Biology subjects

Ou, Y.

Publications and source records attributed to Ou, Y..

34 records · Page 2Linked to original sources

bioRxiv2023

HER2 overexpression initiates breast tumorigenesis non-cell-autonomously by inducing oxidative stress in the tissue microenvironment

HER2 is considered as a driver oncogene responsible for the HER2+ subtype of breast cancer. However, it is still unclear how HER2 induces the oncogenic transformation of breast cancer stem cells (BCSCs) and initiates tumorigenesis during premalignant stage breast cancer. Here, we used clinical samples and mouse models of HER2+ breast cancer to demonstrate that neither BCSCs nor their cell-of-origin express HER2/Neu in early-stage breast tumors. Instead, our results demonstrate that Neu overexpression results in the transformation of BCSCs in a non-cell-autonomous manner via triggering DNA damage and somatic mutagenesis in their Neu-negative cell-of-origin. This is caused by the increased oxidative stress in the tissue microenvironment generated by altered energy metabolism and increased reactive oxygen species levels in Neu-overexpressing mammary ducts. Therefore, our findings illustrate a previously unrecognized mechanism of HER2-induced breast tumor initiation in vivo with potential impacts on future preventive treatments for HER2+ premalignant breast cancer.

cancer biology↗

bioRxiv2023

BOston Neonatal Brain Injury Dataset for HypoxicIschemic Encephalopathy (BONBID-HIE): Part I. MRI and Manual Lesion Annotation

Hypoxic ischemic encephalopathy (HIE) is a brain injury that occurs in 1 [~]5/1000 term neonates. Accurate identification and segmentation of HIE-related lesions in neonatal brain magnetic resonance images (MRIs) is the first step toward predicting prognosis, identifying high-risk patients, and evaluating treatment effects. It will lead to a more accurate estimation of prognosis, a better understanding of neurological symptoms, and a timely prediction of response to therapy. We release the first public dataset containing neonatal brain diffusion MRI and expert annotation of lesions from 133 patients diagnosed with HIE. HIE-related lesions in brain MRI are often diffuse (i.e., multi-focal), and small (over half the patients in our data having lesions occupying <1% of brain volume). Segmentation for HIE MRI data is remarkably different from, and arguably more challenging than, other segmentation tasks such as brain tumors with focal and relatively large lesions. We hope that this dataset can help fuel the development of MRI lesion segmentation methods for HIE and small diffuse lesions in general.

neuroscience↗

bioRxiv2023

Can deep learning predict human intelligence from structural brain MRI?

Can brain structure predict human intelligence? T1-weighted structural brain magnetic resonance images (sMRI) have been correlated with intelligence. Nevertheless, population-level association does not fully account for individual variability in intelligence. To address this, individual prediction studies emerge recently. However, they are mostly on predicting fluid intelligence (the ability to solve new problems). Studies are lacking to predict crystallized intelligence (the ability to accumulate knowledge) or general intelligence (fluid and crystallized intelligence combined). This study tests whether deep learning of sMRI can predict an individual subjects verbal, comprehensive, and full-scale intelligence quotients (VIQ, PIQ, FSIQ), which reflect both fluid and crystallized intelligence. We performed a comprehensive set of 432 experiments, using different input images, six deep learning models, and two outcome settings, on 850 autistic and healthy subjects 6-64 years of age. Results show promise with statistical significance, and also open up questions inviting further future studies.

bioengineering↗

bioRxiv2023

Influence of Demographic, Socio-economic, and Brain Structural Factors on Adolescent Neurocognition: A Correlation Analysis in the ABCD Initiative

The Adolescent Brain Cognitive Development (ABCD) initiative is a longitudinal study aimed at characterizing brain development from childhood through adolescence and identifying key biological and environmental factors that influence this development. The study measures neurocognitive abilities across a multidimensional array of functions, with a focus on the critical period of adolescence during which physical and socio-emotional changes occur and the structure of the cortical and white matter changes. In this study, we perform a correlation analysis to examine the linear relation of adolescent neurocognition functions with the demographic, socio-economic, and magnetic resonance imaging-based brain structural factors. The overall goal is to obtain a comprehensive understanding of how natural and nurtural factors influence adolescent neurocognition. Our results on > 10,000 adolescents show many positive and negative statistical significance interrelations of different neurocognitive functions with the demographic, socioeconomic, and brain structural factors, and also open up questions inviting further future studies.

