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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 coliacyl 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.

The gut microbiota is increasingly recognised as a key player in influencing human health and changes in the gut microbiota have been strongly linked with many non-communicable conditions in humans such as type 2 diabetes, obesity and cardiovascular disease. However, characterising the molecular mechanisms that underpin these associations remains an important challenge for researchers. The gut microbiota is a complex microbial community that acts as a metabolic interface to transform ingested food (and other xenobiotics) into metabolites that are detected in the host faeces, urine and blood. Many of these metabolites are only produced by microbes and there is accumulating evidence to suggest that these microbe-specific metabolites do act as effectors to influence human physiology. For example, the gut microbiota can digest dietary complex polysaccharides (such as fibre) into short-chain fatty acids (SCFA) such as acetate, propionate and butyrate that have a pervasive role in host physiology from nutrition to immune function. In this review we will outline our current understanding of the role of some key microbial metabolites, such as SCFA, indole and bile acids, in human health. Whilst many studies linking microbial metabolites with human health are correlative we will try to highlight examples where genetic evidence is available to support a specific role for a microbial metabolite in host health and well-being.

ABSTRACTThe Banister impulse-response (IR) model was designed to predict an athlete’s performance ability from their past training. Despite its long history, the model’s usefulness remains limited due to difficulties in obtaining precise parameter estimates and performance predictions. To help address these challenges, we developed a Bayesian implementation of the IR model, which formalises the combined use of prior knowledge and data. We report the following methodological contributions: 1) we reformulated the model to facilitate the specification of informative priors, 2) we derived the IR model in Bayesian terms, and 3) we developed a method that enabled the JAGS software to be used while enforcing parameter constraints. To demonstrate proof-of-principle, we applied the model to the data of a national-class middle-distance runner. We specified the priors from published values of IR model parameters, followed by estimating the posterior distributions from the priors and the athlete’s data. The Bayesian approach led to more precise and plausible parameter estimates than nonlinear least squares. We conclude that the Bayesian implementation of the IR model shows promise in addressing a primary challenge to its usefulness for athlete monitoring.

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.

3′-O-β-Glucosyl-4′,5′-didehydro-5′-deoxyadenosine 13is identified as a natural product of Streptomyces calvusand Streptomyces virens. It is also generated in vitroby direct β-glucosylation of 4′,5′-didehydro-5′-deoxyadenosine 12with the enzyme NucGT. The intact incorporation of oxygen-18 and deuterium isotopes from (±)[1-18O,1-2H2]-glycerol 14into C-5′ of nucleocidin 1and its related metabolites precludes 3′-O-β-glucosyl-4′,5′-didehydro-5′-deoxyadenosine 13as a biosynthetic precursor to nucleocidin 1.

Purpose: Behaviours occur across complex, dynamic timelines. Research methods to analyse these complex timelines have repeatedly used behaviour sequence analysis (BSA) as a primary method. Traditional BSA outputs, however, are limited in that they do not show how prevalent a behaviour sequence is throughout a sample or group. Until now, how many people in a sample showed the sequence was not analysed and reported. This paper aims to provide a new metric to calculate prevalence scores in BSA data sets. Design/methodology/approach: Open access recorded responses including nonverbal communication of deceptive and truthful individuals were analysed initially with a standard BSA approach and then the prevalence scores of transitions were calculated. Findings: Prevalence scores offered new insights into the distribution of sequences across groups. The prevalence score showed differences in which transitions were seen across the truthful and guilty samples. This offers new approaches to analysing nonverbal communication. Originality/value: This is the first paper to provide a prevalence score for BSA research and show how it can be used in applied research. The current prevalence score metric is provided and suggested for all future research into sequences.

