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A sense of school belonging has been associated with a number of positive outcomes for young people Two core aspects are feeling part of the school, and feeling safe. This paper examines qualitative data from a mixed methods questionnaire designed to inform schools on the barriers and supports to participation in school life and the relationship with students' feelings of belonging. It contributes to the limited existing qualitative data and can be set alongside students' quantitative measures to provide new insights. We explore responses from 595 students, to the open questions of a survey. Students frequently mentioned relationships with teachers and peers, often in the context of feeling safe to be themselves, suggesting that feeling part of the school and feeling safe are intertwined. The comments reveal the importance of being recognised and accepted and not having their identity purely defined in relation to attainment on a narrowly defined curriculum.

Human well-being is critically linked to the condition of marine ecosystems. Intangible services, benefits, and values derived from ecosystems play a vital role in human well-being and promote conservation efforts that ultimately support ecosystem sustainability. Similar to many regions, communities along the west coast of Hawai‘i Island are intertwined with their diverse and productive ecosystem. Though multiple resource management programs focus on operationalizing ecosystem-based management in this region, they lack adequate inclusion of connections between people and their environment. To address this, we used the Cultural Ecosystem Services (CES) framework to investigate intangible connections and opportunities to include them in resource management. Through unstructured interviews with community members on Hawai‘i Island, we explored relationships between CES and human well-being. We found that certain CES seem to be strongly related and/or connected to a large number of other CES. We also describe emergent interview themes, which include the ecosystem’s influence on well-being, types of access to CES, and the values that people ascribe to their ecosystem-derived connections. Importantly, these themes represent necessary modifications to ecosystem assessment frameworks. Additionally, we suggest stepping away from discussing CES as if they exist in segregated categories that contribute to individual facets of human well-being. Taken collectively, our findings support deepening the scope of ecosystem assessments and improving sociocultural indicators for the benefit of marine ecosystems and human well-being alike.

This study investigated the relationship of children's autism symptoms with their toxic metal body burden and red blood cell (RBC) glutathione levels. In children ages 3–8 years, the severity of autism was assessed using four tools: ADOS, PDD-BI, ATEC, and SAS. Toxic metal body burden was assessed by measuring urinary excretion of toxic metals, both before and after oral dimercaptosuccinic acid (DMSA). Multiple positive correlations were found between the severity of autism and the urinary excretion of toxic metals. Variations in the severity of autism measurements could be explained, in part, by regression analyses of urinary excretion of toxic metals before and after DMSA and the level of RBC glutathione (adjusted 𝑅2 of 0.22–0.45, 𝑃

Abstract Individual motivation for the rural use of common‐pool resources (CPRs) can be fluid, with the line between subsistence and commercial often unclear and in flux. Implications of fluid motivation are understudied yet important for social–ecological systems (SESs), such as bushmeat hunting throughout Central Africa that is essential to local protein/nutrition, income and culture. Making locally informative predictions of multiple SESs nested within a landscape‐scale SES has been historically difficult, but community‐driven participatory approaches provide new kinds and quantities of data, opening previously inaccessible doors for research and governance. We apply hierarchical Bayesian structural equation modelling to a novel dataset of 910 hunts from 111 gun and trap hunters across nine villages in Gabon, generated in a participatory process whereby hunters conducted GPS self‐follows in conjunction with paraecologist surveys of their motivation, behaviour and offtake. We (i) establish the human behaviour driving gun‐hunting and trapping success and predict its effect on offtake across villages and (ii) link fluid motivation of gun hunters to their behaviour, number of animals hunted, biomass yielded and income earned. Gun hunts across villages yielded more animals during the night than the day, and when hunters brought high amounts of ammunition and walked far distances from villages. Gun hunts were less successful when coupled with trapping while per‐hunt success of trapping itself was generally low and difficult to predict. Fluid gun hunters hunted fewer animals when motivated strictly by subsistence, despite no reduction in ammunition brought or distance walked, while offtake from strictly commercial versus mixed motivation was the same. Numbers of animals hunted, biomass and income were tightly linked. We discuss the implications of these results for the ecological sustainability of hunting and participatory forecasting in bushmeat research and policy. Read the free Plain Language Summary for this article on the Journal blog.

Summary: How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical isolates from two species, we show that the type 3 secretion system (T3SS) is required to induce cell death in human macrophages by inflammasome-dependent pyroptosis. Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 undergo pyroptosis upon bacterial internalization, but those deficient in both NLRC4 and NLRP3 do not, suggesting either sensor mediates pyroptosis in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicates that the intracellular bacteria reside in a late phagolysosome. Using an intranasal mouse infection model, we observe that Achromobacter damages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate that Achromobacter species can survive phagocytosis by promoting macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction in a T3SS-dependent manner.

