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Background As of November 2020, SARS-CoV-2 has resulted in 55 million infections worldwide and over 1.3 million deaths from COVID-19. Outcomes following SARS-CoV-2 infection in individuals with primary immunodeficiency or symptomatic secondary immunodeficiency remain uncertain. Objectives To document the outcomes of individuals with primary or symptomatic secondary immunodeficiency following COVID-19 in the United Kingdom. Methods At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network (UK PIN) established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. Results 100 patients had been enrolled by 1st July 2020, 60 with primary immunodeficiency (PID), 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency and 33 with symptomatic secondary immunodeficiency (SID). In individuals with PID, 53.3% (n=32/60) were hospitalized, the infection fatality rate (IFR) was 20.0% (n=12/60), the case fatality rate (CFR) was 31.6% (n=12/38) and the inpatient mortality 37.5% (n=12/32). Individuals with SID had worse outcomes than those with PID. 75.8% (n=25/33) were hospitalized, the IFR was 33.3% (n=11/33), the CFR was 39.2% (n=11/28), and inpatient mortality 44.0% (n=11/25). Conclusions In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus.

BackgroundWhile there is now a significant body of research correlating apple (Malus x domestica) fruit softening with the cell wall hydrolase ENDO-POLYGALACTURONASE1 (PG1), there is currently little knowledge of its physiological effects in planta. This study examined the effect of down regulation of PG1 expression in ‘Royal Gala’ apples, a cultivar that typically has high levels of PG1, and softens during fruit ripening.ResultsPG1-suppressed ‘Royal Gala’ apples harvested from multiple seasons were firmer than controls after ripening, and intercellular adhesion was higher. Cell wall analyses indicated changes in yield and composition of pectin, and a higher molecular weight distribution of CDTA-soluble pectin. Structural analyses revealed more ruptured cells and free juice in pulled apart sections, suggesting improved integrity of intercellular connections and consequent cell rupture due to failure of the primary cell walls under stress. PG1-suppressed lines also had reduced expansion of cells in the hypodermis of ripe apples, resulting in more densely packed cells in this layer. This change in morphology appears to be linked with reduced transpirational water loss in the fruit.ConclusionsThese findings confirm PG1’s role in apple fruit softening and suggests that this is achieved in part by reducing cellular adhesion. This is consistent with previous studies carried out in strawberry but not with those performed in tomato. In apple PG1 also appears to influence other fruit texture characters such as juiciness and water loss.

During climacteric fruit ripening, autocatalytic (Type II) ethylene production initiates a transcriptional cascade that controls the production of many important fruit quality traits including flavour production and softening. The last step in ethylene biosynthesis is the conversion of 1-aminocyclopropane-1-carboxylic acid (ACC) to ethylene by the enzyme ACC oxidase (ACO). Ten independent kiwifruit (Actinidia chinensis) lines were generated targeting suppression of fruit ripening-related ACO genes and the fruit from one of these lines (TK2) did not produce detectable levels of climacteric ethylene. Ripening behaviour in a population of kiwifruit at harvest is asynchronous, so a short burst of exogenous ethylene was used to synchronize ripening in TK2 and control fruit. Following such a treatment, TK2 and control fruit softened to an 'eating-ripe' firmness. Control fruit produced climacteric ethylene and softened beyond eating-ripe by 5 d. In contrast, TK2 fruit maintained an eating-ripe firmness for >25 d and total volatile production was dramatically reduced. Application of continuous exogenous ethylene to the ripening-arrested TK2 fruit re-initiated fruit softening and typical ripe fruit volatiles were detected. A 17 500 gene microarray identified 401 genes that changed after ethylene treatment, including a polygalacturonase and a pectate lyase involved in cell wall breakdown, and a quinone oxidoreductase potentially involved in volatile production. Many of the gene changes were consistent with the softening and flavour changes observed after ethylene treatment. However, a surprisingly large number of genes of unknown function were also observed, which could account for the unique flavour and textural properties of ripe kiwifruit.

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Integrin ␣v␤6 is generally not expressed in adult epithelia but is induced in wound healing, cancer, and certain fibrotic disorders. Despite this generalized absence, we observed that ␣v␤6 integrin is constitutively expressed in the healthy junctional epithelium linking the gingiva to tooth enamel. Moreover, expression of ␣v␤6 integrin was down-regulated in human periodontal disease, a common medical condition causing tooth loss and also contributing to the development of cardiovascular diseases by increasing the total systemic inflammatory burden. Remarkably, integrin ␤6 knockout mice developed classic signs of spontaneous, chronic periodontal disease with characteristic inflammation, epithelial down-growth, pocket formation, and bone loss around the teeth. Integrin ␣v␤6 acts as a major activator of transforming growth factor-␤1 (TGF-␤1), a key anti-inflammatory regulator in the immune system. Co-expression of TGF-␤1 and ␣v␤6 integrin was observed in the healthy junctional epithelium. Moreover, an antibody that blocks ␣v␤6 integrin-mediated activation of TGF-␤1 initiated inflammatory periodontal disease in a rat model of gingival inflammation. Thus, ␣v␤6 integrin is constitutively expressed in the epithelium sealing the gingiva to the tooth and plays a central role in protection against inflammatory periodontal disease through activation of TGF-␤1. (Am J Pathol

SUMMARY Basal metabolic rate (BMR) is highly variable, both between and within species. One hypothesis is that this variation may be linked to the capacity for sustained rate of energy expenditure, leading to associations between high BMR and performance during energy-demanding periods of life history, such as reproduction. However, despite the attractive nature of this hypothesis,previous studies have failed to show an association between BMR and fecundity. Our approach was to mate 304 C57BL/6J mice and allow them to wean pups before measuring BMR by indirect calorimetry. We did not find an association between BMR and litter mass, size or pup mass at birth or weaning that could not be accounted for by the body mass of the dam. There was also no relationship between BMR (or BMR corrected for body mass) and birth or weaning success,losses during weaning, or sex ratio. However, a significant relationship was found between BMR and gestational weight loss indicative of foetal resorption. This suggests that during pregnancy the available energy may be limited and partitioned away from the growing foetus and towards maintenance of the mother. In this context, a high BMR may actually be disadvantageous,conflicting with the idea that high BMR may bring reproductive benefits.

Background Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. Objectives COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination. Methods Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs. Results A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine. Conclusion SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.