Spirocycles as Rigidified sp3-Rich Scaffolds for a Fragment Collection.

Novel divergent methodology to access sp3-rich spirocyclic fragments is reported. First, a robust modular synthesis of bis-alkene amino ester building blocks was developed. Three different carbocycles and six heterocycles were then constructed to assemble eight spirocycles. Importantly, strategic exit vectors were incorporated within each scaffold to aid fragment growth and were elaborated via chemical modifications. Finally, computational methods demonstrate higher levels of rigidity, three-dimensionality, and structural diversity of the library compared to a commercial collection

The ORIGINS project biobank: A collaborative bio resource for investigating the developmental origins of health and disease

Early onset Non-Communicable Diseases (NCDs), including obesity, allergies, and mental ill-health in childhood, present a serious and increasing threat to lifelong health and longevity. The ORGINS Project (ORIGINS) addresses the urgent need for multidisciplinary efforts to understand the detrimental multisystem impacts of modern environments using well-curated large-scale longitudinal biological sample collections. ORGINS is a prospective community birth cohort aiming to enrol 10,000 pregnant people and follow each family until the children reach 5 years of age. A key objective is to generate a comprehensive biorepository on a sub-group of 4000 families invited to contribute blood, saliva, buccal cells, urine, stool, hair, house dust, cord blood, placenta, amniotic fluid, meconium, breastmilk, and colostrum over eight timepoints spanning the antenatal period and early childhood. Uniquely, ORIGINS includes a series of nested sub-projects, including interventions and clinical trials addressing different aspects of health. While this adds complexity as the project expands, it provides the opportunity for comparative studies. This research design promotes a multidisciplinary, multisystem approach to biological sample collection, analysis, and data sharing to ensure more integrated perspectives and solutions. This paper details the evolving protocol of our collaborative biobanking concept. Further, we outline our future visions for local, national, and ultimately international, comparative, and collaborative opportunities to advance our understanding of early onset NCDs and the opportunities to improve health outcomes for future generations

Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections

Fragment-based drug discovery (FBDD) is a well-established approach for the discovery of novel medicines, illustrated by the approval of two FBBD-derived drugs. This methodology is based on the utilization of small “fragment” molecules (<300 Da) as starting points for drug discovery and optimization. Organic synthesis has been identified as a significant obstacle in FBDD, however, in particular owing to the lack of novel 3-dimensional (3D) fragment collections that feature useful synthetic vectors for modification of hit compounds. Diversity-oriented synthesis (DOS) is a synthetic strategy that aims to efficiently produce compound collections with high levels of structural diversity and three-dimensionality and is therefore well-suited for the construction of novel fragment collections. This Mini-Review highlights recent studies at the intersection of DOS and FBDD aiming to produce novel libraries of diverse, polycyclic, fragment-like compounds, and their application in fragment-based screening projects

Ras-Related Small GTPases RalA and RalB Regulate Cellular Survival After Ionizing Radiation

Oncogenic activation of Ras renders cancer cells resistant to ionizing radiation (IR), but the mechanisms have not been fully characterized. The Ras-like small GTPases, RalA and RalB, are downstream effectors of Ras function and are critical for both tumor growth and survival. The Ral effector RalBP1/RLIP76 mediates survival of mice after whole body irradiation but the role of the Ral GTPases themselves in response to IR is unknown. We have investigated the role of RalA and RalB in cellular responses to IR

Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity

Background: Seasonal influenza A infection affects a significant cohort of the global population annually, resulting in considerable morbidity and mortality. Therapeutic strategies are of limited efficacy, and during a pandemic outbreak would only be available to a minority of the global population. Over-the-counter medicines are routinely taken by individuals suffering from influenza, but few studies have been conducted to determine their effectiveness in reducing pulmonary immunopathology or the influence they exert upon the generation of protective immunity. Methods: A mouse model of influenza infection was utilised to assess the efficacy of paracetamol (acetaminophen) in reducing influenza-induced pathology and to examine whether paracetamol affects generation of protective immunity. Results: Administration (intraperitoneal) of paracetamol significantly decreased the infiltration of inflammatory cells into the airway spaces, reduced pulmonary immunopathology associated with acute infection and improved the overall lung function of mice, without adversely affecting the induction of virus-specific adaptive responses. Mice treated with paracetamol exhibited an ability to resist a second infection with heterologous virus comparable with that of untreated mice. Conclusions: Our results demonstrate that paracetamol dramatically reduces the morbidity associated with influenza but does not compromise the development of adaptive immune responses. Overall, these data support the utility of paracetamol for reducing the clinical symptoms associated with influenza virus infection

The Impact of COVID-19 on Perceived Barriers and Facilitators to the Healthfulness of Communities With Low-Income

