Case report: HLA-haploidentical HSCT rescued with donor lymphocytes infusions in a patient with X-linked chronic granulomatous disease

Chronic granulomatous disease is an inborn error of immunity due to disrupted function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. This results in impaired respiratory burst of phagocytes and insufficient killing of bacteria and fungi. Patients with chronic granulomatous disease are at increased risk for infections, autoinflammation and autoimmunity. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only widely available curative therapy. While HSCT from human leukocyte antigen (HLA) matched siblings or unrelated donors are standard of care, transplantation from HLA-haploidentical donors or gene therapy are considered alternative options. We describe a 14-month-old male with X-linked chronic granulomatous disease who underwent a paternal HLA-haploidentical HSCT using T-cell receptor (TCR) alpha/beta(+)/CD19(+) depleted peripheral blood stem cells followed by mycophenolate graft versus host disease prophylaxis. Decreasing donor fraction of CD3(+) T cells was overcome by repeated infusions of donor lymphocytes from the paternal HLA-haploidentical donor. The patient achieved normalized respiratory burst and full donor chimerism. He remained disease-free off any antibiotic prophylaxis for more than three years after HLA-haploidentical HSCT. In patients with x-linked chronic granulomatous disease without a matched donor paternal HLA-haploidentical HSCT is a treatment option worth to consider. Administration of donor lymphocytes can prevent imminent graft failure

AGMEMOD Outlook for Agricultural and Food Markets in EU Member States 2018-2030

Policy, administration and industry need medium-term projections of the expected developments in the agri-food markets for their decision-making processes. The EU Commission presents such projections for the EU as a whole in December of each year. Those projections and their assumptions regarding policy and macroeconomic developments are depicted to the level of individual EU Member States with the exception of Luxembourg, which is included in the figures of Belgium, by applying the partial equilibrium model AGMEMOD. The working paper briefly describes the approach to establish projections for the EU Member States. The projections cover the markets of main agricultural products, in particular for cereals and oilseeds (rapeseed and sunflower seed), livestock (cattle, pigs, goats and sheep), meat (beef, pork, and poultry), milk and dairy products (drinking milk, butter, cheese, skimmed milk powder, whole milk and semiskimmed milk powder). The outcomes comprise items like areas, livestock numbers, yields, production, trade and use, as well as prices. The individual projection results are displayed in tables

Metabolic memory underlying minimal residual disease in breast cancer.

Funder: European Molecular Biology LaboratoryFunder: European Molecular Biology Laboratory (EMBL)Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer-related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi-omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small-molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence

RPA-based point-of-need detection assay for the invasive Mediterranean fanworm Sabella spallanzanii

The Mediterranean fanworm Sabella spallanzanii was first sighted in New Zealand in 2009 (most likely introduced via hull fouling) and has spread across multiple coastal locations. The species presents significant risks to ecological, economic, and societal values, and therefore is subject to targeted surveillance in 11 major ports and marinas, that were identified as high-risk marine biosecurity sites. Great effort and financial resources are put into bi-annual diving surveys that include removal of individuals to contain population growth and spread. In that context, sensitive molecular detection techniques gain great interest and are being increasingly tested for the fanworm detection in New Zealand and Australia. However, conventional molecular detection via PCR assays from environmental DNA (eDNA) samples requires specific laboratory resources and scientific expertise, which restricts the applicability of this approach by biosecurity practitioners or citizen scientists. In order to provide end-users with a fast, easy, and highly specific way to detect S. spallanzanii at the site of interest, a recombinase polymerase amplification assay (RPA) was designed for read-out with lateral flow detection. RPA generates amplification within 20 minutes at 39°C, which makes it possible to run assays hand-held. Because of this, RPA presents an excellent tool for the point-of-need application in targeted biosecurity surveillance. Here we present the results of the successful in silico and in vitro validation of the newly designed RPA assay for S. spallanzanii

Integrating knowledge and omics to decipher mechanisms via large‐scale models of signaling networks

Abstract Signal transduction governs cellular behavior, and its dysregulation often leads to human disease. To understand this process, we can use network models based on prior knowledge, where nodes represent biomolecules, usually proteins, and edges indicate interactions between them. Several computational methods combine untargeted omics data with prior knowledge to estimate the state of signaling networks in specific biological scenarios. Here, we review, compare, and classify recent network approaches according to their characteristics in terms of input omics data, prior knowledge and underlying methodologies. We highlight existing challenges in the field, such as the general lack of ground truth and the limitations of prior knowledge. We also point out new omics developments that may have a profound impact, such as single‐cell proteomics or large‐scale profiling of protein conformational changes. We provide both an introduction for interested users seeking strategies to study cell signaling on a large scale and an update for seasoned modelers

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination.

Funder: Canadian Institutes for Health Research (CA)Funder: Natural Sciences and Engineering Research Council of Canada; doi: http://dx.doi.org/10.13039/501100000038Funder: Fondation Brain Canada; doi: http://dx.doi.org/10.13039/100009408Funder: Azrieli Foundation; doi: http://dx.doi.org/10.13039/501100005155The dietary consumption of cuprizone - a copper chelator - has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis. We term this mode of action 'intrinsic cell damage'. And 2) damage to the oligodendrocyte exerted by inflammatory molecules, brain resident cells, such as oligodendrocytes, astrocytes, and microglia or peripheral immune cells - neutrophils or T-cells. We term this mode of action 'extrinsic cellular damage'. Lastly, we summarize recent developments in research on different forms of cell death induced by cuprizone, which could add valuable insights into the mechanisms of cuprizone toxicity. With this review we hope to provide a modern understanding of cuprizone-induced demyelination to understand the causes behind the demyelination in MS

Die jungneolithischen Erdwerke von Altheim

In 2012, fieldwork recommenced at the Altheim earthwork, discovered more than a century ago. The investigations in its immediate environs revealed a second ditched earthwork of the Altheim period, south-east of the previously known enclosure. The two monuments are spatially related to one another. It was found that several tens of centimetres of soil have been eroded during the last hundred years in the area of the northern earthwork; the very substance of both monuments is acutely threatened. The first radiocarbon measurements, carried out on samples of domestic animal bone, allow us to date both enclosures to the 37th/36th century BC and suggest that the ditches followed a chronological sequence. Certain earlier observations, namely the high proportion of arrowheads among the flaked stone tools and the very low proportion of bones from wild animals, were confirmed by the new excavations. The northwest-southeast orientation of the structures' long axes permits an archaeo-astronomical interpretation: knowledge obtained from the observation of natural phenomena was transferred to architecture. The new investigations sheds further doubt on the interpretation of the enclosures as fortifications