bioinformatics↗

bioRxiv2022

Development of an affinity-enhanced clinical candidate TCR targeting NY-ESO-1 with optimal potency and high specificity

The clinical success of T-cell receptor (TCR)-based immunotherapy depends on the efficacy and specificity of TCRs. Naturally occurring TCRs have limited anti-tumor potency due to their low affinity for tumor antigens. Affinity enhancement is a promising strategy to generate highly potent TCRs. However, it is concerned that affinity-enhanced TCRs are prone to lose specificity. We isolated low affinity TCRs specific for NY-ESO-1157-165/HLA-A*02:01 from peripheral blood mononuclear cells of healthy donors. An affinity-enhanced TCR candidate with optimal affinity and specificity was generated using phage display and an extensive set of in vitro and in vivo assays. Alanine scanning mutagenesis showed that the TCR candidate retained specificity by making extensive contacts to the side chains of NY-ESO-1157-165 peptide. Adoptive transfer of T cells engineered with this candidate (termed TAEST16001) significantly inhibited tumor growth in subcutaneous, metastatic, and patient-derived xenograft (PDX) mouse tumor models. This study demonstrates that sophisticated engineering and screening techniques can be utilized to generate a clinical candidate TCR with potent anti-tumor activity without losing specificity. TAEST16001 was approved by the Center for Drug Evaluation (CDE) as the first TCR-based immunotherapy clinical trial in China (ClinicalTrials.gov Identifier: NCT03159585).

immunology↗

bioRxiv2022

Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans

Chemokine driven leukocyte recruitment is a key component of the immune response and is central to a wide range of diseases. However, there has yet to be a clinically successful therapeutic approach that targets the chemokine system during inflammatory disease; possibly due to the supposed redundancy of the chemokine system. A range of recent studies have demonstrated that the chemokine system is in fact based on specificity of function. Here we have generated a resource to analyse chemokine gene (ligand and receptor) expression across different species, tissues and diseases; revealing complex expression patterns whereby multiple chemokine ligands that mediate recruitment of the same leukocyte type are expressed in the same context, e.g. the CXCR3 ligands CXCL9, 10 and 11. We use biophysical approaches to show that CXCL9, 10 and 11 have very different interactions with extracellular matrix glycosaminoglycans (GAGs) which is exacerbated by specific GAG sulphation. Finally, in vivo approaches demonstrate that GAG-binding is critical for CXCL9 driven recruitment of specific T cell subsets (e.g. CD4+) but not others (e.g. CD8+), independent of CXCR3 expression. Our data demonstrate that chemokine expression is complex and that multiple ligands are likely needed for robust leukocyte recruitment across tissues and diseases. We also demonstrate that ECM GAGs facilitate decoding of these complex chemokine signals so that they are either primarily presented on GAG-coated cell surfaces or remain more soluble. Our findings represent a new mechanistic understanding of chemokine mediated immune cell recruitment and identify novel avenues to target specific chemokines during inflammatory disease.

immunology↗

bioRxiv2022

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimers disease, wherein the {varepsilon}4 allele confers a dramatically elevated risk compared to the more common {varepsilon}3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without A{beta} accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human A{beta}1-42. In male ApoE3-TR mice, introduction of A{beta} caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of A{beta} had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry an APOE {varepsilon}4 allele. The fact that ApoE4 generally failed to exacerbate the effects of A{beta} on glucose further highlights the growing distinction between the glycemic effects of A{beta} versus those of peripheral insulin resistance.

physiology↗

bioRxiv2022

Generating New Musical Preferences from Hierarchical Mapping of Predictions to Reward

