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.

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.

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.

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks.

Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundance-dependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double- and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiation-promoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation.

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.

ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.

Embryonic stem (ES) cells are in a dynamic equilibrium of distinct functional states, characterized by the heterogeneous expression of critical pluripotency factors and regulated by a spectrum of reversible histone modifications. Maintenance of this equilibrium is a hallmark of pluripotency. Here we find that the ADP-ribosyltransferases Parp1 and Parp7 play a critical role in safeguarding this state by occupying key pluripotency genes, notably Nanog, Pou5f1, Sox2, Stella, Tet1 and Zfp42, thereby protecting them from progressive epigenetic repression. In the absence of either Parp1 or Parp7, or upon inhibition of the ADP-ribosylating activity, ES cells exhibit a decrease in ground state pluripotency as they cannot maintain the typical heterogeneity characteristic of the metastable state. As a consequence, they display a higher propensity to differentiate. These findings place Parp1 and Parp7 at the genetic-epigenetic interface of pluripotency networks, fine-tuning the transcriptional heterogeneity and thereby determining the developmental plasticity of ES cells.

Catalytic Amine Oxidation under Ambient Aerobic Conditions: Mimicry of Monoamine Oxidase†B.

The flavoenzyme monoamine oxidase (MAO) regulates mammalian behavioral patterns by modulating neurotransmitters such as adrenaline and serotonin. The mechanistic basis which underpins this enzyme is far from agreed upon. Reported herein is that the combination of a synthetic flavin and alloxan generates a catalyst system which facilitates biomimetic amine oxidation. Mechanistic and electron paramagnetic (EPR) spectroscopic data supports the conclusion that the reaction proceeds through a radical manifold. This data provides the first example of a biorelevant synthetic model for monoamine oxidase B activity.

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.

Factors affecting variation in mortality of marine Atlantic salmon Salmo salar in Scotland.

Databases of site production have an important role to play in the investigation and understanding of diseases, since they store valuable amounts of disease and management data. Diseases pose an important constraint to economic expansion of aquaculture. They are dependent on the complex interacting factors of pathogen, environment, and host, and the causes of death can be related to nutritional, environmental, and genetic factors of the host or infectious agents. We examined the drivers of mortality from a single site-production database, which represented one-third of Scottish farmed salmon Salmo salar L. production in 2005, to determine whether mortality 'benchmarking' data could be generalised across sites and production cycles. We show that farm mortality records play an important role in studying mortality losses and identifying of management problems in production. We found that mortalities varied across the months of the year and with the time of year of initial stocking. Production cycles that started in the third quarter of the year had the highest mortality overall. Furthermore, we found site-to-site variation in mortality that may have been caused by either random occurrence of epidemics and environmental events or other local effects.

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.

Safety and tolerability of zoster vaccine in adults ≥60 years old.

OBJECTIVE: To evaluate the general safety of zoster vaccine (ZV) in adults ≥60 years old. PATIENTS/METHODS: Subjects were enrolled in a 1:1 ratio to receive 1 dose of ZV or placebo. Subjects were followed for serious adverse experiences (SAEs) for 42 days (primary follow-up period) and 182 days (secondary follow-up period) postvaccination. Relative-risks (ZV/placebo) for SAEs during both safety periods were calculated. STUDY PERIOD: 17-Sep­2007 to 09-Jan-2009. RESULTS: Overall, 5,983 subjects received ZV and 5,997 received placebo. Within the primary 42-day follow-up period, 84 ZV subjects and 67 placebo subjects reported SAEs. The estimated risk of SAEs within 42 days was 1.41% for ZV versus 1.12% for placebo, with a relative-risk of 1.26 (95% CI 0.91,1.73); indicating no statistically significant difference between groups, meeting the pre-specified success criterion. During the 182-day follow-up period, 340 ZV subjects and 300 placebo subjects reported SAEs. The estimated risk of SAEs within 182 days was 5.68% for ZV versus 5.01% for placebo, with a relative-risk of 1.13 (95% CI 0.98,1.32), indicating no statistically significant difference between groups. Two subjects in the ZV group reported SAEs deemed by the investigator to be vaccine-related (uveitis and sciatica; onset Day 5 and 4, respectively). One subject in the placebo group reported a SAE deemed by the investigator to be vaccine-related (lumbar radiculopathy; onset Day 51). There were 24 fatal SAEs in the ZV group and 17 in the placebo group (relative risk = 1.41; CI: 0.77, 2.60); 6 and 5, respectively, with SAE onset during the primary 42-day follow-up period. No deaths were deemed vaccine-related. CONCLUSIONS: ZV and placebo groups had similar safety profiles in terms of SAEs during the primary (Day 1 to 42) and secondary (Day 1 to 182) follow-up periods.

