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α-Synuclein (αSyn), a 140-residue intrinsically disordered protein, comprises the primary proteinaceous component of pathology-associated Lewy body inclusions in Parkinson’s disease (PD). Due to its association with PD, αSyn is studied extensively; however, the endogenous structure and physiological roles of this protein are yet to be fully understood. Here, ion mobility-mass spectrometry and native top-down electron capture dissociation fragmentation have been used to elucidate the structural properties associated with a stable, naturally occurring dimeric species of αSyn. This stable dimer appears in both wild-type (WT) αSyn and the PD-associated variant A53E. Furthermore, we integrated a novel method for generating isotopically depleted protein into our native top-down workflow. Isotope depletion increases signal-to-noise ratio and reduces the spectral complexity of fragmentation data, enabling the monoisotopic peak of low abundant fragment ions to be observed. This enables the accurate and confident assignment of fragments unique to the αSyn dimer to be assigned and structural information about this species to be inferred. Using this approach, we were able to identify fragments unique to the dimer, which demonstrates a C-terminal to C-terminal interaction between the monomer subunits. The approach in this study holds promise for further investigation into the structural properties of endogenous multimeric species of αSyn.

Recent decades have seen growing and widespread adoption of glass as an architectural material that can be used not only as window panes but also as facades, walls, and roofs. This is despite glass traditionally being considered a brittle material, not readily capable of handling the high loads required of architectural materials. Architectural glass has enabled the vaulted, transparent structures of many modern airport terminals and eye-catching buildings, such as the ubiquitous all-glass Apple Stores found around the world. Glass has enabled architects to expand their visions of buildings, using light and space to create wonderful new designs. As described in this review, these dramatic new possibilities for how glass is used in architecture have been the result of a convergence of many developments, including a better understanding of the fracture of glass, new processes for strengthening glass, confidence in large-scale finite element modeling of gravitational and wind loads, advances in the lamination of glass sheets, and the availability of ever larger individual sheets of float glass. The concurrent evolution of standards for the use of glass in buildings has also played a role in advancing the use of architectural glass. Advances in the architectural use of glass have their roots in the traditional uses and physical understanding of the properties of glass that have developed over hundreds of years.

ICH S6 (R1) states that safety evaluation of biotherapeutics should normally include 2 relevant species when available (i.e., a rodent and non-rodent species in which the test material is pharmacologically active), at least for short-term toxicology studies (generally supporting Phase I trials). For subsequent long-term toxicology studies (e.g., chronic studies up to 6 months dosing duration), there are options to reduce to only one species when justified, including when the mechanism of action of the biologic is well-understood or the toxicity findings in the short-term studies are “similar” in both the rodent and non-rodent species. Across the industry, around 25 to 33% of biologics assess multiple species within short-term toxicity studies but it is often unclear how different companies and regulators are applying the ICH S6 (R1) principles of “similar toxicity profiles” to progress with either 1 or 2 species in the long-term studies, in particular whether the absence of toxicities is considered within this definition. Sponsors may potentially continue to use 2 species to avoid regulatory risk and potential delays in development timelines, representing missed opportunities for reducing animal use, particularly of non-human primates, during drug development. This article summarizes presentations from a symposium at the 41st Annual meeting of the American College of Toxicology (ACT) in November 2020, in which industry case studies and regulatory perspectives addressed considerations and decisions for using 1 or 2 species for long-term toxicity studies, highlighting any common themes or experience that could be applicable for use in future decision-making.

