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Brandt Vilstrup posted an update 6 months, 2 weeks ago
These data indicate that the magnitude of the GC reaction is restricted by a fixed number of permissive GC niches containing preassembled FDC clusters. This finding may help in the future design of vaccination strategies and in the modulation of antibody-mediated autoimmunity.In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. ZYS-1 mouse Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.The dynamic change of cell-surface glycans is involved in diverse biological and pathological events such as oncogenesis and metastasis. Despite tremendous efforts, it remains a great challenge to selectively distinguish and label glycans of different cancer cells or cancer subtypes. Inspired by biomimetic cell membrane-coating technology, herein, we construct pH-responsive azidosugar liposomes camouflaged with natural cancer-cell membrane for tumor cell-selective glycan engineering. With cancer cell-membrane camouflage, the biomimetic liposomes can prevent protein corona formation and evade phagocytosis of macrophages, facilitating metabolic glycans labeling in vivo. More importantly, due to multiple membrane receptors, the biomimetic liposomes have prominent cell selectivity to homotypic cancer cells, showing higher glycan-labeling efficacy than a single-ligand targeting strategy. Further in vitro and in vivo experiments indicate that cancer cell membrane-camouflaged azidosugar liposomes not only realize cell-selective glycan imaging of different cancer cells and triple-negative breast cancer subtypes but also do well in labeling metastatic tumors. Meanwhile, the strategy is also applicable to the use of tumor tissue-derived cell membranes, which shows the prospect for individual diagnosis and treatment. This work may pave a way for efficient cancer cell-selective engineering and visualization of glycans in vivo.Postoperative pulmonary complications contribute to perioperative morbidity and mortality in addition to being associated with increased health care costs. In this review article, we outline risk factors for the development postoperative pulmonary complications, describe their impact on perioperative outcomes, and focus on the role of intraoperative ventilation strategies in decreasing postoperative pulmonary complications.Many correlated systems feature an insulator-to-metal transition that can be triggered by an electric field. Although it is known that metallization takes place through filament formation, the details of how this process initiates and evolves remain elusive. We use in-operando optical reflectivity to capture the growth dynamics of the metallic phase with space and time resolution. We demonstrate that filament formation is triggered by nucleation at hotspots, with a subsequent expansion over several decades in time. By comparing three case studies (VO2, V3O5, and V2O3), we identify the resistivity change across the transition as the crucial parameter governing this process. Our results provide a spatiotemporal characterization of volatile resistive switching in Mott insulators, which is important for emerging technologies, such as optoelectronics and neuromorphic computing.Stochastic fluctuations in gene expression (“noise”) are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as “discordant transcription through repair” (“DiThR,” which is pronounced “dither”), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.Understanding the causes and consequences of the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is crucial to pandemic control yet difficult to achieve because they arise in the context of variable human behavior and immunity. We investigated the spatial invasion dynamics of lineage B.1.1.7 by jointly analyzing UK human mobility, virus genomes, and community-based polymerase chain reaction data. We identified a multistage spatial invasion process in which early B.1.1.7 growth rates were associated with mobility and asymmetric lineage export from a dominant source location, enhancing the effects of B.1.1.7’s increased intrinsic transmissibility. We further explored how B.1.1.7 spread was shaped by nonpharmaceutical interventions and spatial variation in previous attack rates. Our findings show that careful accounting of the behavioral and epidemiological context within which variants of concern emerge is necessary to interpret correctly their observed relative growth rates.
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