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Two recent studies show that cotranslational N-terminal protein acetylation (NTA) promotes proteome stability in humans (Mueller et al.) and plants (Linster et al.) by masking nonacetylated N-degrons that would otherwise destabilise proteins. This is in contrast to previous findings linking NTA to degradation, suggesting that this widespread mark has complex and context-specific functions in regulating protein half-lives. [ABSTRACT FROM AUTHOR]

• Mining can divide communities and reconfigure community cohesion and landscapes. • Backlash steers some activists to execute and emphasise strategy in particular ways. • Citizens may place sites of struggle outside of their communities to avoid tension. • Research design and approach needs to be sensitive to communities under threat. • Emotional geographies inform and support sensitive research design. This paper explores citizen perceptions of mining operations located in the Gloucester Valley, New South Wales (NSW), Australia. With an already lengthy history of two coal operations, tensions were exacerbated in the Valley upon the announcement of new unconventional gas operations and a third coal mine proposal. Concerned citizens highlight how mistrust in State processes and legislation combined with reservations about safety resulting from a deeply divided community, impacted both place attachments, community cohesion, and steered activist strategy towards locating the sites of struggle outside of local places. Employing emotional geographies literature as an exploratory frame and research approach, we explore the unique case of the Gloucester Valley struggle against unconventional gas and new coal mining. By doing so, we explore the role of emotions in these mining struggles. This framing also builds understandings of the emotional geographies of place-based citizens that shift and evolve in response to the threat of extractive resource operations, and responds to an Ey et al. (2017) call for additional research that explores emotions and mining. The framing and approach to the project offers an insight towards research sensitivity towards communities already stressed by mining operations. By centring emotions in our approach, and emphasising relationship-building and trust between the researcher and participants, we were able to explore the deeper underpinnings of citizens' concerns for local mining operations than those typically captured by social impact and community engagement approaches. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI) is one of the most transformative technologies of the 21st century. The extent and scope of future AI capabilities remain a key uncertainty, with widespread disagreement on timelines and potential impacts. As nations and technology companies race toward greater complexity and autonomy in AI systems, there are concerns over the extent of integration and oversight of opaque AI decision processes. This is especially true in the subfield of machine learning (ML), where systems learn to optimize objectives without human assistance. Objectives can be imperfectly specified or executed in an unexpected or potentially harmful way. This becomes more concerning as systems increase in power and autonomy, where an abrupt capability jump could result in unexpected shifts in power dynamics or even catastrophic failures. This study presents a hierarchical complex systems framework to model AI risk and provide a template for alternative futures analysis. Survey data were collected from domain experts in the public and private sectors to classify AI impact and likelihood. The results show increased uncertainty over the powerful AI agent scenario, confidence in multiagent environments, and increased concern over AI alignment failures and influence-seeking behavior. • As AI systems become more capable and are given meaningful control, there is greater risk of unanticipated effects. • Through a complex systems framework, this study structures the dimensions of AI risk to anticipate alternate futures. • This study determined that the highest impact risks include monopolistic race dynamics, AI alignment failures, and power-seeking behavior. [ABSTRACT FROM AUTHOR]

China currently faces a water resource sustainability problem which is likely to worsen into the future. The Chinese government is attempting to address this problem through legislative action, but faces severe challenges in delivering its high ambitions. The key challenges revolve around the need to balance water availability with the need to feed a growing population under a changing climate and its ambitions for increased economic development. This is further complicated by the complex and multi-layered government departments, often with overlapping jurisdictions, which are not always aligned in their policy implementation and delivery mechanisms. There remain opportunities for China to make further progress and this paper reports on the outcomes of a science-to-policy roundtable meeting involving scientists and policy-makers in China. It identifies, in an holistic manner, new opportunities for additional considerations for policy implementation, continued and new research requirements to ensure evidence-based policies are designed and implemented and identifies the needs and opportunities to effectively monitor their effectiveness. Other countries around the world can benefit from assessing this case study in China. [ABSTRACT FROM AUTHOR]

