Ybp2 Associates with the Central Kinetochore of Saccharomyces cerevisiae and Mediates Proper Mitotic Progression

The spindle checkpoint ensures the accurate segregation of chromosomes by monitoring the status of kinetochore attachment to microtubules. Simultaneous mutations in one of several kinetochore and cohesion genes and a spindle checkpoint gene cause a synthetic-lethal or synthetic-sick phenotype. A synthetic genetic array (SGA) analysis using a mad2Δ query mutant strain of yeast identified YBP2, a gene whose product shares sequence similarity with the product of YBP1, which is required for H2O2-induced oxidation of the transcription factor Yap1. ybp2Δ was sensitive to benomyl and accumulated at the mitotic stage of the cell cycle. Ybp2 physically associates with proteins of the COMA complex (Ctf19, Okp1, Mcm21, and Ame1) and 3 components of the Ndc80 complex (Ndc80, Nuf2, and Spc25 but not Spc24) in the central kinetochore and with Cse4 (the centromeric histone and CENP-A homolog). Chromatin-immunoprecipitation analyses revealed that Ybp2 associates specifically with CEN DNA. Furthermore, ybp2Δ showed synthetic-sick interactions with mutants of the genes that encode the COMA complex components. Ybp2 seems to be part of a macromolecular kinetochore complex and appears to contribute to the proper associations among the central kinetochore subcomplexes and the kinetochore-specific nucleosome

Assembly of Inflammation-Related Genes for Pathway-Focused Genetic Analysis

Recent identifications of associations between novel variants in inflammation-related genes and several common diseases emphasize the need for systematic evaluations of these genes in disease susceptibility. Considering that many genes are involved in the complex inflammation responses and many genetic variants in these genes have the potential to alter the functions and expression of these genes, we assembled a list of key inflammation-related genes to facilitate the identification of genetic associations of diseases with an inflammation-related etiology. We first reviewed various phases of inflammation responses, including the development of immune cells, sensing of danger, influx of cells to sites of insult, activation and functional responses of immune and non-immune cells, and resolution of the immune response. Assisted by the Ingenuity Pathway Analysis, we then identified 17 functional sub-pathways that are involved in one or multiple phases. This organization would greatly increase the chance of detecting gene-gene interactions by hierarchical clustering of genes with their functional closeness in a pathway. Finally, as an example application, we have developed tagging single nucleotide polymorphism (tSNP) arrays for populations of European and African descent to capture all the common variants of these key inflammation-related genes. Assays of these tSNPs have been designed and assembled into two Affymetrix ParAllele customized chips, one each for European (12,011 SNPs) and African (21,542 SNPs) populations. These tSNPs have greater coverage for these inflammation-related genes compared to the existing genome-wide arrays, particularly in the African population. These tSNP arrays can facilitate systematic evaluation of inflammation pathways in disease susceptibility. For additional applications, other genotyping platforms could also be employed. For existing genome-wide association data, this list of key inflammation-related genes and associated subpathways can facilitate comprehensive inflammation pathway- focused association analyses

Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord

Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit σ1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord

The International HapMap Project

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62838/1/nature02168.pd

Fatores intrínsecos do custo energético da locomoção durante a natação Factores intrínsecos del desgaste energético de locomoción durante la natación Intrinsic factors of the locomotion energy cost during swimming

