Targeting an Initiator Allergen Provides Durable and Expansive Protection against House Dust Mite Allergy.

Whereas treatment of allergic diseases such as asthma relies largely on the targeting of dysregulated effector pathways, the conceptually attractive alternative of preventing them by a pharmaceutical, at-source intervention has been stymied until now by uncertainties about suitable targets and the challenges facing drug design. House dust mites (HDMs) are globally significant triggers of allergy. Group 1 HDM allergens, exemplified by Der p 1, are cysteine proteases. Their degradome has a strong disease linkage that underlies their status as risk and initiator allergens acting directly and through bystander effects on other allergens. Our objective was to test whether target-selective inhibitors of group 1 HDM allergens might provide a viable route to novel therapies. Using structure-directed design to optimize a series of pyruvamides, we undertook the first examination of whether pharmaceutically developable inhibitors of group 1 allergens might offer protection against HDM exposure. Developability criteria included durable inhibition of clinically relevant signals after a single aerosolized dose of the drug. The compounds suppressed acute airway responses of rats and mice when challenged with an HDM extract representing the HDM allergome. Inhibitory effects operated through a miscellany of downstream pathways involving, among others, IL-33, thymic stromal lymphopoietin, chemokines, and dendritic cells. IL-13 and eosinophil recruitment, indices of Th2 pathway activation, were strongly attenuated. The surprisingly expansive benefits arising from a unique at-source intervention suggest a novel approach to multiple allergic diseases in which HDMs play prominent roles and encourage exploration of these pharmaceutically developable molecules in a clinical setting.

Evidence for active upper mantle flow in the Atlantic and Indo-Australian realms since the Upper Jurassic from hiatus maps and spreading rate changes.

Histories of large-scale horizontal and vertical lithosphere motion hold important information on mantle convection. Here, we compare continent-scale hiatus maps as a proxy for mantle flow induced dynamic topography and plate motion variations in the Atlantic and Indo-Australian realms since the Upper Jurassic, finding they frequently correlate, except when plate boundary forces may play a significant role. This correlation agrees with descriptions of asthenosphere flow beneath tectonic plates in terms of Poiseuille/Couette flow, as it explicitly relates plate motion changes, induced by evolving basal shear forces, to non-isostatic vertical motion of the lithosphere. Our analysis reveals a timescale, on the order of a geological series, between the occurrence of continent-scale hiatus and plate motion changes. This is consistent with the presence of a weak upper mantle. It also shows a spatial scale for interregional hiatus, on the order of 2000-3000 km in diameter, which can be linked by fluid dynamic analysis to active upper mantle flow regions. Our results suggest future studies should pursue large-scale horizontal and vertical lithosphere motion in combination, to track the expressions of past mantle flow. Such studies would provide powerful constraints for adjoint-based geodynamic inverse models of past mantle convection.

Computation of vertical fluid mobility of CO[Formula: see text], methane, hydrogen and hydrocarbons through sandstones and carbonates.

Over the last decade, there has been an irreversible shift from hydrocarbon exploration towards carbon storage, low-carbon energy generation and hydrogen exploration. Whilst basin modelling techniques may be used to predict the migration of hydrocarbons through sedimentary basins on geological timescales, there remains little understanding of how fluids behave at the basin scale on present-day timescales. We apply the Darcy flow equation to present an algorithm to determine the basin-scale mobilities and maximum vertical velocity, [Formula: see text], of CO[Formula: see text], methane, hydrogen and hydrocarbons with depth for sandstone and carbonate. [Formula: see text] for CO[Formula: see text] and methane are on scales of m/year, whilst values for hydrocarbon fluids are an order of magnitude smaller than for other fluids. Our results indicate that the fluid mobility of subsurface CO[Formula: see text] may be sensitive to surface and near-surface temperature variations. [Formula: see text] for hydrogen is approximately 2-10 times greater than hydrocarbon fluids, yielding important consequences for the future use of basin modelling software for determining hydrogen migration for exploration and storage.

Remanufacturing of single-use medical devices: a case study on cross-border collaboration between the UK and Nigeria.