Background: Obesity is a multifactorial condition influenced by genetics, lifestyle, and environment. Objective: We investigated whether the association of a validated genetic profile risk score for obesity (GPRS-obesity) with body mass index (BMI) and waist circumference (WC) was modified by sleep characteristics. Design: This study included cross-sectional data from 119,859 white European adults, aged 37–73 y, participating in the UK Biobank. Interactions of GPRS-obesity and sleep characteristics (sleep duration, chronotype, day napping, and shift work) with their effects on BMI and WC were investigated. Results: b Values are expressed as the change in BMI (in kg/m2 ) or WC per 1-SD increase in GPRS-obesity. The GPRS-obesity was associated with BMI (b: 0.57; 95% CI: 0.55, 0.60; P = 6.3 3 102207) and WC (1.21 cm; 95% CI: 1.15, 1.28 cm; P = 4.2 3 102289). There were significant interactions of GPRS-obesity and a variety of sleep characteristics with their relation with BMI (P-interaction , 0.05). In participants who slept ,7 or .9 h daily, the effect of GPRS-obesity on BMI was stronger (b: 0.60; 95% CI: 0.54, 0.65 and b: 0.73; 95% CI: 0.49, 0.97, respectively) than in normal-length sleepers (7–9 h; b: 0.52; 95% CI: 0.49, 0.55). A similar pattern was observed for shift workers (b: 0.68; 95% CI: 0.59, 0.77 compared with b: 0.54; 95% CI: 0.51, 0.58 for non–shift workers) and for night-shift workers (b: 0.69; 95% CI: 0.56, 0.82 compared with b: 0.55; 95% CI: 0.51, 0.58 for non–night-shift workers), for those taking naps during the day (b: 0.65; 95% CI: 0.52, 0.78 compared with b: 0.51; 95% CI: 0.48, 0.55 for those who never or rarely had naps), and for those with a self-reported evening chronotype (b: 0.72; 95% CI: 0.61, 0.82 compared with b: 0.52; 95% CI: 0.47, 0.57 for morning chronotype). Similar findings were obtained by using WC as the outcome. Conclusion: This study shows that the association between genetic risk for obesity and phenotypic adiposity measures is exacerbated by adverse sleeping characteristics. [ABSTRACT FROM AUTHOR]

Aims To investigate the feasibility of delivering titrated oxygen therapy to adults with return of spontaneous circulation (ROSC) following out-of-hospital cardiac arrest (OHCA) caused by ventricular fibrillation (VF) or ventricular tachycardia (VT). Methods We used a multicentre, randomised, single blind, parallel groups design to compare titrated and standard oxygen therapy in adults resuscitated from VF/VT OHCA. The intervention commenced in the community following ROSC and was maintained in the emergency department and the Intensive Care Unit. The primary end point was the median oxygen saturation by pulse oximetry (SpO 2 ) in the pre-hospital period. Results 159 OHCA patients were screened and 18 were randomised. 17 participants were analysed: nine in the standard care group and eight in the titrated oxygen group. In the pre-hospital period, SpO 2 measurements were lower in the titrated oxygen therapy group than the standard care group (difference in medians 11.3%; 95% CI 1.0–20.5%). Low measured oxygen saturation (SpO 2 < 88%) occurred in 7/8 of patients in the titrated oxygen group and 3/9 of patients in the standard care group ( P = 0.05). Following hospital admission, good separation of oxygen exposure between the groups was achieved without a significant increase in hypoxia events. The trial was terminated because accumulated data led the Data Safety Monitoring Board and Management Committee to conclude that safe delivery of titrated oxygen therapy in the pre-hospital period was not feasible. Conclusions Titration of oxygen in the pre-hospital period following OHCA was not feasible; it may be feasible to titrate oxygen safely after arrival in hospital. [ABSTRACT FROM AUTHOR]

Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/chicken β-actin (CBA)-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for green fluorescent protein (GFP)-treated mice. ssAAV9/CBA-MECP2-treated mice also showed significant improvement in the phenotype severity score, in locomotor function, and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type (WT) mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary (sc) adeno-associated virus (AAV) vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously (IV) into juvenile (4-5 weeks old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2-4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT. [ABSTRACT FROM AUTHOR]

Hypothesis: The purpose of this study was to accurately map the insertional footprint of the distal biceps tendon and to test our hypothesis that a superior anatomic repair can be achieved by a 2-incision technique when compared with a 1-incision technique. Methods: We randomly assigned 20 cadaveric arms to 1 of 2 groups: 1 incision (group I) or 2 incision (group II). The bicipital tuberosity was exposed through either a single anterior incision (group I) or a posterolateral approach (group II). A guide pin was placed into the tuberosity to mark the axis for creating a virtual bone tunnel. Each radius was harvested with the biceps insertion intact. The length, width, and area of the insertion footprint for each tendon were determined with a 3-dimensional computerized digitizer. A 7.5 mm-diameter virtual bone tunnel was centered over the drill hole created by the guidewire. The percentage of the virtual tunnel within the original footprint was determined. Results: The percentage of the virtual tunnel (repair site) within the original tendon footprint was 73.4% for the posterolateral approach and only 9.7% for the anterior approach. There was a statistically significant difference (P ≤ .001) in the median values of footprint covered when the 2 types of repair were compared. Discussion and conclusion: The 2-incision technique results in a significantly improved anatomic repair of the biceps tendon to the original insertion site. Prospective clinical studies directly comparing the 2 techniques with regard to the strength of supination after repair may be helpful. [ABSTRACT FROM AUTHOR]

Abstract: The cyclability of manganese dioxide samples with a wide range of initial properties has been investigated using electrochemical methods. Cycling revealed that a common change occurs in all materials irrespective of initial properties, with the discharge behaviour standardised by the tenth cycle. Modeling of the discharge behaviour revealed the steady decline in the capacity with cycling can primarily be assigned to lower potential pyrolusite domains. Furthermore, an examination of chemically reduced and re-oxidised γ-MnO2 revealed an irreversible expansion of the γ-MnO2 lattice upon reduction arising from localised buckling of the oxygen framework. [Copyright &y& Elsevier]

Abstract: The role of relationships between regulators and consultants engaged in environmental impact assessment (EIA) is explored. A Partnering Agreement between Western Australian regulators and consultants gave rise to a survey and interviews with representatives of these EIA practitioners to understand levels of cooperation between them and ways to improve EIA practice locally. A mixture of quantitative and qualitative responses are presented with an emphasis on practitioner comments reproduced in their own words and ‘voice’. The results suggest that while relationships are strained because of staff resources and levels of expertise brought about by a major resource boom in recent years, there is a great desire for cooperation and collaboration. Greater clarification and understanding of each stakeholder''s purpose and role in the EIA process along with opportunities for EIA practitioners to interact, communicate and socialise are identified as positive ways forward. The value of establishing the relatively simple Partnering Agreement approach is demonstrated and is put forward as something that practitioners internationally might equally benefit from as a means of improving the effectiveness of EIA practice. [Copyright &y& Elsevier]

Abstract: Cutaneous leishmaniasis is a widespread tropical infection caused by numerous different species of Leishmania protozoa that are transmitted by sandflies. Its clinical presentations are extremely diverse and dependent on a variety of parasite and host factors that are poorly understood. Diagnosis should aim to identify the exact species involved, but this requires laboratory investigations that are not widely available. No single ideal treatment has been identified, and those available are limited by variable success rates and toxicity. Clinical guidelines are needed to make better use of the investigations and treatments that do exist. Prevention is currently limited to bite prevention measures. [Copyright &y& Elsevier]

Abstract: This paper will discuss the findings from the studies carried out as part of the soil biodiversity programme (SBP) in examining the diversity and functions of soil microbes. We will discuss the results obtained describing the taxonomic diversity of organisms found at the site and the consequences of experimental perturbations on microbial community structure. Much of the work carried out utilised molecular methods to describe or ‘fingerprint’ the microbial communities without the biases associated with traditional culture-based assays. One of the fundamental aims of the SBP was to link the activity and diversity of microbes with functional roles in the cycling of plant derived carbon through the soil food web. For this purpose novel isotope tracer approaches were applied, whereby stable isotope (13C) labelled CO2 was fed to plants and the root-released labelled carbon was traced into soil microbial biomarkers. We will review the data obtained and show how agricultural practices or trophic manipulations impact upon soil biodiversity and community functioning, and discuss the potential merit of these approaches in increasing our understanding of soil ecosystems. [Copyright &y& Elsevier]