A quantidade de energia metabólica gasta em transportar a massa corporal de um sujeito por unidade de distância tem sido definida como custo energético da locomoção, ou especificamente para natação, o custo de nado. As diferenças no custo de nado entre os indivíduos parecem ser influenciadas por dois principais fatores, a resistência hidrodinâmica e habilidade técnica do nadador. O menor custo de nado apresentado pelas mulheres tem sido atribuído a menor resistência hidrodinâmica decorrente de menor tamanho corporal, maior percentagem de gordura e melhor posicionamento horizontal. Porém, essas diferenças no custo de nado entre homens e mulheres desaparecem quando corrigidos para o tamanho corporal. Em relação às crianças, o maior custo de nado comparado com o dos adultos quando corrigidos para o tamanho corporal pode ser explicado principalmente por menor habilidade técnica apresentada por elas. Para indivíduos com as mesmas características antropométricas, melhor habilidade técnica e maior tamanho da superfície de propulsão, associados a aumento na eficiência propulsiva, podem reduzir o custo de nado. Quando se comparam os diferentes estilos, o mais econômico é o crawl seguido pelo de costas em qualquer velocidade de nado. O borboleta é o estilo menos econômico a baixas velocidades (< 0,8m·s¹). Entretanto, acima dessa velocidade o peito passa a ser o estilo menos econômico.<br>La cantidad de energía metabólica gastada en transportar la masa corporal de un individuo por unidad de distancia ha sido definida como el desgaste energético de locomoción, o específicamente para la natación, el desgaste de nado. Las diferencias en el desgaste de nado entre los individuos parecen ser influenciadas por dos principales factores, la resistencia hidrodinámica y la habilidad técnica del nadador. El menor desgaste de nado presentado por las mujeres ha sido atribuido a una menor resistencia hidrodinámica proveniente de un menor tamaño corporal, mayor porcentaje de grasa, y mejor posicionamiento horizontal. Sin embargo, estas diferencias en el desgaste de nado entre hombres y mujeres desaparece cuando se corrige el tamaño corporal. En relación a los niños, el mayor desgaste de nado comparado a los adultos cuando se corrige el tamaño corporal puede ser explicado principalmente por una menor habilidad técnica presentada por los mismos. Para individuos con las mismas características antropométricas, una mejor habilidad técnica y mayor tamaño de superficie de propulsión, asociados a un aumento en la eficacia de propulsión, pueden reducir el desgaste de nado. Cuando se comparan los diferentes estilos, el más económico es el de pecho seguido por el de espalda a cualquier velocidad de nado. El estilo mariposa es el estilo menos económico a bajas velocidades (< 0,8 m·s-1). A pesar de esto, por encima de esta velocidad el estilo pecho pasa a ser el estilo menos económico.<br>The amount of metabolic energy spent in transporting the body mass of the subject over a unit of distance has been defined as the energy cost of locomotion, or regarding to swimming, cost of swimming. The differences in the cost of swimming between the individuals seem to be influenced by two main factors, the hydrodynamic resistance and technical skill of the swimmer. The lower cost of swimming showed by females has been attributed to a smaller hydrodynamic resistance due to their smaller size, larger percentage fat and more streamlined position. However, the difference in cost of swimming between males and females disappears when correcting for body size. With regard to children, the higher energy cost of swimming when correcting for body size may be caused by the lower swimming technique showed by them. For individuals with the same anthropometric characteristics, the better swimming technique and larger size of propelling surface, associated with higher propelling efficiency, may decrease the energy cost of swimming. When comparing different types of strokes, the most economical stroke is crawl, followed by backstroke, irrespective the swimming velocity. Butterfly is the less economical at low velocities (< 0.8 m·s¹). However, above that velocity the breaststroke become the less economical stroke

A role for Gle1, a regulator of DEAD-box RNA helicases, at centrosomes and basal bodies

Control of organellar assembly and function is critical to eukaryotic homeostasis and survival. Gle1 is a highly conserved regulator of RNA-dependent DEAD-box ATPase proteins, with critical roles in both mRNA export and translation. In addition to its well-defined interaction with nuclear pore complexes, here we find that Gle1 is enriched at the centrosome and basal body. Gle1 assembles into the toroid-shaped pericentriolar material around the mother centriole. Reduced Gle1 levels are correlated with decreased pericentrin localization at the centrosome and microtubule organization defects. Of importance, these alterations in centrosome integrity do not result from loss of mRNA export. Examination of the Kupffer’s vesicle in Gle1-depleted zebrafish revealed compromised ciliary beating and developmental defects. We propose that Gle1 assembly into the pericentriolar material positions the DEAD-box protein regulator to function in localized mRNA metabolism required for proper centrosome function