Global indicators of the environmental impacts of invasive alien species and their information adequacy.

Monitoring the extent to which invasive alien species (IAS) negatively impact the environment is crucial for understanding and mitigating biological invasions. Indeed, such information is vital for achieving Target 6 of the Kunming-Montreal Global Biodiversity Framework. However, to-date indicators for tracking the environmental impacts of IAS have been either lacking or insufficient. Capitalizing on advances in data availability and impact assessment protocols, we developed environmental impact indicators to track realized and potential impacts of IAS. We also developed an information status indicator to assess the adequacy of the data underlying the impact indicators. We used data on 75 naturalized amphibians from 82 countries to demonstrate the indicators at a global scale. The information status indicator shows variation in the reliability of the data and highlights areas where absence of impact should be interpreted with caution. Impact indicators show that growth in potential impacts are dominated by predatory species, while potential impacts from both predation and disease transmission are distributed worldwide. Using open access data, the indicators are reproducible and adaptable across scales and taxa and can be used to assess global trends and distributions of IAS, assisting authorities in prioritizing control efforts and identifying areas at risk of future invasions. This article is part of the theme issue 'Ecological novelty and planetary stewardship: biodiversity dynamics in a transforming biosphere'.

A nature-positive future with biological invasions: theory, decision support and research needs.

In 2050, most areas of biodiversity significance will be heavily influenced by multiple drivers of environmental change. This includes overlap with the introduced ranges of many alien species that negatively impact biodiversity. With the decline in biodiversity and increase in all forms of global change, the need to envision the desired qualities of natural systems in the Anthropocene is growing, as is the need to actively maintain their natural values. Here, we draw on community ecology and invasion biology to (i) better understand trajectories of change in communities with a mix of native and alien populations, and (ii) to frame approaches to the stewardship of these mixed-species communities. We provide a set of premises and actions upon which a nature-positive future with biological invasions (NPF-BI) could be based, and a decision framework for dealing with uncertain species movements under climate change. A series of alternative management approaches become apparent when framed by scale-sensitive, spatially explicit, context relevant and risk-consequence considerations. Evidence of the properties of mixed-species communities together with predictive frameworks for the relative importance of the ecological processes at play provide actionable pathways to a NPF in which the reality of mixed-species communities are accommodated and managed. This article is part of the theme issue 'Ecological novelty and planetary stewardship: biodiversity dynamics in a transforming biosphere'.

Utilising Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) to track the oxidation of lignin by an alkaliphilic laccase.

Lignin is a complex heteroaromatic polymer which is one of the most abundant and diverse biopolymers on the planet. It comprises approximately one third of all woody plant matter, making it an attractive candidate as an alternative, renewable feedstock to petrochemicals to produce fine chemicals. However, the inherent complexity of lignin makes it difficult to analyse and characterise using common analytical techniques, proving a hindrance to the utilisation of lignin as a green chemical feedstock. Herein we outline the tracking of lignin degradation by an alkaliphilic laccase in a semi-quantitative manner using a combined chemical analysis approach using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) to characterise shifts in chemical diversity and relative abundance of ions, and NMR to highlight changes in the structure of lignin. Specifically, an alkaliphilic laccase was used to degrade an industrially relevant lignin, with compounds such as syringaresinol being almost wholly removed (95%) after 24 hours of treatment. Structural analyses reinforced these findings, indicating a >50% loss of NMR signal relating to ß-ß linkages, of which syringaresinol is representative. Ultimately, this work underlines a combined analytical approach that can be used to gain a broader semi-quantitative understanding of the enzymatic activity of laccases within a complex, non-model mixture.

Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers.

The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions.

FIVE YEARS OF PARTULA SNAIL PRE-EXPORT HEALTH SCREENING.

