Lot-to-lot immunogenicity consistency of the respiratory syncytial virus prefusion F protein vaccine in older adults.

Background: Previous phase 3 studies showed that the AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) is well tolerated and efficacious in preventing RSV-associated lower respiratory tract disease in adults ≥ 60 years of age. This study evaluated lot-to-lot immunogenicity consistency, reactogenicity, and safety of three RSVPreF3 OA lots. Methods: This phase 3, multicenter, double-blind study randomized (1:1:1) participants ≥ 60 years of age to receive one of three RSVPreF3 OA lots. Serum RSVPreF3-binding immunoglobulin G (IgG) concentration was assessed at baseline and 30 days post-vaccination. Lot-to-lot consistency was demonstrated if the two-sided 95 % confidence intervals (CIs) of the RSVPreF3-binding IgG geometric mean concentration (GMC) ratios between each lot pair at 30 days post-vaccination were within 0.67 and 1.50. Solicited adverse events (AEs) within four days, unsolicited AEs within 30 days, and serious AEs (SAEs) and potential immune-mediated diseases within six months post-vaccination were recorded. Results: A total of 757 participants received RSVPreF3 OA, of whom 708 were included in the per-protocol set (234, 237, and 237 participants for each lot). Lot-to-lot consistency was demonstrated: GMC ratios were 1.06 (95 % CI: 0.94-1.21), 0.92 (0.81-1.04), and 0.87 (0.77-0.99) between the lot pairs (lot 1/2; 1/3; 2/3). For the three lots, the RSVPreF3-binding IgG concentration increased 11.84-, 11.29-, and 12.46-fold post-vaccination compared to baseline. The reporting rates of solicited and unsolicited AEs, SAEs, and potential immune-mediated diseases were balanced between lots. Twenty-one participants reported SAEs; one of these-a case of atrial fibrillation-was considered by the investigator as vaccine-related. SAEs with a fatal outcome were reported for four participants, none of which were considered by the investigator as vaccine-related. Conclusion: This study demonstrated lot-to-lot immunogenicity consistency of three RSVPreF3 OA vaccine lots and indicated that the vaccine had an acceptable safety profile.ClinicalTrials.gov: NCT05059301.

Association of ectoparasite Lepeophtheirus salmonis counts on farmed Atlantic salmon and wild sea trout in Scotland.

Parasitic sea lice (Copepoda: Caligidae) colonising marine salmonid (Salmoniformes: Salmonidae) aquaculture production facilities have been implicated as a possible pressure on wild salmon and sea trout populations. This investigation uses monitoring data from the mainland west coast and Western Isles of Scotland to estimate the association of the abundance of adult female Lepeophtheirus salmonis (Krøyer) colonising farmed Atlantic salmon Salmo salar L. with the occurrence of juvenile and mobile L. salmonis on wild sea trout, anadromous S. trutta L. The associations were evaluated using generalised linear mixed models incorporating farmed adult female salmon louse abundances which are temporally lagged relative to dependent wild trout values. The pattern of lags, which is consistent with time for L. salmonis development between egg and infective stage, was evaluated using model deviances. A significant positive association is identified between adult female L. salmonis abundance on farms and juvenile L. salmonis on wild trout. This association is consistent with a causal relationship in which increases in the number of L. salmonis copepodids originating from lice colonising farmed Atlantic salmon cause an increase of L. salmonis abundance on wild sea trout.

Protected areas slow declines unevenly across the tetrapod tree of life.

Protected areas (PAs) are the primary strategy for slowing terrestrial biodiversity loss. Although expansion of PA coverage is prioritized under the Convention on Biological Diversity, it remains unknown whether PAs mitigate declines across the tetrapod tree of life and to what extent land cover and climate change modify PA effectiveness1,2. Here we analysed rates of change in abundance of 2,239 terrestrial vertebrate populations across the globe. On average, vertebrate populations declined five times more slowly within PAs (-0.4% per year) than at similar sites lacking protection (-1.8% per year). The mitigating effects of PAs varied both within and across vertebrate classes, with amphibians and birds experiencing the greatest benefits. The benefits of PAs were lower for amphibians in areas with converted land cover and lower for reptiles in areas with rapid climate warming. By contrast, the mitigating impacts of PAs were consistently augmented by effective national governance. This study provides evidence for the effectiveness of PAs as a strategy for slowing tetrapod declines. However, optimizing the growing PA network requires targeted protection of sensitive clades and mitigation of threats beyond PA boundaries. Provided the conditions of targeted protection, adequate governance and well-managed landscapes are met, PAs can serve a critical role in safeguarding tetrapod biodiversity.

