Compound wind and rainfall extremes: Drivers and future changes over the UK and Ireland

\ua9 2024The co-occurrence of wind and rainfall extremes can yield larger impacts than when either hazard occurs in isolation. This study assesses compound extremes produced by Extra-tropical cyclones (ETCs) during winter from two perspectives. Firstly, we assess ETCs with extreme footprints of wind and rainfall; footprint severity is measured using the wind severity index (WSI) and rain severity index (RSI) which account for the intensity, duration, and area of either hazard. Secondly, we assess local co-occurrences of 6-hourly wind and rainfall extremes within ETCs. We quantify the likelihood of compound extremes in these two perspectives and characterise a number of their drivers (jet stream, cyclone tracks, and fronts) in control (1981–2000) and future (2060–2081, RCP8.5) climate simulations from a 12-member ensemble of local convection-permitting 2.2 km climate projections over the UK and Ireland. Simulations indicate an increased probability of ETCs producing extremely severe WSI and RSI in the same storm in the future, occurring 3.6 times more frequently (every 5 years compared to every 18 years in the control). This frequency increase is mainly driven by increased rainfall intensities, pointing to a predominantly thermodynamic driver. However, future winds also increase alongside a strengthened jet stream, while a southward displaced jet and cyclone track in these events leads to a dynamically-enhanced increase in temperature. This intensifies rainfall in line with Clausius-Clapeyron, and potentially wind speeds due to additional latent heat energy. Future simulations also indicate an increase in the land area experiencing locally co-occurring wind and rainfall extremes; largely explained by increased rainfall within warm and cold fronts, although the relative increase is highest near cold fronts suggesting increased convective activity. These locally co-occurring extremes are more likely in storms with severe WSI and RSI, but not exclusively so as local co-occurrence requires the coincidence of separate drivers within ETCs. Overall, our results reveal many contributing factors to compound wind and rainfall extremes and their future changes. Further work is needed to understand the uncertainty in the future response by sampling additional climate models

Compound wind and rainfall extremes: Drivers and future changes over the UK and Ireland

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordData availability: Wind and rainfall data is freely available. Other data can be made available upon reasonable request.The co-occurrence of wind and rainfall extremes can yield larger impacts than when either hazard occurs in isolation. This study assesses compound extremes produced by Extra-tropical cyclones (ETCs) during winter from two perspectives. Firstly, we assess ETCs with extreme footprints of wind and rainfall; footprint severity is measured using the wind severity index (WSI) and rain severity index (RSI) which account for the intensity, duration, and area of either hazard. Secondly, we assess local co-occurrences of 6-hourly wind and rainfall extremes within ETCs. We quantify the likelihood of compound extremes in these two perspectives and characterise a number of their drivers (jet stream, cyclone tracks, and fronts) in control (1981-2000) and future (2060-2081, RCP8.5) climate simulations from a 12-member ensemble of local convection-permitting 2.2 km climate projections over the UK and Ireland. Simulations indicate an increased probability of ETCs producing extremely severe WSI and RSI in the same storm in the future, occurring 3.6 times more frequently (every 5 years compared to every 18 years in the control). This frequency increase is mainly driven by increased rainfall intensities, pointing to a predominantly thermodynamic driver. However, future winds also increase alongside a strengthened jet stream, while a southward displaced jet and cyclone track in these events leads to a dynamically-enhanced increase in temperature. This intensifies rainfall in line with Clausius-Clapeyron, and potentially wind speeds due to additional latent heat energy. Future simulations also indicate an increase in the land area experiencing locally co-occurring wind and rainfall extremes; largely explained by increased rainfall within warm and cold fronts, although the relative increase is highest near cold fronts suggesting increased convective activity. These locally co-occurring extremes are more likely in storms with severe WSI and RSI, but not exclusively so as local co-occurrence requires the coincidence of separate drivers within ETCs. Overall, our results reveal many contributing factors to compound wind and rainfall extremes and their future changes. Further work is needed to understand the uncertainty in the future response by sampling additional climate models.Natural Environment Research Council (NERC)Joint UK BEIS/Defra Hadley Centre Climate ProgrammeEuropean Union Horizon 202

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue.