Between 2015 and 2019, a health screening was carried out annually on captive-bred Partula snails prior to export for reintroduction as part of an international effort to repopulate areas of French Polynesia, where the snails were extinct or critically endangered. In total, 129 separate tank populations of 12 different species were screened at ZSL London Zoo. Wet mounts and smears stained with modified Ziehl-Neelsen (MZN) of 535 fecal samples were examined, and 45% contained flagellated protozoa, and 35.5% had MZN-positive oocysts, measuring 3-5 µm in diameter. Smaller (2 µm) presumptive spores, MZN-positive bacilli, ciliated protozoa and nematodes were recorded less frequently. Fecal bacterial culture yielded mixed species, with a clear predominance of Myroides species (88.9% of samples). The MZN-positive oocysts (3-5 µm) were present in 6.5% of impression smears from the apices of 432 snails examined postmortem, plus acid-fast bacilli in a few cases, but no 2 µm spores. Mixed bacteria were cultured from coelomic swabs, with Myroides species again the most common (63.5%). Histologic examination was carried out on 292 snails. Autolysis affected almost 90% of those found dead but only 3.4% of euthanized snails. Histology commonly identified microsporidial sporocysts in the digestive gland and midgut epithelium of all but two species. Intracellular, extracytoplasmic Cryptosporidium-like organisms were also common in the midgut but were only observed when snails were fixed in 10% formalin (2017-2019), not ethanol. There were no clear pathologic changes associated with either organism. Pigmented hemocytic nodules were commonly observed, most frequently in the foot process; these were either age related or evidence of prior chronic inflammatory reaction and of low clinical significance. With no evidence of poor health and no significant organisms found, a total of 4,978 individuals representing 12 species were exported for reintroduction.

Off-road vehicle crashes: dangers of alcohol and drug impairment.

BACKGROUND: Impaired driving is a public health issue, yet little is known concerning the prevalence of substance use in drivers involved in off-road vehicle crashes. The goal of the present study was to describe the demographics and prevalence of alcohol and drug use in drivers of off-road vehicle crashes. METHODS: In this observational substudy, we collected clinical and toxicological data on all moderately or severely injured off-road vehicle drivers who had blood samples obtained within 6 h of the crash. Clinical data were extracted from patients' medical charts and toxicology analyses were performed for blood alcohol, cannabinoids, recreational drugs, and impairing medications. RESULTS: Thirty-three injured drivers met the inclusion criteria. The mean age was 37.6 ± 13.4 years and 79% were male. Blood alcohol was detected in 58% of drivers and 42% of these were above the legal limit. Tetrahydrocannabinol was positive in 12% of drivers, and 18% were positive for recreational drugs. Opiates were detected in 21% of drivers. Overall, 85% were positive for at least one substance and 39% tested positive for multiple substances. CONCLUSION: This study presents the first evidence of alcohol and drug use in off-road vehicle drivers after cannabis legalization in Canada. Our results show that over half of drivers in off-road vehicle crashes test positive for alcohol and 30% tested positive for THC, cocaine, or amphetamines. Opiates are also commonly detected in off-road vehicle drivers. Emergency department (ED) visits resulting from drug driving of off-road vehicles serve as an opportunity for screening, initiating treatment, and connecting patients to interventions for substance use disorders.