This paper aims to evaluate the current state of the remanufacturing of medical devices, considering the differences between developed and developing countries. With reference to various socio-economic factors, the impact of remanufacturing to sustainability was evaluated and from this, single-use medical devices were deemed to be critical in minimising waste within the medical industry. This is even more critical with increasing use of single-use devices in the Coronavirus disease 2019 (COVID 19) pandemic. It was identified that cleaning is a key consideration for ensuring a safe remanufacturing process that would minimise the risk of infection to patients. Therefore, this process was evaluated and appropriate recommendations made. Although there may be some challenges, further research would be required for integration of the methodology and process outlined into the medical sector.

A Personalized Approach Bias Modification Smartphone App ("SWiPE") to Reduce Alcohol Use: Open-Label Feasibility, Acceptability, and Preliminary Effectiveness Study.

BACKGROUND: Approach bias modification (ApBM), a computerized cognitive intervention that trains people to "avoid" alcohol-related images and "approach" nonalcohol images, reduces the likelihood of relapse when administered during residential alcohol treatment. However, most individuals experiencing alcohol problems do not require, do not seek, or have difficulty accessing residential treatment. Smartphone-delivered ApBM could offer an easily accessible intervention to reduce alcohol consumption that can be personalized (eg, allowing selection of personally relevant alcohol and positive nonalcohol training images) and gamified to optimize engagement. OBJECTIVE: We examined the feasibility, acceptability, and preliminary effectiveness of "SWiPE," a gamified, personalized alcohol ApBM smartphone app, and explored alcohol consumption and craving outcomes in people drinking at hazardous levels or above (Alcohol Use Disorders Identification Test [AUDIT] score ≥8) who wanted to reduce their alcohol use. METHODS: In this open-label trial, frequency and quantity of alcohol consumption, alcohol dependence severity, and craving were measured prior to participants downloading SWiPE. Participants (n=1309) were instructed to complete at least 2 sessions per week for 4 weeks. Recruitment and completion rates were indicators of feasibility. Functionality, aesthetics, and quality ratings were indicators of acceptability. Participants were prompted to report frequency and quantity of alcohol consumption weekly during training and 1 month after training. They completed measures of craving and dependence after 4 weeks of training. RESULTS: We recruited 1309 participants (mean age 47.0, SD 10.0 years; 758/1309, 57.9% female; mean AUDIT score 21.8, SD 6.5) over 6 months. Participants completed a median of 5 sessions (IQR 2-9); 31.2% (409/1309) completed ≥8 sessions; and 34.8% (455/1309) completed the posttraining survey. Mean Mobile Application Rating Scale scores indicated good acceptability for functionality and aesthetics and fair acceptability for subjective quality. Among those who completed the posttraining assessment, mean past-week drinking days reduced from 5.1 (SD 2.0) pre-training to 4.2 (SD 2.3) in week 4 (t454=7.87; P<.001), and mean past-week standard drinks reduced from 32.8 (SD 22.1) to 24.7 (SD 20.1; t454=8.58; P<.001). Mean Craving Experience Questionnaire frequency scores reduced from 4.5 (SD 2.0) to 2.8 (SD 1.8; t435=19.39; P<.001). Severity of Dependence scores reduced from 7.7 (SD 3.0) to 6.0 (SD 3.2; t435=12.44; P<.001). For the 19.4% (254/1309) of participants who completed a 1-month follow-up, mean past-week drinking days and standard drinks were 3.9 (SD 2.5) and 23.9 (SD 20.7), respectively, both significantly lower than at baseline (P<.001). CONCLUSIONS: The findings suggest SWiPE is feasible and acceptable and may be effective at reducing alcohol consumption and craving in a predominantly nontreatment-seeking sample of adult Australians drinking at hazardous levels. SWiPE's efficacy, relative to a control condition, now needs establishing in a randomized controlled trial. Smartphone-delivered personalized ApBM could be a highly scalable, widely accessible support tool for reducing alcohol use. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000638932; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000638932p. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/21278.

The Early Youth Engagement in first episode psychosis (EYE-2) study: pragmatic cluster randomised controlled trial of implementation, effectiveness and cost-effectiveness of a team-based motivational engagement intervention to improve engagement.

