The rapid release of tight-binding inhibitors from dead-end ribulose-bisphosphate carboxylase/oxygenase (Rubisco) complexes requires the activity of Rubisco activase, an AAA+ ATPase that utilizes ...chemo-mechanical energy to catalyze the reactivation of Rubisco. Activase is thought to play a central role in coordinating the rate of CO2 fixation with the light reactions of photosynthesis. Here, we present a 1.9 Å crystal structure of the C-domain core of creosote activase. The fold consists of a canonical four-helix bundle, from which a paddle-like extension protrudes that entails a nine-turn helix lined by an irregularly structured peptide strand. The residues Lys-313 and Val-316 involved in the species-specific recognition of Rubisco are located near the tip of the paddle. An ionic bond between Lys-313 and Glu-309 appears to stabilize the glycine-rich end of the helix. Structural superpositions onto the distant homolog FtsH imply that the paddles extend away from the hexameric toroid in a fan-like fashion, such that the hydrophobic sides of each blade bearing Trp-302 are facing inward and the polar sides bearing Lys-313 and Val-316 are facing outward. Therefore, we speculate that upon binding, the activase paddles embrace the Rubisco cylinder by placing their hydrophobic patches near the partner protein. This model suggests that conformational adjustments at the remote end of the paddle may relate to selectivity in recognition, rather than specific ionic contacts involving Lys-313. Additionally, the superpositions predict that the catalytically critical Arg-293 does not interact with the bound nucleotide. Hypothetical ring-ring stacking and peptide threading models for Rubisco reactivation are briefly discussed.
Background: Rubisco activase has been linked to the inhibition of net photosynthesis upon warming.
Results: The structure of the C-terminal domain adopts an unusually elongated shape.
Conclusions: Reactivation of Rubisco may involve movement of a paddle-like extension.
Significance: This work will aid in gaining a better understanding of Rubisco regulation.
Baroreflex activation therapy (BAT) has been demonstrated to decrease office blood pressure (BP) in the randomized, double-blind Rheos trial. There are limited data on 24-hour BP changes measured by ...ambulatory BP measurements (ABPMs) using the first generation rheos BAT system suggesting a significant reduction but there are no information about the effect of the currently used, unilateral BAT neo device on ABPM. Patients treated with the BAT neo device for uncontrolled resistant hypertension were prospectively included into this study. ABPM was performed before BAT implantation and 6 months after initiation of BAT. A total of 51 patients were included into this study, 7 dropped out from analysis because of missing or insufficient follow-up. After 6 months, 24-hour ambulatory systolic (from 148 ± 17 mm Hg to 140 ± 23 mm Hg, P<0.01), diastolic (from 82 ± 13 mm Hg to 77 ± 15 mm Hg, P<0.01), day- and night-time systolic and diastolic BP (all P ≤ 0.01) significantly decreased while the number of prescribed antihypertensive classes could be reduced from 6.5 ± 1.5 to 6.0 ± 1.8 (P=0.03). Heart rate and pulse pressure remained unchanged. BAT was equally effective in reducing ambulatory BP in all subgroups of patients. This is the first study demonstrating a significant BP reduction in ABPM in patients undergoing chronically stimulation of the carotid sinus using the BAT neo device. About that BAT-reduced office BP and improved relevant aspects of ABPM, BAT might be considered as a new therapeutic option to reduce cardiovascular risk in patients with resistant hypertension. Randomized controlled trials are needed to evaluate BAT effects on ABPM in patients with resistant hypertension accurately.
Aims
We sought to describe the baseline characteristics of PARALLAX a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure (HF) with mildly reduced ...and preserved ejection fraction (HFpEF); compare PARALLAX to recent HFpEF trials; and examine the clinical characteristics associated with quality of life (QOL) and 6‐min walk test distance (6MWD).
Methods and results
A total of 2566 patients with HF and left ventricular ejection fraction (LVEF) >40% were randomized, of whom 96% had an LVEF ≥45%. Multivariable linear regression was used to determine characteristics associated with Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS) and 6MWD. Mean age was 73 ± 8 years, 51% were female, and comorbidities were common. Of the QOL measures tested in PARALLAX, the Short Form Health Survey‐36 physical functioning score was most closely correlated with 6MWD (R = 0.41, P < 0.001), and outperformed the KCCQ physical limitation score (R = 0.33) and KCCQ‐CSS (R = 0.31) on multivariable analyses. Female sex, higher body mass index, history of coronary artery disease, lower LVEF, and higher N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were associated with worse (lower) KCCQ‐CSS; older age, female sex, higher body mass index, diabetes, coronary artery disease, chronic obstructive pulmonary disease, prior HF hospitalization, lower LVEF, and higher NT‐proBNP were associated with shorter 6MWD (P < 0.05 for all associations).
Conclusions
PARALLAX is the largest HFpEF study to date to examine 6MWD together with QOL. The KCCQ‐CSS and 6MWD were modestly correlated, and several factors were associated with worse values of both. These results provide insight into the association between QOL and exercise capacity in HFpEF.
Summary of the PARALLAX trial and the relationship between N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), 6‐min walk test distance (6MWD), Kansas City Cardiomyopathy Questionnaire (KCCQ), Short Form Health Survey‐36 (SF‐36), and heart failure signs and symptoms. ACE‐I, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RASi, renin–angiotensin system inhibitor; RCT, randomized controlled trial.
