Spontaneous, pro-arrhythmic calcium signals disrupt electrical pacing in mouse pulmonary vein sleeve cells

The pulmonary vein, which returns oxygenated blood to the left atrium, is ensheathed by a population of unique, myocyte- like cells called pulmonary vein sleeve cells (PVCs). These cells autonomously generate action potentials that propagate into the left atrial chamber and cause arrhythmias resulting in atrial fibrillation; the most common, often sustained, form of cardiac arrhythmia. In mice, PVCs extend along the pulmonary vein into the lungs, and are accessible in a lung slice preparation. We exploited this model to study how aberrant Ca2+ signaling alters the ability of PVC networks to follow electrical pacing. Cellular responses were investigated using real-time 2-photon imaging of lung slices loaded with a Ca2+- sensitive fluorescent indicator (Ca2+ measurements) and phase contrast microscopy (contraction measurements). PVCs displayed global Ca2+ signals and coordinated contraction in response to electrical field stimulation (EFS). The effects of EFS relied on both Ca2+ influx and Ca2+ release, and could be inhibited by nifedipine, ryanodine or caffeine. Moreover, PVCs had a high propensity to show spontaneous Ca2+ signals that arose via stochastic activation of ryanodine receptors (RyRs). The ability of electrical pacing to entrain Ca2+ signals and contractile responses was dramatically influenced by inherent spontaneous Ca2+ activity. In PVCs with relatively low spontaneous Ca2+ activity (2+ activity (>1.5 Hz), electrical pacing was less effective; PVCs became unpaced, only partially-paced or displayed alternans. Because spontaneous Ca2+ activity varied between cells, neighboring PVCs often had different responses to electrical pacing. Our data indicate that the ability of PVCs to respond to electrical stimulation depends on their intrinsic Ca2+ cycling properties. Heterogeneous spontaneous Ca2+ activity arising from stochastic RyR opening can disengage them from sinus rhythm and lead to autonomous, pro-arrhythmic activity

“My Lung Disease Won’t Go Away, it’s There to Stay”: Profiles of Adaptation to Functional Limitations in Workers with Asthma and COPD

Purpose Earlier research has shown that adaptation (i.e., the way in which employees cope with limitations resulting from their disease) is associated with sick leave. Our aim was to investigate signs of adequate or inadequate adaptation in employees with asthma and COPD. Methods A Q-methodological study was carried out among 34 workers with asthma or COPD. Results Four adaptation profiles were distinguished: the eager, the adjusted, the cautious, and the worried workers. The adaptation profiles provide insight into the different ways in which workers with asthma and COPD cope with their illness at work. Conclusions The adaptation profiles serve as a starting point for the design of appropriate (occupational) care. The eager workers experience little difficulties at work; the cautious workers may need assistance in learning how to accept their disease; the worried workers need reassurance, and may need reactivation; the adjusted workers deserve extra attention, and, when necessary, advice on how to live with their asthma or COPD

Impact of Sarcoplasmic Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial Myocytes: A Computational Study

Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca2+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca2+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca2+ dynamics: 1) the biphasic increment during the upstroke of the Ca2+ transient resulting from the delay between the peripheral and central SR Ca2+ release, and 2) the relative contribution of SL Ca2+ current and SR Ca2+ release to the Ca2+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca2+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca2+ release sites define the interface between Ca2+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca2+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na+ concentration. Finally, the results indicate that the SR Ca2+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca2+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes

Investigations into a putative role for the novel BRASSIKIN pseudokinases in compatible pollen-stigma interactions in Arabidopsis thaliana.

BACKGROUND: In the Brassicaceae, the early stages of compatible pollen-stigma interactions are tightly controlled with early checkpoints regulating pollen adhesion, hydration and germination, and pollen tube entry into the stigmatic surface. However, the early signalling events in the stigma which trigger these compatible interactions remain unknown. RESULTS: A set of stigma-expressed pseudokinase genes, termed BRASSIKINs (BKNs), were identified and found to be present in only core Brassicaceae genomes. In Arabidopsis thaliana Col-0, BKN1 displayed stigma-specific expression while the BKN2 gene was expressed in other tissues as well. CRISPR deletion mutations were generated for the two tandemly linked BKNs, and very mild hydration defects were observed for wild-type Col-0 pollen when placed on the bkn1/2 mutant stigmas. In further analyses, the predominant transcript for the stigma-specific BKN1 was found to have a premature stop codon in the Col-0 ecotype, but a survey of the 1001 Arabidopsis genomes uncovered three ecotypes that encoded a full-length BKN1 protein. Furthermore, phylogenetic analyses identified intact BKN1 orthologues in the closely related outcrossing Arabidopsis species, A. lyrata and A. halleri. Finally, the BKN pseudokinases were found to be plasma-membrane localized through the dual lipid modification of myristoylation and palmitoylation, and this localization would be consistent with a role in signaling complexes. CONCLUSION: In this study, we have characterized the novel Brassicaceae-specific family of BKN pseudokinase genes, and examined the function of BKN1 and BKN2 in the context of pollen-stigma interactions in A. thaliana Col-0. Additionally, premature stop codons were identified in the predicted stigma specific BKN1 gene in a number of the 1001 A. thaliana ecotype genomes, and this was in contrast to the out-crossing Arabidopsis species which carried intact copies of BKN1. Thus, understanding the function of BKN1 in other Brassicaceae species will be a key direction for future studies

