Magneto-hydrodynamics of multi-phase flows in heterogeneous systems with large property gradients.

The complex interplay between thermal, hydrodynamic, and electromagnetic, forces governs the evolution of multi-phase systems in high technology applications, such as advanced manufacturing and fusion power plant operation. In this work, a new formulation of the time dependent magnetic induction equation is fully coupled to a set of conservation laws for multi-phase fluid flow, energy transport and chemical species transport that describes melting and solidification state transitions. A finite-volume discretisation of the resulting system of equations is performed, where a novel projection method is formulated to ensure that the magnetic field remains divergence free. The proposed framework is validated by accurately replicating a Hartmann flow profile. Further validation is performed through correctly predicting the experimentally observed trajectory of Argon bubbles rising in a liquid metal under varying applied magnetic fields. Finally, the applicability of the framework to technologically relevant processes is illustrated through the simulation of an electrical arc welding process between dissimilar metals. The proposed framework addresses an urgent need for numerical methods to understand the evolution of multi-phase systems with large electromagnetic property contrast.

Phase-Field Simulation of Grain Boundary Evolution In Microstructures Containing Second-Phase Particles with Heterogeneous Thermal Properties.

Understanding the interaction between complex thermal fields and metallic structures at the meso-scale is crucial for the prediction of microstructural evolution during thermomechanical processing. The competitive growth of crystal grains, driven by thermodynamic forces at the grain boundaries, is one of the most fundamental phenomena in metallurgy and solid state physics. The presence of second phase particles, which act as pinning sites for boundaries, drastically alters the coarsening behaviour of the system; particularly when considering that these particles have different thermal properties to the primary phase. In this work a multi-phase field model, incorporating thermal gradient and curvature driving forces, is used to predict grain growth in a Ti6Al4V alloy system with second phase particle inclusions representative of oxide and carbide precipitates. The multi-phase field framework is fully coupled to the heat equation. The incorporation of the thermal gradient driving force enables the detailed behaviour of the grain boundaries around the particles to be predicted. It is shown that the inclusion of particles with a lower thermal conductivity has a significant influence on the coarsening behaviour of various systems of grains, due to the combined effects of thermal shielding and the generation of thermal gradient driving forces between the boundaries and pinning particles.

Straight-to-test for the two-week-wait colorectal cancer pathway under the updated NICE guidelines reduces time to cancer diagnosis and treatment.

INTRODUCTION: The 2015 National Institute for Health and Care Excellence guidelines widened the referral criteria for the two-week-wait pathway for suspected lower gastrointestinal cancer. We implemented a straight-to-test protocol to accommodate the anticipated increase in referrals. We evaluated the impact of these changes for relevant pathway metrics and clinical outcomes using a retrospective cohort study with historic controls. MATERIALS AND METHODS: We analysed data from all patients referred to a teaching hospital via the two-week-wait pathway for suspected lower gastrointestinal cancer under the previous guidelines between 1 March and 31 August 2015 compared with the same period in 2016, when the updated guidelines and straight-to-test protocol had been implemented. RESULTS: In the 2015 cohort, there were 64 cancer diagnoses from 664 referrals (9.6% pick-up) compared with 58 cancer diagnoses from 954 referrals in the 2016 cohort (6.1% pick-up). Our straight-to-test protocol reduced the median time to cancer diagnosis by 12.5 days (P < 0.001) and reduced the median time to cancer treatment by 7.5 days (P < 0.05) An increased proportion of non-colorectal cancers were diagnosed in 2016 compared with 2015, (37.9% vs 17.2%, P < 0.05) and more adenomas were removed in 2016 compared with 2015 (377 vs 193). DISCUSSION AND CONCLUSION: Our straight-to-test protocol has resulted in a reduction in times to cancer diagnosis and cancer treatment, despite an increase in the number of referrals. The new referral criteria have considerable resource implications, but their implementation did not result in an increase in the total number of cancers diagnosed.

Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.