The lower 3.5 km of Eighteenmile Creek, a tributary to Lake Ontario in New York, was designated as an Area of Concern (AOC) in 1985 under the Great Lakes Water Quality Agreement due to extensive contamination of bed sediments by polychlorinated biphenyls (PCBs) and other toxicants. Five beneficial use impairments (BUIs) have been identified in this AOC, including degraded fish and wildlife populations. We surveyed fish communities in the Eighteenmile Creek AOC and in a comparable section of a nearby reference stream (Oak Orchard Creek) during June 2019 to infer whether legacy contaminants are currently impairing fish communities in the AOC to an extent that they differ from the regional reference condition. Estimates of community abundance, biomass, diversity, and fish condition from each system were compared using a noninferiority testing framework. Biomass, diversity, and fish condition in the Eighteenmile Creek AOC were similar or superior to that in Oak Orchard Creek, while abundance was 20% lower in the AOC. These findings and those of a 2007 sampling effort suggest that fish communities in the Eighteenmile Creek AOC are not impaired despite recent studies indicating that PCBs are bioaccumulating in fish tissues at 1–2 orders of magnitude above background levels. Future assessments in the Eighteenmile Creek AOC might focus on the condition of benthic macroinvertebrate communities and potential toxicity of local contaminants to piscivorous wildlife in order to fully address the remaining aspects of the fish and wildlife populations beneficial use impairment.

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 comprehensive tracking of lignin degradation by an alkaliphilic laccase in a semi-quantitative manner using a combined chemical analysis approach utilising 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. Additionally, structural analyses reinforced these findings, indicating a >50% loss of signal relating to β-β 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.

Bacteria produce an array of diverse, dynamic and often complex lipid structures, some of which function beyond their typical role in membrane structure. The model organism, E. coli , has three major membrane lipids, which are glycerophosphoglycerol (phosphatidylglycerol), glycerophosphoethanolamine (phosphatidylethanolamine) and cardiolipin. However, it is now appreciated that some bacteria have the capacity to synthesize a range of lipids, including glycerophosphocholines, glycerophosphoinositols, ‘phosphorous-free’ N-acyl amines, sphingolipids and plasmalogens. In recent years, some of these bacterial lipids have emerged as influential contributors to the microbe–host molecular dialogue. This review outlines our current knowledge of bacterial lipid diversity, with a focus on the membrane lipids of microbiome-associated bacteria that have documented roles as signalling molecules.

Background Mental health disorders are a common sequelae of traumatic brain injury (TBI) and are associated with worse health outcomes including increased mental health care utilization. The objective of this study was to determine the association between TBI and use of mental health services in a population-based sample. Methods Using data from a national Canadian survey, this study evaluated the association between TBI and mental health care utilization, while adjusting for confounding variables. A log-Poisson regression model was used to estimate unadjusted and adjusted prevalence ratios (PR) and 95% confidence intervals (CI). Results The study sample included 158,287 TBI patients and 25,339,913 non-injured individuals. Compared with those were not injured, TBI patients reported higher proportions of chronic mental health conditions (27% vs. 12%, p p = 0.005). The adjusted prevalence of mental health care utilization was 60% higher in patients with TBI than those who were not injured (PR = 1.60, 95%; CI 1.05–2.43). Conclusions This study suggests that chronic mental health conditions and heavy drinking are more common in individuals with TBI. The prevalence of mental health care utilization is 60% higher in TBI patients compared with those who are not injured after adjusting for sociodemographic factors, mental health conditions, and heavy drinking. Future longitudinal research is required to examine the temporality and direction of the association between TBI and the use of mental health services.

There has been increasing interest in bacterial lipids in recent years due, in part, to their emerging role as molecular signalling molecules. Bacteroides thetaiotaomicron is an important member of the mammalian gut microbiota that has been shown to produce sphingolipids (SP) that pass through the gut epithelial barrier to impact host SP metabolism and signal into host inflammation pathways. B. thetaiotaomicron also produces a novel family of N-acyl amines (called glycine lipids) that are potent ligands of host Toll-like receptor 2 (TLR2). Here, we specifically examine the lipid signatures of 4 species of gut associated Bacteroides. In total we identify 170 different lipids and we report that the range and diversity of Bacteroides lipids is species-specific. Multi-variate analysis reveals that the differences in the lipid signatures are largely driven by the presence/absence of plasmalogens, glycerophosphoinositols and certain SP. Moreover, we show that, in B. thetaiotaomicron, mutations altering either SP or glycine lipid biosynthesis results in significant changes in the levels of other lipids suggesting the existence of compensatory mechanisms required to maintain the functionality of the bacterial membrane.ImportanceBacteroides are important beneficial members of the gut microbiome that produce lipids that can function as cross-kingdom signalling molecules. We describe, for the first time, a comprehensive and qualitative comparison of the lipid signatures of 4 important Bacteroides species. We identify a group of Bacteroides core lipids and uncover species-specific differences in plasmalogen, glycerophospholipid and SP metabolism with more subtle differences observed in glycine lipid production. This data will provide a useful platform for the further characterisation of the lipid-based host-microbe dialogue and the influence of microbial lipids on host health and disease states.

