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Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) following high-intensity interval exercise (HIIE) were examined in young healthy men (n  = 8; age, 21.9±2.2 yrs; VO2peak, 53.1±6.4 ml/min/kg; peak work rate, 317±23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (∼730 kJ) while average power output (73%, 237±21; 100%, 323±26; 133%, 384±35 watts) and EMG derived muscle activation (73%, 1262±605; 100%, 2089±737; 133%, 3029±1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1α mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (∼9 fold, p<0.05) compared to both the 73 and 133% conditions (∼4 fold). When expressed relative to muscle activation, the increase in PGC-1α mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (∼1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1α mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1α mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1α may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (T FH ) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that T FH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of T FH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that T FH cells support stromal cell responses to vaccines. Linterman and colleagues examine germinal center formation in older individuals. They find that aged T FH cells have dysregulated CXCR4 expression, which causes spatial mislocalization of these cells in germinal centers, impairing their ability to provide help to B cells and to promote antibody production.

Purpose The present study examined the effect of reducing sprint interval training (SIT) work-interval duration on increases in maximal and submaximal performance. Methods Subjects ( n  = 36) were assigned to one of three training groups: endurance training (ET; 60 min per session for weeks 1–2, increasing to 75 min per session for weeks 3–4), or sprint interval training consisting of either repeated 30 (SIT 30) or 15 (SIT 15) second all-out intervals (starting with 4 bouts per session for weeks 1–2, increasing to 6 intervals per session for weeks 3–4). Training consisted of cycling 3 times per week for 4 weeks. Results While there was a significant main effect of training on V ˙ O 2peak such that V ˙ O 2peak was elevated post-training, no significant difference was observed in the improvements observed between groups (ET ~13 %, SIT 30–4 %, SIT 15–8 %). A significant main effect of training was observed such that lactate threshold and critical power were higher during post-testing across all groups ( p  < 0.05). There was a main effect of training ( p  < 0.05) on Wingate peak power with no differences observed between groups at post-training. Conclusions Together, these results indicate that reducing SIT work-interval duration from 30 to 15 s had no impact on training-induced increases in aerobic or anaerobic power, or on increases in lactate threshold (absolute) and critical power.

Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1[alpha]) following high-intensity interval exercise (HIIE) were examined in young healthy men (n = 8; age, 21.9±2.2 yrs; VO.sub.2 peak, 53.1±6.4 ml/min/kg; peak work rate, 317±23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (~730 kJ) while average power output (73%, 237±21; 100%, 323±26; 133%, 384±35 watts) and EMG derived muscle activation (73%, 1262±605; 100%, 2089±737; 133%, 3029±1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1[alpha] mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (~9 fold, p<0.05) compared to both the 73 and 133% conditions (~4 fold). When expressed relative to muscle activation, the increase in PGC-1[alpha] mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (~1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1[alpha] mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1[alpha] mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1[alpha] may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m 2 ) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m 2 ). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI ( P  = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies. Epidemiological analyses coupled with immunological phenotyping suggest that humoral immunity induced by COVID-19 vaccines wanes more rapidly in individuals with severe obesity compared to individuals with a BMI within the normal range.

Immunization strategies are central to pathogen control, where efficacy relies on antigen uptake, distribution, persistence, and inflammatory context. We recently demonstrated that dermal lymphatic capillaries regulate antigen presentation in lymph nodes (LN) by restraining fluid and virion transport following vaccinia virus (VACV) infection by skin scarification. Concurrently, a perifollicular, LN lymphangiogenic response encapsulates expanding B cell follicles. Given the important role of antigen transport and uptake on humoral immunity, we tested the hypothesis that lymphatic remodeling in the skin and LNs regulates germinal center (GC)-dependent antibody responses during infection. Using a model of lymphatic-specific VEGFR2 inhibition, we found that inhibiting viral-induced lymphatic remodeling in skin and LNs prompted significant GC expansion but paradoxically decreases protective VACV-specific class-switched antibodies. While the larger GC responses appeared structurally normal, they failed to support a proliferative burst consistent with clonal selection. Mathematical modeling revealed that this disconnect between GC size and function arises from impaired productive T follicular cell interactions in larger GC volumes and consistent with this finding, the optimal GC size was evolutionarily conserved across diverse mammals. Finally, we found that the presence of virus in the LN initiates these changes in GC function, inhibits LN lymphangiogenesis, increases B cell follicle size, and reduces selection efficiency. Therefore, protecting LN lymphatic vessels from virus-induced interferons rescues perifollicular lymphatic growth and follicle size, indicating that LN lymphangiogenesis directly constrains the follicular response. In summary, this study underscores the central role of lymphatic remodeling in compartmentalizing antigen and inflammatory signals to optimize GC fitness and protective antibody responses.

T follicular helper cells (TFH) are a CD4 T cell subset required for effective humoral immunity; promoting antibody responses to vaccines and natural infections. The mechanisms by which human TFH differentiate are not fully understood, and given the anatomical localization to the secondary lymphoid tissues, and asynchronous nature of in vivo TFH populations, studying TFH differentiation in vitro represents an attractive alternative, through which the mechanisms which govern TFH differentiation can be explored. Here we demonstrate reliable differentiation of in vitro TFH from naive human CD4 T cells in a STAT3 dependent fashion. Cooperation between STAT3 and SMAD signaling cytokines led to expression of the lineage defining transcriptional regulator BCL6, multiple downstream proteins required for TFH function and localization (including PD1 and CXCR5), and potent IL-21 production capacity by these in vitro TFH. Critically we found that autocrine production of IL-2 acted as an intrinsic brake on TFH differentiation in vitro; promoting proliferation but limiting the acquisition of a TFH phenotype resembling that found in germinal centers in vivo; neutralization of IL-2 resulting in the emergence of this phenotype. Overall, we show that human TFH expansion, differentiation and function relies on careful regulation of pro- and anti-TFH cytokine signaling.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE191251

