Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiati...
Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9-based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.
Cholera is a highly contagious and lethal waterborne disease induced by an infection with Vibrio cholerae (V. cholerae) secreting cholera toxin (CTx). Cholera toxin subunit B (CTxB) from the CTx specifically binds wit...
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Preservation of executive function, like inhibition, closely links to the quality of life in senior adults. Although neuroimaging literature has shown enhanced inhibitory function followed by aerobic exercise, current...
Preservation of executive function, like inhibition, closely links to the quality of life in senior adults. Although neuroimaging literature has shown enhanced inhibitory function followed by aerobic exercise, current evidence implies inconsistent neuroplasticity patterns along different time durations of exercise. Hence, we conducted a 12-week exercise intervention on 12 young and 14 senior volunteers and repeatedly measured the inhibitory functionality of distinct aspects (facilitation and interference effects) using the numerical Stroop task and functional Magnetic Resonance Imaging. Results showcased improved accuracy and reduced reaction times (RT) after 12-week exercise, attributed to frontoparietal and default mode network effects. In young adults, the first phase (0 to six weeks) exercise increased the activation of the right superior medial frontal gyrus, associated with reduced RT in interference, but in the second intervention phase (six to twelve weeks), the decreased activation of the left superior medial frontal gyrus positively correlated with reduced RT in facilitation. In senior adults, the first six-week intervention led to reduced activations of the inferior frontal gyrus, inferior parietal gyrus, and default mode network regions, associated with the reduced RT in interference. Still, in the second intervention phase, only the visual area exhibited increased activity, associated with reduced RT in interference. Except for the distinctive brain plasticity between the two phases of exercise intervention, the between-group comparison also presented that the old group gained more cognitive benefits within the first six weeks of exercise intervention;however, the cognitive improvements in the young group occurred after six weeks of intervention. Limited by the sample size, these preliminary findings corroborated the benefits of aerobic exercise on the inhibitory functions, implying an age × exercise interaction on the brain plasticity for both facilita
In this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type...
In this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type (WT) samples are available. Without using any information from real KO samples, GenKI is designed to capture shifting patterns in gene regulation caused by the KO perturbation in an unsupervised manner and provide a robust and scalable framework for gene function studies. To achieve this goal, GenKI adapts a variational graph autoencoder (VGAE) model to learn latent representations of genes and interactions between genes from the input WT scRNA-seq data and a derived single-cell gene regulatory network (scGRN). The virtual KO data is then generated by computationally removing all edges of the KO gene-the gene to be knocked out for functional study-from the scGRN. The differences between WT and virtual KO data are discerned by using their corresponding latent parameters derived from the trained VGAE model. Our simulations show that GenKI accurately approximates the perturbation profiles upon gene KO and outperforms the state-of-the-art under a series of evaluation conditions. Using publicly available scRNA-seq data sets, we demonstrate that GenKI recapitulates discoveries of real-animal KO experiments and accurately predicts cell type-specific functions of KO genes. Thus, GenKI provides an in-silico alternative to KO experiments that may partially replace the need for genetically modified animals or other genetically perturbed systems.
Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including c...
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Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have divergent effects on the tumor microenvironment, immune response, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug-response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, additive compound pairs with distinct growth/death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.
Pseudomonas aeruginosa is a widespread pathogen known to cause infections in various hosts, particularly threatening immunocompromised patients. Although determining antibiotic sensitivity is crucial for appropriate p...
Pseudomonas aeruginosa is a widespread pathogen known to cause infections in various hosts, particularly threatening immunocompromised patients. Although determining antibiotic sensitivity is crucial for appropriate patient care, existing diagnostic methods remain time-consuming, which can delay targeted therapy. In this study, we propose a novel, interpretable, and cost-effective framework that combines ultraviolet-visible-near-infrared (UV–Vis-NIR) spectroscopy with subgroup discovery and a one-vs-all multilayer perceptron (MLP) model to predict antibiotic sensitivity without the need for traditional culture methods. Unlike prior approaches that depend on expensive instruments or black-box algorithms, our method leverages spectral pattern interpretability to identify key wavelength features associated with distinct resistance categories. Testing on clinical isolates of P. aeruginosa , the model achieved optimal prediction accuracy within 10 min of culture time, significantly reducing the typical 48–72 h turnaround time of conventional culture-based susceptibility testing. This work demonstrates a promising direction for rapid, low-cost, and clinically actionable antimicrobial susceptibility testing that balances performance with explainability.
Single-cell multi-omics is a transformative technology that measures both gene expression and chromatin accessibility in individual cells. However, most studies concentrate on a single tissue and are unable to determi...
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Vascular complications are responsible for most of the morbidity and mortality in diabetic patients. Effective strategies to improve circulation appear to be another important issue in addition to the interventions of...
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Infectious disease threats to individual and public health are numerous, varied and frequently unexpected. Artificial intelligence (AI) and related technologies, which are already supporting human decision making in e...
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