Protein misfolding and aggregation into oligomeric and fibrillar structures is a common feature of many neurogenerative disorders. Single-molecule techniques have enabled characterization of these lowly abundant, highly heterogeneous protein aggregates, previously inaccessible using ensemble averaging techniques. However, they usually rely on the use of recombinantly-expressed labeled protein, or on the addition of amyloid stains that are not protein-specific. To circumvent these challenges, we have made use of a high affinity antibody labeled with orthogonal fluorophores combined with fast-flow microfluidics and single-molecule confocal microscopy to specifically detect α-synuclein, the protein associated with Parkinson's disease. We used this approach to determine the number and size of α-synuclein aggregates down to picomolar concentrations in biologically relevant samples.

The lab-on-a-chip concept, enabled by microfluidic technology, promises the integration of multi-ple discrete laboratory techniques into a miniaturised system. Research into microfluidics has generally focused on the development of individual elements of the total system (often with rela-tively limited functionality), without full consideration for integration into a complete fully opti-mised and miniaturised system. Typically, the operation of many of the reported lab-on-a-chip devices is dependent on the support of a laboratory framework. In this paper, a demonstrator platform for routine laboratory analysis is designed and built, which fully integrates a number of technologies into a single device with multiple domains such as fluidics, electronics, pneumatics, hydraulics, and photonics. This facilitates the delivery of breakthroughs in research, by incorpo-rating all physical requirements into a single device. To highlight this proposed approach, this demonstrator microsystem acts as a fully integrated biochemical assay reaction system. The re-sulting design determines enzyme kinetics in an automated process and combines reservoirs, three-dimensional fluidic channels, optical sensing, and electronics in a low-cost, low-power and portable package.

The human skin barrier, a biological imperative, is impaired in inflammatory skin diseases such as atopic dermatitis (AD). Staphylococcus aureus is associated with AD lesions and contributes to pathological inflammation and further barrier impairment. S. aureus secretes extracellular proteases, such as V8 (or ‘SspA’), which cleave extracellular proteins to reduce skin barrier. Previous studies demonstrated that the host defence peptide human beta-defensin 2 (HBD2) prevented V8-mediated damage. Here, the mechanism of HBD2-mediated barrier protection in vitro is examined. Application of exogenous HBD2 provided protection against V8, irrespective of timeline of application or native peptide folding, raising the prospect of simple peptide analogues as therapeutics. HBD2 treatment, in context of V8-mediated damage, modulated the proteomic/secretomic profiles of HaCaT cells, altering levels of specific extracellular matrix proteins, potentially recovering V8 damage. However, HBD2 alone did not substantially modulate cellular proteomic/secretomics profiles in the absence of damage, suggesting possible therapeutic targeting of lesion damage sites only. HBD2 did not show any direct protease inhibition or induce expression of known antiproteases, did not alter keratinocyte migration or proliferation, or form protective nanonet structures. These data validate the barrier-protective properties of HBD2 in vitro and establish key protein datasets for further targeted mechanistic analyses.

