Elaboration of AlSi10Mg casting alloys using directional solidification processing

The effects of pulling velocity on the solidification behavior and microstructural parameters of AlSi10Mg alloys prepared in a Bridgman-type directional solidification furnace were investigated. The microstructure, particularly the secondary dendritic arm spacing (SDAS), and the Brinell hardness (BH) of the solidified AlSi10Mg alloys were characterized for samples with cylindrical shapes and different conicities (θ=0°, 5°, and 10°). Microstructural studies revealed an increased density of α-Al phase dendrites and a decreased interdendritic distance with increasing pulling velocity. The dendrites were found to be preferentially oriented along the pulling direction for low pulling velocities. For larger pulling velocities, the dendrites grew first in the cooling direction but then broke as others nucleated and coarsened. The HB values of the solidified samples increased as the pulling velocity increased. In regard to sample conicity, smaller dendrites were observed for an apex angle of θ=5°, resulting in the largest HB value. This result was interpreted in terms of the favorable orientation of the dendrite along the pulling direction.     

A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease

Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant.     

Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature

We report mapping of a quantitative trait locus (QTL) with a major effect on bovine stature to a ～780-kb interval using a Hidden Markov Model-based approach that simultaneously exploits linkage and linkage disequilibrium. We re-sequenced the interval in six sires with known QTL genotype and identified 13 clustered candidate quantitative trait nucleotides (QTNs) out of >9,572 discovered variants. We eliminated five candidate QTNs by studying the phenotypic effect of a recombinant haplotype identified in a breed diversity panel. We show that the QTL influences fetal expression of seven of the nine genes mapping to the ～780-kb interval. We further show that two of the eight candidate QTNs, mapping to the PLAG1-CHCHD7 intergenic region, influence bidirectional promoter strength and affect binding of nuclear factors. By performing expression QTL analyses, we identified a splice site variant in CHCHD7 and exploited this naturally occurring null allele to exclude CHCHD7 as single causative gene.     

Heat-shock protein 60 translocates to the surface of apoptotic cells and differentiated megakaryocytes and stimulates phagocytosis

Heat-shock protein 60 (Hsp60) is a highly conserved stress protein which has chaperone functions in prokaryotes and mammalian cells. Hsp60 is associated with the mitochondria and the plasma membrane through phosphorylation by protein kinase A, and is incorporated into lipid membranes as a protein-folding chaperone. Its diverse intracellular chaperone functions include the secretion of proteins where it maintains the conformation of precursors and facilitates their translocation through the plasma membrane. We report here that Hsp60 is concentrated in apoptotic membrane blebs and translocates to the surface of cells undergoing apoptosis. Hsp60 is also enriched in platelets derived from terminally differentiated megakaryocytes and expressed at the surface of senescent platelets. Furthermore, the exposure of monocytic U937 cells to Hsp60 enhanced their phagocytic activity. Our results suggests that externalized Hsp60 in apoptotic cells and senescent platelets influences events subsequent to apoptosis, such as the clearance of apoptotic cells by phagocytes.     

Biology and defensive secretion of myrmecophilous Thiasophila spp. (Coleoptera: Staphylinidae: Aleocharinae) associated with the Formica rufa species group

Various aspects of the biology of the myrmecophilous Thiasophila angulata and T. szujeckii (Staphylinidae; Aleocharinae), mainly associated with the Formica rufa species group, are studied. The composition of defensive gland secretions from adults of T. angulata has been analysed. The complete development (egg-L_1-3-pupa-adult form), including adult overwintering, of both species takes place solely in ant nests. Under laboratory conditions, this lasts for about 22 days in T. angulata, and the period elapsing between the old and new generations of insects is approximately two months. The mean fecundity of adults of this species (28 eggs) was determined, as well as the duration of its reproductive period (mean 28.5 days), and lifespan (mean 67 days). In natural conditions T. angulata, found within nests of Formica polyctena and F. rufa, produces three generations, and the sibling species T. szujeckii one generation per year. These two species differ in their phenologies and abundance dynamics of adults and larvae, which is linked to the size and temperature regime of the host nest. The results of this study uphold the recent separation of T. angulata and T. szujeckii based on morphological features of adults and selected molecular markers. Adults and larvae of T. angulata forage on both live and dead food items accumulated by the host, as well as on the host’s eggs and larvae. Both the beetle larvae and adults remain unmolested among the host workers. The adults use their defensive gland secretions, which contains substantial quantities of toxic quinones, when necessary. According to the current categories of myrmecophiles, T. angulata (and by analogy, T. szujeckii as well) should be classified as a species wholly integrated with the host.     

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).     

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.     

Megasatellites: a new class of large tandem repeats discovered in the pathogenic yeast Candida glabrata

Megasatellites are DNA tandem arrays made of large motifs; they were discovered in the yeast Candida glabrata. They are widespread in this species (40 copies) but are not found in any other hemiascomycete so far, raising the intriguing question of their origin. They are found mainly in genes encoding cell wall products, suggesting that megasatellites were selected for a function linked to cell–cell adhesion or to pathogenicity. Their putative role in promoting genome rearrangements by interfering with DNA replication will also be discussed.     

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.     

迷向周期和方法在β-簮结构折褶模拟中的应用

采用新近提出的迷向周期和方法(IPS),结合自导Lang evin动态模拟,模拟研究9余肽折褶成β簮结构的情况,表明了该结构与NMR观察到的基本一致,而Ewald模拟由于是强烈的镜像相互作用会产生构型偏差,获得致密构型的几率增大,表明IPS方法更适合于周期边界条件的模拟.