Biology subjects

Yu, X.

Publications and source records attributed to Yu, X..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Efficacy and Safety of a novel virulent phage against acute pulmonary infection of Acinetobacter baumanniii in mice

Acinetobacter baumannii (A.baumannii) is a notable opportunistic pathogen responsible for severe hospital-acquired infections, with multidrug-resistant strains posing significant treatment challenges. Phage therapy, which employs bacteriophages as natural bacterial antagonists, has gained renewed attention as a promising solution to combat antibiotic-resistant infections. In this study, we isolated and characterized a novel virulent phage, vB_AbaS_qsb1, which specifically lyses A.baumannii. Phylogenetic and genomic analyses indicate that vB_AbaS_qsb1 is the founding member of a previously unreported genus, which we have named as Acinibactriovirus, with Acinibactriovirus lysinus as the type species. vB_AbaS_qsb1 demonstrated robust stability across diverse temperature and pH ranges, a short latent period, and no known virulence or antibiotic resistance genes within its 54,713 bp dsDNA genome. Safety assessments showed that high-dose vB_AbaS_qsb1 induced no adverse effects in mice, with histopathology confirming its safety profile. Therapeutic experiments further indicated that vB_AbaS_qsb1 provided at least 50% protection against A.baumannii-induced pneumonia, significantly reducing bacterial loads and inflammation markers, while maintaining high phage titers in lung tissue.This study introduces vB_AbaS_qsb1 as a promising candidate for phage therapy against A.baumannii, offering both innovative insights and a valuable framework for future isolation, genomic characterization, and efficacy evaluation of phages targeting antibiotic-resistant bacteria. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/617119v3_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@17bf4cdorg.highwire.dtl.DTLVardef@104c49eorg.highwire.dtl.DTLVardef@89e1dorg.highwire.dtl.DTLVardef@1c4b018_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Bergeyella cardium variant induces unique cytoplasmic vacuolization cell death

Bacterial pathogens have evolved multiple mechanisms to modulate host cell death, evade host immunity, and establish persistent infection. Here, we show that an emerging pathogen Bergeyella cardium variant (BCV) survives serum killing, inducing unique cytoplasmic vacuolization cell death in the majority of cells and apoptosis in a small number of bystanders. The cytoplasmic vacuolization cell death triggered by BCV is characterized by fused lysosome-associated termination and is inhibited by the sodium channel inhibitor amiloride. Endosomal solute carrier family 9 member A9 (SLC9A9) was identified as a critical regulator in the process of BCV-triggered cytoplasmic vacuolization cell death. Moreover, outer membrane vesicles (OMVs) or transfection of barrel-like membrane proteins lipocalin, {beta}-barrel, and PorV dramatically induced cytoplasmic vacuolization. BCV hijacked SLC9A9 by maintaining its high expression, increasing cytoplasmic vacuolization, and enhancing pathogenicity. These findings contribute to the development of novel approaches to modulate cytoplasmic vacuolization cell death and treat infectious diseases. HighlightsO_LIBCV triggers unique cytoplasmic vacuolization cell death. C_LIO_LISLC9A9 is essential for BCV-induced cytoplasmic vacuolization cell death. C_LIO_LIOMVs and the transfection of barrel-like proteins derived from BCV induce cytoplasmic vacuolization cell death. C_LIO_LIBCV increases pathogenicity via cytoplasmic vacuolization cell death. C_LI

cell biology↗

bioRxiv2024

Reduced Hydrogen Sulfide Bioavailability Contributes to Cardiometabolic Heart Failure with Preserved Ejection Fraction