BACKGROUND: Early Intervention in Psychosis (EIP) services improve health outcomes for young people with psychosis in the medium-long term, but 25% of young people disengage in the first 12 months with costs to their mental health, families, society and the NHS. This study will evaluate the effectiveness, cost-effectiveness and implementation of a team-based motivational Early Youth Engagement (EYE-2) intervention. METHOD: The study design is a cluster randomised controlled trial (RCT) with economic evaluation, comparing the EYE-2 intervention + standardised EIP service to standardised EIP service alone, with randomisation at the team level. A process evaluation will evaluate the delivery of the intervention qualitatively and quantitatively across contexts. The setting is 20 EIP teams in 5 sites: Manchester, South London, East Anglia, Thames Valley and Hampshire. Participants are young people (14-35 years) with first episode psychosis, and EIP staff. The intervention is the team-based motivational engagement (EYE-2) intervention, delivered alongside standardised EIP services, and supported by additional training, website, booklets and social groups. The comparator is the standardised EIP service. Both interventions are delivered by EIP clinicians. The primary outcome is time to disengagement (time in days from date of allocation to care coordinator to date of last contact following refusal to engage with EIP service, or lack of response to EIP contact for a consecutive 3-month period). Secondary outcomes include mental and physical health, deaths, social and occupational function, recovery, satisfaction and service use at 6, 12, 18 and 24 months. A 12-month within-trial economic evaluation will investigate cost-effectiveness from a societal perspective and from an NHS perspective. DISCUSSION: The trial will provide the first test of an engagement intervention in standardised care, with the potential for significant impact on the mental health and wellbeing of young people and their families, and economic benefits for services. The intervention will be highly scalable, supported by the toolkit including manuals, commissioning guide, training and resources, adapted to meet the needs of the diverse EIP population, and based on an in-depth process evaluation. TRIAL REGISTRATION: ISRCTN 51629746 prospectively registered 7th May 2019. Date assigned 10th May 2019.

Assessment of Binding Affinity via Alchemical Free-Energy Calculations.

Free-energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free-energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace, and OpenMM and uses the AMBER 14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset, the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall's τ was 0.53 ± 0.05, which are broadly comparable to or better than previously reported results using other methods.

New inhibitor targeting human transcription factor HSF1: effects on the heat shock response and tumor cell survival.

Comparative modeling of the DNA-binding domain of human HSF1 facilitated the prediction of possible binding pockets for small molecules and definition of corresponding pharmacophores. In silico screening of a large library of lead-like compounds identified a set of compounds that satisfied the pharmacophoric criteria, a selection of which compounds was purchased to populate a biased sublibrary. A discriminating cell-based screening assay identified compound 001, which was subjected to systematic analysis of structure-activity relationships, resulting in the development of compound 115 (IHSF115). IHSF115 bound to an isolated HSF1 DNA-binding domain fragment. The compound did not affect heat-induced oligomerization, nuclear localization and specific DNA binding but inhibited the transcriptional activity of human HSF1, interfering with the assembly of ATF1-containing transcription complexes. IHSF115 was employed to probe the human heat shock response at the transcriptome level. In contrast to earlier studies of differential regulation in HSF1-naïve and -depleted cells, our results suggest that a large majority of heat-induced genes is positively regulated by HSF1. That IHSF115 effectively countermanded repression in a significant fraction of heat-repressed genes suggests that repression of these genes is mediated by transcriptionally active HSF1. IHSF115 is cytotoxic for a variety of human cancer cell lines, multiple myeloma lines consistently exhibiting high sensitivity.

Acoustic wave and eikonal equations in a transformed metric space for various types of anisotropy.

Acoustic waves propagating in anisotropic media are important for various applications. Even though these wave phenomena do not generally occur in nature, they can be used to approximate wave motion in various physical settings. We propose a method to derive wave equations for anisotropic wave propagation by adjusting the dispersion relation according to a selected type of anisotropy and transforming it into another metric space. The proposed method allows for the derivation of acoustic wave and eikonal equations for various types of anisotropy, and generalizes anisotropy by interpreting it as a change of the metric instead of a change of velocity with direction. The presented method reduces the scope of acoustic anisotropy to a selection of a velocity or slowness surface and a tensor that describes the transformation into a new metric space. Experiments are shown for spatially dependent ellipsoidal anisotropy in homogeneous and inhomogeneous media and sandstone, which shows vertical transverse isotropy. The results demonstrate the stability and simplicity of the solution process for certain types of anisotropy and the equivalency of the solutions.