Helical structures are ubiquitous in nature and impart unique mechanical properties and multifunctionality1. So far, synthetic architectures that mimic these natural systems have been fabricated by winding, twisting and braiding of individual filaments1–7, microfluidics8,9, self-shaping1,10–13and printing methods14–17. However, those fabrication methods are unable to simultaneously create and pattern multimaterial, helically architected filaments with subvoxel control in arbitrary two-dimensional (2D) and three-dimensional (3D) motifs from a broad range of materials. Towards this goal, both multimaterial18–23and rotational243D printing of architected filaments have recently been reported; however, the integration of these two capabilities has yet to be realized. Here we report a rotational multimaterial 3D printing (RM-3DP) platform that enables subvoxel control over the local orientation of azimuthally heterogeneous architected filaments. By continuously rotating a multimaterial nozzle with a controlled ratio of angular-to-translational velocity, we have created helical filaments with programmable helix angle, layer thickness and interfacial area between several materials within a given cylindrical voxel. Using this integrated method, we have fabricated functional artificial muscles composed of helical dielectric elastomer actuators with high fidelity and individually addressable conductive helical channels embedded within a dielectric elastomer matrix. We have also fabricated hierarchical lattices comprising architected helical struts containing stiff springs within a compliant matrix. Our additive-manufacturing platform opens new avenues to generating multifunctional architected matter in bioinspired motifs.

The Regenerative Braking Energy (RBE) of metro trains plays an important role in metro energy saving. If the regenerative energy can be directly absorbed by the adjacent trains, the investment in other RBE usage equipments like super capacitors will be reduced. To increase the RBE usage, the overlaps of traction and braking processes of adjacent trains can be increased by timetable optimization or real-time train regulation. But if the overlaps cannot be realized, the RBE cannot be efficiently absorbed by the other trains. To solve this problem, this paper proposes an optimal train control method to absorb the RBE of the braking train by adjusting the speed profile of an adjacent train that runs at non-braking stage. A speed profile adjustment algorithm for the adjacent train is given considering the speed limits and gradients, in which a traction process is incorporated in the adjusted speed profile. Connected and unconnected DC power supply networks are both considered. In the connected DC power supply network, the RBE of the braking train can be absorbed by the adjacent adjusted train, which runs in the different power supply section. To test the robustness of the proposed algorithm, random train delays are considered in the simulations. The interstation running time will be regulated to reduce the train delay by a linear programming model, based on which, the speed profile of the cooperative train will be adjusted. Simulations are conducted based on a whole day data of Beijing Metro Line 4. The simulation results show that the proposed method improves the energy efficiency over 13% by improving RBE usage, and the proposed method also shows strong robustness in the train delay simulations, which makes it a promising method to be applied in real metro system.

Background: We report a case of an intraosseous cavernous hemangioma originating from the middle turbinate that expanded into the anterior skull base, without traversing the cribriform plate.Methods: The mass was found incidentally after a computed tomography head was ordered for unrelated reasons. On questioning, the patient denied any nasal symptoms. Magnetic resonance imaging showed an enhancing mass and the radiological imaging supported a broad differential.Results: The lesion was removed by endoscopic image-guided surgery, and the pathology was that of a benign intraosseous cavernous hemangioma. There was no residual hemangioma on postoperative imaging and the nasal mucosa healed well. This is the first report of an intraosseous cavernous hemangioma of the middle turbinate showing superior expansion to the anterior skull base.Conclusion: This case demonstrates the extent to which cavernous hemangiomas may expand into surrounding tissues. While these lesions are uncommon, they can be considered as part of a broad differential diagnosis of sinonasal tumors.

AbstractThey thought they felt something, perhaps. The wisp of an outline not distinct enough to trace. Good. They circled it, at times, and at other times found themselves within. As they walked (a sort of walking. Figurative but real. Digital, but here. Over months of events), it curled open and headed in several directions. Foldings in the backcloth that furrowed them along until, as they walked and talked, they felt that perhaps a territory was becoming simultaneously clearer and more obscure, that they might find a way to enquire, even as it meant becoming the folds themselves. As they coalesce, Scott, Jamie, and Dave each come to this project differently (of course). From their own situations, with their own problems and with different voices and ways of writing. We (for the first shift in voice) take post-qualitative inquiry to be infused with a question mark, wary of attempts to make it a ‘thing’. Yet here we are, drawn to potentials, to the opening of conditions, to the possibility of something still to come. We hope to make a shift, to realise (as in make manifest) ontology and its everyday performance as synonymous with environmental education. Environmental education as a life.

Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)–derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.

The article explores the complexities and potential of regenerative agriculture as a solution to contemporary agricultural and environmental challenges. Topics discussed include the historical context and resurgence of regenerative agriculture, its differentiation from other farming practices, and the nuanced effectiveness of its applications in varying contexts and ecosystems.

