Epigenetic insights into multiple sclerosis disease progression.

Multiple sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system, is today a leading cause of unpredictable lifelong disability in young adults. The treatment of patients in progressive stages remains highly challenging, alluding to our limited understanding of the underlying pathological processes. In this review, we provide insights into the mechanisms underpinning MS progression from a perspective of epigenetics, that refers to stable and mitotically heritable, yet reversible, changes in the genome activity and gene expression. We first recapitulate findings from epigenetic studies examining the brain tissue of progressive MS patients, which support a contribution of DNA and histone modifications in impaired oligodendrocyte differentiation, defective myelination/remyelination and sustained neuro-axonal vulnerability. We next explore possibilities for identifying factors affecting progression using easily accessible tissues such as blood by comparing epigenetic signatures in peripheral immune cells and brain tissue. Despite minor overlap at individual methylation sites, nearly 30% of altered genes reported in peripheral immune cells of progressive MS patients were found in brain tissue, jointly converging on alterations of neuronal functions. We further speculate about the mechanisms underlying shared epigenetic patterns between blood and brain, which likely imply the influence of internal (genetic control) and/or external (e.g. smoking and ageing) factors imprinting a common signature in both compartments. Overall, we propose that epigenetics might shed light on clinically relevant mechanisms involved in disease progression and open new avenues for the treatment of progressive MS patients in the future.

Structural, Dielectric, and Magnetic Properties of Multiferroic ( 1 - x ) La0.5Ca0.5MnO3-( x ) BaTi0.8Sn0.2O3 Laminated Composites.

High-performance lead-free multiferroic composites are desired to replace the lead-based ceramics in multifunctional device applications. Laminated compounds were prepared from ferroelectric and ferromagnetic materials. In this work, we present the laminated ceramics compound by considering the ferromagnetic La0.5Ca0.5MnO3 (LCMO) and the ferroelectric BaTi0.8Sn0.2O3 (BTSO) in two different proportions. Compounds ( 1-x ) LCMO-( x ) BTSO with x = 1 and 0 (pure materials) were synthesized by the sol-gel method, and x = 0.7 and 0.5 (laminated) compounds were elaborated by welding appropriate mass ratios of each pure material by using the silver paste technique. Structural, dielectric, ferroelectric, microstructure, and magnetic characterizations were conducted on these samples. X-ray scattering results showed pure perovskite phases confirming the successful formation of both LCMO and BTSO. Scanning electron microscope (SEM) images evidenced the laminated structure and good quality of the interfaces. The laminated composite materials have demonstrated a multiferroic behavior characterized by the ferroelectric and the ferromagnetic hysteresis loops. Furthermore, the enhancement of the dielectric constant in the laminated composite samples is mainly attributed to the Maxwell-Wagner polarization.

VAV1 regulates experimental autoimmune arthritis and is associated with anti-CCP negative rheumatoid arthritis.

Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (ß=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.

The multiple sclerosis risk gene IL22RA2 contributes to a more severe murine autoimmune neuroinflammation.

Single-nucleotide polymorphisms close to IL22RA2, coding for the soluble interleukin (IL)-22-binding protein (IL-22BP), are strongly and reproducibly associated with multiple sclerosis (MS), but there is little data on how this molecule may affect neuroinflammation. Here, we have studied the mouse ortholog in C57BL/6 wild-type and Il22ra2-deficient mice in the context of experimental autoimmune encephalomyelitis (myelin oligodendrocyte glycoprotein-EAE). In wild-type mice, we demonstrated changes in the levels of transcripts for IL-22, the signaling IL-22 receptor and IL-22BP in lymphoid tissues at the time of T-cell priming and in the inflamed central nervous system (CNS). Because IL-22BP is known to antagonize IL-22 signaling, a primarily pro-inflammatory cytokine, we hypothesized that the Il22ra2-deficient mice would have more severe EAE. Paradoxically, the knockout mice displayed a less severe disease course, less demyelination and less infiltration of immune cells in the CNS. The most straightforward interpretation of our findings is that lack of IL-22BP leads to a higher availability of IL-22, which in the case of CNS inflammation, surprisingly acts in a protective fashion. Thus, deletion of the ortholog of the MS risk gene Il22ra2 in mice has beneficial effects on EAE, which may be considered in new therapeutic strategies for treating neuroinflammation.

