A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.

Common and rare variants of the renin-angiotensin system and their relation to antihypertensive drug responses

Most of the diseases affecting public health, like hypertension, are multifactorial by etiology. Hypertension is influenced by genetic, life style and environmental factors. Estimation of the influence of genes to the risk of essential hypertension varies from 30 to 50%. It is plausible that in most of the cases susceptibility to hypertension is determined by the action of more than one gene. Although the exact molecular mechanism underlying essential hypertension remains obscure, several monogenic forms of hypertension have been identified. Since common genetic variations may predict, not only to susceptibility to hypertension, but also response to antihypertensive drug therapy, pharmacogenetic approaches may provide useful markers in finding relations between candidate genes and phenotypes of hypertension. The aim of this study was to identify genetic mutations and polymorphisms contributing to human hypertension, and examine their relationships to intermediate phenotypes of hypertension, such as blood pressure (BP) responses to antihypertensive drugs or biochemical laboratory values. Two groups of patients were investigated in the present study. The first group was collected from the database of patients investigated in the Hypertension Outpatient Ward, Helsinki University Central Hospital, and consisted of 399 subjects considered to have essential hypertension. Frequncies of the mutant or variant alleles were compared with those in two reference groups, healthy blood donors (n = 301) and normotensive males (n = 175). The second group of subjects with hypertension was collected prospectively. The study subjects (n=313) underwent a protocol lasting eight months, including four one-month drug treatment periods with antihypertensive medications (thiazide diuretic, β-blocker, calcium channel antagonist, and an angiotensin II receptor antagonist). BP responses and laboratory values were related to polymorphims of several candidate genes of the renin-angiotensin system (RAS). In addition, two patients with typical features of Liddle’s syndrome were screened for mutations in kidney epithelial sodium channel (ENaC) subunits. Two novel mutations causing Liddle’s syndrome were identified. The first mutation identified located in the beta-subunit of ENaC and the second mutation found located in the gamma-subunit, constituting the first identified Liddle mutation locating in the extracellular domain. This mutation showed 2-fold increase in channel activity in vitro. Three gene variants, of which two are novel, were identified in ENaC subunits. The prevalence of the variants was three times higher in hypertensive patients (9%) than in reference groups (3%). The variant carriers had increased daily urinary potassium excretion rate in relation to their renin levels compared with controls suggesting increased ENaC activity, although in vitro they did not show increased channel activity. Of the common polymorphisms of the RAS studied, angiotensin II receptor type I (AGTR1) 1166 A/C polymorphism was associated with modest changes in RAS activity. Thus, patients homozygous for the C allele tended to have increased aldosterone and decreased renin levels. In vitro functional studies using transfected HEK293 cells provided additional evidence that the AGTR1 1166 C allele may be associated with increased expression of the AGTR1. Common polymorphisms of the alpha-adducin and the RAS genes did not significantly predict BP responses to one-month monotherapies with hydroclorothiazide, bisoprolol, amlodipin, or losartan. In conclusion, two novel mutations of ENaC subunits causing Liddle’s syndrome were identified. In addition, three common ENaC polymorphisms were shown to be associated with occurrence of essential hypertension, but their exact functional and clinical consequences remain to be explored. The AGTR1 1166 C allele may modify the endocrine phenotype of hypertensive patients, when present in homozygous form. Certain widely studied polymorphisms of the ACE, angiotensinogen, AGTR1 and alpha-adducin genes did not significantly affect responses to a thiazide, β-blocker, calcium channel antagonist, and angiotensin II receptor antagonist.

Antipyrine complexes of rare-earth nitrates

Antipyrine complexes of eight rare-earth nitrates of the composition M(C11H12N2O)3 (NO3)3 where M = La, Ce, Pr, Nd, Sm, Gd, Er, and Y, have been prepared by a new, simple method and characterised. The complexes undergo exothermic decomposition at ~3oo°C. Infrared and U.V. spectral studies of the complexes indicate that antipyrine coordinates to metal through oxygen. The nature of the nitrate bonding is discussed in the light of infrared evidence, and conductivity studies in nitromethane and dimethylformamide.