Obesity is associated with an increased risk of severe Covid-19. However, the effectiveness of SARS-CoV-2 vaccines in people with obesity is unknown. Here we studied the relationship between body mass index (BMI), hospitalization and mortality due to Covid-19 amongst 3.5 million people in Scotland. Vaccinated people with severe obesity (BMI>40 kg/m2) were significantly more likely to experience hospitalization or death from Covid-19. Excess risk increased with time since vaccination. To investigate the underlying mechanisms, we conducted a prospective longitudinal study of the immune response in a clinical cohort of vaccinated people with severe obesity. Compared with normal weight controls, six months after their second vaccine dose, significantly more people with severe obesity had unquantifiable titres of neutralizing antibody against authentic SARS-CoV-2 virus, reduced frequencies of antigen-experienced SARS-CoV-2 Spike-binding B cells, and a dissociation between anti-Spike antibody levels and neutralizing capacity. Neutralizing capacity was restored by a third dose of vaccine, but again declined more rapidly in people with severe obesity. We demonstrate that waning of SARS-CoV-2 vaccine-induced humoral immunity is accelerated in people with severe obesity and associated with increased hospitalization and mortality from breakthrough infections. Given the prevalence of obesity, our findings have significant implications for global public health. Competing Interest Statement AS is a member of the Scottish Governments Standing Committee on Pandemic Preparedness and the Risk Stratification Subgroup of the UK Governments New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG). He was a member of AstraZenecas Thrombotic Thrombocytopenic Task Force. All roles are unremunerated. SJD is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. All other authors have no conflict of interest to declare. Funding Statement The epidemiological study is part of the EAVE II project. EAVE II is funded by the MRC with the support of BREATHE The Health Data Research Hub for Respiratory Health which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through the Health Data Research UK. This research is part of the Data and Connectivity National Core Study led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation and the National Core Studies Immunity. Additional support has been provided through Public Health Scotland the Scottish Government Director-General Health and Social Care and the University of Edinburgh. The original EAVE project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme. The SCORPIO study was supported by the Medical Research Council (MR/W020564/1, a core award to J.E.T.; MC_UU_0025/12 and MR/T032413/1, an award to N.J.M.) and the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798). Additional support was provided by NHSBT (WPA15-02 to N.J.M.), Addenbrookes Charitable Trust (900239 to N.J.M.) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (N.J.M. and I.S.F.) and NIHR BioResource. M.A.L is supported by the Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0427, BBS/E/B/000C0428) and is a Lister Institute Fellow and an EMBO Young Investigator. I.M.H. is supported by a CIMR PhD studentship; H.J.S. by a Sir Henry Dale Fellowship jointly funded by Wellcome and the Royal Society [109407] and a BBSRC institutional programme grant [BBS/E/B/000C0433]. I.S.F. is supported by Wellcome (207462/Z/17/Z), Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and a NIHR Senior Investigator Award. The PITCH study was funded by the UK Department of Health and Social Care. S.J.D. is funded by an NIHR Global Research Professorship (NIHR300791). P.K. is an NIHR Senior Investigator and is funded by Wellcome (WT109965MA). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was granted by the National Research Ethics Service Committee, Southeast Scotland 02 (reference number: 12/SS/0201) for the study using the Early Pandemic Evaluation and Enhanced Surveillance of Covid-19 (EAVE II) platform. Clinical studies in people with severe obesity and normal weight controls were approved by the National Research Ethics Committee and Health Research Authority (East of England, Cambridge Research Ethics Committee (SCORPIO study, SARS-CoV-2 vaccination response in obesity amendment of NIHR BioResource 17/EE/0025)). Additional normal weight controls were recruited in Oxford, UK as part of the PITCH study under the GI Biobank Study 16/YH/0247, approved by Yorkshire & Humber Sheffield Research Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors

Abstract The spread of SARS-CoV-2 has caused a global pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection, and may enable the relaxation of social distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection, therefore it is desirable that any new vaccine candidates should elicit a robust immune response in older adults. Here, we test the immunogenicity of the adenoviral vectored vaccine ChAdOx1 nCoV-19 (AZD-1222) in aged mice. We find that a single dose of this vaccine induces cellular and humoral immunity in aged mice, but at a reduced magnitude than in younger adult mice. Furthermore, we report that a second dose enhances the immune response to this vaccine in aged mice, indicating that a primeboost strategy may be a rational approach to enhance immunogenicity in older persons. Competing Interest Statement Sarah Gilbert and Teresa Lambe are named on a patent application covering ChAdOx1 nCoV-19. The remaining authors declare no competing interests. The funders played no role in the conceptualisation, design, data collection, analysis, decision to publish, or preparation of the manuscript. Footnotes * ↵* Joint first authors * ↵^ Joint authors * ↵§ Joint senior authors

Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha ) following high-intensity interval exercise (HIIE) were examined in young healthy men (n = 8; age, 21.9 plus or minus 2.2 yrs; VO2peak, 53.1 plus or minus 6.4 ml/min/kg; peak work rate, 317 plus or minus 23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (~730 kJ) while average power output (73%, 237 plus or minus 21; 100%, 323 plus or minus 26; 133%, 384 plus or minus 35 watts) and EMG derived muscle activation (73%, 1262 plus or minus 605; 100%, 2089 plus or minus 737; 133%, 3029 plus or minus 1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1 alpha mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (~9 fold, p<0.05) compared to both the 73 and 133% conditions (~4 fold). When expressed relative to muscle activation, the increase in PGC-1 alpha mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (~1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1 alpha mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1 alpha mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1 alpha may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).