Stabilization mechanism of γ-Mg17Al12 and ß-Mg2Al3 complex metallic alloys.

Large-unit-cell complex metallic alloys (CMAs) frequently achieve stability by lowering the kinetic energy of the electron system through formation of a pseudogap in the electronic density of states (DOS) across the Fermi energy εF. By employing experimental techniques that are sensitive to the electronic DOS in the vicinity of εF, we have studied the stabilization mechanism of two binary CMA phases from the Al-Mg system: the γ-Mg17Al12 phase with 58 atoms in the unit cell and the ß-Mg2Al3 phase with 1178 atoms in the unit cell. Since the investigated alloys are free from transition metal elements, orbital hybridization effects must be small and we were able to test whether the alloys obey the Hume-Rothery stabilization mechanism, where a pseudogap in the DOS is produced by the Fermi surface-Brillouin zone interactions. The results have shown that the DOS of the γ-Mg17Al12 phase exhibits a pronounced pseudogap centered almost exactly at εF, which is compatible with the theoretical prediction that this phase is stabilized by the Hume-Rothery mechanism. The disordered cubic ß-Mg2Al3 phase is most likely entropically stabilized at high temperatures, whereas at lower temperatures stability is achieved by undergoing a structural phase transition to more ordered rhombohedral ß' phase at 214 ° C, where all atomic sites become fully occupied. No pseudogap in the vicinity of εF was detected for the ß' phase on the energy scale of a few 100 meV as determined by the 'thermal observation window' of the Fermi-Dirac function, so that the Hume-Rothery stabilization mechanism is not confirmed for this compound. However, the existence of a much broader shallow pseudogap due to several critical reciprocal lattice vectors [Formula: see text] that simultaneously satisfy the Hume-Rothery interference condition remains the most plausible stabilization mechanism of this phase. At Tc = 0.85 K, the ß' phase undergoes a superconducting transition, which slightly increases the cohesive energy and may contribute to relative stability of this phase against competing neighboring phases.

Anti-MOG antibodies are under polygenic regulation with the most significant control coming from the C-type lectin-like gene locus.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is genetically complex. There is evidence supporting a role of myelin oligodendrocyte glycoprotein (MOG) humoral immunity in MS. We aimed to determine the genetic regulation of anti-MOG antibodies and their involvement in disease, by using MOG-induced experimental autoimmune encephalomyelitis (EAE) in rat, an animal model that closely mimics human MS. We show polygenic regulation of anti-MOG antibodies in two backcross populations, including a major genetic determinant for antibody expression on chromosome 4, Amig3. We fine-mapped the region to 539 kilobases (kb) consisting of a complex of seven C-type lectin receptor genes (Dcir4, Dcir3, Dcir2, Dcir1, Dcar1, Mcl and Mincle) that was captured in the APLEC congenic strain. We confirmed that Amig3 regulates anti-MOG antibody levels in MOG-EAE, and further showed that immune reactions during initiation of EAE were skewed toward increased numbers of B cells in the EAE-protected APLEC strain, together with higher anti-MOG IgG1 and lower IgG2b levels. Taken together, our data demonstrated complex regulation of the antibody response during EAE and that skewing the antibody response toward Th2 contributed to protection from EAE.

Multiple sclerosis risk genotypes correlate with an elevated cerebrospinal fluid level of the suggested prognostic marker CXCL13.