Modelling parasite impacts of aquaculture on wild fish: The case of the salmon louse (Lepeophtheirus salmonis) on out-migrating wild Atlantic salmon (Salmo salar) smolt.

For effective wild salmon (Salmo salar) conservation in areas where aquaculture of salmon is practiced it is necessary to identify where the key parasite, the salmon louse (Lepeophtheirus salmonis), will have an impact on these wild salmon. A simple modelling structure is implemented in a sample system in Scotland for assessing interaction between wild salmon and salmon lice from salmon farms. The model is demonstrated for case studies of smolt sizes and migration routes through salmon lice concentration fields derived for average farm loads from 2018 to 2020. Lice modelling describes production and distribution of lice, infection rates on hosts and biological development of lice. The modelling framework allows explicit assessment of the relationships between lice production, lice concentration and impact on hosts as they grow and migrate. Lice distribution in the environment is determined using a kernel model, which summarises mixing in a complex hydrodynamic system. Smolt modelling describes their initial size, growth and migration pathways. This is illustrated for a set of parameter values applied to 10 cm, 12.5 cm and 15 cm salmon smolts. We found that salmon lice impact depends on initial size of host, smaller smolts will be more susceptible, while larger smolts are less impacted by a given number of lice encounters and migrate more rapidly. This modelling framework can be adapted to allow evaluation of threshold concentrations of lice in the water that should not be exceeded to avoid impacts on smolt populations.

Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis.

INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis. METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis. ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means. TRIAL REGISTRATION NUMBER: ISRCTN23256704.

nMOWChIP-seq: low-input genome-wide mapping of non-histone targets.

Genome-wide profiling of interactions between genome and various functional proteins is critical for understanding regulatory processes involved in development and diseases. Conventional assays require a large number of cells and high-quality data on tissue samples are scarce. Here we optimized a low-input chromatin immunoprecipitation followed by sequencing (ChIP-seq) technology for profiling RNA polymerase II (Pol II), transcription factor (TF), and enzyme binding at the genome scale. The new approach produces high-quality binding profiles using 1,000-50,000 cells. We used the approach to examine the binding of Pol II and two TFs (EGR1 and MEF2C) in cerebellum and prefrontal cortex of mouse brain and found that their binding profiles are highly reflective of the functional differences between the two brain regions. Our analysis reveals the potential for linking genome-wide TF or Pol II profiles with neuroanatomical origins of brain cells.

A preliminary assessment of indirect impacts on aquaculture species health and welfare in Scotland during COVID-19 lockdown.

COVID-19 led to sudden changes in human activities, mainly due to restrictive measures required to supress the virus. We assess the preliminary evidence for impacts on animal health and welfare in Scottish aquaculture, a key economic activity in remoter areas of the country. We summarise the industry structure, explore pathways of vulnerability to aquatic animal disease within a One Health framework that may be accentuated by impacts of COVID-19, and use basic routine data collection on the key welfare indicators of salmon mortality and parasitic sea lice counts. The indicators were published on schedule and provide no evidence of gross impact on health and welfare, at least for salmon, during the period of intensive lockdown restrictions in Scotland. Longer term effects cannot be ruled out and we do not assess impacts on the economic or social aspects of aquaculture production.

Evaluating totipotency using criteria of increasing stringency.

Totipotency is the ability of a single cell to give rise to all of the differentiated cell types that build the conceptus, yet how to capture this property in vitro remains incompletely understood. Defining totipotency relies on a variety of assays of variable stringency. Here, we describe criteria to define totipotency. We explain how distinct criteria of increasing stringency can be used to judge totipotency by evaluating candidate totipotent cell types in mice, including early blastomeres and expanded or extended pluripotent stem cells. Our data challenge the notion that expanded or extended pluripotent states harbour increased totipotent potential relative to conventional embryonic stem cells under in vitro and in vivo conditions.

Ionicity-dependent proton-coupled electron transfer of supramolecular self-assembled electroactive heterocycles.

Herein, we investigate the electrochemical properties of a class of Supramolecular Self-associated Amphiphilic salts (SSAs). We show that varying ionic strength of an SSA solution can cause a switching of the thermodynamics and kinetics of electron transfer. The effect of self-assembly on proton-coupled electron transfer has implications for the understanding of electron transfer kinetics in aqueous organic redox flow batteries, especially at high concentration where organic-organic intermolecular interactions become dominant even for highly soluble organic species.

Local adaptation policy responses to extreme weather events.

