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To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.

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Intestinal fibrosis, a severe complication of Crohn's disease (CD), is characterized by excessive extracellular matrix (ECM) deposition and induces intestinal strictures, but there are no effective antifibrosis drugs available for clinical application. We performed single-cell RNA sequencing (scRNA-Seq) of fibrotic and nonfibrotic ileal tissues from patients with CD with intestinal obstruction. Analysis revealed mesenchymal stromal cells (MSCs) as the major producers of ECM and the increased infiltration of its subset FAP+ fibroblasts in fibrotic sites, which was confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomic profiling of chronic dextran sulfate sodium salt murine colitis model revealed that CD81+Pi16- fibroblasts exhibited transcriptomic and functional similarities to human FAP+ fibroblasts. Consistently, FAP+ fibroblasts were identified as the key subtype with the highest level of ECM production in fibrotic intestines. Furthermore, specific knockout or pharmacological inhibition of TWIST1, which was highly expressed by FAP+ fibroblasts, could significantly ameliorate fibrosis in mice. In addition, TWIST1 expression was induced by CXCL9+ macrophages enriched in fibrotic tissues via IL-1ß and TGF-ß signal. These findings suggest the inhibition of TWIST1 as a promising strategy for CD fibrosis treatment.

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ETHNOPHARMACOLOGICAL RELEVANCE: Biling Weitong Granules (BLWTG) are a newly developed traditional Chinese medicine prescription based on the ancient prescription Jinlingzi San and Zuojin Wan. It is used for the treatment of functional gastrointestinal disorders (FGIDs) featured as visceral hypersensitivity (VH). However, its active ingredients and protein targets involved still remain unknown. AIM OF THE STUDY: To explore the potential targets of BLWTG for the treatment of visceral hypersensitivity. MATERIALS AND METHODS: Active components and their protein targets of BLWTG were screened from TCMSP database and the component-target network were constructed with Cytoscape software. Irritable bowel syndrome (IBS) was the representative disease in this study and information on its linked pathways was obtained from NCBI, Drugbank and Genecard. Target pathways of BLWTG were analyzed through KEGG to verify the correlation with IBS related pathways.Then, the VH mouse models was induced by maternal separation (MS), randomly divided into normal saline (NS),BLWTG1 (low-dosage) and BLWTG2 (high-dosage) group. After intervention, threshold intensity of colorectal distension (CRD) and body weight were measured to evaluate relief of IBS symptoms. Elisa was performed to evaluate 5-HT concentration changes of colon tissues. Flow cytometry was performed to assess changes of colon eosinophils and mast cells proportion. Transcriptome sequencing was employed to analyze changes of pathways and differential genes. RESULTS: 199 protein targets and 132 active components of BLWTG were identified. KEGG analysis revealed the overlap between BLWTG target pathways and IBS related pathways such as neuroactive ligand-receptor interaction, tryptophan metabolism and inflammatory reaction. 34 genes were not only BLWTG target proteins but also recognized targets for treating IBS. After maternal separation (MS), the mice showed a significant decrease in threshold intensity of CRD, a progressive decrease in body weight and an increase of 5-HT concentration of colon tissue. The proportion of mast cells and eosinophils in the colon increased. Differential genes including Hp,Ido1 and Aqp7 were significantly increased in MS mice group and IBS-related pathways were upregulated. After treatment of BLWTG, threshold intensity of CRD and body weight were significantly improved and IBS related pathways were downregulated. In addition, among BLWTG protein targets, Il1b,Tnf,Adrb1 and Nos2 were found upregulated in MS+NS mice and downregulated after BLWTG intervention through combination of transcriptome sequencing. CONCLUSIONS: In maternal separation-induced mouse models, BLWTG could alleviate visceral hypersensitivity, possibly through downregulation of 5-HT concentration and eosinophils and mast cells proportion in colon and critical pathways such as neuroactive ligand-receptor pathway. Potential targets of BLWTG including Il1b,Tnf,Adrb1 and Nos2 were found through integration of network pharmacology database and transcriptome sequencing, providing evidence for further study on mechanisms underlying visceral hypersensitivity.