Background: The COVID-19 pandemic brought new challenges affecting the wellbeing of individuals in communities with low income. Understanding where people live and how those environments can facilitate or hinder living a healthy lifestyle is essential for developing interventions that target behavior change and health promotion. Objective: This study compares Extension Nutrition Educators’ (NEs) perceptions of the barriers and facilitators impacting the healthfulness of the environment of communities with low income in eleven states before and during the COVID-19 pandemic

Pulmonary oedema measured by MRI correlates with late-phase response to allergen challenge

Purpose: Asthma is associated with reversible airway obstruction, leucocyte infiltration, airways hyperresponsiveness (AHR) and airways remodelling. Fluid accumulation causes pulmonary oedema contributing to airways obstruction. We examined the temporal relationship between the late asthmatic response (LAR) following allergen challenge of sensitised guinea-pigs and pulmonary oedema measured by magnetic resonance imaging (MRI). Materials and Methods: Ovalbumin (OVA) sensitised guinea-pigs received either a single OVA inhalation (acute) or nine OVA inhalations at 48 h intervals (chronic). Airways obstruction was measured as specific airways conductance (sGaw) by whole body plethysmography. AHR to inhaled histamine and bronchoalveolar lavage for leucocyte counts were measured 24 h after a single or the final chronic ovalbumin challenges. MRI was performed at intervals after OVA challenge and high intensity oedemic signals quantified. Results: Ovalbumin caused early bronchoconstriction, followed at 7 h by a LAR and at 24 h AHR and leucocyte influx. The bright intensity MRI oedema signal, peaking at 7 h, was significantly (P<0.05) greater after chronic (9.0±0.7x103 mm3) than acute OVA (7.6±0.2x103 mm3). Dexamethasone treatment before acute OVA abolished the AHR and LAR and significantly reduced eosinophils and the bright intensity MRI oedema from 9.1±1.0 to 6.4±0.3x103 mm3. Conclusion: We show a temporal relationship between oedema and the LAR and their parallel reduction, along with eosinophils and AHR, by dexamethasone. This suggests a close causative association between pulmonary oedema and impaired airways function

eB4CAST Approach Improves Science Communication With Stakeholders in a College-Based Health Program

Communicating scientific results with community partners is often lacking in intervention programs, thus eB4CAST was developed to facilitate impact sharing. This article investigated using the eB4CAST dissemination tool to communicate impact from a campus-based obesity prevention program. Data from Get Fruved RCT university sites collected at baseline were used to generate eB4CAST reports. Experts (n = 13) and RCT sites (n = 15) were asked to provide feedback on eB4CAST reports based on appeal, understanding, and clarity. On all Likert items, participants rated above 7 on each (out of 10). Positive responses from open-ended questions included eB4CAST reports being clear, visually appealing, and aid in program understanding. Overall, eB4CAST was successful in relaying data and information for the Get Fruved program, thus a means for science communication that could be used in interventions. Utilizing infographics to report data and information is a feasible way to disseminate and communicate in a cost-effective, timely manner

Professional learning needs in using video calls identified through workshops

BACKGROUND: Most people want to die at home but only half do. Supporting patients in rural locations is challenging. Video calls such as Skype, might help but are not routinely used; we should consider learning needs to increase uptake and ensure effective use. We aimed to identify learning needs of healthcare professionals (HCPs) in using video calls to support patients (and their carers) to die at home. METHODS: Face-to-face workshops were held in five Southwest England locations. Participants discussed advantages, disadvantages, scenarios for use, and the learning needs of video call users. Ideas were documented on flipcharts and discussions audio-recorded. The 116 participants included nurses, allied HCPs, doctors and previously bereaved volunteers. Lists of advantages, disadvantages, scenarios and learning needs were compiled and circulated to participants. In a subsequent online workshop, 21 participants ranked seven groups of learning needs in priority order. RESULTS: Most participants thought video calls could be used to advantage in many end-of-life scenarios, especially in rural areas. Seven themes, covering 59 learning needs for HCPs, were identified (in priority order): (i) confidence and technical ability in using video calls; (ii) being aware of how video calls fit into clinical practice; (iii) managing video calls; (iv) communication skills on ‘camera’; (v) understanding how patients and families may be affected by video call use; (vi) presenting video calls as an option to patients and families to assess their readiness; (vii) normal professional skills that become essential for effective video calls. CONCLUSIONS: Although almost ubiquitous, video call software is not routinely and effectively used in British clinical practice. Supporting patients and families at end-of-life is one example where it could be used to advantage, but clinicians need to plan and practise before using it in real situations. Learning needs were identified that could be developed into learning modules and/or courses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12909-016-0657-6) contains supplementary material, which is available to authorized users