Early protective effect of a (“pan”) coronavirus vaccine (PanCoVac) in Roborovski dwarf hamsters after single-low dose intranasal administration

Introduction: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the danger posed by human coronaviruses. Rapid emergence of immunoevasive variants and waning antiviral immunity decrease the effect of the currently available vaccines, which aim at induction of neutralizing antibodies. In contrast, T cells are marginally affected by antigen evolution although they represent the major mediators of virus control and vaccine protection against virus-induced disease. Materials and methods: We generated a multi-epitope vaccine (PanCoVac) that encodes the conserved T cell epitopes from all structural proteins of coronaviruses. PanCoVac contains elements that facilitate efficient processing and presentation of PanCoVac-encoded T cell epitopes and can be uploaded to any available vaccine platform. For proof of principle, we cloned PanCoVac into a non-integrating lentivirus vector (NILV-PanCoVac). We chose Roborovski dwarf hamsters for a first step in evaluating PanCoVac in vivo. Unlike mice, they are naturally susceptible to SARS-CoV-2 infection. Moreover, Roborovski dwarf hamsters develop COVID-19-like disease after infection with SARS-CoV-2 enabling us to look at pathology and clinical symptoms. Results: Using HLA-A*0201-restricted reporter T cells and U251 cells expressing a tagged version of PanCoVac, we confirmed in vitro that PanCoVac is processed and presented by HLA-A*0201. As mucosal immunity in the respiratory tract is crucial for protection against respiratory viruses such as SARS-CoV-2, we tested the protective effect of single-low dose of NILV-PanCoVac administered via the intranasal (i.n.) route in the Roborovski dwarf hamster model of COVID-19. After infection with ancestral SARS-CoV-2, animals immunized with a single-low dose of NILV-PanCoVac i.n. did not show symptoms and had significantly decreased viral loads in the lung tissue. This protective effect was observed in the early phase (2 days post infection) after challenge and was not dependent on neutralizing antibodies. Conclusion: PanCoVac, a multi-epitope vaccine covering conserved T cell epitopes from all structural proteins of coronaviruses, might protect from severe disease caused by SARS-CoV-2 variants and future pathogenic coronaviruses. The use of (HLA-) humanized animal models will allow for further efficacy studies of PanCoVac-based vaccines in vivo

Fast and efficient demultiplexing of single photons from a quantum dot with resonantly enhanced electro-optic modulators

We report on a multi-photon source based on active demultiplexing of single photons emitted from a resonantly excited GaAs quantum dot. Active temporal-to-spatial mode demultipexing is implemented via resonantly enhanced free-space electro-optic modulators, making it possible to route individual photons at high switching rates of 38 MHz. We demonstrate routing into four spatial modes with a high end-to-end efficiency of 79% and measure a four-photon coincidence rate of 0.17 Hz mostly limited by the single-photon source brightness and not by the efficiency of the demultiplexer itself. We use the demultiplexer to characterize the pairwise indistinguishability of consecutively emitted photons from the quantum dot with variable delay time.Comment: The supplementary material is included as ancillary fil

Early protective effect of a ("pan") coronavirus vaccine (PanCoVac) in Roborovski dwarf hamsters after single-low dose intranasal administration

