Small molecule interactions were central to the origin of life

Many scientists believe life began with the spontaneous formation of a replicator. This idea has been supported by "prebiotic" syntheses carried out by chemists using modern apparatus and purified reagents. The probability that such reactions would take place spontaneously on the early Earth is minute. These points are illustrated here by considering the often cited oligomerization of activated RNA components by clay minerals. A more likely alternative for the origin of life is one in which a collection of small organic molecules multiply their numbers through catalyzed reaction cycles, driven by a flow of available free energy. Although a number of possible systems of this type have been discussed, no experimental demonstration has been made. The inclusion of a "driver" reaction, directly coupled to the energy source, may lead to a solution.     

Endogenous cardiotonic steroids and salt-sensitive hypertension

Endogenous cardiotonic steroids (CTS), also called digitalis like factors, have been postulated to play important roles in pathogenesis of hypertension for nearly half of a century. For the past 50 years biomedical scientists have been in quest of an unidentified factor or hormone that both increases blood pressure and renal sodium excretion; this “natriuretic hormone” was, in fact, postulated to interact with the Na/K-ATPase. Recent discoveries have led to the identification of steroid molecules which are present in humans, rodents and amphibians, and which, in a complex manner, interact with each other and with the other systems that regulate renal salt handling and contribute to the salt-sensitivity of blood pressure.Recent findings include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of mechanisms by which CTS can signal through the Na/K-ATPase. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the central regulation of blood pressure and regulation of cell growth, and development of cardiovascular and renal fibrosis in particular.     

Propenylamide and propenylsulfonamide cephalosporins as a novel class of anti-MRSA β-lactams

Novel C(3) propenylamide and propenylsulfonamide cephalosporins have been synthesized and tested for their ability to inhibit the penicillin-binding protein 2′ (PBP2′) from Staphylococcus epidermidis and the growth of a panel of clinically relevant bacterial species, including methicillin-resistant Staphylococcus aureus (MRSA). The most potent compounds inhibited the growth of MRSA strains with minimum inhibitory concentrations (MIC) as low as 1 μg/mL. The structure–activity relationship revealed the potential for further optimization of this new cephalosporin class.     

Observation of a chloride-dependent intermediate during catalysis by angiotensin converting enzyme using radiationless energy transfer

Stopped-flow radiationless energy-transfer kinetics have been used to examine the effects of chloride on the hydrolysis of Dns-Lys-Phe-Ala-Arg by angiotensin converting enzyme. The kinetic constants for hydrolysis at pH 7.5 and 22 degrees C in the presence of 300 mM sodium chloride were KM = 28 microM and kcat = 110 s-1, and in its absence, KM = 240 microM and kcat = 68 s-1. The apparent binding constant for chloride was 4 mM, and the extent of chloride activation in terms of kcat/KM was 14-fold. The effects of chloride on the pre-steady-state were examined at 2 degrees C. In the presence of chloride, two distinct enzyme-substrate complexes were observed, suggesting multiple steps in substrate binding. The initial complex was formed during the mixing period (kobsd greater than 200 s-1) while the second complex was formed much more slowly (kobsd = 40 s-1 when [S] = 5 microM and [NaCl] = 150 mM). Strikingly, in the absence of chloride, only a single, rapidly formed enzyme-substrate complex was observed. These results are consistent with a nonessential activator kinetic mechanism in which the slow step reflects conversion of an initially formed complex, (E X Cl- X S)1, to a more tightly bound complex, (E X Cl- X S)2.     

The occurrence of the transposable elementpogo inDrosophila melanogaster

We examined the genomic occurrence of the transposable elementpogo in over 120 strains ofDrosophila melanogaster, from around the world and from different eras. All had multiple copies of a 2.1 kilobase (kb)pogo element, and multiple copies of several size classes between 1.0 and 1.8 kb. There were differences between strains in intensities or presences of deletion-derivative size classes, suggesting current or recent mobility in the species. We were unable to find anypogo-hybridization in eight other species in the genus, in three subgenera, or in the relatedScaptomyza pallida. Thepogo element may be a ‘middle-aged’ element in the genome ofD. melanogaster, having entered the species since its divergence from its sibling species, but long before theP andhobo elements.     

MathSBML: a package for manipulating SBML-based biological models

MathSBML is a Mathematica package designed for manipulating Systems Biology Markup Language (SBML) models. It converts SBML models into Mathematica data structures and provides a platform for manipulating and evaluating these models. Once a model is read by MathSBML, it is fully compatible with standard Mathematica functions such as NDSolve (a differential-algebraic equations solver). MathSBML also provides an application programming interface for viewing, manipulating, running numerical simulations; exporting SBML models; and converting SBML models in to other formats, such as XPP, HTML and FORTRAN. By accessing the full breadth of Mathematica functionality, MathSBML is fully extensible to SBML models of any size or complexity. AVAILABILITY: Open Source (LGPL) at http://www.sbml.org and http://www.sf.net/projects/sbml     

The Nuclear Family versus the Men's House? A re-examination of Mundurucú Sociality

It has been posited that in communities with residential men's houses there is perforce no nuclear family. This position is examined with reference to the published data on the Mundurucú of Central Brazil. Comparative data are also examined from Oceania and elsewhere. The conclusion is that the two institutions do indeed co-exist in the Mundurucú case.     

CD13 regulates dendritic cell cross-presentation and T cell responses by inhibiting receptor-mediated antigen uptake

Dendritic cell (DC) Ag cross-presentation is generally associated with immune responses to tumors and viral Ags, and enhancement of this process is a focus of tumor vaccine design. In this study, we found that the myeloid cell surface peptidase CD13 is highly and specifically expressed on the subset of DCs responsible for cross-presentation, the CD8(+) murine splenic DCs. In vivo studies indicated that lack of CD13 significantly enhanced T cell responses to soluble OVA Ag, although development, maturation, and Ag processing and presentation of DCs are normal in CD13KO mice. In vitro studies showed that CD13 regulates receptor-mediated, dynamin-dependent endocytosis of Ags such as OVA and transferrin but not fluid-phase or phagocytic Ag uptake. CD13 and Ag are cointernalized in DCs, but CD13 did not coimmunoprecipitate with Ag receptors, suggesting that CD13 does not control internalization of specific receptors but regulates endocytosis at a more universal level. Mechanistically, we found that phosphorylation of the endocytic regulators p38MAPK and Akt was dysregulated in CD13KO DCs, and blocking of these kinases perturbed CD13-dependent endocytic uptake. Therefore, CD13 is a novel endocytic regulator that may be exploited to enhance Ag uptake and T cell activation to improve the efficacy of tumor-targeted vaccines.