Across the planet, biodiversity is facing ever-growing threats including habitat loss, climate change, overexploitation, and pollution. Pangolins of the order Pholidota are the only scaly mammal species worldwide and are considered the most trafficked wild mammals in the world, being widely exploited for their meat and scales. The giant pangolin (Smutsia gigantea, GP) is one of the least studied species of this order, with little being known about their response to environmental and anthropogenic variables, as well as their distribution patterns in forest-savannah transition areas. Our study aimed to increase ecological knowledge about GP by investigating the environmental factors associated with the distribution of suitable habitat for GP within a protected forest/savannah transition area of Cameroon. Using data on the locations of GP resting burrows collected using line transects and employing a maximum entropy (MaxEnt) modelling approach, we explored GP habitat suitability within a forest-savannah transition area of Cameroon. Our model revealed a good level of accuracy based on the average test area under the Receiver Operator Curve metric. The jackknife test found that Euclidian distance to the national park’s boundaries, normalized difference vegetation index, elevation, and distance to river were the most important predictors determining the distribution of GP burrows. Areas predicted to be suitable for GP burrows were patchily distributed within dense forests, ecotone and savannah, with 19.24% of the study area being suitable and 1% very suitable. Overall, our study shows the possible importance of habitat suitability modeling for understanding GP distribution, as well as planning and prioritising their conservation actions.

Abstract Pangolin species are notoriously difficult to detect and monitor in the wild and, as a result, commonly used survey techniques fall short in gathering sufficient data to draw confident conclusions on pangolin populations, conservation status, and natural history. The white‐bellied pangolin is a semiarboreal species that may be poorly detected in general mammal surveys even with modern techniques such as camera‐trapping. As a result, population status information is often derived from hunting, market, and trafficking data. There is therefore a crucial need to improve camera‐trap survey methods to reliably detect this species in its natural environment. Here, we test the influence of camera‐trap placement strategy on the detectability of the white‐bellied pangolin by comparing estimates from targeted ground‐viewing camera‐trapping and a novel log‐viewing placement strategy adapted from local hunters' knowledge. Our results suggest that (1) deploying camera‐traps to detect animals walking along logs is an effective strategy for recording several forest species, including the white‐bellied pangolin, and (2) that camera‐traps targeting logs are more efficient at detecting white‐bellied pangolins than camera‐traps viewing the ground (>100% increase in detection probability). We also found moderate evidence that there is a relationship between the white‐bellied pangolin occurrence at our locality and elevation and weak evidence of an association with distance to the nearest river. Our results suggest an effective new monitoring approach allowing consistent detection of the white‐bellied pangolin with moderate survey effort. This highlights the importance of harnessing local knowledge to guide the design of monitoring protocols for cryptic species.

This study analyzes the interplay of factors which drive states’ approaches to the repatriation and reintegration of Foreign Terrorist Fighters (FTFs) and their family members. The literature is dominated by descriptive studies of state policies that tend to explain states’ failure to repatriate and reintegrate citizens as the result of deference to governments’ national security decisions. Our study builds on these foundations to offer the scholarly and policy fields both a framework to explain why governments adopt distinct policy postures, and a means to enable these same actors to engage in more systematic analysis and development of repatriation and reintegration policy. This study argues that a balance of four considerations are crucial for explaining state behavior in this policy context: (i.) the scope of the issue, including the number of citizens considered FTFs or affiliated persons, geographic proximity, and access to the conflict, (ii.) existing legal basis for repatriation and reintegration, (iii.) instrumentalization for institution building, and (iv.) programming strategy for repatriation and reintegration. As a pilot study, this paper applies the framework to assess cases of the United States, the Netherlands, Kosovo, and Iraq. As FTF management issues are not a relic of the recent past but a persistent policy concern that warrants more nuanced and forward-looking attention, this study also considers the continued application of the framework to explore the different ways in which states may balance these four considerations in policy design and practice in the future.

Abstract Habitat loss and overexploitation are the most severe threats to wild animals in Central Africa. One mammalian group under pressure from hunting is the Pholidota (pangolins), with three species of pangolin inhabiting the region. While local uses of pangolins have been investigated in several Central African countries, data originating from the Republic of the Congo are lacking. To address this knowledge gap, we conducted a semistructured questionnaire survey in 65 rural communities around the Odzala‐Kokoua National Park. Our research focused on collecting baseline information on local knowledge of species ecology, and perceived economic values and uses of pangolins in local communities. We identified significant differences in our data corresponding to respondents' sociocultural and demographic profiles in the surveyed villages. Recognition of pangolins was high (98.2%), we recorded 22 traditional medicinal or cultural uses of pangolins by respondents, and the taste of pangolin meat was ranked highly (71.3%). Respondents based along the northern boundary of the park were more familiar with pangolins and the market value of their meat and scales, which could be due to better quality roads in the area and proximity to Cameroon. We then provide guidelines for further research to better understand the dynamics of local use, needed for conservation policy and actions.

Patients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice.

Reversible electrochemical magnesium plating/stripping processes are important for the development of high-energy-density Mg batteries based on Mg anodes. Ether glyme solutions such as monoglyme (G1), diglyme (G2), and triglyme (G3) with the MgTFSI2 salt are one of the conventional and commonly used electrolytes that can obtain the reversible behavior of Mg electrodes. However, the electrolyte cathodic efficiency is argued to be limited due to the enormous parasitic reductive decomposition and passivation, which is governed by impurities. In this work, a systematic identification of the impurities in these systems and their effect on the Mg deposition–dissolution processes is reported. The mitigation methods generally used for eliminating impurities are evaluated, and their beneficial effects on the improved reactivity are also discussed. By comparing the performances, we proposed a necessary conditioning protocol that can be easy to handle and much safer toward the practical application of MgTFSI2/glyme electrolytes containing impurities.

