Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection

TANK-binding kinase 1 (TBK1) is a key signalling component in the pro-duction of type-I interferons, which have essential antiviral activities,including against SARS-CoV-2. TBK1, and its homologue IκB kinase-ε (IKKε), can also induce pro-inflammatory responses that contribute to pathogen clearance. While initially protective, sustained engagement of type-I interferons is associated with damaging hyper-inflammation found in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKε signalling through destabilisation of TBK1/IKKε protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper inflammation

Influence of Lifestyle Redesign® on health, social participation, leisure and mobility of older French-Canadians

Importance: Developed in California to enable community-dwelling older adults to maintain healthy and meaningful activities, Lifestyle Redesign® is a well-known cost-effective preventive occupational therapy intervention. The impact of a newly adapted French version on older French-Canadians was, however, unknown. Objective: To explore the influence of Lifestyle Redesign on older French-Canadians’ health, social participation, leisure, and mobility. Design: A mixed-methods design included a preexperimental component (questionnaires administered before and after the intervention and 3 and 6 mo postintervention) and an exploratory descriptive qualitative clinical study. Individual semidirected interviews were digitally audiotaped and transcribed, then underwent thematic content analysis using mix extraction grids. Setting: Community. Participants: Sixteen volunteers (10 women) aged 65–90 yr (mean = 76.4, standard deviation = 7.6), 10 without and 6 with disabilities. Inclusion criteria were age ≥65 yr, normal cognitive functions, residence in a conventional or senior home, and French speaking. Intervention: French-Canadian 6-mo version of Lifestyle Redesign. Outcomes and Measures: Health, social participation, leisure, and mobility were measured using the 36-item Short Form Health Survey, Social Participation Scale, Leisure Profile, and Life-Space Assessment, as well as a semistructured interview guide. Results: The French-Canadian Lifestyle Redesign had a beneficial effect on participants’ mental health (p = .02) and interest in leisure (p = .02) and, in those with disabilities, social participation (p = .03) and attitudes toward leisure (p = .04). Participants reported positive effects on their mental health, leisure, mobility, and social participation, including frequency and quality of social interactions, and indicated that having an occupational routine fostered better health. None of the participants reported no effect. Conclusion and Relevance: The translated and culturally adapted Lifestyle Redesign is a promising occupational therapy intervention for community-dwelling older French-Canadians

A falls prevention programme to improve quality of life, physical function and falls efficacy in older people receiving home help services: study protocol for a randomised controlled trial

BACKGROUND: Falls and fall-related injuries in older adults are associated with great burdens, both for the individuals, the health care system and the society. Previous research has shown evidence for the efficiency of exercise as falls prevention. An understudied group are older adults receiving home help services, and the effect of a falls prevention programme on health-related quality of life is unclear. The primary aim of this randomised controlled trial is to examine the effect of a falls prevention programme on quality of life, physical function and falls efficacy in older adults receiving home help services. A secondary aim is to explore the mediating factors between falls prevention and health-related quality of life. METHODS: The study is a single-blinded randomised controlled trial. Participants are older adults, aged 67 or older, receiving home help services, who are able to walk with or without walking aids, who have experienced at least one fall during the last 12 months and who have a Mini Mental State Examination of 23 or above. The intervention group receives a programme, based on the Otago Exercise Programme, lasting 12 weeks including home visits and motivational telephone calls. The control group receives usual care. The primary outcome is health-related quality of life (SF-36). Secondary outcomes are leg strength, balance, walking speed, walking habits, activities of daily living, nutritional status and falls efficacy. All measurements are performed at baseline, following intervention at 3 months and at 6 months' follow-up. Sample size, based on the primary outcome, is set to 150 participants randomised into the two arms, including an estimated 15-20% drop out. Participants are recruited from six municipalities in Norway. DISCUSSION: This trial will generate new knowledge on the effects of an exercise falls prevention programme among older fallers receiving home help services. This knowledge will be useful for clinicians, for health managers in the primary health care service and for policy makers

Constraints on the Onset of Color Transparency from Quasielastic ¹²C(e, e′p) up to Q² = (14.2 GeV /c)²

