Molecular Modeling of Calixarenes with Group I Metal Ions

Molecular mechanics calculations have been used to model the geometries of the complexes of Group I metal ions with calix[n]arenes (n = 4,5). A simple procedure in which the calixarene atoms are assigned partial charges on the basis of AM1 calculations and the metal ions are allowed to bind electrostatically to the calixarenes produces surprising good results when the resulting structures are compared to known crystallographic data on the complexes. Encapsulated solvent molecules and/or counterions can be included in the calculations and, indeed, are necessary to reproduce the X-ray data. Electronic Supplementary Material available.     

Discovery of novel sphingosine kinase-1 inhibitors. Part 2

Building on our initial work, we have identified additional novel inhibitors of sphingosine kinase-1 (SK1). These new analogs address the shortcomings found in our previously reported compounds. Inhibitors 51 and 54 demonstrated oral bioavailability in a rat PK study.     

DNA bridging and antibridging: a role for bacterial nucleoid-associated proteins in regulating the expression of laterally acquired genes

Horizontal DNA transfer plays a major role in the evolution of bacteria. It allows them to acquire new traits rapidly and these may confer fitness advantages as the bacteria compete with others in the environment. Historically, the mechanisms of horizontal DNA transfer, chiefly conjugation, transformation and transduction, have received a great deal of attention. Less attention has been focused on the regulatory problems that may accompany the acquisition of new genes by lateral routes. How are these genes integrated into the existing regulatory circuits of the cell? Does a process of 'plug-and-play' operate, or are the new genes silenced pending the evolution of regulatory mechanisms that make their expression not only safe but also beneficial to both the gene and its new host? Recent research shows that bacterial nucleoid-associated proteins such as H-NS, HU and Fis are important contributors to the processes of regulatory integration that accompany horizontal gene transfer. A key emerging theme is the antagonism that exists between the DNA–protein–DNA bridging activity of the H-NS repressor and the DNA-bending and DNA-wrapping activities of regulatory proteins that oppose H-NS.     

Global Burden of Leptospirosis: Estimated in Terms of Disability Adjusted Life Years

Background

Leptospirosis, a spirochaetal zoonosis, occurs in diverse epidemiological settings and affects vulnerable populations, such as rural subsistence farmers and urban slum dwellers. Although leptospirosis can cause life-threatening disease, there is no global burden of disease estimate in terms of Disability Adjusted Life Years (DALYs) available.

Methodology/Principal Findings

We utilised the results of a parallel publication that reported global estimates of morbidity and mortality due to leptospirosis. We estimated Years of Life Lost (YLLs) from age and gender stratified mortality rates. Years of Life with Disability (YLDs) were developed from a simple disease model indicating likely sequelae. DALYs were estimated from the sum of YLLs and YLDs. The study suggested that globally approximately 2·90 million DALYs are lost per annum (UIs 1·25–4·54 million) from the approximately annual 1·03 million cases reported previously. Males are predominantly affected with an estimated 2·33 million DALYs (UIs 0·98–3·69) or approximately 80% of the total burden. For comparison, this is over 70% of the global burden of cholera estimated by GBD 2010. Tropical regions of South and South-east Asia, Western Pacific, Central and South America, and Africa had the highest estimated leptospirosis disease burden.

Conclusions/Significance

Leptospirosis imparts a significant health burden worldwide, which approach or exceed those encountered for a number of other zoonotic and neglected tropical diseases. The study findings indicate that highest burden estimates occur in resource-poor tropical countries, which include regions of Africa where the burden of leptospirosis has been under-appreciated and possibly misallocated to other febrile illnesses such as malaria.     

An Evolutionary Comparison of the Handicap Principle and Hybrid Equilibrium Theories of Signaling

The handicap principle has come under significant challenge both from empirical studies and from theoretical work. As a result, a number of alternative explanations for honest signaling have been proposed. This paper compares the evolutionary plausibility of one such alternative, the “hybrid equilibrium,” to the handicap principle. We utilize computer simulations to compare these two theories as they are instantiated in Maynard Smith’s Sir Philip Sidney game. We conclude that, when both types of communication are possible, evolution is unlikely to lead to handicap signaling and is far more likely to result in the partially honest signaling predicted by hybrid equilibrium theory.     

Testing Models of the APC Tumor Suppressor/β-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling

The Wnt pathway is a conserved signal transduction pathway that contributes to normal development and adult homeostasis, but is also misregulated in human diseases such as cancer. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling inactivated in >80% of colorectal cancers. APC participates in a multiprotein “destruction complex” that targets the proto-oncogene β-catenin for ubiquitin-mediated proteolysis; however, the mechanistic role of APC in the destruction complex remains unknown. Several models of APC function have recently been proposed, many of which have emphasized the importance of phosphorylation of high-affinity β-catenin-binding sites [20-amino-acid repeats (20Rs)] on APC. Here we test these models by generating a Drosophila APC2 mutant lacking all β-catenin-binding 20Rs and performing functional studies in human colon cancer cell lines and Drosophila embryos. Our results are inconsistent with current models, as we find that β-catenin binding to the 20Rs of APC is not required for destruction complex activity. In addition, we generate an APC2 mutant lacking all β-catenin-binding sites (including the 15Rs) and find that a direct β-catenin/APC interaction is also not essential for β-catenin destruction, although it increases destruction complex efficiency in certain developmental contexts. Overall, our findings support a model whereby β-catenin-binding sites on APC do not provide a critical mechanistic function per se, but rather dock β-catenin in the destruction complex to increase the efficiency of β-catenin destruction. Furthermore, in Drosophila embryos expressing some APC2 mutant transgenes we observe a separation of β-catenin destruction and Wg/Wnt signaling outputs and suggest that cytoplasmic retention of β-catenin likely accounts for this difference.     

Topographic controls on black carbon accumulation in Alaskan black spruce forest soils: implications for organic matter dynamics

There is still much uncertainty as to how wildfire affects the accumulation of burn residues (such as black carbon (BC)) in the soil, and the corresponding changes in soil organic carbon (SOC) composition in boreal forests. We investigated SOC and BC composition in black spruce forests on different landscape positions in Alaska, USA. Mean BC stocks in surface mineral soils (0.34 ± 0.09 kg C m^?2) were higher than in organic soils (0.17 ± 0.07 kg C m^?2), as determined at four sites by three different ¹³C Nuclear Magnetic Resonance Spectroscopy-based techniques. Aromatic carbon, protein, BC, and the alkyl:O-alkyl carbon ratio were higher in mineral soil than in organic soil horizons. There was no trend between mineral soil BC stocks and fire frequencies estimated from lake sediment records at four sites, and soil BC was relatively modern (<54–400 years, based on mean Δ¹⁴C ranging from 95.1 to ?54.7‰). A more extensive analysis (90 soil profiles) of mineral soil BC revealed that interactions among landscape position, organic layer depth, and bulk density explained most of the variance in soil BC across sites, with less soil BC occurring in relatively cold forests with deeper organic layers. We suggest that shallower organic layer depths and higher bulk densities found in warmer boreal forests are more favorable for BC production in wildfire, and more BC is integrated with mineral soil than organic horizons. Soil BC content likely reflected more recent burning conditions influenced by topography, and implications of this for SOC composition (e.g., aromaticity and protein content) are discussed.