COVID-19 as a global challenge: towards an inclusive and sustainable future

COVID-19 is a global challenge that demands researchers, policy makers, and governments address multiple dimensions which go far beyond the implications of this pandemic for health and wellbeing. Just as the UN Sustainable Development Goals call for focus on the connections between development policy sectors, the pandemic has exposed the complex global interdependencies that underpin economies and highlighted fault lines in societal structures that perpetuate ethnic, economic, social, and gender inequalities.Here,wehighlightthepandemic’semerging potential consequences for achieving sustainable development with respect to the six global challenge areas we collectively address at the UK Research and Innovation’s Global Challenges Research Fund:1 food systems; education; cities and sustainable infrastructure; security, protracted conflict, refugee crises, and forced displacement; environmental resilience; and global health. As the immediate health consequences of the pandemic unfold and begin to be superseded by the impact of public health containment measures, we call for a refocusing of research and action not only to mitigate these impacts but to build sustainability and strengthened resilience into future recovery.COVID-19 is a global challenge that demands researchers, policy makers, and governments address multiple dimensions which go far beyond the implications of this pandemic for health and wellbeing. Just as the UN Sustainable Development Goals call for focus on the connections between development policy sectors, the pandemic has exposed the complex global interdependencies that underpin economies and highlighted fault lines in societal structures that perpetuate ethnic, economic, social, and gender inequalities. Here, we highlight the pandemic’s emerging potential consequences for achieving sustainable development with respect to the six global challenge areas we collectively address at the UK Research and Innovation’s Global Challenges Research Fund:1 food systems; education; cities and sustainable infrastructure; security, protracted conflict, refugee crises, and forced displacement; environmental resilience; and global health. As the immediate health consequences of the pandemic unfold and begin to be superseded by the impact of public health containment measures, we call for a refocusing of research and action not only to mitigate these impacts but to build sustainability and strengthened resilience into future recovery

TNF superfamily members promote hepatitis C virus entry via an NF-κB and myosin light chain kinase dependent pathway

Preventing viral induced liver disease begins with an understanding 1 of the host factors that define susceptibility to infection. Hepatitis C Virus (HCV) is a global health issue with an estimated 170 million infected individuals at risk of developing liver disease including fibrosis and hepatocellular carcinoma. The liver is the major reservoir supporting HCV replication and this hepatocellular tropism is defined by HCV engagement of cellular entry receptors. Hepatocytes are polarised in vivo and this barrier function limits HCV entry. We previously reported that activated macrophages promote HCV entry into polarised hepatocytes via a TNF-α dependent process, however, the underlying mechanism was not defined. In this study we show that several TNF superfamily members, including TNF-α, TNF-β, TWEAK and LIGHT promote HCV entry via NF-κB mediated activation of myosin light chain kinase (MLCK) and disruption of tight junctions. These observations support a model where HCV hijacks an inflammatory immune response to stimulate infection and uncovers a role for NF-κB-MLCK signaling in maintaining hepatocellular tight junctions

A call to introduce newborn screening for spinal muscular atrophy (SMA) in Scotland

Peer reviewedPublisher PD

Safety and immunogenicity of boosting BCG vaccinated subjects with BCG: comparison with boosting with a new TB vaccine, MVA85A.

OBJECTIVES: To investigate the safety and immunogenicity of a booster BCG vaccination delivered intradermally in healthy, BCG vaccinated subjects and to compare with a previous clinical trial where BCG vaccinated subjects were boosted with a new TB vaccine, MVA85A. DESIGN: Phase I open label observational trial, in the UK. Healthy, HIV-negative, BCG vaccinated adults were recruited and vaccinated with BCG. The primary outcome was safety; the secondary outcome was cellular immune responses to antigen 85, overlapping peptides of antigen 85A and tuberculin purified protein derivative (PPD) detected by ex vivo interferon-gamma (IFN-gamma) ELISpot assay and flow cytometry. RESULTS AND CONCLUSIONS: BCG revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing PPD-specific T cell responses was observed. However, when these results were compared with data from a previous clinical trial, where BCG was boosted with MVA85A (BCG-MVA85A), MVA85A induced significantly higher levels (>2-fold) of antigen 85-specific CD4+ T cells (both antigen and peptide pool responses) than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009). To identify antigen 85A-specific CD8+ T cells that were not detectable by ex vivo ELISpot and flow cytometry, dendritic cells (DC) were used to amplify CD8+ T cells from PBMC samples. We observed low, but detectable levels of antigen 85A-specific CD8+ T cells producing IFNgamma (1.5% of total CD8 population) in the BCG primed subjects after BCG boosting in 1 (20%) of 5 subjects. In contrast, in BCG-MVA85A vaccinated subjects, high levels of antigen 85A-specific CD8+ T cells (up to 14% total CD8 population) were observed after boosting with MVA85A, in 4 (50%) of 8 subjects evaluated. In conclusion, revaccination with BCG resulted in modest boosting of pre-existing immune responses to PPD and antigen 85, but vaccination with BCG-MVA85A induced a significantly higher response to antigen 85 and generated a higher frequency of antigen 85A-specific CD8+ T cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT00654316 NCT00427830

