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Mashup Score: 2
CD8+ T-cell activation is initiated by the recognition of epitopes presented on class I major histocompatibility complex (MHC-I) molecules. Identifying such epitopes is useful for molecular understanding of cellular immune responses and can guide the development of personalized vaccines for various diseases including cancer. Here, we capitalize on high-quality MHC-I peptidomics data available from different species and an expanded architecture of our MHC-I ligand predictor (MixMHCpred) to carefully explore how much predictions can be extrapolated to MHC-I alleles without known ligands. Our results reveal high prediction accuracy for most MHC-I alleles in human and in laboratory mouse strains, but significantly lower accuracy in other species. Our work further outlines some of the molecular determinants of MHC-I ligand predictions accuracy across alleles and species. Robust benchmarking on external data shows that the pan-allele version of MixMHCpred (v3.0) outperforms other state-of-th
Source: www.biorxiv.orgCategories: General Medicine News, General HCPsTweet
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Mashup Score: 0Exploring the Limits of EPR-driven Tumor Accumulation with Non-opsonizing Nanomaterials - 8 hour(s) ago
The Enhanced Permeability and Retention (EPR) effect is a foundational concept used to rationalize nanomedicine development for cancer treatment and diagnostics. The attainable efficacy of passive tumor targeting due to EPR remains ambiguous owing to pervasive opsonization of nanoparticles. To address this, we developed nanomaterials with complete resistance to opsonization, exceptionally long systemic circulation, and used them to study the limits of the EPR in triple-negative breast cancer. Tumors exerted no impact on pharmacokinetic profiles, which were indistinguishable between healthy and tumor-bearing mice. Tumors were the primary accumulation sites and our data revealed that the maximum average achievable tumor Fsuppaccumulation via EPR is proximate to 60 %ID/g, tumor-to-liver selectivity is 4-to-1, and the optimal DH to fully exploit EPR lies between 18 and 54 nm. The significant heterogeneity observed in tumor accumulation, however, indicates that nanomedicines cannot achieve
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Mashup Score: 0
Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer-promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, mediated by Polycomb repression. We show that histone genes are expressed with allelic imbalance in mESCs, are involved in haplotype-specific chromatin contact marked by H3K27me3, and are targets of Polycomb repression
Source: www.biorxiv.orgCategories: General Medicine News, General HCPsTweet
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Mashup Score: 1Genome assembly of the southern pine beetle (Dendroctonus frontalis Zimmerman) reveal the origins of gene content reduction in Dendroctonus - 9 hour(s) ago
Dendroctonus frontalis, also known as southern pine beetle (SPB), represents the most damaging forest pest in the southeastern United States. Strategies to predict, monitor and suppress SPB outbreaks have had limited success. Genomic data are critical to inform on pest biology and to identify molecular targets to develop improved management approaches. Here, we produced a chromosome-level genome assembly of SPB using long-read sequencing data. Synteny analyses confirmed the conservation of the core coleopteran Stevens elements and validated the bona fide SPB X chromosome. Transcriptomic data were used to obtain 39,588 transcripts corresponding to 13,354 putative protein-coding loci. Comparative analyses of gene content across 14 beetle and 3 other insects revealed several losses of conserved genes in the Dendroctonus clade and gene gains in SPB and Dendroctonus that were enriched for loci encoding membrane proteins and extracellular matrix proteins. While lineage-specific gene losses c
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Mashup Score: 0Comparative genomics of three non-hematophagous leeches (Whitmania spp.): focusing on antithrombotic genes - 9 hour(s) ago
Leeches are well known for their blood-feeding habits and are widely used for medicinal purposes as they secrete various antithrombotic substances. However, some leeches such as Whitmania spp. exhibit non-hematophagous feeding habits and their significance for medicinal use is debated. In this study, we provide chromosome-level genomes of two non-hematophagous leeches Whitmania acranulata and Whitmania laevis, and combined with our previous results of Whitmania pigra, we systematically analyzed the similarities and differences on the genomes and especially their antithrombotic genes among the three non-hematophagous Whitmania leeches. For W. acranulata, W. laevis, and W. pigra, the genome size (181.72 Mb, 173.87 Mb, and 173.56), the percentage of repeat sites (29.55%, 28.28%, and 27.02%), and the number of protein-coding genes (27,068, 23,805, and 24,156) were close to each other, respectively. In contrast, both the total number of the antithrombotic genes (100, 63, and 79), and the de
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Mashup Score: 0Environment by environment interactions (ExE) differ across genetic backgrounds (ExExG) - 9 hour(s) ago
