Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia.

Blockage in myeloid differentiation characterizes acute myeloid leukemia (AML); the stage of the blockage defines distinct AML subtypes (AML1/2 to AML5). Differentiation therapy in AML has recently raised interest because the survival of AML3 patients has been greatly improved using the differentiating agent retinoic acid. However, this molecule is ineffective in other AML subtypes. The CD44 surface antigen, on leukemic blasts from most AML patients, is involved in myeloid differentiation. Here, we report that ligation of CD44 with specific anti-CD44 monoclonal antibodies or with hyaluronan, its natural ligand, can reverse myeloid differentiation blockage in AML1/2 to AML5 subtypes. The differentiation of AML blasts was evidenced by the ability to produce oxidative bursts, the expression of lineage antigens and cytological modifications, all specific to normal differentiated myeloid cells. These results indicate new possibilities for the development of CD44-targeted differentiation therapy in the AML1/2 to AML5 subtypes.     

Invasive shrub distribution varies with distance to roads and stand age in eastern deciduous forests in Indiana, USA

We documented the relationship between densities of invasive exotic shrubs, distance to road, and successional age of the forest in 14 forested sites throughout central and southern Indiana. Roadways are increasingly abundant, human-made features that can be conduits for the spread of invasive exotic plants in a number of ecosystems. Little is known, however, about the role of roads in eastern deciduous forest ecosystems where road density is high. Further, it is not known whether the distribution of exotic plants along roads depends on the successional age of the forest. In this study, densities of four of seven exotic shrub species declined with increasing distance to the nearest road across all successional ages. Greater densities of exotic shrubs were found in young and mid-successional forests than mature forests. However, there was no interaction between distance to road and forest age, suggesting that the role of roads in the invasion process does not change across forest successional ages. We outline several potential mechanisms that may drive patterns of shrub distribution along roadside edges as a guide for future research.     

THE FINE STRUCTURE OF THE EXOERYTHROCYTIC STAGES OF PLASMODIUM FALLAX

The fine structure of the exoerythrocytic cycle of an avian malarial parasite, Plasmodium fallax, has been analyzed using preparations grown in a tissue culture system derived from embryonic turkey brain cells which were fixed in glutaraldehyde-OsO₄. The mature merozoite, an elongated cell 3- to 4-µ long and 1- to 2-µ wide, is ensheathed in a complex double-layered pellicle. The anterior end consists of a conoid, from which emanate two lobed paired organelles and several closely associated dense bodies. A nucleus is situated in the mid portion of the cell, while a single mitochondrion wrapped around a spherical body is found in the posterior end. On the pellicle of the merozoite near the nucleus a cytostomal cavity, 80 to 100 mµ in diameter, is located. Based on changes in fine structure, the subsequent sequence of development is divided into three phases: first, the dedifferentiation phase, in which the merozoite loses many complex structures, i.e. the conoid, paired organelles, dense bodies, spherical body, and the thick inner layers of the pellicle, and transforms into a trophozoite; second, the growth phase, which consists of many nuclear divisions as well as parallel increases in mitochondria, endoplasmic reticulum, and ribosomes; and third, the redifferentiation and cytoplasmic schizogony phase, in which the specialized organelles reappear as the new merozoites bud off from the mother schizont.     

Identification and characterization of in vitro expanded hematopoietic stem cells

Hematopoietic stem cells (HSCs) cultured outside the body are the fundamental component of a wide range of cellular and gene therapies. Recent efforts have achieved > 200‐fold expansion of functional HSCs, but their molecular characterization has not been possible since the majority of cells are non‐HSCs and single cell‐initiated cultures have substantial clone‐to‐clone variability. Using the Fgd5 reporter mouse in combination with the EPCR surface marker, we report exclusive identification of HSCs from non‐HSCs in expansion cultures. By directly linking single‐clone functional transplantation data with single‐clone gene expression profiling, we show that the molecular profile of expanded HSCs is similar to proliferating fetal HSCs and reveals a gene expression signature, including Esam, Prdm16, Fstl1, and Palld, that can identify functional HSCs from multiple cellular states. This “repopulation signature” (RepopSig) also enriches for HSCs in human datasets. Together, these findings demonstrate the power of integrating functional and molecular datasets to better derive meaningful gene signatures and opens the opportunity for a wide range of functional screening and molecular experiments previously not possible due to limited HSC numbers.     

Unraveling polyketide synthesis in members of the genus Aspergillus

Aspergillus species have the ability to produce a wide range of secondary metabolites including polyketides that are generated by multi-domain polyketide synthases (PKSs). Recent biochemical studies using dissected single or multiple domains from PKSs have provided deep insight into how these PKSs control the structural outcome. Moreover, the recent genome sequencing of several species has greatly facilitated the understanding of the biosynthetic pathways for these secondary metabolites. In this review, we will highlight the current knowledge regarding polyketide biosynthesis in Aspergillus based on the domain architecture of non-reducing, highly reducing, and partially reducing PKSs, and PKS-non-ribosomal peptide synthetases.     

Estimating the oxidative ratio of the global terrestrial biosphere carbon

The oxidative ratio (OR) is the amount of CO₂ sequestered in the terrestrial biosphere for each mol of O₂ produced. The OR governs the efficiency of a terrestrial biome’s O₂ production and it has been used to calculate the balance of terrestrial and oceanic carbon sinks across the globe. However, the value used in carbon cycle calculations comes from only one study of one environment. Here we perform a meta-analysis of studies of soil organic matter and vegetation composition to calculate the first global ecosystem OR value. We use data from 138 samples across 31 studies covering 9 USDA global soil orders, 7 global biomes and 5 continents and combine this information as a weighted average based upon biome land area or organic carbon content of the soil order. Organic matter fractions could not be shown to be reliable proxies for whole soil or vegetation OR. The resulting analysis suggests that although the presently used value of 1.1 is within the range of natural occurrence, it is not the most accurate choice, representing between the 97th and 99th percentile value. Our study yields a global terrestrial OR = 1.04 ± 0.03. This value of OR means that the sink of anthropogenic carbon fluxes to land has been underestimated (and the sink to the ocean overestimated) by up to 14 %. Recalculating with our OR value, the fossil fuel carbon flux to land is 1.48 ± 0.04 Gt C/year and flux to oceans is 2.02 ± 0.03 Gt C/year.     

The measurement of small-scale environmental heterogeneity using clonal transplants of Anthoxanthum odoratum and Danthonia spicata

Summary To assess the scale of micro-environmental heterogeneity perceived by two co-occurring grass species, Anthoxanthum odoratum and Danthonia spicata, cloned tillers of each species were planted into the natural habitat at a range of spacings (from 2 cm to more than 2 m apart) and measured for survival and fecundity over three years. A. odoratum responded to heterogeneity at a scale of 4–8 cm and at a scale of 2–8 m but not to intermediate scales. D. spicata did not respond significantly to heterogeneity. However one genotype infected with the systemic fungus Atkinsonella hypoxylon showed a large response to heterogeneity at both small and large spatial scales. The results showed that the scale and level of environmental heterogeneity as measured by its fitness impact depends on the species and genotype involved. The results indicate that small scale environmental heterogeneity could play a role in the maintenance of sexual reproduction in A. odoratum.     

Androgen Receptor and Histone Lysine Demethylases in Ovine Placenta

Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR). Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs) to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE) in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders.