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Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 × 10−4 (OR=1.24 (1.10-1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA. [ABSTRACT FROM AUTHOR]

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10). [ABSTRACT FROM AUTHOR]

The article discusses a study on the Zinc Finger Protein 804A gene (ZNF804A) genotype. It investigates the association of ZNF804A at the disease-associated single nucleotide polymorphism rs1344706 with variation in neuro-psychological performance of both patients and control. The study used a large discovery sample and implemented a study design where replication of findings in an independent data set was allowed. It suggests that the study can have potential use in the nosologic classification of schizophrenia and related psychotic disorders.

Aims: We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. Methods: We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ2 test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10–45. Results: We found 40,593 SNPs which are genome-wide significantly (p ≤ 10–8) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development. Conclusion: Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Multiple rare nonsynonymous variants in APC predispose to colorectal adenomas. The mechanisms through which such variants act have been unclear, but it has been proposed that a specific ('just-right') level of β-catenin signaling is required for colorectal tumorigenesis. This appears to be mediated by selection for APC genotypes that retain one, or rarely two, 20 amino acid β-catenin downregulating repeats (20AARs). We investigated the mechanism through which the variant p.Glu1317Gln (c.3949G>C) contributes to colorectal tumorigenesis. We compared the patterns of somatic APC mutations in tumors from patients with attenuated familial adenomatous polyposis (AFAP) who did, or did not, coinherit p.Glu1317Gln with their AFAP-causing APC mutations. Only 8.2% (4/49) of tumors carrying p.Glu1317Gln had somatic mutations predicted to result in mutant polypeptides retaining a single 20AAR, compared to 62.1% (36/58) of those which did not carry this variant ( P=5.64×10−9). Furthermore, tumors with p.Glu1317Gln often carried somatic mutations that were unusually early or late (downstream of the second 20AAR) in the APC open reading frame. These data support a novel mechanism in which p.Glu1317Gln in combination with other weak mutant APC alleles (generating polypepetides with zero, two, or three 20AARs) can provide the necessary growth advantage for colorectal tumorigenesis. Hum Mutat 30:1-7, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the impact of nitric oxide synthase 1 (NOS1) gene to cognition of schizophrenic patients and healthy control subjects. It states that the study used several methodologies such as the genotyping of Irish and German patients, assessment cognitive functioning, and statistical analyses. Results show that NOS1 genotype on verbal intelligence quotient (IQ) affects the Irish patient. It concludes the association between NOS1 and cognition.

The objectives of this study were to examine sex differences in depressive symptom patterns in 475 sib pairs with well-defined recurrent major depression and to test the hypotheses that (a) symptom patterns show higher intraclass correlations within same sex sib pairs versus mixed sex sib pairs; and (b) symptoms more associated with women, e.g. atypical depressive and anxiety symptoms, account for differences between male and female siblings within the same family. A total of 878 individuals, with a past history of at least two depressive episodes, were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry interview and diagnosed according to DSM-IV using a computerized scoring program (CATEGO5). Intraclass correlations were compared between mixed and same sex sibs, and a conditional regression analysis in mixed sex sib pairs was performed to test whether specific symptoms account for differences between male and female siblings within the same family. Women showed a significantly earlier onset of depression compared with men (23.0 years, SD=10.6 versus 25.5, SD=12.5 years, P=0.0004), and a significantly greater frequency of several aspects of depressed mood was found in women compared with men, including atypical depressive features of fatiguability, appetite gain, weight gain and hypersomnia. Discordant sib-pair data analyses revealed five symptoms that accounted for the sex differences between siblings (P=.000035): phobia (exp(B)=2.04, P=0.017), hypersomnia (exp(B)=1.37, P=0.055), appetite loss (exp(B)=1.38, P=0.004) and appetite gain (exp(B)=2.19, P<0.001). Sex significantly modifies clinical features of depression and an earlier onset of depression and atypical depressive symptoms occur more frequently in women. Depression and Anxiety 0:1–8, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Both childhood trauma (CT) and genetic factors contribute to the pathophysiology of depression. We studied the relationship of CT to age of onset (AO) of depression, personality traits, and expression of symptom dimensions in 324 adults with recurrent unipolar depression. Subjects received structured psychiatric interviews and completed CT, depressive symptom, and personality rating questionnaires. Experience of at least one type of trauma was reported by 79.9% of subjects, and the most common forms of trauma were physical neglect, emotional abuse, and emotional neglect. There was an earlier AO of depression in the groups that reported CT compared to those that reported none, with earliest AO occurring in those who had experienced the highest levels of CT. There were no significant correlations between overall CT scores and neuroticism or extraversion. Total CT was a significant (P=.008) predictor of the Mood symptom dimension, mostly accounted for by emotional abuse (P=.019), and physical neglect predicted the Anxiety symptom dimension (P=.002). All types of CT are commonly reported in individuals with depression, and emotional abuse and physical neglect, though previously less well identified, appear to have an important role in the pathogenesis of depressive disorders. The effect of CT on individuals with an underlying genetic vulnerability to depression may result in differences in depressive phenotype characterized by earlier AO of depression and the expression of specific depressive symptom dimensions. Depression and Anxiety 24:163–168, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Synergistic interaction between genes on chromosome 22q11 recently has been proposed as a possible mechanism which could confer increased risk for schizophrenia. Based on this hypothesis, our study aimed to explore main, cis- and trans-interacting effects of three candidate genes on 22q11, ProDH, COMT and ZDHHC8. We selected four putative risk variants, residing within these genes, ProDH 1945, ProDH 2026, COMT ValMet and ZDHHC8 rs175174, and studied these in a large family-based schizophrenia association sample of European origin (488 Bulgarian parent–offspring trios). The presence of interaction between the variants was tested by conditional logistic regression analysis based on a case–pseudocontrol design. Our study did not find statistical evidence for allelic (investigation of ProDH markers only), genotypic, haplotypic, or interactive effects between ProDH, COMT and ZDHHC8. Our data do not support the hypothesis that an interaction between these genes influences susceptibility to schizophrenia. [Copyright &y& Elsevier]

OBJECTIVES: To investigate behavioral components of Alzheimer's disease (AD) and to analyze behavioral components in relation to disease severity, apolipoprotein E genotype (APOE), sex, years of education, age at onset, and cognitive impairment. DESIGN: Cross-sectional study. SETTING: Data were collected from community-dwelling individuals and those residing in nursing homes. PARTICIPANTS: A total of 1,120 individuals meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for late-onset probable AD. MEASUREMENTS: Behavioral symptoms were assessed using the Neuropsychiatric Inventory. First-order polychoric correlations, controlling for disease severity, between the 12 symptom domain scores were estimated, and the resulting matrix underwent principal components analysis. RESULTS: Four interpretable components were identified: behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability). Scores on the four components were associated with severity of cognitive impairment. Higher behavioral dysfunction, agitation, and mood component scores were associated with lower age at onset. Behavioral dysfunction and mood component scores were associated with sex. None of the components were associated with age at assessment, years of education, or number of APOE ℇ4 alleles. CONCLUSION: Four behavioral components were identified that were comparable with those observed previously. Future analysis of these components will strengthen understanding of the underlying pathology of behavioral symptoms and AD. [ABSTRACT FROM AUTHOR]

Objectives: In view of the linkage disequilibrium structure of the genome, the selection of maximally informative SNP markers is a fundamental issue in the design of association studies. Currently used selection methods rely on pairwise marker correlation or informativity measures for subsets of markers. Nevertheless, the selected markers do not provide a completely satisfactory description of the individual remaining markers. The number of tag markers can be further reduced by using haplotypic information, but then the results of association analysis are difficult to interpret. Methods and Results: We propose a non-linear Gauss-type algorithm selecting a subset of markers which is optimal with respect to the informativity measures and allows an explicit reconstruction of all other known markers, thus permitting direct inference of allelic association. The selection is based on the haplotype distribution in the population, but can be adapted to work with unphased genotypes directly. Conclusions: The proposed algorithm provides a rational methodology of informative marker selection, allowing for control and optimisation of information content and full marker reconstruction. Moreover, the reconstruction step can also be applied to tag markers selected using a different method at the stage of study design, identifying those markers which cannot be uniquely recovered from the chosen tags. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = ≈1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10-7) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function. [ABSTRACT FROM AUTHOR]