The impact of changes incurred by agricultural biotechnology has led to concern regarding soil ecosystems and, rightly or wrongly, this has focused on the introduction of genetically modified (GM) crops. Soils are key resources, with essential roles in supporting ecosystems and maintaining environmental quality and productivity. The complexity of soils presents difficulties to their inclusion in the risk assessment process conducted for all GM plants. However, a combined approach, informed by both soil ecology and soil quality perspectives, that considers the impacts of GM crops in the context of conventional agricultural practices can provide a regulatory framework to ensure the protection of soils without being overly restrictive. [Copyright &y& Elsevier]

The metabolic conjugation of exogenous and endogenous carboxylic acid substrates with endogenous glucuronic acid, mediated by the uridine diphosphoglucuronosyl transferase (UGT) superfamily of enzymes, leads to the formation of acyl glucuronide metabolites. Since the late 1970s, acyl glucuronides have been increasingly identified as reactive electrophilic metabolites, capable of undergoing three reactions: intramolecular rearrangement, hydrolysis, and intermolecular reactions with proteins leading to covalent drug–protein adducts. This essential dogma has been accepted for over a decade. The key question proposed by researchers, and now the pharmaceutical industry, is: does or can the covalent modification of endogenous proteins, mediated by reactive acyl glucuronide metabolites, lead to adverse drug reactions, perhaps idiosyncratic in nature? This review evaluates the evidence for acyl glucuronide-derived perturbation of homeostasis, particularly that which might result from the covalent modification of endogenous proteins and other macromolecules. Because of the availability of acyl glucuronides for test tube/in vitro experiments, there is now a substantial literature documenting their rearrangement, hydrolysis and covalent modification of proteins in vitro. It is certain from in vitro experiments that serum albumin, dipeptidyl peptidase IV, tubulin and UGTs are covalently modified by acyl glucuronides. However, these in vitro experiments have been specifically designed to amplify any interference with a biological process in order to find biological effects. The in vivo situation is not at all clear. Certainly it must be concluded that all humans taking carboxylate drugs that form reactive acyl glucuronides will form covalent drug–protein adducts, and it must also be concluded that this in itself is normally benign. However, there is enough in vivo evidence implicating acyl glucuronides, which, when backed up by in vivo circumstantial and documented in vitro evidence, supports the view that reactive acyl glucuronides may initiate toxicity/immune responses. In summary, though acyl glucuronide-derived covalent modification of endogenous macromolecules is well-defined, the work ahead needs to provide detailed links between such modification and its possible biological consequences. [Copyright &y& Elsevier]

Acyl glucuronides are reactive metabolites of carboxylate drugs, able to undergo a number of reactions in vitro and in vivo, including isomerization via intramolecular rearrangement and covalent adduct formation with proteins. The intrinsic reactivity of a particular acyl glucuronide depends upon the chemical makeup of the drug moiety. The least reactive acyl glucuronide yet reported is valproic acid acyl glucuronide (VPA-G), which is the major metabolite of the antiepileptic agent valproic acid (VPA). In this study, we showed that both VPA-G and its rearrangement isomers (iso-VPA-G) interacted with bovine brain microtubular protein (MTP, comprised of 85% tubulin and 15% microtubule associated proteins {MAPs}). MTP was incubated with VPA, VPA-G and iso-VPA-G for 2 h at room temperature and pH 7.5 at various concentrations up to 4 mM. VPA-G and iso-VPA-G caused dose-dependent inhibition of assembly of MTP into microtubules, with 50% inhibition (IC50) values of 1.0 and 0.2 mM respectively, suggesting that iso-VPA-G has five times more inhibitory potential than VPA-G. VPA itself did not inhibit microtubule formation except at very high concentrations (≥2 mM). Dialysis to remove unbound VPA-G and iso-VPA-G (prior to the assembly assay) diminished inhibition while not removing it. Comparison of covalent binding of VPA-G and iso-VPA-G (using [14C]-labelled species) showed that adduct formation was much greater for iso-VPA-G. When [14C]-iso-VPA-G was reacted with MTP in the presence of sodium cyanide (to stabilize glycation adducts), subsequent separation into tubulin and MAPs fractions by ion exchange chromatography revealed that 78 and 22% of the covalent binding occurred with the MAPs and tubulin fractions respectively. These experiments support the notion of both covalent and reversible binding playing parts in the inhibition of microtubule formation from MTP (though the acyl glucuronide of VPA is less important than its rearrangement isomers in this regard), and that both tubulin and (perhaps more importantly) MAPs form adducts with acyl glucuronides. [Copyright &y& Elsevier]