BACKGROUND: Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. METHODS AND FINDINGS: In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08-0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24-0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11-0.90, p = 0.031 and 0.53, 0.28-0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics. CONCLUSIONS: Preconceptional folate supplementation is associated with a 50%-70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.

Búsqueda genómica basada en el mapeo de homocigosidad y el uso de microarrays en 25 familias cubanas con trastorno afectivo bipolar muestra evidencias sugestivas de ligamiento en las regiones 6q26-27 y 17q25.3 / A genome-wide search for risk genes using homozygosity mapping and microarrays in 25 Eastern Cuban families with bipolar disorder shows suggestive evidence of linkage to chromosomes 6q26-q27 and 17q25.3

Se reportan los resultados de una búsqueda genómica utilizando una versión del GeneChip Mapping 10K Xba array de Affymetrix (con 10 043 marcadores SNPs), en 33 individuos con diagnóstico trastorno afectivo bipolar que son miembros de 25 famlias cubanas en las cuales los padres de los individuos enfermos son primos hermanos, primos segundos o primos terceros. En cada familia se genotipo el descendiente afectado, con el objetivo de identificar alelos de riesgo para el trastorno afectivo bipolar con efecto recesivo, en uno o más locis, mediante la búsqueda de segmentos cromosómicos homocigóticos idénticos por descendencia. Se encontraron evidencias sugestivas de ligamiento genético en las regiones cromosómicas 6q26-27 y 17q25.3. El hallazgo en el cromosoma 17q confirma resultados previos que obtuvimos en una búsqueda genómica anterior utilizando 1494 SNPs, mientras que lo encontrado en la región 6q podría representar un nuevo locus de susceptibilidad no reportado en la literatura con anterioridad. Otras regiones de potencial interés fueron localizadas en los cromosomas 2p14, 5q14.1, 10q21.1, 11q13.5-14.1 y14q24.1-24.2. Los resultados obtenidos sugieren que el mapeo de homocigosidad, utilizando el análisis de ligamiento paramétrico en individuos afectados descendientes de matrimonios consanguíneos, es una estrategia útil para la búsqueda de alelos de riesgo con un efecto recesivo en las enfermedades complejas…(AU)

A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.

Ubiquitin expression in muscle from horses with polysaccharide storage myopathy.

Serial sections of formalin-fixed, paraffin-embedded muscle biopsy specimens from 28 Quarter Horse, Paint, and draft-related breeds, aged 0.5-23 years, were treated with periodic acid-Schiff (PAS) stain for glycogen and were immunostained to detect ubiquitin expression. On the basis of findings in PAS-stained sections, a diagnosis of equine polysaccharide storage myopathy (EPSSM) was made in 22 horses aged 2-23 years (mean, 9.4 years); samples from 6 horses aged 0.5-15 years (mean, 7.3 years) had a normal PAS staining pattern, with no relevant lesions. Ubiquitin expression was detected in all but a 2-year-old EPSSM-affected horse and was not detected in the non-EPSSM-affected horses. Ubiquitin expression was greater than the degree of PAS-positive, amylase-resistant material, and ubiquitin was detected in aggregates of amylase-sensitive glycogen as well as in aggregates of amylase-resistant material. Results suggest that glycogen aggregates develop and are ubiquitinated prior to development of amylase-resistant inclusions. Ubiquitin immunostaining may be most useful for confirming the diagnosis of EPSSM in horses with only amylase-sensitive glycogen aggregates and in horses with early amylase-resistant inclusions. However, ubiquitin immunostaining is no more sensitive than is PAS staining for diagnosis of EPSSM.

A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands.