The article cites a study which identifies 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) as a possible susceptibility gene for schizophrenia. It is suggested that reduced expression of CNP gene was present among schizophrenics. The objective of this study was to determine the correlation between CNP expression and DNA polymorphisms. In conclusion, this study supported the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology.

Objectives: It is well known that genotyping error adversely affects the power of genetic case-control association studies but there is little research on its effects on type I error, and none that has addressed possible differences in genotype error rates between cases and controls. Methods: We used simulations to examine the influence of genotyping error on the type I error probability given by case-control studies. The effect of genotyping error on the magnitude of type I error was explored for a single marker of varying minor allele frequency (MAF), and for haplotypic tests based on two markers with varying MAF and linkage disequilibrium (LD) measure r2. Results: We show that even with low genotyping error rates (<0.01), systematic differences in the error rate between samples can result in type I error rates substantially above 0.05. The effect was maximal for markers with small MAF, markers in strong LD, and where a common allele is more frequently misclassified as a rare allele than vice versa. The problem was also exacerbated by the use of large samples. Conclusions: Our results show that small differential genotyping error rates between cases and controls pose significant problems for association analyses. Differential genotyping error rates are particularly likely to arise where genotype data are combined from multiple sites, or where case genotypes are examined against archived reference population cohort genotypes that are being generated in several countries. Although these strategies may be necessary to obtain adequately powered samples, our data show the importance of stringent quality control. Furthermore, associations based on rare haplotypes should be treated with caution. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Depression is a clinically heterogeneous disorder thought to result from multiple genes interacting with environmental and developmental components. A dimensional rather than a categorical approach to depressive phenotype definition may be more useful for identification of susceptibility genes. To perform an exploratory factor analysis on a range of depressive and anxiety symptoms in a large, well-defined sample of depressed siblings, as well as a confirmatory factor analysis in a separate large group of unrelated depressed subjects, and to analyze correlations of identified symptom dimensions between depressed siblings. Subjects (N = 1034),including475siblingpairs, with a history of at least 2 depressive episodes were recruited from the Depression Network Study, a large-scale multicenter collection of families affected by recurrent unipolar depression. Subjects were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to the DSM-IV and the International Classification of Diseases, 10th Revision, using a computerized scoring program (CATEGO5). Factor analysis was carried out on 26 depression symptom items, including 4 anxiety screening items. Confirmatory factor analysis was performed on an independent sample of 485 depressed individuals. Four interpretable factors were identified: (1) mood symptoms and psychomotor retardation; (2) anxiety; (3) psychomotor agitation, guilt, and suicidality; and (4) appetite gain and hypersomnia. For each symptom group, a quantitative scale was constructed, and correlations between siblings were calculated. There was a moderate degree of siblings homotypia for some depressive symptoms, and factors 1, 2, and 3 showed significant positive familial correlation (0.145 [P=.001], 0.335 [P<0.001], and 0.362 [P<.001], respectively). This is the first study of large, well-defined samples of depressed subjects in whom symptom dimensions have been derived and then confirmed using independent material. The significant correlations between siblings for 3 of the dimensions suggest substantial familial, perhaps genetic, etiologies. [ABSTRACT FROM AUTHOR]

There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium. [ABSTRACT FROM AUTHOR]