New admission scoring criteria for patients with odontogenic infections: a pilot study.

Odontogenic infections are often referred to the oral and maxillofacial surgical department, which can cause a dilemma for junior clinicians who have to decide whether such patients require admission. We have devised a score to be used on admission to our unit to help junior on-call staff, and designed a prospective pilot study to assess it.

Odontogenic infections: a national survey to assess confidence of the OMFS "first on-call".

Odontogenic infections can range from simple toothache to life-threatening swellings in the neck. We conducted a national survey to assess the confidence of the "first on-call" in oral and maxillofacial surgery (OMFS) to admit or discharge these patients, and to see if local protocols or guidelines were in place to aid decision-making. We designed a questionnaire and emailed it to all OMFS units across the UK over a 3-week period in June 2015. We also contacted first on-call OMFS juniors by phone. A total of 54 respondents were confident and 24 were very confident to admit patients with odontogenic infections without a senior review, but only 45 were confident and 9 very confident to discharge patients from the emergency department without a senior review. Twenty-one were fairly confident to admit patients, and 37 were fairly confident to discharge them. One respondent was not confident to admit patients at all, and 9 did not feel confident to discharge patients without a senior review. Seventy-eight reported that no local protocols or structured guidance on odontogenic infections were used in their unit. This survey highlights the need for admission criteria to help junior clinicians decide whether to admit or discharge these patients.

Management of trauma to the palate in toddlers.

Trauma of the palate in children is a common presentation in emergency departments. Children have a tendency to place objects in their mouths, which leaves them at risk of traumatising the oral cavity. Most traumatic injuries, including those that penetrate the palate, can be treated conservatively, but some require surgical intervention. Careful assessment, appropriate intervention, and follow up by experienced clinicians are essential to ensure correct management and prevent long-term complications. This article presents two case studies involving children who had experienced traumatic injuries to the palate that required surgical intervention.

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.

Clostridium difficile has a single sortase, SrtB, that can be inhibited by small-molecule inhibitors.

BACKGROUND: Bacterial sortases are transpeptidases that covalently anchor surface proteins to the peptidoglycan of the Gram-positive cell wall. Sortase protein anchoring is mediated by a conserved cell wall sorting signal on the anchored protein, comprising of a C-terminal recognition sequence containing an "LPXTG-like" motif, followed by a hydrophobic domain and a positively charged tail. RESULTS: We report that Clostridium difficile strain 630 encodes a single sortase (SrtB). A FRET-based assay was used to confirm that recombinant SrtB catalyzes the cleavage of fluorescently labelled peptides containing (S/P)PXTG motifs. Strain 630 encodes seven predicted cell wall proteins with the (S/P)PXTG sorting motif, four of which are conserved across all five C. difficile lineages and include potential adhesins and cell wall hydrolases. Replacement of the predicted catalytic cysteine residue at position 209 with alanine abolishes SrtB activity, as does addition of the cysteine protease inhibitor MTSET to the reaction. Mass spectrometry reveals the cleavage site to be between the threonine and glycine residues of the (S/P)PXTG peptide. Small-molecule inhibitors identified through an in silico screen inhibit SrtB enzymatic activity to a greater degree than MTSET. CONCLUSIONS: These results demonstrate for the first time that C. difficile encodes a single sortase enzyme, which cleaves motifs containing (S/P)PXTG in-vitro. The activity of the sortase can be inhibited by mutation of a cysteine residue in the predicted active site and by small-molecule inhibitors.

Positively charged residues at the five-fold symmetry axis of cell culture-adapted foot-and-mouth disease virus permit novel receptor interactions.

