Genetic determinants of serum testosterone concentrations in men

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone''s high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10⁻⁴¹ and rs6258, p = 2.3×10⁻²²). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10⁻¹⁶). The rs6258 polymorphism in exon 4 of SHBG affected SHBG''s affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.     

Phase state and surface topography of palmitoyl-ceramide monolayers

In cell biology (and in many biophysical) studies there is a natural tendency to consider ceramide as a highly condensed, solid-type lipid conferring rigidity and close packing to biomembranes. In the present work we advanced the understanding of the phase behavior of palmitoyl-ceramide restricted to a planar interface using Langmuir monolayers under strictly controlled and known surface packing conditions. Surface pressure–molecular area isotherms were complemented with molecular area–temperature isobars and with observations of the surface topography by Brewster Angle Microscopy. The results described herein indicate that palmitoyl-ceramide can exhibit expanded, as well as condensed phase states. Formation of three phases was found, depending on the surface pressure and temperature: a solid (1.80 nm thick), a liquid-condensed (1.73 nm thick, likely tilted) and a liquid-expanded (1.54 nm thick) phase over the temperature range 5–62 °C. A large hysteretic behavior is observed for the S phase monolayer that may indicate high resistance to domain boundary deformation. A second (or higher) order S → LC phase transition is observed at about room temperature while a first order LC → LE transition occurs in a range of temperature encompassing the physiological one (observed above 30 °C at low surface pressure). This phase behavior broadens the view of ceramide as a type of lipid not-always-rigid but able to exhibit polymorphic properties.     

Modulation of the domain topography of biphasic monolayers of stearic acid and dimyristoyl phosphatidylcholine

The phase diagram of mixed monolayers composed of dimyristoyl phosphatidylcholine (DMPC) and stearic acid (SA) on different subphases was previously reported. It was observed that on acid subphases, liquid-condensed domains with shapes that depend on the SA proportion are formed. For mixtures with 40-45mole% of SA, the domain shape changes from flower-like to circular domains. In this work, we carried out a detailed study of the driving force for the shape change. We find that it is related to the domain density which, in turn, is driven by the domain nucleation process and thus by oversaturation of the system leading to phase segregation. This could be a way of self-regulating the local electrostatics and mechanical properties in membrane surfaces with segregated phase domains.     

A Modified Hai–Murphy Model of Uterine Smooth Muscle Contraction

We extend and analyze the Wang and Politi modified Hai–Murphy model of smooth muscle cell contractions to capture uterine muscle cell response to variations in intracellular calcium concentrations. This model is used to estimate values of unknown parameters in uterine smooth muscle cell cross-bridging. Uterine motility is responsible for carrying out important processes throughout all phases of the nonpregnant female reproductive cycle, including sperm transport, menstruation, and embryo implantation. The modified Hai–Murphy partial differential equation model accounts for the displacement of myosin cross-bridge heads relative to their binding sites. This model was originally developed for the study of airway contractions; we now extended it for use in modeling nonisometric uterine contractions. Our extended model incorporates cross-bridge position and contractile velocity into the original model, resulting in more accurate modeling of the initial stages of contraction and modeling nonisometric contractions. Numerical simulations show that the contraction rate in our extended model is faster than the original Hai–Murphy model. These simulations provide quantitative estimates for the increased level of responsiveness of our extended model to intracellular calcium concentrations. The extended model and new parameter estimates for the cross-bridging can be coupled with uterine flow models to advance our understanding of embryonic motility and intrauterine flow.     

Efficacy and toxicity of the antimicrobial peptide M33 produced with different counter-ions

The tetra-branched peptide M33 (Pini et al. in FASEB J 24:1015-1022, 2010) is under evaluation in animal models for its activity as antimicrobial agent in lung infections and sepsis. The preclinical development of a new drug requires medium-scale manufacture for tests of efficacy, biodistribution, pharmacokinetics and toxicity. In order to produce the most suitable peptide form for these purposes, we evaluated the behaviour of the peptide M33 obtained with different counter-ions. We compared activity and toxicity in vitro and in vivo of the peptide M33 produced as trifluoroacetate salt (TFacetate) and as acetate salt. The two forms did not differ substantially in terms of efficacy in vitro or in vivo but showed different toxicities for human cells and in animals. M33-TFacetate proved to be 5-30% more toxic than M33-acetate for cells derived from normal bronchi and cells carrying ΔF508 mutation in the CFTR gene, the most frequent variant in cystic fibrosis. M33-TFacetate produced manifest signs of in vivo toxicity immediately after administration, whereas M33-acetate only generated mild signs, which disappeared within a few hours. The peptide M33-acetate proved more suitable for the development of a new drug, and was therefore chosen for further characterization.     

