Biology subjects

Yin, X.

Publications and source records attributed to Yin, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Improving Functional Muscle Regeneration in Volumetric Muscle Loss Injuries by Shifting the Balance of Inflammatory and Pro-Resolving Lipid Mediators

Severe tissue loss resulting from extremity trauma, such as volumetric muscle loss (VML), poses significant clinical challenges for both general and military populations. VML disrupts the endogenous tissue repair mechanisms, resulting in acute and unresolved chronic inflammation and immune cell presence, impaired muscle healing, scar tissue formation, persistent pain, and permanent functional deficits. The aberrant healing response is preceded by acute inflammation and immune cell infiltration which does not resolve. We analyzed the biosynthesis of inflammatory and specialized pro-resolving lipid mediators (SPMs) after VML injury in two different models; muscle with critical-sized defects had a decreased capacity to biosynthesize SPMs, leading to dysregulated and persistent inflammation. We developed a modular poly(ethylene glycol)-maleimide hydrogel platform to locally release a stable isomer of Resolvin D1 (AT-RvD1) and promote endogenous pathways of inflammation resolution in the two muscle models. The local delivery of AT-RvD1 enhanced muscle regeneration, improved muscle function, and reduced pain sensitivity after VML by promoting molecular and cellular resolution of inflammation. These findings provide new insights into the pathogenesis of VML and establish a pro-resolving hydrogel therapeutic as a promising strategy for promoting functional muscle regeneration after traumatic injury.

bioengineering↗

bioRxiv2024

PSMA-specific CAR-engineered macrophages for therapy of prostate cancer

Chimeric antigen receptor (CAR)-modified macrophages (CAR-Ms) are a promising approach for the treatment of solid tumors due to its high infiltration and immune-regulation activity. Prostate cancer is a typical solid tumor associated with highly immunosuppressive microenvironment. To date, the potential application of CAR-M cell therapy in prostate cancer has been infrequently explored. The prostate-specific membrane antigen (PSMA) functions as a specific biomarker for prostate cancer. In this study, we assessed the antitumor efficacy of PSMA-targeted CAR-Ms in preclinical models. CAR-Ms were engineered to express a PSMA-specific single-chain variable fragment (scFv) and co-stimulatory domains. In vitro data demonstrated specific cytotoxicity of CAR-Ms against PSMA-expressing prostate cancer cells, which was further supported by transcriptome analysis demonstrating the pro-inflammatory phenotypes of CAR-Ms. In vivo studies using xenograft mouse models confirmed significant tumor regression after administration of PSMA-targeted CAR-Ms compared to controls. Histopathological analysis showed infiltration of CAR-Ms into tumor tissues without off-target toxicity. These results highlight the strong antitumor activity and safety of PSMA-targeted CAR-Ms, supporting their potential as a new immunotherapy for prostate cancer.

bioengineering↗

bioRxiv2024

Uncovering Individualized Cerebellar Atrophy Pattern and Behavioral Links in Children with Brainstem Tumor

Background and PurposeBrainstem tumors are rare but cause enduring behavioral issues, challenging patients and surgeons. Research on cerebellar changes in these patients limited, despite symptoms similar to cerebellar injuries. This study aims to investigate cerebellar damage pattern resulting from brainstem tumors and its association with behavioral disorders. MethodsIn this study, a U-Net-based segmentation algorithm was used to divide the cerebellum into 26 lobules, which were then used to build a normative model for assessing individual structural deviations. Furthermore, a behavior prediction model was developed using the total outlier count (tOC) index and brain volume as predictive features. ResultsMost patients were found to have negative deviations in cerebellar regions, particularly in anterior lobules like Left V. Higher tOC was significantly associated with severe social problems (r = 0.31, p = 0.001) and withdrawal behavior (r = 0.28, p = 0.001). Smaller size of cerebellar regions strongly correlated with more pronounced social problems (r = 0.27, p = 0.007) and withdrawal behavior (r = 0.25, p = 0.015). Notably, lobules Right X, V, IV, VIIB, Left IX, VIII, and X influenced social problems, while Left V, Right IV, Vermis VI, and VIII impacted withdrawal behavior. ConclusionsOur study revealed cerebellar damage patterns in patients with brainstem tumors, emphasizing the role of both anterior and posterior cerebellar lobes in social problems and withdrawal behavior. This research sheds light on the brain mechanisms underlying complex behavioral disorders in brainstem tumor patients.

