Immune Requirements of Post-Exposure Immunization with Modified Vaccinia Ankara of Lethally Infected Mice

Current prophylactic vaccines work via the induction of B and T cell mediated memory that effectively control further replication of the pathogen after entry. In the case of therapeutic or post-exposure vaccinations the situation is far more complex, because the pathogen has time to establish itself in the host, start producing immune-inhibitory molecules and spread into distant organs. So far it is unclear which immune parameters have to be activated in order to thwart an existing lethal infection. Using the mousepox model, we investigated the immunological mechanisms responsible for a successful post-exposure immunization with modified vaccinia Ankara (MVA). In contrast to intranasal application of MVA, we found that intravenous immunization fully protected mice infected with ectromelia virus (ECTV) when applied three days after infection. Intravenous MVA immunization induced strong innate and adaptive immune responses in lethally infected mice. By using various gene-targeted and transgenic mouse strains we show that NK cells, CD4 T cells, CD8 T cells and antibodies are essential for the clearance of ECTV after post-exposure immunization. Post-exposure immunization with MVA is an effective measure in a murine model of human smallpox. MVA activates innate and adaptive immune parameters and only a combination thereof is able to purge ECTV from its host. These data not only provide a basis for therapeutic vaccinations in the case of the deliberate release of pathogenic poxviruses but possibly also for the treatment of chronic infections and cancer

Scaling up agricultural interventions: Case studies of climate-smart agriculture

If climate-smart agriculture (CSA) is meaningfully to address the development challenges posed by climate change, effective approaches will be needed to scale up research findings. Here, eleven case studies are used to exemplify scaling-up strategies based on (1) value chains and private sector involvement, (2) information and communication technologies and agro-advisory services, and (3) policy engagement. We evaluated these case studies and the scaling strategies they exemplify, using a simple conceptual framework from the field of scaling up nutrition interventions. Results showed that these different strategies exhibit different characteristics; all offer considerable potential for taking CSA interventions to scale, but there still may be unavoidable trade-offs to consider when choosing one strategy over another, particularly between reaching large numbers of farmers and addressing farmers' specific contexts. The case studies highlighted several challenges: estimating the costs and benefits of different scaling activities, integrating knowledge across multiple levels, and addressing equity issues in scaling up. The case studies outlined here will continue to be monitored and evaluated, thus strengthening the evidence base around effective scaling-up strategies that can contribute to achieving food and nutrition security under climate change in the coming decades

Psychologische Merkmale jugendlicher Patienten vor einer Gewichtsreduktionsbehandlung

Übergewicht und Adipositas zeigen bei Kindern und Jugendlichen eine hohe Prävalenz und Persistenz. Entsprechende Therapien sind kaum individualisiert und zeigen nur moderate Erfolge. Die Psychopathologie bleibt zumeist unberücksichtigt. Die vorliegende Studie hat die Psychopathologie von Jugendlichen mit Übergewicht und Adipositas (N = 201, Alter 12 – 17 Jahre) vor einer Gewichtsreduktionsbehandlung erhoben und Alters- sowie Geschlechtseffekte untersucht. Mittels Fragebögen wurden selbstberichtet die allgemeine Symptombelastung, Essstörungs- und allgemeine Psychopathologie, gewichtsbezogene Selbststigmatisierung und die körperliche und psychische Lebensqualität erhoben. Mädchen zeigten hypothesenkonform ein höheres Maß an gewichtsbezogener Selbststigmatisierung und eine stärkere Essstörungspsychopathologie als Jungen. Ältere Jugendliche berichteten eine geringere Lebensqualität als jüngere. Vergleiche zu Referenzgruppen aus Bevölkerungs- und Normierungsstichproben zeigten auffälligere Werte bei Jugendlichen mit Übergewicht und Adipositas für alle untersuchten Parameter. Eine auffällige Psychopathologie ist demzufolge ein wichtiges Korrelat bei Jugendlichen mit hohem Gewichtsstatus und ein potenzieller Einflussfaktor auf den Erfolg einer Gewichtsreduktionsbehandlung. Zukünftige Studien sollten die Psychopathologie bei Übergewicht und Adipositas weiter differenzieren und therapeutische Ressourcen evaluieren.Overweight and obesity in children and adolescents are highly prevalent and persistent. Current weight loss treatments are rarely individualized and show only small to moderate efficacy. Only rarely, psychopathological parameters are considered. The present study evaluated the psychopathology of adolescents with overweight and obesity (N = 201, ages 12 – 17 years) prior to obesity treatment. The data were analyzed for age and sex effects. Self-report questionnaires assessed general symptom burden, eating disorder and general psychopathology, weight-related self-stigmatization, and physical and mental quality of life. Girls showed higher rates of weight-related self-stigmatization and higher disordered eating behavior compared to boys. Older adolescents reported a lower quality of life compared to younger adolescents. In normative comparisons with population-based samples and norms, adolescents with overweight and obesity showed significantly adverse outcomes in all parameters. Thus, this study identified psychopathology as an important factor in adolescents with high weight status that may affect obesity treatment. Future studies should examine psychopathology more differentially and determine therapeutic resources in adolescent overweight and obesity

Climate Services Can Support African Farmers' Context-Specific Adaptation Needs at Scale

