Hyperactivated Notch signalling has been implicated in breast cancer, but how elevated levels of Notch signalling contribute to mammary dysplasia and tumorigenesis is not fully understood. In this ...study, we express an activated form of Notch1 in the mouse mammary luminal lineage and analyse the consequences for tumour formation and the transcriptomic landscape in the luminal lineage. Simultaneous conditional activation of a Notch1 intracellular domain (Notch1 ICD) and EGFP in the luminal lineage was achieved by removal of a stop cassette by CRE-recombinase expression from the whey acidic protein (WAP) promoter. Mice in which Notch1 ICD was activated in the luminal lineage (WAP-CRE;R26-N1ICD mice) exhibit ductal hyperplasia after lactation with an increase in branching frequency and in the number of side-branch ends in the ductal tree. A subset of the mice developed mammary tumours and the majority of the tumour cells expressed EGFP (as a proxy for Notch1 ICD), indicating that the tumours originate from the Notch1 ICD-expressing cells. Single-cell transcriptome analysis of the EGFP-positive mammary cells identified six subtypes of luminal cells. The same six subtypes were found in control mice (WAP-CRE;R26-tdTomato mice expressing the tdTomato reporter from WAP-CRE-mediated activation), but the proportion of cells in the various subtypes differed between the WAP-CRE;R26-N1ICD and control WAP-CRE;R26-tdTomato mice. In conclusion, we show that Notch1 ICD expression in the luminal lineage produces a ductal hyperplasia and branching phenotype accompanied by altered luminal cell subtype partitioning.
Patients with severe coronavirus disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with ARDS. Respiratory failure in COVID-19 might ...represent a novel pathologic entity.
How does the lung histopathology described in COVID-19 compare with the lung histopathology described in SARS and H1N1 influenza?
We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020, using search terms for COVID-19, H1N1 influenza, and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-Individual Participant Data guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients.
In COVID-19, acute-phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared with 24% of H1N1 influenza patients.
DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza, and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared with H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.
Cystic fibrosis (CF) is caused by defects in an anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Recently, a new airway epithelial cell type has been discovered and ...dubbed the pulmonary ionocyte. Unexpectedly, these ionocytes express higher levels of CFTR than any other airway epithelial cell type. However, ionocytes are not the sole CFTR-expressing airway epithelial cells, and CF-associated disease genes are in fact expressed in multiple airway epithelial cell types. The experimental depletion of ionocytes perturbs epithelial physiology in the mouse trachea, but the role of these rare cells in the pathogenesis of human CF remains mysterious. Ionocytes have been described in diverse tissues(kidney and inner ear) and species (frog and fish). We draw on these prior studies to suggest potential roles of airway ionocytes in health and disease. A complete understanding of ionocytes in the mammalian airway will ultimately depend on cell type-specific genetic manipulation
Direct control of microRNA (miRNA) expression by oncogenic and tumor suppressor networks results in frequent dysregulation of miRNAs in cancer cells and contributes to tumorigenesis. We previously ...demonstrated that activation of the c-Myc oncogenic transcription factor (Myc) broadly influences miRNA expression and in particular leads to widespread miRNA down-regulation. miRNA transcripts repressed by Myc include several with potent tumor suppressor activity such as miR-15a/16-1, miR-34a, and let-7 family members. In this study, we have investigated mechanisms downstream of Myc that contribute to miRNA repression. Consistent with transcriptional down-regulation, Myc activity results in the decreased abundance of multiple miRNA primary transcripts. Surprisingly, however, primary transcripts encoding several let-7 miRNAs are not reduced in the high Myc state, suggesting a posttranscriptional mechanism of repression. The Lin-28 and Lin-28B RNA binding proteins were recently demonstrated to negatively regulate let-7 biogenesis. We now show that Myc induces Lin-28B expression in multiple human and mouse tumor models. Chromatin immunoprecipitation and reporter assays reveal direct association of Myc with the Lin-28B promoter resulting in transcriptional transactivation. Moreover, we document that activation of Lin-28B is necessary and sufficient for Myc-mediated let-7 repression. Accordingly, Lin-28B loss-of-function significantly impairs Myc-dependent cellular proliferation. These findings highlight an important role for Lin-28B in Myc-driven cellular phenotypes and uncover an orchestration of transcriptional and posttranscriptional mechanisms in Myc-mediated reprogramming of miRNA expression.
The chiral Lagrangian for Goldstone-boson scattering is a power-series expansion in numbers of derivatives. Each successive term is suppressed by powers of a scale, Lambdasub chi, which must be less ...than of order 4piital f/ radicalital N where ital f is the Goldstone-boson decay constant and ital N is the number of flavors. The chiral expansion therefore breaks down at or below 4piital f/ radicalital N . Because of crossing symmetry, some isospin'' channels will deviate from their low-energy behavior well before they approach the scale at which their low-energy amplitudes would violate unitarity. The breakdown of the chiral expansion is associated with the appearance of physical states other than Goldstone bosons. We speculate that, since the bound on Lambdasub chi falls as ital N increases, the masses of resonances will decrease relative to ital fsub pi at least as fast as 1/ radicalital N and argue that the estimates of oblique'' corrections from technicolor obtained by scaling from QCD are untrustworthy.
MicroRNAs (miRNAs) have attracted considerable attention because of their important roles in development, normal physiology, and disease states including cancer. Recent studies have identified ...specific miRNAs that regulate the cell cycle and have documented that the loss or gain of miRNA-mediated cell-cycle control contributes to malignancy. miRNAs regulate classic cell-cycle control pathways by directly targeting proteins such as E2F transcription factors, cyclin-dependent kinases (Cdks), cyclins and Cdk inhibitors. Moreover, from recent findings, it has been suggested that miRNAs themselves might be subject to cell-cycle dependent regulation. Together, these observations indicate that the reciprocal control of RNA silencing and the metazoan cell cycle impacts cellular behavior and disease.
