Dunngertsen7784

Radiotherapy (RT) is a highly effective anticancer treatment that is delivered to more than half of all patients with cancer. In addition to the well-documented direct cytotoxic effects, RT can have immunomodulatory effects on the tumour and surrounding tissues. These effects are thought to underlie the so-called abscopal responses, whereby RT generates systemic antitumour immunity outside the irradiated tumour. The full scope of these immune changes remains unclear but is likely to involve multiple components, such as immune cells, the extracellular matrix, endothelial and epithelial cells and a myriad of chemokines and cytokines, including transforming growth factor-β (TGFβ). In normal tissues exposed to RT during cancer therapy, acute immune changes may ultimately lead to chronic inflammation and RT-induced toxicity and organ dysfunction, which limits the quality of life of survivors of cancer. Here we discuss the emerging understanding of RT-induced immune effects with particular focus on the lungs and gut and the potential immune crosstalk that occurs between these tissues.Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.Altered metabolic activity contributes to the pathogenesis of a number of diseases, including diabetes, heart failure, cancer, fibrosis and neurodegeneration. These diseases, and organismal metabolism more generally, are only partially recapitulated by cell culture models. Accordingly, it is important to measure metabolism in vivo. Over the past century, researchers studying glucose homeostasis have developed strategies for the measurement of tissue-specific and whole-body metabolic activity (pathway fluxes). The power of these strategies has been augmented by recent advances in metabolomics technologies. Here, we review techniques for measuring metabolic fluxes in intact mammals and discuss how to analyse and interpret the results. In tandem, we describe important findings from these techniques, and suggest promising avenues for their future application. Given the broad importance of metabolism to health and disease, more widespread application of these methods holds the potential to accelerate biomedical progress.MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. click here Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m6A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared m6A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m6A QTLs with disease genetics, identifying 184 GWAS-colocalized m6A QTL, including brain m6A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m6A QTLs underlying expiratory flow and asthma; and muscle/heart m6A QTLs underlying coronary artery disease. Last, we predict novel m6A regulators that show preferential binding in m6A QTLs, protein interactions with known m6A regulators and expression correlation with the m6A levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease.Substance use disorders (SUDs) are conditions in which the use of legal or illegal substances, such as nicotine, alcohol or opioids, results in clinical and functional impairment. SUDs and, more generally, substance use are genetically complex traits that are enormously costly on an individual and societal basis. The past few years have seen remarkable progress in our understanding of the genetics, and therefore the biology, of substance use and abuse. Various studies - including of well-defined phenotypes in deeply phenotyped samples, as well as broadly defined phenotypes in meta-analysis and biobank samples - have revealed multiple risk loci for these common traits. A key emerging insight from this work establishes a biological and genetic distinction between quantity and/or frequency measures of substance use (which may involve low levels of use without dependence), versus symptoms related to physical dependence.Extracellular-vesicle-based cell-to-cell communication is conserved across all kingdoms of life. There is compelling evidence that extracellular vesicles are involved in major (patho)physiological processes, including cellular homoeostasis, infection propagation, cancer development and cardiovascular diseases. Various studies suggest that extracellular vesicles have several advantages over conventional synthetic carriers, opening new frontiers for modern drug delivery. Despite extensive research, clinical translation of extracellular-vesicle-based therapies remains challenging. Here, we discuss the uniqueness of extracellular vesicles along with critical design and development steps required to utilize their full potential as drug carriers, including loading methods, in-depth characterization and large-scale manufacturing. We compare the prospects of extracellular vesicles with those of the well established liposomes and provide guidelines to direct the process of developing vesicle-based drug delivery systems.Modern and contemporary art materials are generally prone to irreversible colour changes upon exposure to light and oxidizing agents. Graphene can be produced in thin large sheets, blocks ultraviolet light, and is impermeable to oxygen, moisture and corrosive agents; therefore, it has the potential to be used as a transparent layer for the protection of art objects in museums, during storage and transportation. Here we show that a single-layer or multilayer graphene veil, produced by chemical vapour deposition, can be deposited over artworks to protect them efficiently against colour fading, with a protection factor of up to 70%. We also show that this process is reversible since the graphene protective layer can be removed using a soft rubber eraser without causing any damage to the artwork. We have also explored a complementary contactless graphene-based route for colour protection that is based on the deposition of graphene on picture framing glass for use when the direct application of graphene is not feasible due to surface roughness or artwork fragility. Overall, the present results are a proof of concept of the potential use of graphene as an effective and removable protective advanced material to prevent colour fading in artworks.Adenine base editors (ABEs) catalyze specific A-to-G conversions at genomic sites of interest. However, ABEs also induce cytosine deamination at the target site. To reduce the cytosine editing activity, we engineered a commonly used adenosine deaminase, TadA7.10, and found that ABE7.10 with a D108Q mutation in TadA7.10 exhibited tenfold reduced cytosine deamination activity. The D108Q mutation also reduces cytosine deamination activity in two recently developed high-activity versions of ABE, ABE8e and ABE8s, and is compatible with V106W, a mutation that reduces off-target RNA editing. ABE7.10 containing a P48R mutation displayed increased cytosine deamination activity and a substantially reduced adenine editing rate, yielding a TC-specific base editing tool for TC-to-TT or TC-to-TG conversions that broadens the utility of base editors.