Large-scale human genetic data1–3have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)4–6. VHLloss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization6,7. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYCexpression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.

Hip fractures represent a significant workload of both emergency and orthopaedic departments within the National Health Service (NHS). Pain relief is key in treating hip fractures as highlighted by both National Institute of Clinical Excellence (NICE) and British Orthopaedic Association Standards for Trauma (BOAST) guidelines. However, the literature shows that patients with cognitive impairment tend to have inconsistent pain management, leading to worse outcomes. We conducted a case–control study looking at 296 patients who presented with hip fractures to a major trauma centre between 1 December 2019 and 30 May 2020. Cognition was assessed using pre-recorded Abbreviated Mental Test Scores (AMTS). There was no significant difference between pain relief provided to patients with or without cognitive impairment in both the pre-hospital (p = 0.208) and Accident & Emergency (A&E) (p = 0.154) setting. A larger proportion of patients in A&E did not receive any pain relief (18.6% versus 42.2%). Pre-hospital, the higher the pain score, the stronger the analgesia given (R = 0.435, p = 0.000). This relationship was present in both the cognitively impaired (R = 0.572, p = 0.000) and cognitively intact groups (R = 0.390 p = 0.000). Strength of analgesia and pain scores did not correlate in A&E (R = 0.014, p = 0.826). Cognition did not impact the time to analgesia both pre-hospital (p = 0.291) and in A&E (p = 0.332); however, patients waited significantly longer to receive pain relief in A&E (29.61 minutes versus 150.28 minutes). Fascia-iliaca blocks were administered to 58.4% of the cohort, with no significant difference noted between cognition status. Overall, cognition does not impact pain management both pre-hospital and in A&E. There is still room for improvement, particularly in the assessment of pain in the cognitively impaired. A possible solution is the utilisation of the Bolton Pain Assessment Tool, a validated pain assessment tool for the cognitively impaired that has been utilised in the trauma setting with good effect.

The article discusses the pervasive issue of plastic pollution, emphasizing its detrimental impacts on biodiversity and human health, as highlighted in recent hearings and studies. Topics discussed include legislative efforts to address plastic waste, growing concerns about the health effects of microplastics, and the need for coordinated action among government, industry, and consumers to mitigate the plastic pollution crisis.

The article discusses the outcomes of the United Nations' COP28 agreement, where 194 countries endorsed transitioning away from fossil fuels, marking a significant step towards addressing climate change, with specific measures such as reducing methane emissions and commitments to halt new coal plants without proper emission controls.

Study Design: Literature Review (Narrative).Objective: To contextualize AO Spine RECODE-DCM research priority number 5: What is the socio-economic impact of DCM? (The financial impact of living with DCM to the individual, their supporters, and society as a whole).Methods: In this review, we introduce the methodology of health-economic investigation, including potential techniques and approaches. We summarize the current health-economic evidence within DCM, so far focused on surgical treatment. We also cover the first national estimate, in partnership with Myelopathy.orgfrom the United Kingdom, of the cost of DCM to society. We then demonstrate the significance of this question to advancing care and outcomes in the field.Results: DCM is a common and often disabling condition, with a significant lack of recognition. While evidence demonstrates the cost-effectives of surgery, even among higher income countries, health inequalities exist. Further the prevalent residual disability in myelopathy, despite treatment affects both the individual and society as a whole. A report from the United Kingdom provides the first cost-estimate to their society; an annual cost of ∼£681.6 million per year, but this is likely a significant underestimate.Conclusion: A clear quantification of the impact of DCM is needed to raise the profile of a common and disabling condition. Current evidence suggests this is likely to be globally substantial.

Covalent adaptive networks combine the advantages of cross-linked elastomers and dynamic bonding in a single system. In this work, we demonstrate a simple one-pot method to prepare thiol–ene elastomers that exhibit reversible photoinduced switching from an elastomeric gel to fluid state. This behavior can be generalized to thiol–ene cross-linked elastomers composed of different backbone chemistries (e.g., polydimethylsiloxane, polyethylene glycol, and polyurethane) and vinyl groups (e.g., allyl, vinyl ether, and acrylate). Photoswitching from the gel to fluid state occurs in seconds upon exposure to UV light and can be repeated over at least 180 cycles. These thiol–ene elastomers also exhibit the ability to heal, remold, and serve as reversible adhesives.

