Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells

Studies have shown that DNA (cytosine-5-)-methyltransferase 1 (DNMT1) is the principal enzyme responsible for maintaining CpG methylation and is required for embryonic development and survival of somatic cells in mice. The role of DNMT1 in human cancer cells, however, remains highly controversial. Using homologous recombination, here we have generated a DNMT1 conditional allele in the human colorectal carcinoma cell line HCT116 in which several exons encoding the catalytic domain are flanked by loxP sites. Cre recombinase-mediated disruption of this allele results in hemimethylation of approximately 20% of CpG-CpG dyads in the genome, coupled with activation of the G2/M checkpoint, leading to arrest in the G2 phase of the cell cycle. Although cells gradually escape from this arrest, they show severe mitotic defects and undergo cell death either during mitosis or after arresting in a tetraploid G1 state. Our results thus show that DNMT1 is required for faithfully maintaining DNA methylation patterns in human cancer cells and is essential for their proliferation and survival.     

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.     

Chimpanzees are indifferent to the welfare of unrelated group members

Humans are an unusually prosocial species-we vote, give blood, recycle, give tithes and punish violators of social norms. Experimental evidence indicates that people willingly incur costs to help strangers in anonymous one-shot interactions, and that altruistic behaviour is motivated, at least in part, by empathy and concern for the welfare of others (hereafter referred to as other-regarding preferences). In contrast, cooperative behaviour in non-human primates is mainly limited to kin and reciprocating partners, and is virtually never extended to unfamiliar individuals. Here we present experimental tests of the existence of other-regarding preferences in non-human primates, and show that chimpanzees (Pan troglodytes) do not take advantage of opportunities to deliver benefits to familiar individuals at no material cost to themselves, suggesting that chimpanzee behaviour is not motivated by other-regarding preferences. Chimpanzees are among the primates most likely to demonstrate prosocial behaviours. They participate in a variety of collective activities, including territorial patrols, coalitionary aggression, cooperative hunting, food sharing and joint mate guarding. Consolation of victims of aggression and anecdotal accounts of solicitous treatment of injured individuals suggest that chimpanzees may feel empathy. Chimpanzees sometimes reject exchanges in which they receive less valuable rewards than others, which may be one element of a 'sense of fairness', but there is no evidence that they are averse to interactions in which they benefit more than others.     

Immunological reactivity of a synthetic polymannan

Zusammenfassung Ein Stickstoff-freies Polysaccharid bewirkt eine cutane Überempfindlichkeit beim Meerschweinchen sowie Komplement fixierende Antikörper bei Mäusen.     

Glucose transporter recycling in response to insulin is facilitated by myosin Myo1c

Insulin stimulates glucose uptake in muscle and adipocytes by signalling the translocation of GLUT4 glucose transporters from intracellular membranes to the cell surface. The translocation of GLUT4 may involve signalling pathways that are both independent of and dependent on phosphatidylinositol-3-OH kinase (PI(3)K). This translocation also requires the actin cytoskeleton, and the rapid movement of GLUT4 along linear tracks may be mediated by molecular motors. Here we report that the unconventional myosin Myo1c is present in GLUT4-containing vesicles purified from 3T3-L1 adipocytes. Myo1c, which contains a motor domain, three IQ motifs and a carboxy-terminal cargo domain, is highly expressed in primary and cultured adipocytes. Insulin enhances the localization of Myo1c with GLUT4 in cortical tubulovesicular structures associated with actin filaments, and this colocalization is insensitive to wortmannin. Insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane is augmented by the expression of wild-type Myo1c and inhibited by a dominant-negative cargo domain of Myo1c. A decrease in the expression of endogenous Myo1c mediated by small interfering RNAs inhibits insulin-stimulated uptake of 2-deoxyglucose. Thus, myosin Myo1c functions in a PI(3)K-independent insulin signalling pathway that controls the movement of intracellular GLUT4-containing vesicles to the plasma membrane.     

Biodiversity (Communications arising): maize transgene results in Mexico are artefacts

Quist and Chapela's conclusion that the transgenes they claim to have detected in native maize in Oaxaca, Mexico, are predominantly reassorted and inserted into a "diversity of genomic contexts" seems to be based on an artefact arising from the inverse polymerase chain reaction (i-PCR) they used to amplify sequences flanking 35S transgenes from cauliflower mosaic virus (CaMV).     

Diversity, phenology, and elevational distribution of Ephemeroptera, Plecoptera, and Trichoptera in American Fork Canyon, Utah

Although the aquatic insect fauna of Utah and their associated adult forms are well documented taxonomically and biogeographically, little is known about seasonal and elevational patterns of aquatic insect diversity in individual Wasatch streams. We selected the American Fork River, a relatively pristine stream with little anthropogenic disturbance, as our target stream to investigate elevational distribution and seasonal phenology of adult forms of Ephemeroptera, Plecoptera, and Trichoptera (EPT). From April to October in 2003 through 2005, a total of 71 adult forms of EPT species were documented along the American Fork River. No single sampling period captured more than 30 species, and richness per sampling period averaged 8 species for all sites combined. The mid-elevational site (1862 msl) was the most species rich, with 54 species of transitional fauna captured along the elevational gradient. As such, this site is an important reference for maximum potential richness. Plecoptera emerged earlier in the year than Trichoptera, with the Plecoptera-dominated community being most rich in June, and the Trichoptera-dominated community being most rich in August. We observed 3 distinct seasonal species suites and 3 elevationally zoned community assemblages that were recurrent in their timing and location from year to year. The compiled species lists, life histories, and preliminary investigation of ecological trends provide a firm basis for further systematic studies on the ecology, water quality, and conservation of the aquatic insects of the American Fork River and similar mountain streams, particularly in the Wasatch region. Aunque la fauna de insectos acuáticos de Utah y sus formas adultas asociadas están bien documentadas taxonómica y biogeográficamente, se conoce poco sobre los patrones de distribución estacionales y altitudinales de la diversidad de insectos acuáticos en arroyos individuales de la cordillera Wasatch. Seleccionamos el Río American Fork, un arroyo relativamente prístino con poca perturbación antropogénica, como nuestro objetivo para investigar la distribución altitudinal de las formas adultas de Ephemeroptera, Plecoptera y Trichoptera (EPT), así como su fenología estacional. De abril a octubre del año 2003 al 2005, se documentó un total de 71 formas adultas de especies de EPT a lo largo del Río American Fork. No se encontraron más de 30 especies en ninguno de los períodos de muestreo, y combinando los datos de todos los sitios, el promedio de especies por período fue ocho. El sitio de elevación media (1862 msnm) fue el más rico con 54 especies constituidas por una fauna transicional entre los sitios a lo largo del gradiente de elevación, y como tal éste es un importante punto de referencia para determinar el máximo potencial de riqueza de especies. Los plecópteros aparecieron más temprano en el año que los tricópteros—la comunidad predominada por Plecoptera fue más rica en especies en junio—mientras que la comunidad predominantemente Trichoptera alcanzó su mayor riqueza en agosto. Observamos tres distintos conjuntos estacionales de especies y tres comunidades distribuidas por elevación, las cuales fueron recurrentes en su temporalidad y localización año tras año. La lista recopilada de especies, las historias de vida y la investigación preliminar de tendencias ecológicas aportan una firme base para más estudios sistemáticos y ecológicos, así como de calidad de agua y conservación de los insectos acuáticos del Río American Fork y otros arroyos semejantes a este, particularmente en la región de la cordillera Wasatch.     

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.