The Female Athlete Triad (Triad) and the more encompassing Relative Energy Deficiency in Sport (RED-S) are disorders caused by low energy availability (LEA). LEA is a state of insufficient energy intake by an athlete relative to their energy expenditure. Persistent LEA results in the deleterious consequences to health and performance that comprise RED-S. With respect to both the Triad and RED-S, researchers have called for more education of those involved with sport, particularly coaches, to help reduce the incidence of these disorders. Recent studies have shown that as few as 15% of coaches are aware of the Triad, with up to 89% unable to identify even one of its symptoms. RED-S is a more recently established concept such that coach knowledge regarding it has only begun to be assessed, but the results of these initial studies indicate similar trends as for the Triad. In this review, we synthesize research findings from 1986 to 2021 that pertains to LEA and RED-S, which coaches should know so they can better guide their athletes.

Structurally colored materials can switch colors in response to external stimuli, which makes them potentially useful as colorimetric sensors, dynamic displays, and camouflage. However, their applications are limited by the angular dependence, slow response, and absence of synchronous control in time and space. In addition, out-of-plane deformation from shape instability easily occurs in photonic films, leading to inhomogeneous colors in photonic-crystal materials. To address these challenges, we combine structurally colored photonic glasses and dielectric elastomer actuators. We use an external voltage signal to tune color changes quickly (much less than 0.1 s). The photonic glassses produce colors with low angular dependence, so that their colors are homogeneous even when they become curved due to voltage-triggered instabilities (buckling or wrinkling). As proof of concept, we present a pixelated display in which segments can be independently and rapidly turned on and off. This wide-angle, instability-tolerant, color-changing platform could be used in next-generation soft and curved color displays, camouflage with both shape and color changes, and multifunctional sensors.

In this short paper I discuss a day spent with a group of students in Glen Almond, Perthshire, in 2018. As I write this now, in 2022, I have the opportunity to situate my present thinking in the story and to think with the idea of a political ecology of ecologies, derived from an immanent ethics. I speculate that competing ecologies are themselves ecological as they perform materially in the world, and that creative research of the everyday enactments of multiple ecologies provides a form of critical environmental and social education.

Dielectric elastomer actuators (DEAs) are electrically driven soft actuators that generate fast and reversible deformations, enabling lightweight actuation of many novel soft robots and haptic devices. However, the high-voltage operation of DEAs combined with the paucity of soft, small high-voltage microelectronics has limited the number of discrete DEAs that can be incorporated into soft robots. This has hindered the versatility as well as complexity of the tasks that they can perform which, in practice, depends on the number of independently addressable actuating elements. This paper presents a new class of optically addressable dielectric elastomer actuators that utilize the photoconductivity of semiconducting zinc oxide nanowires to create optically switchable and stretchable electrical channels. This enables non-contact, optical control of local actuation. To illustrate the versatility of the new capabilities of this integration, we describe the response of dielectric elastomer actuators with integrated photoconductive channels, formed from thin films of percolating semiconducting nanoparticles. By using a switchable array of small light emitting diodes to optically address the actuator array, its actuation can be controlled both spatially and temporally.

Background Sellar masses (SM) frequently present with insidious hormonal dysfunction. We previously showed that, by utilizing a combined reflex/reflecting approach involving a laboratory clinician (LC) on common endocrine test results requested by non-specialists, and subsequently adding further warranted tests, previously undiagnosed pituitary disorders can be identified. However, manually employing these strategies by an LC is not feasible for wider screening of pituitary disorders. Objective The aim of this study was to compare the accuracy and financial impact of an Artificial Intelligence (AI) based, fully computerized reflex protocol with manual reflex/reflective intervention protocol led by an LC. Methods We developed a proof-of-concept AI-based framework to fully computerize multi-stage reflex testing protocols for pituitary dysfunction using automated reasoning methods. We compared the efficacy of this AI-based protocol with a reflex/reflective protocol based on manually curated retrospective data in identifying pituitary dysfunction based on 12 months of laboratory testing. Results The AI-based reflex protocol, as compared with the manual protocol, would have identified laboratory tests for add-on that either directly matched or included all manual add-on tests in 92% of cases, and recommended a similar specialist referral in 90% of the cases. The AI-based protocol would have issued 2.8 times the total number of manual add-on laboratory tests at an 85% lower operation cost than the manual protocol when considering marginal test costs, technical staff and specialist salary. Conclusion/Discussion Our AI-based reflex protocol can successfully identify patients with pituitary dysfunction, with lower estimated laboratory cost. Future research will focus on enhancing the protocol’s accuracy and incorporating the AI-based reflex protocol into institutional laboratory and hospital information systems for the detection of undiagnosed pituitary disorders.

