Quantifying the effects of extreme events and oceanographic variability on the spatiotemporal biomass and distribution of two key euphausiid prey species

Euphausiids form a critical component of oceanic food chains and individual species vary in their responses to perturbation events. We aimed to establish if patterns of fine scale oceanographic variability and larger-scale climate events such as marine heatwaves (MHWs) could be linked with spring variability in the biomass of two key forage species in the northeast Pacific Ocean, Euphausia pacifica and Thysanoessa spinifera. To achieve this, we used long-term datasets from the west coast of Vancouver Island Canada, an important commercial fishing area, to first quantify interannual signals of variability in fine-scale oceanographic conditions using multivariate analysis. We then used geostatistical spatiotemporal modelling to quantify the effects on species-specific euphausiid biomass. Oceanographic data showed that the effects of warm events are not always observable, and effects vary across small spatial scales. Warming due to the 2014-2016 MHW was relatively mild on the continental shelf during spring (<1°C above climatology). Spring biomass of euphausiids, particularly E. pacifica, peaked in 2015, and all euphausiid groups analysed (E. pacifica, T. spinifera and total euphausiids) exhibited significant correlations with positive phases of the Pacific Decadal Oscillation. These results have implications for marine predators as euphausiids may act as system stabilisers in the northeast Pacific, thereby potentially increasing ecosystem resilience during extreme events

Rounding and uncertainties in parameters determined from fits to experimental data, or a failure to round data-analysis fit parameters properly may make them useless

Almost no physically interesting physico/chemical parameter is determined directly from a measurement. Rather, they are determined by performing a least-squares fit of some model to a set of data. Unfortunately, there seems to be no commonly accepted set of `best practices' for determining how to round off such fitted parameter values to a minimum number of significant digits while ensuring that they retain the ability to reproduce the experimental data within their uncertainties. This sometimes results in lists of fitted parameters with no quoted uncertainties that have 2--3 times as many significant digits as the data being fitted, or to the results of an analysis being defined by parameters that are (unnecessarily?) quoted to more digits than normal computer double precision, which makes those results difficult or impossible to apply. Alternatively, it may also lead to fitted parameters being `over-rounded' so that the model no longer accurately represents the experimental data. This presentation describes a `best practice' to address these problems, offers a general-purpose least-squares fitting program that applies it, and provides an illustrative application of this approach in a study of the A\,^1\Sigma_u^+ - X\,^1\Sigma_g^+ system of Mg$_2$.Ope

A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultured DRG neurones from neonatal rats

BACKGROUND: Gabapentin and pregabalin have wide-ranging therapeutic actions, and are structurally related to the inhibitory neurotransmitter GABA. Gabapentin, pregablin and GABA can all modulate voltage-activated Ca(2+ )channels. In this study we have used whole cell patch clamp recording and fura-2 Ca(2+ )imaging to characterise the actions of pregabalin on the electrophysiological properties of cultured dorsal root ganglion (DRG) neurones from neonatal rats. The aims of this study were to determine whether pregabalin and gabapentin had additive inhibitory effects on high voltage-activated Ca(2+ )channels, evaluate whether the actions of pregabalin were dependent on GABA receptors and characterise the actions of pregabalin on voltage-activated potassium currents. RESULTS: Pregabalin (25 nM – 2.5 μM) inhibited 20–30% of the high voltage-activated Ca(2+ )current in cultured DRG neurones. The residual Ca(2+ )current recorded in the presence of pregabalin was sensitive to the L-type Ca(2+ )channel modulator, Bay K8644. Saturating concentrations of gabapentin failed to have additive effects when applied with pregabalin, indicating that these two compounds act on the same type(s) of voltage-activated Ca(2+ )channels but the majority of Ca(2+ )current was resistant to both drugs. The continual application of GABA, the GABA(B )receptor antagonist CGP52432, or intracellular photorelease of GTP-γ-S had no effect on pregabalin-induced inhibition of Ca(2+ )currents. Although clear inhibition of Ca(2+ )influx was produced by pregabalin in a population of small neurones, a significant population of larger neurones showed enhanced Ca(2+ )influx in response to pregabalin. The enhanced Ca(2+ )influx evoked by pregabalin was mimicked by partial block of K(+ )conductances with tetraethylammonium. Pregabalin produced biphasic effects on voltage-activated K(+ )currents, the inhibitory effect of pregabalin was prevented with apamin. The delayed enhancement of K(+ )currents was attenuated by pertussis toxin and by intracellular application of a (Rp)-analogue of cAMP. CONCLUSIONS: Pregabalin reduces excitatory properties of cultured DRG neurones by modulating voltage-activated Ca(2+ )and K(+ )channels. The pharmacological activity of pregabalin is similar but not identical to that of gabapentin. The actions of pregabalin may involve both extracellular and intracellular drug target sites and modulation of a variety of neuronal conductances, by direct interactions, and through intracellular signalling involving protein kinase A

Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis

Background: The extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration. Methods: To better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages. Results: Complement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion. Interpretation: The presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination

Selective reduction of APP-BACE1 activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PDAPP mice