ABSTRAIT: CONTEXTE: La conduite avec facultés affaiblies est un problème de santé publique, mais on sait peu de choses sur la prévalence de la toxicomanie chez les conducteurs impliqués dans des accidents de la route. L'objectif de la présente étude était de décrire la démographie et la prévalence de la consommation d'alcool et de drogues chez les conducteurs de véhicules hors route. MéTHODES: Dans le cadre de cette sous-étude observationnelle, nous avons recueilli des données cliniques et toxicologiques sur tous les conducteurs de véhicules hors route ayant subi des blessures modérées ou graves qui avaient reçu des échantillons de sang dans les 6 heures suivant l'accident. Les données cliniques ont été extraites des dossiers médicaux des patients et des analyses toxicologiques ont été effectuées pour l'alcool dans le sang, les cannabinoïdes, les drogues récréatives et les médicaments pour les facultés affaiblies. RéSULTATS: Trente-trois conducteurs blessés répondaient aux critères d'inclusion. L'âge moyen était de 37,6 13,4 ans et 79 % étaient des hommes. L'alcool dans le sang a été détecté chez 58 % des conducteurs et 42 % d'entre eux dépassaient la limite légale. Le tétrahydrocannabinol était positif chez 12 % des conducteurs et 18 % étaient positifs aux drogues récréatives. Des opiacés ont été détectés chez 21 % des conducteurs. Dans l'ensemble, 85 % étaient positifs pour au moins une substance et 39 % étaient positifs pour plusieurs substances. CONCLUSION: Cette étude présente les premières preuves de la consommation d'alcool et de drogues chez les conducteurs de véhicules hors route après la légalisation du cannabis au Canada. Nos résultats montrent que plus de la moitié des conducteurs de véhicules hors route ont un résultat positif au test de dépistage de l'alcool et 30 % ont un résultat positif au test de dépistage du THC, de la cocaïne ou des amphétamines. Les opiacés sont également couramment détectés chez les conducteurs de véhicules hors route. Les visites aux services d'urgence (SU) découlant de la conduite de véhicules hors route avec facultés affaiblies par la drogue constituent une occasion de dépistage, d'amorcer un traitement et de mettre les patients en contact avec des interventions pour les troubles liés à la consommation de substances.

Visualizing the Interface of Biotin and Fatty Acid Biosynthesis through SuFEx Probes.

Site-specific covalent conjugation offers a powerful tool to identify and understand protein-protein interactions. In this study, we discover that sulfur fluoride exchange (SuFEx) warheads effectively crosslink the Escherichia coli acyl carrier protein (AcpP) with its partner BioF, a key pyridoxal 5'-phosphate (PLP)-dependent enzyme in the early steps of biotin biosynthesis by targeting a tyrosine residue proximal to the active site. We identify the site of crosslink by MS/MS analysis of the peptide originating from both partners. We further evaluate the BioF-AcpP interface through protein crystallography and mutational studies. Among the AcpP-interacting BioF surface residues, three critical arginine residues appear to be involved in AcpP recognition so that pimeloyl-AcpP can serve as the acyl donor for PLP-mediated catalysis. These findings validate an evolutionary gain-of-function for BioF, allowing the organism to build biotin directly from fatty acid biosynthesis through surface modifications selective for salt bridge formation with acidic AcpP residues.

Kinetic modeling of leucine-mediated signaling and protein metabolism in human skeletal muscle.

Skeletal muscle protein levels are governed by the relative rates of muscle protein synthesis (MPS) and breakdown (MPB). The mechanisms controlling these rates are complex, and their integrated behaviors are challenging to study through experiments alone. The purpose of this study was to develop and analyze a kinetic model of leucine-mediated mTOR signaling and protein metabolism in the skeletal muscle of young adults. Our model amalgamates published cellular-level models of the IRS1-PI3K-Akt-mTORC1 signaling system and of skeletal-muscle leucine kinetics with physiological-level models of leucine digestion and transport and insulin dynamics. The model satisfactorily predicts experimental data from diverse leucine feeding protocols. Model analysis revealed that total levels of p70S6K are a primary determinant of MPS, insulin signaling substantially affects muscle net protein balance via its effects on MPB, and p70S6K-mediated feedback of mTORC1 signaling reduces MPS in a dose-dependent manner.

Blood-Brain Barrier Dysfunction and Exposure to Head Impacts in University Football Players.