We study the effect of ion-plasma surface nitriding on the phase composition, microstructure, surface microhardness, and tensile properties of the AISI 321-type stainless steel produced by wire-feed electron-beam additive manufacturing (EBAM). Ion-plasma nitriding at 550 °C for 12 h in N2/H2 gases provides the formation of a 10-μm thick surface layer with solid solution strengthening by nitrogen atoms (Fe-γN и Fe-αN) and dispersion hardening (γ'-Fe4N) with a fivefold increase in surface hardness up to ≈12 GPa. Surface ion-plasma nitriding of additively produced steel does not affect the anisotropy of mechanical properties, but rather increases the yield strength and ultimate tensile strength while maintaining high plasticity in the specimens. In specimens after ion-plasma nitriding, the fracture mechanism changes from initially ductile to a quasi-brittle fracture near the surface and ductile transgranular mode in the central parts of the specimens. The nitrided layer fractured in a transgranular brittle manner with the formation of quasi-cleavage facets and secondary cracks near the surface of the specimens. Brittle fracture of the compositional layer occurs due to the complex solid solution strengthening and particle hardening of austenite. [ABSTRACT FROM AUTHOR]

The microstructure, deformation mechanisms, tensile properties and fracture micromechanisms of ultrahigh-interstitial austenitic Fe-22Cr-26Mn-1.3V-0.7C-1.2N (mass.%) steel were investigated in wide temperature interval. After conventional homogenization and solid-solution treatment, the steel possesses complex hardening which includes grain boundary, solid-solution and dispersion strengthening. In the temperature interval of −60 to +60 °C, steel demonstrates striking temperature dependence of a yield strength which could be enhanced by the increase in solid-solution treatment temperature. The variation in test temperature does not change the dominating deformation mechanism of the steel, dislocation slip and insufficiently influences tensile elongation and fracture micromechanisms. The insignificant increase in the fraction of brittle cleavage-like component on the fracture surfaces of the specimens in low-temperature deformation regime is promoted by increase in planarity of dislocation arrangement and the gaining activity of mechanical twinning. In high-temperature range (200–300 °C) of deformation, a negative strain-rate dependence, serrations on the stress-strain diagrams and improved strain-hardening associated with a dynamic strain aging phenomenon have been observed. [ABSTRACT FROM AUTHOR]

The experimental evidence for the realization of a superplastic behavior with 900% elongation in V-alloyed high-nitrogen austenitic Fe-19Cr-22Mn-1.5V-0.3C-0.6N steel was proposed. Using thermomechanical processing, a misoriented grain/subgrain austenitic microstructure with a high density of deformation-assisted defects and precipitates was developed in the steel. During high-temperature tensile deformation in a temperature interval from 850 to 1000 °C and strain-rate range from 4 × 10−4 s−1 to 6 × 10−3 s−1, this microstructure demonstrated the characteristics of superplastic flow: elongation in the interval 400–900%, strain-rate sensitivity exponent m = 0.40–0.49, grain boundary sliding mechanism. The maximum elongation to failure (900%) was reached at deformation temperature 950 °C and strain rate 4 × 10−4 s−1. [ABSTRACT FROM AUTHOR]

A billet of an AISI 304-type austenitic stainless steel has been built using a wire-feed electron beam additive manufacturing (EBAM) in a layer-by-layer strategy. A microstructure, grain boundary assemble, phase composition and tensile properties of steel billet have been investigated in as-built specimens and after post-built solid-solution treatment. As-built austenitic stainless steel is a highly anisotropic heterophase material with high fraction of interphase boundaries (austenite/ferrite) and intergranular boundaries (austenite/austenite). A macroscopically inhomogeneous (layered) structure with columnar austenitic grain growth has been produced during EBAM processing. The coarse-grained austenitic structure contains δ-ferrite of dendritic morphology in as-built specimens. Ductility and strength properties of the additively manufactured steel show substantial anisotropy, which is strongly correlated with macro- and microstructural peculiarities of the as-built billet. Post-built solid-solution treatment decreases a volume fraction of ferrite in the microstructure, changes the morphology of ferrite phase and, therefore, varies the distribution of interphase boundaries (ferrite/austenite). The effect of post-built solid-solution treatment on tensile properties of the EBAM manufactured steel is discussed taking into account a change in microstructure and phase composition, grain and phase boundary distribution in the specimens. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Role of the Oxidative DNA Damage Repair Gene OGG1 in Colorectal Tumorigenesis" in the 2013 issue is presented.