BackgroundSelf-harm is complex, multifaceted, and dynamic, typically starts in adolescence, and is prevalent in young people. A novel research tool (the Card Sort Task for Self-harm; CaTS) offers a systematic approach to understanding this complexity by charting the dynamic interplay between multidimensional factors in the build-up to self-harm. Sequential analysis of CaTS has revealed differences in key factors between the first and the most recent episode of self-harm in adolescence. Rates of self-harm typically decline post-adolescence, but self-harm can continue into adulthood. A comparison between factors linked to self-harm in young people vs. adults will inform an understanding of how risk unfolds over time and clarify age-specific points for intervention. A pilot online adaptation (CaTS-online) and a new method (Indicator Wave Analysis; IWA) were used to assess key factors in the build-up to self-harm.MethodsCommunity-based young people (n = 66; 18–25 years, M = 21.4; SD = 1.8) and adults (n = 43; 26–57 years, M = 35; SD = 8.8) completed CaTS-online, documenting thoughts, feelings, events, and behaviours over a 6-month timeline for the first ever and most recent self-harm. A notable interdependence between factors and time points was identified using IWA.ResultsPositive emotion at and immediately after self-harm exceeded the threshold for both groups for both episodes. Feeling better following self-harm was more pronounced for the first-ever episodes. Impulsivity was an important immediate antecedent to self-harm for both groups at both episodes but most markedly for young people. Acquired capability was notable for adults’ most recent episodes, suggesting this develops over time. Burdensomeness was only more notable for adults and occurred 1 week prior to a recent episode. Both groups revealed patterns of accessing support that were helpful and unhelpful.ConclusionCommonalities and differences in the temporal organisation of factors leading to and following self-harm were identified in young people and adult pathways which shed light on age-specific factors and possible points of intervention. This has implications for clinical support and services around approaches to positive feelings after self-harm (especially for first-ever self-harm), feeling of burdensomeness, impulsivity, and acquired capability leading up to self-harm. Support is provided for card-sort approaches that enable the investigation of the complex and dynamic nature of pathways to self-harm.

The successful enzymatic degradation of polyester substrates has fueled worldwide investigation into the treatment of plastic waste using bio-based processes. Within this realm, marine-associated microorganisms have emerged as a promising source of polyester-degrading enzymes. In this work, we describe the hydrolysis of the synthetic polymer PET by SM14est, a polyesterase which was previously identified from Streptomyces sp. SM14, an isolate of the marine sponge Haliclona simulans. The PET hydrolase activity of purified SM14est was assessed using a suspension-based assay and subsequent analysis of reaction products by UV-spectrophotometry and RP-HPLC. SM14est displayed a preference for high salt conditions, with activity significantly increasing at sodium chloride concentrations from 100 mM up to 1,000 mM. The initial rate of PET hydrolysis by SM14est was determined to be 0.004 s−1 at 45°C, which was increased by 5-fold to 0.02 s−1 upon addition of 500 mM sodium chloride. Sequence alignment and structural comparison with known PET hydrolases, including the marine halophile PET6, and the highly efficient, thermophilic PHL7, revealed conserved features of interest. Based on this work, SM14est emerges as a useful enzyme that is more similar to key players in the area of PET hydrolysis, like PHL7 and IsPETase, than it is to its marine counterparts. Salt-tolerant polyesterases such as SM14est are potentially valuable in the biological degradation of plastic particles that readily contaminate marine ecosystems and industrial wastewaters.

Contains fulltext : 290916.pdf (Publisher’s version ) (Open Access) To support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is necessary to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs. 01 februari 2023

Background: Mental health disorders are a common sequelae of traumatic brain injury (TBI) and are associated with worse health outcomes including increased mental health care utilization. This study addresses the methodical limitations of previous studies by examining the effect of TBI on mental health care utilization using propensity score matching analysis. Methods: Using data from a national survey, this study assessed mental health care utilization among those with a TBI, compared with a non-injured control group. Propensity score matching for age, sex, education, income, marital status, race, mental health comorbidities, and chronic conditions in a 4:1 ratio using nearest neighbor was performed. Conditional logistic regression then compared matched patients in terms of mental health care utilization. E-value sensitivity analysis was used to assess how strong an unmeasured confounder would have to be to explain away an observed relationship. Results: The matched study sample included 76,727 TBI patients and 307,510 non-injured controls with significantly improved balance in all baseline covariates. After conditional regression of the propensity-matched cohort, TBI remained a significant predictor of mental health care utilization (95% CI, 1.38-3.67), showing a 2.25-fold increased probability of mental health care utilization in TBI patients. Conclusions: This study is the first to evaluate the probability of mental health care utilization in TBI patients through a well-matched national cohort. TBI patients were more than twice as likely to use health care services for mental health complaints relative to those who were uninjured. Further longitudinal research is needed to evaluate the long-term mental health care utilization of TBI patients.

The European bass (Dicentrarchus labrax) support high value commercial and recreational fisheries, however the Spawning Stock Biomass (SSB) of the northern Atlantic stock (ICES divisions 4.b–c, 7.a, and 7.d–h) has rapidly declined to an unsustainable level. The decline in SSB has been attributed to high fishing pressure combined with poor recruitment. By tracking juvenile fish their spatial ecology can be identified, and appropriate fisheries management policies designed to boost recruitment can be implemented. Using acoustic telemetry 146 sub-adult European bass (25.2–60 cm fork length) were tracked for up to 370 d across three sites in the southwest of the UK. Tagged fish were detected 2 724 548 times (Range: 166–106 393 detections per fish). Linear modelling estimated tagged fish were resident within 2.4–20.1 km of the site where they were first caught for 42.9–75.5% of the year. Some fish were however resident throughout summer and winter. Individual fish were also tracked moving up to 317 km to other coastal sites, 81% of which returned to their original capture site. Fisheries management should account for the high site fidelity displayed by juveniles and sub-adults of this species and coastal nursery sites should be considered essential habitat.

Data Science advances in sports commonly involve "big data", i.e., large sport-related data sets. However, such big data sets are not always available, necessitating specialized models that apply to relatively few observations. One important area of sport-science research that features small data sets is the study of recovery from exercise. In this area, models are typically fitted to data collected from exhaustive exercise test protocols, which athletes can perform only a few times. Recent findings highlight that established recovery such as the so-called work-balance models are too simple to adequately fit observed trends in the data. Therefore, we investigated a hydraulic model that requires the same few data points as work-balance models to be applied, but promises to predict recovery dynamics more accurately. To compare the hydraulic model to established work-balance models, we retrospectively applied them to data compiled from published studies. In total, one hydraulic model and three work-balance models were compared on data extracted from five studies. The hydraulic model outperformed established work-balance models on all defined metrics, even those that penalize models featuring higher numbers of parameters. These results incentivize further investigation of the hydraulic model as a new alternative to established performance models of energy recovery., 26 pages, 9 figures, 6 tables, this manuscript has been submitted and is currently under review

Contemporary medicinal chemistry considers fragment-based drug discovery (FBDD) and inhibition of protein-protein interactions (PPI) as important means of expanding the volume of druggable chemical space. However, the ability to robustly identify valid fragments and PPI inhibitors is an enormous challenge, requiring the application of sensitive biophysical methodology. Accordingly, in this study, we exploited the speed and sensitivity of nanoelectrospray (nano-ESI) native mass spectrometry to identify a small collection of fragments which bind to the TPR2AB domain of HOP. Follow-up biophysical assessment of a small selection of binding fragments confirmed binding to the single TPR2A domain, and that this binding translated into PPI inhibitory activity between TPR2A and the HSP90 C-terminal domain. An in-silico assessment of binding fragments at the PPI interfacial region, provided valuable structural insight for future fragment elaboration strategies, including the identification of losartan as a weak, albeit dose-dependent inhibitor of the target PPI.

