Marfanoid habitus and intellectual disability (MHID) co-occur in multiple neurodevelopmental disorders (NDD). Among those, Lujan-Fryns, an X-linked genetic disorder associated with variants in MED12 was the first such syndrome identified. Accurate molecular diagnosis for these MHID syndromes remains a challenge due to significant clinical and genetic heterogeneity.
View Article and Find Full Text PDFTo obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically.
View Article and Find Full Text PDFThe estimation of metabolic fluxes in photosynthetic organisms represents an important challenge that has gained interest over the last decade with the development of C-Metabolic Flux Analysis at isotopically non-stationary steady-state. This approach requires a high level of accuracy for the measurement of Carbon Isotopologue Distribution in plant metabolites. But this accuracy has still not been evaluated at the isotopologue level for GC-MS, leading to uncertainties for the metabolic fluxes calculated based on these fragments.
View Article and Find Full Text PDFMetabolic engineering involves the manipulation of microbes to produce desirable compounds through genetic engineering or synthetic biology approaches. Metabolomics involves the quantitation of intracellular and extracellular metabolites, where mass spectrometry and nuclear magnetic resonance based analytical instrumentation are often used. Here, the experimental designs, sample preparations, metabolite quenching and extraction are essential to the quantitative metabolomics workflow.
View Article and Find Full Text PDFIntroduction: Stable isotope tracer studies are increasingly applied to explore metabolism from the detailed analysis of tracer incorporation into metabolites. Untargeted LC/MS approaches have recently emerged and provide potent methods for expanding the dimension and complexity of the metabolic networks that can be investigated. A number of software tools have been developed to process the highly complex MS data collected in such studies; however, a method to optimize the extraction of valuable isotopic data is lacking.
View Article and Find Full Text PDFBackground: Myocardial infarction is a major cause of morbidity and mortality. Guidelines have been published to optimize medical care and involve optimization of the care pathway and hospital-city coordination.
Aims: To describe the myocardial infarction care pathway during the year following hospital discharge, and the use of and adherence to secondary prevention drugs.
We have developed a robust workflow to measure high-resolution fluxotypes (metabolic flux phenotypes) for large strain libraries under fully controlled growth conditions. This was achieved by optimizing and automating the whole high-throughput fluxomics process and integrating all relevant software tools. This workflow allowed us to obtain highly detailed maps of carbon fluxes in the central carbon metabolism in a fully automated manner.
View Article and Find Full Text PDFThe fused filament fabrication (FFF) of ceramics enables the additive manufacturing of components with complex geometries for many applications like tooling or prototyping. Nevertheless, due to the many factors involved in the process, it is difficult to separate the effect of the different parameters on the final properties of the FFF parts, which hinders the expansion of the technology. In this paper, the effect of the fill pattern used during FFF on the defects and the mechanical properties of zirconia components is evaluated.
View Article and Find Full Text PDFIn this study, the processing parameters mechanical performance, corrosion and tribological evaluation of a low carbon content Co-Cr-Mo alloy are discussed. The production of parts using the Metal Injection Moulding (MIM) process is optimized, specifically concerning the rheological analysis of the prepared feedstocks, the optimum choice of the powder loading and the design of the debinding and sintering cycles. The mechanical properties as regards hardness, tensile strength and bending strength, as well as fatigue tests and wear characterization, are discussed for the full densified specimens obtained.
View Article and Find Full Text PDFAllogeneic hematopoietic stem cell transplantation is the only curative treatment option for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of a graft-versus-host disease (GvHD) after transplantation is a high risk and a severe complication with high morbidity and mortality causing therapeutic challenges. Current pharmacological therapies of GvHD lead to generalized immunosuppression followed by severe adverse side effects including infections and relapse of leukemia.
View Article and Find Full Text PDFTumor necrosis factor-alpha (TNF-α) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-α is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF-α and deliver it into various cancer cell lines and dendritic cells.
View Article and Find Full Text PDFMultiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression.
View Article and Find Full Text PDFIntroduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co-transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)-a potentially life-threatening complication.
View Article and Find Full Text PDFThe rise of high throughput (HT) strain engineering tools accompanying the area of synthetic biology is supporting the generation of a large number of microbial cell factories. A current bottleneck in process development is our limited capacity to rapidly analyze the metabolic state of the engineered strains, and in particular their intracellular fluxes. HT C-fluxomics workflows have not yet become commonplace, despite the existence of several HT tools at each of the required stages.
