Memory trace replay:The shaping of memory consolidation by neuromodulation

The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed

Protocol paper for the ‘Harnessing resources from the internet to maximise outcomes from GP consultations (HaRI)’ study: a mixed qualitative methods study

Introduction Many patients now turn to the internet as a resource for healthcare information and advice. However, patients’ use of the internet to manage their health has been positioned as a potential source of strain on the doctor–patient relationship in primary care. The current evidence about what happens when internet-derived health information is introduced during consultations has relied on qualitative data derived from interview or questionnaire studies. The ‘Harnessing resources from the internet to maximise outcomes from GP consultations (HaRI)’ study combines questionnaire, interview and video-recorded consultation data to address this issue more fully. Methods and analysis Three data collection methods are employed: preconsultation patient questionnaires, video-recorded consultations between general practitioners (GP) and patients, and semistructured interviews with GPs and patients. We seek to recruit 10 GPs practising in Southeast England. We aim to collect up to 30 patient questionnaires and video-recorded consultations per GP, yielding up to 300. Up to 30 patients (approximately three per participating GP) will be selected for interviews sampled for a wide range of sociodemographic characteristics, and a variety of ways the use of, or information from, the internet was present or absent during their consultation. We will interview all 10 participating GPs about their views of online health information, reflecting on their own usage of online information during consultations and their patients’ references to online health information. Descriptive, conversation and thematic analysis will be used respectively for the patient questionnaires, video-recorded consultations and interviews. Ethics and dissemination Ethical approval has been granted by the London–Camden & Kings Cross Research Ethics Committee. Alongside journal publications, dissemination activities include the creation of a toolkit to be shared with patients and doctors, to guide discussions of material from the internet in consultation

Federated Identity Management for Research Collaborations

This white-paper expresses common requirements of Research Communities seeking to leverage Identity Federation for Authentication and Authorisation. Recommendations are made to Stakeholders to guide the future evolution of Federated Identity Management in a direction that better satisfies research use cases. The authors represent research communities, Research Services, Infrastructures, Identity Federations and Interfederations, with a joint motivation to ease collaboration for distributed researchers. The content has been edited collaboratively by the Federated Identity Management for Research (FIM4R) Community, with input sought at conferences and meetings in Europe, Asia and North America

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

The Health Resort Sector in Australia: A Positioning Study

This study provides a profile of the health resort sector in Australia. The study was based on resort directories, an analysis of promotional materials produced by each of the resorts within the population and discussions with representatives of Australia's various state tourism organisations. It was found that most properties in the health resort category may be described as being mainstream and offering a tourism focus. The smallest number are found in the alternative and medical treatment focus categories though these components of the health resort sector do appear to be dynamic and innovative. The development of a dynamic and innovative health resort sector may owe something to the absence of a strong tradition of spas in Australia

Intracellular solutions.

<p>Intracellular solutions.</p

Effect of DIDS, the absence of nucleotides and KF on evoked IPSCs.

<p>Upper panels of A-D: Example traces during the diffusion of three intracellular pipette solutions (K-Gluconate +DIDS (A), K-Gluconate without ATP or GTP (B), and K-Fluoride at -80mV (C) and -50mV (D)). Each trace shows the IPSC at the start of recording (black, time point i in middle panels), in the last minute before bath application of picrotoxin (magenta, time point ii in middle panels) and at the end of the bath application of picrotoxin (blue, time point iii in middle panels). Middle panels of A-D: Normalised IPSC amplitudes. Blue bar indicates the presence of bath picrotoxin. Lower panels of A-D: Corresponding series resistance during experiments. NBQX and AP5 were present throughout the experiments. E) Group data of the normalised IPSC amplitudes, taken at time point ii, individual data points marked with magenta dots. Summary statistics represent tests comparing the normalised evoked IPSC amplitudes at time point ii with the normalised baseline amplitude for each data set. Data are plotted as mean ± SEM.</p

Effect of Fluoride on spontaneous and evoked EPSCs.

<p>A-B) Example traces (upper panel) of sharp waves (black) and corresponding spontaneous EPSCs from the 1^st (left, grey) and last (right, magenta) 5 minutes of recording in K-Gluconate (A) and K-Fluoride (B) intracellular pipette solutions. Lower panel: Group normalised EPSC amplitude time course, during wash-in. Grey bar (time point i) and magenta bar (time point ii) indicate the times during which the example traces in the upper panels are taken from. Upper panels of D-E): Example traces of pharmacologically isolated, evoked EPSCs during the wash-in of K-Gluconate (D) and K-Fluroride (E). Each trace shows the EPSC at the start of wash-in (black, time point i in middle panels) and at the end of the wash-in period (magenta, time point ii in middle panels). Middle panels of D-E: Normalised EPSC amplitudes during wash-in. Lower panels of D-E: Corresponding series resistance during wash-in. Picrotoxin was present in the bath throughout the experiments. C&F) Average group data of the normalised EPSC amplitudes, taken in the last 5 minutes of recording for the spontaneous (C) and evoked (F) EPSCs, individual data points marked by magenta dots. Summary statistics represent tests comparing the normalised EPSC amplitudes in the last 5 minutes of recording with the normalised baseline amplitude for each data set. Data are plotted as mean ± SEM.</p