Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity.

The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by "funny" current (If) through HCN4 channels (the "Membrane Clock" hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two ("Coupled Clock"). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice. NCX1 protein was undetectable in KO atrial tissue, including the SAN. Surface ECG and intracardiac electrograms showed no atrial depolarization and a slow junctional escape rhythm in KO that responded appropriately to β-adrenergic and muscarinic stimulation. Although KO atria were quiescent they could be stimulated by external pacing suggesting that electrical coupling between cells remained intact. Despite normal electrophysiological properties of If in isolated patch clamped KO SAN cells, pacemaker activity was absent. Recurring Ca sparks were present in all KO SAN cells, suggesting that Ca cycling persists but is uncoupled from the sarcolemma. We conclude that NCX1 is required for normal pacemaker activity in murine SAN

Seconds after impact: Insights into the thermal history of impact ejecta from diffusion between lechatelierite and host glass in tektites and experiments

Tektites contain inclusions of lechatelierite, nearly pure SiO_2 glass formed by quenching of quartz grains melted during hypervelocity impacts. We report the discovery in a tektite of chemically zoned boundary layers (ca 20 μm) between lechatelierite and host felsic glass. These boundary layers in tektites formed by chemical diffusion between molten silicainclusions (quenched to lechatelierite on cooling) and surrounding felsic melt. We reproduced the details of these boundary layers via experiments on mixtures of powdered natural tektite plus quartz grains heated to 1800–2400 °C for 1–120 s using an aerodynamic levitation laser heating furnace. The results of these experiments were used to provide quantitative constraints on possible thermal histories of the natural sample. The experiments successfully reproduced all major aspects of the concentration profiles from the natural sample including diffusion length scale, strong asymmetry of the concentration profiles with respect to the Matano plane (due to the strong concentration dependence of the diffusivities of all oxides on SiO_2 content), similarities in lengths of the diffusive profiles (due to control by the diffusion of SiO_2 on the diffusivity of the other oxides), and differences in the shapes of the profiles among the oxides (including a maximum in the diffusion profile of K_2O due to uphill diffusion). The characteristic lengths of all non-alkali oxide profiles are proportional to t from which diffusivities and activation energies can be derived; these results are consistent with measurements in melts with lower SiO_2 contents and at lower temperatures reported in the literature. We also fit the experimental profiles of SiO_2 and Al_2O_3 using simple formulations of the dependence of their diffusivities on SiO_2 content and temperature, yielding results similar to those obtained from the t dependence of the characteristic profile lengths. The quantitative characterization of diffusion in boundary layers based on our experiments allow us to set limits on the thermal history of the natural tektite in which the boundary layers were discovered. If the interdiffusion between the silica and felsic melts occurred at constant temperature, the duration of heating experienced by the natural tektite we studied depends on temperature; possible solutions include heating at ∼2000 °C for ∼70 s, −2400 °C for ∼3 s. We also explored non-isothermal, asymptotic cooling histories; for a maximum temperature of 2400 °C, a characteristic cooling time scale of ∼50 s is implied, whereas, for 2000 °C, the time scale is ∼1400 s. Further, a maximum temperature of ∼2360 °C yields an effective diffusive time scale of ∼5 s, a cooling time scale of ∼90 s, and a cooling rate at the glass transition temperature of ∼5 °C/s; results that are consistent with independent estimates of cooling time scales for ∼1 cm clasts (Xu and Zhang, 2002), as well as cooling rates at the glass transition temperature (Wilding et al., 1996) – thus satisfying all currently available relevant data. More complex T-t paths are possible and can also be modeled using our experimental results and compared with and used as tests of the accuracy of physical models of tektite-forming impact events

CD25 expression distinguishes functionally distinct alloreactive CD4+ CD134+ (OX40+) T-cell subsets in acute graft-versus-host disease