E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments

Allocating HIV Prevention Funds in the United States: Recommendations from an Optimization Model

The Centers for Disease Control and Prevention (CDC) had an annual budget of approximately $327 million to fund health departments and community-based organizations for core HIV testing and prevention programs domestically between 2001 and 2006. Annual HIV incidence has been relatively stable since the year 2000 [1] and was estimated at 48,600 cases in 2006 and 48,100 in 2009 [2]. Using estimates on HIV incidence, prevalence, prevention program costs and benefits, and current spending, we created an HIV resource allocation model that can generate a mathematically optimal allocation of the Division of HIV/AIDS Prevention’s extramural budget for HIV testing, and counseling and education programs. The model’s data inputs and methods were reviewed by subject matter experts internal and external to the CDC via an extensive validation process. The model projects the HIV epidemic for the United States under different allocation strategies under a fixed budget. Our objective is to support national HIV prevention planning efforts and inform the decision-making process for HIV resource allocation. Model results can be summarized into three main recommendations. First, more funds should be allocated to testing and these should further target men who have sex with men and injecting drug users. Second, counseling and education interventions ought to provide a greater focus on HIV positive persons who are aware of their status. And lastly, interventions should target those at high risk for transmitting or acquiring HIV, rather than lower-risk members of the general population. The main conclusions of the HIV resource allocation model have played a role in the introduction of new programs and provide valuable guidance to target resources and improve the impact of HIV prevention efforts in the United States

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time

Listening for the landing: seismic detections of perseverance's arrival at Mars with InSight

The entry, descent, and landing (EDL) sequence of NASA's Mars 2020 Perseverance Rover will act as a seismic source of known temporal and spatial localization. We evaluate whether the signals produced by this event will be detectable by the InSight lander (3,452 km away), comparing expected signal amplitudes to noise levels at the instrument. Modeling is undertaken to predict the propagation of the acoustic signal (purely in the atmosphere), the seismoacoustic signal (atmosphere-to-ground coupled), and the elastodynamic seismic signal (in the ground only). Our results suggest that the acoustic and seismoacoustic signals, produced by the atmospheric shock wave from the EDL, are unlikely to be detectable due to the pattern of winds in the martian atmosphere and the weak air-to-ground coupling, respectively. However, the elastodynamic seismic signal produced by the impact of the spacecraft's cruise balance masses on the surface may be detected by InSight. The upper and lower bounds on predicted ground velocity at InSight are 2.0 × 10−14 and 1.3 × 10−10 m s−1. The upper value is above the noise floor at the time of landing 40% of the time on average. The large range of possible values reflects uncertainties in the current understanding of impact-generated seismic waves and their subsequent propagation and attenuation through Mars. Uncertainty in the detectability also stems from the indeterminate instrument noise level at the time of this future event. A positive detection would be of enormous value in constraining the seismic properties of Mars, and in improving our understanding of impact-generated seismic waves

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

Emerging role of the calcium-activated, small conductance, SK3 K ⁺ channel in distal tubule function: Regulation by TRPV4

The Ca2+-activated, maxi-K (BK) K+ channel, with low Ca2+-binding affinity, is expressed in the distal tubule of the nephron and contributes to flow-dependent K+ secretion. In the present study we demonstrate that the Ca2+-activated, SK3 (KCa2.3) K + channel, with high Ca2+-binding affinity, is also expressed in the mouse kidney (RT-PCR, immunoblots). Immunohistochemical evaluations using tubule specific markers demonstrate significant expression of SK3 in the distal tubule and the entire collecting duct system, including the connecting tubule (CNT) and cortical collecting duct (CCD). In CNT and CCD, main sites for K+ secretion, the highest levels of expression were along the apical (luminal) cell membranes, including for both principal cells (PCs) and intercalated cells (ICs), posturing the channel for Ca2+- dependent K+ secretion. Fluorescent assessment of cell membrane potential in native, split-opened CCD, demonstrated that selective activation of the Ca2+-permeable TRPV4 channel, thereby inducing Ca2+ influx and elevating intracellular Ca2+ levels, activated both the SK3 channel and the BK channel leading to hyperpolarization of the cell membrane. The hyperpolarization response was decreased to a similar extent by either inhibition of SK3 channel with the selective SK antagonist, apamin, or by inhibition of the BK channel with the selective antagonist, iberiotoxin (IbTX). Addition of both inhibitors produced a further depolarization, indicating cooperative effects of the two channels on Vm. It is concluded that SK3 is functionally expressed in the distal nephron and collecting ducts where induction of TRPV4-mediated Ca2+ influx, leading to elevated intracellular Ca2+ levels, activates this high Ca2+- affinity K+ channel. Further, with sites of expression localized to the apical cell membrane, especially in the CNT and CCD, SK3 is poised to be a key pathway for Ca2+-dependent regulation of membrane potential and K+ secretion. © 2014 Berrout et al

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps