Drug block of the hERG potassium channel: insight from modeling

Many commonly used, structurally diverse, drugs block the human ether-a-go-go-related gene (hERG) K(+) channel to cause acquired long QT syndrome, which can lead to sudden death via lethal cardiac arrhythmias. This undesirable side effect is a major hurdle in the development of safe drugs. To gain insight about the structure of hERG and the nature of drug block we have produced structural models of the channel pore domain, into each of which we have docked a set of 20 hERG blockers. In the absence of an experimentally determined three-dimensional structure of hERG, each of the models was validated against site-directed mutagenesis data. First, hERG models were produced of the open and closed channel states, based on homology with the prokaryotic K(+) channel crystal structures. The modeled complexes were in partial agreement with the mutagenesis data. To improve agreement with mutagenesis data, a KcsA-based model was refined by rotating the four copies of the S6 transmembrane helix half a residue position toward the C-terminus, so as to place all residues known to be involved in drug binding in positions lining the central cavity. This model produces complexes that are consistent with mutagenesis data for smaller, but not larger, ligands. Larger ligands could be accommodated following refinement of this model by enlarging the cavity using the inherent flexibility about the glycine hinge (Gly648) in S6, to produce results consistent with the experimental data for the majority of ligands tested.     

Community-based natural resource use and management of Bigodi Wetland Sanctuary,Uganda, for livelihood benefits

Conservation and sustainable management of wetlands requires participation of local stakeholders, including communities. The Bigodi Wetland is unusual because it is situated in a common property landscape but the local community has been running a successful community-based natural resource management programme (CBNRM) for the wetland for over a decade. Whilst external visitors to the wetland provide ecotourism revenues we sought to quantify community benefits through the use of wetland goods such as firewood, plant fibres, and the like, and costs associated with wild animals damaging farming activities. We interviewed 68 households living close to the wetland and valued their cash and non-cash incomes from farming and collection of non-timber forest products (NTFPs) and water. The majority of households collected a wide variety of plant and fish resources and water from the wetland for household use and livestock. Overall, 53% of total household cash and non-cash income was from collected products, mostly the wetland, 28% from arable agriculture, 12% from livestock and 7% from employment and cash transfers. Female-headed households had lower incomes than male-headed ones, and with a greater reliance on NTFPs. Annual losses due to wildlife damage were estimated at 4.2% of total gross income. Most respondents felt that the wetland was important for their livelihoods, with more than 80% identifying health, education, craft materials and firewood as key benefits. Ninety-five percent felt that the wetland was in a good condition and that most residents observed the agreed CBNRM rules regarding use of the wetland. This study confirms the success of the locally run CBNRM processes underlying the significant role that the wetland plays in local livelihoods.     

Leaf wax n‐alkane patterns of six tropical montane tree species show species‐specific environmental response

It remains poorly understood how the composition of leaf wax n‐alkanes reflects the local environment. This knowledge gap inhibits the interpretation of plant responses to the environment at the community level and, by extension, inhibits the applicability of n‐alkane patterns as a proxy for past environments. Here, we studied the n‐alkane patterns of five Miconia species and one Guarea species, in the Ecuadorian Andes (653–3,507 m a.s.l.). We tested for species‐specific responses in the average chain length (ACL), the C₃₁/(C₃₁ + C₂₉) ratio (ratio), and individual odd n‐alkane chain lengths across an altitudinally driven environmental gradient (mean annual temperature, mean annual relative air humidity, and mean annual precipitation). We found significant correlations between the environmental gradients and species‐specific ACL and ratio, but with varying magnitude and direction. We found that the n‐alkane patterns are species‐specific at the individual chain length level, which could explain the high variance in metrics like ACL and ratio. Although we find species‐specific sensitivity and responses in leaf n‐alkanes, we also find a general decrease in “shorter” (<C₂₉) and an increase in “longer” (>C₃₁) chain lengths with the environmental gradients, most strongly with temperature, suggesting n‐alkanes are useful for reconstructing past environments.     

A preliminary study on genetic differentiation in Littorina saxatilis from Galway Bay,Ireland: Littorina tenebrosa Montagu – a valid species or ecotype?

Littorina tenebrosa is a small fragile-shelled periwinkle which lives on permanently submerged algae in coastal lagoons and non-tidal brackish pools. This periwinkle is a member of the rough periwinkle group which also comprises Littorina saxatilis, L. arcana, L. compressa and L. neglecta and is most closely related to L. saxatilis although its exact systematic status is in some doubt. Based on its unique ecology many believe L. tenebrosa to be a valid species. However, shell morphometric and allozyme analyses on Scottish and Swedish populations of L. tenebrosa and L. saxatilis have indicated that the two periwinkles are virtually identical. Preliminary results on five allozyme loci (AAT-1, GPI, PGM-1, PGM-2 and PNP) in samples of L. tenebrosa and L. saxatilis from Golam Head, Lettermullen, and other locations on the west coast of Ireland show L. tenebrosa to be genetically differentiated from L. saxatilis At Golam Head, where opportunities for gene flow occur between the two taxa, L. tenebrosa is as genetically differentiated from local L. saxatilis as it is from L. saxatilis from more geographically distant locations.     

Daily Online Testing in Large Classes: Boosting College Performance while Reducing Achievement Gaps

An in-class computer-based system, that included daily online testing, was introduced to two large university classes. We examined subsequent improvements in academic performance and reductions in the achievement gaps between lower- and upper-middle class students in academic performance. Students (N = 901) brought laptop computers to classes and took daily quizzes that provided immediate and personalized feedback. Student performance was compared with the same data for traditional classes taught previously by the same instructors (N = 935). Exam performance was approximately half a letter grade above previous semesters, based on comparisons of identical questions asked from earlier years. Students in the experimental classes performed better in other classes, both in the semester they took the course and in subsequent semester classes. The new system resulted in a 50% reduction in the achievement gap as measured by grades among students of different social classes. These findings suggest that frequent consequential quizzing should be used routinely in large lecture courses to improve performance in class and in other concurrent and subsequent courses.     

A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis

Introduction

Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.

Methods

1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.

Results

We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10⁻⁴). This variant was also significant after Bonferroni correction.

Conclusions

These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.     

Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases.     

Responses of Amazonian ecosystems to climatic and atmospheric carbon dioxide changes since the last glacial maximum

The aims of this paper are to review previously published palaeovegetation and independent palaeoclimatic datasets together with new results we present from dynamic vegetation model simulations and modern pollen rain studies to: (i) determine the responses of Amazonian ecosystems to changes in temperature, precipitation and atmospheric CO2 concentrations that occurred since the last glacial maximum (LGM), ca. 21 000 years ago; and (ii) use this long-term perspective to predict the likely vegetation responses to future climate change. Amazonia remained predominantly forested at the LGM, although the combination of reduced temperatures, precipitation and atmospheric CO2 concentrations resulted in forests structurally and floristically quite different from those of today. Cold-adapted Andean taxa mixed with rainforest taxa in central areas, while dry forest species and lianas probably became important in the more seasonal southern Amazon forests and savannahs expanded at forest-savannah ecotones. Net primary productivity (NPP) and canopy density were significantly lower than today. Evergreen rainforest distribution and NPP increased during the glacial-Holocene transition owing to ameliorating climatic and CO2 conditions. However, reduced precipitation in the Early-Mid-Holocene (ca. 8000-3600 years ago) caused widespread, frequent fires in seasonal southern Amazonia, causing increased abundance of drought-tolerant dry forest taxa and savannahs in ecotonal areas. Rainforests expanded once more in the Late Holocene owing to increased precipitation caused by greater austral summer insolation, although some of this forest expansion (e.g. in parts of the Bolivian Beni) is clearly caused by palaeo Indian landscape modification. The plant communities that existed during the Early-Mid-Holocene may provide insights into the kinds of vegetation response expected from similar increases in temperature and aridity predicted for the twenty-first century. We infer that ecotonal areas near the margins of the Amazon Basin are liable to be most sensitive to future environmental change and should therefore be targeted with conservation strategies that allow 'natural' species movements and plant community re-assortments to occur.