Using IRAP markers for analysis of genetic variability in populations of resource and rare species of plants

Species specific LTR retrotransposons were first cloned in five rare relic species of drug plants located in the Perm’ region. Sequences of LTR retrotransposons were used for PCR analysis based on amplification of repeated sequences from LTR or other sites of retrotransposons (IRAP). Genetic diversity was studied in six populations of rare relic species of plants Adonis vernalis L. by means of the IRAP method; 125 polymorphic IRAP markers were analyzed. Parameters for DNA polymorphism and genetic diversity of A. vernalis populations were determined.

Rare-earth trichloroacetates

The rare-earth trichloroacetates having the formula Ln(Cl3CCOO)3. 3H2O, where Ln = La, Pr, Nd, Sm, Gd or Y, were investigated by conductimetric, cryoscopic and infrared methods. The results suggest a structure in which the acetate anion coordinates to the metal through both the oxygen and the water molecules remain outside the coordination sphere.

Antipyrine complexes of rare earth perchlorates

Rare earth perchlorate-antipyrine (ap) complexes of the formula Ln (ClO4)3.6 ap have been prepared and characterised. Infrared and electronic spectra showed the co-ordination through carbonyl oxygen. Conductivity and molecular weight data indicated a co-ordination number of six for these complexes.

Dimethyl sulphoxide complexes of rare-earth perchlorates

Dimethylsulphoxide (DMSO) complexes of rare-earth perchlorates of the formula M(ClO4)3·n DMSO (M = La, Ce, Pr and Nd, n = 8; M = Sm, Gd and Y, n = 7) have been prepared. I.r. studies indicate co-ordination through oxygen. Cryoscopic and conductivity data show co-ordination number of 7 and 8.

Dimethyl formamide complexes of rare-earth nitrates

Dimethyl formamide complexes of five rare-earth nitrates, M(DMF)4(NO3)3 where M = La, Pr, Nd, Sm or Y have been prepared and their infra-red spectra and conductivities in nitromethane and DMF studied. It is suggested that the co-ordination number of the metal ion in these complexes is nine.

Search for the rare decays B+→μ+μ-K+, B0→μ+μ-K*(892)0, and Bs0→μ+μ-ϕ at CDF

We search for b to s\mu^+\mu^- transitions in B meson (B^+, B^0, or B^0_s) decays with 924pb^{-1} of p pbar collisions at sqrt(s)=1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. We find excesses with significances of 4.5, 2.9, and 2.4 standard deviations in the B^+ to \mu^+\mu^-K^+, B^0 to \mu^+\mu^-K^*(892)^0, and B_s^0 to \mu^+\mu^-\phi decay modes, respectively. Using B to J/psi h (h = K^+, K^*(892)^0, phi) decays as normalization channels, we report branching fractions for the previously observed B^+ and B^0 decays, BR(B^+ to \mu^+\mu^-K^+)=(0.59\pm0.15\pm0.04) x 10^{-6}, and BR(B^0 to \mu^+\mu^-K^*(892)^0)=(0.81\pm0.30\pm0.10) x 10^{-6}, where the first uncertainty is statistical, and the second is systematic. These measurements are consistent with the world average results, and are competitive with the best available measurements. We set an upper limit on the relative branching fraction BR(B_s^0 to \mu^+\mu^-\phi)/BR(B_s^0 to J/\psi\phi)

Using IRAP markers for analysis of genetic variability in populations of resource and rare species of plants

Species specific LTR retrotransposons were first cloned in five rare relic species of drug plants located in the Perm’ region. Sequences of LTR retrotransposons were used for PCR analysis based on amplification of repeated sequences from LTR or other sites of retrotransposons (IRAP). Genetic diversity was studied in six populations of rare relic species of plants Adonis vernalis L. by means of the IRAP method; 125 polymorphic IRAP markers were analyzed. Parameters for DNA polymorphism and genetic diversity of A. vernalis populations were determined.