β-Amyloid (Aβ) accumulation is an early event of Alzheimer's disease (AD) pathogenesis. Inhibition of Aβ production by β-secretase (BACE) has been proposed as a potential therapeutic strategy for AD. However, BACE inhibitors lack specificity and have had limited clinical benefit. To better study the consequences of reducing BACE metabolism, specifically of APP, we used an antibody, 2B3, that binds to APP at the BACE cleavage site, inhibiting Aβ production. 2B3 was administered either directly into the lateral ventricles or by intraperitoneal injection to (platelet-derived growth factor promoter hAPP717V (PDAPP) mice and WT mice. 2B3 reduced soluble Aβ40 and βCTF (β-amyloid derived C-terminal fragment) and improved memory for object-in-place associations and working memory in a foraging task in PDAPP mice. 2B3 also normalized the phosphorylation of the N-methyl-D-aspartate receptor NR2B subunit and subsequent extracellular signal-regulated kinase signaling. The importance of this NR2B pathway for OiP memory was confirmed by administering the NR2B antagonist, Ro25-6981, to 18-month-old WT. In contrast, 2B3 impaired associative recognition memory in young WT mice. These data provide novel insights into the mechanism by which selective modulation of APP metabolism by BACE influences synaptic and cognitive processes in both normal mice and aged APP transgenic mice

Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO− levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients

Adverse childhood experiences and child mental health : an electronic birth cohort study

Acknowledgement We thank the SAIL databank for assisting in the statistical disclosure process. Declarations and Funding Data is collected routinely and access to this was granted via the SAIL databank. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit for publication. The data sets generated and analysed during the current study are available in the SAIL databank repository, https://saildatabank.com/. This work was supported by funds from the Economic and Social Research Council, the Medical Research Council, and Alcohol Research UK to the ELAStiC Project (ESL015471/1) and Public Health Wales. The views expressed are those of the authors and should not be assumed to be of the funding body. The research was also supported by The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement, a UK Clinical Research Collaboration Public Health Research Centre of Excellence. This work was supported by Health Data Research UK, which receives its funding from HDR UK Ltd (HDR-9006) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust. The funders had no role in designing the study, data collection, analysis, or interpretation, or in writing the report; MAB’s role in the design, analysis, and writing was independent of the funding from Public Health Wales. SP, SL and MAB had the original idea for this study. SP, AE, RA, EL and RD designed the study and developed the analysis plan. AJ provided advice on the mental health codes used in this analysis. AB extracted the data and prepared data sets for analysis. EM, AE and RA analysed the data. EM and RA wrote the first draft of the paper. All authors were involved in interpreting the findings, revising drafts and agreeing the final version.Peer reviewedPublisher PD

Hacking Techniques Improve Health and Nutritional Status of Nestling White-tailed Eagles

Abstract Birds of prey frequently feature in reintroductions and the hacking technique is typically used. Hacking involves removing large nestlings from donor populations, transferring them to captivity, feeding them ad libitum. Potentially, via the hacking method, the stress of captivity and disruption of parental feeding may be detrimental. Alternatively, the provision of ad libitum food may be advantageous. Although hacking has underpinned reintroduction project successes there has been no research on how the method may affect the health and nutritional status of translocated birds during captivity. We compared blood chemistry data from 55 young White‐tailed Eagles, translocated from Norway as part of the species' reintroduction to Scotland, from sampling soon after arriving in captivity and again (≈42 days later) before their release. Numerous significant differences between the first and second samples were found, but no significant interactions showed that the sexes responded similarly to captivity. According to hematological and biochemical metrics, individuals showed several changes during captivity, including in red blood cell parameters, plasma proteins, and white cellular parameters related to the immune system, that indicated improved health status. Captivity with ad libitum food was associated with decreased urea and uric acid values: high values can indicate nutritional stress. Urea values became more normally distributed before release, indicating that ad libitum food had reduced nutritional differences between early nestlings in the season and later ones. Despite plentiful food, both sexes lost body mass before release, suggesting an inherent physiological mechanism to improve flight performance in fledglings. We conclude that hacking improved the health and nutritional status of released eagles which is likely to enable birds to cope with greater costs of exploratory behavior which they may require in reintroduction projects. In this context, we note the absence of survival differences between hacked and wild raptors in previous research

A 5-year evaluation of the emergency contraception enhanced community pharmacy service provided in Wales

Background Access to emergency contraception (EC) has been a core component of attempts to address high teenage pregnancy rates in Wales. A national service was commissioned in 2011, allowing supply of EC free of charge from community pharmacies (CPs). This study investigated 5 years of the EC service, to describe its use and investigate changes in the pattern of use over time. Methods Secondary analyses of data from all National Health Service funded CP EC consultations in Wales between 1 August 2012 and 31 July 2017 (n=181 359). Data comprised standardised clinical and demographic information, in the form of predefined service user responses, submitted for reimbursement by CPs. Results Overall service provision remained relatively consistent over the study period, with women aged between 13 and 59 years accessing the service. An association was observed between the time since unprotected sexual intercourse and the day on which the service was accessed (Χ2(18)=16 292.327, p<0.001). Almost half (47.9%) of requests were because no contraception had been used, with a strong and positive association for teenagers and women aged 40+ years. A statistically significant and increasing percentage of consultations were accompanied by further sexual health advice (r=0.7, p<0.01). Conclusions Access to EC through CPs is contributing to reducing teenage conceptions and termination rates. However, action is needed to increase contraception use in all age groups. Reduced availability of CP services on Sundays is a barrier to timely EC access. Findings support an expanded role for community pharmacists in provision of regular contraception