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H2S) in HFpEF. ObjectivesThis study evaluated H2S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H2S on HFpEF severity through alterations in endogenous H2S production and pharmacological supplementation. We also evaluated the effects of the H2S donor, diallyl trisulfide (DATS) in combination with the GLP-1/glucagon receptor agonist, survodutide, in HFpEF. MethodsHFpEF patients and two rodent models of HFpEF ("two-hit" L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H2S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-{gamma}-lyase (EC-CSE) knockout; (2) H2S donor, JK-1, supplementation. DATS and survodutide combination therapy was tested in ZSF1 obese rats. ResultsH2S levels were significantly reduced (i.e., 81%) in human HFpEF patients and in both preclinical HFpEF models. This depletion was associated with reduced CSE expression and activity, and increased SQR expression. Genetic knockout of H2S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H2S supplementation restored H2S bioavailability, improved diastolic function and attenuated cardiac fibrosis corroborating an improved HFpEF phenotype. DATS synergized with survodutide to attenuate obesity, improve diastolic function, exercise capacity, and reduce oxidative stress and cardiac fibrosis. ConclusionsH2S deficiency is evident in HFpEF patients and conserved across multiple preclinical HFpEF models. Increasing H2S bioavailability improved cardiovascular function, while knockout of endogenous H2S production exacerbated HFpEF pathology and mortality. These results suggest H2S dysregulation contributes to HFpEF and increasing H2S bioavailability may represent a novel therapeutic strategy for HFpEF. Furthermore, our data demonstrate that combining H2S supplementation with GLP-1/glucagon receptor agonist may provide synergistic benefits in improving HFpEF outcomes. HighlightsO_LIH2S deficiency is evident in both human HFpEF patients and two clinically relevant models. C_LIO_LIReduced H2S production by CSE and increased metabolism by SQR impair H2S bioavailability in HFpEF. C_LIO_LIPharmacological H2S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models. C_LIO_LITargeting H2S dysregulation presents a novel therapeutic strategy for managing HFpEF. C_LIO_LIH2S synergizes with GLP-1/glucagon agonist and ameliorates HFpEF C_LI

pharmacology and toxicology↗

bioRxiv2024

Coat protein of TCV suppresses RNA decay via ubiquitination and autophagy pathways to facilitate viral infection

Highlight statementThe findings highlight that TCV manipulates 26S proteasome and autophagy pathways to obstruct antiviral RNA decay defenses and ultimately enhance its ability to infect host cells. RNA decay is a pervasive process in eukaryotic cells. Viruses utilize the host cells intracellular machinery to gain access to essential molecules and subcellular structures required for infection during the pathogenesis process. The study demonstrates that turnip crinkle virus (TCV) infection enhances the expression of Arabidopsis Dcp1 (AtDcp1), which negatively regulates the accumulation of TCV RNA, indicating its involvement in antiviral defense. Nevertheless, TCV circumvents the antiviral defense based on RNA decay, as indicated by the capsid protein (CP) of TCV stabilizing the known nonsense-mediated RNA decay targeted transcripts. In vivo, CP physically interacts with AtDcp1, promoting AtDcp1 degradation via ubiquitination and autophagy pathways. This is evidenced by the observation that the degradation is inhibited by both 26S proteasome and autophagy inhibitors. Furthermore, CP elevates the polyubiquitination of Dcp1-Flag and the quantity of pre-autophagosome or autophagosome structures. These data indicate that CP suppresses RNA decay by interacting with AtDcp1 and mediating its degradation through the 26S proteasome and autophagy pathways, effectively subduing antiviral RNA decay. This study uncovers a previously unidentified virulence strategy in the ongoing conflict between plants and viruses.

pathology↗

bioRxiv2024

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG[~]MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation. Significance statementMITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.