The involvement of genetic factors in the etiology of autism has been clearly established. We undertook a genome-wide search for regions containing susceptibility genes for autism in 12 subjects with childhood autism and related pervasive developmental disorders (PDDs) and 44 controls from the relatively isolated population of the Faroe Islands. In total, 601 microsatellite markers distributed throughout the human genome with an average distance of 5.80 cM were genotyped, including 502 markers in the initial scan. The Faroese population structure and genetic relatedness of cases and controls were also evaluated. Based on a combined approach, including an assumption-free test as implemented in CLUMP, Fisher's exact test for specific alleles and haplotypes, and IBD(0) probability calculations, we found association between autism and microsatellite markers in regions on 2q, 3p, 6q, 15q, 16p, and 18q. The most significant finding was on 3p25.3 (P(T1)=0.00003 and P(T4)=0.00007), which was also supported by other genetic studies. Furthermore, no evidence of population substructure was found, and a higher degree of relatedness among cases could not be detected, decreasing the risk of inflated P-values. Our data suggest that markers in these regions are in linkage disequilibrium with genes involved in the etiology of autism, and we hypothesize susceptibility genes for autism and related PDDs to be localized within these regions.

A genome-wide search for risk genes using homozygosity mapping and microarrays with 1,494 single-nucleotide polymorphisms in 22 eastern Cuban families with bipolar disorder.

Homozygosity mapping is a very powerful method for finding rare recessive disease genes in monogenic disorders and may also be useful for locating risk genes in complex disorders, late onset disorders where parents often are not available, and for rare phenotypic subgroups. In the present study, homozygosity mapping was applied to 24 persons with bipolar disorder from 22 inbred families. The families were selected irrespective of whether other affected family members were present or not. A genome wide screen using genotypes from only a single affected person in each family was performed using the AFFYMETRIX GeneChip HuSNP Mapping Assay, which contains 1,494 single nucleotide polymorphisms. At chromosome 17q24-q25 a parametric multipoint LOD score of 1.96 was found at WIAF-2407 and WIAF-2405. When analyzing 19 additional microsatellite markers on chromosome 17q the maximum parametric multipoint LOD score was 2.08, 1.5 cM proximal to D17S668. The present study replicates a recent significant linkage finding.

Possible evidence for a common risk locus for bipolar affective disorder and schizophrenia on chromosome 4p16 in patients from the Faroe Islands.

Patients with schizophrenia (n=11) and bipolar affective disorder (n=17) from the relatively isolated population of the Faroe Islands were genotyped for 34 polymorphic markers on chromosome 4 in a search for allelic association and haplotype sharing among distantly related patients. When considering bipolar patients only, there was no clearcut support for any region on chromosome 4. The two-marker segment D4S394-D4S2983 at 4p16.1 was, however, supported by a P-value of 0.0162. For patients with schizophrenia, there was reasonable support for 4p16.1 as marker D4S2281 (P=0.0019), a two-marker segment (D4S2281-D4S1605, P=0.0009) and a three-marker segment (D4S2923-D4S2928-D4S1582, P-0.0005) appeared to be associated with schizophrenia, with some alleles/haplotypes occurring with different frequencies in patients compared to controls. When combining both psychiatric disorders, chromosome 4p16.1 received further support from five partially overlapping two- and three-marker segments (D4S394-D4S2983, P=0.0039; D4S2281-D4S1605, P=0.0027 and D4S394-D4S2983-D4S2923, P=0.006; D4S2923-D4S2928-D4S1582, P=0.00007; D4S1582-D4S1599-D4S2281, P=0.005). Increased haplotype sharing in patients with schizophrenia and in the combined data set was partly supported by Fisher's exact test and tests based on the genealogy. Our study yields support for a common risk gene for schizophrenia and bipolar affective disorder on the short arm of chromosome 4, as suggested by previous findings in the neighbouring Scottish population.

A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3.

The present study reports a genomewide scan using linkage analysis for risk genes involved in bipolar disorder with 613 microsatellite markers including additional testing of promising regions. As previously published significant linkage was obtained at chromosome 12q24.3 with a two-point parametric lod score of 3.42 at D12S1639 including all members in both families (empirical P-value 0.00004, genome-wide P-value 0.0417). The multipoint parametric lod score at D12S1639 was 3.63 (genome-wide P-value 0.0265). At chromosome 1p22-p21 a parametric, affecteds-only two-point lod score of 2.75 at marker D1S216 was found (empirical P-value 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide P-value 0.1022) at D1S216, and a multipoint non-parametric analysis with a maximum NPL-all score of 17.60 (P-value 0.00079) at D1S216 further supported this finding. A number of additional loci on chromosomes 4p16, 6q14-q22, 10q26 and 16p13.3 yielded parametric lod scores around or above 2.

