Computational protein design with backbone plasticity

The computational algorithms used in the design of artificial proteins have become increasingly sophisticated in recent years, producing a series of remarkable successes. The most dramatic of these is the de novo design of artificial enzymes. The majority of these designs have reused naturally occurring protein structures as “scaffolds” onto which novel functionality can be grafted without having to redesign the backbone structure. The incorporation of backbone flexibility into protein design is a much more computationally challenging problem due to the greatly increase search space but promises to remove the limitations of reusing natural protein scaffolds. In this review, we outline the principles of computational protein design methods and discuss recent efforts to consider backbone plasticity in the design process

The donor heart and organ perfusion technology.

Recent advancement in organ perfusion technology has led to increase clinical transplantation of marginal donor organs and allow for distant procurement of cardiac allograft beyond the time limitation of cold static storage. Ex-situ heart perfusion also provides essential nutrients to maintain cell integrity, thereby reducing the risk of ischaemic injury for functional preservation and provides a platform to assess organ viability and feasibility, with the potential for pharmacotherapy to recover these hearts. Notably, the use of NMP has led to the first distant procurement cardiac transplantation from a donation after circulatory death (DCD) in 2014, which resulted in the adoption of DCD heart transplantation in 4 centres between the United Kingdom and Australia. To date, over 100 DCD heart transplants have been performed utilising cardiac perfusion system with an estimated 10-15% increase in transplant activity in the individual units. This review aims to provide an overview of current experience and outcomes using cardiac perfusion technology, including future technologies and recent advancement within the field

Atrial fibrillation and thromboprophylaxis in heart failure: The need for patient-centered approaches to address adherence

Atrial fibrillation is a common arrhythmia in heart failure and a risk factor for stroke. Risk assessment tools can assist clinicians with decision making in the allocation of thromboprophylaxis. This review provides an overview of current validated risk assessment tools for atrial fibrillation and emphasizes the importance of tailoring individual risk and the importance of weighing the benefits of treatment. Further, this review provides details of innovative and patient-centered methods for ensuring optimal adherence to prescribed therapy. Prior to initiating oral anticoagulant therapy, a comprehensive risk assessment should include evaluation of associated cardiogeriatric conditions, potential for adherence to prescribed therapy, frailty, and functional and cognitive ability. © 2013 Ferguson et al, publisher and licensee Dove Medical Press Ltd

Barriers and enablers to adherence to anticoagulation in heart failure with atrial fibrillation: patient and provider perspectives

© 2017 John Wiley & Sons Ltd Aims & Objectives: The purpose of this study was to elucidate the barriers and enablers to adherence to anticoagulation in individuals with chronic heart failure (CHF) with concomitant atrial fibrillation (AF) from the perspective of patients and providers. Background: CHF and AF commonly coexist and are associated with increased stroke risk and mortality. Oral anticoagulation significantly reduces stroke risk and improves outcomes. Yet, in approximately 30% of cases, anticoagulation is not commenced for a variety of reasons. Design: Qualitative study using narrative inquiry. Methods: Data from face-to-face individual interviews with patients and information retrieved from healthcare file note review documented the clinician perspective. This study is a synthesis of the two data sources, obtained during patient clinical assessments as part of the Atrial Fibrillation And Stroke Thromboprophylaxis in hEart failuRe (AFASTER) Study. Results: Patient choice and preference were important factors in anticoagulation decisions, including treatment burden, unfavourable or intolerable side effects and patient refusal. Financial barriers included cost of travel, medication cost and reimbursement. Psychological factors included psychiatric illness, cognitive impairment and depression. Social barriers included homelessness and the absence of a caregiver or lack of caregiver assistance. Clinician reticence included fear of falls, frailty, age, fear of bleeding and the challenges of multimorbidity. Facilitators to successful prescription and adherence were caregiver support, reminders and routine, self-testing and the use of technology. Conclusions: Many barriers remain to high-risk individuals being prescribed anticoagulation for stroke prevention. There are a number of enabling factors that facilitate prescription and optimise treatment adherence. Nurses should challenge these treatment barriers and seek enabling factors to optimise therapy. Relevance to clinical practice: Nurses can help patients and caregivers to understand complex anticoagulant risk-benefit information, and act as a patient advocate when making complex stroke prevention decisions

Oxygen use in chronic heart failure to relieve breathlessness: A systematic review

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. To appraise published studies on the use of supplemental oxygen in chronic heart failure. Chronic breathlessness is a characterizing symptom of symptomatic heart failure resulting in substantial disability and healthcare utilization and is the primary reason for emergency room visits and hospitalizations. In spite of the variable evidence, oxygen therapy is commonly administered both acutely and chronically. Moreover, the role of oxygen therapy to relieve chronic breathlessness in heart failure is not well described, particularly in normoxemic or mild or intermittent hypoxemic states. In fact, several studies have shown the detrimental effects of oxygen therapy with normal oxygen saturation levels. A systematic review using PRISMA guidelines. Four databases PubMed, Embase, CINAHL, and Web of Science were systematically searched from January 2001 to January 2019 investigating the use of oxygen in heart failure. Duplicate articles were removed from the review. Titles and abstracts were screened for inclusion and exclusion criteria. The remaining full-text articles were reviewed and hand-searched for additional references. The quality of the full-text articles was assessed using standardized critical appraisal instruments by the Joanna Briggs Institute. A total of 11 studies, including three intervention and eight non-interventions studies, were included in this review from 1072 non-duplicated records retrieved. Sample size ranged from 4 to 5862. In spite of common usage, this review suggests that there are scant data available to justify the use of oxygen in individuals with non-hypoxemic chronic heart failure and chronic breathlessness