Summary: British military personnel account for 45% of cutaneous leishmaniasis (CL) cases seen in the UK and 103 cases from Belize were seen in 1998–2009. Systemic treatment of CL from Belize should not be considered essential in immunocompetent patients because mucosal leishmaniasis very rarely occurs. [Copyright &y& Elsevier]

• Wastewater treatment caused significant changes in wastewater AMR. • Wastewater drives elevated AMR levels in freshwater sediments. • AMR is correlated with the human gut-associated crAssphage. • Minimal seasonal impacts of wastewater AMR on freshwater sediments. Antimicrobial resistance (AMR) is a global health hazard. Although clinical and agricultural environments are well-established contributors to the evolution and dissemination of AMR, research on wastewater treatment works (WwTWs) has highlighted their potential role as disseminators of AMR in freshwater environments. Using metagenomic sequencing and analysis, we investigated the changes in resistomes and associated mobile genetic elements within untreated wastewater influents and treated effluents of five WwTWs, and sediments collected from corresponding river environments in Oxfordshire, UK, across three seasonal periods within a year. Our analysis demonstrated a high diversity and abundance of antimicrobial resistance genes (ARGs) in untreated wastewater influents, reflecting the varied anthropogenic and environmental origins of wastewater. WwTWs effectively reduced AMR in the final effluent, with an average 87 % reduction in normalised ARG abundance and an average 63 % reduction in richness. However, wastewater effluents significantly impacted the antimicrobial resistome of the receiving rivers, with an average 543 % increase in ARG abundance and a 164 % increase in richness from upstream sediments to downstream sediments. The normalised abundance of the human gut-associated bacteriophage crAssphage was highly associated with both ARG abundance and richness. We observed seasonal variation in the resistome of raw influent which was not found in the effluent-receiving sediments. We illustrate the potential of WwTWs as focal points for disseminating ARGs and resistance-selecting chemicals, contributing to the elevation of environmental AMR. Our study emphasises the need for a comprehensive understanding of the anthropogenic impacts on AMR evolution and dissemination in wastewater and river environments, informing efforts to mitigate this growing public health crisis. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Aims: The pattern of interruptions to chest compressions in pre-hospital cardiac arrests in Wellington, New Zealand, was examined prospectively to determine whether the mode of defibrillation chosen by paramedics influenced interruptions, shock success and the return of spontaneous circulation (ROSC). Methods: A prospective observational cohort study of 44 adult cardiac arrests in which 203 shocks were administered by Wellington Free Ambulance (WFA) paramedics was undertaken to compare Code-stat® electronic records from Medtronic® Lifepak 12 and Lifepak 15 defibrillators used in semi-automated (AED) or manual mode. Interruptions during the 30s prior to shock delivery as well as pre-shock and post-shock pauses were calculated. Shock success and ROSC were the outcome measures. Results: Pre-shock pauses were shorter in manual mode (median 3s, IQR 2–5) versus AED mode (median 4s, IQR 3–6; p =0.003). Interruptions of CPR in the 30s prior to shock delivery were also shorter in manual mode (median 7s, IQR 4–11) versus AED mode (median 14s, IQR 12–16; p =<0.001). Shock success rates and post-shock pauses were not statistically different between modes. ROSC was significantly higher in manual mode (18.49%) versus AED mode (8.33%, p =0.042). Conclusion: When paramedics used the defibrillator in manual mode as compared to AED mode, interruptions to CPR during the 30s prior to shock delivery were significantly reduced and pre-shock pauses were also shorter. This was associated with increased ROSC. Manual defibrillation should be the preferred option for appropriately trained paramedics. Training in this locality has been changed accordingly. [Copyright &y& Elsevier]

