New lessons about old molecules: how type I interferons shape Th1/Th17-mediated autoimmunity in the CNS.

Type I interferons (IFN-alpha and IFN-beta) were discovered more than five decades ago and are widely used for the treatment of human autoimmune diseases such as multiple sclerosis (MS). Despite their highly beneficial features, the precise mechanism of action remains speculative. Given the frequent side effects of IFN-alpha/beta therapy, understanding its action in an in vivo setting is vital to further improve this therapeutic approach.

Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS.

Myeloid cells are mediators of central nervous system (CNS) damage and recovery in neuroinflammatory and neurodegenerative disorders. Besides endogenous myelomonocytic cell populations that reside in the brain already during development, newly migrated leukocytes are considered as important disease modulators in the adult brain. Thus, understanding of myeloid cell recruitment is pivotal for manipulating immune cell entry into the CNS and potentially reducing disease burden.

TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer.

The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappaB in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis.

Induction of inhibitory central nervous system-derived and stimulatory blood-derived dendritic cells suggests a dual role for granulocyte-macrophage colony-stimulating factor in central nervous system inflammation.

The mononuclear phagocyte system, particularly dendritic cells, plays several pivotal roles in the development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Here, we demonstrate that functionally distinct dendritic cell subpopulations are present in the central nervous system during experimental autoimmune encephalomyelitis. At peak experimental autoimmune encephalomyelitis, the majority of dendritic cells consisted of a CD11b(+)F4/80(+) inflammatory dendritic cell subtype.

Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis.

Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing-remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-beta inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation.

Novel components of an active mitochondrial K(+)/H(+) exchange.

Defects of the mitochondrial K(+)/H(+) exchanger (KHE) result in increased matrix K(+) content, swelling, and autophagic decay of the organelle. We have previously identified the yeast Mdm38 and its human homologue LETM1, the candidate gene for seizures in Wolf-Hirschhorn syndrome, as essential components of the KHE. In a genome-wide screen for multicopy suppressors of the pet(-) (reduced growth on nonfermentable substrate) phenotype of mdm38Delta mutants, we now characterized the mitochondrial carriers PIC2 and MRS3 as moderate suppressors and MRS7 and YDL183c as strong suppressors.

Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with beta-amyloid, acetylcholine, and butyrylcholine esterases.

Approved drugs for the treatment of Alzheimer's disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here.

A star-shaped heteronuclear Cr(III)Mn(II)3 species and its precise electronic and magnetic structure: spin frustration studied by X-ray spectroscopic, magnetic, and theoretical methods.

Molecular magnets incorporate transition-metal ions with organic groups providing a bridge to mediate magnetic exchange interactions between the ions. Among them are star-shaped molecules in which antiferromagnetic couplings between the central and peripheral atoms are predominantly present. Those configurations lead to an appreciable spin moment in the nonfrustrated ground state.

Affect-related personality traits and contextual interference processing during perception of facial affect.

We investigated the influence of different personality dimensions on neural emotional conflict processing. A cluster analysis separated two different subsamples of subjects. One sample scored high on neuroticism, anxiety, depressivity and low on extraversion and was found to be highly sensitive to emotional conflicts during processing of negative and positive expressions.

Antiinflammatory properties of a plant-derived nonsteroidal, dissociated glucocorticoid receptor modulator in experimental autoimmune encephalomyelitis.

Compound A (CpdA), a plant-derived phenyl aziridine precursor, was recently characterized as a fully dissociated nonsteroidal antiinflammatory agent, acting via activation of the glucocorticoid receptor, thereby down-modulating nuclear factor-kappaB-mediated transactivation, but not supporting glucocorticoid response element-driven gene expression. The present study demonstrates the effectiveness of CpdA in inhibiting the disease progress in experimental autoimmune encephalomyelitis (EAE), a well-characterized animal model of multiple sclerosis. CpdA treatment of mice, both early and at the peak of the disease, markedly suppressed the clinical symptoms of EAE induced by myelin oligodendrocyte glycoprotein peptide immunization.

DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction.

DNA methylation is a dynamic epigenetic mark that undergoes extensive changes during differentiation of self-renewing stem cells. However, whether these changes are the cause or consequence of stem cell fate remains unknown. Here, we show that alternative functional programs of hematopoietic stem cells (HSCs) are governed by gradual differences in methylation levels.

A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis.

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-beta in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-beta for a minimum of 2 years and classified as responders and non-responders based on clinical criteria.

CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system.

The chemokine receptor CCR2 plays a vital role for the induction of autoimmunity in the central nervous system. However, it remains unclear how the pathogenic response is mediated by CCR2-bearing cells. By combining bone marrow chimerism with gene targeting we detected a mild disease-modulating role of CCR2 during experimental autoimmune encephalomyelitis, a model for central nervous system autoimmunity, on radio-resistant cells that was independent from targeted CCR2 expression on endothelia.

Multi-focal occurrence of cortical dysplasia in epilepsy patients.

This study describes the existence and the clinical and electrophysiological features of multi-focal cortical dysplasia in epilepsy patients. Five patients with intractable focal epilepsy are reported. All patients underwent invasive presurgical video-electroencephalography monitoring.

Vaccination with Abeta-displaying virus-like particles reduces soluble and insoluble cerebral Abeta and lowers plaque burden in APP transgenic mice.

In transgenic animal models, humoral immunity directed against the beta-amyloid peptide (Abeta), which is deposited in the brains of AD patients, can reduce Abeta plaques and restore memory. However, initial clinical trials using active immunization with Abeta1-42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Abeta. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens.