Inherent work suit buoyancy distribution:effects on lifejacket self-righting performance

Introduction: Accidental immersion in cold water is an occupational risk. Work suits and life jackets (LJ) should work effectively in combination to keep the airway clear of the water (freeboard) and enable self-righting. We hypothesized that inherent buoyancy, in the suit or LJ, would be beneficial for enabling freeboard, but its distribution may influence LJ self-righting. Methods: Six participants consented to complete nine immersions. Suits and LJ tested were: flotation suit (FLOAT; 85 N inherent buoyancy); oilskins 1 (OS-1) and 2 (OS-2), both with no inherent buoyancy; LJs (inherent buoyancy/buoyancy after inflation/total buoyancy), LJ-1 50/150/200 N, LJ-2 0/290/290 N, LJ-3 80/190/270 N. Once dressed, the subject entered an immersion pool where uninflated freeboard, self-righting performance, and inflated freeboard were measured. Data were compared using Friedman’s test to the 0.05 alpha level. Results: All suits and LJs enabled uninflated and inflated freeboard, but differences were seen between the suits and LJs. Self-righting was achieved on 43 of 54 occasions, irrespective of suit or LJ. On all occasions that self-righting was not achieved, this occurred in an LJ that included inherent buoyancy (11/54 occasions). Of these 11 failures, 8 occurred (73% of occasions) when the FLOAT suit was being worn. Discussion: LJs that included inherent buoyancy, that are certified as effective on their own, worked less effectively from the perspective of self-righting in combination with a work suit that also included inherent buoyancy. Equipment that is approved for use in the workplace should be tested in combination to ensure adequate performance in an emergency scenario

EXTOD-Immune: a randomised controlled trial to investigate whether a remotely monitored, home-based exercise intervention can reduce disease activity in people with type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease in which the adaptive immune system targets insulin-producing β-cells of pancreatic islets, leading to dependence on exogenous insulin therapy. Cytotoxic (CD8+) T-cells specific for islet antigens are major players in T1D autoimmunity. Data indicate that regular exercise may preserve β-cell function in people recently diagnosed with T1D, but the role of islet-reactive CD8+ T-cells is unclear. In a randomised crossover design, this study will determine the impact of a 12-week exercise programme on the frequency and proliferative state of islet-reactive CD8+ T-cells in the peripheral blood of 20 adults diagnosed with T1D within the past 3 years. The exercise intervention will consist of three high-intensity interval training sessions per week (6–10 1 min intervals >80% maximum heart rate, with 1 min rest), the duration of which will incrementally increase from 14 to 22 min. Habitual physical activity and diet will be maintained during control and washout periods. At weeks 0, 12, 24 and 36, a fasting blood sample will be collected to quantify the frequency, phenotype and proliferative activity of islet-reactive CD8+ T-cells (primary outcome) and various clinical parameters. Glycaemic control will also be evaluated using 14-day continuous glucose monitoring at the start and end of each study arm. Findings may provide a rationale for conducting large-scale trials to evaluate the implementation of exercise into routine clinical care, particularly for people recently diagnosed with T1D when maintenance of β-cell function is critical to counteract disease progression. Trial registration number: ISRCTN79006041

T Cell Detection of a B-Cell Tropic Virus Infection: Newly-Synthesised versus Mature Viral Proteins as Antigen Sources for CD4 and CD8 Epitope Display

Viruses that naturally infect cells expressing both MHC I and MHC II molecules render themselves potentially visible to both CD8+ and CD4+ T cells through the de novo expression of viral antigens. Here we use one such pathogen, the B-lymphotropic Epstein-Barr virus (EBV), to examine the kinetics of these processes in the virally-infected cell, comparing newly synthesised polypeptides versus the mature protein pool as viral antigen sources for MHC I- and MHC II-restricted presentation. EBV-transformed B cell lines were established in which the expression of two cognate EBV antigens, EBNA1 and EBNA3B, could be induced and then completely suppressed by doxycycline-regulation. These cells were used as targets for CD8+ and CD4+ T cell clones to a range of EBNA1 and EBNA3B epitopes. For both antigens, when synthesis was induced, CD8 epitope display rose quickly to near maximum within 24 h, well before steady state levels of mature protein had been reached, whereas CD4 epitope presentation was delayed by 36–48 h and rose only slowly thereafter. When antigen expression was suppressed, despite the persistence of mature protein, CD8 epitope display fell rapidly at rates similar to that seen for the MHC I/epitope half-life in peptide pulse-chase experiments. By contrast, CD4 epitope display persisted for many days and, following peptide stripping, recovered well on cells in the absence of new antigen synthesis. We infer that, in virally-infected MHC I/II-positive cells, newly-synthesised polypeptides are the dominant source of antigen feeding the MHC I pathway, whereas the MHC II pathway is fed by the mature protein pool. Hence, newly-infected cells are rapidly visible only to the CD8 response; by contrast, latent infections, in which viral gene expression has been extinguished yet viral proteins persist, will remain visible to CD4+ T cells

The influence of depth and velocity on age‐0 Scaphirhynchus sturgeon prey consumption: Implications for aquatic habitat restoration