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the danger posed by human coronaviruses. Rapid emergence of immunoevasive variants and waning antiviral immunity decrease the effect of the currently available vaccines, which aim at induction of neutralizing antibodies. In contrast, T cells are marginally affected by antigen evolution although they represent the major mediators of virus control and vaccine protection against virus-induced disease.MATERIALS AND METHODS: We generated a multi-epitope vaccine (PanCoVac) that encodes the conserved T cell epitopes from all structural proteins of coronaviruses. PanCoVac contains elements that facilitate efficient processing and presentation of PanCoVac-encoded T cell epitopes and can be uploaded to any available vaccine platform. For proof of principle, we cloned PanCoVac into a non-integrating lentivirus vector (NILV-PanCoVac). We chose Roborovski dwarf hamsters for a first step in evaluating PanCoVac in vivo. Unlike mice, they are naturally susceptible to SARS-CoV-2 infection. Moreover, Roborovski dwarf hamsters develop COVID-19-like disease after infection with SARS-CoV-2 enabling us to look at pathology and clinical symptoms.RESULTS: Using HLA-A*0201-restricted reporter T cells and U251 cells expressing a tagged version of PanCoVac, we confirmed in vitro that PanCoVac is processed and presented by HLA-A*0201. As mucosal immunity in the respiratory tract is crucial for protection against respiratory viruses such as SARS-CoV-2, we tested the protective effect of single-low dose of NILV-PanCoVac administered via the intranasal (i.n.) route in the Roborovski dwarf hamster model of COVID-19. After infection with ancestral SARS-CoV-2, animals immunized with a single-low dose of NILV-PanCoVac i.n. did not show symptoms and had significantly decreased viral loads in the lung tissue. This protective effect was observed in the early phase (2 days post infection) after challenge and was not dependent on neutralizing antibodies.CONCLUSION: PanCoVac, a multi-epitope vaccine covering conserved T cell epitopes from all structural proteins of coronaviruses, might protect from severe disease caused by SARS-CoV-2 variants and future pathogenic coronaviruses. The use of (HLA-) humanized animal models will allow for further efficacy studies of PanCoVac-based vaccines in vivo.</p

Lack of Structural Brain Alterations associated with Insomnia: Findings from the ENIGMA-Sleep working group

Existing neuroimaging studies have reported divergent structural alterations in insomnia. Here, we performed a large-scale coordinated meta-analysis by pooling structural brain measures from 1,085 subjects with and without insomnia symptoms across three international ENIGMA-Sleep cohorts. The influence of insomnia on MRI-based brain morphometry using an insomnia brain score was assessed. We collected case-control data from two sites, as well as population-based data from another site. Within each cohort, we used an ordinary least-squares linear regression to investigate the link between the individual regional cortical thickness and subcortical volumes and the presence of insomnia symptoms. Then, we performed a fixed-effects meta-analysis across cohorts based on the first-level results. For the insomnia brain score, weighted logistic ridge regression was performed on one sample, which separated patients with insomnia disorder from controls to train a model based on the segmentation measurements. Afterward, the insomnia brain scores were validated using the other two samples. The model was used to predict the log-odds of the subjects with insomnia given individual insomnia-related brain atrophy. After adjusting for multiple comparisons, we did not detect any significant associations between insomnia symptoms and cortical or subcortical volumes, nor could we identify a global insomnia-related brain atrophy pattern. The current study found inconsistent brain morphology differences between individuals with and without insomnia across three independent cohorts. Further large-scale cross-sectional and longitudinal studies using both structural and functional neuroimaging data are warranted to decipher the pathophysiology of insomnia at the brain level

The migratory behaviour of North Sea plaice: currents, clocks and clues

Water currents are a dominant feature of the open sea and often play an important part in the life cycle of the fish that live there. For over three decades, a focus of research at Lowestoft has been the role of tidal water currents as a part of wider understanding of the population dynamics of plaice (Pleuronectes platessa) in the North Sea. Increasingly sophisticated telemetry methods have been developed and used, initially to describe the migratory behaviour of individual fish, and latterly to describe the spatial dynamics of whole populations. Here, the authors review cues and clues for environmental transport at different life stages, with a critical evaluation of the facultative use of selective tidal stream transport in relation to water current speed. The clues that trigger movement into mid-water by adult fish are reconsidered in light of new findings. Finally, the orientation capabilities of plaice, together with evidence of repeat migrations and spawning site fidelity were examined

Associations between sleep health and grey matter volume in the UK Biobank cohort ( N = 33,356)

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes.Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33,356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication, and sleep apnoea were examined.Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes).To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalised in the UK Biobank do not translate into grey matter volume findings

Associations between sleep health and grey matter volume in the UK Biobank cohort (n=33 356)

Investigating associations between sleep health and grey matter volume in over 33 000 individuals, Schiel et al. report that insomnia symptoms do not translate directly into brain morphometry. Long sleep duration was associated with larger grey matter volume of basal ganglia substructures, possibly indicating early stage sleep apnoea in old age.As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.Peer reviewe