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Phytopathogenic bacteria rely on type III effectors to suppress host immunity and facilitate colonization. While necessary for virulence, effectors can also trigger effector-triggered immunity (ETI) if hosts have appropriate NLR immune receptors, resulting in a coevolutionary arms races driving high diversity in both the pathogen "effectorome" and the host "NLRome." Here, we synthesize current knowledge of effectoromes into an "interconnected module model", that emphasizes how functional...

Ubiquitin-Specific Protease 18 (USP18) is a deISGylation enzyme and antineoplastic target. To develop USP18 inhibitors, an enzymatically active human recombinant USP18 protein was engineered suitable for high-throughput screening of ~80,000 chemical compounds. Three of them substantially inhibited USP18 enzymatic activity with β-lapachone having prominent antineoplastic activity. Independent β-lapachone treatments of murine and human lung cancer cell lines statistically-significantly reduced...

The Hippo signaling pathway, first identified in Drosophila, is a conserved regulator of organ size and tissue homeostasis that balances proliferation and apoptosis. In mammals, its core kinases mammalian Sterile 20-like kinases 1 and 2 (MST1/2) and large tumor suppressor kinases 1 and 2 (LATS1/2) restrict the transcriptional coactivators Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), whose nuclear translocation drives cell proliferation and...

Polycomb repressive complex 2 (PRC2)-mediated histone H3 K27 trimethylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, Polycomb-regulated genes can display long-range three-dimensional interactions, many of which resolve during lineage differentiation. Here we report that Polycomb-anchored looping is controlled by H3K27me3 spreading and regulates target gene silencing to influence cell fate specification. Using glioma-derived H3 Lys27-to-Met...

Intrinsically disordered regions (IDRs) represent at least one-third of the human proteome and defy the established structure-function paradigm. Because IDRs often have limited positional sequence conservation, the functional classification of IDRs using standard bioinformatics is generally not possible. Here, we show that evolutionarily conserved molecular features of IDRs enable clustering of the human disordered proteome (IDRome) into a map with strong functional enrichments. We quantify how...

Anaplastic thyroid cancer (ATC) is highly lethal. Although patients with the BRAF^(V600E) alteration respond to the type I RAF inhibitor (RAFi) dabrafenib with trametinib, most rapidly develop adaptive or acquired resistance. Here, multi-region whole-genome, high-coverage whole-exome, and single-nuclei RNA sequencing of tumors from ATC patients undergoing type I RAFi and MEKi therapy reveals that reactivation of the mitogen-activated protein kinase (MAPK) pathway, along with immunosuppressive...

The human coronavirus HCoV-OC43 (OC43) is the most widespread of the four common cold-causing seasonal coronaviruses, and tissue culture-adapted strains of it have been used for ~50 years. Nevertheless, clinical isolates of OC43 differ from tissue culture-adapted OC43 in ways that call into question the value of the latter as a model. Among these are differences in their entry mechanisms and the activities of their hemagglutinin-esterases (HE). We now show that the spike proteins of OC43...

CONCLUSIONS: We identified a significant serological benefit of SCV2 vaccination relative to infection, in terms of antibody avidity, level, and durability. These data can support clinicians in making evidence-based vaccine recommendations for children with ALL.

Episignatures are increasingly valuable for variant interpretation in rare neurodevelopmental disorders, especially when optimized to capture the impact of specific variant types and locations across a gene. Here, we generated a next-generation DNA methylation (DNAm) episignature for Kabuki syndrome type 1 (KS1) using the largest cohort studied to date, aiming to clarify the epigenomic and phenotypic effects of diverse KMT2D variant types and positions. Genome-wide DNAm profiles were obtained...

PER: and polyfluoroalkyl substances (PFAS) are persistent contaminants frequently detected in surface waters, yet their behavior in cold-region river basins remains insufficiently characterized. In this study, 26 PFAS were measured in river water and sediments at 27 sites across the Songhua River Basin, Northeast China, during warm and cold seasons. The objectives were to characterize PFAS occurrence, evaluate spatial and seasonal variability at the basin scale, examine sediment-water...

In this study, for the first time, the distribution and fractionation of persistent organic pollutants (POPs) along both latitudinal and longitudinal transects are investigated simultaneously in surface soil. Distributions and fractionations of two isomers of hexachlorocyclohexane (HCH), α- and β-HCH, were analyzed in Chinese rural surface soil using a set of soil samples collected in 2005, 2012, and 2019 to study the lifecycle of the global/latitudinal fractionation of POPs. The primary...

Genetic variants produce complex phenotypic effects that confound current assays and predictive models. We developed variant in situ sequencing (VIS-seq), a pooled, image-based method measuring variant effects on molecular and cellular phenotypes in diverse cell types. Applying VIS-seq to ∼3,000 LMNA and PTEN variants yielded high-dimensional morphological profiles capturing changes in protein abundance, localization, activity, and cell architecture. VIS-seq identified a subset of...

Spontaneous fluctuations in attention can impede adaptation to changing goals and environments. Endogenous control over attentional shifts, referred to as attentional flexibility, is prone to disruption in children with attention deficit disorders. Here we studied in vivo intracranial recordings in children with epilepsy to identify a reproducible neural signature of attentional control that could predict and prevent impending lapses in real time. Machine learning classifiers were trained on...

There are around 100 genes or copy-number variations used in genetic testing for autism spectrum disorder (ASD)^(1,2). The established genes are protein coding, and the associated phenotypes usually extend beyond sociobehavioural traits seen in autism, including cognitive/medical complexities and attention deficit hyperactivity disorder (ADHD)^(3,4). We examined whole-genome sequencing data in cases of ASD (9,349) and controls (8,332) and identify 27 male individuals with ASD with X-chromosome...

Reactive oxygen species (ROS) burst and subsequent recruitment to the ischemic brain characterize neutrophil activation in the hyperacute phase of ischemic stroke, yet the underlying metabolic drivers remain elusive. Here, we report that neutrophil-intrinsic chemokine-like factor 1 (CKLF1) acts as a key immunometabolic regulator following stroke. CKLF1 was rapidly upregulated in neutrophils within 6 h post-ischemia in both humans and mice. Mechanistically, CKLF1 bound directly to the tetrameric...

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In recent years, a deluge of big and diverse datasets from hundreds of plant species coupled with spectacular innovations in artificial intelligence (AI) and generative AI (GenAI), has altered the landscape of plant science. These developments are increasingly democratizing the field, reducing the entry barriers to complex data analysis and enabling a new wave of innovative research while introducing new challenges. Therefore, in this era, it is critical that we train the next generation of...

CONCLUSION: ATRIP plays a critical role in DNA damage response and genomic stability. Our findings support its candidacy as a novel ovarian cancer susceptibility gene.

The increasing global prevalence of droughts due to climate change poses a major threat to food security, necessitating the development of drought-tolerant crops. To respond appropriately to environmental perturbations, plants undergo widespread transcriptional reprogramming at both the gene expression and splicing levels. Differential splicing dynamically alters the ratio of splice isoforms, generating transcriptomic diversity that can be translated into novel protein isoforms or fine-tune gene...

CONCLUSIONS: Modern radiotherapy techniques allow safe delivery of high radiation doses for LAPC. SBRT provides excellent and durable local control with low rates of treatment-related grades ≥3 toxicities.