AbstractCD134 (OX40) is expressed on activated CD4+ donor T cells in allogeneic stem cell transplant recipients with acute graft-versus-host disease. The data presented here reveal that differential expression of CD25 by CD4+ CD134+ T cells allows separation of these activated cells into 2 phenotypically and functionally distinct alloreactive T-cell subsets. These subsets exhibit distinct tissue associations, with CD4+ CD134+ CD25− T cells preferentially found in lymphoid tissues and CD4+ CD134+ CD25+ T cells located in lymphoid tissues and inflamed extralymphoid tissues. The CD25− T-cell subset exhibited potent proliferative responses to both concanavalin A and allogeneic host leukocytes. By contrast, the CD25+ T-cell subset proliferated minimally in response to either treatment and inhibited alloantigen-induced proliferation of the CD25− subset. Proliferative unresponsiveness associated with the CD25+ T-cell subset did not extend to cytokine secretion. When stimulated with alloantigen, both CD4+ CD134+ T-cell subsets responded by secreting interferon-γ and interleukin (IL)-10, and neither T-cell subset produced detectable levels of IL-2 or IL-4. Three-day treatment of the CD25+ T-cell subset with IL-2 restored the proliferative responsiveness of these cells to host alloantigens, suggesting that the proliferative unresponsiveness associated with this T-cell subset reflected a requirement for IL-2. The preferential tissue associations and distinct functional properties associated with these separable alloreactive CD4+ CD134+ T-cell subsets suggest that they participate differentially in clinical graft-versus-host disease

Lake Michigan’s suitability for bigheaded carp: The importance of diet flexibility and subsurface habitat

As bighead (Hypophthalmichthys nobilis) and silver carp (Hypophthalmichthys molitrix)—collectively bigheaded carp (BHC)—arrive at Lake Michigan’s doorstep, questions remain as to whether there is sufficient food to support these invasive filter‐feeding fishes in the upper Laurentian Great Lakes. Previous studies suggest that suitable BHC habitat is limited to a few productive, nearshore areas. However, those studies did not consider the influence of BHC’s diet plasticity or the presence of spatially‐discrete subsurface prey resources. This study aimed to characterise Lake Michigan’s suitability for BHC and evaluate the importance of these considerations in habitat suitability assessments.We used simulated outputs of prey biomass (phytoplankton, zooplankton, and detritus) and water temperature from a three‐dimensional biophysical model of Lake Michigan to evaluate growth rate potential (GRP, quantitative index of habitat suitability) of adult BHC throughout the entire volume of the lake. Our GRP model applied a foraging model and a bioenergetics model to translate prey concentrations and water temperatures into habitat quality indexed by individual fish growth rate. We defined suitable habitat as habitats that can support GRP ≥ 0 g g−1 day−1. We developed six feeding scenarios to evaluate the impact of diet flexibility and subsurface prey resources on suitable habitat quantity. Scenarios were defined by the number of prey types the fish could consume and the depths at which they could feed (surface or whole water column).Consistent with previous studies, we found that habitats with the highest quality were concentrated near river mouths and in eutrophic areas of Green Bay. However, in contrast to previous studies, we found suitable offshore habitat for bighead carp owing to our added considerations of diet plasticity and subsurface prey resources. For silver carp, these considerations extended suitable habitat within Green Bay and in some tributary‐influenced nearshore areas, but offshore areas remained predominantly unsuitable in all feeding scenarios. Differences in simulated habitat suitability between these two species probably reflect differences in energy density and mass of the specific fishes we used in our model. However, reports of these two species in environments where they coexist indicate that bighead carp grow at faster rates than silver carp, as our model simulated.Our vertical analysis at Muskegon, MI, U.S.A. indicates that subsurface temperature and prey biomass are not only sufficient to support bighead carp growth but provide maximum habitat quality during late summer stratification.Overall, our study demonstrates that BHC are capable of surviving and growing in much larger areas of Lake Michigan than predicted by previous studies, and thus suggests that the risk of establishment is not sufficiently reduced by low plankton concentrations. Maps generated by our model identified the potential for cross‐lake migration corridors that may facilitate and accelerate lake‐wide movements. We believe these maps could be used to prioritise surveillance protocols by identifying areas to which BHC might spread upon entering the lake. More broadly, this research demonstrates how the physiology and trophic ecology of BHC contributes to their high invasive capacity and can permit their survival in novel environments.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151968/1/fwb13382_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151968/2/fwb13382.pd

Challenges in the postsurgical recovery of cushing syndrome: glucocorticoid withdrawal syndrome

Glucocorticoid withdrawal syndrome is a challenging clinical phenomenon that can complicate the postsurgical recovery of Cushing syndrome. It is characterized by physical tolerance and dependence to supraphysiologic glucocorticoid exposure during active Cushing syndrome followed by the abrupt decline in cortisol levels after surgical treatment. The symptoms of glucocorticoid withdrawal often overlap with those of postoperative adrenal insufficiency and can be difficult for patients to cope with and for clinicians to treat. This mini review will discuss the clinical characteristics, pathophysiology, and management of glucocorticoid withdrawal syndrome while highlighting recent data in the field

What Makes Theatrical Performances Successful in China's Tourism Industry?