We consider the question of what is needed for climate services to support sub-Saharan African farmers' adaptation needs at the scale of the climate challenge. Consistent with an earlier assessment that mutually reinforcing supply-side and demand-side capacity constraints impede the development of effective climate services in Africa, our discussion of strategies for scaling up practices that meet farmers' needs, and opportunities to address long-standing obstacles, is organized around: (a) meeting farmers' climate information needs; (b) supporting access, understanding and use; and (c) co-production of services. A widespread gap between available information and farmers' needs is associated with entrenched seasonal forecast convention and obstacles to using observational data. Scalable innovations for producing more locally relevant historical and forecast climate information for farm decision-making are beginning to be adopted. Structured participatory communication processes help farmers relate complex climate information to their experience, and integrate it into their management decisions. Promising efforts to deliver rural climate services strategically combine communication channels that include participatory processes embedded in existing agricultural advisory systems, and innovations in interactive broadcast media. Efforts to engage farmers in co-production of climate services improve delivery to farmers and dialogue among stakeholders, but often with little impact on the usability of available information. We discuss challenges and options for capturing farmers' evolving demands, and aggregating and incorporating this information into iterative improvements to climate services at a national scale. We find evidence that key weaknesses in the supply and the demand sides of climate services continue to reinforce each other to impede progress toward meeting farmers' needs at scale across Africa. Six recommendations target these weaknesses: (1) change the way seasonal forecasts are produced and presented regionally and nationally, (2) use merged gridded data as a foundation for national climate information products, (3) remove barriers to using historical data as a public good, (4) mobilize those who work on the demand side of climate services as an effective community of practice, (5) collectively assess and improve tools and processes for communicating climate information with rural communities, and (6) build iterative co-production processes into national climate service frameworks

Distribution and habitat segregation on different spatial scales among diploid, tetraploid and hexaploid cytotypes of Senecio carniolicus (Asteraceae) in the Eastern Alps

The spatial distribution of cytotypes can provide valuable insights into evolutionary patterns of polyploid complexes. In a previous study the macro-scale distribution of the three main cytotypes in Senecio carniolicus (Asteraceae) within the Eastern Alps was characterized. Employing a roughly 12-fold extended sampling, the present study focuses on unravelling patterns of cytotype distribution on the meso- and microscale and on correlating those with ecological properties of the growing sites. DAPI flow cytometry of dried samples was used to determine DNA ploidy level in 5033 individuals from 100 populations spread over the entire Eastern Alpine distribution area of S. carniolicus. Descriptors of microhabitats as well as spatial data were recorded in the field, and analysed with a mixed-effects ANOVA. Extensive variation in DNA ploidy levels (2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x) was detected. Of the main cytotypes, diploids and hexaploids were widespread and had strongly overlapping distributions resulting in the frequent occurrence of cytotype mixtures (half of the investigated populations), whereas tetraploids were disjunctly distributed and occurred in the south-west and the east of the species' distribution area. In spite of the frequent co-occurrence of cytotypes, only 1 % of the samples belonged to secondary cytotypes (3x, 5x, 7x, 8x, 9x). Diploids, tetraploids and hexaploids were altitudinally segregated, but with broad overlap. Similarly, highly significant differences in vegetation and rock cover as well as microhabitat exposure were found between the main cytotypes. Senecio carniolicus shows a remarkable diversity of cytotypes. The distribution of the three main cytotypes (2x, 4x, 6x) has been shaped by Pleistocene glaciations to different extents. Whereas tetraploids are nearly entirely restricted to refugia, hexaploids colonized areas that were extensively glaciated. Diploid and hexaploid individuals often co-occur in mixed populations, where they are spatially and ecologically segregated at both the meso-scale (altitudinal differentiation, exposure of the growing site) and the micro-scale (cover of vegetation and bare rock). With regard to the ecological parameters investigated, the tetraploid cytotype occupies an intermediate position. The rareness of secondary cytotypes suggests the presence of strong pre- or post-zygotic mating barriers

Genetic and Evolutionary Analyses of the Human Bone Morphogenetic Protein Receptor 2 (BMPR2) in the Pathophysiology of Obesity

Human bone morphogenetic protein receptor 2 (BMPR2) is essential for BMP signalling and may be involved in the regulation of adipogenesis. The BMPR2 locus has been suggested as target of recent selection in human populations. We hypothesized that BMPR2 might have a role in the pathophysiology of obesity.Evolutionary analyses (dN/dS, Fst, iHS) were conducted in vertebrates and human populations. BMPR2 mRNA expression was measured in 190 paired samples of visceral and subcutaneous adipose tissue. The gene was sequenced in 48 DNA samples. Nine representative single nucleotide polymorphisms (SNPs) were genotyped for subsequent association studies on quantitative traits related to obesity in 1830 German Caucasians. An independent cohort of 925 Sorbs was used for replication. Finally, relation of genotypes to mRNA in fat was examined.The evolutionary analyses indicated signatures of selection on the BMPR2 locus. BMPR2 mRNA expression was significantly increased both in visceral and subcutaneous adipose tissue of 37 overweight (BMI>25 and <30 kg/m²) and 80 obese (BMI>30 kg/m²) compared with 44 lean subjects (BMI< 25 kg/m²) (P<0.001). In a case-control study including lean and obese subjects, two intronic SNPs (rs6717924, rs13426118) were associated with obesity (adjusted P<0.05). Combined analyses including the initial cohort and the Sorbs confirmed a consistent effect for rs6717924 (combined P = 0.01) on obesity. Moreover, rs6717924 was associated with higher BMPR2 mRNA expression in visceral adipose tissue.Combined BMPR2 genotype-phenotype-mRNA expression data as well as evolutionary aspects suggest a role of BMPR2 in the pathophysiology of obesity

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα.

Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-κB α (IκBα) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the IκBα S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-κB signaling. Lymphotoxin β receptor (LTβR)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-κB pathways was impaired, and levels of p100 were markedly diminished in the mutant. IκBα mutant → Rag2(-/-), but not WT→IκBα mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with IκBα deficiency and suggests that correction of this niche is critical for reconstituting their immune function