Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening

Janus kinase 2 (JAK2) plays a crucial role in the pathomechanism of myeloproliferative disorders and hematologic malignancies. A somatic mutation of JAK2 (Val617Phe) was previously shown to occur in 98% of patients with polycythemia vera and 50% of patients with essential thrombocythemia and primary myelofibrosis. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. Here, we applied a structure-based virtual screen to identify novel JAK2 inhibitors. One JAK2 inhibitor in particular, G6, demonstrated remarkable potency as well as specificity, which makes it as a potential lead candidate against diseases related to elevated JAK2 tyrosine kinase activity.     

How too much care kills species: Grassland reserves,agri-environmental schemes and extinction of <Emphasis Type=Italic>Colias myrmidone</Emphasis> (Lepidoptera: Pieridae) from its former stronghold

We describe a rapid extirpation of a strong population of globally threatened butterfly, Colias myrmidone, from the White Carpathians, Czech Republic. The area is renowned for a high plant and insect diversity associated with savannah-like Carpathian meadows, traditionally managed by mowing once a year and subsequent autumn grazing. Although many meadows fell victim to land consolidation schemes in the 1970s and 1980s, over 2000 hectares have been preserved in a dense network of reserves. The reserve management practised since the mid-1990s has consisted of uniform machine mowing of entire areas and this was further accelerated after accession of the Czech Republic to the EU, when agri-environmental schemes (AES) required two cuts per year. This starkly conflicted with the life history of C. myrmidone, because both spring and autumn cuts interfere with larval development. Despite intensive surveys, only five and then two C. myrmidone individuals were seen in the area in 2005 and 2006, respectively, rendering the species effectively extinct. Conservation authorities failed by neglecting early warning signals issued by amateur entomologists, and by ignoring the basic tenets of conservation of insect diversity, such as the need to maintain heterogeneity of resources. Unless AES provide for this crucial aspect of habitat suitability for invertebrates, they may turn from a great hope into a massive failure.     

A tumor suppressor homolog,AtPTEN1, is essential for pollen development in Arabidopsis

Although it is well known that Tyr phosphatases play a critical role in signal transduction in animal cells, little is understood of the functional significance of Tyr phosphatases in higher plants. Here, we describe the functional analysis of an Arabidopsis gene (AtPTEN1) that encodes a Tyr phosphatase closely related to PTEN, a tumor suppressor in animals. The recombinant AtPTEN1 protein, like its homologs in animals, is an active phosphatase that dephosphorylates phosphotyrosine and phosphatidylinositol substrates. RNA gel blot analysis and examination of promoter-reporter constructs in transgenic Arabidopsis plants revealed that the AtPTEN1 gene is expressed exclusively in pollen grains during the late stage of development. Suppression of AtPTEN1 gene expression by RNA interference caused pollen cell death after mitosis. We conclude that AtPTEN1 is a pollen-specific phosphatase and is essential for pollen development.     

Estimation of Multimedia Inorganic Arsenic Intake in the U.S. Population

Arsenic is widely distributed in the environment by natural and human means. The potential for adverse health effects from inorganic arsenic depends on the level and route of exposure. To estimate potential health risks of inorganic arsenic, the apportionment of exposure among sources of inorganic arsenic is critical. In this study, daily inorganic arsenic intake of U.S. adults from food, water, and soil ingestion and from airborne particle inhalation was estimated. To account for variations in exposure across the U.S., a Monte Carlo approach was taken using simulations for 100,000 individuals representing the age, gender, and county of residence of the U.S. population based on census data. Our analysis found that food is the greatest source of inorganic arsenic intake and that drinking water is the next highest contributor. Inhalation of airborne arsenic-containing particles and ingestion of arsenic-containing soils were negligible contributors. The exposure is best represented by the ranges of inorganic arsenic intake (at the 10^th and 90^th percentiles), which were 1.8 to 11.4 µg/day for males and 1.3 to 9.4 µg/day for females. Regional differences in inorganic arsenic exposure were due mostly to consumption of drinking water containing differing inorganic arsenic content rather than to food preferences.