Quasielastic scattering on 12C(e,e′p) was measured in Hall C at Jefferson Lab for spacelike four-momentum transfer squared Q2 in the range of 8–14.2(GeV/c)2 with proton momenta up to 8.3GeV/c. The experiment was carried out in the upgraded Hall C at Jefferson Lab. It used the existing high-momentum spectrometer and the new super-high-momentum spectrometer to detect the scattered electrons and protons in coincidence. The nuclear transparency was extracted as the ratio of the measured yield to the yield calculated in the plane wave impulse approximation. Additionally, the transparency of the 1s1/2 and 1p3/2 shell protons in 12C was extracted, and the asymmetry of the missing momentum distribution was examined for hints of the quantum chromodynamics prediction of color transparency. All of these results were found to be consistent with traditional nuclear physics and inconsistent with the onset of color transparency

HERON: Demonstrating a Novel Biological Platform for Small Satellite Missions

Long-duration deep space missions pose a significant health risk for both humans and their resident microorganisms. The GeneSat, PharmaSat and O/OREOS missions have previously explored biological questions regarding the effects of spaceflight on S. cerevisiase, B. subtilis, and E. coli. However, there currently exists both a knowledge and an accessibility gap in small satellite biological experiments. These payloads require precise instrumentation and complex platforms that are usually reserved for large research organizations. This makes it difficult for smaller organizations to perform biological research in low Earth orbit (LEO). To address these challenges, the University of Toronto Aerospace Team (UTAT) Space Systems Division is currently developing the HERON CubeSat. HERON houses a payload platform which measures the effects of the LEO environment on the gene expression and drug resistance of Candida albicans, a yeast commonly found in the human gut microbiome. Previous research has suggested that C. albicans might display increased pathogenicity and drug resistance in response to microgravity, which has important implications for long-duration human spaceflight. The yeast cells are housed in custom acrylic microfluidics chips containing 32 wells with channels for media and drug delivery. A measurement printed circuit board (PCB) contains custom optics capable of measuring minute changes in cell fluorescence. The entire payload stack is then housed in a temperature- and humidity-controlled 2U pressure vessel. Space Systems as a whole is an undergraduate student-led and student-funded design team, dedicated to the development of small satellite missions with a focus on education and undergraduate learning. HERON is scheduled to launch Q1 2022 into a Sun-synchronous orbit via a SpaceX Falcon 9 rocket at an altitude of approximately 550 km. Our platform is open-source and can serve as a low-cost template for future biological CubeSat missions. This paper serves as a technical and scientific description of the platform, along with the lessons learned during the payload design, assembly, and validation processes

Factors Associated with herb and dietary supplement use by young adults in the United States

<p>Abstract</p> <p>Background</p> <p>Little is known about the association between use of herbs and dietary supplements (HDS) and lifestyle/behavior factors in young adults in the US.</p> <p>Methods</p> <p>Analyzing the 2002 National Health Interview Survey (NHIS), we examined the patterns of HDS (excluding vitamins/minerals) use among young adults in the United States using descriptive statistics and logistic regression.</p> <p>Results</p> <p>In our sample of 18 to 30 year olds (n = 6666), 26% were current smokers, 24% were moderate/heavy drinkers, 43% had high physical activity, and 54% and 76% use prescription and over the counter (OTC) medications respectively. Non-vitamin, non-mineral HDS was used by 17% of the overall sample in the last 12 months. In the multivariable analysis, the lifestyle and behavioral factors associated with HDS use include: current smoking (odds ratio 1.41 95% CI [1.16–1.72]); being a former smoker (1.50 [1.15–1.95]); moderate/heavy alcohol use (2.02 [1.53–2.65]); high physical activity levels (2.45 [1.98–3.03]); and prescription medication use (1.51 [1.26–1.81]). Among HDS users, only 24% discussed their use with a health care professional.</p> <p>Conclusion</p> <p>Nearly one in five young adults report using non-vitamin/non-mineral HDS.</p

Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection

TANK-binding kinase 1 (TBK1) is a key signalling component in the production of type-I interferons, which have essential antiviral activities, including against SARS-CoV-2. TBK1, and its homologue IκB kinase-ε (IKKε), can also induce pro-inflammatory responses that contribute to pathogen clearance. While initially protective, sustained engagement of type-I interferons is associated with damaging hyper-inflammation found in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKε signalling through destabilisation of TBK1/IKKε protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation.Tomalika R. Ullah ... Benjamin T. Kile ... et al