neuroscience↗

bioRxiv2024

Normative Growth Modeling of Cortical Thickness Identify Neuroanatomical Variability and Distinct Subtypes in Brainstem Tumor Patients

BackgroundBrainstem tumors can cause structural brain changes, but the resulting heterogeneity within wholebrain structure is not well-studied. This study examines cortical thickness to identify patterns of structural alterations and explore underlying biological subtypes and their associations with clinical factors. Materials and MethodsThis study involved 124 pediatric brainstem tumor patients, aged 4-18 years. Cortical thickness was measured using CAT12 segmentation of 3D T1-weighted structural MRI. A normative model was established using data from 849 healthy children. Deviations in cortical thickness were estimated, and patients were classified into two subtypes using spectral clustering. Clinical statistical analyses were conducted with SPSS 26.0. ResultsThe normative model revealed significant heterogeneity in cortical thickness deviations, which correlated with tumor size and growth patterns. Focal tumors primarily caused negative deviations (t = 3.14, p = 0.02). There was a significant positive correlation between extreme positive deviations and tumor volume (r = 0.214, p = 0.010), and between extreme negative deviations and progression-free survival (r = 0.39, p = 0.008). Two subtypes were identified: Subtype 1, consisting of diffuse tumors with extreme positive deviations, and Subtype 2, consisting of focal tumors with extreme negative deviations. Subtype and tumor growth pattern significantly influenced duration (p < 0.01). The Kaplan-Meier survival curves for Subtype 1 and Subtype 2 demonstrated a significant difference in survival probabilities over time (p = 0.03). ConclusionOverall, this study identifies two major patterns of cortical thickness changes in brainstem tumor patients, enhancing our understanding of their relationship with cortical morphology. The findings suggest that cortical thickness alterations could serve as valuable biomarkers for predicting progression-free survival, which is crucial for clinical assessment and personalized treatment strategies. This research provides new insights into the physiological mechanisms by which brainstem tumors affect brain structure, supporting more precise clinical interventions and efficacy monitoring in the future.

neuroscience↗

bioRxiv2024

Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication

Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased towards the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published datasets to reveal pathways supported by orthogonal datasets, including transcriptional regulation, epigenetic modifications, and MAPK signalling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 27 proteins that were determined to impact assembly and release. Additionally, a subset of proteins were tested across other coronaviruses revealing 17 potential pan-coronavirus targets. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry, and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.

systems biology↗

bioRxiv2024

Multi-omics reveals AKR1B1-regulated galactose metabolic as a driver of gastrointestinal stromal tumor progression

The underlying mechanism of malignant progression in gastrointestinal stromal tumors (GISTs) is not fully understood. Despite recent advancements, a comprehensive profile of metabolome, transcriptome, and proteome of GISTs is lacking. This study conducted an integrated multi-omics analysis of GISTs across different risk classifications. By integrating metabolomics, transcriptomics, and proteomics, we identify distinct metabolic patterns and associated biological pathways implicated in the malignant progression of GISTs. Moreover, we identified galactose metabolism and the pivotal rate-limiting enzyme AKR1B1 is dysregulated in GISTs progression. AKR1B1 was upregulated and predicted poor prognosis in GISTs. In addition, AKR1B1 knockdown resulted in trehalose accumulation in GIST cells, thereby inhibiting cell proliferation and mitosis. These findings not only enhance our comprehension of the underlying mechanisms governing GIST progression from a metabolic reprogramming standpoint but also furnish prognostic biomarkers and potential therapeutic targets for GISTs.