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Targeting diastolic dysfunction by genetic engineering of calcium handling proteins.

Diastolic heart failure (HF) is associated with significant morbidity and mortality, and is a growing medical problem in this country. Diastolic dysfunction is defined as an abnormality in myocardial relaxation that impairs filling during diastole and contributes to the clinical syndrome of HF. Effective clinical strategies to treat diastolic dysfunction are limited. This article focuses on the potential application of parvalbumin--a fast skeletal muscle calcium buffer--for remediation of slow relaxation in the failing heart

Predictive Value of Multiparametric Magnetic Resonance Imaging in Risk Group Stratification of Prostate Adenocarcinoma

Purpose: The aim of this study was to further assess the clinical utility of multiparametric magnetic resonance imaging (MP-MRI) in prostate cancer (PC) staging following 2023 clinical guideline changes, both as an independent predictor of high-stage (>T3a) or high-risk PC and when combined with patient characteristics. Methods and Materials: The present study was a retrospective review of 171 patients from 2008 to 2018 who underwent MP-MRI before radical prostatectomy at a single institution. The accuracy of clinical staging was compared between conventional staging and MP-MRI-based clinical staging. Sensitivity, specificity, positive predictive value, and negative predictive value were compared, and receiver operating characteristic curves were generated. Linear regression analyses were used to calculate concordance (C-statistic). Results: Of the 171 patients, final pathology revealed 95 (55.6%) with T2 disease, 62 (36.3%) with T3a disease, and 14 (8.2%) with T3b disease. Compared with conventional staging, MP-MRI-based staging demonstrated significantly increased accuracy in identifying T3a disease, intermediate risk, and high/very-high-risk PC. When combined with clinical characteristics, MP-MRI-based staging improved the area under the curve from 0.753 to 0.808 (P = .0175), compared with conventional staging. Conclusions: MP-MRI improved the identification of T3a PC, intermediate-risk PC, and high- or very-high-risk PC. Further, when combined with clinical characteristics, MP-MRI-based staging significantly improved risk stratification, compared with conventional staging. These findings represent further evidence to support the integration of MP-MRI into prostate adenocarcinoma clinical staging guidelines

Survival and hsp70 gene expression in Plutella xylostella and its larval parasitoid Diadegma insulare varied between slowly ramping and abrupt extreme temperature regimes.

BACKGROUND: In nature, insects have evolved behavioural and physiological adaptations to cope with short term exposure to extreme temperatures. Extreme heat events may increase as a result of climate change; this in turn will affect insect population dynamics. We examined the effect of abrupt and ecologically relevant gradual exposure to high temperatures on the survival and hsp70 gene expression in diamondback moth (DBM) adults and the parasitoid Diadegma insulare, as well as in parasitized and non-parasitized DBM larvae. PRINCIPAL FINDINGS: Tolerance to high temperatures in DBM adults was higher than in D. insulare adults. There was no difference in the survival of DBM adults between abrupt and ramped increases from 25 to 38°C; however, at 40°C survival was higher when the temperature increased gradually. In contrast, more D. insulare adults survived when the temperature was ramped rather than shifted abruptly to both 38 and 40°C. There was no heat stress effect of up to 40°C on the survival of either parasitized or non-parasitized DBM larvae. In adults of both species, more hsp70 expression was observed when temperatures increased abruptly to 38°C compared to ramping. In contrast, at 40°C significantly more expression was found in insects exposed to the ramping rather than the abrupt regime. Hsp70 expression level was in agreement with adult survival data and appears to be a good indicator of stress levels. In parasitized and non-parasitized larvae, hsp70 expression was significantly higher after abrupt shifts compared to ramping at both temperatures. CONCLUSIONS/SIGNIFICANCE: Hsp70 gene expression was responsive to extreme temperatures in both DBM and D. insulare, which may underlie the ability of these insects to survive in extreme temperatures. Survival and hsp70 expression upon abrupt changes are distinctly different from those after ramping indicating that experimental protocol must be considered before extrapolating laboratory results to natural field situations