Traumatic brain injury (TBI) is a leading cause of death and disability among adults. Falls and motor vehicle collisions (MVCs) are the most common causes of TBI hospitalizations in Canada. The purpose of this study was to determine whether, at the provincial level, there have been significant changes in the injury rate and causes of major TBI. This was a retrospective cohort study of all patients in Nova Scotia who presented with major TBI (Abbreviated Injury Scale Head score ≥ 3) between 2002 and 2018. Prospectively entered data were collected from the Nova Scotia Trauma Registry. Annual injury rates were calculated based on 100,000 population (all ages) using population estimates from Statistics Canada. Linear regression was performed to analyze annual trends of major TBI within the province. There were 5590 major TBI patients in Nova Scotia during the 16-year study period. The overall annual rate of major TBI was 37 per 100,000 population. There was a 39% increase in the rate of major TBI over the study period (r = − 0.72, R2 = 0.51, p

The majority of geographical profiling research focuses on the relationship between offender and location, which works particularly well when a burial site is known. In real-world investigations, however, burial or dump sites are often not known. The aim of the current paper is to outline a relatively under-used method of geographic profiling: Winthropping. While the method has been around for several decades, few studies have provided any research findings using it. There are two likely reasons for Winthropping being under-used: first, it has not been clearly, theoretically explained; second, given its relative novelty, it may not be immediately clear how to use it in research and real-world scenarios. The current paper outlines several key psychological (e.g., satisficing and affordances) and criminological (e.g., rational choice theory and crime geometry) theories that may explain why Winthropping works. Case studies are provided, and a methodological approach (matrix forecasting) is then provided to show how it could work in research practice and real-world applications. Overall, Winthropping is deemed to be highly useful, and it is hoped that experts in the field will begin developing this tool for wider, applied use.

Controlling the spatial and temporal behavior of peptide segments is essential in the fabrication of functional peptide-based materials and nanostructures. To achieve a desired structure, complex sequence design is often required, coupled with the inclusion of unnatural amino acids or synthetic modifications. Herein, we investigate the structural properties of 1:1 inclusion complexes between specific oligopeptides and cucurbit[8]uril (CB[8]), inducing the formation of turns, and by alteration of the peptide sequence, tunable structural chirality. We also explore extended peptide sequence binding with CB[8], demonstrating a simple approach to construct a peptide hairpin.

Concussion is a frequent injury in many sports and is also common in para athletes. However, there is a paucity of concussion research related to para sport, and prior International Concussion in Sport (CIS) consensus papers have not substantively addressed this population. To remedy this and to improve concussion care provided to para athletes, the concussion in para sport (CIPS) multidisciplinary expert group was created. This group analysed and discussed in-depth para athlete-specific issues within the established key clinical domains of the current (2017) consensus statement on CIS. Due to the onset of the COVID-19 pandemic, the group held all meetings by video conferencing. The existing Sport Concussion Assessment Tool 5 (SCAT5) for the immediate on-field and office-based off-field assessment of concussion was evaluated as part of this process, to identify any para athlete-specific concerns. Regular preparticipation and periodic health examinations are essential to determine a baseline reference point for concussion symptoms but pose additional challenges for the interpreting clinician. Further considerations for concussion management for the para athlete are required within the remove, rest, reconsider and refer consensus statement framework. Considering return to sport (RTS), the 2017 CIS consensus statement has limitations when considering the RTS of the para athlete. Case-by-case decision making related to RTS following concussion is imperative for para athletes. Additional challenges exist for the evaluation and management of concussion in para athletes. There is a need for greater understanding of existing knowledge gaps and attitudes towards concussion among athlete medical staff, coaches and para athletes. Future research should investigate the use and performance of common assessment tools in the para athlete population to better guide their clinical application and inform potential modifications. Concussion prevention strategies and sport-specific rule changes, such as in Para Alpine Skiing and Cerebral Palsy Football, also should be carefully considered to reduce the occurrence of concussion in para athletes.