Abstract Background Transitioning care from hospital to home is associated with risks of adverse events and poor continuity of care. These transitions are even more challenging when new approaches to care, such as palliative care, are introduced before discharge. Family caregivers (FCGs) are expected to navigate these transitions while also managing care. In addition to extensive caregiving responsibilities, FCGs often have their own health needs that can inhibit their ability to provide care. Those living in rural areas have even fewer resources to meet their self-care and caregiving needs. The purpose of this study is to test the efficacy and cost-effectiveness of an intervention to improve FCGs’ health and well-being. The intervention uses video visits to teach, guide, and counsel FCGs in rural areas during hospital-to-home transitions. The intervention is based on evidence of transitional and palliative care principles, which are individualized to improve continuity of care, provide caregiver support, enhance knowledge and skills, and attend to caregivers’ health needs. It aims to test whether usual care practices are similar to this technology-enhanced intervention in (1) caregiving skills (e.g., caregiving preparedness, communication with clinicians, and satisfaction with care), (2) FCG health outcomes (e.g., quality of life, burden, coping skills, depression), and (3) cost. We describe the rationale for targeting rural caregivers, the methods for the study and intervention, and the analysis plan to test the intervention’s effect. Methods The study uses a randomized controlled trial design, with FCGs assigned to the control condition or the caregiver intervention by computer-generated lists. The intervention period continues for 8 weeks after care recipients are discharged from the hospital. Data are collected at baseline, 2 weeks, 8 weeks, and 6 months. Time and monetary costs from a societal perspective are captured monthly. Discussion This study addresses 2 independent yet interrelated health care foci—transitional care and palliative care—by testing an intervention to extend palliative care practice and improve transition management for caregivers of seriously ill patients in rural areas. The comprehensive cost assessment will quantify the commitment and financial burden of FCGs. Trial registration ClinicalTrials.gov NCT03339271 . Registered on 13 November 2017. Protocol version: 11.

Wild animals are captured or taken opportunistically, and the meat, body parts, and/or eggs are consumed for local subsistence or used for traditional purposes to some extent across most of the world, particularly in the tropics and subtropics. The consumption of aquatic animals is widespread, in some places has been sustained for millennia, and can be an important source of nutrition, income, and cultural identity to communities. Yet, economic opportunities to exploit wildlife at higher levels have led to unsustainable exploitation of some species. In the literature, there has been limited focus on the exploitation of aquatic non-fish animals for food and other purposes. Understanding the scope and potential threat of aquatic wild meat exploitation is an important first step toward appropriate inclusion on the international policy and conservation management agenda. Here, we conduct a review of the literature, and present an overview of the contemporary use of aquatic megafauna (cetaceans, sirenians, chelonians, and crocodylians) in the global tropics and subtropics, for species listed on the Appendices of the Convention on the Conservation of Migratory Species of Wild Animals (CMS). We find that consumption of aquatic megafauna is widespread in coastal regions, although to varying degrees, and that some species are likely to be at risk from overexploitation, particularly riverine megafauna. Finally, we provide recommendations for CMS in the context of the mandate of the Aquatic Wild Meat Working Group.

This study's purpose is to characterize the performance of a prototype functional near-infrared spectroscopy (fNIRS) headband meant to enable quick and easy measurements from the sensorimotor cortices. The fact that fNIRS is well-suited to ergonomic designs (i.e., their ability to be made wireless, their relative robustness to movement artifacts among other characteristics) has resulted in many recent examples of novel ergonomic fNIRS systems; however, the optical nature of fNIRS measurement presents an inherent challenge to measurement at areas of the brain underlying haired parts of the head. It is for this reason that the majority of ergonomic fNIRS systems that have been developed to date target the prefrontal cortex. In the present study we compared the performance of a novel, portable fNIRS headband compared with a stationary full headcap fNIRS system to measure sensorimotor activity during simple upper- and lower-extremity tasks, in healthy individuals >50 years of age. Both fNIRS systems demonstrated the expected pattern of hemodynamic activity in both upper- and lower-extremity tasks, and a comparison of the contrast-to-noise ratio between the two systems suggests the prototype fNIRS headband is non-inferior to a full head cap fNIRS system regarding the ability to detect a physiological response at the sensorimotor cortex during these tasks. These results suggest the use of a wireless and fibreless fNIRS design is feasible for measurement at the sensorimotor cortex.

Pasture-based dairy systems rely on the accurate allocation of pasture to both meet livestock requirements and maintain the growth of herbage. Currently, physical fences are used to contain livestock however they can be labor-intensive to shift and maintain. Alternatively, virtual fence (VF) systems offer flexibility and real-time control of livestock location. Pre-commercial neckbands (eShepherd®, Agersens, Melbourne, VIC) emit a warning audio tone (AT) when a cow approaches a VF boundary, paired with an electrical pulse (EP) if the cow continues forward into the exclusion zone (EZ). However, the ability of VF technology to control animal location when pasture is restricted to the previous day's residual, remains unknown. Ten non-lactating Holstein-Friesian dairy cows were trained to use a VF system for 6 days before strip grazing a 1.2 ha paddock of annual ryegrass. Over 10 days the cows grazed eight pasture allocations at a pre-grazing pasture mass of 2,324 ± 81 kg DM/ha (mean ± SE) and post-grazing pasture-mass (post-grazing residual) of 1,649 ± 48 kg/DM/ha with a front VF. The allocations had a physical backing fence that included the fresh allocation and a small area of residual to cater for any GPS drift of the front VF. On each day, with the exception of days 5 and 10, the VF was moved forward, and the cows were provided a new pasture allocation. On days 5 and 10, the VF was not shifted, and cows were only offered the previous allocation's residual pasture. The location of each animal (inclusion, buffer, and exclusion zones) and number of stimuli (AT and EP) delivered were recorded. The number of stimuli delivered between the grazing and hold-off days was similar. Cows spent 89% of time within the inclusion zone (IZ), with significant peaks observed on day 5 and 10. Distance that cows traveled into the EZ reduced across time. There was also evidence of individual variation in the number of stimuli and thus time spent in each zone. Overall, the VF system was successful in containing the dairy cows during strip grazing even when only offered the previous days post-grazing residual.