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.

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.

The cover and last page of the July/August issue tell me that my 40-year journey with Car and Driver is approaching the end of the road. After months of low-content issues (dis-content?), you devote practically an entire two-month issue to EVs?! - Michael Barton Lake Havasu City, AZ Elana Scherr took a deep dive into roadside assistance [see "Static Electricity", page 26] and found that EVs rarely need rescuing - Ed. We're guessing that once EVs stop being subsidized, states will collect a road tax based on actual mileage when EV drivers renew their registration - Ed. [Extracted from the article]

ABSTRACT:Background:Patients with sellar masses undergoing transsphenoidal surgery (TSS) frequently develop endocrine dysfunction; therefore, in-hospital endocrinology consultation (IHEC) is recommended. However, we wondered whether routine endocrinology assessment of all TSS patients is always necessary.Methods:We developed an IHEC Physician’s Guide to identify patients who would require peri-operative IHEC. An analysis of all patients undergoing TSS for a sellar mass over a 4-year period was conducted to assess the predictive value of the IHEC Physician’s Guide in identifying patients who required IHEC.Results:A total of 116 patients underwent TSS; 24 required IHEC. As expected, the risk of endocrine complications requiring peri-operative endocrine management was significantly higher in the IHEC group versus no-IHEC group (96% vs. 1%; p< 0.001). The negative predictive value of the IHEC Physician’s Guide in identifying patients who did not require IHEC was 0.99 (95% CI 0.9409–0.9997); Fisher’s exact test, p< 0.001), meaning that the IHEC Physician’s Guide successfully identified all but one patient who truly required IHEC.Conclusion:Results from our study show that most patients do not need IHEC after TSS and that those patients requiring IHEC can be reliably predicted at surgery by using a simple IHEC Physician’s Guide.

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.

AbstractSequence-specific protein-basedribonucleases are not found in nature. Absolute sequence selectivity in RNA cleavage in vivonormally requires multi-component complexes that recruit a guide RNA or DNA for target recognition and a protein–RNA assembly for catalytic functioning (e.g. RNAi molecular machinery, RNase H). Recently discovered peptidyl-oligonucleotide synthetic ribonucleases selectively knock down pathogenic RNAs by irreversible cleavage to offer unprecedented opportunities for control of disease-relevant RNA. Understanding how to increase their potency, selectivity and catalytic turnover will open the translational pathway to successful therapeutics. Yet, very little is known about how these chemical ribonucleases bind, cleave and leave their target. Rational design awaits this understanding in order to control therapy, particularly how to overcome the trade-off between sequence specificity and potency through catalytic turnover. We illuminate this here by characterizing the interactions of these chemical RNases with both complementary and non-complementary RNAs using Tmprofiles, fluorescence, UV-visible and NMR spectroscopies. Crucially, the level of counter cations, which are tightly-controlled within cellular compartments, also controlled these interactions. The oligonucleotide component dominated interaction between conjugates and complementarytargets in the presence of physiological levels of counter cations (K+), sufficient to prevent repulsion between the complementary nucleic acid strands to allow Watson-Crick hydrogen bonding. In contrast, the positively-charged catalytic peptide interacted poorly with target RNA, when counter cations similarly screened the negatively-charged sugar-phosphate RNA backbones. The peptide only became the key player, when counter cations were insufficient for charge screening; moreover, only under such non-physiological conditions did conjugates form strong complexes with non-complementaryRNAs.Communicated by Ramaswamy H. Sarma

Herein we discuss recent developments in mass spectrometry (MS)-based approaches for exploring the challenging interfaces of transiently interacting protein–protein interactions (PPIs).This includes an overview of liquid chromatography (LC)-MS linked protein footprinting and protein painting as tools for inferring the interacting interface of PPIs.In addition, we describe the development of native MS as a tool for developing PPI modulators and identifying PPI mediating short linear motifs (SLiMs)This is placed in the context of the significant potential that PPI characterizing, and modulation has for developing novel chemotherapeutics to address unmet medical needs.