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The Altaids is generally considered to be the largest Phanerozoic accretionary orogen on Earth, but it is unclear whether it was associated with extensive continental crustal growth and whether there is a link between the crustal growth and ore mineralization. This paper reviews whole-rock Nd and zircon Hf isotope data for felsic-intermediate-mafic igneous rocks in the Altaids and presents Nd + Hf isotopic contour maps for this region. The maps highlight the 3D lithospheric compositional architecture of the Altaids and make it possible to quantitatively evaluate the crustal growth and its relationship with ore deposits. The Altaids hosts ∼4 107 350 km2 and ∼184 830 750 km3 (assuming a crustal thickness of 40-50 km) juvenile crust (ϵ Nd(t) > 0), accounting for 58% by isotope-mapped area (∼7 010 375 km2) of almost all outcrops of the Altaids (∼8 745 000 km2) and formed during 1000-150 Ma (mainly 600-150 Ma). The juvenile crustal, slightly juvenile-reworked crustal and slightly reworked crustal provinces controlled the Cu-Au, the Pb-Zn-Ag and the Li-Be, Nb-Ta and W-Sn ore deposits. According to the crustal architecture and background of deep compositions, we propose that the ore deposits can be grouped into three types: juvenile crust-related, mixed-source (or slightly juvenile crust)-related and reworked crust-related. This highlights the close relationship between accretion, continental growth and mineralization, and will facilitate exploration for specific ore-deposit types in the Altaids.

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INTRODUCTION: Multidrug-resistant organisms (MDROs) are pathogenic bacteria that are the leading cause of hospital-acquired infection which is associated with high morbidity and mortality rates in intensive care units, increasing hospitalisation duration and cost. Predicting the risk of MDRO colonisation or infection for critically ill patients supports clinical decision-making. Several models predicting MDRO colonisation or infection have been developed; however, owing to different disease scenarios, bacterial species and few externally validated cohorts in different prediction models; the stability and applicability of these models for MDRO colonisation or infection in critically ill patients are controversial. In addition, there are currently no standardised risk scoring systems to predict MDRO colonisation or infection in critically ill patients. The aim of this systematic review is to summarise and assess models predicting MDRO colonisation or infection in critically ill patients and to compare their predictive performance. METHODS AND ANALYSIS: We will perform a systematic search of PubMed, Cochrane Library, CINAHL, Embase, Web of science, China National Knowledge Infrastructure and Wanfang databases to identify all studies describing the development and/or external validation of models predicting MDRO colonisation or infection in critically ill patients. Two reviewers will independently extract and review the data using the Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist; they will also assess the risk of bias using the Prediction Model Risk of Bias Assessment Tool. Quantitative data on model predictive performance will be synthesised in meta-analyses, as applicable. ETHICS AND DISSEMINATION: Ethical permissions will not be required because all data will be extracted from published studies. We intend to publish our results in peer-reviewed scientific journals and to present them at international conferences on critical care. PROSPERO REGISTRATION NUMBER: CRD42022274175.

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Sodium and potassium-ion batteries are promising for energy storage owing to their source abundance and low cost; however, most active materials still suffer from sluggish kinetics, huge volume variations, and poor conductivity and cycle stability. It remains a great challenge to explore appropriate electrode materials for scaled practical applications. Herein, mesoporous FeCo-incorporated MoS2 nanosheets encapsulated into a porous carbon framework (FeCo@C@MoS2) are smartly designed, artistically fabricated and evaluated for sodium and potassium storage. The FeCo@C@MoS2 electrode displays high reversible capacities of 380 mA h g-1 and 147 mA h g-1 at 500 mA g-1 for sodium and potassium storage, respectively. FeCo derived from a Prussian blue analogue promotes fast reaction kinetics of Na+/K+ transport, introduces the formation of a stable solid electrolyte interphase layer (SEI) in both the interior and exterior of the cube-like porous nanostructure and controls the Na+/K+ fluxes, suppressing the growth of metal dendrites. The porous carbon framework with large interstitial voids can effectively buffer volume variations and mitigate mechanical stress, contributing significantly to alleviate strain intensification on the surface layer between MoS2 and FeCo during repeated plating/stripping processes. Density functional theoretical calculations (DFT) further confirm that the synthesized nanostructure shows an intensified electron state, elevated anti-stress ability, high-quality SEI film and preferable Na+/K+ adsorption energies. This in-depth investigation of the electrochemical performance and the extended energy storage mechanism based on metal alloy/sulfide nanostructures for sodium and potassium storage provides guidance for the smart design of heterojunctions for remarkable energy storage.

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Reading frame maintenance is critical for accurate translation. We show that the conserved eukaryotic/archaeal protein Mbf1 acts with ribosomal proteins Rps3/uS3 and eukaryotic Asc1/RACK1 to prevent frameshifting at inhibitory CGA-CGA codon pairs in the yeast Saccharomyces cerevisiae. Mutations in RPS3 that allow frameshifting implicate eukaryotic conserved residues near the mRNA entry site. Mbf1 and Rps3 cooperate to maintain the reading frame of stalled ribosomes, while Asc1 also mediates distinct events that result in recruitment of the ribosome quality control complex and mRNA decay. Frameshifting occurs through a +1 shift with a CGA codon in the P site and involves competition between codons entering the A site, implying that the wobble interaction of the P site codon destabilizes translation elongation. Thus, eukaryotes have evolved unique mechanisms involving both a universally conserved ribosome component and two eukaryotic-specific proteins to maintain the reading frame at ribosome stalls.

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