After the pallid sturgeon (Scaphirhynchus albus) was listed as endangered in 1990, a variety of management actions focusing on early life history needs have been implemented to aid species recovery. Given the scarcity of age‐0 pallid sturgeon, managers and scientists have relied on sympatric congeners to evaluate the effectiveness of management actions in the short term; however, increased understanding of habitat requirements for age‐0 Scaphirhynchus sturgeon is still needed to appropriately focus management efforts. Recently, a lack of food‐producing and foraging habitats were proposed as potential limiting factors for pallid sturgeon, and the purpose of this study was to evaluate the current definition of these habitats at multiple spatial scales using data from age‐0 Scaphirhynchus sturgeon (shovelnose sturgeon [Scaphirhynchus platyrhynchus] or hybrid [shovelnose sturgeon x pallid sturgeon]). Results showed the water depths and velocities that currently define age‐0 pallid sturgeon foraging habitat had little effect on age‐0 Scaphirhynchus sturgeon prey consumption. Similar results occurred when evaluating the relationship between prey consumption and food‐producing habitat present 10, 20, and 30 days before capture. Assuming that individuals captured during this study were a valid surrogate, these results suggest that increasing foraging and food‐producing habitat as defined by the current depth and velocity criteria is unlikely to result in the desired benefits of increased growth and survival of age‐0 pallid sturgeon

Smoking-gun signatures of little Higgs models

Little Higgs models predict new gauge bosons, fermions and scalars at the TeV scale that stabilize the Higgs mass against quadratically divergent one-loop radiative corrections. We categorize the many little Higgs models into two classes based on the structure of the extended electroweak gauge group and examine the experimental signatures that identify the little Higgs mechanism in addition to those that identify the particular little Higgs model. We find that by examining the properties of the new heavy fermion(s) at the LHC, one can distinguish the structure of the top quark mass generation mechanism and test the little Higgs mechanism in the top sector. Similarly, by studying the couplings of the new gauge bosons to the light Higgs boson and to the Standard Model fermions, one can confirm the little Higgs mechanism and determine the structure of the extended electroweak gauge group.Comment: 59 pages, 10 figures. v2: refs added, typos fixed, JHEP versio

Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4+ T cell immunity

CD4+ T cells recognize a broad range of peptide epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which contribute to immune memory and limit COVID-19 disease. We demonstrate that the immunogenicity of SARS-CoV-2 peptides, in the context of the model allotype HLA-DR1, does not correlate with their binding affinity to the HLA heterodimer. Analyzing six epitopes, some with very low binding affinity, we solve X-ray crystallographic structures of each bound to HLA-DR1. Further structural definitions reveal the precise molecular impact of viral variant mutations on epitope presentation. Omicron escaped ancestral SARS-CoV-2 immunity to two epitopes through two distinct mechanisms: (1) mutations to TCR-facing epitope positions and (2) a mechanism whereby a single amino acid substitution caused a register shift within the HLA binding groove, completely altering the peptide-HLA structure. This HLA-II-specific paradigm of immune escape highlights how CD4+ T cell memory is finely poised at the level of peptide-HLA-II presentation

Structural divergence creates new functional features in alphavirus genomes

Alphaviruses are mosquito-borne pathogens that cause human diseases ranging from debilitating arthritis to lethal encephalitis. Studies with Sindbis virus (SINV), which causes fever, rash, and arthralgia in humans, and Venezuelan equine encephalitis virus (VEEV), which causes encephalitis, have identified RNA structural elements that play key roles in replication and pathogenesis. However, a complete genomic structural profile has not been established for these viruses. We used the structural probing technique SHAPE-MaP to identify structured elements within the SINV and VEEV genomes. Our SHAPE-directed structural models recapitulate known RNA structures, while also identifying novel structural elements, including a new functional element in the nsP1 region of SINV whose disruption causes a defect in infectivity. Although RNA structural elements are important for multiple aspects of alphavirus biology, we found the majority of RNA structures were not conserved between SINV and VEEV. Our data suggest that alphavirus RNA genomes are highly divergent structurally despite similar genomic architecture and sequence conservation; still, RNA structural elements are critical to the viral life cycle. These findings reframe traditional assumptions about RNA structure and evolution: rather than structures being conserved, alphaviruses frequently evolve new structures that may shape interactions with host immune systems or co-evolve with viral proteins

Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology

ABSTRACT Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million cases of viral arthralgia. Despite the major impact of CHIKV on global health, viral determinants that promote CHIKV-induced disease are incompletely understood. Most CHIKV strains contain a conserved opal stop codon at the end of the viral nsP3 gene. However, CHIKV strains that encode an arginine codon in place of the opal stop codon have been described, and deep-sequencing analysis of a CHIKV isolate from the Caribbean identified both arginine and opal variants within this strain. Therefore, we hypothesized that the introduction of the arginine mutation in place of the opal termination codon may influence CHIKV virulence. We tested this by introducing the arginine mutation into a well-characterized infectious clone of a CHIKV strain from Sri Lanka and designated this virus Opal524R. This mutation did not impair viral replication kinetics in vitro or in vivo . Despite this, the Opal524R virus induced significantly less swelling, inflammation, and damage within the feet and ankles of infected mice. Further, we observed delayed induction of proinflammatory cytokines and chemokines, as well as reduced CD4 + T cell and NK cell recruitment compared to those in the parental strain. Therefore, the opal termination codon plays an important role in CHIKV pathogenesis, independently of effects on viral replication. IMPORTANCE Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes significant outbreaks of viral arthralgia. Studies with CHIKV and other alphaviruses demonstrated that the opal termination codon within nsP3 is highly conserved. However, some strains of CHIKV and other alphaviruses contain mutations in the opal termination codon. These mutations alter the virulence of related alphaviruses in mammalian and mosquito hosts. Here, we report that a clinical isolate of a CHIKV strain from the recent outbreak in the Caribbean islands contains a mixture of viruses encoding either the opal termination codon or an arginine mutation. Mutating the opal stop codon to an arginine residue attenuates CHIKV-induced disease in a mouse model. Compared to infection with the opal-containing parental virus, infection with the arginine mutant causes limited swelling and inflammation, as well as dampened recruitment of immune mediators of pathology, including CD4 + T cells and NK cells. We propose that the opal termination codon plays an essential role in the induction of severe CHIKV disease