As we amass more LHC data, we continue to search for new and improved methods of visualizing search results, in ways that are as model independent as possible. The simplified limits framework is an ...approach developed to recast limits on searches for narrow resonances in terms of products of branching ratios (BRs) corresponding to the resonance's production and decay modes. In this work, we extend the simplified limits framework to a multidimensional parameter space of BRs, which can be used to unfold an ambiguity in the simplified parameter ζ introduced when more than one channel contributes to the production of the resonance. It is also naturally applicable to combining constraints from experimental searches with different observed final states. Constraints can be visualized in a three-dimensional space of branching ratios by employing ternary diagrams, triangle plots which utilize the inherent unitarity of the sum of the resonance's BRs. To demonstrate this new methodology, we recast constraints from recent ATLAS searches in diboson final states for spin-0, -1, and -2 narrow resonances into constraints on the resonance's width-to-mass ratio and display them in the space of relevant branching ratios. We also demonstrate how to generalize the method to cases where more than three branching ratios are relevant by using N -simplex diagrams, and we suggest a broader application of the general method to digital datasets.
MicroRNAs (miRNAs) pair to sites in mRNAs to direct the degradation of these RNA transcripts. Conversely, certain RNA transcripts can direct the degradation of particular miRNAs. This target-directed ...miRNA degradation (TDMD) requires the ZSWIM8 E3 ubiquitin ligase. Here, we report the function of ZSWIM8 in the mouse embryo.
embryos were smaller than their littermates and died near the time of birth. This highly penetrant perinatal lethality was apparently caused by a lung sacculation defect attributed to failed maturation of alveolar epithelial cells. Some mutant individuals also had heart ventricular septal defects. These developmental abnormalities were accompanied by aberrant accumulation of more than 50 miRNAs observed across 12 tissues, which often led to enhanced repression of their mRNA targets. These ZSWIM8-sensitive miRNAs were preferentially produced from genomic miRNA clusters, and in some cases, ZSWIM8 caused a switch in the dominant strand or isoform that accumulated from a miRNA hairpin-observations suggesting that TDMD provides a mechanism to uncouple coproduced miRNAs from each other. Overall, our findings indicate that the regulatory influence of ZSWIM8, and presumably TDMD, in mammalian biology is widespread and consequential, and posit the existence of many yet-unidentified transcripts that trigger miRNA degradation.
Abstract
ProteoVision is a web server designed to explore protein structure and evolution through simultaneous visualization of multiple sequence alignments, topology diagrams and 3D structures. ...Starting with a multiple sequence alignment, ProteoVision computes conservation scores and a variety of physicochemical properties and simultaneously maps and visualizes alignments and other data on multiple levels of representation. The web server calculates and displays frequencies of amino acids. ProteoVision is optimized for ribosomal proteins but is applicable to analysis of any protein. ProteoVision handles internally generated and user uploaded alignments and connects them with a selected structure, found in the PDB or uploaded by the user. It can generate de novo topology diagrams from three-dimensional structures. All displayed data is interactive and can be saved in various formats as publication quality images or external datasets or PyMol Scripts. ProteoVision enables detailed study of protein fragments defined by Evolutionary Classification of protein Domains (ECOD) classification. ProteoVision is available at http://proteovision.chemistry.gatech.edu/.
Graphical Abstract
Graphical Abstract
ProteoVision is a webserver designed to visualize phylogenetic, structural, and physicochemical properties of proteins by integration of four mutually synchronized applets that visually represent map data for each amino-acid simultaneously on levels of a (i) multiple sequence alignment; (ii) secondary structure; (iii) 3D structure and (iv) frequency box plot graph.
Flow in sidewall cerebral aneurysms can be ideally modelled as the combination of flow over a spherical cavity and flow in a curved circular pipe, two canonical flows. Flow in a curved pipe is known ...to depend on the Dean number $De$, combining the effects of Reynolds number $\textit {Re}$ and of the curvature along the pipe centreline, $\kappa$. Pulsatility in the flow introduces a dependence on the Womersley number $Wo$. Using stereo particle image velocimetry measurements, this study investigated the effect of these three key non-dimensional parameters, by modifying pipe curvature ($De$), flow rate ($Re$) and pulsatility frequency ($Wo$), on the flow patterns in a spherical cavity. A single counter-rotating vortex was observed in the cavity for all values of pipe curvature $\kappa$ and Reynolds number $\textit {Re}$, for both steady and pulsatile inflow conditions. Increasing the pipe curvature impacted the flow patterns in both the pipe and the cavity, by shifting the velocity profile towards the cavity opening and increasing the flow rate in to the cavity. The circulation in the cavity was found to collapse well with only the Dean number, for both steady and pulsatile inflows. For pulsatile inflow, the counter-rotating vortex was unstable and the location of its centre over time was impacted by the curvature of the pipe, as well as $\textit {Re}$ and $Wo$ in the free stream. The circulation in the cavity was higher for steady inflow than for the equivalent average Reynolds number and Dean number pulsatile inflow, with very limited impact of the Womersley number in the range studied. A second part of this study, that focuses on the changes in fluid dynamics when the intracranial aneurysm is treated with a flow-diverting stent, can be found in this issue (Barbour et al., J. Fluid Mech., vol. 915, 2021, A124).
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