Lack of association between common polymorphisms in the 17beta-hydroxysteroid dehydrogenase type V gene (HSD17B5) and precocious pubarche

BACKGROUND: 17beta-Hydroxysteroid dehydrogenase (type V; HSD17B5) is a key enzyme involved in testosterone production in females. A single nucleotide polymorphism (SNP) in the promoter region of its gene was recently found to be associated with polycystic ovary syndrome (PCOS) and its related hyperandrogenaemia. Precocious pubarche (PP) is a clinical entity pointing to adrenal androgen excess from mid-childhood onward and is associated with ovarian androgen excess from puberty onward. It is therefore a strong risk factor for PCOS. METHODS: To investigate associations between this promoter SNP along with three exonic SNPs (one non-synonymous and two synonymous) from the same gene, and PP, a case-control study was performed in 190 girls with PP (84 of which were also tested for functional ovarian hyperandrogenism) from Barcelona, Spain and 71 healthy controls. Clinical features and hormone concentrations relevant to hyperandrogenism were compared by HSD17B5 genotype and haplotype. RESULTS: Neither HSD17B5 genotypes nor haplotype were associated with PP, or subsequent androgen excess in girls from Barcelona (all P>0.05). CONCLUSIONS: HSD17B5 SNPs predicted to have functional effects do not appear to be a risk factor for PP in girls from Barcelona, despite these girls being at high risk of developing androgen excess in adulthood.     

Dominance of the alpha1B-adrenergic receptor and its subcellular localization in human and TRAMP prostate cancer cell lines

The function and distribution of alpha1-adrenergic receptor (AR) subtypes in prostate cancer cells is well characterized. Previous studies have used RNA localization or low-avidity antibodies in tissue or cell lines to determine the alpha1-AR subtype and suggested that the alpha1A-AR is dominant. Two androgen-insensitive, human metastatic cancer cell lines DU145 and PC3 were used as well as the mouse TRAMP C1-C3 primary and clonal cell lines. The density of alpha1-ARs was determined by saturation binding and the distribution of the different alpha1-AR subtypes was examined by competition-binding experiments. In contrast to previous studies, the major alpha1-AR subtype in DU145, PC3 and all of the TRAMP cell lines is the alpha1B-AR. DU145 cells contained 100% of the alpha1B-AR subtype, whereas PC3 cells were composed of 21% alpha1 A-AR and 79% alpha1B-AR. TRAMP cell lines contained between 66% and 79% of the alpha1B-AR with minor fractions of the other two subtypes. Faster doubling time in the TRAMP cell lines correlated with decreasing alpha 1B-AR and increasing alpha1 A- and alpha1D-AR densities. Transfection with EGFP-tagged alpha1B-ARs revealed that localization was mainly intracellular, but the majority of the receptors translocated to the cell surface after extended preincubation (18 hr) with either agonist or antagonist. Localization was confirmed by ligand-binding studies and inositol phosphate assays where prolonged preincubation with either agonist and/or antagonist increased the density and function of alpha 1-ARs, suggesting that the native receptors were mostly intracellular and nonfunctional. Our studies indicate that alpha1B-ARs are the major alpha1-AR subtype expressed in DU145, PC3, and all TRAMP cell lines, but most of the receptor is localized in intracellular compartments in a nonfunctional state, which can be rescued upon prolonged incubation with any ligand.     

The early evolution of land plants,from fossils to genomics: a commentary on Lang (1937) ‘On the plant-remains from the Downtonian of England and Wales'

During the 1920s, the botanist W. H. Lang set out to collect and investigate some very unpromising fossils of uncertain affinity, which predated the known geological record of life on land. His discoveries led to a landmark publication in 1937, ‘On the plant-remains from the Downtonian of England and Wales’, in which he revealed a diversity of small fossil organisms of great simplicity that shed light on the nature of the earliest known land plants. These and subsequent discoveries have taken on new relevance as botanists seek to understand the plant genome and the early evolution of fundamental organ systems. Also, our developing knowledge of the composition of early land-based ecosystems and the interactions among their various components is contributing to our understanding of how life on land affects key Earth Systems (e.g. carbon cycle). The emerging paradigm is one of early life on land dominated by microbes, small bryophyte-like organisms and lichens. Collectively called cryptogamic covers, these are comparable with those that dominate certain ecosystems today. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.     