Background It is reported that the longer-term outcomes for stroke survivors are poor, with a range of unmet needs identified. Objectives The aims were to develop and test a longer-term stroke care strategy focused on improving the quality of life of stroke survivors and their carers by addressing unmet needs, and maintenance and enhancement of participation (i.e. involvement in life situations). Design Five overlapping workstreams were undertaken – (1) refinement of content by semistructured interviews with stroke survivors and their carers and by a review of the literature to inform content and delivery of the care strategy; (2) exploration of service models by national survey and focus groups with purposely selected services; (3) intervention development by interaction with a reference group of stroke survivors, carers, and health and social care professionals; (4) refinement and pilot implementation of the developed intervention in three stroke services (case studies); and (5) a cluster randomised controlled feasibility trial in 10 stroke services across England and Wales. Setting The intervention development work and feasibility trial were in stroke services (inclusive of primary, secondary, community and social care provision) across England and Wales. Participants Participants were stroke survivors resident in the community and their carers, and health and social care professionals in the included stroke services. Data sources Interviews with 28 stroke survivors and their carers at least 9 months post stroke ascertained their needs and the barriers to and facilitators of addressing those needs. Additional literature reviews identified 23 needs. No evidence-based interventions to address these needs were reported; self-management was highlighted as a possible delivery mechanism. In workstream 2, a national survey revealed that the most common model of stroke service provision was care up to 12 months post stroke, reported by 46 (40%) services. Thirty-five (30%) services provided care up to 6 months post stroke and 35 (30%) provided care beyond 12 months, thus identifying 6 months post stroke as an appropriate delivery point for a new intervention. Through focus groups in a range of services, stroke survivors’ perceived unmet needs and the barriers to and enablers of service provision were identified. Intervention Using information obtained in workstreams 1 and 2 and working closely with a stakeholder reference group, we developed an intervention based on the unmet needs prioritised by stroke survivors and their carers (workstream 3). In workstream 4, action groups (clinicians, stroke survivors and researchers) were established in three stroke services that led implementation in their service and contributed to the iterative refinement of the intervention, associated training programme and implementation materials. The intervention (called New Start) was delivered at 6 months post stroke. Key components were problem-solving self-management with survivors and carers, help with obtaining usable information, and helping survivors and their carers build sustainable, flexible support networks. Results A cluster randomised feasibility trial (workstream 5) was successfully implemented in 10 stroke services across England and Wales, with associated process and health economic evaluations. Five services were randomised to provide New Start, while five continued with usual care; 269 participants were recruited. Progression criteria – in terms of our pre-determined (red, amber, green) criteria for progress to a full trial: target stroke survivor recruitment rates were achieved, on average, across sites (24.1 per site over 6 months, green); 216 (80.3%) registered stroke survivors returned follow-up questionnaires at 9 months (84.1% in the intervention arm and 75.8% in the usual care arm, green); according to data reported by sites, overall, 95.2% of registered stroke survivors were offered at least one session of the intervention (green); all five intervention sites had at least two facilitators deemed competent, delivered the New Start intervention and provided it to stroke survivors (green). However, at some sites, there were concerns regarding the number of stroke survivors being offered, accepting and receiving the intervention. Only small differences in outcomes and costs were observed between the New Start and usual care groups, and considerable uncertainty around the cost-effectiveness remains. Conclusions We report a complex programme of work that has described the longer-term needs of stroke survivors and highlighted evidence and service gaps. Working closely with stroke survivors, an intervention was developed that has been refined in three services and feasibility tested in a cluster randomised controlled trial. Further refinement of the target population and optimisation of the intervention materials is required prior to a full randomised controlled trial evaluation. Future work Optimisation of the intervention, and clearer specification of recipients, are required prior to a full trial evaluation. Trial registration Current Controlled Trials ISRCTN38920246. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 3. See the NIHR Journals Library website for further project information.