Biology subjects

Ho, L.

Publications and source records attributed to Ho, L..

13 recordsLinked to original sources

bioRxiv2026

A Multi-Omics Study of Cognitive Resilience to Alzheimer's Disease

Alzheimers disease (AD) is the most severe form of dementia. While significant efforts have been made to identify AD risk factors and develop therapeutics, much less attention has been given to neurobiological factors and molecular signatures associated with cognitive resilience. Substantial evidence suggests that modifiable factors, such as physical and mental activity, may contribute to cognitive reserve and resilience. To this end, we developed a resilient cohort of paired genetics, transcriptomics and proteomics data from the prefrontal cortex of 282 cognitively normal older adults. We conducted extensive preprocessing and rigorous quality control (QC), including QC on sequence metrics and sample matching across multiomics. This cohort can be leveraged for identification of molecular signatures of cognitive resilience to AD and is freely shared with the research community.

genomics↗

bioRxiv2026

iPSC Neurodegenerative Disease Initiative isogenic CAG repeat iPSC line for Huntingtons disease

STRUCTURED ABSTRACTO_ST_ABSPurpose of ResearchC_ST_ABSThe generation of iPSC lines expressing 21, 56 and 79 glutamine repeats within the HTT protein and homozygous KO of HTT in the KOLF2.1J background as an additional disease series within the iPSC Neurodegenerative Disease Initiative (iNDI) collection. Major FindingsAll iPSCs, even those expressing long repeats of 79Q or HTT KO, were capable of differentiating to striatal and cortical neurons, astrocytes and microglia using established protocols. General quality control stains and morphological analyses are described for each differentiation. A selected set of assays were carried out on differentiated cells; expanded repeat expressing astrocytes showed altered expression of astrocyte protein markers and morphological characteristics, and striatal neurons showed altered DARPP-32/CTIP2 colocalization. mRNAseq carried out for striatal neurons showed high similarities in gene expression changes between 79Q and KO lines compared to the unexpanded repeat. ConclusionsThe KOLF2.1J isogenic CAG repeat series serves as a community resource to study HD mechanisms with the potential for direct comparison across other neurodegenerative diseases through the iNDI collection.

neuroscience↗

bioRxiv2026

Reduced Complex III assembly dampens host inflammation as an adaptive response to viral infection

Mitochondrial electron transport and oxidative respiration are required for immunity and host tolerance. How the ETC contributes to viral infections - where a proinflammatory anti-viral response needs to be finely balanced with host-protective anti-inflammatory mechanisms - remains unclear. Here, we demonstrate that following infection by H1N1 influenza virus, murine macrophages reduce Complex III levels by downregulating the early CIII assembly factor called the COMB complex. To determine the effect of CIII suppression, we utilized Brawnin (Br or UQCC6) knockout mice, which lack COMB complexes and have reduced Complex III. Following H1N1 infection, Br KO bone marrow-derived macrophages (BMDMs) had reduced inflammation due to reduced CIII Qo site ROS. Br KO mice infected with a non-lethal dose of H1N1 had reduced lung immune pathology, viral burden and enhanced recovery following H1N1 infection. Single-cell RNAseq analysis revealed that H1N1-infected Br KO lungs had reduced abundance of hyper-inflammatory monocytes known to cause severe respiratory disease and reduced monocyte chemotaxis. Our study demonstrates that ETC Complex III suppression is part of an innate immune response to viral infection, and is a potential strategy to control host inflammation in acute respiratory viral infections.

immunology↗

bioRxiv2024

Human brain aging heterogeneity observed from multi-region omics data reveals a subtype closely related to Alzheimer's disease

INTRODUCTION: The interconnection between brain aging and Alzheimers disease (AD) remain to be elucidated. METHODS: We investigated multi-omics (transcriptomics and proteomics) data from multiple brain regions (i.e., the hippocampus (HIPP), prefrontal cortex (PFC), and cerebellum (CRBL)) in cognitively normal individuals. RESULTS: We found that brain samples could be divided into ADL (AD-like) and NL (normal) subtypes which were correlated across brain regions. The differentially expressed genes in the ADL samples highly overlapped with AD gene signatures and the changes were consistent across brain regions (PFC and HIPP) in the multi-omics data. Intriguingly, the ADL subtype in PFC showed more differentially expressed genes than other brain regions, which could be explained by the baseline gene expression differences in the PFC NL samples. DISCUSSION: We conclude that brain aging heterogeneity widely exists, and our findings corroborate with the hypothesis that AD-related changes occur decades before the clinical manifestation of cognitive impairment in a sub-population.