A correction to the article "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease," that appeared in the September 6, 2009 issue is presented.

We investigated the phase composition, microstructure, mechanical properties, and fracture mechanisms of Nb-alloyed austenitic stainless steel, produced by electron beam additive manufacturing (EBAM), after different regimes of the post-EBAM solid-solution treatments. As-build EBAM-produced steel has a predominantly austenitic structure, contains vermicular δ-ferrite (V δ = 5–7%) and Nb-enriched precipitates (Laves phase Fe 2 Nb, FeNb and NbC). Niobium-alloying assists the stabilization of austenitic phase but does not suppress the columnar grain growth during EBAM-fabrication of austenitic stainless steels. Solid-solution treatments provide a change in morphology of δ-ferrite, a decrease in the ferrite volume fraction and the dissolution of intermetallic phases (Fe 2 Nb, FeNb), which all affect the tensile properties. Post-EBAM treatments contribute a decrease in the yield strength of the steel and improve the elongation-to-failure. All EBAM-produced specimens have good mechanical properties, which are comparable with those for steels produced by conventional methods. Irrespective of treatment regime, EBAM-fabricated specimens exhibit ductile transgranular fracture. For the EBAM-produced Nb-alloyed steel, the phase composition is described from the point of view solidification mode, and the effects of the precipitate hardening and solid-solution strengthening on the mechanical properties and fracture mechanisms were discussed. [Display omitted] • Nb-alloyed austenitic stainless steel was produced by electron beam additive manufacture. • As-build steel has austenitic structure with δ-ferrite and Nb-enriched precipitates. • NbC and intermetallic phases (Laves-Fe 2 Nb, FeNb) are typical of as-built material. • Mechanical properties of EBAM-produced steel are comparable with conventional steels. • EBAM-fabricated steel fracture in ductile transgranular mode. [ABSTRACT FROM AUTHOR]

This paper describes the results of an investigation into a microstructure formation on a wire-feed electron beam additive manufactured "steel–copper" bimetallic sample. The peculiarities of a gradient zone structure with a smooth change of components' concentration are revealed. The heterogeneity of copper and steel distribution in the gradient zone is provided by copper solidification and precipitation mechanisms. Both solidification of coarse copper inclusions in the interdendrite areas or along the dendrite boundaries and precipitation of fine Cu-based particles at the cooling stage from the solid solution of Cu in γ-Fe are the main factors of structure formation during the double wire gradient zone deposition. The presence of such fine copper precipitates from the supersaturated solid solution was revealed by means of transmission electron microscopy. The shape of copper particles in the gradient zone varies from spherical to oblong and irregular. The shape of steel particles and/or grains is mainly determined by the peculiarities of the crystallization zone and is characterized by the primary crystallization of γ-iron dendrites from the liquid melt. A physical scheme describing a variation in phase composition and microstructure in gradient zone of the bimetallic specimen was proposed. [ABSTRACT FROM AUTHOR]

Using thermal-mechanical treatments, specimens with different grain sizes were produced for two Cr-Ni-based austenitic stainless steels with different stacking fault energies (analogues of AISI 316L and AISI 321 steels). The effect of strain-rate on the tensile deformation behavior and strength properties was evaluated for these steels. In given grain size interval, (3–73)μm for 316 steel and (0.2–32)μm for 321 steel, the yield strength σ 0.2 varies with grain size D in accordance with Hall-Petch relationship σ 0.2 = σ 0 + k H P D − 1 / 2 . The Hall-Petch coefficient k HP depends on steel composition (stacking fault energy) and possesses higher value for 321 steel as compared to 316 steel. Increase in strain-rate in the interval of 1.0 × 10−4 s−1 to 1.0 × 10−2 s−1 causes growth in stress σ 0 , but weakly changes coefficient k HP in Hall-Petch relationship: 322–327 MPa × m0.5 for 316 steel and 404–413 MPa × m0.5 for 321 steel. The strain-rate dependence of the constants in Hall-Petch relationship was discussed in terms of deformation mechanism and dislocation arrangement in both steels. [ABSTRACT FROM AUTHOR]

Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10−3; and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10−4; P = 1.4×10−5 combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1Gly308Glu carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1Gly308Glu may act as a low-penetrance allele that contributes to colorectal tumorigenesis. [ABSTRACT FROM PUBLISHER]

Abstract: AKT1 (V-akt murine thyoma viral oncogene homolog 1) is involved in intracellular signalling pathways postulated as of aetiological importance in schizophrenia. Markers in the AKT1 gene have also recently been associated with schizophrenia in two samples of European origin and in Japanese and Iranian samples. Aiming to replicate these findings, we examined ten SNPs spanning AKT1 in a UK case-control sample (schizophrenia cases n =673, controls n =716). These included all SNPs previously reported to be associated in European, Japanese and Iranian samples, alone or in haplotypes, as well as additional markers defined by the Haploview Tagger program (pair-wise tagging, minimum r 2 =0.8, minor allele frequency=0.02). We found no association with single markers (min p =0.17). We found weak evidence for association (p =0.04) with a four marker haplotype reported as significant in the original positive European sample of Emamian et al. [Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M., Gogos, J.A., 2004. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet. 36, 131–137] and also an overlapping three marker haplotype (p =0.016) that had previously been reported as significant in a Japanese sample. Nominal p-values for these haplotypes did not survive correction for multiple testing. Our study provides at best weak support for the hypothesis that AKT1 is a susceptibility gene for schizophrenia. Examination of our own data and those of other groups leads us to conclude that overall, the evidence for association of AKT1 as a susceptibility gene for schizophrenia is weakly positive, but not yet convincing. [Copyright &y& Elsevier]

Background: The glutamatergic system, the major excitatory neurotransmitter system in the central nervous system (CNS) has been proposed as contributing a possible role in the etiology of attention deficit hyperactivity disorder (ADHD). This is based upon observations from animal, neuroimaging, neuroanatomical and neuropsychological studies. Genes related to glutamate function are therefore good functional candidates for this disorder. The SLC1A3 (Solute Carrier Family 1, member 3) gene encodes a glial glutamate transporter which maps to chromosome 5p12, a region of linkage that coincides in two published ADHD genome scans so far. SLC1A3 is thus both a functional and positional candidate gene for ADHD. Methods: We have undertaken detailed association analysis of SLC1A3 using a multi-stage approach for candidate gene analysis. Results: In a family-based sample (n = 299) we found a significant association between marker rs2269272 (p = .007) and ADHD. Two, two-marker haplotypes, rs2269272/rs3776581 (p = .016) and rs2269272/rs2032893 (p = .013) also yielded evidence of association. Conclusions: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD. [Copyright &y& Elsevier]

Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (∼2–3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P<.01&minus.003 ). After redundant SNPs were P< .01−.003 excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at were next genotyped in a semi-independent sample of 143 trios of probands with DD and P&les; .05 their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P&les;.04−.002 ), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an P&les; .04−.002 amino acid ( ; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global in the case-control sample; in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P=.00003 in the case-control sample; P=.006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown. [ABSTRACT FROM AUTHOR]

High nitrogen steel billets were successfully produced using electron-beam additive manufacturing technique with a Fe-20.7Cr-22.2Mn-0.3Ni-0.6Si-0.15C-0.53 N (wt. %) steel rods as a raw material. Additively manufactured steel possesses a dual-phase structure with a 40% of ferrite phase. An increase in volume content of ferrite and dendritic morphology of the microstructure is associated with the significant decrease in manganese concentration in the melt from 22.2 to 10.8 wt% during additive manufacturing process and change in solidification mode. A preferential formation of austenitic dendrites with high nitrogen content (about 0.9 wt% of nitrogen) during early stages of solidification process leads to a depletion of the melt by N, Mn, Cr and further formation of interstitial-free ferrite in interdendritic regions. The inhomogeneity in phase composition assists lower strain hardening and ductility in the additively manufactured high-nitrogen steel in comparison with conventionally produced material at the preservation of high values of the yield strength. In tension of additively produced high nitrogen steel, plastic deformation develops in both phases but more intensive deformation, strain localization and nucleation of microcracks occur in ferrite. Fracture of additively manufactured steel develops mainly in transgranular regime with ductile fracture of ferritic regions and brittle fracture of austenitic dendrites due to high nitrogen content in γ-phase. • High-nitrogen chromium-manganese steel was produced by EBAM technique. • Nitrogen concentration does not change during additive manufacturing. • AM steels has dual phase austenite/ferrite structure. • Austenitic phase is supersaturated with nitrogen. • Yield strength of AM steel are close to those in conventionally produced steels. [ABSTRACT FROM AUTHOR]