cancer biology↗

bioRxiv2024

A single-molecule nanopore sequencing platform

Nanopore sequencing, a third-generation sequencing technology, has revolutionized the gene sequencing industry with its advantages of long reads, fast speed, real-time sequencing and analysis, and potential in detecting base modifications. This technology allows researchers to sequence longer DNA fragments in a single read, providing more comprehensive genomic information compared to previous methods. Nanopore sequencing operates on electrical signals generated by a nanopore embedded in a membrane separating two electrolyte-filled chambers. When single-stranded DNA (ssDNA) passes through the nanopore, it creates variations in the current that correspond to different DNA bases. By analyzing these current fluctuations with machine learning algorithms, the DNA sequence can be determined. In this study, we introduced several improvements to nanopore sequencing, including nanopore local chemistry sequencing, novel motor and pore proteins, chip design, and basecalling algorithms. Our new nanopore sequencing platform, CycloneSEQ, demonstrated long-duration sequencing (107 hours) on a single chip with high yield (>50 Gb). In human genomic DNA sequencing, CycloneSEQ was able to produce long reads with N50 33.6 kb and modal identity 97.0%. Preliminary findings on human whole-genome de novo assembly, variant calling, metagenomics sequencing, and single-cell RNA sequencing have further highlighted CycloneSEQs potential across different areas of genomics.

genomics↗

bioRxiv2024

Bioinspired Bimetallic Ions Functionalized MOF SAzyme Nanocomposites for Synergistic Ferroptosis/Cuproptosis-Enhanced Immune Checkpoint Therapy

Immune checkpoint blockade (ICB) generates sustained responses in immunogenic cancers, but its effectiveness is limited in tumors lacking immune activity. Here, we construct a bioinspired bimetallic ions functionalized nanoscale metal-organic framework (NMOF) single-atom nanozyme (SAzyme) loaded with doxorubicin (Dox) (NMOF-Fe/Cu-Dox nanocomposite) to effectively trigger anti-tumor immune responses while addressing the immunosuppressive tumor microenvironment (TME). The NMOF-Fe/Cu-Dox nanocomposite has been demonstrated to efficiently reverse the TME by generating reactive oxygen species and oxidizing glutathione. Camouflaging NMOF-Fe/Cu-Dox nanocomposites with bioinspired cancer cell membrane (NMOF-Fe/Cu-Dox@M) enables its navigation to the tumor region through homologous targeting. The highly efficient uptaken by cancer cells selectively induced synergistic ferroptosis and cuproptosis in these cells. Furthermore, in vitro and in vivo experiments demonstrate that the ferroptosis in cancer cells can polarize tumor-associated macrophages (TAMs) towards anti-tumoral M1 phenotype and significantly diminish pro-tumoral M2 phenotype. We find that NMOF-Fe/Cu-Dox@M could induce the ferroptosis of M2 macrophages, while no effect to M1 macrophages. In addition, a significant increase of anti-tumor infiltrating CD8+ T cells, while a remarkable decrease of CD4+ regulatory T cells were observed. These findings suggested that NMOF-Fe/Cu-Dox@M could efficiently modulate TME, enhance tumoricidal immunity and elevate the therapeutic efficiency of ICB. Moreover, the combination of NMOF-Fe/Cu-Dox@M with PD-1 effectively eradicated hepatocellular carcinoma cells in vivo, outperforming the use of either NMOF-Fe/Cu-Dox@M or PD-1 alone. In summary, our study presents a therapeutic strategy that leverages coordinated ferroptosis and cuproptosis with therapeutic efficiency of ICB, underscoring the promise of combined chemoimmunotherapy.

bioengineering↗

bioRxiv2024

A novel hybrid Wireless Integrated Sensing Detector for simultaneous EEG and MRI (WISDEM)

Concurrent recording of EEG/fMRI signals reveals cross-scale neurovascular dynamics that are crucial for elucidating fundamental linkage between function and behaviors. However, MRI scanners generate tremendous artifacts for EEG detection. Despite existing denoising methods, cabled connections to EEG receivers are susceptible to environmental fluctuations inside MRI scanners, creating baseline drifts that complicate EEG signal retrieval from the noisy background. Here, a Wireless Integrated Sensing Detector for simultaneous EEG and MRI (WISDEM) is developed to encode fMRI and EEG signals on distinct sidebands of the detectors oscillation carrier wave for detection by a standard MRI console over the entire duration of fMRI sequence. Local field potential (LFP) and fMRI maps are retrieved through low-pass and high-pass filtering of frequency-demodulate signals. From optogenetically-stimulated somatosensory cortex, the positive correlation between evoked LFP and fMRI signals validates strong neurovascular coupling, enabling cross-scale brain mapping with this 2-in-1 transducer as a research and diagnostic tool.