Introduction: Discordance in kidney disease severity between affected relatives is a recognized feature of autosomal dominant polycystic kidney disease (ADPKD). Here, we report a systematic study of a large cohort of families to define the prevalence and clinical features of intrafamilial discordance in ADPKD. Methods: The extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease (eTGESP) cohort includes 1390 patients from 612 unrelated families with ADPKD ascertained in a regional polycystic kidney disease center. All probands underwent comprehensive PKD1 and PKD2 mutation screening. Total kidney volume by magnetic resonance imaging (MRI) was available in 500 study patients. Results: Based on (i) rate of estimated glomerular filtration rate (eGFR) decline, (ii) age at onset of end-stage renal disease (ESRD), and (iii) Mayo Clinic Imaging Classification (MCIC), 20% of patients were classified as having mild disease, and 33% as having severe disease. Intrafamilial ADPKD discordance with at least 1 mild and 1 severe case was observed in 43 of 371 (12%) families, at a similar frequency regardless of the responsible gene (PKD1/PKD2/no mutation detected) or mutation type (protein-truncating versus nontruncating). Intrafamilial discordance was more common in larger families and was present in 30% of families with more than 5 affected members. The heritability of age at onset of ESRD was similar between different mutation types. Conclusion: Extreme kidney disease discordance is present in at least 12% of families with ADPKD, regardless of the underlying mutated gene or mutation class. Delineating genetic and environmental modifiers underlying the observed intrafamilial ADPKD variability will provide novel insights into the mechanisms of progression in ADPKD. Keywords: polycystic kidney disease, ADPKD, genetics

Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a protein with roles in early development, activation of the transcription factor NF-κB, and production of mitochondrial reactive oxygen species (mROS) that facilitates clearance of intracellular bacteria like Salmonella. ECSIT is also an important assembly factor for mitochondrial complex I. Unlike the murine form of Ecsit (mEcsit), we demonstrate here that human ECSIT (hECSIT) is highly labile. To explore whether the instability of hECSIT affects functions previously ascribed to its murine counterpart, we created a potentially novel transgenic mouse in which the murine Ecsit gene is replaced by the human ECSIT gene. The humanized mouse has low levels of hECSIT protein, in keeping with its intrinsic instability. Whereas low-level expression of hECSIT was capable of fully compensating for mEcsit in its roles in early development and activation of the NF-κB pathway, macrophages from humanized mice showed impaired clearance of Salmonella that was associated with reduced production of mROS. Notably, severe cardiac hypertrophy was manifested in aging humanized mice, leading to premature death. The cellular and molecular basis of this phenotype was delineated by showing that low levels of human ECSIT protein led to a marked reduction in assembly and activity of mitochondrial complex I with impaired oxidative phosphorylation and reduced production of ATP. Cardiac tissue from humanized hECSIT mice also showed reduced mitochondrial fusion and more fission but impaired clearance of fragmented mitochondria. A cardiomyocyte-intrinsic role for Ecsit in mitochondrial function and cardioprotection is also demonstrated. We also show that cardiac fibrosis and damage in humans correlated with low expression of human ECSIT. In summary, our findings identify a role for ECSIT in cardioprotection, while generating a valuable experimental model to study mitochondrial dysfunction and cardiac pathophysiology.

Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.

The NLRP3 inflammasome is important for inducing IL-1β and IL-18 inflammatory responses. Here the authors show, by generating and characterizing Peli2 deficient mice and immune cells, that an E3 ubiquitin ligase Pellino2 promotes inflammasome priming by inducing NLRP3 ubiquitination and by targeting IRAK1.

Abstract Background As part of the NHS desire to move services closer to where people live, and provide greater accessibility and convenience to patients, Brighton and Hove Clinical Commissioning Group (CCG) underwent a review of their anticoagulation services during 2008. The outcome was to shift the initiation and monitoring service in secondary care for non-complex patients, including domiciliary patients, into the community. This was achieved via a procurement process in 2008 resulting in the Community Pharmacy Anticoagulation Management Service (CPAMs) managed by Boots UK (a large chain of community pharmacies across the United Kingdom). Methods This evaluation aims to review the outcomes (International Normalised Ratio [INR] readings) and experiences of those patients attending the anticoagulation monitoring service provided by community pharmacists in Brighton and Hove. All patients on warfarin are given a target INR range they need to achieve; dosing of and frequency of appointment are dependent on the INR result. Outcome measures for patients on the CPAM service included percentage INR readings that were within target range and the percentage time the patient was within therapeutic range. Data collected from 2009 to 2016 were analysed and results compared to the service targets. Patient experience of the service was evaluated via a locally developed questionnaire that was issued to patients annually in the pharmacy. Results The evaluation shows that community pharmacy managed anticoagulation services can achieve outcomes at a level consistently exceeding national and local targets for both percentage INR readings in therapeutic target range (65.4%) compared to the recommended minimum therapeutic target range of 60.0% and percentage time in therapeutic range (72.5%, CI 71.9–73.1%) compared to the national target of 70.0%. Patients also indicated they were satisfied with the service, with over 98.6% patients rating the service as good, very good or excellent. Conclusion The Brighton and Hove CPAM service achieved above average national target management of INR and positive patient feedback, demonstrating that community pharmacy is ideally placed to provide this service safely and deliver enhanced clinical outcomes and positive patient experience.