Search for common haplotypes on chromosome 22q in patients with schizophrenia or bipolar disorder from the Faroe Islands.

Chromosome 22q may harbor risk genes for schizophrenia and bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. Patients with schizophrenia and bipolar affective disorder from the Faroe Islands were typed for 35 evenly distributed polymorphic markers on 22q in a search for shared risk genes in the two disorders. No single marker was strongly associated with either disease, but five two-marker segments that cluster within two regions on the chromosome have haplotypes occurring with different frequencies in patients compared to controls. Two segments were of most interest when the results of the association tests were combined with the probabilities of identity by descent of single haplotypes. For bipolar patients, the strongest evidence for a candidate region harboring a risk gene was found at a segment of at least 1.1 cM including markers D22S1161 and D22S922 (P=0.0081 in the test for association). Our results also support the a priori evidence of a susceptibility gene to schizophrenia at a segment of at least 0.45 cM including markers D22S279 and D22S276 (P=0.0075). Patients were tested for the presence of a missense mutation in the WKL1 gene encoding a putative cation channel close to segment D22S1161--D22S922, which has been associated with schizophrenia. We did not find this mutation in schizophrenic or bipolar patients or the controls from the Faroe Islands.

Structural analysis of photosystem II in far-red-light-adapted thylakoid membranes. New crystal forms provide evidence for a dynamic reorganization of light-harvesting antennae subunits.

We studied two-dimensional crystals of the major pigment-protein complex, photosystem II, in far-red-light-adapted thylakoid membranes of the viridis-zb63 mutant of barley. Significantly larger grana membranes were produced with an increased synthesis of the entire photosystem II complex. These red-light-adapted membranes also contained two-dimensional crystals with a high frequency. Three different crystal forms of photosystem II were observed, providing the following data which further our understanding of the architecture of the native complex. (a) The oligomeric form of photosystem II in the membrane was monomeric in all crystal forms, but with a clear non-crystallographic pseudo-twofold symmetry. This was more apparent on the lumenal face of the complex. (b) The variability of unit cell contacts in different crystal forms implied that the peripheral light-harvesting antenna complex and the core of the complex were loosely connected. These peripheral subunits were predicted to rearrange so that they can either encircle the core complex or associate in parallel channels separated by lines of core complexes. (c) Grana membranes were found to retain a double-layered inside-out character, with a stromal face-to-stromal face packing. However, the presence of a crystal in one membrane did not necessarily impose crystallinity on its pair.

A functional variant of the serotonin transporter gene in families with bipolar affective disorder.

BACKGROUND: The serotonin transporter protein (SERT) reuptakes serotonin from synapses and has been implied as the site of therapeutic action of many antidepressant drugs. SERT is one of the most relevant candidate genes for bipolar affective disorder. Recently a functionally important 44 basepair deletion in the regulatory region of the SERT gene was described. Association between this variant and affective disorder has been suggested. METHODS: The present study analysed this variation and another variation in the SERT gene and nearby DNA markers in order to test for linkage between SERT and bipolar affective disorder in two Danish families. RESULTS AND CONCLUSION: There was no evidence that variants in the SERT gene were a stronger dominant disease gene for the development of affective disorder in the families. The possibility of a recessive disease gene at or near SERT could not be excluded. LIMITATIONS: The present study cannot exclude if variations at or near the SERT gene were weak susceptibility genes or determine if they are important for other characteristics than presence or absence of disease. CLINICAL RELEVANCE: Further studies of the SERT gene in affective and other disorders, as well as in relation to treatment response to antidepressants are needed.