This review article describes the current state of affairs concerning in vivo, in vitro and in numero studies on the hemodynamics in vascular access for hemodialysis. The use and complications of ...autogenous and non-autogenous fistulas and catheters and access port devices are explained in the first part. The major hemodynamic complications are stenosis, initiated by intimal hyperplasia development, and thrombosis. The different in literature proposed conceivable causes of intimal hyperplasia development like surgical interventions, compliance mismatch, wall shear stress (WSS) and shear rate, vessel wall thrill and blood pressure are discussed on the basis of in vivo, in vitro and in numero studies.
Clinical communities are an emerging approach to quality improvement (QI) to which several large-scale projects have attributed some success. In 2011 the Armstrong Institute for Patient Safety and ...Quality established clinical communities as a core strategy to connect frontline providers from six different hospitals to improve quality of care, patient safety, and value across the health system. CLINICAL COMMUNITIES: Fourteen clinical communities that presented great opportunity for improvement were established. A community could focus on a clinical area, a patient population, a group, a process, a safety-related issue, or nearly any health care issue. The collaborative spirit of the communities embraced interdisciplinary membership and representation from each hospital in each community. Communities engaged in team-building activities and facilitated discussions, met monthly, and were encouraged to meet in person to develop relationships and build trust. After a community was established, patients and families were invited to join and share their perspectives and experiences. ENABLING STRUCTURES: The clinical community structure provided clinicians access to resources, such as technical experts and safety and QI researchers, that were not easily otherwise accessible or available. Communities convened clinicians from each hospital to consider safety problems and their resolution and share learning with workplace peers and local unit safety teams.
The clinical communities engaged 195 clinicians from across the health system in QI projects and peer learning. Challenges included limited financial support and time for clinicians, timely access to data, limited resources from the health system, and not enough time with improvement experts.
Effects of global warming on animal distribution and performance become visible in many marine ecosystems. The present study was designed to develop a concept for a cause and effect understanding ...with respect to temperature changes and to explain ecological findings based on physiological processes. The concept is based on a wide comparison of invertebrate and fish species with a special focus on recent data obtained in two model species of fish. These fish species are both characterized by northern and southern distribution limits in the North Atlantic: eelpout (
Zoarces viviparus), as a typical non-migrating inhabitant of the coastal zone and the cod (
Gadus morhua), as a typical inhabitant of the continental shelf with a high importance for fisheries.
Mathematical modelling demonstrates a clear significant correlation between climate induced temperature fluctuations and the recruitment of cod stocks. Growth performance in cod is optimal at temperatures close to 10°C, regardless of the population investigated in a latitudinal cline. However, temperature specific growth rates decrease at higher latitudes. Also, fecundity is less in White Sea than in North and Baltic Sea cod or eelpout populations. These findings suggest that a cold-induced shift in energy budget occurs which is unfavorable for growth performance and fecundity. Thermal tolerance limits shift depending on latitude and are characterized by oxygen limitation at both low or high temperatures. Oxygen supply to tissues is optimized at low temperature by a shift in hemoglobin isoforms and oxygen binding properties to lower affinities and higher unloading potential. Protective stimulation of heat shock protein synthesis was not observed.
According to a recent model of thermal tolerance the downward shift of tolerance limits during cold adaptation is associated with rising mitochondrial densities and, thus, aerobic capacity and performance in the cold, especially in eurythermal species. At the same time the costs of mitochondrial maintenance reflected by mitochondrial proton leakage should rise leaving a lower energy fraction for growth and reproduction. The preliminary conclusion can be drawn that warming will cause a northern shift of distribution limits for both species with a rise in growth performance and fecundity larger than expected from the Q
10 effect in the north and lower growth or even extinction of the species in the south. Such a shift may heavily affect fishing activities in the North Sea.
Hydrocarbon stapling has been applied to restore and stabilize the α-helical structure of bioactive peptides for biochemical, structural, cellular, and in vivo studies. The peptide sequence, in ...addition to the composition and location of the installed staple, can dramatically influence the properties of stapled peptides. As a result, constructs that appear similar can have distinct functions and utilities. Here, we perform a side-by-side comparison of stapled peptides modeled after the pro-apoptotic BIM BH3 helix to highlight these principles. We confirm that replacing a salt-bridge with an i, i + 4 hydrocarbon staple does not impair target binding affinity and instead can yield a biologically and pharmacologically enhanced α-helical peptide ligand. Importantly, we demonstrate by electron microscopy that the pro-apoptotic activity of a stapled BIM BH3 helix correlates with its capacity to achieve cellular uptake without membrane disruption and accumulate at the organellar site of mechanistic activity.
Development of a coherent literature evaluating patient safety practices has been hampered by the lack of an underlying conceptual framework. The authors describe issues and choices in describing and ...classifying diverse patient safety practices (PSPs).
The authors developed a framework to classify PSPs by identifying and synthesising existing conceptual frameworks, evaluating the draft framework by asking a group of experts to use it to classify a diverse set of PSPs and revising the framework through an expert-panel consensus process.
The 11 classification dimensions in the framework include: regulatory versus voluntary; setting; feasibility; individual activity versus organisational change; temporal (one-time vs repeated/long-term); pervasive versus targeted; common versus rare events; PSP maturity; degree of controversy/conflicting evidence; degree of behavioural change required for implementation; and sensitivity to context.
This framework offers a way to classify and compare PSPs, and thereby to interpret the patient-safety literature. Further research is needed to develop understanding of these dimensions, how they evolve as the patient safety field matures, and their relative utilities in describing, evaluating and implementing PSPs.
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