BACKGROUND: The mechanisms of multiple sclerosis (MS) pathogenesis are still largely unknown. The heterogeneity of disease manifestations make the prediction of prognosis and choice of appropriate treatment protocols challenging. Recently, increased cerebrospinal fluid (CSF) levels of the B-cell chemokine CXCL13 was proposed as a possible marker for a more severe disease course and conversion from clinically isolated syndrome (CIS) to relapsing-remitting MS (RRMS). OBJECTIVE: To investigate whether there are genetic susceptibility variants in MS that correlate with the levels of CXCL13 present in the CSF of MS patients. METHODS: We genotyped the human leukocyte antigens HLA-DRB1 and HLA-A, plus a panel of single nucleotide polymorphisms (SNPs) that have been associated with susceptibility to MS and then correlated the genotypes with the levels of CXCL13, as measured with ELISA in the CSF of a total of 663 patients with MS, CIS, other neurological diseases (OND) or OND with an inflammatory component (iOND). RESULTS: Presence of the HLA-DRB1*15 and the MS risk genotypes for SNPs in the RGS1, IRF5 and OLIG3/TNFAIP3 gene regions correlated significantly with increased levels of CXCL13. CONCLUSION: Our results pointed towards a genetic predisposition for increased CXCL13 levels, which in MS patients correlates with the severity of the disease course. These findings encourage further investigation and replication, in an independent patient cohort.

Synthesis, characterization, DFT studies and catalytic activities of manganese(II) complex with 1,4-bis(2,2':6,2''-terpyridin-4'-yl) benzene.

A new di-manganese complex with "back-to-back" 1,4-bis(2,2':6,2''-terpyridin-4'-yl) benzene ligation has been synthesized and characterised by a variety of techniques. The back-to-back ligation presents a novel new mononuclear manganese catalytic centre that functions as a heterogeneous catalysis for the evolution of oxygen in the presence of an exogenous oxidant. We discuss the synthesis and spectroscopic characterizations of this complex and propose a mechanism for oxygen evolution activity of the compound in the presence of oxone. The di-manganese complex also shows efficient and selective catalytic oxidation of sulfides in the presence of H(2)O(2). Density functional theory calculations were used to assess the structural optimization of the complex and a proposed reaction pathway with oxone. The calculations show that middle benzene ring is distorted respect to both of metallic centers, and this in turn leads to negligible resonance of electrons between two sides of complex. The calculations also indicate the unpaired electron located on oxyl-ligand emphasizes the radical mechanism of water oxidation for the system.

Exchange bias in bulk layered hydroxylammonium fluorocobaltate (NH3OH)2CoF4.

The magnetic properties of layered hydroxylammonium fluorocobaltate (NH(3)OH)(2)CoF(4) were investigated by measuring its dc magnetic susceptibility in zero-field-cooled (ZFC) and field-cooled (FC) regimes, its frequency dependent ac susceptibility, its isothermal magnetization curves after ZFC and FC regimes, and its heat capacity. Effects of pressure and magnetic field on magnetic phase transitions were studied by susceptibility and heat capacity measurements, respectively. The system undergoes a magnetic phase transition from a paramagnetic state to a canted antiferromagnetic state exhibiting a weak ferromagnetic behavior at T(C) = 46.5 K and an antiferromagnetic transition at T(N) = 2.9 K. The most spectacular manifestation of the complex magnetic behavior in this system is a shift of the isothermal magnetization hysteresis loop in a temperature range below 20 K after the FC regime-an exchange bias phenomenon. We investigated the exchange bias as a function of the magnetic field during cooling and as a function of temperature. The observed exchange bias was attributed to the large exchange anisotropy which exists due to the quasi-2D structure of the layered (NH(3)OH)(2)CoF(4) material.

RGMA and IL21R show association with experimental inflammation and multiple sclerosis.

Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31. Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA, IL21R and IL4R. We tested the association with multiple sclerosis (MS) in a Nordic case-control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR)=1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-gamma (IFN-gamma) and TNF in cerebrospinal fluid of MS patients. In IL21R, there was one positively associated (OR=1.14) and two protective (OR=0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-gamma expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets.

Multiple loci comprising immune-related genes regulate experimental neuroinflammation.