View Article and Find Full Text PDFAcute graft-versus-host disease (aGvHD) is still a major cause of transplant-related mortality after allogeneic stem cell transplantation (ASCT). It requires immunosuppressive treatments that broadly abrogate T cell responses including beneficial ones directed against tumor cells or infective pathogens. Polo-like kinase 1 (PLK1) is overexpressed in many cancer types including leukemia, and clinical studies demonstrated that targeting PLK1 using selective PLK1 inhibitors resulted in inhibition of proliferation and induction of apoptosis predominantly in tumor cells, supporting the feasibility of PLK1 as target for anticancer therapy.
View Article and Find Full Text PDFAcute graft-versus-host disease is still a major cause of transplant-related mortality after allogeneic stem cell transplantation. It requires immunosuppressive treatments that broadly abrogate T cell responses, including beneficial ones directed against tumor cells or infective pathogens. Inhibition of the heat shock protein of 90 kDa has been demonstrated to eliminate tumor cells, as well as alloreactive T cells while preserving antiviral T cell immunity.
View Article and Find Full Text PDFUnlike induced Foxp3(+) regulatory T cells (Foxp3(+) iTreg) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity.
View Article and Find Full Text PDFThe well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic α-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with β-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses.
View Article and Find Full Text PDFViral and fungal infections remain a leading cause of mortality in patients after hematopoietic stem cell transplantation (HSCT). Adoptive transfer of multipathogen-specific T cells is promising in restoring immunity and thereby preventing and treating infections, but approaches are currently limited because of time-consuming and laborious procedures. Therefore, we investigated a new strategy to simultaneously select T cells specific for viral and fungal pathogens based on activation-dependent expression of CD154.
View Article and Find Full Text PDFWe have previously shown that inhibition of the proteolytic activity of the proteasome induces apoptosis and suppresses essential functions of activated human CD4(+) T cells, and we report now the detailed mechanisms of apoptosis following proteasome inhibition in these cells. Here we show that proteasome inhibition by bortezomib activates the mitochondrial pathway of apoptosis in activated CD4(+) T cells by disrupting the equilibrium of pro-apoptotic and anti-apoptotic proteins at the outer mitochondrial membrane (OMM) and by inducing the generation of reactive oxygen species (ROS). Proteasome inhibition leads to accumulation of pro-apoptotic proteins PUMA, Noxa, Bim and p53 at the OMM.
View Article and Find Full Text PDFHelenalin is a naturally occuring sesquiterpene lactone extracted from Arnica montana and Arnica chamissonis ssp. foliosa. Helenalin and its derivatives are known for anti-cancer and anti-inflammatory effects via inhibiting NF-kappaB and telomerase activity and impairing protein and DNA synthesis, suggesting that helenalin is a potential candidate for the treatment of deregulated and unwanted T cell-mediated immune responses.
View Article and Find Full Text PDFSimvastatin is a competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway required for the biosynthesis of cholesterol and higher isoprenoids such as geranylgeranyl pyrophosphate (GGPP). Apart from its capacity to lower cholesterol plasma levels and to protect against cardiovascular disease, simvastatin induces apoptosis in various cancer cells. We have generated human Namalwa Burkitt lymphoma cells that display general apoptosis resistance and hyperproliferation due to increased expression and proteolytic activity of 26S proteasomes in response to continuous treatment of the cells with the proteasome inhibitor bortezomib.
View Article and Find Full Text PDFThe proteasome constitutes the central proteolytic component of the highly conserved ubiquitin-proteasome system, which is required for the maintenance and regulation of basic cellular processes, including differentiation, proliferation, cell cycling, gene transcription and apoptosis. Here we show that inhibition of proteasomal proteolytic activity by the proteasome inhibitors bortezomib and lactacystin suppresses essential immune functions of human CD4(+) T cells activated by allogeneic dendritic cells (DCs). In activated CD4(+) T cells, proteasome inhibition induces apoptosis accompanied by rapid accumulation and stabilization of the tumour suppressor protein p53.
View Article and Find Full Text PDFBiochim Biophys Acta
September 2007
The highly conserved ubiquitin-proteasome system is the principal machinery for extralysosomal protein degradation in eukaryotic cells. The 26S proteasome, a large multicatalytic multisubunit protease that processes cell proteins by limited and controlled proteolysis, constitutes the central proteolytic component of the ubiquitin-proteasome system. By processing cell proteins essential for development, differentiation, proliferation, cell cycling, apoptosis, gene transcription, signal transduction, senescence, and inflammatory and stress response, the 26S proteasome plays a key role in the regulation and maintenance of basic cellular processes.
View Article and Find Full Text PDF