cancer biology↗

bioRxiv2024

Targeting oncogenic K-Ras mutants with a small-molecule degrader through Nedd4-1

K-Ras mutations represent a most prevalent oncogenic alteration in human cancers. Despite of tremendous efforts, it remains a big challenge to develop inhibitors that can target the oncogenic K-Ras mutants, especially mutants without specific active or charged side chains such as K-RasG12V. Here, taking advantage of our previous finding that Nedd4-1 is a bona fide E3 ubiquitin ligase for wild-type Ras proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-Ras mutants including K-RasG12V, and significantly inhibit proliferation and tumor development of K-Ras mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of Nedd4-1 and an allosteric site of K-Ras to enhance Nedd4-1 and K-Ras interaction, and to induce a conformational change of Nedd4-1/K-Ras complex to allow Nedd4-1 targeting K128 of K-Ras for ubiquitination. Hence, our study presents a robust strategy to develop small-molecule degrader of K-Ras mutants, and also sheds light on the development of small-molecule degraders for H-Ras and N-Ras mutants.

cancer biology↗

bioRxiv2024

DeepGene: An Efficient Foundation Model for Genomics based on Pan-genome Graph Transformer

Decoding the language of DNA sequences is a fundamental problem in genome research. Mainstream pre-trained models like DNABERT-2 and Nucleotide Transformer have demonstrated remarkable achievements across a spectrum of DNA analysis tasks. Yet, these models still face the pivotal challenge of (1) genetic language diversity, or the capability to capture genetic variations across individuals or populations in the foundation models; (2) model efficiency, specifically how to enhance performance at scalable costs for large-scale genetic foundational models; (3) length extrapolation, or the ability to accurately interpret sequences ranging from short to long within a unified model framework. In response, we introduce DeepGene, a model leveraging Pan-genome and Minigraph representations to encompass the broad diversity of genetic language. DeepGene employs the rotary position embedding to improve the length extrapolation in various genetic analysis tasks. On the 28 tasks in Genome Understanding Evaluation, DeepGene reaches the top position in 9 tasks, second in 5, and achieves the overall best score. DeepGene outperforms other cutting-edge models for its compact model size and superior efficiency in processing sequences of varying lengths. The datasets and source code of DeepGene are available at GitHub (https://github.com/wds-seu/DeepGene).

bioinformatics↗

bioRxiv2024

Rapid, simultaneous increases in the effective sizes of adaptively divergent yellow perch (Perca flavescens) populations

Aquatic ecosystems are highly dynamic environments vulnerable to natural and anthropogenic disturbances. High-economic value fisheries are one of many ecosystem services affected by these disturbances and it is critical to accurately characterize the genetic diversity and effective population sizes of valuable fish stocks through time. We used genome-wide data to reconstruct the demographic histories of economically important yellow perch (Perca flavescens) populations. In two isolated and genetically divergent populations, we provide independent evidence for simultaneous increases in effective population sizes over both historic and contemporary time scales including negative genome-wide estimates of Tajimas D, 3.1 times more SNPs than adjacent populations, and contemporary effective population sizes that have increased 10- and 47-fold from their minimum, respectively. The excess of segregating sites and negative Tajimas D values likely arose from mutations accompanying historic population expansions with insufficient time for purifying selection, whereas linkage disequilibrium-based estimates of Ne also suggest contemporary increases that may have been driven by reduced fishing pressure or environmental remediation. We also identified parallel, genetic adaptation to reduced visual clarity in the same two habitats. These results suggest that the synchrony of key ecological and evolutionary processes can drive parallel demographic and evolutionary trajectories across independent populations.

evolutionary biology↗

bioRxiv2024

Distinct Type 1 Immune Networks Underlie the Severity of Restrictive Lung Disease after COVID-19

The variable etiology of persistent breathlessness after COVID-19 have confounded efforts to decipher the immunopathology of lung sequelae. Here, we analyzed hundreds of cellular and molecular features in the context of discrete pulmonary phenotypes to define the systemic immune landscape of post-COVID lung disease. Cluster analysis of lung physiology measures highlighted two phenotypes of restrictive lung disease that differed by their impaired diffusion and severity of fibrosis. Machine learning revealed marked CCR5+CD95+ CD8+ T-cell perturbations in mild-to-moderate lung disease, but attenuated T-cell responses hallmarked by elevated CXCL13 in more severe disease. Distinct sets of cells, mediators, and autoantibodies distinguished each restrictive phenotype, and differed from those of patients without significant lung involvement. These differences were reflected in divergent T-cell-based type 1 networks according to severity of lung disease. Our findings, which provide an immunological basis for active lung injury versus advanced disease after COVID-19, might offer new targets for treatment.

immunology↗

bioRxiv2024

Integrative analysis of the genome, transcriptome, and proteome identifies causal mechanisms of complex traits.