Understanding immune responses to native antigens in response to natural infections can lead to improved approaches to vaccination. This study sought to characterize the humoral immune response to anthrax toxin components, capsule and spore antigens in individuals (n = 46) from the Kayseri and Malatya regions of Turkey who had recovered from mild or severe forms of cutaneous anthrax infection, compared to regional healthy controls (n = 20). IgG antibodies to each toxin component, the poly-γ-D-glutamic acid capsule, the Bacillus collagen-like protein of anthracis (BclA) spore antigen, and the spore carbohydrate anthrose, were detected in the cases, with anthrax toxin neutralization and responses to Protective Antigen (PA) and Lethal Factor (LF) being higher following severe forms of the disease. Significant correlative relationships among responses to PA, LF, Edema Factor (EF) and capsule were observed among the cases. Though some regional control sera exhibited binding to a subset of the tested antigens, these samples did not neutralize anthrax toxins and lacked correlative relationships among antigen binding specificities observed in the cases. Comparison of serum binding to overlapping decapeptides covering the entire length of PA, LF and EF proteins in 26 cases compared to 8 regional controls revealed that anthrax toxin-neutralizing antibody responses elicited following natural cutaneous anthrax infection are directed to conformational epitopes. These studies support the concept of vaccination approaches that preserve conformational epitopes.

Ecosystem-based management approaches are increasingly used to address the critical linkages between human and biophysical systems. Yet, many of the social-ecological systems (SES) frameworks typically used in coastal and marine management neither represent the social and ecological aspects of the system in equal breadth or depth, nor do they adequately operationalize the social, or human, dimensions. The National Oceanic and Atmospheric Administration’s West Hawai‘i Integrated Ecosystem Assessment, a program grounded in ecosystem-based management, recognizes the importance of place-based human dimensions in coastal and marine resource management that speak to a fuller range of social and cultural dimensions of ecosystem-based management. Previous work with stakeholders in West Hawai‘i revealed noteworthy SES dynamics and highlighted both the importance and lack of understanding of the links between ecosystem services and human well-being, particularly services that enhance and maintain active cultural connections to a place. While cultural ecosystem services and human well-being are often recognized as important elements of SES, there have been substantial barriers to fully representing them, likely due to perceived difficulties of measuring non-material benefits and values, many of which are socially constructed and subjective. This study examined SES frameworks related to cultural ecosystem services and human well-being to advance the representation and operationalization of these important concepts in coastal and marine management. We describe key insights and questions focused on: (1) points of inclusion for human dimensions in SES models, (2) culturally relevant domains of human well-being and related indicators, (3) the importance of place and its interaction with scale, and finally (4) the tension between a gestalt vs. discrete approach to modeling, assessing, and sustainably managing social-ecological systems.

The mouse primary visual cortex (V1) has become an important brain area for exploring how neural circuits process information. Optogenetic tools have helped to outline the connectivity of a local V1 circuit comprising excitatory pyramidal neurons and several genetically-defined inhibitory interneuron subtypes that express parvalbumin, somatostatin, or vasoactive intestinal peptide. Optogenetic modulation of individual interneuron subtypes can alter the visual responsiveness of pyramidal neurons with distinct forms of inhibition and disinhibition. However, different interneuron subtypes have potentially opposing actions, and the potency of their effects relative to each other remains unclear. Therefore, in this study we simultaneously optogenetically activated all interneuron subtypes during visual processing to explore whether any single inhibitory effect would predominate. This aggregate interneuron activation consistently inhibited pyramidal neurons in a divisive manner, which was essentially identical to the pattern of inhibition produced by activating parvalbumin-expressing interneurons alone.

Standardised methods to monitor populations of many species are lacking but are important for detecting presence, changes in populations and species status, and for conservation management. Pangolins (Family: Manidae), are one such group of mammals that are native to Africa and Asia. Here, we conduct a systematic review of methods used to detect and monitor populations of species ecologically similar to pangolins to inform the development of pangolin monitoring methods. The primary question of this review is: how effective have methods been at detecting and monitoring populations of species ecologically similar to pangolins? We also investigated their applicability to each species of pangolin, considering the lessons learnt from the identified studies. Of the 379 articles identified by Web of Science, 159 were included, and supplemented with 87 studies from Google Scholar searches. In total, across all studies and 24 taxonomic groups, 28 different survey methods were used to detect and/or monitor the selected taxa. Based on this review, several methods have potential application to the different pangolin species. Camera-trapping may be useful for monitoring all species of pangolin, including the arboreal species. Burrow counts could be used to monitor fossorial pangolins, but there are several challenges to using this method including correct identification of burrows and identifying the ways in which pangolins use burrows/dens. Keywords: Burrow count, Camera-trap, Conservation, Manidae, Population

Abstract The PREDICTS project—Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (https://www.nhm.ac.uk/our-science/our-work/biodiversity/predicts.html)—has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.

Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.

Humans and pangolins have a long and intertwined history in Africa and Asia, with the species having been used for subsistence, livelihood, medicinal, and cultural purposes. Populations of Asian pangolins have severely declined, and intercontinental trafficking of African pangolin scales to Asia has emerged in the last decade. Coastal countries in the Gulf of Guinea have been highlighted as hotspots of illegal pangolin trade, and in 2017, international commercial trade in pangolins was banned. We characterise the trade and international trafficking of African pangolins in the coastal countries around the Gulf of Guinea using data across three tiers. First, we investigated which countries were most heavily involved in international trafficking using seizure data. Second, we investigated where domestic seizures of pangolins took place, and whether they were seized with other species. Finally, we tracked the open sale of pangolins across 20-years at the main wild meat market in Malabo, Equatorial Guinea, to investigate patterns of pangolin sales in a capital city. We found a total of 55893 kg of pangolin scales in 33 seizures between 2012 and 2018, with Cameroon and Nigeria being the most common export countries for international trafficking of pangolin scales. Cameroon had the largest number of domestic seizures (45); we also observed a shift from seizures of meat to scales from 2013 onwards. At the Malabo market a total of 11207 Phataginus pangolins and 366 Smutsia pangolins were sold between 1997 and 2017, and the number and price of pangolins increased over time for both genera and corresponded to a shift in the import of pangolins from Cameroon. Together, these results highlight the scale of trade and trafficking in pangolins within and from this region. Keywords: Africa, Bushmeat, Conservation, Phataginus, Smutsia, Wild meat

The behaviours, ecologies and morphologies of pangolins make them challenging to survey and monitor, and non-targeted wildlife surveys have not produced robust status assessments, especially where population densities are low because of overexploitation. To inform the development of feasible survey and monitoring techniques for pangolins, we conducted a systematic review of all traceable efforts used to survey and monitor pangolins to date: 87 articles were included in the review. Pitfalls of current approaches are discussed and recommendations made on suitable methods. Recommendations include the use of mark-recapture for burrow-dwelling species, community interviews, sign-based surveys in arid and open habitats, detection dog teams, and targeted camera-trapping. Occupancy sampling using camera-traps could be used to monitor some pangolin populations, particularly ground-dwelling species, but the rarity of all species makes it uncertain whether this would provide enough data for monitoring; combinations of methods used within an occupancy sampling framework are likely to be the most effective. There will be many circumstances where direct monitoring of a population at a site, to a level that will generate precise data, is not financially viable nor the best use of conservation resources. In many sites, particularly in Asia, pangolins are too rare as a result of overexploitation, and/or occur in inaccessible areas where significant resources will be needed to implement a targeted monitoring programme. Under such circumstances, the use of proxy variables, including status of other hunting-sensitive species that are easier to record, in combination with enforcement or patrol data and/or community interviews, is likely to be the most cost-effective method for assessing the impact of conservation interventions on pangolin status. The publication of incidental observations and survey ‘by-catch’ would significantly improve understanding of pangolin status and ecology, and therefore how best to identify, conserve and monitor priority populations.

Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with K. pneumoniae by launching bacterial growth-controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 (Ifnar1)-deficient mice infected with K. pneumoniae failed to activate NK cell-derived IFN-γ production. IFN-γ was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-γ were rescued in Ifnar1-deficient hosts by Ifnar1-proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-γ activation. The failure of Ifnar1-deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-γ which restored endogenous IFN-γ production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of K. pneumoniae clearance, and reveal specific targets for future therapeutic exploitations.

ABSTRACT The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins. IMPORTANCE Current research on antibiotic action and resistance focuses on targeting essential functions within bacterial cells. We discovered a previously unrecognized mode of general bacterial antibiotic resistance operating in the extracellular space, which depends on bacterial protein molecules called lipocalins. These molecules are highly conserved in most bacteria and have the ability to capture different classes of antibiotics outside bacterial cells. We also discovered that liposoluble vitamins, such as vitamin E, overcome in vitro and in vivo antibiotic resistance mediated by bacterial lipocalins, providing an unexpected new alternative to combat resistance by using this vitamin or its derivatives as antibiotic adjuvants.

Abstract Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local‐scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – https://www.nhm.ac.uk/our-science/our-work/biodiversity/predicts.html). We make site‐level summary data available alongside this article. The full database will be publicly available in 2015.

School librarians currently speak about school libraries as the largest classroom in the building. If so, how can these librarians describe what they teach? This article explains the user-centered instructional role of secondary school librarians in teaching information and technology literacy skills, as well as how they can authoritatively ensure that other educators, students, and the public know what they teach. To be certain, school librarians teach students how to use computer and information technology as tools to communicate and ethically conduct research. School librarians also have specialized expertise and skills, not only to facilitate, but to evaluate the accessed information. This evaluation is research-based and involves a knowledge building process that includes identification of five key terms: (1) data; (2) information; (3) knowledge; (4) wisdom; and (5) cognitive authority. This approach to information evaluation clarifies the complex digital world where information is self-organizing, self-correcting, and never finished. For future funding and survival, school librarians must make clear their critical role in improving instruction, boosting student achievement, and preparing today's children and youth for higher education and the work force. As this article points out, school librarians teach the use of computers and information technology as tools to improve communication, practice legal and ethical access, evaluate and use information, and to competently conduct research. School librarians, along with their school administrators and state department of education officials, should report that this specialized content is taught by the school librarian. (Contains 2 figures.)