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.

Epidemiological investigation into the re-emergence and control of an outbreak of infectious salmon anaemia in the Shetland Islands, Scotland.

Infectious salmon anaemia (ISA) is an orthomyxoviral disease, primarily affecting marine-phase farmed Atlantic salmon, which can result in high levels of mortality. ISA first emerged in Norway in the 1980s and subsequently has occurred in Canada, the USA, the Faeroe Islands and Chile. An outbreak occurred in Scotland in 1998-1999, but was eradicated at a cost of over pounds sterling 20M. The epidemiology of a new outbreak of ISA in the Scottish Shetland Islands during 2008-2009 is described. Six sites have been confirmed ISA-positive. Spread of the virus via transport of fish between marine sites, harvest vessels, smolts and wild fish appears to have been of little or no importance, with spread primarily associated with marine water currents. The use of management areas by Marine Scotland to control the event appears to have been effective in restricting spread to a small area. This localised outbreak contrasts with the 1998-1999 outbreak that spread over a wide geographic area with transported fish and harvest vessels. The development and application of industry codes of good practice, good husbandry and biosecurity practices, limited marine site-to-site movement of live fish and improved disinfection of vessels and processing plant waste that occurred subsequent to the 1998-1999 outbreak may explain the localised spread of infection in 2008-2009. Depopulation of confirmed sites has been achieved within 7 wk (mean = 3.7 wk); however, it is likely that subclinical infection persisted undetected for months on at least 1 site. The origin of the 2008-2009 outbreak remains unknown. Potential sources include evolution from a local reservoir of infection or importation. Synchronous fallowing of management areas, with good husbandry and biosecurity, reduces the risk of ISA recurring. Movement of fish between sites in different management areas represents the greatest risk of regional-scale spread, should this occur.

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.

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.

Using simple models to review the application and implications of different approaches used to simulate transmission of pathogens among aquatic animals.

Disease is an important issue affecting aquatic animal populations. Aquatic pathogens may be transmitted in ways that could result in qualitatively different impacts to those of terrestrial diseases. I analyse simple SIR epidemic models with different functions to describe transmission. Four forms of transmission are applied: density-dependent, density-independent, non-linear density-dependent and constant infection pressure; the first two are similar to terrestrial systems, the second two are based on specifically aquatic modes of transmission. Observed diseases and existing models are reviewed in terms of these simple forms. The significance of mode of transmission to host populations, to strategies to prevent or control diseases, and to wild-farm interactions are analysed. Different diseases are simulated by different transmission models, for example furunculosis depends on host density, while spread of phocine distemper virus is density-independent, and sea lice infestation pressure may result from open transmission processes that are not dependent on local infested hosts. Appropriate transmission model may also depend on the scale of interest (inter- or intra-population). These different models result in very different responses to intervention strategies, for example culling may be effective for controlling density-dependent disease but may be counter-productive when pathogens depend on open recruitment. It is therefore important for management that appropriate models (whether existing or novel) be selected and this paper aims to provide a basic framework for cataloguing and management of aquatic diseases.