Much of what we know and love about music hinges on our ability to make successful predictions, which appears to be an intrinsically rewarding process. Yet the exact process by which learned predictions become pleasurable is unclear. Here, we created novel melodies in an alternative scale different from any established musical culture, to show how musical preference is generated de novo. Across nine studies (n=1185), participants learned to like more frequently-presented items that adhered to this rapidly-learned structure, suggesting that exposure and prediction errors both affected self-report liking ratings. Learning trajectories varied by music reward sensitivity, but were similar for USA and Chinese participants. Furthermore, fMRI activity in auditory areas reflected prediction errors whereas functional connectivity between auditory and medial prefrontal regions reflected both exposure and prediction errors. Collectively, results support predictive coding as a cognitive mechanism by which new musical sounds become rewarding.

neuroscience↗

bioRxiv2022

The actin nucleator Spire cooperates with Rab11 to initiate nascent dendrite branches.

Dendrites form arbors whose size, shape and complexity define how neurons cover their receptive territories. Actin dynamics contribute to growth and remodeling of dendrite arbors. Here we examined how Spire, a conserved actin nucleation factor, promotes formation of new branches in vivo. In live imaging of Drosophila class IV dendritic arborization (c4da) neurons, Spire was observed at new sites of branch initiation, where it assembled new actin polymer in a burst just prior to filopodial outgrowth. For dendrite arborization, Spire required intact structural domains to nucleate actin and target the secretory network, and interacted with Rab11 GTPase, a key regulator of recycling endosomes. Together, these findings support a model in which Spire cooperates with Rab11 to promote new dendrite branches by linking localized actin dynamics with intracellular trafficking of endosomes that deliver lipids and cargoes to fuel protrusive outgrowth of nascent dendrites.

neuroscience↗

bioRxiv2022

Respiratory mucosal vaccination of peptide-poloxamine-DNA nanoparticles provides complete protection against lethal SARS-CoV-2 challenge

The ongoing SARS-CoV-2 pandemic represents a brutal reminder of the continual threat of mucosal infectious diseases. Mucosal immunity may provide robust protection at the predominant sites of SARS-CoV-2 infection. However, it remains unclear whether respiratory mucosal administration of DNA vaccines could confer protective immune responses against SARS-CoV-2 challenge due to the insurmountable barriers posed by the airway. Here, we applied self-assembled peptide-poloxamine nanoparticles with mucus-penetrating properties for pulmonary inoculation of a COVID-19 DNA vaccine (pSpike/PP-sNp). Not only displays the pSpike/PP-sNp superior gene-transfection and favorable biocompatibility in the mouse airway, but pSpike/PP-sNp promotes a tripartite immunity consisting of systemic, cellular and mucosal immune responses that are characterized by mucosal IgA secretion, high levels of neutralizing antibodies, and resident memory phenotype T-cell responses in the lungs of mice. Most importantly, pSpike/PP-sNp completely eliminates SARS-CoV-2 infection in both upper and lower respiratory tracts and enables 100% survival rate of mice following lethal SARS-CoV-2 challenge. Our findings indicate PP-sNp might be a promising platform in mediating DNA vaccines to elicit all-around mucosal immunity against SARS-CoV-2.

immunology↗

bioRxiv2022

High Frequency of Dynamic Rearrangements in CRISPR Loci

AO_SCPLOWBSTRACTC_SCPLOWCRISPR-Cas immunization of prokaryotes proceeds by the acquisition of short fragments of invading DNA and integrating them into specific positions within the host genome in a process called adaptation. Adaptation is thought to be polarised, which suggests that CRISPR array spacer order reflects the recentness of the infection. The detailed processes through which CRISPR loci arise, and how they evolve are not completely clear. In this study, we collected 12,461 prokaryotic genomes, and using a combination of four different approaches and a series of conservative filters, we identified CRISPR arrays in 82.7% of Archaea and 40.6% of Bacteria. To understand spacer evolution in these CRISPR loci we firstly tracked point mutations in CRISPR repeats, and secondly, we carried out a comparative analysis of arrays that share multiple similar spacers. Both results indicate that CRISPR arrays are frequently dynamically rearranged. These findings are at odds with a model that suggests that spacer order is likely to reflect the recentness of infection. We conclude that the order of spacers in a CRISPR array, as well as the spacer content of the array, is likely to arise from a combination of events, such as insertion in the middle of the array, recombination within or between arrays, or Horizontal transfer of all or part of an array. We suggest these rearrangements are favoured by natural selection in complex and dynamic environments.