OBJECTIVE: To investigate the link between dysfunction of the blood-brain barrier (BBB) and exposure to head impacts in concussed football athletes. DESIGN: This was a prospective, observational pilot study. SETTING: Canadian university football. PARTICIPANTS: The study population consisted of 60 university football players, aged 18 to 25. Athletes who sustained a clinically diagnosed concussion over the course of a single football season were invited to undergo an assessment of BBB leakage. INDEPENDENT VARIABLES: Head impacts detected using impact-sensing helmets were the measured variables. MAIN OUTCOME MEASURES: Clinical diagnosis of concussion and BBB leakage assessed using dynamic contrast-enhanced MRI (DCE-MRI) within 1 week of concussion were the outcome measures. RESULTS: Eight athletes were diagnosed with a concussion throughout the season. These athletes sustained a significantly higher number of head impacts than nonconcussed athletes. Athletes playing in the defensive back position were significantly more likely to sustain a concussion than remain concussion free. Five of the concussed athletes underwent an assessment of BBB leakage. Logistic regression analysis indicated that region-specific BBB leakage in these 5 athletes was best predicted by impacts sustained in all games and practices leading up to the concussion-as opposed to the last preconcussion impact or the impacts sustained during the game when concussion occurred. CONCLUSIONS: These preliminary findings raise the potential for the hypothesis that repeated exposure to head impacts may contribute to the development of BBB pathology. Further research is needed to validate this hypothesis and to test whether BBB pathology plays a role in the sequela of repeated head trauma.

Venomous gland transcriptome and venom proteomic analysis of the scorpion Androctonus amoreuxi reveal new peptides with anti-SARS-CoV-2 activity.

The recent COVID-19 pandemic shows the critical need for novel broad spectrum antiviral agents. Scorpion venoms are known to contain highly bioactive peptides, several of which have demonstrated strong antiviral activity against a range of viruses. We have generated the first annotated reference transcriptome for the Androctonus amoreuxi venom gland and used high performance liquid chromatography, transcriptome mining, circular dichroism and mass spectrometric analysis to purify and characterize twelve previously undescribed venom peptides. Selected peptides were tested for binding to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and inhibition of the spike RBD - human angiotensin-converting enzyme 2 (hACE2) interaction using surface plasmon resonance-based assays. Seven peptides showed dose-dependent inhibitory effects, albeit with IC50 in the high micromolar range (117-1202 µM). The most active peptide was synthesized using solid phase peptide synthesis and tested for its antiviral activity against SARS-CoV-2 (Lineage B.1.1.7). On exposure to the synthetic peptide of a human lung cell line infected with replication-competent SARS-CoV-2, we observed an IC50 of 200 nM, which was nearly 600-fold lower than that observed in the RBD - hACE2 binding inhibition assay. Our results show that scorpion venom peptides can inhibit the SARS-CoV-2 replication although unlikely through inhibition of spike RBD - hACE2 interaction as the primary mode of action. Scorpion venom peptides represent excellent scaffolds for design of novel anti-SARS-CoV-2 constrained peptides. Future studies should fully explore their antiviral mode of action as well as the structural dynamics of inhibition of target virus-host interactions.

Spatial Hotspots and Sociodemographic Profiles Associated With Traumatic Brain Injury in Nova Scotia.