neuroscience↗

bioRxiv2024

Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expression in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.

molecular biology↗

bioRxiv2023

Inhibition of an immunometabolic axis of mTORC1 activation extends mammalian healthspan

Human ageing is associated with metabolic dysfunction, sarcopenia and frailty that taken together reduce healthspan. For age-associated diseases and lifespan, ERK, AMPK and mTORC1 represent critical pathways, across species1-7. Here we examined the hypothesis that IL11, recently shown to regulate ERK/mTORC1, is an inflammaging factor important for healthspan. As mice age, IL11 is progressively upregulated in liver, skeletal muscle, and fat to stimulate an ERK/AMPK/mTORC1 axis of cellular, tissue- and organismal-level ageing pathologies. In old mice, deletion of Il11 or Il11ra1 protects against metabolic multi-morbidity, sarcopenia, and frailty. Administration of anti-IL11 therapy to elderly mice for six months reactivates an age-repressed program of white fat beiging, reverses metabolic dysfunction, restores muscle function, and reduces frailty. Across studies, inhibition of IL11 lowers epigenetic age, reduces telomere attrition, and preserves mitochondrial function. Towards clinical translation, we generated, humanised, and engineered a neutralising, high-affinity IL11 antibody. These studies identify IL11 as a key inflammaging factor and therapeutic target for mammalian healthspan.

molecular biology↗

bioRxiv2023

Hippo Signaling Modulates Mechano-inflammatory Responses of Chondrocytes

Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NF{kappa}B) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NF{kappa}B and induced the expression of NF{kappa}B target genes for inflammation and matrix degradation (i.e., IL1{beta} and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NF{kappa}B pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1{beta} and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NF{kappa}B p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NF{kappa}B p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NF{kappa}B p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NF{kappa}B-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA.

cell biology↗

bioRxiv2023

Permutation-based group sequential analyses for cognitive neuroscience

Cognitive neuroscientists have been grappling with two related experimental design problems. First, the complexity of neuroimaging data (e.g. often hundreds of thousands of correlated measurements) and analysis pipelines demands bespoke, non-parametric statistical tests for valid inference, and these tests often lack an agreed-upon method for performing a priori power analyses. Thus, sample size determination for neuroimaging studies is often arbitrary or inferred from other putatively but questionably similar studies, which can result in underpowered designs - undermining the efficacy of neuroimaging research. Second, when meta-analyses estimate the sample sizes required to obtain reasonable statistical power, estimated sample sizes can be prohibitively large given the resource constraints of many labs. We propose the use of sequential analyses to partially address both of these problems. Sequential study designs - in which the data is analyzed at interim points during data collection and data collection can be stopped if the planned test statistic satisfies a stopping rule specified a priori - are common in the clinical trial literature, due to the efficiency gains they afford over fixed-sample designs. However, the corrections used to control false positive rates in existing approaches to sequential testing rely on parametric assumptions that are often violated in neuroimaging settings. We introduce a general permutation scheme that allows sequential designs to be used with arbitrary test statistics. By simulation, we show that this scheme controls the false positive rate across multiple interim analyses. Then, performing power analyses for seven evoked response effects seen in the EEG literature, we show that this sequential analysis approach can substantially outperform fixed-sample approaches (i.e. require fewer subjects, on average, to detect a true effect) when study designs are sufficiently well-powered. To facilitate the adoption of this methodology, we provide a Python package "niseq" with sequential implementations of common tests used for neuroimaging: cluster-based permutation tests, threshold-free cluster enhancement, t-max, F-max, and the network-based statistic with tutorial examples using EEG and fMRI data.

neuroscience↗

bioRxiv2022

Single-cell Transcriptomic Atlas of the Human Substantia Nigra in Parkinson's Disease

