optimized SNP arrays for the Han Chinese populations that enable genetic analyses such as genome-wide association, phenome-wide association, and polygenic risk score studies to evaluate common disease risk and pharmacogenetic response. Furthermore, the TPMI participants agree to be contacted for future research opportunities related to their genetic risks and receive personalized genetic risk profiles with health management recommendations. TPMI has established the TPMI Data Access Platform (TDAP), a central database and analysis platform that both safeguards the security of the data and facilitates academic research. The TPMI is the largest non-European cohort that merges genetic profiles with EMR in the world. With a cohort that can be followed over time, it can be utilized to validate genetic risk prediction models, conduct clinical trials to show the efficacy of risk-based health management, and optimize health policies based on genetic risks. In this report, we describe the TPMI study design, the population and genetic characteristics of the TPMI cohort, and the power it provides to conduct crucial studies in developing precision medicine on a population and personal level. As Han Chinese represent almost 20% of the worlds population, the results of TPMI studies will benefit >1.4 billion people around the world and serve as a model for developing population-based precision medicine.

genetics↗

bioRxiv2022

Expression and functional evaluation of recombinant human ABO blood group antigen cleaving glycoside hydrolases α-N-acetylgalactosaminidase, α-galactosidase, and endo-β-galactosidase produced in Escherichia coli

Blood transfusions are an integral component of healthcare; however, availability of viable blood is limited by patient-donor blood type specificity, which contributes to seasonal shortages as well as shortages worldwide, especially in developing countries, and during pandemics or natural disasters. Attempts to increase blood supply with commercial incentives have raised ethical concerns, and current proposed artificial blood substitutes are unable to fully replicate the function of native red blood cells (RBCs). In this study, we explore the potential strategy of alleviating blood shortages through enzymatic conversion of A, B, and AB blood types to blood type O. In theory, this process eliminates ABO patient-donor incompatibility, which increases the supply of universal donor blood. Three glycoside hydrolases, -N-acetylgalactosaminidase, -galactosidase, and endo-{beta}-galactosidase, were selected to act as molecular scissors to cleave terminal residues on A and B RBC surface antigens and catalyze the conversion process. These enzymes were recombinantly expressed in BL21(DE3) Escherichia coli and purified through nickel ion affinity chromatography. A combination of colorimetric substrate assays, thin-layer chromatography, and mass spectroscopy were utilized to evaluate enzyme functionality. Enzyme efficiency was modeled using Michaelis-Menten kinetics. Partial enzymatic A-to-O blood type conversion on porcine red blood cells was observed with slide agglutination tests. Results confirm recombinant enzyme-mediated blood type conversion as a potential strategy for alleviating blood shortages.

biochemistry↗

bioRxiv2020

Multiplexed fractionated proteomics reveals synaptic factors associated with cognitive resilience in Alzheimer's Disease

Alzheimers disease (AD) is a complex neurodegenerative disease defined by the presence of amyloid-{beta} (A{beta}) plaques and tau neurofibrillary tangles, and driven by dysproteostatis, inflammation, metabolic dysfunction, and oxidative injury, eventually leading to synapse loss and cell death. Synapse loss correlates with cognitive impairment and may occur independently of the extent of AD pathology. To understand how synaptic composition is changed in relation to AD neuropathology and cognition, highly sensitive multiplexed liquid chromatography mass-spectrometry was used to quantify biochemically enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting AD pathology and cognitive performance. Functional analysis showed preservation of synaptic signaling, ion transport, and mitochondrial proteins in normal aged and "resilient" (cognitively unimpaired with AD pathology) individuals. Compared to these individuals, those with cognitive impairment showed significant metabolic differences and increased immune- and inflammatory-related proteins, establishing the synapse as a potential integration point for multiple AD pathophysiologies.

neuroscience↗