bioengineering↗

bioRxiv2024

Utility of cellular imaging modality in subcellular spatial transcriptomic profiling of tumor tissues

Spatial transcriptomics (ST) technologies, like GeoMx Digital Spatial Profiler, are increasingly utilized to reveal the role of diverse tumor microenvironment components, particularly in relation to cancer progression, treatment response, and therapeutic resistance. However, in many ST studies, the spatial information obtained from immunofluorescence imaging is primarily used for identifying regions of interest, rather than as an integral part of downstream transcriptomic data interpretation. We developed ROICellTrack, a deep learning-based framework, to better integrate cellular imaging with spatial transcriptomic profiling. By examining 56 ROIs from urothelial carcinoma of the bladder (UCB) and upper tract urothelial carcinoma (UTUC), ROICellTrack accurately identified cancer-immune mixtures and associated cellular morphological features. This approach also revealed different sets of spatial clustering patterns and receptor-ligand interactions. Our findings underscore the importance of combining imaging and transcriptomics for comprehensive spatial omics analysis, offering potential new insights into within-sample heterogeneity and implications for targeted therapies and personalized medicine.

bioinformatics↗

bioRxiv2024

A finite set of content-free pointers in visual working memory: MEG evidence

Human visual working memory (VWM) is known to be capacity-limited, but the nature of this limit continues to be debated. Recent work has proposed that VWM is supported by a finite ([~] 3) set of content-free pointers, acting as stand-ins for individual objects and binding features together. Here, based on two visual working memory experiments (N=20 each) examining memory for simple and complex objects, we report a sustained MEG response over right posterior cortex whose magnitude tracks the core hypothesized properties of this system: load-dependent, capacity-limited and content-free. These results provide novel evidence for a finite set of content-free pointers underlying VWM.

neuroscience↗

bioRxiv2024

Chemical Induction of Longevity-Promoting Colanic Acid in the Host's Microbiota

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that specific Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased lifespan in host Caenorhabditis elegans. In the mouse gut, oral administration of low-dose cephaloridine induces the transcription of the capsular biosynthesis operon responsible for CA biosynthesis in commensal E. coli, which overcomes the inhibition of CA biosynthesis above 30{degrees}C and enables its induction directly from the microbiota. Importantly, low-dose cephaloridine induces CA independently of its antibiotic properties through a previously unknown mechanism mediated by the membrane-bound histidine kinase ZraS. Our work lays the foundation for microbiota-based therapeutics through the chemical modulation of bacterial metabolism and reveals the promising potential of bacteria-targeting drugs in promoting host longevity.

developmental biology↗

bioRxiv2024

Nuclear FAK aggravates CD8+ T cell exhaustion via the SP1-IL-6 axis in colorectal cancer

Nuclear abnormalities such as nuclear deformation are hallmarks of many diseases, including cancer. Accumulating evidence suggests that the dense and mechanically stiff tumor microenvironment promotes nuclear deformation in cancer cells. However, little is known about how nuclear deformation in neoplastic cells regulates immune exhaustion in the tumor microenvironment. Here, we found that lamin A/C-mediated nuclear stiffening in neoplastic cells promotes the nuclear translocation of phosphorylated focal adhesion kinase (pFAK), which is strongly correlated with the heterogeneity and exhaustion of CD8+ T cells within the spatial context of the tumor microenvironment in human colorectal cancer. Mechanistically, we revealed that increased nuclear tension within tumor cells promotes pFAK nuclear translocation, where nuclear pFAK was found to regulate SP1/IL-6-mediated T-cell exhaustion and the transcription of proinflammatory cytokines/chemokines. Pharmacological inhibition or disruption of pFAK nuclear translocation enhanced antitumor immune responses and synergistically potentiated PD-1 and TIM-3 immunotherapy by increasing CD8+ T-cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. These findings highlight the pivotal role of nuclear tension-mediated pFAK translocation into the tumor cell nucleus in regulating CD8+ T-cell exhaustion, suggesting that pFAK is a promising target for advancing cancer immunotherapy.