This study aims to explore the factors affecting the success of a popular tourist product, namely, theatrical performance, within the context of China's tourism industry and develop a model based on previously successful productions. Using qualitative software, 22 Chinese-language articles on theatrical performances are analyzed to generate a list of success factors, classified as internal and external. The internal factors are storyline and performing, market positioning and marketing strategy, investment and financial support, operation and management, performing team, outdoor venue, indoor/outdoor stage supporting facilities, continuous improvement, and production team. The external factors are collaboration between cultural industries and local tourism, government support, privatization, and social and cultural effect. This study also provides suggestions for the future development of theatrical performances in China

Local atomic stacking and symmetry in twisted graphene trilayers

Moir\'e superlattices formed from twisting trilayers of graphene are an ideal model for studying electronic correlation, and offer several advantages over bilayer analogues, including more robust and tunable superconductivity and a wide range of twist angles associated with flat band formation. Atomic reconstruction, which strongly impacts the electronic structure of twisted graphene structures, has been suggested to play a major role in the relative versatility of superconductivity in trilayers. Here, we exploit an inteferometric 4D-STEM approach to image a wide range of trilayer graphene structures. Our results unveil a considerably different model for moir\'e lattice relaxation in trilayers than that proposed from previous measurements, informing a thorough understanding of how reconstruction modulates the atomic stacking symmetries crucial for establishing superconductivity and other correlated phases in twisted graphene trilayers.Comment: 18 pages, 5 figure

Acute glycogen synthase kinase-3 inhibition modulates human cardiac conduction

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered

Chamber-specific transcriptional responses in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a murine genetic model is sufficient to increase ploidy in both atrial chambers. Notch activation within LA CMs generated a transcriptomic fingerprint resembling AF, with dysregulation of transcription factor and ion channel genes, including Pitx2, Tbx5, Kcnh2, Kcnq1, and Kcnip2. Notch activation also produced distinct cellular electrophysiologic responses in LA versus right atrial CMs, prolonging the action potential duration (APD) without altering the upstroke velocity in the left atrium and reducing the maximal upstroke velocity without altering the APD in the right atrium. Our results support a shared human/murine model of increased Notch pathway activity predisposing to AF

Development of a quality assessment tool for systematic reviews of observational studies (QATSO) of HIV prevalence in men having sex with men and associated risk behaviours

<p>Abstract</p> <p>Background</p> <p>Systematic reviews based on the critical appraisal of observational and analytic studies on HIV prevalence and risk factors for HIV transmission among men having sex with men are very useful for health care decisions and planning. Such appraisal is particularly difficult, however, as the quality assessment tools available for use with observational and analytic studies are poorly established.</p> <p>Methods</p> <p>We reviewed the existing quality assessment tools for systematic reviews of observational studies and developed a concise quality assessment checklist to help standardise decisions regarding the quality of studies, with careful consideration of issues such as external and internal validity.</p> <p>Results</p> <p>A pilot version of the checklist was developed based on epidemiological principles, reviews of study designs, and existing checklists for the assessment of observational studies. The Quality Assessment Tool for Systematic Reviews of Observational Studies (QATSO) Score consists of five items: External validity (1 item), reporting (2 items), bias (1 item) and confounding factors (1 item). Expert opinions were sought and it was tested on manuscripts that fulfil the inclusion criteria of a systematic review. Like all assessment scales, QATSO may oversimplify and generalise information yet it is inclusive, simple and practical to use, and allows comparability between papers.</p> <p>Conclusion</p> <p>A specific tool that allows researchers to appraise and guide study quality of observational studies is developed and can be modified for similar studies in the future.</p