Functional characterization of synthetic leukotriene B and its stereochemical isomers.

Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups

Pattern formation by lateral inhibition with feedback: a mathematical model of Delta-Notch intercellular signalling

In many developing tissues, adjacent cells diverge in character so as to create a fine-grained pattern of cells in contrasting states of differentiation. It has been proposed that such patterns can be generated through lateral inhibition—a type cells–cell interaction whereby a cell that adopts a particular fate inhibits its immediate neighbours from doing likewise. Lateral inhibition is well documented in flies, worms and vertebrates. In all of these organisms, the transmembrane proteins Notch and Delta (or their homologues) have been identified as mediators of the interaction—Notch as receptor, Delta as its ligand on adjacent cells. However, it is not clear under precisely what conditions the Delta-Notch mechanism of lateral inhibition can generate the observed types of pattern, or indeed whether this mechanism is capable of generating such patterns by itself. Here we construct and analyse a simple and general mathematical model of such contact-mediated lateral inhibition. In accordance with experimental data, the model postulates that receipt of inhibition (i.e. activation of Notch) diminishes the ability to deliver inhibition (i.e. to produce active Delta). This gives rise to a feedback loop that can amplify differences between adjacent cells. We investigate the pattern-forming potential and temporal behavior of this model both analytically and through numerical simulation. Inhomogeneities are self-amplifying and develop without need of any other machinery, provided the feedback is sufficiently strong. For a wide range of initial and boundary conditions, the model generates fine-grained patterns similar to those observed in living systems

Elastic precursor of the transformation from glycolipid-nanotube to -vesicle

By the combination of optical tweezer manipulation and digital video microscopy, the flexural rigidity of single glycolipid "nano" tubes has been measured below the transition temperature at which the lipid tubules are transformed into vesicles. Consequently, we have found a clear reduction of the rigidity obviously before the transition as temperature increasing. Further experiments of infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) have suggested a microscopic change of the tube walls, synchronizing with the precursory softening of the nanotubes.Comment: 9 pages, 6 figure

Use of Statin Therapy to Reduce Cardiovascular Risk in Older Patients

Background. Cardiovascular disease is the principal cause of mortality in older individuals, and more than 80% of deaths due to coronary heart disease or stroke occur in patients over 65 years of age. Hyperlipidemia is one of the main modifiable risk factors for cardiovascular disease. Current guidelines recommend the use of statins to reduce low-density lipoprotein cholesterol to appropriate targets based on an individual's cardiovascular risk, and clearly state that older age should not be a barrier to treatment. Despite extensive evidence demonstrating clear benefit with statin therapy in older individuals, this population remains chronically undertreated. Scope. This paper provides an overview of the current evidence available regarding the efficacy and safety of statin therapy to reduce cardiovascular risk in older patients. We use hypothetical case studies to address some of the questions frequently posed by physicians responsible for the cardiovascular health of older patients. Conclusions. Various factors may account for the failure to provide appropriate treatment, including a lack of awareness of clinical benefits and perceived safety issues. However, if current guidelines are followed and older patients treated to appropriate LDL-C goals, the likelihood of cardiovascular events will be reduced in this high-risk population. Employing an evidence-based approach to the management of cardiovascular risk in older patients is likely to yield benefits in terms of overall cardiovascular burden

Antigenic and genetic evolution of contemporary swine H1 influenza viruses in the United States

Several lineages of influenza A viruses (IAV) currently circulate in North American pigs. Genetic diversity is further increased by transmission of IAV between swine and humans and subsequent evolution. Here, we characterized the genetic and antigenic evolution of contemporary swine H1N1 and H1N2 viruses representing clusters H1-α (1A.1), H1-β (1A.2), H1pdm (1A.3.3.2), H1-γ (1A.3.3.3), H1-δ1 (1B.2.2), and H1-δ2 (1B.2.1) currently circulating in pigs in the United States. The δ1-viruses diversified into two new genetic clades, H1-δ1a (1B.2.2.1) and H1-δ1b (1B.2.2.2), which were also antigenically distinct from the earlier H1-δ1-viruses. Further characterization revealed that a few key amino acid changes were associated with antigenic divergence in these groups. The continued genetic and antigenic evolution of contemporary H1 viruses might lead to loss of vaccine cross-protection that could lead to significant economic impact to the swine industry, and represents a challenge to public health initiatives that attempt to minimize swine-to-human IAV transmission

The ISSI international study team on the martian PBL – status report and plan

Dynamical processes in the Martian boundary layer provide the means of communication between surface ice deposits and the free atmosphere, and the means of lifting dust from the surface. The boundary layer is therefore one of the most important components of the Martian climate system. The Martian boundary layer differs from that of the Earth in that it is more strongly forced, it is deeper, and the relative importance of radiative and convective heat fluxes in the lower boundary layer can be quite different. In order to understand the Martian boundary layer, a combination of theoretical, modeling and observational studies are necessary. Interactions between theorists, modelers, and observational scientists are needed to make progress and to provide a basis for analysis of data expected from Phoenix, Mars Science Laboratory, ExoMars and other future landed missions (such as a surface network mission), or missions such as balloons or other aircraft operating in the neutral atmosphere. The prime goal of this project under the auspices of the International Space Science Institute (ISSI) is to review and assess the current knowledge and understanding of Martian planetary boundary layer and its interactions with the surface and free atmosphere. We aim to promote international communication and collaboration to enhance the rate of acquisition of knowledge and understanding. This will be achieved through an International Study Team and publication of overview papers and individual reports on recent advances in this area