immunology↗

bioRxiv2024

CGPA: multi-context insights from the cancer gene prognosis atlas

Cancer transcriptomic data are used extensively to interrogate the prognostic value of targeted genes, yet basic scientists and clinicians have predominantly relied on univariable survival analysis for this purpose. This method often fails to capture the full prognostic potential and contextual relevance of the genes under study, inadvertently omitting a group of genes we term univariable missed-opportunity prognostic (UMOP) genes. Recognizing the complexity of revealing multifaceted prognostic implications, especially when extending the analysis to include various covariates and thresholds, we present the Cancer Gene Prognosis Atlas (CGPA). This platform greatly enhances gene-centric biomarker research across cancer types by offering an interactive and user-friendly interface for highly customized, in-depth prognostic analysis. CGPA notably supports data-driven exploration of gene pairs and gene-hallmark relationships, elucidating key composite biological mechanisms like synthetic lethality and immunosuppression. It further expands its capabilities to assess multi-gene panels using both public and user-provided data, facilitating a seamless mechanism-to-machine analysis. Additionally, CGPA features a designated portal for discovering prognostic gene modules using curated cancer immunotherapy data. Ultimately, CGPAs comprehensive, accessible tools allow cancer researchers, including those without statistical expertise, to precisely investigate the prognostic landscape of genes, customizing the model to fit specific research hypotheses and enhancing biomarker discovery and validation through a synergy of mechanistic and data-driven strategies. SignificanceCGPA is a streamlined, interactive platform for multi-context gene-centric prognostic analysis, simplifying biomarker discovery and validation in oncology for clinicians and basic scientists, and bridging a critical gap in translational cancer research.

bioinformatics↗

bioRxiv2024

Systematic Multi-Omics Investigation of Androgen Receptor Driven Gene Expression and Epigenetics changes in Prostate Cancer

Background: Prostate cancer, a common malignancy, is driven by androgen receptor (AR) signaling. Understanding the function of AR signaling is critical for prostate cancer research. Methods: We performed multi-omics data analysis for the AR+, androgen-sensitive LNCaP cell line, focusing on gene expression (RNAseq), chromatin accessibility (ATACseq), and transcription factor binding (ChIPseq). High-quality datasets were curated from public repositories and processed using state-of-the-art bioinformatics tools. Results: Our analysis identified 1004 up-regulated and 707 down-regulated genes in response to androgen deprivation therapy (ADT) which diminished AR signaling activity. Gene-set enrichment analysis revealed that AR signaling influences pathways related to neuron differentiation, cell adhesion, P53 signaling, and inflammation. ATACseq and ChIPseq data demonstrated that as a transcription factor, AR primarily binds to distal enhancers, influencing chromatin modifications without affecting proximal promoter regions. In addition, the AR-induced genes maintained higher active chromatin states than AR-inhibited genes, even under ADT conditions. Furthermore, ADT did not directly induce neuroendocrine differentiation in LNCaP cells, suggesting a complex mechanism behind neuroendocrine prostate cancer development. In addition, a publicly available online application LNCaP-ADT (https://pcatools.shinyapps.io/shinyADT/) was launched for users to visualize and browse data generated by this study. Conclusion: This study provides a comprehensive multi-omics dataset, elucidating the role of AR signaling in prostate cancer at the transcriptomic and epigenomic levels. The reprocessed data is publicly available, offering a valuable resource for future prostate cancer research.