Traumatic brain injury (TBI) is a leading cause of death and disability, primarily caused by falls and motor vehicle collisions (MVCs). Although many TBIs are preventable, there is a notable lack of studies exploring the association of geographically defined TBI hotspots with social deprivation. Geographic information systems (GIS) can be used to identify at-risk neighborhoods (hotspots) for targeted interventions. This study aims to determine the spatial distribution of TBI by major causes and to explore the sociodemographic and economic characteristics of TBI hotspots and cold spots in Nova Scotia. Patient data for TBIs from 2003 to 2019 were obtained from the Nova Scotia Trauma Registry. Residential postal codes were geocoded and assigned to dissemination areas (DA). Area-based risk factors and deprivation status (residential instability [RI], economic dependency [ED], ethnocultural composition [EC], and situational vulnerability [SV]) from the national census data were linked to DAs. Spatial autocorrelation was assessed using Moran's I, and hotspot analysis was performed using Getis-Ord Gi* statistic. Differences in risk factors between hot and cold spots were evaluated using the Mann-Whitney U test for numerical variables and the χ2 test or Fisher's exact test for categorical variables. A total of 5394 TBI patients were eligible for inclusion in the study. The distribution of hotspots for falls exhibited no significant difference between urban and rural areas (p = 0.71). Conversely, hotspots related to violence were predominantly urban (p = 0.001), whereas hotspots for MVCs were mostly rural (p < 0.001). Distinct dimensions of deprivation were associated with falls, MVCs, and violent hotspots. Fall hotspots were significantly associated with areas characterized by higher RI (p < 0.001) and greater ethnocultural diversity (p < 0.001). Conversely, the same domains exhibited an inverse relationship with MVC hotspots; areas with low RI and ethnic homogeneity displayed a higher proportion of MVC hotspots. ED and SV exhibited a strong gradient with MVC hotspots; the most deprived quintiles displayed the highest proportion of MVC hotspots compared with cold spots (ED; p = 0.002, SV; p < 0.001). Areas with the highest levels of ethnocultural diversity were found to have a significantly higher proportion of violence-related hotspots than cold spots (p = 0.005). This study offers two significant contributions to spatial epidemiology. First, it demonstrates the distribution of TBI hotspots by major injury causes using the smallest available geographical unit. Second, we disentangle the various pathways through which deprivation impacts the risk of main mechanisms of TBI. These findings provide valuable insights for public health officials to design targeted injury prevention strategies in high-risk areas.

Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury.

Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals (N = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.

The governance behaviours: a proposed approach for the alignment of the public and private sectors for better health outcomes.

Health systems are 'the ensemble of all public and private organisations, institutions and resources mandated to improve, maintain or restore health.' The private sector forms a major part of healthcare practice in many health systems providing a wide range of health goods and services, with significant growth across low-income and middle-income countries. WHO sees building stronger and more effective health systems through the participation and engagement of all health stakeholders as the pathway to further reducing the burden of disease and meeting health targets and the Sustainable Development Goals. However, there are governance and public policy gaps when it comes to interaction or engagement with the private sector, and therefore, some governments have lost contact with a major area of healthcare practice. As a result, market forces rather than public policy shape private sector activities with follow-on effects for system performance. While the problem is well described, proposed normative solutions are difficult to apply at country level to translate policy intentions into action. In 2020, WHO adopted a strategy report which argued for a major shift in approach to engage the private sector based on the performance of six governance behaviours. These are a practice-based approach to governance and draw on earlier work from Travis et al on health system stewardship subfunctions. This paper elaborates on the governance behaviours and explains their application as a practice approach for strengthening the capacity of governments to work with the private sector to achieve public policy goals.

Two-color coincidence single-molecule pulldown for the specific detection of disease-associated protein aggregates.

Protein misfolding and aggregation is a characteristic of many neurodegenerative disorders, including Alzheimer's and Parkinson's disease. The oligomers generated during aggregation are likely involved in disease pathogenesis and present promising biomarker candidates. However, owing to their small size and low concentration, specific tools to quantify and characterize aggregates in complex biological samples are still lacking. Here, we present single-molecule two-color aggregate pulldown (STAPull), which overcomes this challenge by probing immobilized proteins using orthogonally labeled detection antibodies. By analyzing colocalized signals, we can eliminate monomeric protein and specifically quantify aggregated proteins. Using the aggregation-prone alpha-synuclein protein as a model, we demonstrate that this approach can specifically detect aggregates with a limit of detection of 5 picomolar. Furthermore, we show that STAPull can be used in a range of samples, including human biofluids. STAPull is applicable to protein aggregates from a variety of disorders and will aid in the identification of biomarkers that are crucial in the effort to diagnose these diseases.