We present multi-integration of transcriptome-wide association studies and colocalization (Multi-INTACT), an algorithm that models multiple gene products (e.g. encoded RNA transcript and protein levels) to implicate causal genes and relevant gene products. In simulations, Multi-INTACT achieves higher power than existing methods, maintains calibrated false discovery rates, and detects the true causal gene product(s). We apply Multi-INTACT to GWAS on 1,408 metabolites, integrating the GTEx expression and UK Biobank protein QTL datasets. Multi-INTACT infers 52% to 109% more metabolite causal genes than protein-alone or expression-alone analyses and indicates both gene products are relevant for most gene nominations.

bioinformatics↗

bioRxiv2024

Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy

The efficacy of FDA-approved tyrosine kinase inhibitors (TKIs) targeting EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment. This study aimed to investigate the impact of the glycolytic regulator 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the metabolic adaptivity of lung cancer cells to EGFR TKI therapies. Using two EGFR-driven non-small cell lung cancer cell lines, PC9 and HCC827, we analyzed metabolic changes in cells exposed to EGFR inhibitors and evaluated the effect of PFKFB3 inhibition on metabolic adaptations during TKI treatment. Our results indicate that PFKFB3-mediated glycolysis sustains ATP production upon TKI treatment. Metabolomics studies revealed that PFKFB3 inhibition in TKI-treated cells limits glucose utilization in glycolysis, TCA cycle, and polyol pathway. Additionally, we show that pharmacological inhibition of PFKFB3 overcomes TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), which in turn, exacerbates oxidative stress. Our study also revealed that PFKFB3 contributes to DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. In TKI-treated cells, PFKFB3 inhibition reduced ATM expression and limited DNA damage repair, increasing sensitivity to DNA integrity insults. In summary, our results suggest that inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR-TKI therapy before they enter the drug-resistant state. STATEMENT OF IMPLICATIONTargeting PFKFB3 can improve the efficacy of EGFR-targeting TKIs by restricting non-genetic adaptations embraced by drug-tolerant cells.

cancer biology↗

bioRxiv2024

Enolase inhibitors as therapeutic leads for Naegleria fowleri infection

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate that these agents are potent inhibitors of N. fowleri ENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50 value of 0.14 {+/-} 0.04 {micro}M) that was toxic to trophozoites (EC50 value of 0.21 {+/-} 0.02 {micro}M) while the reported CC50 was >300 {micro}M. Molecular docking simulation revealed that HEX binds strongly to the active site of NfENO with a binding affinity of -8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of NfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the conclusion of the experiment, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. Brains of six of the eight survivors were positive for amoebae, suggesting the agent at the tested dose suppressed, but did not eliminate, infection. These findings suggest that HEX is a promising lead for the treatment of PAM.

biochemistry↗

bioRxiv2023

Chlamydial protease-like activating factor targets SLC7A11 for degradation to induce ferroptosis and facilitate dissemination.

Chlamydia trachomatis, the most prevalent bacterial agent of sexually transmitted infections, possesses remarkable capacities for dissemination within the host, leading to reproductive health complications. The release of progeny through the orchestrated lysis of host cells plays a crucial role in Chlamydia dissemination, but the underlying molecular mechanisms remain largely elusive. Here, we uncovered a novel mechanism by which Chlamydia induces host cells ferroptosis to facilitate its dissemination. This process involves the degradation of host protein SLC7A11 by the chlamydial protease-like activating factor (CPAF), resulting in glutathione depletion, oxidative damage, and subsequent host cell lysis characterized by lipid peroxidation. Infection with CPAF-deficient strain fails to induce host cells ferroptosis, leading to restricted progeny release. Importantly, inhibiting ferroptosis effectively limits the release of Chlamydia progeny, highlighting its potential as a therapeutic strategy for controlling Chlamydia dissemination. These findings provide insights into the chlamydial conserved dissemination strategy and enhance understanding of its pathogenesis.

microbiology↗

bioRxiv2023

Melon: metagenomic long-read-based taxonomic identification and quantification using marker genes