Signaling networks regulating leukocyte podosome dynamics and function

Podosomes are ventral adhesion structures prominent in cells of the myeloid lineage. A common aspect of these cells is that they are highly motile and must to traverse multiple tissue barriers in order to perform their functions. Recently podosomes have gathered attention from researchers as important cellular structures that can influence cell adhesion, motility and matrix remodeling. Adhesive and soluble ligands act via transmembrane receptors and propagate signals to the leukocyte cytoskeleton via small G proteins of the Rho family, tyrosine kinases and scaffold proteins and are able to induce podosome formation and rearrangements. Manipulation of the signals that regulate podosome formation and dynamics can therefore be a strategy to interfere with leukocyte functions in a multitude of pathological settings, such as infections, atherosclerosis and arthritis. Here, we review the major signaling molecules that act in the formation and regulation of podosomes.     

Relationships of stable carbon isotopes, plant water potential and growth: an approach to asses water use efficiency and growth strategies of dry land agroforestry species

The relationships between annual wood stable carbon isotope composition (δ¹³C), dry season midday plant water potential, and annual growth rate were investigated to asses the ability of agroforestry species to adapt to climate changes. 6–8 stem disks from four co-occurring species (Acacia senegal, A. seyal, A. tortilis and Balanites aegyptiaca) were collected for radial growth measurements using tree-ring analysis spanning 1930–2003. Annual δ¹³C was measured on three tree disks per species for the period 1970–2002. Midday plant water potential was measured during the dry season. Annual radial growth and midday plant water potential ranged from 0.27 to 9.12 mm and −1.0 to −5.0 MPa, respectively, with statistically significant differences. After correcting annual wood δ¹³C for atmospheric changes in δ¹³C, carbon isotopic composition ranged from −22.22 to −26.58‰. Relationships between δ¹³C, radial growth and plant water potentials revealed the interaction of water availability, stomatal conductance, δ¹³C values and growth. Two contrasting water use strategies and competitive advantages can be distinguished. Species with lower mean δ¹³C values (A. senegal and A. seyal) show high plant water potential and, hence, better growth during moist years. Thus, they indicate low water use efficiency (WUE) and opportunistic water use strategy. On the other hand, species with lower water potentials (A. tortilis and B. aegyptiaca) showed relative better growth performance and less increase in δ¹³C in drought years, reflecting their high WUE and conservative water use strategy. These results suggest that δ¹³C in tree rings can be useful in estimating historic changes in plant WUE and hence in screening drought tolerant species in the face of expected climate changes, as well as for assessing the functional diversity and risk reduction in mixed vegetation.     

Evidence for increased exposure of the Notch1 metalloprotease cleavage site upon conversion to an activated conformation

Notch proteins are transmembrane receptors that normally adopt a resting state poised to undergo activating proteolysis upon ligand engagement. Receptor quiescence is maintained by three LIN12/Notch repeats (LNRs), which wrap around a heterodimerization domain (HD) divided by furin cleavage at site S1 during maturation. Ligand binding initiates signaling by inducing sensitivity of the HD to proteolysis at the regulated S2 cleavage site. Here, we used hydrogen exchange mass spectrometry to examine the solution dynamics of the Notch1 negative regulatory region in autoinhibited states before and after S1 cleavage, in a proteolytically sensitive "on" state, and in a complex with an inhibitory antibody. Conversion to the "on" state leads to accelerated deuteration in the S2 region and in nearby secondary structural elements within the HD. In contrast, complexation with the inhibitory antibody retards deuteration around the S2 site. Together, these studies reveal how S2 site exposure is promoted by receptor activation and suppressed by inhibitory antibodies.     

Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial

Background and Aims

The association between hygiene and prevalence of autoimmune disease has been attributed in part to enteric helminth infection. A pilot study of experimental infection with the hookworm Necator americanus was undertaken among a group of otherwise healthy people with celiac disease to test the potential of the helminth to suppress the immunopathology induced by gluten.

Methods

In a 21-week, double-blinded, placebo-controlled study, we explored the effects of N. americanus infection in 20 healthy, helminth-naïve adults with celiac disease well controlled by diet. Staged cutaneous inoculations with 10 and 5 infective 3^rd stage hookworm larvae or placebo were performed at week-0 and -12 respectively. At week-20, a five day oral wheat challenge equivalent to 16 grams of gluten per day was undertaken. Primary outcomes included duodenal Marsh score and quantification of the immunodominant α-gliadin peptide (QE65)-specific systemic interferon-γ-producing cells by ELISpot pre- and post-wheat challenge.

Results

Enteric colonisation with hookworm established in all 10 cases, resulting in transiently painful enteritis in 5. Chronic infection was asymptomatic, with no effect on hemoglobin levels. Although some duodenal eosinophilia was apparent, hookworm-infected mucosa retained a healthy appearance. In both groups, wheat challenge caused deterioration in both primary and several secondary outcomes.

Conclusions

Experimental N. americanus infection proved to be safe and enabled testing its effect on a range of measures of the human autoimmune response. Infection imposed no obvious benefit on pathology.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00671138","term_id":"NCT00671138"}}NCT00671138