At a global level, climate change is expected to result in more frequent and higher-intensity weather events, with impacts ranging from inconvenient to catastrophic. The potential for disasters to act as "focusing events" for policy change, including adaptation to climate change risk, is well known. Moreover, local action is an important element of climate change adaptation and related risk management efforts. As such, there is a good reason to expect local communities to mobilize in response to disaster events, both with immediate response and recovery-focused activities, as well as longer-term preparedness and adaptation-focused public policy changes. However, scholars also note that the experience of disaster does not always yield policy change; indeed, disasters can also result in policy inertia and failure, perhaps as often or more often than major policy change. This study poses two key research questions. First, we ask to what degree policy change occurs in communities impacted by an extreme weather event. Second, we seek to understand the conditions that lead to adaptation-oriented policy adoption in response to an extreme weather event. Our results suggest two main recipes for future-oriented policy adoption in the wake of an extreme weather event. For both recipes, a high-impact event is a necessary condition for future-oriented policy adoption. In the first recipe for change, policy adoption occurs in Democratic communities with highly focused media attention. The second, less expected recipe for change involves Republican communities that have experienced other uncommon weather events in the recent past. We use a comparative case approach with 15 cases and fuzzy set qualitative comparative analysis methods. Our approach adds to the existing literature on policy change and local adaptation by selecting a mid-N range of cases where extreme weather events have the potential to act as focusing events, thereby sidestepping selection on the dependent variable. Our approach also takes advantage of a novel method for measuring attention, the latent Dirichlet allocation approach.

EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity.

Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.

Placentation defects are highly prevalent in embryonic lethal mouse mutants.

Large-scale phenotyping efforts have demonstrated that approximately 25-30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies. Early lethality (embryonic days 9.5-14.5) is almost always associated with severe placental malformations. Placental defects correlate strongly with abnormal brain, heart and vascular development. Analysis of mutant trophoblast stem cells and conditional knockouts suggests that a considerable number of factors that cause embryonic lethality when ablated have primary gene function in trophoblast cells. Our data highlight the hugely under-appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes that govern placenta formation.

A GIS-based tool for an integrated assessment of spatial planning trade-offs with aquaculture.

The increasing demand for protein from aquaculture will trigger a global expansion of the sector in coastal and offshore waters. While contributing to food security, potential conflicts with other traditional activities such as fisheries or tourism are inevitable, thus calling for decision-support tools to assess aquaculture planning scenarios in a multi-use context. Here we introduce the AquaSpace tool, one of the first Geographic Information System (GIS)-based planning tools empowering an integrated assessment and mapping of 30 indicators reflecting economic, environmental, inter-sectorial and socio-cultural risks and opportunities for proposed aquaculture systems in a marine environment. A bottom-up process consulting more than 350 stakeholders from 10 countries across southern and northern Europe enabled the direct consideration of stakeholder needs when developing the GIS AddIn. The AquaSpace tool is an open source product and builds in the prospective use of open source datasets at a European scale, hence aiming to improve reproducibility and collaboration in aquaculture science and research. Tool outputs comprise detailed reports and graphics allowing key stakeholders such as planners or licensing authorities to evaluate and communicate alternative planning scenarios and to take more informed decisions. With the help of the German North Sea case study we demonstrate here the tool application at multiple spatial scales with different aquaculture systems and under a range of space-related development constraints. The computation of these aquaculture planning scenarios and the assessment of their trade-offs showed that it is entirely possible to identify aquaculture sites, that correspondent to multifarious potential challenges, for instance by a low conflict potential, a low risk of disease spread, a comparable high economic profit and a low impact on touristic attractions. We believe that a transparent visualisation of risks and opportunities of aquaculture planning scenarios helps an effective Marine Spatial Planning (MSP) process, supports the licensing process and simplifies investments.

Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation.

Gene loci that are hypermethylated and repressed in embryonic (ESCs) but hypomethylated and expressed in trophoblast (TSCs) stem cells are very rare and may have particularly important roles in early developmental cell fate decisions, as previously shown for Elf5. Here, we assessed another member of this small group of genes, Placenta Expressed Transcript 1 (Plet1), for its function in establishing trophoblast lineage identity and modulating trophoblast differentiation. We find that Plet1 is tightly repressed by DNA methylation in ESCs but expressed on the cell surface of TSCs and trophoblast giant cells. In hypomethylated ESCs that are prone to acquire some trophoblast characteristics, Plet1 is required to confer a trophoblast-specific gene expression pattern, including up-regulation of Elf5. Plet1 displays an unusual biphasic expression profile during TSC differentiation and thus may be pivotal in balancing trophoblast self-renewal and differentiation. Furthermore, overexpression and CRISPR/Cas9-mediated knockout in TSCs showed that high Plet1 levels favour differentiation towards the trophoblast giant cell lineage, whereas lack of Plet1 preferentially induces syncytiotrophoblast formation. Thus, the endogenous dynamics of Plet1 expression establish important patterning cues within the trophoblast compartment by promoting differentiation towards the syncytiotrophoblast or giant cell pathway in Plet1-low and Plet1-high cells, respectively.