[This corrects the article DOI: 10.1371/journal.ppat.1004627.].

Microorganisms are vital in mediating the earth’s biogeochemical cycles; yet, despite our rapidly increasing ability to explore complex environmental microbial communities, the relationship between microbial community structure and ecosystem processes remains poorly understood. Here, we address a fundamental and unanswered question in microbial ecology: ‘When do we need to understand microbial community structure to accurately predict function?’ We present a statistical analysis investigating the value of environmental data and microbial community structure independently and in combination for explaining rates of carbon and nitrogen cycling processes within 82 global datasets. Environmental variables were the strongest predictors of process rates but left 44% of variation unexplained on average, suggesting the potential for microbial data to increase model accuracy. Although only 29% of our datasets were significantly improved by adding information on microbial community structure, we observed improvement in models of processes mediated by narrow phylogenetic guilds via functional gene data, and conversely, improvement in models of facultative microbial processes via community diversity metrics. Our results also suggest that microbial diversity can strengthen predictions of respiration rates beyond microbial biomass parameters, as 53% of models were improved by incorporating both sets of predictors compared to 35% by microbial biomass alone. Our analysis represents the first comprehensive analysis of research examining links between microbial community structure and ecosystem function. Taken together, our results indicate that a greater understanding of microbial communities informed by ecological principles may enhance our ability to predict ecosystem process rates relative to assessments based on environmental variables and microbial physiology.

Bacillus anthracis secretes exotoxins which act through several mechanisms including those that can subvert adaptive immunity with respect both to antigen presenting cell and T cell function. The combination of Protective Antigen (PA) and Lethal Factor (LF) forming Lethal Toxin (LT), acts within host cells to down-regulate the mitogen activated protein kinase (MAPK) signaling cascade. Until recently the MAPK kinases were the only known substrate for LT; over the past few years it has become evident that LT also cleaves Nlrp1, leading to inflammasome activation and macrophage death. The predicted downstream consequences of subverting these important cellular pathways are impaired antigen presentation and adaptive immunity. In contrast to this, recent work has indicated that robust memory T cell responses to B. anthracis antigens can be identified following natural anthrax infection. We discuss how LT affects the adaptive immune response and specifically the identification of B. anthracis epitopes that are both immunogenic and protective with the potential for inclusion in protein sub-unit based vaccines.

Pulses of aeolian transport following fire can profoundly affect the biogeochemical cycling of nutrients in semi-arid and arid ecosystems. Our objective was to determine horizontal nutrient fluxes occurring in the saltation zone during an episodic pulse of aeolian transport that occurred following a wildfire in a semi-arid sagebrush steppe ecosystem in southern Idaho, USA. We also examined how temporal trends in nutrient fluxes were affected by changes in particle sizes of eroded mass as well as nutrient concentrations associated with different particle size classes. In the burned area, total carbon (C) and nitrogen (N) fluxes were as high as 235 g C m−1 d−1 and 19 g N m−1 d−1 during the first few months following fire, whereas C and N fluxes were negligible in an adjacent unburned area throughout the study. Temporal variation in C and N fluxes following fire was largely attributable to the redistribution of saltation-sized particles. Total N and organic C concentrations in the soil surface were significantly lower in the burned relative to the unburned area one year after fire. Our results show how an episodic pulse of aeolian transport following fire can affect the spatial distribution of soil C and N, which, in turn, can have important implications for soil C storage. These findings demonstrate how an ecological disturbance can exacerbate a geomorphic process and highlight the need for further research to better understand the role aeolian transport plays in the biogeochemical cycling of C and N in recently burned landscapes.

We describe the HadGEM2 family of climate configurations of the Met Office Unified Model, MetUM. The concept of a model "family" comprises a range of specific model configurations incorporating different levels of complexity but with a common physical framework. The HadGEM2 family of configurations includes atmosphere and ocean components, with and without a vertical extension to include a well-resolved stratosphere, and an Earth-System (ES) component which includes dynamic vegetation, ocean biology and atmospheric chemistry. The HadGEM2 physical model includes improvements designed to address specific systematic errors encountered in the previous climate configuration, HadGEM1, namely Northern Hemisphere continental temperature biases and tropical sea surface temperature biases and poor variability. Targeting these biases was crucial in order that the ES configuration could represent important biogeochemical climate feedbacks. Detailed descriptions and evaluations of particular HadGEM2 family members are included in a number of other publications, and the discussion here is limited to a summary of the overall performance using a set of model metrics which compare the way in which the various configurations simulate present-day climate and its variability.

The scientific understanding of the Earth's climate system, including the central question of how the climate system is likely to respond to human-induced perturbations, is comprehensively captured in GCMs and Earth System Models (ESM). Diagnosing the simulated climate response, and comparing responses across different models, is crucially dependent on transparent assumptions of how the GCM/ESM has been driven – especially because the implementation can involve subjective decisions and may differ between modelling groups performing the same experiment. This paper outlines the climate forcings and setup of the Met Office Hadley Centre ESM, HadGEM2-ES for the CMIP5 set of centennial experiments. We document the prescribed greenhouse gas concentrations, aerosol precursors, stratospheric and tropospheric ozone assumptions, as well as implementation of land-use change and natural forcings for the HadGEM2-ES historical and future experiments following the Representative Concentration Pathways. In addition, we provide details of how HadGEM2-ES ensemble members were initialised from the control run and how the palaeoclimate and AMIP experiments, as well as the "emission-driven" RCP experiments were performed.

