Biology subjects

Chiu, Y.

Publications and source records attributed to Chiu, Y..

9 recordsLinked to original sources

bioRxiv2024

A Mouse-adapted SARS-CoV-2 Model for Investigating Post-acute Sequelae of COVID infection

The coronavirus disease of 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), remains a major health issue after nearly 7 millions of death toll in the last four years. As the world is recovering with improving vaccines and antiviral treatments, the alarming rate of long-COVID, or Post-acute Sequelae of COVID-19 (PASC), calls for further investigations. Among a list of symptoms associated with multi-organ dysfunctions, the neurological complications are particularly intriguing, yet the underlying mechanisms remain elusive. With the recently developed mouse adapted SARS-CoV-2 stain, we are now able to model the mild COVID infection in C57BL/6 mice and study the chronic immune responses and subsequent damages in different organs long after the viruses are clearly naturally in the body. More specifically, we found adult C57BL/6J mice developed neurological impairments, including behavior changes related to sensorimotor coordination, depression- and anxiety-like behaviors, and inflammation in multiple organs including lung, liver and brain, which persisted over at least 4 weeks in mice even with mild infection. Therefore, this model can be used to further explopred the mechanisms of PASC, as well as potential intervention or therapeutic approaches.

neuroscience↗

bioRxiv2024

A polyketide-based biosynthetic platform for diols, amino alcohols and hydroxyacids

Medium- and branched-chain diols and amino alcohols are important industrial solvents, polymer building blocks, cosmetics and pharmaceutical ingredients, yet biosynthetically challenging to produce. Here, we present a novel approach utilising a modular polyketide synthase (PKS) platform for the efficient production of these compounds. This platform takes advantage of a versatile loading module from the rimocidin PKS and NADPH-dependent terminal thioreductases (TRs), previously untapped in engineered PKSs. Reduction of the terminal aldehyde with specific alcohol dehydrogenases enables production of diols, oxidation enables production of hydroxy acids, and transamination with specific transaminases enables production of various amino alcohols. Furthermore, replacement of the malonyl-coenzyme A (CoA)-specific acyltransferase (AT) in the extension module with methyl- or ethylmalonyl- CoA-specific ATs enables production of branched-chain diols and amino alcohols. In total, we demonstrated production of nine 1,3-diols (including the difficult-to-produce insect repellent and cosmetic ingredient 2-ethyl-1,3-hexanediol), six amino alcohols, and two carboxylic acids using our PKS platform in Streptomyces albus. Finally, tuning production of the PKS acyl-CoA substrates enabled production of high titers of specific diols and amino alcohols (1 g/L diol titer in shake flasks), demonstrating high tunability and efficiency of the platform.

bioengineering↗

bioRxiv2024

SARS-COV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice

The coronavirus disease of 2019 (COVID-19) pandemic that has led to more than 700 million confirmed cases and near 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains as an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to the neurological complications both acutely and in long COVID.

neuroscience↗

bioRxiv2023

Place field precision during an episode predicts place field fate across episodes

Spatial memories are represented by hippocampal place cells during navigation. This spatial code is dynamic, undergoing changes across time - known as drift - and across changes in internal state, even while navigating the same spatial environment with consistent behavior. A dynamic spatial code may be a way for the hippocampus to track distinct episodes that occur at different times or during different internal states and update spatial memories. Changes to the spatial code include place fields that remap to new locations and place fields that vanish, while others are stable. However, what determines place field fate across episodes remains unclear. We measured the lap-by-lap properties of place cells in mice during navigation for a block of trials in a rewarded virtual environment. We then had mice navigate the same spatial environment for another block of trials either separated by a day (a distinct temporal episode) or during the same session but with reward removed to change reward expectation (a distinct internal state episode). We found that, as a population, place cells with remapped place fields across episodes had lower spatial precision during navigation in the initial episode. Place cells with stable or vanished place fields generally had higher spatial precision. We conclude that place cells with less precise place fields have greater spatial flexibility, allowing them to respond to, and track, distinct episodes in the same spatial environment, while place cells with precise place fields generally preserve spatial information when their fields reappear.

neuroscience↗

bioRxiv2023

An interpretable ML model to characterize patient-specific HLA-I antigen presentation

Personalized immunotherapy holds the promise of revolutionizing cancer prevention and treatment. However, selecting HLA-bound peptide targets that are specific to patient tumors has been challenging due to a lack of patient-specific antigen presentation models. Here, we present epiNB, a white-box, positive-example-only, semi-supervised method based on Naive Bayes formulation, with information content-based feature selection, to achieve accurate modeling using Mass Spectrometry data eluted from mono-allelic cell lines and patient-derived cell lines. In addition to achieving state-of-the-art accuracy, epiNB yields novel insights into the structural properties, such as interactions of peptide positions, that appear important for modeling personalized, tumor-specific antigen presentation. epiNB uses substantially less parameters than neural networks, does not require hyperparameter tweaking and can efficiently train and run on our web portal (https://epinbweb.streamlit.app/) or a regular PC/laptop, making it easily applicable in translational settings.

bioinformatics↗

bioRxiv2022

Time-resolved transcriptomic profiling of senescence-associated secretory phenotype (SASP) in multiple senescent cell subtypes

