Mechanosensitive calcium flashes promote sustained RhoA activation during tight junction remodeling

Epithelial cell–cell junctions remodel in response to mechanical stimuli to maintain barrier function. Previously, we found that local leaks in tight junctions (TJs) are rapidly repaired by local, transient RhoA activation, termed “Rho flares,” but how Rho flares are regulated is unknown. Here, we discovered that intracellular calcium flashes and junction elongation are early events in the Rho flare pathway. Both laser-induced and naturally occurring TJ breaks lead to local calcium flashes at the site of leaks. Additionally, junction elongation induced by optogenetics increases Rho flare frequency, suggesting that Rho flares are mechanically triggered. Depletion of intracellular calcium or inhibition of mechanosensitive calcium channels (MSCs) reduces the amplitude of calcium flashes and diminishes the sustained activation of Rho flares. MSC-dependent calcium influx is necessary to maintain global barrier function by regulating reinforcement of local TJ proteins via junction contraction. In all, we uncovered a novel role for MSC-dependent calcium flashes in TJ remodeling, allowing epithelial cells to repair local leaks induced by mechanical stimuli

Discriminatory behavior in New York restaurants: 1950 and 1981

Survey techniques are combined with behavioral observations in this attempt to replicate a 1950 baseline study in order to examine trends in racial discrimination. In the 1950 study, treatment of black and white couples was compared in a sample of 62 restaurants drawn from a population of all restaurants in a large area of East Side Manhattan. In 1981 we carried out similar comparisons in a sample of 20 restaurants (plus four replications) drawn from the same area, following as closely as possible the procedures used in the baseline study. A substantial amount of discrimination was found in 1981, though somewhat less than in 1950. The difficult problems of determining when discrimination has and has not occurred are discussed from the standpoints of both black customers and social science investigators.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43682/1/11205_2005_Article_BF02193666.pd

Incremental benefit in correlation with histology of native T1 mapping, partition coefficient and extracellular volume fraction in patients with aortic stenosis

Background: We investigated the histological correlation of native T1 maps, partition coefficient and extracellular volume fraction (ECV) using an 11 heart beat (11 HB) MOLLI for identification of overall burden of fibrosis. Methods: Ten patients (8 male, age 73 ± 7 years; all in sinus rhythm, 2 with ventricular ectopy) with severe aortic stenosis (3 with coexisting coronary artery disease) scheduled for surgical aortic valve replacement underwent CMR on a 1.5T scanner (MAGNETOM Avanto, Siemens Healthcare, Erlangen). The 11HB MOLLI sequence (Siemens investigational prototype WIP 448B) was acquired before and 15 minutes post 0.1 mmol/kg gadolinium administration. Incorporating hematocrit results from the same day. This allowed native T1 maps, partition coefficient and ECV calculation. Images were obtained twice at end diastole at basal, and twice at mid left ventricular level. The average of all measurements was used to calculate ECV using the standard formula Partition Coefficient= [(1/T1myocardium post contrast-1/T1 myocardium native)]/[(1/T1 blood post contrast-1/T1 blood native)] with x(1-HCt) for ECV. Similar regions of interest were drawn in the septum at both levels for T1 values. Intraoperatively, trucut biopsies were taken from the left ventricular apical anterior/ lateral wall through the epicardium to allow histological characterization of the full myocardial wall, and fixed in warm buffered formalin. Histological analysis of formalin-fixed paraffin-embedded, transmural myocardial biopsies of the left ventricle was performed on hematoxylin/eosin and Picrosirius red-stained 3-micron-thick sections by a blinded experienced cardiac pathologist. Images were analysed using a purpose-built software (Nikon NIS elements BR) on a NIKON Eclipse light projection microscope to determine the extent of overall and reactive interstitial fibrosis, which was expressed as collagen volume fraction (%) per square millimetre. Results: Native T1 mapping, partition coefficient and ECV all correlated with histologically measured fibrosis. However, native T1 mapping showed the least accuracy (panel A, R2 = 0.42) and ECV showed the highest accuracy (panel B, R2 = 0.83). Partition coefficient was more accurate than native T1 mapping but only very marginally less so than ECV (panel C, R2 = 0.80). Conclusions: These results suggest that native T1 mapping is less accurate than partition coefficient and ECV for overall fibrosis. Therefore, post gadolinium images to enable calculation of partition coefficient and ECV should be routinely obtained to increase accuracy

A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005)

Fanny Copeland and the geographical imagination

Raised in Scotland, married and divorced in the English south, an adopted Slovene, Fanny Copeland (1872 – 1970) occupied the intersection of a number of complex spatial and temporal conjunctures. A Slavophile, she played a part in the formation of what subsequently became the Kingdom of Yugoslavia that emerged from the First World War. Living in Ljubljana, she facilitated the first ‘foreign visit’ (in 1932) of the newly formed Le Play Society (a precursor of the Institute of British Geographers) and guided its studies of Solčava (a then ‘remote’ Alpine valley system) which, led by Dudley Stamp and commended by Halford Mackinder, were subsequently hailed as a model for regional studies elsewhere. Arrested by the Gestapo and interned in Italy during the Second World War, she eventually returned to a socialist Yugoslavia, a celebrated figure. An accomplished musician, linguist, and mountaineer, she became an authority on (and populist for) the Julian Alps and was instrumental in the establishment of the Triglav National Park. Copeland’s role as participant observer (and protagonist) enriches our understanding of the particularities of her time and place and illuminates some inter-war relationships within G/geography, inside and outside the academy, suggesting their relative autonomy in the production of geographical knowledge

Essential indicators for measuring site‐based conservation effectiveness in the post‐2020 global biodiversity framework

Abstract: Work on the post‐2020 global biodiversity framework is now well advanced and will outline a vision, goals, and targets for the next decade of biodiversity conservation and beyond. For the effectiveness of Protected areas and Other Effective area‐based Conservation Measures, an indicator has been proposed for “areas meeting their documented ecological objectives.” However, the Convention on Biological Diversity (CBD) has not identified or agreed on what data should inform this indicator. Here we draw on experiences from the assessment of protected area effectiveness in the CBD's previous strategic plan to provide recommendations on the essential elements related to biodiversity outcomes and management that need to be captured in this updated indicator as well as how this could be done. Our proposed protected area effectiveness indicators include a combination of remotely derived products for all protected areas, combined with data from monitoring of both protected area management and trends in species and ecosystems based on field observations. Additionally, we highlight the need for creating a digital infrastructure to operationalize national‐level data‐capture. We believe these steps are critical and urge the adoption of suitable protected area effectiveness indicators before the post‐2020 framework is agreed in 2021

Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy : Insights From Wave Intensity Analysis and Magnetic Resonance

Background: Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Objectives: Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Methods: Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Results: Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Conclusions: Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment