Insulin's discovery 100 years ago and its ongoing use since that time to treat diabetes belies the molecular complexity of its structure and that of its receptor. Advances in single-particle ...cryo-electron microscopy have over the past three years revolutionized our understanding of the atomic detail of insulin-receptor interactions.
This review describes the three-dimensional structure of insulin and its receptor and details on how they interact. This review also highlights the current gaps in our structural understanding of the system.
A near-complete picture has been obtained of the hormone receptor interactions, providing new insights into the kinetics of the interactions and necessitating a revision of the extant two-site cross-linking model of hormone receptor engagement. How insulin initially engages the receptor and the receptor's traversed trajectory as it undergoes conformational changes associated with activation remain areas for future investigation.
Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold ...in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract The popularity of the term polycrisis suggests a growing demand for new thinking about the world's intersecting crises, but loose and haphazard uses of the concept impede knowledge ...generation. The special issue, ‘Polycrisis in the Anthropocene’, aims to close the gap. This introductory comment first elaborates upon three key contributions of the lead article ‘Global Polycrisis: The Causal mechanisms of Crisis Entanglement’: a conceptualization of crisis as systemic disequilibrium; the distinction between the slow-moving stresses and the fast-moving trigger events that interact to generate a crisis; and a grammar with which to map the causality of crisis interactions. The commentary then explores three key debates around the polycrisis concept: Are we in a polycrisis, at risk of a polycrisis, or neither? Is the present polycrisis truly unique and unprecedented? And where are power and agency in a systemic approach to polycrisis? These ongoing debates suggest promising directions for polycrisis research that could feature in this special issue and advance the field of polycrisis analysis. Non-technical summary This commentary introduces the special issue ‘Polycrisis in the Anthropocene’ by elaborating upon three major contributions of its lead article, ‘Global Polycrisis: The Causal Mechanisms of Crisis Entanglement’, and exploring three key debates surrounding the polycrisis concept. It invites others to contribute to the special issue in order to advance polycrisis analysis, build a community of knowledge and practice, and generate new insights and strategies with which to address the world's worsening crises. Technical summary The popularity of the term polycrisis suggests a growing demand for new thinking about the world's intersecting crises, but loose and haphazard uses of the concept impede knowledge generation. The special issue, ‘Polycrisis in the Anthropocene’, aims to close the gap. This introductory comment first elaborates upon three key contributions of the lead article ‘Global Polycrisis: The Causal mechanisms of Crisis Entanglement’: a conceptualization of crisis as systemic disequilibrium; the distinction between the slow-moving stresses and the fast-moving trigger events that interact to generate a crisis; and a grammar with which to map the causality of crisis interactions. The commentary then explores three key debates around the polycrisis concept: Are we in a polycrisis, at risk of a polycrisis, or neither? Is the present polycrisis truly unique and unprecedented? And where are power and agency in a systemic approach to polycrisis? These ongoing debates suggest promising directions for polycrisis research that could feature in this special issue and advance the field of polycrisis analysis. Social media summary Inviting contributions and debates to Global Sustainability journal's special issue ‘ Polycrisis in the Anthropocene ’.
Abstract
The insulin receptor (IR) gene undergoes differential splicing that generates two IR isoforms, IR-A and IR-B. The physiological roles of IR isoforms are incompletely understood and appear to ...be determined by their different binding affinities for insulin-like growth factors (IGFs), particularly for IGF-2. Predominant roles of IR-A in prenatal growth and development and of IR-B in metabolic regulation are well established. However, emerging evidence indicates that the differential expression of IR isoforms may also help explain the diversification of insulin and IGF signaling and actions in various organs and tissues by involving not only different ligand-binding affinities but also different membrane partitioning and trafficking and possibly different abilities to interact with a variety of molecular partners. Of note, dysregulation of the IR-A/IR-B ratio is associated with insulin resistance, aging, and increased proliferative activity of normal and neoplastic tissues and appears to sustain detrimental effects. This review discusses novel information that has generated remarkable progress in our understanding of the physiology of IR isoforms and their role in disease. We also focus on novel IR ligands and modulators that should now be considered as an important strategy for better and safer treatment of diabetes and cancer and possibly other IR-related diseases.
We discuss recent work on the physiology of IR isoforms and their role in disease including new findings on IR ligands and modulators that are relevant to the treatment of diabetes and other disorders.
Transition row metal ions are both essential and toxic to microorganisms. Zinc in excess has significant toxicity to bacteria, and host release of Zn(II) at mucosal surfaces is an important innate ...defence mechanism. However, the molecular mechanisms by which Zn(II) affords protection have not been defined. We show that in Streptococcus pneumoniae extracellular Zn(II) inhibits the acquisition of the essential metal Mn(II) by competing for binding to the solute binding protein PsaA. We show that, although Mn(II) is the high-affinity substrate for PsaA, Zn(II) can still bind, albeit with a difference in affinity of nearly two orders of magnitude. Despite the difference in metal ion affinities, high-resolution structures of PsaA in complex with Mn(II) or Zn(II) showed almost no difference. However, Zn(II)-PsaA is significantly more thermally stable than Mn(II)-PsaA, suggesting that Zn(II) binding may be irreversible. In vitro growth analyses show that extracellular Zn(II) is able to inhibit Mn(II) intracellular accumulation with little effect on intracellular Zn(II). The phenotype of S. pneumoniae grown at high Zn(II):Mn(II) ratios, i.e. induced Mn(II) starvation, closely mimicked a ΔpsaA mutant, which is unable to accumulate Mn(II). S. pneumoniae infection in vivo elicits massive elevation of the Zn(II):Mn(II) ratio and, in vitro, these Zn(II):Mn(II) ratios inhibited growth due to Mn(II) starvation, resulting in heightened sensitivity to oxidative stress and polymorphonuclear leucocyte killing. These results demonstrate that microbial susceptibility to Zn(II) toxicity is mediated by extracellular cation competition and that this can be harnessed by the innate immune response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the ...clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional (“T-class”) asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative (“R-class”) asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.
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•Replicative and transcriptional mutational asymmetries are widespread across cancer•APOBEC mutagenesis in humans primarily occurs on the lagging-strand template•Mismatch repair balances asymmetric replication errors•Transcription-coupled damage (TCD) introduces sense-strand mutations in liver cancer
Using an approach that distinguishes whether mutations in cancer genomes occurred on the transcribed or non-transcribed DNA strand with respect to transcription and on the leading or lagging strand with respect to replication, the predominant mutational mechanisms associated with different types of cancers and mutational patterns can be inferred.
Coronavirus disease 2019 (COVID-19) spurred a rapid rise in telemedicine, but it is unclear how use has varied by clinical and patient factors during the pandemic. We examined the variation in total ...outpatient visits and telemedicine use across patient demographics, specialties, and conditions in a database of 16.7 million commercially insured and Medicare Advantage enrollees from January to June 2020. During the pandemic, 30.1 percent of all visits were provided via telemedicine, and the weekly number of visits increased twenty-three-fold compared with the prepandemic period. Telemedicine use was lower in communities with higher rates of poverty (31.9 percent versus 27.9 percent for the lowest and highest quartiles of poverty rate, respectively). Across specialties, the use of any telemedicine during the pandemic ranged from 68 percent of endocrinologists to 9 percent of ophthalmologists. Across common conditions, the percentage of visits provided during the pandemic via telemedicine ranged from 53 percent for depression to 3 percent for glaucoma. Higher rates of telemedicine use for common conditions were associated with smaller decreases in total weekly visits during the pandemic.
Cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage to cancer cells. The discovery of driver ...genes and mutations relies on the assumption that exact positional recurrence is unlikely by chance; thus, the precise sharing of mutations across patients identifies drivers. Examining the mutation landscape in cancer genomes, we found that many recurrent cancer mutations previously designated as drivers are likely passengers. Our integrated bioinformatic and biochemical analyses revealed that these passenger hotspot mutations arise from the preference of APOBEC3A, a cytidine deaminase, for DNA stem-loops. Conversely, recurrent APOBEC-signature mutations not in stem-loops are enriched in well-characterized driver genes and may predict new drivers. This demonstrates that mesoscale genomic features need to be integrated into computational models aimed at identifying mutations linked to diseases.
Detection of somatic point substitutions is a key step in characterizing the cancer genome. However, existing methods typically miss low-allelic-fraction mutations that occur in only a subset of the ...sequenced cells owing to either tumor heterogeneity or contamination by normal cells. Here we present MuTect, a method that applies a Bayesian classifier to detect somatic mutations with very low allele fractions, requiring only a few supporting reads, followed by carefully tuned filters that ensure high specificity. We also describe benchmarking approaches that use real, rather than simulated, sequencing data to evaluate the sensitivity and specificity as a function of sequencing depth, base quality and allelic fraction. Compared with other methods, MuTect has higher sensitivity with similar specificity, especially for mutations with allelic fractions as low as 0.1 and below, making MuTect particularly useful for studying cancer subclones and their evolution in standard exome and genome sequencing data.
In Rspondin-based 3D cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. We report the establishment of tumor organoid cultures ...from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely recapitulate several properties of the original tumor. The spectrum of genetic changes within the “living biobank” agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell-line- and xenograft-based drug studies, and allow personalized therapy design.
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•Tumor and normal organoids were derived from colorectal carcinoma patients•Tumor organoids recapitulate somatic copy number and mutation spectra found in CRC•Organoids are amenable to high-throughput drug screening•Patient-derived organoids allow personalized therapy design
3D organoid cultures derived from healthy and tumor tissue from colorectal cancer patients are used for a high throughput drug screen to identify gene-drug associations that may facilitate personalized therapy.
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