Monocyte NOTCH2 expression predicts interferon-beta immunogenicity in multiple sclerosis patients

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β–treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration

Structure and Ionic Conductivity in the Mixed-Network Former Chalcogenide Glass System [Na2S]2/3[(B2S3)x(P2S5)1–x]1/3

Glasses in the system [Na2S]2/3[(B2S3)x(P2S5)1–x]1/3 (0.0 ≤ x ≤ 1.0) were prepared by the melt quenching technique, and their properties were characterized by thermal analysis and impedance spectroscopy. Their atomic-level structures were comprehensively characterized by Raman spectroscopy and 11B, 31P, and 23Na high resolution solid state magic-angle spinning (MAS) NMR techniques. 31P MAS NMR peak assignments were made by the presence or absence of homonuclear indirect 31P–31P spin–spin interactions as detected using homonuclear J-resolved and refocused INADEQUATE techniques. The extent of B–S–P connectivity in the glassy network was quantified by 31P{11B} and 11B{31P} rotational echo double resonance spectroscopy. The results clearly illustrate that the network modifier alkali sulfide, Na2S, is not proportionally shared between the two network former components, B and P. Rather, the thiophosphate (P) component tends to attract a larger concentration of network modifier species than predicted by the bulk composition, and this results in the conversion of P2S74–, pyrothiophosphate, Na/P = 2:1, units into PS43–, orthothiophosphate, Na/P = 3:1, groups. Charge balance is maintained by increasing the net degree of polymerization of the thioborate (B) units through the formation of covalent bridging sulfur (BS) units, B–S–B. Detailed inspection of the 11B MAS NMR spectra reveals that multiple thioborate units are formed, ranging from neutral BS3/2 groups all the way to the fully depolymerized orthothioborate (BS33–) species. On the basis of these results, a comprehensive and quantitative structural model is developed for these glasses, on the basis of which the compositional trends in the glass transition temperatures (Tg) and ionic conductivities can be rationalized. Up to x = 0.4, the dominant process can be described in a simplified way by the net reaction equation P1 + B1 P0 + B4, where the superscripts denote the number of BS atoms for the respective network former species. Above x = 0.4, all of the thiophosphate units are of the P0 type and both pyro- (B1) and orthothioborate (B0) species make increasing contributions to the network structure with increasing x. In sharp contrast to the situation in sodium borophosphate glasses, four-coordinated thioborate species are generally less abundant and heteroatomic B–S–P linkages appear to not exist. On the basis of this structural information, compositional trends in the ionic conductivities are discussed in relation to the nature of the charge-compensating anionic species and the spatial distribution of the charge carriers

Computer Aided Design of Radiofrequency and Microwave Circuits

Radiofrequency and microwave CAD computer programs enabling for signal and yield analysis and circuit optimization have been developed. Program is used both in circuit design and student education

Static Load Balancing Applied to Time Dependent Mechanical Problems. Seminar on Numerical Analysis. Modelling and Simulation of Challenging Engineering Problems

Time dependent mechanical problems are used in many branches of engineering practise, e.g., in analysis of reactor vessels of nuclear power plants. The notion time dependent mechanical problem is used for tasks depending on time but with negligible inertial forces. A typical example of such problems is the creep analysis. Time integration is performed by a numerical metho