cancer biology↗

bioRxiv2024

A pan-cancer gamma delta T cell repertoire

This report presents the largest collection of gamma-delta T cell receptor ({gamma}{delta} TCR) reads in human cancer to date, analyzing about 11,000 patient tumor samples across 33 cancer types using the TRUST4 algorithm. Despite {gamma}{delta} T cells being a small fraction of the T cell population, they play a key role in both innate and adaptive immunity. Our comprehensive analysis reveals their significant presence across all cancer types, specifically highlighting the diverse spectrum and clonality patterns of their {gamma}{delta} receptors. This research highlights the complex roles of {gamma}{delta} T cells in tumor tissues and their potential as prognostic biomarkers. We also demonstrate the utility of T cell receptor gamma (TRG) and delta (TRD) gene expression values from standard RNA-seq data. Ultimately, our work establishes a fundamental resource for future tumor-infiltrating {gamma}{delta} T cell research and may facilitate the development of novel {gamma}{delta}-T-cell-based therapeutic strategies. Together, we demonstrate the strong diversity and prognostic potential of {gamma}{delta} T cells in multiple cancer types. HighlightsComprehensive analysis of {gamma}{delta} TCRs from 11,473 tumor samples Significant variability and overall consistency in {gamma}{delta} gene expression and clonotype {gamma}{delta}TCR expression and diversity as prognostic biomarkers across multiple cancers Centralized {gamma}{delta} TCR repertoire database for future therapeutic discovery

genomics↗

bioRxiv2024

Beyond Auditory Relay: Dissecting the Inferior Colliculus's Role in Sensory Prediction, Cognitive Decision-Making, and Reward Prediction

The Inferior Colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a "climbing effect" in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

neuroscience↗

bioRxiv2024

GPS-Net: discovering prognostic pathway modules based on network regularized kernel learning

The search for prognostic biomarkers capable of predicting patient outcomes, by analyzing gene expression in tissue samples and other molecular profiles, remains largely on single-gene-based or global-gene-search approaches. Gene-centric approaches, while foundational, fail to capture the higher-order dependencies that reflect the activities of co-regulated processes, pathway alterations, and regulatory networks, all of which are crucial in determining the patient outcomes in complex diseases like cancer. Here, we introduce GPS-Net, a computational framework that fills the gap in efficiently identifying prognostic modules by incorporating the holistic pathway structures and the network of gene interactions. By innovatively incorporating advanced multiple kernel learning techniques and network-based regularization, the proposed method not only enhances the accuracy of biomarker and pathway identification but also significantly reduces computational complexity, as demonstrated by extensive simulation studies. Applying GPS-Net, we identified key pathways that are predictive of patient outcomes in a cancer immunotherapy study. Overall, our approach provides a novel framework that renders genome-wide pathway-level prognostic analysis both feasible and scalable, synergizing both mechanism-driven and data-driven for precision genomics.

bioinformatics↗

bioRxiv2024

SmartImpute: A Targeted Imputation Framework for Single-cell Transcriptome Data

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity and tissue transcriptomic complexity. However, the high frequency of dropout events in scRNA-seq data complicates downstream analyses such as cell type identification and trajectory inference. Existing imputation methods address the dropout problem but face limitations such as high computational cost and risk of over-imputation. We present SmartImpute, a novel computational framework designed for targeted imputation of scRNA-seq data. SmartImpute focuses on a predefined set of marker genes, enhancing the biological relevance and computational efficiency of the imputation process while minimizing the risk of model misspecification. Utilizing a modified Generative Adversarial Imputation Network architecture, SmartImpute accurately imputes the missing gene expression and distinguishes between true biological zeros and missing values, preventing overfitting and preserving biologically relevant zeros. To ensure reproducibility, we also provide a function based on the GPT4 model to create target gene panels depending on the tissue types and research context. Our results, based on scRNA-seq data from head and neck squamous cell carcinoma and human bone marrow, demonstrate that SmartImpute significantly enhances cell type annotation and clustering accuracy while reducing computational burden. Benchmarking against other imputation methods highlights SmartImputes superior performance in terms of both accuracy and efficiency. Overall, SmartImpute provides a lightweight, efficient, and biologically relevant solution for addressing dropout events in scRNA-seq data, facilitating deeper insights into cellular heterogeneity and disease progression. Furthermore, SmartImputes targeted approach can be extended to spatial omics data, which also contain many missing values.

bioinformatics↗