Refined localization of the pyruvate dehydrogenase E1 alpha gene (PDHA1) by linkage analysis.

Pyruvate dehydrogenase (PDH) E1 alpha is a key component in the PDH complex which catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. Defects in the gene coding for PDH E1 alpha (PDHA1) are associated with a variety of clinical symptoms, often of a severe character. In the present study, the segregation of three polymorphic CA repeats located in PDHA1 was followed in the 40 CEPH reference pedigrees. Using these data, multipoint linkage analysis was carried out, refining the genetic location of PDHA1. The 16-point map presented locates PDHA1 in an approximately 3-cM interval between DXS999 and DXS365 with odds of more than 1000:1. From known physical localizations of the flanking marker loci, PDHA1 could be regionally assigned to Xp22.1-p22.2. The information provided should be of value in clinical settings.

Structural changes in photosystem II after treatment with the zero-length bifunctional cross-linker 1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide: an electron microscopic study.

Two-dimensional (2D) crystals of photosystem II (PS II) treated with various concentrations of the zero-length crosslinker 1-ethyl-3-(3-dimethylaminopropyl))carbodi-imide (EDC) were analysed by electron microscopy in conjunction with crystallographic image processing. The preparations were characterized by SDS/PAGE and oxygen-evolution measurements, and the effectiveness of cross-linking was monitored by measuring the level of protection afforded against high concentrations of NaCl and CaCl2, which normally remove extrinsic proteins from PS II. We found that low concentrations of EDC (0.25%) increase the order of 2D crystals of PS II. Treatments with EDC concentrations higher than 0.5% did not improve the order of 2D crystals but induced gross structural changes, which were correlated with a decrease in oxygen evolution activity. Structural changes due to cross-linking did not affect packing or symmetry of the 2D crystals, further supporting the conclusion that PS II has a monomeric nature in vivo.

Linkage study between manic-depressive illness and chromosome 21.

Chromosome 21, of interest as potentially containing a disease gene for manic-depressive illness as possible evidence for a gene pre-disposing to affective disorder, has recently been reported in a single large family as well as samples of families. The present study investigates for linkage between manic-depressive illness and markers covering the long arm of chromosome 21 in two manic-depressive families, using ten microsatellite polymorphisms as markers. No conclusive evidence for a disease gene on the long arm of chromosome 21 was found. Assuming either a dominant or recessive mode of inheritance, close linkage to the marker PFKL, which has been reported as possibly linked to affective disorder, seems unlikely in the families studied here. PFKL and more telomeric markers yielded small positive lod scores at higher recombination fractions in the largest family, and small positive lod scores at lower recombination fractions in the affected-only analyses in the smallest family.

Assignment of the human tryptophanyl-tRNA synthetase gene (WARS) to chromosome 14q32.2 --> q32.32.

Tryptophanyl-tRNA synthetase catalyzes the aminoacylation of tRNAtrp with tryptophan, an essential function in the cell's protein synthesis machinery. It has been shown that tryptophanyl-tRNA synthetase is induced by interferon, and this has led to hypotheses about other possible functions of tryptophanyl-tRNA synthetase. We have mapped a cDNA probe of the tryptophanyl-tRNA synthetase gene (WARS) by a combination of somatic cell hybrid analysis, fluorescence in situ hybridization (FISH), and linkage analysis. Both FISH and linkage analysis independently supported a more distal position of WARS than had been previously reported. FISH mapping indicated a most likely location at 14q32.31. Linkage analysis was based on the 40 reference families from the CEPH collaboration and resulted in a 13-point map, placing WARS, with odds of more than 1,000:1, within an area of approximately 10 cM and, with odds of 198:1, in an approximately 6 cM interval between pCMM101 and D14S27. The study provides additional integration of the physical and genetic maps of the distal part of 14q, as well as genetic tools enabling a more complete understanding of the function of tryptophanyl-tRNA synthetase, especially with regard to the cryptic inducibility of interferon.