Flavonoids in Subtribe Centaureinae (Cass.) Dumort. (Tribe Cardueae,Asteraceae): Distribution and 13C‐NMR Spectral Data

This review reports the occurrence of flavonoids in subtribe Centaureinae of Asteraceae family. It extensively covers the literature up to 2010 and collects all available ¹³C‐NMR data.     

Assessing the effect of solar radiation on plant salt tolerance as defined by the static and dynamic indices

Any interaction between plant salt tolerance and environment is critical to crop breeders, geneticists, molecular biologists, soil-water-crop modelers and all researchers interested in 'global change'. A common criterion used for plant salt tolerance is a threshold value of root zone salinity, a static index that delimits the onset of yield reduction. According to this criterion, it was discovered that tomato salt tolerance decreases significantly with reduced solar radiation. In contrast, the threshold values of a new index based on the dynamic processes of salt accumulation relative to growth, are invariant to solar radiation. The variability and stability of the respective indices provides new insights for accessing physical and biochemical processes governing plant response in saline environments.     

Large-scale de novo transcriptome analysis reveals specific gene expression and novel simple sequence repeats markers in salinized roots of the euhalophyte <Emphasis Type="Italic">Salicornia europaea</Emphasis>

Glycophytic plants suffer from severe stress and injury when roots are exposed to high salinity in the rhizosphere. In contrast, the euhalophyte Salicornia europaea grows well at 200 mM NaCl and can withstand up to 1000 mM NaCl in the root zone. Analysis of gene expression profiles and the underlying molecular mechanisms responsible for this tolerance have been largely overlooked. Using the Illumina sequencing platform and the short-reads assembly programme Trinity, we generated a total of 40 and 39 million clean reads and further 140,086 and 122,728 unigenes from the 200 mM NaCl and 0 mM NaCl treated tissues of S. europaea roots, respectively. All unigenes in this study were functionally annotated within context of the COG, GO and KEGG pathways. Unigene functional annotation analysis allowed us to identify hundreds of ion transporters related to homeostasis and osmotic adaptation as well as a variety of proteins related to cation, amino acid, lipid and sugar transport. We found significant enrichment in response to stress including the functional categories of “antioxidant activity”, “catalytic activity” and “response to stimuli”. These findings represent for a useful resource for the scientific community working on salt tolerance mechanisms. Conversely, a total of 8639 EST-SSRs from 131,594 unigenes were identified and 4539 non-redundant SSRs primers pairs were developed. These data provide a good foundation for future studies on molecular adaptation mechanisms of euhalophytes roots under saline environments and will likely facilitate the identification of critical salt tolerance traits to be transferred in economically important crops.     

Ganglioside GD3 and GD3-lactone mediated regulation of the intermolecular organization in mixed monolayers with dipalmitoylphosphatidylcholine

The interactions of dpPC with ganglioside GD3 and two lactones, GD3LacI or GD3LacII, in lipid monolayers occur with reduced, unaltered, or increased molecular area and surface potential/molecule, respectively. dpPC is fully miscible with GD3 and GD3LacI but films with GD3LacII show immiscibility above 75 mol% lactone. At low proportions of GD3 in mixtures with dpPC, GD3 undergoes condensation and depolarization; dpPC is depolarized and its molecular area is reduced above 50 mol% GD3. GD3LacI forms ideally mixed films with dpPC. Mixtures of dpPC with GD3LacII at mole fractions below 0.3 show increased mean molecular area and surface potential/molecule mostly due to lactone alterations. Between mole fractions of 0.3 and 0.75 the surface parameters of dpPC are altered, and above these proportions both lipids are immiscible. Defined variations of molecular properties induced by ganglioside lactonization are selectively transduced to changes of the intermolecular organization and surface electrostatics in mixed interfaces with dpPC. Thus, changes in the relative proportions of a ganglioside and its lactone forms may act as sensitive biotransducers for membrane-mediated cellular functions, without the need for metabolically altering the concentration of gangliosides.