Central or postural set theory suggests that the central nervous system uses short term, trial to trial adaptation associated with repeated exposure to a perturbation in order to improve postural responses and stability. It is not known if longer-term prior experiences requiring challenging balance control carryover as long-term adaptations that influence ability to react in response to novel stimuli. The purpose of this study was to determine if individuals who had long-term exposure to balance instability, such as those who train on specific skills that demand balance control, will have improved ability to adapt to complex continuous multidirectional perturbations. Healthy adults from three groups: 1) experienced maritime workers (n = 14), 2) novice individuals with no experience working in maritime environments (n = 12) and 3) individuals with training in dance (n = 13) participated in the study. All participants performed a stationary standing task while being exposed to five 6 degree of freedom motions designed to mimic the motions of a ship at sea. The balance reactions (change-in-support (CS) event occurrences and characteristics) were compared between groups. Results indicate dancers demonstrated significantly fewer CS events than novices during the first trial, but did not perform as well as those with offshore experience. Linear trend analyses revealed that short-term adaptation across all five trials was dependent on the nature of participant experience, with dancers achieving postural stability earlier than novices, but later than those with offshore experience. These results suggest that long term previous experiences also have a significant influence on the neural control of posture and balance in the development of compensatory responses.

Background: Coronary calcification in patients with end-stage renal disease (ESRD) is associated with an increased risk of cardiovascular outcomes and death from all causes. Previous evidence has been limited by short follow-up periods and inclusion of a heterogeneous cluster of events in the primary analyses. Objective: To describe coronary calcification in patients incident to ESRD, and to identify whether calcification predicts vascular events or death. Design: Prospective substudy of an inception cohort. Setting: Tertiary care haemodialysis centre in Ontario (St Joseph's Healthcare Hamilton). Participants: Patients starting haemodialysis who were new to ESRD. Measurements: At baseline, clinical characterization and spiral computed tomography (CT) to score coronary calcification by the Agatston-Janowitz 130 scoring method. A primary outcome composite of adjudicated stroke, myocardial infarction, or death. Methods: We followed patients prospectively to identify the relationship between cardiac calcification and subsequent stroke, myocardial infarction, or death, using Cox regression. Results: We recruited 248 patients in 3 centres to our main study, which required only biochemical markers. Of these 164 were at St Joseph's healthcare, and eligible to participate in the substudy; of these, 51 completed CT scanning (31 %). Median follow up was 26 months (Q 1 , Q 3 : 14, 34). The primary outcome occurred in 16 patients; 11 in the group above the median and 5 in the group below ( p = 0.086). There were 26 primary outcomes in 16 patients; 20 (77 %) events in the group above the coronary calcification median and 6 (23 %) in the group below ( p = 0.006). There were 10 deaths; 8 in the group above the median compared with 2 in the group below ( p = 0.04). The hazard ratios for coronary calcification above, compared with below the median, for the primary outcome composite were 2.5 (95 % CI 0.87, 7.3; p = 0.09) and 1.7 (95 % CI 0.55, 5.4; p = 0.4), unadjusted and adjusted for age, respectively. For death, the hazard ratios were 4.6 (95 % CI 0.98, 21.96; p = 0.054) and 2.4 (95 % CI 0.45, 12.97; p = 0.3) respectively. Limitations: We were limited by a small sample size and a small number of events. Conclusions: Respondent burden is high for additional testing around the initiation of dialysis. High coronary calcification in patients new to ESRD has a tendency to predict cardiovascular outcomes and death, though effects are attenuated when adjusted for age.

Klebsiella pneumoniae is a significant human pathogen, in part due to high rates of multidrug resistance. RamA is an intrinsic regulator in K. pneumoniae established to be important for the bacterial response to antimicrobial challenge; however, little is known about its possible wider regulatory role in this organism during infection. In this work, we demonstrate that RamA is a global transcriptional regulator that significantly perturbs the transcriptional landscape of K. pneumoniae, resulting in altered microbe-drug or microbe-host response. This is largely due to the direct regulation of 68 genes associated with a myriad of cellular functions. Importantly, RamA directly binds and activates the lpxC, lpxL-2 and lpxO genes associated with lipid A biosynthesis, thus resulting in modifications within the lipid A moiety of the lipopolysaccharide. RamA-mediated alterations decrease susceptibility to colistin E, polymyxin B and human cationic antimicrobial peptide LL-37. Increased RamA levels reduce K. pneumoniae adhesion and uptake into macrophages, which is supported by in vivo infection studies, that demonstrate increased systemic dissemination of ramA overexpressing K. pneumoniae. These data establish that RamA-mediated regulation directly perturbs microbial surface properties, including lipid A biosynthesis, which facilitate evasion from the innate host response. This highlights RamA as a global regulator that confers pathoadaptive phenotypes with implications for our understanding of the pathogenesis of Enterobacter, Salmonella and Citrobacter spp. that express orthologous RamA proteins.