Modelling flavoenzymatic charge transfer events: development of catalytic indole deuteration strategies.

The formation and chemistry of flavin-indole charge transfer (CT) complexes has been studied using a model cationic flavin. The ability to form a CT complex is sensitive to indole structure as gauged by spectroscopic, kinetics and crystallographic studies. Single crystals of sufficient quality of a flavin-indole CT complex, suitable for X-ray diffraction, have been grown, allowing solid-state structural analysis. When CT complex formation is conducted in d4-methanol, an efficient and synthetically useful C-3 indole deuteration is observed.

Using the H-index to assess disease priorities for salmon aquaculture.

Atlantic salmon's (Salmo salar) annual aquaculture production exceeds 2M tonnes globally, and for the UK forms the largest single food export. However, aquaculture production is negatively affected by a range of different diseases and parasites. Effort to control pathogens should be focused on those which are most "important" to aquaculture. It is difficult to specify what makes a pathogen important; this is particularly true in the aquatic sector where data capture systems are less developed than for human or terrestrial animal diseases. Mortality levels might be one indicator, but these can cause a range of different problems such as persistent endemic losses, occasional large epidemics or control/treatment costs. Economic and multi-criteria decision methods can incorporate this range of impacts, however these have not been consistently applied to aquaculture and the quantity and quality of data required is large, so their potential for comparing aquatic pathogens is currently limited. A method that has been developed and applied to both human and terrestrial animal diseases is the analysis of published scientific literature using the H-index method. We applied this method to salmon pathogens using Web of Science searches for 23 pathogens. The top 3 H-indices were obtained for: sea lice, furunculosis, and infectious salmon anaemia; post 2000, Amoebic Gill Disease (AGD) replaced furunculosis. The number of publications per year describing bacterial disease declined significantly, while those for viruses and sea lice increased significantly. This reflects effective bacterial control by vaccination, while problems related to viruses and sea lice have increased. H-indices by country reflected different national concerns (e.g. AGD ranked top for Australia). Averaged national H-indices for salmon diseases tend to increase with log of salmon production; countries with H-Indices significantly below the trend line have suffered particularly large disease losses. The H-index method, supported by other literature analyses, is consistent with the nature and history of salmon diseases and so provides a useful quantitative measure for comparing different diseases in the absence of other measures.

Distribution of Infectious Pancreatic Necrosis Virus (IPNV) Based on Surveillance Programs in Freshwater Trout Farms of Mexico.

Diagnostic testing was performed between 2000 and 2012 to determine the distribution of infectious pancreatic necrosis virus (IPNV) in the main states of the Mexican Republic with freshwater Rainbow Trout Oncorhynchus mykiss (Walbaum) farms. This virus was positively identified from Rainbow Trout farms in seven of the eight states assessed. Due to nonnormal data distribution, a logistic regression model was applied for statistical analysis, the results of which indicated that virus prevalence was variable between states, with moderate but significant differences. Regarding the time periods evaluated, IPNV prevalence was higher during the first years of the study. The susceptible, infected, removed model was used to examine this phenomenon, which indicated that the decreased prevalence during the latter years of the study could be associated with a real elimination of the infection. The information of the cases analyzed also suggests a relationship with the irregularity in the submission of samples to the laboratory and emphasizes other factors that have contributed to the transmission of IPNV throughout the country. Received November 10, 2014; accepted December 5, 2015.

Increased frequency and changed methods in the treatment of sea lice (Lepeophtheirus salmonis) in Scottish salmon farms 2005-2011.

BACKGROUND: The sea louse is the most economically and environmentally serious ectoparasite of marine salmonids. Sea lice have been largely controlled by treatment with a variety of medicines. In order to understand the sustainability of medicine usage, an analysis of sea louse treatment data has been carried out for all Scottish salmon farms from 2005 to 2011. RESULTS: Overall, there was an increase from 0.156 to 0.282 treatments month(-1) ; treatments could involve one or multiple agents. This increase was mostly in bath treatments (cypermethrin in 2007, largely replaced by deltamethrin and azamethiphos in 2008). Treatments using in-feed treatments (emamectin benzoate and teflubenzuron) increased only slowly. Treatments involving more than one medicine in a single month also increased, as did the probability of follow-up treatments. Treatments were seasonal, with peaks of in-feed treatments in March and August and bath treatments more frequent between August and December. CONCLUSION: Frequency of sea louse treatment increased substantially, with an increase in multiagent and follow-up treatments. This increase in treatment activity is expensive to the industry and increases exposure of the neighbouring environment. This indicates that earlier louse control practices were not sustainable and so adapted.