Auxin Control of Embryo Patterning

Plants start their life as a single cell, which, during the process of embryogenesis, is transformed into a mature embryo with all organs necessary to support further growth and development. Therefore, each basic cell type is first specified in the early embryo, making this stage of development excellently suited to study mechanisms of coordinated cell specification—pattern formation. In recent years, it has emerged that the plant hormone auxin plays a prominent role in embryo development. Most pattern formation steps in the early Arabidopsis embryo depend on auxin biosynthesis, transport, and response. In this article, we describe those embryo patterning steps that involve auxin activity, and we review recent data that shed light on the molecular mechanisms of auxin action during this phase of plant development.     

Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase

Gamma-secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of gamma-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that gamma-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of gamma-secretase. Moreover, the level of EGFR is inversely correlated with the level of gamma-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of gamma-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking gamma-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of gamma-secretase and that mice with genetic reduction of gamma-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer.     

Warsaw Breakage Syndrome, a Cohesinopathy Associated with Mutations in the XPD Helicase Family Member DDX11/ChlR1

The iron-sulfur-containing DNA helicases XPD, FANCJ, DDX11, and RTEL represent a small subclass of superfamily 2 helicases. XPD and FANCJ have been connected to the genetic instability syndromes xeroderma pigmentosum and Fanconi anemia. Here, we report a human individual with biallelic mutations in DDX11. Defective DDX11 is associated with a unique cellular phenotype in which features of Fanconi anemia (drug-induced chromosomal breakage) and Roberts syndrome (sister chromatid cohesion defects) coexist. The DDX11-deficient patient represents another cohesinopathy, besides Cornelia de Lange syndrome and Roberts syndrome, and shows that DDX11 functions at the interface between DNA repair and sister chromatid cohesion.     

Testicular morphology and expression of aromatase in testes of mice with the mosaic mutation (Atp7a mo-ms)

The aim of this study was to determine whether testicular cells of mice with the mosaic mutation, associated with abnormal copper metabolism, are able to aromatize androgens to estrogens, and what is the putative role of estrogens in the gonad of the mutant male. Mosaic is a lethal mutation; affected males usually die on about day 16. Those, which survive to reach sexual maturity, are valuable research subjects. In testes of young and adult mutants, histological analysis revealed the presence of many degenerating seminiferous tubules besides normal-looking ones. Additionally, high numbers of apoptotic germ cells were observed, especially in young mutants when compared with the controls. Positive immunostaining for aromatase was found in cultured Leydig cells and testicular sections of both control and mutant males. The intensity of immunostaining was always stronger in the mosaic mice. In both groups, Western-blot analysis revealed the presence of aromatase protein as a single band of approximately 55 kDa. In the mosaic males, levels of testosterone in cultured Leydig cells, whole testes, and in blood plasma were lower than in those of the respective controls. On the contrary, estradiol concentrations were always higher in the mutants. Both in vivo and in vitro studies indicate that morphological and functional changes in the testes of the mosaic mice mainly result from defective copper metabolism. The higher level of endogenous estrogens can additionally enhance morphological alterations within the testes. It seems also likely that excess estrogens may affect the survival rate of the mosaic males.     

The above-ground coarse wood productivity of 104 Neotropical forest plots

The net primary production of tropical forests and its partitioning between long‐lived carbon pools (wood) and shorter‐lived pools (leaves, fine roots) are of considerable importance in the global carbon cycle. However, these terms have only been studied at a handful of field sites, and with no consistent calculation methodology. Here we calculate above‐ground coarse wood carbon productivity for 104 forest plots in lowland New World humid tropical forests, using a consistent calculation methodology that incorporates corrections for spatial variations in tree‐size distributions and wood density, and for census interval length. Mean wood density is found to be lower in more productive forests. We estimate that above‐ground coarse wood productivity varies by more than a factor of three (between 1.5 and 5.5 Mg C ha^?1 a^?1) across the Neotropical plots, with a mean value of 3.1 Mg C ha^?1 a^?1. There appear to be no obvious relationships between wood productivity and rainfall, dry season length or sunshine, but there is some hint of increased productivity at lower temperatures. There is, however, also strong evidence for a positive relationship between wood productivity and soil fertility. Fertile soils tend to become more common towards the Andes and at slightly higher than average elevations, so the apparent temperature/productivity relationship is probably not a direct one. Coarse wood productivity accounts for only a fraction of overall tropical forest net primary productivity, but the available data indicate that it is approximately proportional to total above‐ground productivity. We speculate that the large variation in wood productivity is unlikely to directly imply an equivalent variation in gross primary production. Instead a shifting balance in carbon allocation between respiration, wood carbon and fine root production seems the more likely explanation.     