Search for the rare decays B+→μ+μ-K+, B0→μ+μ-K*(892)0, and Bs0→μ+μ-ϕ at CDF

We search for b→sμ+μ- transitions in B meson (B+, B0, or Bs0) decays with 924  pb-1 of pp̅ collisions at √s=1.96  TeV collected with the CDF II detector at the Fermilab Tevatron. We find excesses with significances of 4.5, 2.9, and 2.4 standard deviations in the B+→μ+μ-K+, B0→μ+μ-K*(892)0, and Bs0→μ+μ-ϕ decay modes, respectively. Using B→J/ψh (h=K+, K*(892)0, ϕ) decays as normalization channels, we report branching fractions for the previously observed B+ and B0 decays, B(B+→μ+μ-K+)=(0.59±0.15±0.04)×10-6, and B(B0→μ+μ-K*(892)0)=(0.81±0.30±0.10)×10-6, where the first uncertainty is statistical, and the second is systematic. We set an upper limit on the relative branching fraction B(Bs0→μ+μ-ϕ)/B(Bs0→J/ψϕ)<2.6(2.3)×10-3 at the 95(90)% confidence level, which is the most stringent to date.

Investigation of activated transport in hole doped rare earth manganites in the high temperature paramagnetic regime

Electronic transport in the high temperature paramagnetic regime of the colossal magnetoresistive oxides, La(1-x)A(x)MnO(3), A=Ca, Sr, Ba, x similar or equal to 0.1-0.3, has been investigated using resistivity measurements. The main motivation for this work is to relook into the actual magnitude of the activation energy for transport in a number of manganites and study its variation as a function of hole doping (x), average A-site cation radius (< r(A)>), cationic disorder (sigma(2)) and strain (epsilon(zz)). We show that contrary to current practice, the description of a single activation energy in this phase is not entirely accurate. Our results clearly reveal a strong dependence of the activation energy on the hole doping as well as disorder. Comparing the results across different substituent species with different < r(A)> reveals the importance of sigma(2) as a metric to qualify any analysis based on (r(A)). (c) 2006 Elsevier Ltd. All rights reserved.

Charge-order driven multiferroic and magneto-dielectric properties of rare earth manganates

Charge-order driven magnetic ferroelectricity is shown to occur in several rare earth manganates of the general formula, Ln(1-x)A(x)MnO(3) (In = rare earth, A = alkaline earth). Charge-ordered manganates exhibit dielectric constant anomalies around the charge-ordering or the antiferromagnetic transition temperature. Magnetic fields have a marked effect on the dielectric properties of these compounds, indicating the presence of coupling between the magnetic and electrical order parameters. Magneto-dielectric properties are retained in small particles of the manganates. The observation of magneto-ferroelectricity in these manganates is in accordance with theoretical predictions.

Charge-order driven multiferroic and magneto-dielectric properties of rare earth manganates

Charge-order driven magnetic ferroelectricity is shown to occur in several rare earth manganates of the general formula, Ln(1-x)A(x)MnO(3) (In = rare earth, A = alkaline earth). Charge-ordered manganates exhibit dielectric constant anomalies around the charge-ordering or the antiferromagnetic transition temperature. Magnetic fields have a marked effect on the dielectric properties of these compounds, indicating the presence of coupling between the magnetic and electrical order parameters. Magneto-dielectric properties are retained in small particles of the manganates. The observation of magneto-ferroelectricity in these manganates is in accordance with theoretical predictions.

Piezoresistivity (with uniaxial strain) in nanocrystalline films of rare-earth manganites

We present a study of the piezoresistivity in nanostructured. polycrystalline films of La0.67Ca0.33MnO3 and La0.67Sr0.33MnO3 grown on oxidized Si (100) substrates. We have observed that the hole doped rare-earth manganites, which are well known for being colossal magnetoresistive (CMR) show change in its resistance under uniaxial strain even at room temperature. The piezoresistance was measured at room temperature by bending the Si cantilevers (on which the film is grown) in flexural mode both with compressive and tensile strain. The resistance of the film increases with tensile strain and decreases with compressive strain. A large gauge factor of 15-20 is seen in these films at room temperature.