A 58 Mb region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis (EAE) was genetically dissected. High-resolution linkage analysis in an advanced intercross line (AIL) revealed four quantitative trait loci (QTLs), Eae24-Eae27. Both Eae24 and Eae25 regulated susceptibility and severity phenotypes, whereas Eae26 regulated severity and Eae27 regulated susceptibility. Analyses of the humoral immune response revealed that the levels of serum anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobin G1 (IgG1) antibodies are linked to Eae24 and anti-MOG IgG2b antibodies are linked to both Eae24 and Eae26. We tested the parental DA strain and six recombinant congenic strains that include overlapping fragments of this region in MOG-EAE. Eae24 and Eae25 showed significant protection during the acute phase of EAE, whereas Eae25 and Eae26 significantly modified severity but not susceptibility. The smallest congenic fragment, which carries Eae25 alone, influenced both susceptibility and severity, and protected from the chronic phase of disease. These results support the multiple QTLs identified in the AIL. By demonstrating several QTLs comprising immune-related genes, which potentially interact, we provide a significant step toward elucidation of the polygenically regulated pathogenesis of MOG-EAE and possibly multiple sclerosis (MS), and opportunities for comparative genetics and testing in MS case-control cohorts.

Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis.

Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries. A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1* 15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We further identified association to rheumatoid arthritis in CCL2, CCL8 and CCL13, indicating common regulatory mechanisms for complex diseases.

Spin amplitude modulation driven magnetoelectric coupling in the new multiferroic FeTe2O5Br.

The magnetic and ferroelectric properties of the layered geometrically frustrated cluster compound FeTe2O5Br were investigated with single-crystal neutron diffraction and dielectric measurements. An incommensurate transverse amplitude modulated magnetic order with the wave vector q=(1/2,0.463,0) develops below T(N)=10.6(2) K. Simultaneously, a ferroelectric order due to exchange striction involving polarizable Te4+ lone-pair electrons develops perpendicular to q and to Fe3+ magnetic moments. The observed magnetoelectric coupling is proposed to originate from the temperature dependent phase difference between neighboring amplitude modulation waves.

E. coli superdiffusion and chemotaxis-search strategy, precision, and motility.

Escherichia coli motion is characterized by a sequence of consecutive tumble-and-swim events. In the absence of chemical gradients, the length of individual swims is commonly believed to be distributed exponentially. However, recently there has been experimental indication that the swim-length distribution has the form of a power-law, suggesting that bacteria might perform superdiffusive Lévy-walk motion. In E. coli, the power-law behavior can be induced through stochastic fluctuations in the level of CheR, one of the key enzymes in the chemotaxis signal transmission pathway. We use a mathematical model of the chemotaxis signaling pathway to study the influence of these fluctuations on the E. coli behavior in the absence and presence of chemical gradients. We find that the population with fluctuating CheR performs Lévy-walks in the absence of chemoattractants, and therefore might have an advantage in environments where nutrients are sparse. The more efficient search strategy in sparse environments is accompanied by a generally larger motility, also in the presence of chemoattractants. The tradeoff of this strategy is a reduced precision in sensing and following gradients, as well as a slower adaptation to absolute chemoattractant levels.

Definition of arthritis candidate risk genes by combining rat linkage-mapping results with human case-control association data.

OBJECTIVE: To define genomic regions that link to rat arthritis and to determine the potential association with rheumatoid arthritis (RA) of the corresponding human genomic regions. METHODS: Advanced intercross lines (AIL) between arthritis susceptible DA rats and arthritis resistant PVG.1AV1 rats were injected with differently arthritogenic oils to achieve an experimental situation with substantial phenotypic variation in the rat study population. Genotyping of microsatellite markers was performed over genomic regions with documented impact on arthritis, located on rat chromosomes 4, 10 and 12. Linkage between genotypes and phenotypes were determined by R/quantitative trait loci (QTL). Potential association with RA of single nucleotide polymorphisms (SNPs) in homologous human chromosome regions was evaluated from public Wellcome Trust Case Control Consortium (WTCCC) data derived from 2000 cases and 3000 controls. RESULTS: A high frequency of arthritis (57%) was recorded in 422 rats injected with pristane. Maximum linkage to pristane-induced arthritis occurred less than 130 kb from the known genetic arthritis determinants Ncf1 and APLEC, demonstrating remarkable mapping precision. Five novel quantitative trait loci were mapped on rat chromosomes 4 and 10, with narrow confidence intervals. Some exerted sex-biased effects and some were linked to chronic arthritis. Human homologous genomic regions contain loci where multiple nearby SNPs associate nominally with RA (eg, at the genes encoding protein kinase Calpha and interleukin 17 receptor alpha). CONCLUSIONS: High-resolution mapping in AIL populations defines limited sets of candidate risk genes, some of which appear also to associate with RA and thus may give clues to evolutionarily conserved pathways that lead to arthritis.