Structure of a classical MHC class I molecule that binds "non-classical" ligands

Chicken YF1 genes share a close sequence relationship with classical MHC class I loci but map outside of the core MHC region. To obtain insights into their function, we determined the structure of the YF1*7.1/β₂-microgloblin complex by X-ray crystallography at 1.3 Å resolution. It exhibits the architecture typical of classical MHC class I molecules but possesses a hydrophobic binding groove that contains a non-peptidic ligand. This finding prompted us to reconstitute YF1*7.1 also with various self-lipids. Seven additional YF1*7.1 structures were solved, but only polyethyleneglycol molecules could be modeled into the electron density within the binding groove. However, an assessment of YF1*7.1 by native isoelectric focusing indicated that the molecules were also able to bind nonself-lipids. The ability of YF1*7.1 to interact with hydrophobic ligands is unprecedented among classical MHC class I proteins and might aid the chicken immune system to recognize a diverse ligand repertoire with a minimal number of MHC class I molecules.     

Penicillin-binding protein 2x of Streptococcus pneumoniae: three new mutational pathways for remodelling an essential enzyme into a resistance determinant

Mutations in the transpeptidase domain of penicillin-binding protein 2x (PBP2x) of Streptococcus pneumoniae that reduce the affinity to beta-lactams are important determinants of resistance to these antibiotics. We have now analyzed in vitro and in vivo properties of PBP2x variants from cefotaxime-resistant laboratory mutants and a clinical isolate. The patterns of two to four resistance-specific mutations present in each of the proteins, all of which are placed between 6.6 and 24 Å around the active site, fall into three categories according to their positions in the three-dimensional structure. The first PBP2x group is characterized by mutations at the end of helix α11 and carries the well-known T550A change and/or one mutation on the surface of the penicillin-binding domain in close contact with the C-terminal domain. All group I proteins display very low acylation efficiencies, ≤ 1700 M^− 1 s^− 1, for cefotaxime. The second class represented by PBP2x of the mutant C505 shows acylation efficiencies below 100 M^− 1 s^− 1 for both cefotaxime and benzylpenicillin and contains the mutation L403F at a critical site close to the active serine. PBP2x of the clinical isolate 669 reveals a third mutational pathway where at least the two mutations Q552E and S389L are important for resistance, and acylation efficiency is reduced for both beta-lactams to around 10,000 M^− 1 s^− 1. In each group, at least one mutation is located in close vicinity to the active site and mediates a resistance phenotype in vivo alone, whereas other mutations might exhibit secondary effects only in context with other alterations.     

Social Determinants and the Classification of Disease: Descriptive Epidemiology of Selected Socially Mediated Disease Constellations

Background

Most major diseases have important social determinants. In this context, classification of disease based on etiologic or anatomic criteria may be neither mutually exclusive nor optimal.

Methods and Findings

Units of analysis comprised large metropolitan central and fringe metropolitan counties with reliable mortality rates – (n = 416). Participants included infants and adults ages 25 to 64 years with selected causes of death (1999 to 2006). Exposures included that residential segregation and race-specific social deprivation variables. Main outcome measures were obtained via principal components analyses with an orthogonal rotation to identify a common factor. To discern whether the common factor was socially mediated, negative binomial multiple regression models were developed for which the dependent variable was the common factor. Results showed that infant deaths, mortality from assault, and malignant neoplasm of the trachea, bronchus and lung formed a common factor for race-gender groups (black/white and men/women). Regression analyses showed statistically significant, positive associations between low socio-economic status for all race-gender groups and this common factor.

Conclusions

Between 1999 and 2006, deaths classified as “assault” and “lung cancer”, as well as “infant mortality” formed a socially mediated factor detectable in population but not individual data. Despite limitations related to death certificate data, the results contribute important information to the formulation of several hypotheses: (a) disease classifications based on anatomic or etiologic criteria fail to account for social determinants; (b) social forces produce demographically and possibly geographically distinct population-based disease constellations; and (c) the individual components of population-based disease constellations (e.g., lung cancer) are phenotypically comparable from one population to another but genotypically different, in part, because of socially mediated epigenetic variations. Additional research may produce new taxonomies that unify social determinants with anatomic and/or etiologic determinants. This may lead to improved medical management of individuals and populations.