Cellular senescence, irreversible cell cycle arrest, is induced by various triggers including telomere shortening, oncogene activation, and DNA damage. Senescent cells exhibit the senescence-associated secretory phenotype (SASP), a pathological feature that contributes to organismal aging. We previously showed that transient plasma membrane damage (PMD) induces a novel subtype of cellular senescence (PMDS) accompanied by SASP, but the overall expression profiles of SASP during PMDS induction was unknown. Here, using mRNA-seq, qPCR, and bioinformatics, we revealed the time-resolved SASP transcriptomic profile in PMDS in comparison with calcium influx-induced senescence, DNA damage response-induced senescence, and replicative senescence. Although the expression of SASP factors was postulated to increase steadily during senescence, we counterintuitively found that the variety of SASP peaks in early PMDS. The pathway comparison analyses and Ingenuity Pathway Analysis suggest that, in early PMDS, wound-healing SASP factors, namely Il-6, Mmp1, and Mmp3, inhibit the GPVI collagen signaling pathway, which in turn further upregulates the same SASP factors, forming a feedback loop. At late senescence, common SASP factors including Il-6 and Ccl2 are upregulated in all senescent cell subtypes. Thus, SASP is diverse at early senescence and becomes relatively uniform at late senescence. Diverse SASP may contribute to senescent cell subtype-specific paracrine/autocrine functions in vivo.

bioinformatics↗

bioRxiv2021

Immunogenic SARS-CoV2 Epitopes Defined by Mass Spectrometry

SARS-CoV-2 infections elicit both humoral and cellular immune responses. For the prevention and treatment of COVID19, the disease caused by SARS-CoV-2, T cell responses are important in mediating recovery and immune-protection. The identification of immunogenic epitopes that can elicit a meaningful T cell response can be elusive. Traditionally, this has been achieved using sophisticated in silico methods to predict putative epitopes; however, our previous studies find that immunodominant SARS-CoV-2 peptides defined by such in silico methods often fail to elicit T cell responses recognizing SARS-CoV-2. We postulated that immunogenic epitopes for SARS-CoV-2 are best defined by directly analyzing peptides eluted from the peptide-MHC complex and then validating immunogenicity empirically by determining if such peptides can elicit T cells recognizing SARS-CoV-2 antigen-expressing cells. Using a tandem mass spectrometry approach, we identified epitopes of SARS-CoV-2 derived not only from structural but also non-structural genes in regions highly conserved among SARS-CoV-2 strains including recently recognized variants. We report here, for the first time, several novel SARS-CoV-2 epitopes from membrane glycol-protein (MGP) and non-structure protein-13 (NSP13) defined by mass-spectrometric analysis of MHC-eluted peptides, provide empiric evidence for their immunogenicity to induce T cell response. Significance StatementCurrent state of the art uses putative epitope peptides based on in silico prediction algorithms to evaluate the T cell response among COVID-19 patients. However, none of these peptides have been tested for immunogenicity, i.e. the ability to elicit a T cell response capable of recognizing endogenously presented peptide. In this study, we used MHC immune-precipitation, acid elution and tandem mass spectrometry to define the SARS-CoV-2 immunopeptidome for membrane glycol-protein and the non-structural protein. Furthermore, taking advantage of a highly robust endogenous T cell (ETC) workflow, we verify the immunogenicity of these MS-defined peptides by in vitro generation of MGP and NSP13 peptide-specific T cells and confirm T cell recognition of MGP or NSP13 endogenously expressing cell lines.

immunology↗

bioRxiv2021

In Silico Defined SARS-CoV2 Epitopes May Not Predict Immunogenicity to COVID19

SARS-CoV-2 infections elicit both humoral and cellular immune responses. For the prevention and treatment of COVID19, the disease caused by SARS-CoV-2, it has become increasingly apparent that T cell responses are equally, if not more important than humoral responses in mediating recovery and immune-protection. One of the major challenges in developing T cell-based therapies for infectious and malignant diseases has been the identification of immunogenic epitopes that can elicit a meaningful T cell response. Traditionally, this has been achieved using sophisticated in silico methods to predict putative epitopes deduced from binding affinities and consensus data. Our studies find that, in contrast to current dogma, immunodominant SARS-CoV-2 peptides defined by such in silico methods often fail to elicit T cell responses recognizing naturally presented SARS-CoV-2 epitopes.

immunology↗

bioRxiv2018

SoS Notebook: An Interactive Multi-Language Data Analysis Environment

MotivationComplex bioinformatic data analysis workflows involving multiple scripts in different languages can be difficult to consolidate, share, and reproduce. An environment that streamlines the entire processes of data collection, analysis, visualization and reporting of such multi-language analyses is currently lacking.\n\nResultsWe developed Script of Scripts (SoS) Notebook, a web-based notebook environment that allows the use of multiple scripting language in a single notebook, with data flowing freely within and across languages. SoS Notebook enables researchers to perform sophisticated bioinformatic analysis using the most suitable tools for different parts of the workflow, without the limitations of a particular language or complications of cross-language communications.\n\nAvailabilitySoS Notebook is hosted at http://vatlab.github.io/SoS/ and is distributed under a BSD license.\n\nContactbpeng@mdanderson.org

bioinformatics↗