Trends in gabapentinoid prescribing, co-prescribing of opioids and benzodiazepines, and associated deaths in Scotland

Background: Gabapentinoid drugs (gabapentin and pregabalin) are effective in neuropathic pain, which has a prevalence of ~7%. Concerns about increased prescribing have implications for patient safety, misuse, and diversion. Drug-related deaths (DRDs) have increased and toxicology often implicates gabapentinoids. We studied national and regional prescribing rates (2006–2016) and identified associated sociodemographic factors, co-prescriptions and mortality, including DRDs. Methods: National data from the Information Service Division, NHS Scotland were analysed for prescribing, sociodemographic, and mortality data from the Health Informatics Centre, University of Dundee. DRDs in which gabapentinoids were implicated were identified from National Records of Scotland and Tayside Drug Death Databases. Results: From 2006 to 2016, the number of gabapentin prescriptions in Scotland increased 4-fold (164 630 to 694 293), and pregabalin 16-fold (27 094 to 435 490). In 2016 ‘recurrent users’ (three or more prescriptions) had mean age 58.1 yr, were mostly females (62.5%), and were more likely to live in deprived areas. Of these, 60% were co-prescribed an opioid, benzodiazepine, or both (opioid 49.9%, benzodiazepine 26.8%, both 17.1%). The age-standardised death rate in those prescribed gabapentinoids was double that in the Scottish population (relative risk 2.16, 95% confidence interval 2.08–2.25). Increases in gabapentinoids contributing to cause of DRDs were reported regionally and nationally (gabapentin 23% vs 15%; pregabalin 21% vs 7%). In Tayside, gabapentinoids were implicated in 22 (39%) of DRDs, 17 (77%) of whom had not received a prescription. Conclusions: Gabapentinoid prescribing has increased dramatically since 2006, as have dangerous co-prescribing and death (including DRDs). Older people, women, and those living in deprived areas were particularly likely to receive prescriptions. Their contribution to DRDs may be more related to illegal use with diversion of prescribed medication

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

The reversibility of ubiquitination by the action of deubiquitinating enzymes (DUBs) serves as an important regulatory layer within the ubiquitin system. Approximately 100 DUBs are encoded by the human genome, and many have been implicated with pathologies, including neurodegeneration and cancer. Non-lysine ubiquitination is chemically distinct, and its physiological importance is emerging. Here, we couple chemically and chemoenzymatically synthesized ubiquitinated lysine and threonine model substrates to a mass spectrometry-based DUB assay. Using this platform, we profile two-thirds of known catalytically active DUBs for threonine esterase and lysine isopeptidase activity and find that most DUBs demonstrate dual selectivity. However, with two anomalous exceptions, the ovarian tumor domain DUB class demonstrates specific (iso)peptidase activity. Strikingly, we find the Machado–Joseph disease (MJD) class to be unappreciated non-lysine DUBs with highly specific ubiquitin esterase activity rivaling the efficiency of the most active isopeptidases. Esterase activity is dependent on the canonical catalytic triad, but proximal hydrophobic residues appear to be general determinants of non-lysine activity. Our findings also suggest that ubiquitin esters have appreciable cellular stability and that non-lysine ubiquitination is an integral component of the ubiquitin system. Its regulatory sophistication is likely to rival that of canonical ubiquitination.We thank Axel Knebel, Richard Ewan, Clare Johnson, and Daniel Fountaine from the Medical Research Council (MRC) Protein Production and Assay Development team, and MRC Reagents and Services, who all contributed to the generation of protein reagents required for the MALDI-TOF DUB assay platform. We thank Ronald Hay for provision of the plasmid encoding the constitutively active RNF4 E3 ligase. This work was funded by the United Kingdom MRC (MC_UU_12016/8), the Biotechnology and Biological Sciences Research Council (BB/P003982/1), and The Michael J. Fox Foundation (12756). We also acknowledge pharmaceutical companies supporting the Division of Signal Transduction Therapy (Boehringer-Ingelheim, GlaxoSmithKline, and Merck KGaA).Peer reviewe

Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity.

MYCBP2 is a ubiquitin (Ub) E3 ligase (E3) that is essential for neurodevelopment and regulates axon maintenance. MYCBP2 transfers Ub to nonlysine substrates via a newly discovered RING-Cys-Relay (RCR) mechanism, where Ub is relayed from an upstream cysteine to a downstream substrate esterification site. The molecular bases for E2-E3 Ub transfer and Ub relay are unknown. Whether these activities are linked to the neural phenotypes is also unclear. We describe the crystal structure of a covalently trapped E2~Ub:MYCBP2 transfer intermediate revealing key structural rearrangements upon E2-E3 Ub transfer and Ub relay. Our data suggest that transfer to the dynamic upstream cysteine, whilst mitigating lysine activity, requires a closed-like E2~Ub conjugate with tempered reactivity, and Ub relay is facilitated by a helix-coil transition. Furthermore, neurodevelopmental defects and delayed injury-induced degeneration in RCR-defective knock-in mice suggest its requirement, and that of substrate esterification activity, for normal neural development and programmed axon degeneration

The neuropathogenesis of feline immunodeficiency virus infection: Barriers to overcome

Feline immunodeficiency virus (FIV), like human immunodeficiency virus (HIV)-1, is a neurotropic lentivirus, and both natural and experimental infections are associated with neuropathology. FIV enters the brain early following experimental infection, most likely via the blood-brain and blood-cerebrospinal fluid barriers. The exact mechanism of entry, and the factors that influence this entry, are not fully understood. As FIV is a recognised model of HIV-1 infection, understanding such mechanisms is important, particularly as HIV enters the brain early in infection. Furthermore, the development of strategies to combat this central nervous system (CNS) infection requires an understanding of the interactions between the virus and the CNS. In this review the results of both in vitro and in vivo FIV studies are assessed in an attempt to elucidate the mechanisms of viral entry into the brain

Key Principles in Providing Meaningful Experience in Youth Sport

Involvement and persisting in sport are often to with many different factors. When it comes to youth sport, significant participant dropout (Balish et al., 2014; Crane & Temple, 2015), lack of personal meaning and relevance (Bergeron et al., 2015; Knight et al., 2018) are noted. One of the ways to help children to stay in sport and practice it as a value part that enriches everyday life and supports their personal development, is providing them experiences that are meaningful and personally significant. Focusing on meaningfulness, it’s important to support coaches working in youth sport, to identify experiences that are meaningful for the children and provide possibilities for greater quality of everyone`s personal experience. In this regard, within the frames of the Erasmus project: Meaningfulness in Youth Sport (MiYS), a set of five principles were identified and suggested to coaches as relevant for providing meaningful experiences in youth sport. The principles are identified as Building an authentic relationship; Developing a culture of belonging; Positive coaching: A balanced approach to competition and being a reflective coach. All five principles are presented in the Coach resource titled “Getting Started with Meaningfulness in Youth Sport (MiYS)”. The presented principles were tested and implemented by youth coaches working in several different sports (parkour, Gaelic football, floorball, volleyball). Coach’s experiences were valuable for determining the final content of the resource and their examples are implemented within the resource. Principles are designed to be used by all coaches who want to improve their practice, regardless of their level of experience

Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci.

Multiple regulatory elements distant from their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we develop a capture Hi-C (cHi-C) approach to allow an agnostic characterization of these physical interactions on a genome-wide scale. Single-nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci allows us to identify key long-range chromatin interactions in cis and trans involving these loci