Data-Driven Mathematical Model of Apoptosis Regulation in Memory Plasma Cells

Memory plasma cells constitutively produce copious amounts of antibodies, imposing a critical risk factor for autoimmune disease. We previously found that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-κB- and PI3K-dependent signaling pathways to prevent cell death. However, the regulatory properties of the underlying biochemical network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the survival signals APRIL and contact to the stromal cell line ST2, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant nature of the two plasma cell survival signals APRIL and stromal cell contact, and highlights a requirement for differential regulation of individual caspases. The modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.Leibniz associationLeibniz ScienceCampus Chronic inflammationDeutsche ForschungsgemeinschaftInnovative Medicines InitiativeDr. Rolf M. Schwiete FoundationPeer Reviewe

Discrete populations of isotype-switched memory B lymphocytes are maintained in murine spleen and bone marrow

At present, it is not clear how memory B lymphocytes are maintained over time, and whetheronly as circulating cells or also residing in particular tissues. Here we describe distinctpopulations of isotype-switched memory B lymphocytes (Bsm) of murine spleen and bonemarrow, identified according to individual transcriptional signature and B cell receptorrepertoire. A population of marginal zone-like cells is located exclusively in the spleen, while apopulation of quiescent Bsm is found only in the bone marrow. Three further residentpopulations, present in spleen and bone marrow, represent transitional and follicular B cellsand B1 cells, respectively. A population representing 10-20% of spleen and bone marrowmemory B cells is the only one qualifying as circulating. In the bone marrow, all cells individuallydock onto VCAM1+ stromal cells and, reminiscent of resident memory T and plasmacells, are void of activation, proliferation and mobility.Peer Reviewe

Epigenetic regulator function through mouse gastrulation

During ontogeny, proliferating cells become restricted in their fate through the combined action of cell-type-specific transcription factors and ubiquitous epigenetic machinery, which recognizes universally available histone residues or nucleotides in a context-dependent manner1,2. The molecular functions of these regulators are generally well understood, but assigning direct developmental roles to them is hampered by complex mutant phenotypes that often emerge after gastrulation3,4. Single-cell RNA sequencing and analytical approaches have explored this highly conserved, dynamic period across numerous model organisms5,6,7,8, including mouse9,10,11,12,13,14,15,16,17,18. Here we advance these strategies using a combined zygotic perturbation and single-cell RNA-sequencing platform in which many mutant mouse embryos can be assayed simultaneously, recovering robust morphological and transcriptional information across a panel of ten essential regulators. Deeper analysis of central Polycomb repressive complex (PRC) 1 and 2 components indicates substantial cooperativity, but distinguishes a dominant role for PRC2 in restricting the germline. Moreover, PRC mutant phenotypes emerge after gross epigenetic and transcriptional changes within the initial conceptus prior to gastrulation. Our experimental framework may eventually lead to a fully quantitative view of how cellular diversity emerges using an identical genetic template and from a single totipotent cell

Piezoelectric, dielectric and pyroelectric properties of 0-3 ceramic-polymer composites

The circular samples of composites were made from PZT ceramic grains dispersed in polymers (epoxy or rubber). Pressure dependencies of the hydrostatic piezoelectric coefficient dh and permittivity ε were measured in the range up to 60 MPa. The hydrostatic strain coefficient dh, the hydrostatic voltage coefficient gh and figure of merit dh·gh were determined using the static method. The pressure dependence of the hydrostatic coefficients was measured for several successive cycles. Experimental dependence of the charge on pressure and temperature was fitted by multi parameter function. The pressure and temperature dependencies of the hydrostatic dh and pyroelectric p3 coefficients were determined. It was found that the hydrostatic strain coefficient dh and hydrostatic voltage coefficient gh decreased and pyroelectric coefficient p3 increased with pressure at constant temperature.DFG [1102]; ICTP programme for Training and Research in Italian Laboratories (TRIL); German Bundesministerium fur Bildung und Forschung; Czech Republic MEYS Grants [ME492, LA242]; SAIL (CSR), Govt. of India; CERN-RFBR Grants [08-02-91009, 12-02-91500]; Portuguese FCT - Fundacao para a Ciencia e Tecnologia [CERN/FP/109323/2009, CERN/FP/116376/2010, CERN/FP/123600/2011]; MEXT; JSPS [18002006, 20540299, 18540281]; Daiko Foundation; Yamada Foundation; DFG cluster of excellence 'Origin and Structure of the Universe'; EU FP7 (HadronPhysics3) [283286]; Israel Science Foundation; Polish NCN Grant [DEC-2011/01/M/ST2/02350