Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies.

To our knowledge, venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in patients with myeloma harboring the t(11:14) translocation. However, despite the high response rates and prolonged progression-free survival, a significant proportion of patients eventually relapse. Here, we aim to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models.

Discordance between platelet-supported and vesicle-supported factor VIII activity in the presence of anti-C2 domain inhibitory antibodies.

Background: We recently reported that factor VIII (FVIII) binds to a macromolecular complex including fibrin on thrombin-stimulated platelets and that two antibodies against FVIII diminish platelet-supported FVIII activity more than vesicle-supported activity. The C2 domain of FVIII is known to bind to phospholipid membrane and also binds fibrin.

Objectives: We asked whether the degree of inhibition by anti-C2 antibodies would show differences between platelet-supported and the standard activated partial thromboplastin time (aPTT) assay.

CD3-T cell receptor co-stimulation through SLAMF3 and SLAMF6 receptors enhances RORγt recruitment to the IL17A promoter in human T lymphocytes.

Th17 lymphocytes play a key role during immune responses against bacteria and fungi and are involved in the pathophysiology of multiple autoimmune disorders. The co-stimulatory molecules SLAMF3 and SLAMF6 have been implicated in the formation of Th17 phenotypes and IL-17A expression. Increased surface expression of SLAMF3 and SLAMF6 has been linked with disease activity in systemic lupus erythematosus.

Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation.

Altered T cell function in systemic lupus erythematosus (SLE) is determined by various molecular and cellular abnormalities, including increased IL-17 production. Recent evidence suggests a crucial role for signaling lymphocyte activation molecules (SLAMs) in the expression of autoimmunity. In this study, we demonstrate that SLAMF3 and SLAMF6 expression is increased on the surface of SLE T cells compared with normal cells.

SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells.

The CD28 co-stimulatory pathway is well established for T cell activation. However, there is evidence suggesting the existence of additional co-stimulatory pathways. Here we report that a member of the SLAM superfamily, SLAMF6, or CD352 plays an important role in T cell co-stimulation.

Epilepsy in Prader-Willi syndrome: clinical characteristics and correlation to genotype.

Prader-Willi syndrome (PWS) is a genomic imprinting disease secondary to the loss of a functional paternal copy of 15q11-q13. Unlike its related imprinting disorder, Angelman syndrome, PWS has not been regarded as a risk factor for epilepsy. A retrospective analysis of 92 patients with PWS identified 24 (26%) with seizures.

Impaired germinal center responses and suppression of local IgG production during intracellular bacterial infection.

Germinal centers (GCs) are specialized microenvironments in secondary lymphoid organs that facilitate the development of high-affinity, isotype-switched Abs, and immunological memory; consequently, many infections require GC-derived IgG for pathogen clearance. Although Ehrlichia muris infection elicits a robust expansion of splenic, IgM-secreting plasmablasts, we detected only very low frequencies of isotype-switched IgG-secreting cells in mouse spleens, until at least 3 wk postinfection. Instead, Ag-specific IgG was produced in lymph nodes, where it required CD4 T cell help.

Regulation of tyrosine kinase activity during capacitation in goat sperm.

Protein tyrosine phosphorylation is a key event accompanying sperm capacitation. Although this signaling cascade generates an array of tyrosine-phosphorylated polypeptides, their molecular characterization is still limited. It is necessary to differentiate the localization of the tyrosine-phosphorylated proteins in spermatozoa to understand the link between the different phosphorylated proteins and the corresponding regulated sperm function.

Antigen display, T-cell activation, and immune evasion during acute and chronic ehrlichiosis.

How spatial and temporal changes in major histocompatibility complex/peptide antigen presentation to CD4 T cells regulate CD4 T-cell responses during intracellular bacterial infections is relatively unexplored. We have shown that immunization with an ehrlichial outer membrane protein, OMP-19, protects mice against fatal ehrlichial challenge infection, and we identified a CD4 T-cell epitope (IA(b)/OMP-19(107-122)) that elicited CD4 T cells following either immunization or infection. Here, we have used an IA(b)/OMP-19(107-122)-specific T-cell line to monitor antigen display ex vivo during acute and chronic infection with Ehrlichia muris, a bacterium that establishes persistent infection in C57BL/6 mice.

Ixodes ovatus Ehrlichia exhibits unique ultrastructural characteristics in mammalian endothelial and tick-derived cells.

Tick-borne pathogens in the genus Ehrlichia cause emerging zoonoses. Although laboratory mice are susceptible to Ehrlichia infections, many isolates do not cause clinical illness. In contrast, the Ixodes ovatus Ehrlichia-like agent (IOE) causes disease and immune responses in mice comparable to the human illness caused by Ehrlichia chaffeensis.

Diminished hematopoietic activity associated with alterations in innate and adaptive immunity in a mouse model of human monocytic ehrlichiosis.

Human monocytic ehrlichiosis (HME) is a tick-borne disease caused by Ehrlichia chaffeensis. Patients exhibit diagnostically important hematological changes, including anemia and thrombocytopenia, although the basis of the abnormalities is unknown. To begin to understand these changes, we used a mouse model of ehrlichiosis to determine whether the observed hematological changes induced by infection are associated with altered hematopoietic activity.

Early T-cell responses in tuberculosis immunity.

Tuberculosis (TB) has plagued mankind for millennia yet is classified as an emerging infectious disease, because its prevalence in the human population continues to increase. Immunity to TB depends critically on the generation of effective CD4(+) T-cell responses. Sterile immunity has not been achieved through vaccination, although early T-cell responses are effective in controlling steady-state infection in the lungs.

Localization and expression of a 70 kDa protein in goat spermatozoa having Na(+),K(+)-ATPase inhibitory and arylsulphatase A activities.

We have previously isolated and purified a goat sperm protein of 70 kDa molecular weight designated as P70 and characterized it as an inhibitor of Na(+),K(+)-ATPase. Our study reveals that the first 10 amino acid residues from the N-terminal end of P70 has high degree of homology with arylsulphatase A from mice, pig and human. Indirect immunofluorescence study shows the presence of the protein on goat sperm surface.

CD11c expression identifies a population of extrafollicular antigen-specific splenic plasmablasts responsible for CD4 T-independent antibody responses during intracellular bacterial infection.

Although T-independent immunity is known to be generated against bacterial capsular and cell wall polysaccharides expressed by a number of bacterial pathogens, it has not been studied in depth during intracellular bacterial infections. Our previous study demonstrated that Ehrlichia muris, an obligate intracellular tick-borne pathogen, generates protective classical TI responses in CD4 T cell-deficient C57BL/6 mice. We found that E.

Mechanism of regulation of phosphorylation-dephosphorylation of Ca2+, Mg2+ and Ca2+ -Atpases by modulator proteins isolated from rat brain cytosol.

Two proteins of molecular mass 13 kDa, a specific inhibitor of Na+, K+ -ATPase and another of 12 kDa, which can distinguish between Ca2, Mg2+ and Ca2+ -ATPase activities have been obtained from the pooled fractions isolated from rat brain, using Sephadex G-100 chromatography. In order to determine the key step(s), which is affected by the modulators, we have designed an in vitro experiment of phosphorylation and dephosphorylation of these ATPases in the absence and presence of the modulators. The results suggest that the phosphorylation step of Mg2+ -independent Ca2+ -ATPase is inhibited, while in Mg2+ -dependent Ca2 -ATPase, the dephosphorylation step is stimulated by the modulators.