evolutionary biology↗

bioRxiv2022

Bioprinting microporous functional living materials from protein-based core-shell microgels

Living materials bring together material science and biology to allow the engineering and augmenting of living systems with novel functionalities. Bioprinting promises accurate control over the formation of such complex materials through programmable deposition of cells in soft materials, but current approaches had limited success in fine-tuning cell microenvironments while generating robust macroscopic morphologies. Here, we address this challenge through the use of core-shell microgel ink to decouple cell microenvironments from the structural shell for further processing. Cells are microfluidically immobilized in the viscous core that can promote the formation of both microbial populations and mammalian cellular spheroids, followed by interparticle annealing to give covalently stabilized functional scaffolds with controlled microporosity. The results show that the core-shell strategy mitigates cell leakage while affording a favorable environment for cell culture. Furthermore, we demonstrate that different microbial consortia can be printed into scaffolds for a range of applications. By compartmentalizing microbial consortia in separate microgels, the collective bioprocessing capability of the scaffold is significantly enhanced, shedding light on strategies to augment living materials with bioprocessing capabilities.

bioengineering↗

bioRxiv2021

Substantia nigra degradation results in widespread changes in medial zona incerta afferent and efferent connectomics

Parkinsons disease (PD) is a complex disease affecting many facets of movement, especially gait abnormalities such as shuffling and freezing of gait. The nigrostriatal pathways of the basal ganglia are traditionally targeted by existing therapies; however, other pathways may be more relevant to gait, such as the pedunculopontine nucleus and the zona incerta (ZI). The A13 nucleus may be such a target as it has emerged as an area of interest in dopamine motor function. Yet, this area remains understudied compared to other dopamine nuclei, especially in animal models of PD. In 6-OHDA mice, we found a reduction in locomotion in the open field and gait dysfunction during treadmill tests. Medial ZI dopamine cells, containing the A13 nucleus, were preserved following 6-OHDA, in contrast to a marked reduction in substantia nigra pars compacta (SNc) neurons. There was extensive remodelling of the A13 afferent and efferent connectome following nigrostriatal lesions. Afferent input patterns displayed a marked reduction in cross-correlation across brain regions in 6-OHDA mice, while efferent projections showed an increase. In a human PD patient with advanced gait dysfunction we found that the A13 nucleus was preserved, suggesting that remodelling could also occur in humans. This work points to the A13 region as a potential therapeutic target in PD. Significance StatementRecently it was found that the medial zona incerta projects to the cuneiform nucleus suggesting a parallel dopaminergic projection onto motor regions. Here we investigated the connectome of the A13 region and examined the afferent and efferent projections in normal mice and mice with a unilateral Parkinsonian mouse model. We found that the connectome was reconfigured following nigrostriatal degeneration. This work provides a comprehensive insight into the plasticity in a dopaminergic-rich area of the zona incerta in PD injury models.

neuroscience↗

bioRxiv2020

Analysis of genetic signatures of tumor microenvironment yields insight into mechanisms of resistance to immunotherapy

BackgroundTherapeutic intervention targeting immune cells have led to remarkable improvements in clinical outcomes of tumor patients. However, responses are not universal. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, due to the lack of appropriate experimental methods, the reason why the immunotherapeutic resistance still existed on the inflamed tumor microenvironment remains unclear. Materials and methodsHere, based on integrated single-cell RNA sequencing technology, we classified tumor microenvironment into inflamed immunotherapeutic responsive and inflamed non-responsive. Then, phenotype-specific genes were identified to show mechanistic differences between distant TME phenotypes. Finally, we screened for some potential favorable TME phenotypes transformation drugs to aid current immunotherapy. ResultsMultiple signaling pathways were phenotypes-specific dysregulated. For example, Interleukin signaling pathways including IL-4 and IL-13 were activated in inflamed TME across multiple tumor types. PPAR signaling pathways and multiple epigenetic pathways were respectively inhibited and activated in inflamed immunotherapeutic non-responsive TME, suggesting a potential mechanism of immunotherapeutic resistance and target for therapy. We also identified some genetic markers of inflamed non-responsive or responsive TME, some of which have shown its potentials to enhance the efficacy of current immunotherapy. ConclusionThese results may contribute to the mechanistic understanding of immunotherapeutic resistance and guide rational therapeutic combinations of distant targeted chemotherapy agents with immunotherapy.