Parkinsons disease (PD) is a common and complex neurodegenerative disorder. Loss of neuromelanin-containing dopaminergic (DA) neurons in the substantia nigra (SN) is a hallmark of PD neuropathology; the etiology of PD remains unclear. Single-cell (-nucleus) RNA sequencing (sc or snRNAseq) has significantly advanced our understanding of neurodegenerative diseases including Alzheimers, but limited progress has been made in PD. Here we generated by far the largest snRNAseq data of high-quality 315,867 nuclei from the human SN including 9 healthy controls and 23 idiopathic PD cases across different Braak stages. Clustering analysis identified major brain cell types including DA neurons, excitatory neurons, inhibitory neurons, glial cells, endothelial, pericytes, fibroblast and T-cells in the human SN. By combining immunostaining and validating against the datasets from independent cohorts, we identified three molecularly distinct subtypes of DA-related neurons, including a RIT2-enriched population, in human aged SN. All DA neuron subtypes degenerated in PD, whereas the composition of non-neuronal cell clusters including major glial types showed little change. Our study delineated cell-type-specific PD-linked gene expression in the SN and their alterations in PD. Examination of cell-type-based transcriptomic changes suggests the complexity and diversity of molecular mechanisms of PD. Analysis of the remaining DA neurons of the three subtypes from PD demonstrated alterations of common gene sets associated with neuroprotection. Our findings highlight the heterogeneity of DA neurons in the human SN and suggest molecular basis for vulnerability and resilience of human DA neurons in PD. Our cohort thus provides a valuable resource for dissecting detailed mechanisms of DA neuron degeneration and identifying new neuroprotective strategies for PD.

neuroscience↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part III: 2D Shape Recognition by Log-Scaling

Human vision has a remarkable ability to recognize complex 3D objects such as faces that appear with any size and 3D orientations at any 3D location. If we initially memorize a face only with a normalized size and viewed from directly head on, the direct comparison between the one-sized memory and a new incoming image would demand tremendous mental frame translations in 7D. How can we perform such a demanding task so promptly and reliably as we experience the objects in the world around us? Intriguingly, our primary visual cortex exhibits a 2D retinotopy with a log-polar coordinate system, where scaling up/down of shape is converted to linear frame translation. As a result, mental scaling can be performed by linearly translating the memory or the perceptual image until they overlap with each other. According to our new model of NHT (Neural Holography Tomography), alpha brainwaves traveling at a constant speed can conduct this linear translation. With this scheme, every scaling up/down by a factor of two should take the same amount of extra mental time to recognize a smaller/larger face. To test this hypothesis, we designed a reaction time (RT) experiment, where participants were first asked to memorize sets of unfamiliar faces with a given specific size (4{degrees} or 8{degrees}). Following the memorization phase, similar stimuli with a wide range of sizes (from 1{degrees} to 32{degrees}) were presented, and RTs were recorded. As predicted, the increase in RT was proportional to the scaling factor in the log scale. Furthermore, we observed that RTs were fastest for 8{degrees} faces even if the memorized face was 4{degrees}. This supports our hypothesis that we always memorize faces at the exact size of ~8 {degrees}. To our surprise, the increases in RT were also consistent with the mentally-estimated depth sensation, which indicates that the apparent size of the recognized face can create a proper depth sensation.

neuroscience↗

bioRxiv2021

CLIPreg: Constructing translational regulatory networks from CLIP-, Ribo- and RNA-seq

MotivationThe creation and analysis of gene regulatory networks have been the focus of bioinformatic research and underpins much of what is known about gene regulation. However, as a result of a bias in the availability of data-types that are collected, the vast majority of gene regulatory network resources and tools have focused on either transcriptional regulation or protein-protein interactions. This has left other areas of regulation, for instance translational regulation, vastly underrepresented despite them having been shown to play a critical role in both health and disease. ResultsIn order to address this we have developed CLIPreg, a package that integrates RNA, Ribo and CLIP-sequencing data in order to construct translational regulatory networks coordinated by RNA-binding proteins. This is the first tool of its type to be created, allowing for detailed investigation into a previously unseen layer of regulation. Availability and implementationCLIPreg is available at https://github.com/SGDDNB/CLIPreg. Contactowen.rackham@duke-nus.edu.sg or sonia.chothani@u.duke.nus.edu

bioinformatics↗

bioRxiv2020

BRAWNIN: A sORF-encoded Peptide Essential for Vertebrate Mitochondrial Complex III Assembly

The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution1,2. Here, we show that the mitochondria proteome is enriched for proteins smaller than 100 a.a. (defined as SEPs). Using a mitochondrial prediction and validation pipeline for small open-reading-frame (sORF)-encoded peptides (SEPs), we report the discovery of 16 endogenous mitochondrial SEPs (mito-SEPs) associated with oxidative phosphorylation (OXPHOS). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN (BR), a 71 amino acid peptide encoded by the C12orf73 gene, is essential for respiratory chain complex III (CIII) assembly. In human cells, BR is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In vivo, BR is enriched in muscle tissues and its maternal zygotic deletion in zebrafish causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BR is essential for oxidative phosphorylation across vertebrate species. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.

cell biology↗

bioRxiv2019

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimers Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

neuroscience↗