While the terms “gene-by-gene interaction” (GxG) and “gene-by-environment interaction” (GxE) are commonplace within the field of quantitative and evolutionary genetics, “environment-by-environment interaction” (ExE) is a term used less often. However, in this study, we find that environment-by-environment interactions are common and differ for different genotypes (ExExG). To reach this conclusion, we analyzed a large dataset of roughly 1,000 mutant yeast strains with varying degrees of resistance to different antifungal drugs. Many researchers endeavor to predict combinations of drugs that are more lethal than either single drug. But we show that the effectiveness of a drug combination, relative to the effectiveness of single drugs, often varies across different drug resistant mutants. Even mutants that differ by only a single nucleotide change can have dramatically different drug x drug (ExE) interactions. Studying how ExE interactions change across genotypes (ExExG) is not only impor
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Mashup Score: 0Fuel buildup shapes post-fire fuel decomposition through soil heating effects on plants, fungi, and soil chemistry - 9 hour(s) ago
Forty percent of terrestrial ecosystems require recurrent fires engineered by feedbacks between fire and plant fuels. Fuel loads control fire intensity which alters soil nutrients and shapes soil microbial and plant community responses to fire. Changes to post-fire plant fuel production are well known to feed back to future fires, but post-fire decomposition of new fuels is poorly understood. Our study sought to quantify how pre-fire fuel loading impacted post-fire fuel decomposition through soil abiotic properties, plant and soil fungal communities. In a longleaf pine savanna, both near and away from overstory pines, we manipulated pre-fire plot fuel loads to modify soil heating. We then assessed how fuel load and soil heating influenced post-fire plant fuel decomposition through changes to soil chemistry, vegetation, and fungi. Larger fuel loads, particularly beneath pines, increased soil heating and reduced decomposition of newly deposited fuels during the eight months following fir
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Mashup Score: 0Naa10 regulates hippocampal neurite outgrowth via Btbd3 N-α-acetylation-mediated actin dynamics - 9 hour(s) ago
Protein N-α-acetylation is widespread in eukaryotes, yet its neuronal role remains unclear. Mutations in human N-α-acetyltransferase 10 (NAA10) lead to developmental defects affecting brain function, such as intellectual disability and autism. We found that hippocampal CA1-specific Naa10-knockout mice exhibit anxiety and reduced hippocampal dendritic complexity. Mechanistically, Naa10 promotes neurite outgrowth by acetylating BTB/POZ domain-containing protein 3 (Btbd3), crucial for the interaction of Btbd3 with filamentous actin (F-actin)-capping protein subunit beta (CapZb). Disrupting the Btbd3/CapZb interaction, either through Naa10 knockout or by expressing an N-α-acetylation-defective Btbd3 mutant, diminishes CapZb binding to F-actin and reduces neurite outgrowth. Moreover, cytochalasin D, a compound like CapZb in capping the barbed end of F-actin, rescues the Naa10 knockout-induced neurite reduction in hippocampal primary neurons. These findings unveil the role of Naa10 in enhanc
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Mashup Score: 0Barcoding Notch signaling in the developing brain - 9 hour(s) ago
Developmental signaling inputs are fundamental for shaping cell fates and behavior. However, traditional fluorescent-based signaling reporters have limitations in scalability and molecular resolution of cell types. We present SABER-seq, a CRISPR-Cas molecular recorder that stores transient developmental signaling cues as permanent mutations in cellular genomes for deconstruction at later stages via single-cell transcriptomics. We applied SABER-seq to record Notch signaling in developing zebrafish brains. SABER-seq has two components: a signaling sensor and a barcode recorder. The sensor activates Cas9 in a Notch-dependent manner with inducible control while the recorder accumulates mutations that represent Notch activity in founder cells. We combine SABER-seq with an expanded juvenile brain atlas to define cell types whose fates are determined downstream of Notch signaling. We identified examples wherein Notch signaling may have differential impact on terminal cell fates. SABER-seq is
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Mashup Score: 0High Throughput Screening with a Primary Human Mucociliary Airway Model Identifies a Small Molecule with Anti-SARS-CoV-2 Activity - 9 hour(s) ago
Respiratory viruses (e.g. influenza, RSV, SARS etc.) attack the proximal airway and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. Here we present a microscale, primary human stem cell-based proximal airway model of SARS-CoV-2 infection, which is amenable to moderate-to-high throughput drug screening. The model recapitulates the heterogeneity of infection seen among different patients and with different SARS-CoV-2 variants. We applied this model to screen 2100 compounds from targeted drug libraries using an image-based quantification method. While there were heterogeneous responses across variants for the host factor targeting compounds, the direct-acting antivirals showed a consistent response and we characterized a new antiviral drug that is effective against both t
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Predicting MHC-I ligands across alleles and species: How far can we go? https://t.co/CronuZa7tG #bioRxiv