Growth, reproduction and recruitment of Great Barrier Reef food fish stocks

The population characteristics of two of the most important species of fish in the Great Barrier Reef (GBR) handline fishery were, until recently, poorly documented. These species - the coral trout Plectropomus leopardus and the red-throat emperor Lethrinus miniatus have been fished extensively by both recreational and commercial sectors of the industry, and evidence which came to light in the mid 1980's suggested that hshmg pressure, particul arly around reefs in the vicinity of major centres of human population, was having a measurable effect on local stocks of these fish

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Gut Microbiome Metagenomics Analysis Suggests a Functional Model for the Development of Autoimmunity for Type 1 Diabetes

Peer reviewe

A review of new and existing non-extractive techniques for monitoring marine protected areas

Publication history: Accepted - 23 June 2023; Published - 19 July 2023.Ocean biodiversity loss is being driven by several anthropogenic threats and significant efforts are required to halt losses and promote healthy marine ecosystems. The establishment of a network of Marine Protected Areas (MPAs) can help restrict damaging activities and have been recognised as a potential solution to aid marine conservation. When managed correctly they can deliver both ecological and socio-economic benefits. In recent times, MPA designations have increased rapidly while many countries have set future MPA targets for the decades ahead. An integral element of MPA management is adequate monitoring that collects data to assess if conservation objectives are being achieved. Data acquired by monitoring can vary widely as can the techniques employed to collect such data. Ideally, non-destructive and non-invasive methods are preferred to prevent damage to habitats and species, though this may rule out a number of traditional extractive sampling approaches such as dredges and trawls. Moreover, advances in ocean observation technologies enable the collection of large amounts of data at high resolutions, while automated data processing is beginning to make analyses more logistically feasible and less time-consuming. Therefore, developments to existing marine monitoring techniques and new emerging technologies have led to a diverse array of options when choosing to implement an MPA monitoring programme. Here, we present a review of new and existing non-extractive techniques which can be applied to MPA monitoring. We summarise their capabilities, applications, advantages, limitations and possible future developments. The review is intended to aid MPA managers and researchers in determining the suitability of available monitoring techniques based on data requirements and site conditions.This research was funded through the Marine Protected Area Monitoring and Management (MarPAMM) project, which is supported by the European Union’s INTERREG VA Programme, managed by the Special EU Programmes Body (SEUPB) with matching funding from the Government of Ireland, the Northern Ireland Executive, and the Scottish Government. This research was also carried out with the support of the Marine Institute under the Marine Research Programme with the support of the Irish Government

ABCA7 p.G215S as potential protective factor for Alzheimer’s disease

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR=0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

Impact of Resistant Starch on Body Fat Patterning and Central Appetite Regulation

Background: Adipose tissue patterning has a major influence on the risk of developing chronic disease. Environmental influences on both body fat patterning and appetite regulation are not fully understood. This study was performed to investigate the impact of resistant starch (RS) on adipose tissue deposition and central regulation of appetite in mice. Methodology and Principle Findings: Forty mice were randomised to a diet supplemented with either the high resistant starch (HRS), or the readily digestible starch (LRS). Using 1H magnetic resonance (MR) methods, whole body adiposity, intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) were measured. Manganese-enhanced MRI (MEMRI) was used to investigate neuronal activity in hypothalamic regions involved in appetite control when fed ad libitum. At the end of the interventional period, adipocytes were isolated from epididymal adipose tissue and fasting plasma collected for hormonal and adipokine measurement. Mice on the HRS and LRS diet had similar body weights although total body adiposity, subcutaneous and visceral fat, IHCL, plasma leptin, plasma adiponectin plasma insulin/glucose ratios was significantly greater in the latter group. Adipocytes isolated from the LRS group were significantly larger and had lower insulin-stimulated glucose uptake. MEMRI data obtained from the ventromedial and paraventricular hypothalamic nuclei suggests a satiating effect of the HRS diet despite a lower energy intake. Conclusion and Significance: Dietary RS significantly impacts on adipose tissue patterning, adipocyte morphology and metabolism, glucose and insulin metabolism, as well as affecting appetite regulation, supported by changes in neuronal activity in hypothalamic appetite regulation centres which are suggestive of satiation