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1.
ACS Infect Dis ; 7(8): 2546-2564, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1309427

ABSTRACT

The receptor binding domain (RBD) of SARS-CoV-2 is the primary target of neutralizing antibodies. We designed a trimeric, highly thermotolerant glycan engineered RBD by fusion to a heterologous, poorly immunogenic disulfide linked trimerization domain derived from cartilage matrix protein. The protein expressed at a yield of ∼80-100 mg/L in transiently transfected Expi293 cells, as well as CHO and HEK293 stable cell lines and formed homogeneous disulfide-linked trimers. When lyophilized, these possessed remarkable functional stability to transient thermal stress of up to 100 °C and were stable to long-term storage of over 4 weeks at 37 °C unlike an alternative RBD-trimer with a different trimerization domain. Two intramuscular immunizations with a human-compatible SWE adjuvanted formulation elicited antibodies with pseudoviral neutralizing titers in guinea pigs and mice that were 25-250 fold higher than corresponding values in human convalescent sera. Against the beta (B.1.351) variant of concern (VOC), pseudoviral neutralization titers for RBD trimer were ∼3-fold lower than against wildtype B.1 virus. RBD was also displayed on a designed ferritin-like Msdps2 nanoparticle. This showed decreased yield and immunogenicity relative to trimeric RBD. Replicative virus neutralization assays using mouse sera demonstrated that antibodies induced by the trimers neutralized all four VOC to date, namely B.1.1.7, B.1.351, P.1, and B.1.617.2 without significant differences. Trimeric RBD immunized hamsters were protected from viral challenge. The excellent immunogenicity, thermotolerance, and high yield of these immunogens suggest that they are a promising modality to combat COVID-19, including all SARS-CoV-2 VOC to date.


Subject(s)
COVID-19 , Thermotolerance , Animals , Antibodies, Viral , COVID-19/therapy , Guinea Pigs , HEK293 Cells , Humans , Immunization, Passive , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
2.
Cell ; 184(6): 1530-1544, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1118348

ABSTRACT

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.


Subject(s)
COVID-19/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/therapy , Obesity/epidemiology , Obesity/therapy , Pandemics , Precision Medicine/methods , SARS-CoV-2 , COVID-19/virology , Circadian Rhythm , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Epigenesis, Genetic , Genetic Predisposition to Disease , Humans , Inflammation/immunology , Inflammation/metabolism , Obesity/genetics , Obesity/metabolism , Prevalence , Risk Factors , Thermotolerance
3.
J Therm Biol ; 93: 102705, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-739933

ABSTRACT

Heat adaption through acclimatisation or acclimation improves cardiovascular stability by maintaining cardiac output due to compensatory increases in stroke volume. The main aim of this study was to assess whether 2D transthoracic echocardiography (TTE) could be used to confirm differences in resting echocardiographic parameters, before and after active heat acclimation (HA). Thirteen male endurance trained cyclists underwent a resting blinded TTE before and after randomisation to either 5 consecutive daily exertional heat exposures of controlled hyperthermia at 32°C with 70% relative humidity (RH) (HOT) or 5-days of exercise in temperate (21°C with 36% RH) environmental conditions (TEMP). Measures of HA included heart rate, gastrointestinal temperature, skin temperature, sweat loss, total non-urinary fluid loss (TNUFL), plasma volume and participant's ratings of perceived exertion (RPE). Following HA, the HOT group demonstrated increased sweat loss (p = 0.01) and TNUFL (p = 0.01) in comparison to the TEMP group with a significantly decreased RPE (p = 0.01). On TTE, post exposure, there was a significant comparative increase in the HOT group in left ventricular end diastolic volume (p = 0.029), SV (p = 0.009), left atrial volume (p = 0.005), inferior vena cava diameter (p = 0.041), and a significant difference in mean peak diastolic mitral annular velocity (e') (p = 0.044). Cardiovascular adaptations to HA appear to be predominantly mediated by improvements in increased preload and ventricular compliance. TTE is a useful tool to demonstrate and quantify cardiac HA.


Subject(s)
Exercise , Heart/physiology , Sweating , Thermotolerance , Adult , Echocardiography , Heart/diagnostic imaging , Heart Rate , Humans , Male , Plasma Volume , Random Allocation , Vasodilation
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