Synthetic beta-solenoid proteins with the fragment-free computational design of a beta-hairpin extension

The ability to design and construct structures with atomic level precision is one of the key goals of nanotechnology. Proteins offer an attractive target for atomic design, as they can be synthesized chemically or biologically, and can self-assemble. However the generalized protein folding and design problem is unsolved. One approach to simplifying the problem is to use a repetitive protein as a scaffold. Repeat proteins are intrinsically modular, and their folding and structures are better understood than large globular domains. Here, we have developed a new class of synthetic repeat protein, based on the pentapeptide repeat family of beta-solenoid proteins. We have constructed length variants of the basic scaffold, and computationally designed de novo loops projecting from the scaffold core. The experimentally solved 3.56 ˚A resolution crystal structure of one designed loop matches closely the designed hairpin structure, showing the computational design of a backbone extension onto a synthetic protein core without the use of backbone fragments from known structures. Two other loop designs were not clearly resolved in the crystal structures and one loop appeared to be in an incorrect conformation. We have also shown that the repeat unit can accommodate whole domain insertions by inserting a domain into one of the designed loops

The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory Death.

Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation.MethodsWistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity.ResultsUnsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage.ConclusionsReduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age

Environmental pH Affects Photoautotrophic Growth of Synechocystis sp. PCC 6803 Strains Carrying Mutations in the Lumenal Proteins of PSII.

Synechocystis sp. strain PCC 6803 grows photoautotrophically across a broad pH range, but wild-type cultures reach a higher density at elevated pH; however, photoheterotrophic growth is similar at high and neutral pH. A number of PSII mutants each lacking at least one lumenal extrinsic protein, and carrying a second PSII lumenal mutation, are able to grow photoautotrophically in BG-11 medium at pH 10.0, but not pH 7.5. We investigated the basis of this pH effect and observed no pH-specific change in variable fluorescence yield from PSII centers of the wild type or the pH-dependent ΔPsbO:ΔPsbU and ΔPsbV:ΔCyanoQ strains; however, 77 K fluorescence emission spectra indicated increased coupling of the phycobilisome (PBS) antenna at pH 10.0 in all mutants. DNA microarray data showed a cell-wide response to transfer from pH 10.0 to pH 7.5, including decreased mRNA levels of a number of oxidative stress-responsive transcripts. We hypothesize that this transcriptional response led to increased tolerance against reactive oxygen species and in particular singlet oxygen. This response enabled photoautotrophic growth of the PSII mutants at pH 10.0. This hypothesis was supported by increased resistance of all strains to rose bengal at pH 10.0 compared with pH 7.5

Does modafinil enhance activity of patients with myotonic dystrophy?: A double-blind placebo-controlled crossover study

We performed a double-blind placebo-controlled crossover study in 13 patients with myotonic dystrophy to address the question whether modafinil, known to improve hypersomnolence in myotonic dystrophy, may improve levels of activity as well. We used the Epworth Sleepiness Scale as a measure of hypersomnolence and a structured interview of the patient and the partner or housemate as a measure of activity. We additionally used a restricted form of the RAND-36 to relate a possible improvement of activity to perceived general health. We confirmed earlier positive findings of modafinil regarding reduced somnolence (p = 0.015), but no significant effects were seen regarding activity levels (p = 0.2 for patients’ self-reports and 0.5 for partners’ reports)

Impact of frailty on mortality and hospitalization in chronic heart failure: A systematic review and meta-analysis

© 2018 The Authors. Background-—Although frailty has been associated with increased risks for hospitalization and mortality in chronic heart failure, the precise average effect remains uncertain. We performed a systematic review and meta-analysis to summarize the hazards for mortality and incident hospitalization in patients with heart failure and frailty compared with those without frailty and explored the heterogeneity underlying the effect size estimates. Methods and Results-—MEDLINE, EMBASE, and Cochrane databases were queried for articles published between January 1966 and March 2018. Predefined selection criteria were used. Hazard ratios (HRs) were pooled for meta-analyses, and where odds ratios were used previously, original data were recalculated for HR. Overlapping data were consolidated, and only unique data points were used. Study quality and bias were assessed. Eight studies were included for mortality (2645 patients), and 6 studies were included for incident hospitalization (2541 patients) during a median follow-up of 1.82 and 1.12 years, respectively. Frailty was significantly associated with an increased hazard for mortality (HR, 1.54; 95% confidence interval, 1.34–1.75; P<0.001) and incident hospitalization (HR, 1.56; 95% confidence interval, 1.36–1.78; P<0.001) in chronic heart failure. The Fried phenotype estimated a 16.9% larger effect size than the combined Fried/non-Fried frailty assessment for the end point of mortality (HR, 1.80; 95% confidence interval, 1.41–2.28; P<0.001), but not for hospitalization (HR, 1.57; 95% confidence interval, 1.30–1.89; P<0.001). Study heterogeneity was found to be low (I 2 =0%), and high quality of studies was verified by the Newcastle-Ottawa scale. Conclusions-—Overall, the presence of frailty in chronic heart failure is associated with an increased hazard for death and hospitalization by ≈1.5-fold