Long-read sequencing holds great potential for characterizing complex microbial communities, yet taxonomic profiling tools designed specifically for long reads remain lacking. Here we introduce Melon, a novel marker-based taxonomic profiler that capitalizes on the unique attributes of long reads. Melon employs a two-stage classification scheme to reduce computational time and is equipped with an expectation-maximization-based post-correction module to handle ambiguous reads. Melon achieves superior performance compared to other existing tools in both mock and simulated samples. Using wastewater metagenomic samples, we demonstrate the applicability of Melon by showing it is capable in providing reliable estimates of overall genome copies, and species-level taxonomic profiles.

bioinformatics↗

bioRxiv2023

DNA origami assembled spheroid for evaluating cytotoxicity and infiltration of chimeric antigen receptor macrophage (CAR-M)

Chimeric antigen receptor (CAR) T-cell therapies have shown remarkable results in patients with hematological malignancies. However, their success in treating solid tumors has been limited. As an alternative candidate for the CAR approach, CAR-macrophages (CAR-M) have demonstrated activation and phagocytosis directed by tumor antigens, showing promise in the treatment of solid tumors. Nevertheless, the mechanisms by which CARs direct tumor chemotaxis and invasion of CAR-M remain poorly understood. In this study, we aim to investigate the role of CARs in CAR-M attachment and infiltration using 3D tumor micro-spheroids, which were created by utilizing a novel nucleic acid nanostructures decorated living cells (NACs) based origami assembly technique. First, the effectiveness of phagocytosis and killing conducted by CAR-M was validated in the conventional 2D well/plate-surface culture models. Then,peripheral blood mononuclear cell (PBMC) invasion assay confirmed that the 3D tumor micro-spheroids were feasible for cell invasion. Finally, our results demonstrated that CAR-M exhibited higher invasion and killing capacity in 3D tumor micro-spheroids. In summary, the 3D NACs-origami assembled tumor spheroid model provides a suitable platform for target screening and pharmacodynamic evaluation of CAR-M.

bioengineering↗

bioRxiv2023

Gain of function in linc-133 compensates for daf-18/PTEN loss and rescues survival

DAF-18, homology of PTEN, possess tumor suppressor activity. Loss of daf-18 causes cell growth in L1 diapause C. elegans is well studied; however, the reason why survival is dramatically shortened is not well elaborated. We found that linc-133 gain of function can fully restore the shortened survival caused by daf-18 loss. When lipid phosphatase activity of DAF-18 is defective, the linc-133 gain of function interacts with 14-3-3 proteins to obstruct DAF-16 translocation from the nucleus to the cytoplasm. However, the dysfunction of protein phosphatase activity of DAF-18 caused high levels of aggregated proteins. The linc-133 gain of function can induce HSP chaperones to select and process the aggregated proteins for degradation through ubiquitination. Our work demonstrates that protein homeostasis controlled by the protein phosphatase activity of DAF-18 is the main factor affecting survival and identifies a new function of the linc-133 gene, which can compensate for the loss of daf-18.

genetics↗

bioRxiv2023

Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury.

Mitochondrial ion channels are essential for energy production and cell survival. To avoid depleting the electrochemical gradient used for ATP synthesis, channels so far described in the mitochondrial inner membrane open only briefly, are highly ion-selective, have restricted tissue distributions, or have small currents. Here, we identify a mitochondrial inner membrane conductance that has strikingly different behavior from previously described channels. It is expressed ubiquitously, and transports cations non-selectively, producing a large, up to nanoampere-level, current. The channel does not lead to inner membrane uncoupling during normal physiology because it only becomes active at depolarized voltages. It is inhibited by external Ca2+, corresponding to the intermembrane space, as well as amiloride. This large, ubiquitous, non-selective, amiloride-sensitive (LUNA) current appears most active when expression of the mitochondrial calcium uniporter is minimal, such as in the heart. In this organ, we find that LUNA current magnitude increases two- to threefold in multiple mouse models of injury, an effect also seen in cardiac mitochondria from human patients with heart failure with reduced ejection fraction. Taken together, these features lead us to speculate that LUNA current may arise from an essential protein that acts as a transporter under physiological conditions, but becomes a channel under conditions of mitochondrial stress and depolarization.

cell biology↗