Tenth Scientific Biennial Meeting of the Australasian Virology Society-AVS10 2019

The Australasian Virology Society (AVS) aims to promote, support and advocate for the discipline of virology in the Australasian region. The society was incorporated in 2011 after 10 years operating as the Australian Virology Group (AVG) founded in 2001, coinciding with the inaugural biennial scientific meeting. AVS conferences aim to provide a forum for the dissemination of all aspects of virology, foster collaboration, and encourage participation by students and post-doctoral researchers. The tenth Australasian Virology Society (AVS10) scientific meeting was held on 2–5 December 2019 in Queenstown, New Zealand. This report highlights the latest research presented at the meeting, which included cutting-edge virology presented by our international plenary speakers Ana Fernandez-Sesma and Benjamin tenOever, and keynote Richard Kuhn. AVS10 honoured female pioneers in Australian virology, Lorena Brown and Barbara Coulson. We report outcomes from the AVS10 career development session on “Successfully transitioning from post-doc to lab head”, winners of best presentation awards, and the AVS gender equity policy, initiated in 2013. Plans for the 2021 meeting are underway which will celebrate the 20th anniversary of AVS where it all began, in Fraser Island, Queensland, Australia.Karla J. Helbig ... Michael R. Beard ... et al

High Cooperativity of the SV40 Major Capsid Protein VP1 in Virus Assembly

SV40 is a small, non enveloped DNA virus with an icosahedral capsid of 45 nm. The outer shell is composed of pentamers of the major capsid protein, VP1, linked via their flexible carboxy-terminal arms. Its morphogenesis occurs by assembly of capsomers around the viral minichromosome. However the steps leading to the formation of mature virus are poorly understood. Intermediates of the assembly reaction could not be isolated from cells infected with wt SV40. Here we have used recombinant VP1 produced in insect cells for in vitro assembly studies around supercoiled heterologous plasmid DNA carrying a reporter gene. This strategy yields infective nanoparticles, affording a simple quantitative transduction assay. We show that VP1 assembles under physiological conditions into uniform nanoparticles of the same shape, size and CsCl density as the wild type virus. The stoichiometry is one DNA molecule per capsid. VP1 deleted in the C-arm, which is unable to assemble but can bind DNA, was inactive indicating genuine assembly rather than non-specific DNA-binding. The reaction requires host enzymatic activities, consistent with the participation of chaperones, as recently shown. Our results demonstrate dramatic cooperativity of VP1, with a Hill coefficient of ∼6. These findings suggest that assembly may be a concerted reaction. We propose that concerted assembly is facilitated by simultaneous binding of multiple capsomers to a single DNA molecule, as we have recently reported, thus increasing their local concentration. Emerging principles of SV40 assembly may help understanding assembly of other complex systems. In addition, the SV40-based nanoparticles described here are potential gene therapy vectors that combine efficient gene delivery with safety and flexibility

Transcription and Translation Products of the Cytolysin Gene psm-mec on the Mobile Genetic Element SCCmec Regulate Staphylococcus aureus Virulence

The F region downstream of the mecI gene in the SCCmec element in hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) contains two bidirectionally overlapping open reading frames (ORFs), the fudoh ORF and the psm-mec ORF. The psm-mec ORF encodes a cytolysin, phenol-soluble modulin (PSM)-mec. Transformation of the F region into the Newman strain, which is a methicillin-sensitive S. aureus (MSSA) strain, or into the MW2 (USA400) and FRP3757 (USA300) strains, which are community-acquired MRSA (CA-MRSA) strains that lack the F region, attenuated their virulence in a mouse systemic infection model. Introducing the F region to these strains suppressed colony-spreading activity and PSMα production, and promoted biofilm formation. By producing mutations into the psm-mec ORF, we revealed that (i) both the transcription and translation products of the psm-mec ORF suppressed colony-spreading activity and promoted biofilm formation; and (ii) the transcription product of the psm-mec ORF, but not its translation product, decreased PSMα production. These findings suggest that both the psm-mec transcript, acting as a regulatory RNA, and the PSM-mec protein encoded by the gene on the mobile genetic element SCCmec regulate the virulence of Staphylococcus aureus