A network of change: united action on research integrity

The last decade has seen renewed concern within the scientific community over the reproducibility and transparency of research findings. This paper outlines some of the various responsibilities of stakeholders in addressing the systemic issues that contribute to this concern. In particular, this paper asserts that a united, joined-up approach is needed, in which all stakeholders, including researchers, universities, funders, publishers, and governments, work together to set standards of research integrity and engender scientific progress and innovation. Using two developments as examples: the adoption of Registered Reports as a discrete initiative, and the use of open data as an ongoing norm change, we discuss the importance of collaboration across stakeholders

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation.

AIMS: The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress. METHODS AND RESULTS: Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels. CONCLUSIONS: Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes.

Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease

A guide for social science journal editors on easing into open science

Journal editors have a large amount of power to advance open science in their respective fields by incentivising and mandating open policies and practices at their journals. The Data PASS Journal Editors Discussion Interface (JEDI, an online community for social science journal editors: www.dpjedi.org) has collated several resources on embedding open science in journal editing (www.dpjedi.org/resources). However, it can be overwhelming as an editor new to open science practices to know where to start. For this reason, we created a guide for journal editors on how to get started with open science. The guide outlines steps that editors can take to implement open policies and practices within their journal, and goes through the what, why, how, and worries of each policy and practice. This manuscript introduces and summarizes the guide (full guide: https://doi.org/10.31219/osf.io/hstcx)

On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury

The role of peroxisome proliferator activated alpha (PPARα) -mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 weeks before in vivo contractile function was measured using cine magnetic resonance (MR) imaging. In isolated, perfused hearts, energetics were measured using 31P MR spectroscopy and glycolysis and fatty acid oxidation were measured using 3H labelling. Compared with normoxic, chow-fed control mouse heart, hypoxia decreased PPARα expression, fatty acid oxidation and mitochondrial UCP3 levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations and thereby ejection fractions. A high-fat diet increased cardiac PPARα expression, fatty acid oxidation and UCP3 levels, with decreased glycolysis. Hypoxia was unable to alter the high PPARα expression or reverse the metabolic changes caused by the high fat diet, with the result that ATP concentrations and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have already occurred in PPARα-/- mouse hearts, and sustained function in hypoxia despite an inability for further metabolic remodelling. We conclude that decreased cardiac PPARα expression is essential for adaptive metabolic remodelling in hypoxia, but is prevented by dietary fat

Lectin-like bacteriocins from pseudomonas spp. utilise D-rhamnose containing lipopolysaccharide as a cellular receptor

Lectin-like bacteriocins consist of tandem monocot mannose-binding domains and display a genus-specific killing activity. Here we show that pyocin L1, a novel member of this family from Pseudomonas aeruginosa, targets susceptible strains of this species through recognition of the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide that is predominantly a homopolymer of d-rhamnose. Structural and biophysical analyses show that recognition of CPA occurs through the C-terminal carbohydrate-binding domain of pyocin L1 and that this interaction is a prerequisite for bactericidal activity. Further to this, we show that the previously described lectin-like bacteriocin putidacin L1 shows a similar carbohydrate-binding specificity, indicating that oligosaccharides containing d-rhamnose and not d-mannose, as was previously thought, are the physiologically relevant ligands for this group of bacteriocins. The widespread inclusion of d-rhamnose in the lipopolysaccharide of members of the genus Pseudomonas explains the unusual genus-specific activity of the lectin-like bacteriocins

Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival

The aim of this study was to evaluate the expression of CC chemokine receptor 7 (CCR7) in squamous cell cancer of the tonsil with respect to patterns of spread, relapse-free, overall and disease-specific survival. Eighty-four patients with squamous cell cancer of the tonsil were identified. There was a male predominance of 3 : 1 and the median age at diagnosis was 53 (range 35–86) years. The median duration of follow-up was 33 (range 2–124) months. There was a significant association between CCR7 immunopositivity and synchronous cervical nodal metastasis in patients with tonsillar cancer (Spearman's correlation coefficient 0.564; P<0.001). Relapse-free (P=0.0175), overall (P=0.0136) and disease-specific (P=0.0062) survival rates were significantly lower in patients whose tumours expressed high levels of CCR7. On multivariate analysis, high-level CCR7 staining predicted relapse-free (hazard ratio 3.0, 95% confidence intervals 1.1–8.0, P=0.026) and disease-specific (hazard ratio 10.2, 95% confidence intervals 2.1–48.6, P=0.004) survival. Fifteen percent of patients with the highest level of tumour CCR7 immunopositivity relapsed with systemic metastases. These data demonstrated that CCR7 expression was associated with cervical nodal and systemic metastases from tonsillar cancers. High levels of CCR7 expression predicted a poor prognosis

It could be a ‘Golden Goose’: a qualitative study of views in primary care on an emergency admission risk prediction tool prior to implementation

BACKGROUND: Rising demand for health care has prompted interest in new technologies to support a shift of care from hospital to community and primary care, which may require clinicians to undertake new working practices. A predictive risk stratification tool (Prism) was developed for use in primary care to estimate patients’ risk of an emergency hospital admission. As part of an evaluation of Prism, we aimed to understand what might be needed to bring Prism into effective use by exploring clinicians and practice managers’ attitudes and expectations about using it. We were informed by Normalisation Process Theory (NPT) which examines the work needed to bring an innovation into use. METHODS: We conducted 4 focus groups and 10 interviews with a total of 43 primary care doctors and colleagues from 32 general practices. All were recorded and transcribed. Analysis focussed in particular on the construct of ‘coherence’ within NPT, which examines how people understand an innovation and its purpose. RESULTS: Respondents were in agreement that Prism was a technological formalisation of existing practice, and that it would function as a support to clinical judgment, rather than replacing it. There was broad consensus about the role it might have in delivering new models of care based on active management, but there were doubts about the scope for making a difference to some patients and about whether Prism could identify at-risk patients not already known to the clinical team. Respondents did not expect using the tool to be onerous, but were concerned about the work which might follow in delivering care. Any potential value would not be of the tool in isolation, but would depend on the availability of support services. CONCLUSIONS: Policy imperatives and the pressure of rising demand meant respondents were open to trying out Prism, despite underlying uncertainty about what difference it could make. TRIAL REGISTRATION: Controlled Clinical Trials no. ISRCTN55538212

The Psychological Science Accelerator: Advancing Psychology through a Distributed Collaborative Network

Concerns have been growing about the veracity of psychological research. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions, or attempt to replicate prior research, in large, diverse samples. The PSA\u27s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time-limited), efficient (in terms of re-using structures and principles for different projects), decentralized, diverse (in terms of participants and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside of the network). The PSA and other approaches to crowdsourced psychological science will advance our understanding of mental processes and behaviors by enabling rigorous research and systematically examining its generalizability

A tale of two 'opens': intersections between Free and Open Source Software and Open Scholarship

There is no clear-cut boundary between Free and Open Source Software and Open Scholarship, and the histories, practices, and fundamental principles between the two remain complex. In this study, we critically appraise the intersections and differences between the two movements. Based on our thematic comparison here, we conclude several key things. First, there is substantial scope for new communities of practice to form within scholarly communities that place sharing and collaboration/open participation at their focus. Second, Both the principles and practices of FOSS can be more deeply ingrained within scholarship, asserting a balance between pragmatism and social ideology. Third, at the present, Open Scholarship risks being subverted and compromised by commercial players. Fourth, the shift and acceleration towards a system of Open Scholarship will be greatly enhanced by a concurrent shift in recognising a broader range of practices and outputs beyond traditional peer review and research articles. In order to achieve this, we propose the formulation of a new type of institutional mandate. We believe that there is substantial need for research funders to invest in sustainable open scholarly infrastructure, and the communities that support them, to avoid the capture and enclosure of key research services that would prevent optimal researcher behaviours. Such a shift could ultimately lead to a healthier scientific culture, and a system where competition is replaced by collaboration, resources (including time and people) are shared and acknowledged more efficiently, and the research becomes inherently more rigorous, verified, and reproducible