Biology subjects

Ni, K.

Publications and source records attributed to Ni, K..

6 recordsLinked to original sources

bioRxiv2023

Robust and Accurate Doublet Detection of Single-Cell Sequencing Data via Maximizing Area Under Precision-Recall Curve

Single-cell sequencing has revolutionized our understanding of cellular heterogeneity by offering detailed profiles of individual cells within diverse specimens. However, due to the limitations of sequencing technology, two or more cells may be captured in the same droplet and share the same barcode. These incidents, termed doublets or multiplets, can lead to artifacts in single-cell data analysis. While explicit experimental design can mitigate these issues with the help of auxiliary cell markers, computationally annotating doublets has a broad impact on analyzing the existing public single-cell data and reduces potential experimental costs. Considering that doublets form only a minor fraction of the total dataset, we argue that current doublet detection methods, primarily focused on optimizing classification accuracy, might be inefficient in performing well on the inherently imbalanced data in the area under the precision-recall curve (AUPRC) metric. To address this, we introduce RADO (Robust and Accurate DOublet detection) - an algorithm designed to annotate doublets by maximizing the AUPRC, effectively tackling the imbalance challenge. Benchmarked on 18 public datasets, RADO outperforms other methods in terms of doublet score and achieves similar performance to the current best methods in doublet calling. Furthermore, beyond its application in single-cell RNA-seq data, we demonstrate RADOs adaptability to single-cell assays for transposase-accessible chromatin sequencing (scATAC-seq) data, where it outperforms other scATAC-seq doublet detection methods. RADOs open-source implementation is available at: https://github.com/poseidonchan/RADO.

bioinformatics↗

bioRxiv2023

Three Conserved Immune Dysfunction and Exclusion Subtypes in Bladder and Pan-cancers: Prognostic and Immunotherapeutic Significance

Molecular subtyping is expected to enable bladder cancer (BC) precise treatment. However, its clinical application remains defective and controversial. Given the significance of tumor immune dysfunction and exclusion (TIDE) in tumor immune escape and immunotherapy, we aimed to develop a novel TIDE-based subtyping method to facilitate personalized management. Transcriptome data of BC was used to evaluate the heterogeneity and the status of TIDE patterns. We identified 69 TIDE biomarker genes and classified BC samples into three subtypes. Subtype I showed the lowest TIDE status and malignancy with the best prognosis and highest sensitivity to immune checkpoint blockade (ICB) treatment, which was enriched of metabolic related signaling pathways. Subtype III represented the highest TIDE status and malignancy with the poorest prognosis and resistance to ICB treatment, resulting from its inhibitory immune microenvironment and T cell terminal exhaustion. Subtype II was in a transitional state with intermediate TIDE level, malignancy, and prognosis. We further confirmed the existence and characteristics of our novel TIDE subtypes using real-world BC samples. This subtyping method was proved to be more efficient than known methods in identifying non-responders to immunotherapy. We also found that combining our TIDE subtypes with known biomarkers can improve the sensitivity and specificity in predicting ICB response. Moreover, besides guiding ICB treatment, this classification approach can assist in selecting the frontline or recommended drugs. Finally, the TIDE subtypes are conserved across pan-tumors. In conclusion, our novel TIDE-based strategy is a powerful clinical tool for BC and pan-cancer patients, and potentially guiding personalized immunotherapy.

bioinformatics↗

bioRxiv2022

Specialized neuronal modules for economic and single-attribute choice in the orbitofrontal cortex

An important component of biological intelligence lies in the capacity to learn and execute various cognitive tasks. This ability may be facilitated by a neural system comprising functionally dissociable neuronal modules. Within the orbitofrontal cortex (OFC) lies a neural circuit that supports economic decision-making across diverse contexts. To investigate the functional specialization of this circuit, we compared the neural activity of OFC neurons in rhesus monkeys during multi-attribute choice (MC) and single-attribute choice (SC) tasks. In MC, the monkeys made subjective tradeoffs between competing attributes, whereas in SC, choices were deterministic based on a single attributes value. Neuronally, in MC, OFC neurons primarily encoded offer value, chosen value, and choice in goods space. Upon transitioning from MC to SC, a significant portion of MC-modulated neurons disengaged, while a separate set of neurons emerged to encode SC-related variables in a spatial reference frame. Notably, we observed the clustering of value-encoding neurons in MC but not SC. In essence, our findings suggest that choice tasks involving different mental processes are represented by dissociable neuronal modules within the OFC.

neuroscience↗

bioRxiv2021

Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo

The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2 phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the derepression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2 axis. Collectively, our findings define the breath and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.

physiology↗

bioRxiv2021

Transiently increased intercommunity regulation characterizes concerted cell phenotypic transition

Phenotype transition takes place in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of expressions of clusters of genes. Through analyzing single cell RNA sequencing data in the framework of transition path theory, we studied how such a genome-wide expression program switching proceeds in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all processes we observed common pattern that the overall effective number and strength of regulation between different communities increase first and then decrease. The change accompanies with similar change of the GRN frustration, defined as overall conflict between the regulation received by genes and their expression states, and GRN heterogeneity. While studies suggest that biological networks are modularized to contain perturbation effects locally, our analyses reveal a general principle that during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming, and canalize to specific cell phenotype as Waddington visioned.

systems biology↗

bioRxiv2021

Assembly status transition offers an avenue for activity modulation of a supramolecular enzyme

Nature has evolved many supramolecular proteins assembled in certain, sometimes even seemingly oversophisticated, morphological manners. The rationale behind such evolutionary efforts is often poorly understood. Here we provide atomic-resolution insights into how the dynamic building of a structurally complex enzyme with higher-order symmetry offers amenability to intricate allosteric regulation. We have established the functional coupling between enzymatic activity and protein morphological states of glutamine synthetase (GS), an old multi-subunit enzyme essential for cellular nitrogen metabolism. Cryo-EM structure determination of GS in both the catalytically active and inactive assembly states allows us to reveal an unanticipated self-assembly-induced dynamics-driven allosteric paradigm, in which the remote interactions between two subcomplex entities significantly rigidify the otherwise structurally fluctuating active sites, thereby regulating activity. We further show in vivo evidences that how the enzyme morphology transitions could be modulated by cellular factors on demand. Collectively, our data present an example of how assembly status transition offers an avenue for allosteric modulation, and sharpens our mechanistic understanding of allostery, dynamics, cooperativity, and other complex functional and regulatory properties of supramolecular enzymes.

biochemistry↗