Field isolates of foot-and-mouth disease virus (FMDV) have a restricted cell tropism which is limited by the need for certain RGD-dependent integrin receptors. In contrast, cell culture-adapted viruses use heparan sulfate (HS) or other unidentified molecules as receptors to initiate infection. Here, we report several novel findings resulting from cell culture adaptation of FMDV. In cell culture, a virus with the capsid of the A/Turkey/2/2006 field isolate gained the ability to infect CHO and HS-deficient CHO cells as a result of a single glutamine (Q)-to-lysine (K) substitution at VP1-110 (VP1-(Q)110(K)). Using site-directed mutagenesis, the introduction of lysine at this same site also resulted in an acquired ability to infect CHO cells by type O and Asia-1 FMDV. However, this ability appeared to require a second positively charged residue at VP1-109. CHO cells express two RGD-binding integrins (α5ß1 and αvß5) that, although not used by FMDV, have the potential to be used as receptors; however, viruses with the VP1-(Q)110(K) substitution did not use these integrins. In contrast, the VP1-(Q)110(K) substitution appeared to result in enhanced interactions with αvß6, which allowed a virus with KGE in place of the normal RGD integrin-binding motif to use αvß6 as a receptor. Thus, our results confirmed the existence of nonintegrin, non-HS receptors for FMDV on CHO cells and revealed a novel, non-RGD-dependent use of αvß6 as a receptor. The introduction of lysine at VP1-110 may allow for cell culture adaptation of FMDV by design, which may prove useful for vaccine manufacture when cell culture adaptation proves intractable.

The characteristics of bisphosphonate patients developing bisphosphonate-related osteonecrosis of the jaw attending an OMFS department.

UNLABELLED: This case series considers the incidence of patients taking bisphosphonate medication that suffer with bisphosphonate-related osteonecrosis of the jaw (BRONJ) following an exodontia procedure. Forty five such patients who attended the Wigan Royal Albert Edward Infirmary (RAEI) Oral and Maxillofacial Surgery (OMFS) department for an exodontia procedure were examined. A patient's age, gender, exodontia technique, bisphosphonate route (Oral/IV), smoking status and reason for taking the bisphosphonates, eg osteoporosis/cancer/ arthritis was considered. All of the patients that experienced BRONJ were smokers. CLINICAL RELEVANCE: Bisphosphonates are now widely accepted for the management of medical conditions, including arthritis, osteoporosis and various forms of cancer. Such patients are regularly referred to OMFS departments for dental extractions.

De novo ligand design to partially flexible active sites: application of the ReFlex algorithm to carboxypeptidase A, acetylcholinesterase, and the estrogen receptor.

Reflex is a recent algorithm in the de novo ligand design software, SkelGen, that allows the flexibility of amino acid side chains in a protein to be taken into account during the drug-design process. In this paper the impact of flexibility on the solutions generated by the de novo design algorithm, when applied to carboxypeptidase A, acetylcholinesterase, and the estrogen receptor (ER), is investigated. The results for each of the targets indicate that when allowing side-chain movement in the active site, solutions are generated that were not accessible from the multiple static protein conformations available for these targets. Furthermore, an analysis of structures generated in a flexible versus a static ER active site suggests that these additional solutions are not merely noise but contain many interesting chemotypes.

Foot-and-mouth disease virus forms a highly stable, EDTA-resistant complex with its principal receptor, integrin alphavbeta6: implications for infectiousness.

The initial stage of foot-and-mouth disease virus (FMDV) infection is virus binding to cell surface integrins via the RGD motif in the GH loop of the VP1 capsid protein. As for all ligand/integrin interactions, the initial contact between FMDV and its integrin receptors is cation dependent and hence inhibited by EDTA. We have investigated this binding process with RGD-containing peptides derived from the VP1 capsid protein of FMDV and discovered that, upon binding, some of these peptides form highly stable, EDTA-resistant associations with integrin alphavbeta6. Peptides containing specific substitutions show that this stable binding is dependent on a helical structure immediately C terminal to the RGD and, specifically, two leucine residues at positions RGD +1 and RGD +4. These observations have a biological consequence, as we show further that stable, EDTA-resistant binding to alphavbeta6 is a property also exhibited by FMDV particles. Thus, the integrin-binding loop of FMDV appears to have evolved to form very stable complexes with the principal receptor of FMDV, integrin alphavbeta6. An ability to induce such stable complexes with its cellular receptor is likely to contribute significantly to the high infectiousness of FMDV.

Astronomical fire: Richard Carrington and the solar flare of 1859.

An explosion on the Sun in 1859, serendipitously witnessed by amateur astronomer Richard Carrington, plunged telegraphic communications into chaos and bathed two thirds of the Earth's skies in aurorae. Explaining what happened to the Sun and how it could affect Earth, 93 million miles away, helped change the direction of astronomy. From being concerned principally with charting the stars to aid navigation, astronomers became increasingly concerned with what the celestial objects were, how they behaved and how they might affect life on Earth.