Regulation of the number of Ca2+-activated K+ channels at the endothelial cell surface contributes to control of the endothelium-derived hyperpolarizing factor response, although this process is poorly understood. To address the fate of plasma membrane-localized KCa2.3, we utilized an extracellular epitope-tagged channel in combination with fluorescence and biotinylation techniques in both human embryonic kidney cells and the human microvascular endothelial cell line, HMEC-1. KCa2.3 was internalized from the plasma membrane and degraded with a time constant of 18 h. Cell surface biotinylation demonstrated that KCa2.3 was rapidly endocytosed and recycled back to the plasma membrane. Consistent with recycling, expression of a dominant negative (DN) RME-1 or Rab35 as well as wild type EPI64C, the Rab35 GTPase-activating protein, resulted in accumulation of KCa2.3 in an intracellular compartment. Expression of DN RME-1, DN Rab35, or wild type EPI64C resulted in a decrease in steady-state plasma membrane expression. Knock-down of EPI64C increased cell surface expression of KCa2.3. Furthermore, the effect of EPI64C was dependent upon its GTPase-activating proteins activity. Co-immunoprecipitation studies confirmed an association between KCa2.3 and both Rab35 and RME-1. In contrast to KCa2.3, KCa3.1 was rapidly endocytosed and degraded in an RME-1 and Rab35-independent manner. A series of N-terminal deletions identified a 12-amino acid region, Gly206-Pro217, as being required for the rapid recycling of KCa2.3. Deletion of Gly206-Pro217 had no effect on the association of KCa2.3 with Rab35 but significantly decreased the association with RME-1. These represent the first studies elucidating the mechanisms by which KCa2.3 is maintained at the plasma membrane. [ABSTRACT FROM AUTHOR]

Barring bioavailability and nutritional limitations, virtually all organic anthropogenic chemicals can be naturally biodegraded. It is to this phenomenon we owe thanks to the long established ‘tritrophic trinity’ of microbe–plant–insect interactions. Over hundreds of millennia these organisms have coevolved, producing hundreds of thousands of different chemicals that are used to attract, defend, antagonize, monitor and misdirect one another. In comparison, the numbers of truly novel chemicals of anthropogenic origin are negligible. It is only now that we are beginning to appreciate the fortuitous evolution of xenobiotic-degrading enzymes from these interactions. We argue that success in phytoremediation can be hastened through understanding the structure, sources, uses and targets of these secondary metabolites. Owing to recent developments in molecular biology, particularly stable isotope probing, we eagerly anticipate highly significant insights into trophic interactions, particularly in the rhizosphere, providing phytoremediation with a solid mechanistic understanding. [Copyright &y& Elsevier]

Total and active cell counts within soil samples were determined by culture-independent methods using flow cytometry and preparative Nycodenz gradient centrifugation. Whole cells were purified from soil cores and total extractable cell counts assessed by SYBR Green II fluorescence, while active cell counts were determined by 5-cyano-2,3-ditolyl tetrazolium chloride reduction (CTC+ cells). Parallel microcosms, maintained at either field water capacity or subjected to drying, indicated that the total extractable cell count remained between 108 and 109 g−1 (dry weight). In contrast, the CTC+ active count fell threefold in dried microcosms (6% of total cell count) when compared to wetted microcosms (18% of total cell count). Specifically, these data highlighted an overall deactivation of microbial biomass during water stress, with 16S rDNA analyses of flow-sorted CTC+ cells demonstrating shifts within the active diversity. Flow cytometry coupled with cell purification techniques represents a significant tool for operationally defining an active and redundant microbial component within soil communities and is demonstrated during water stress. [Copyright &y& Elsevier]