immunology↗

bioRxiv2020

Pan-cancer analysis identified inflamed microenvironment associated multi-omics signatures

BackgroundImmunotherapy has revolutionized cancer therapy. However, responses are not universal. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, how different tumors shape their tumor microenvironment remains a critical unsolved problem. A deeper insight into the molecular characteristics of inflamed tumor microenvironment may be needed. Materials and methodsHere, based on single-cell RNA sequencing technology and TCGA pan-cancer cohort, we investigated multi-omics molecular features of tumor microenvironment phenotypes. Based on single-cell RNA-seq analysis, we classified pan-cancer tumor samples into inflamed or non-inflamed tumor and identified molecular features of these tumors. Analysis of integrating identified gene signatures with a drug-genomic perturbation database identified multiple drugs which may be helpful for converting non-inflamed tumors to inflamed tumors. ResultsOur results revealed several inflamed/non-inflamed tumor microenvironments-specific molecular characteristics. For example, inflamed tumors highly expressed miR-650 and lncRNA including MIR155HG and LINC00426, these tumors showed activated cytokines-related signaling pathways. Interestingly, non-inflamed tumors tended to express several genes related to neurogenesis. Multi-omics analysis demonstrated the neuro phenotype transformation may be induced by hypomethylated promoters of these genes and down-regulated miR-650. Drug discovery analysis revealed histone deacetylase inhibitors may be a potential choice for helping favorable tumor microenvironment phenotype transformation and aiding current immunotherapy. ConclusionOur results provide a comprehensive molecular-level understanding of tumor cell-immune cell interaction and may have profound clinical implications.

immunology↗

bioRxiv2019

Putative protective neural mechanisms in pre-readers with a family history of dyslexia who subsequently develop typical reading skills

Developmental dyslexia is a learning disability characterized by difficulties in word reading. While the prevalence in the general public is around 10-12%, an increased prevalence of 40-60% has been reported for children with a familial risk. Neural atypicalities in the reading network have been observed in children with (FHD+) compared to without (FHD-) a family history of dyslexia, even before reading onset. Despite the hereditary risk, about half of FHD+ children develop typical reading abilities (FHD+Typical) but the underlying neural characteristics and the developmental trajectories of these favorable reading outcomes remain unknown. Utilizing a retrospective, longitudinal approach, this is the first study to examine whether potential protective neural mechanisms are present before reading onset in FHD+Typical. Functional and structural brain characteristics were examined in 69 pre-readers who subsequently developed typical reading abilities (35 FHD+Typical/34 FHD-Typical) using MRI/fMRI. Searchlight-based multivariate pattern analyses identified distinct activation patterns during phonological processing between FHD+Typical and FHD-Typical in right inferior frontal (RIFG) and left temporo-parietal (LTPC) regions. Hypoactivation in LTPC was further demonstrated in FHD+Typical compared to FHD-Typical, suggesting that this previously reported neural characteristic of dyslexia is primarily associated with familial risk. Importantly, FHD+Typical pre-readers exhibited higher activation in RIFG than FHD-Typical, which was associated with increased interhemispheric functional and structural connectivity. These results suggest that putative protective neural mechanisms are already established in FHD+Typical pre-readers and may therefore support their successful reading development. Further studies are needed to investigate the functional significance and developmental trajectories of these neural mechanisms as well as their enabling factors, which has the potential to inform the design of early preventative/remediation strategies.

neuroscience↗