A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.     

Formation of coastline features by large-scale instabilities induced by high-angle waves.

Along shore sediment transport that is driven by waves is generally assumed to smooth a coastline. This assumption is valid for small angles between the wave crest lines and the shore, as has been demonstrated in shoreline models. But when the angle between the waves and the shoreline is sufficiently large, small perturbations to a straight shoreline will grow. Here we use a numerical model to investigate the implications of this instability mechanism for large-scale morphology over long timescales. Our simulations show growth of coastline perturbations that interact with each other to produce large-scale features that resemble various kinds of natural landforms, including the capes and cuspate forelands observed along the Carolina coast of southeastern North America. Wind and wave data from this area support our hypothesis that such an instability mechanism could be responsible for the formation of shoreline features at spatial scales up to hundreds of kilometres and temporal scales up to millennia.     

Mate sampling in a natural population of Pecos gambusia, Gambusia nobilis

Normal 0 false false false MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;} Much research has been conducted on the mating systems of poeciliid fish in aquaria; however, there are fewer studies that examine mate sampling of these fish in the wild. In general, male poeciliids are characterized as being unselective in their mate choices and will attempt to copulate with seemingly all available females. Females are selective, copulate infrequently, and are often pursued by “ardent” males who may force copulations. To avoid male harassment, females in aquaria will often shelter from males among other females in shoals. Here, we examined the mate-sampling behaviors of male and female Pecos gambusia Gambusia nobilis by following individuals swimming in an outflow pool of Diamond Y Spring in southwestern Texas. In most cases, a male approached a solitary female, followed her briefly, and then left for no apparent reason. Approaching a number of females increased the likelihood that the male would follow one, and the longer a male followed a female, the more likely he was to copulate with her. As females were larger and faster than males, they could avoid males by swimming away from them. We found no evidence of the persistent males that harass seemingly unreceptive females as seen under aquarium conditions, nor did we see females join a shoal to stop pursuit by males. However, the activity of one male following a female did appear to attract other males who would compete to follow and attempt copulation. This competition might ensure that only superior males gain reproductive opportunities. Se han investigado extensamente los sistemas de apareamiento de pecílidos en acuario; no obstante, hay relativamente pocos estudios que examinan la elección de pareja de estos peces en su hábitat natural. Los pecílidos machos no suelen ser selectivos en su elección de pareja y parecen intentar copular con todas las hembras que estén a su alcance. Las hembras son selectivas, no copulan frecuentemente y a menudo las persiguen machos excitados que pueden copular con ellas forzadamente. Para evitar el acosamiento de los machos, en acuario las hembras a menudo se refugian de los machos entre otras hembras en bancos. Para este estudio, examinamos el comportamiento de elección de pareja de gambusias de pecos ( Gambusia nobilis ) machos y hembras al observar algunos individuos en un remanso del Diamond Y Spring en el suroeste de Texas. En la mayoría de los casos, el macho se acercaba a una hembra solitaria, la seguía brevemente y luego se alejaba sin motivo aparente. El acercarse a varias hembras aumentaba la probabilidad de que persiguiera a una de ellas, y cuanto más la seguía, más probable era que copulara con ella. Dado que las hembras son más grandes y más rápidas que los machos, podían eludirlos si no correspondían. No observamos machos persistentes que acosaran hembras aparentemente poco receptivas como se ha documentado en acuario, ni tampoco vimos hembras que se unieran a bancos para evitar la persecución de machos. Pero cuando un macho perseguía una hembra, parecía atraer otros, los cuales competían entre sí para seguirla e intentar copular con ella. Esta competencia podría garantizar que solo los machos superiores tengan oportunidades reproductivas.     

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.     

S-phase feedback control in budding yeast independent of tyrosine phosphorylation of p34cdc28.

In somatic cells, entry into mitosis depends on the completion of DNA synthesis. This dependency is established by S-phase feedback controls that arrest cell division when damaged or unreplicated DNA is present. In the fission yeast Schizosaccharomyces pombe, mutations that interfere with the phosphorylation of tyrosine 15 (Y15) of p34cdc2, the protein kinase subunit of maturation promoting factor, accelerate the entry into mitosis and abolish the ability of unreplicated DNA to arrest cells in G2. Because the tyrosine phosphorylation of p34cdc2 is conserved in S. pombe, Xenopus, chicken and human cells, the regulation of p34cdc2-Y15 phosphorylation could be a universal mechanism mediating the S-phase feedback control and regulating the initiation of mitosis. We have investigated these phenomena in the budding yeast Saccharomyces cerevisiae. We report here that the CDC28 gene product (the S. cerevisiae homologue of cdc2) is phosphorylated on the equivalent tyrosine (Y19) during S phase but that mutations that prevent tyrosine phosphorylation do not lead to premature mitosis and do not abolish feedback controls. We have therefore demonstrated a mechanism that does not involve tyrosine phosphorylation of p34 by which cells arrest their division in response to the presence of unreplicated or damaged DNA. We speculate that this mechanism may not involve the inactivation of p34 catalytic activity.     

Shock effects on plants: Tannic acid and chlorogenic acid in yam roots

Résumé Les tanins de l'acide chlorogénique s'accumulent immédiatement après que les racines d'ignames ont été soumises à des chocs de 10 à 44 (0.6–2.66 kg/cm²), consistant en une pulsation de la pression comparable à une rafale d'air dans un tube. L'accumulation des tanins est inversement proportionelle à la pression. Mais, l'acide chlorogénique s'accumule progressivement avec élèvation du niveau du choc.     

Climate-mediated energetic constraints on the distribution of hibernating mammals

To predict the consequences of human-induced global climate change, we need to understand how climate is linked to biogeography. Energetic constraints are commonly invoked to explain animal distributions, and physiological parameters are known to vary along distributional gradients. But the causal nature of the links between climate and animal biogeography remain largely obscure. Here we develop a bioenergetic model that predicts the feasibility of mammalian hibernation under different climatic conditions. As an example, we use the well-quantified hibernation energetics of the little brown bat (Myotis lucifugus) to parameterize the model. Our model predicts pronounced effects of ambient temperature on total winter energy requirements, and a relatively narrow combination of hibernaculum temperatures and winter lengths permitting successful hibernation. Microhabitat and northern distribution limits of M. lucifugus are consistent with model predictions, suggesting that the thermal dependence of hibernation energetics constrains the biogeography of this species. Integrating projections of climate change into our model predicts a pronounced northward range expansion of hibernating bats within the next 80 years. Bioenergetics can provide the simple link between climate and biogeography needed to predict the consequences of climate change.