The growth of coarse columnar grains and dendritic ferrite is a common problem peculiar for Cr–Ni steels produced by electron beam additive manufacturing. For these heterophase additively fabricated steels, the oriented dendritic microstructure in such columnar grains provides the anisotropy of the mechanical properties. Herein, we study the effect of ultrasonic (US) vibrations during wire-feed electron beam additive manufacturing (WEBAM) on microstructure, phase composition and tensile properties of AISI 304L steel. US vibrations during WEBAM processing provide the refinement of the austenitic grains, partially suppress the directional solidification of austenite and reduce δ-ferrite volume fraction (in 1.5–2%). The regular elongated austenitic grains with long and straight dendritic colonies of δ-ferrite are typical of WEBAM-specimens. Austenitic grains are visibly more spherical in WEBAM-US specimens, and their mean grain size (256 ± 17 μm) is smaller than that of WEBAM-fabricated steel (433 ± 145 μm). The δ-ferritic arms are broken and partially dissolved in WEBAM-US specimens and the most pronounced changes are observed in the middle part of the billets. US-assisted grain refinement, partial columnar-to-equiaxed transition and reducing δ-ferrite content – all positively affect the resultant properties of WEBAM-fabricated steel. The results of present study clearly show that application of US during WEBAM is an effective way to obtain a positive influence in additive manufacturing of austenitic Cr–Ni steel. • Ultrasonic vibrations were applied in additive manufacturing of 304L stainless steel. • Application of US during WEBAM improves strength properties of austenitic steel. • WEBAM-US processing provides the refinement of the austenitic grains. • Directional solidification of austenite is partially suppressed in WEBAM-US production. • Ultrasonic vibrations reduce δ-ferrite volume fraction during WEBAM processing. [ABSTRACT FROM AUTHOR]

• Grain boundary carbides are typical of cast FeMnCrNiCo 0.95 C 0.05 alloy. • A portion of carbon atoms provides a solid-solution hardening of the cast alloy. • Two thermal–mechanical processing regimes were applied for dissolution of carbides. • Thermal-mechanical treatments assist near complete solution of carbon in austenite. • Both processing regimes enhance mechanical properties of the alloy. Different thermal–mechanical processing regimes were used to provide a precipitate-free austenitic structure in interstitial FeMnCrNiCo 0.95 C 0.05 high-entropy alloy containing 1.07 at. % of carbon. Relative to interstitial-free FeMnCrNiCo alloy (a = 0.3599 nm), an expanded FCC crystal lattice (a = 0.3602–0.3603 nm) is typical of as-cast and solution-treated specimens, but grain-boundary carbides are also observed in them. Near complete carbon dissolution in austenite of FeMnCrNiCo 0.95 C 0.05 high-entropy alloy was achieved utilizing two multistage thermal–mechanical processing regimes, which included the combinations of (i) a high-temperature anneal (25 h total), hot forging and cold rolling, and (ii) cold rolling with intermediate high-temperature anneals (6 h total). Despite the fact that both processing regimes provided high solid-solution hardening of austenite (a = 0.3611 nm) and complete dissolution of grain-boundary precipitates, some individual coarse carbides were identified in microstructure of the alloy. Both processing regimes enhanced the mechanical properties of the alloy. [ABSTRACT FROM AUTHOR]