Surface-spin magnetism of antiferromagnetic NiO in nanoparticle and bulk morphology.

The surface-spin magnetism of the antiferromagnetic (AFM) material NiO in nanoparticle and bulk morphology was investigated by magnetic measurements (temperature-dependent zero-field-cooled (zfc) and field-cooled (fc) dc susceptibility, ac susceptibility and zfc and fc hysteresis loops). We addressed the question of whether the multisublattice ordering of the uncompensated surface spins and the exchange bias (EB) effect are only present in the nanoparticles, originating from their high surface-to-volume ratio or if these surface phenomena are generally present in the AFM materials regardless of their bulky or nanoparticle morphology, but the effect is just too small to be detected experimentally in the bulk due to a very small surface magnetization. Performing experiments on the NiO nanoparticles of different sizes and bulk NiO grains, we show that coercivity enhancement and hysteresis loop shift in the fc experiments, considered to be the key experimental manifestations of multisublattice ordering and the EB effect, are true nanoscale phenomena only present in the nanoparticles and absent in the bulk.

Prognostic and predictive value of cathepsins D and L in operable breast cancer patients.

None of the established prognostic factors in breast cancer (BC) is able to determine the final outcome with certainity. Tumor biological factors involved in tumor invasion and metastasis, such as cathepsins and proteins of u-PA system, have been put forward in the recent literature as strong novel prognostic factors in BC. We therefore evaluated prognostic and predictive value of cathepsin-D (CD) and cathepsin-L (CL) in 715 operable BC patients. CD and CL were determined in tumor extracts using immunoradiometric and ELISA assays, respectively. During follow-up (median 37 months), 151 (21%) patients relapsed. In a multivariate analysis of disease-free survival (DFS), CL (p=0.04), nodal status (p<0.001) and hormone receptor status (p<0.001) were the only independent significant prognostic factors. CL thus provided independent prognostic information on DFS and could also predict a response to adjuvant chemotherapy (ChT), while CD had no significant prognostic and predictive impact.

Distinct expression of TGF-beta1 mRNA in the endo- and epineurium after nerve injury.

TGF-beta is a multifunctional regulatory protein with important effects on cell proliferation and differentiation, immune reactivity and extracellular matrix (ECM). During peripheral regeneration it can have growth promoting effects for axonal sprouting, but on the other hand, it may be involved in epineurial scarring and neuroma formation. We studied the expression of TGF-beta1 mRNA in the rat peripheral nerve with real time-PCR at 1, 3, 5, 7, 14, 21, 28, 35, and 42 days after transection. The sciatic nerve was sutured after transection to prevent axonal regeneration. Samples from both proximal and distal stumps were collected. To distinguish the possible different expression in the endo- and epineurium these two compartments were studied separately. The most significant finding was observed in the epineurium of the proximal stump 35 days after the operation. The expression of TGF-beta1 mRNA was over 700 times higher than that found in the non-operated controls. At the same time the expression of TGF-beta1 mRNA in the endoneurium was only twice as high as the values measured from the non-operated controls. Distally the TGF-beta1 mRNA expression in the endoneurium reached its peak after 2 weeks, and at weeks 3-6, the expression was two to four times higher than in the controls. This study supports the concept that TGF-beta1 can affect epineurial scarring.

Current gene-mapping strategies in experimental models of multiple sclerosis.

Both family-based linkage analyses and population-based association studies have failed to identify disease-regulatory non-human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesis-driven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers.