Fur characteristics of the African ice rat Otomys sloggetti robertsi: Modifications for an alpine existence

The African ice rat Otomys sloggetti robertsi is a small rodent confined to cold, alpine habitats. It does not hibernate and is poorly adapted physiologically to low temperatures. We predicted and showed that its fur is denser than its congeners from warmer habitats, but it had shorter fur than expected. Dense fur would provide insulation and piloerection of short fur would facilitate heat gain from solar radiation during sun basking. These traits, in addition to other behavioural and morphological traits, would assist O. s. robertsi in meeting its thermoregulatory requirements in response to low temperatures.     

Major metabolic homocysteine-derivative, homocysteine thiolactone, exerts changes in pancreatic beta-cell glucose-sensing, cellular signal transduction and integrity

Homocysteine can be converted to its reactive thioester, homocysteine thiolactone. Cytotoxic properties of these amino thiols have been attributed to protein homocysteinylation, increased oxidative stress, DNA damage and apoptosis. This study used pancreatic BRIN-BD11 beta-cells to examine functional defects caused by acute and long-term exposure to homocysteine thiolactone in comparison with homocysteine. Acute and long-term exposure to both agents caused concentration-dependent inhibitions of glucose-induced insulin secretion while impairing the insulin-secretory responses to alanine, KCl, elevated Ca(2+), forskolin and PMA. Acute exposures also caused significant reduction in the amplitude of KCl-induced membrane depolarisation but no effects on changes of intracellular Ca(2+) induced by alanine or KCl. Cellular insulin content and DNA damage were not altered following culture, however, there were early signs of apoptosis consistent with impaired cellular integrity. In conclusion, exposure to homocysteine thiolactone, like homocysteine, induced beta-cell dysfunction and demise by mechanisms independent of changes in membrane potential and [Ca(2+)](i).     

Self-assembly of coiled-coil tetramers in the 1.40 A structure of a leucine-zipper mutant

The hydrophobic core of the GCN4 leucine-zipper dimerization domain is formed by a parallel helical association between nonpolar side chains at the a and d positions of the heptad repeat. Here we report a self-assembling coiled-coil array formed by the GCN4-pAe peptide that differs from the wild-type GCN4 leucine zipper by alanine substitutions at three charged e positions. GCN4-pAe is incompletely folded in normal solution conditions yet self-assembles into an antiparallel tetraplex in crystals by formation of unanticipated hydrophobic seams linking the last two heptads of two parallel double-stranded coiled coils. The GCN4-pAe tetramers in the lattice associate laterally through the identical interactions to those in the intramolecular dimer-dimer interface. The van der Waals packing interaction in the solid state controls extended supramolecular assembly of the protein, providing an unusual atomic scale view of a mesostructure.     

Fish oil induced increase in walking distance, but not ankle brachial pressure index, in peripheral arterial disease is dependent on both body mass index and inflammatory genotype

Peripheral arterial disease (PAD) is an atherosclerotic disease. Evidence suggests that atherosclerosis is an inflammatory condition and long chain n-3 fatty acids, found in oily fish and fish oils, have been shown to reduce inflammation. Genetic and lifestyle factors such as body mass index (BMI) also influence inflammation. In this study we have examined the effect of fish oil in patients with claudication secondary to PAD. Fish oil supplementation, providing 1g EPA and 0.7 g DHA per day for 12 weeks, increased walking distance on a treadmill set at 3.2 km/h with a 7% incline. Walking distance to first pain increased from 76.2+/-8.5 m before fish oil to 140.6+/-25.5 m after fish oil (mean+/-SEM, p=0.004) and total distance walked increased from 160.0+/-21.5 m before fish oil to 242.1+/-34.5 m after fish oil (p=0.002). Fish oil supplementation also improved ankle brachial pressure index (ABPI) from 0.599+/-0.017 before fish oil to 0.776+/-0.030 after fish oil (p<0.001). The increase in walking distance was dependent on both BMI and genotype for single nucleotide polymorphisms in the genes encoding the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin (IL)-1beta and the anti-inflammatory cytokine IL-10 (detected using amplification refractory mutation system polymerase chain reaction). Neither BMI nor any of the genotypes examined affected the ability of fish oil to increase ABPI. The mechanisms by which fish oil affects walking distance and ABPI do not appear to be the same.     

Maintenance treatment with esomeprazole following initial relief of non-steroidal anti-inflammatory drug-associated upper gastrointestinal symptoms: the NASA2 and SPACE2 studies

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 (COX-2) inhibitors, cause upper gastrointestinal (GI) symptoms that are relieved by treatment with esomeprazole. We assessed esomeprazole for maintaining long-term relief of such symptoms. Six hundred and ten patients with a chronic condition requiring anti-inflammatory therapy who achieved relief of NSAID-associated symptoms of pain, discomfort, or burning in the upper abdomen during two previous studies were enrolled and randomly assigned into two identical, multicentre, parallel-group, placebo-controlled studies of esomeprazole 20 mg or 40 mg treatment (NASA2 [Nexium Anti-inflammatory Symptom Amelioration] and SPACE2 [Symptom Prevention by Acid Control with Esomeprazole] studies; ClinicalTrials.gov identifiers NCT00241514 and NCT00241553, respectively) performed at various rheumatology, gastroenterology, and primary care clinics. Four hundred and twenty-six patients completed the 6-month treatment period. The primary measure was the proportion of patients with relapse of upper GI symptoms, recorded in daily diary cards, after 6 months. Relapse was defined as moderate-to-severe upper GI symptoms (a score of more than or equal to 3 on a 7-grade scale) for 3 days or more in any 7-day period. Esomeprazole was significantly more effective than placebo in maintaining relief of upper GI symptoms throughout 6 months of treatment. Life-table estimates (95% confidence intervals) of the proportion of patients with relapse at 6 months (pooled population) were placebo, 39.1% (32.2% to 46.0%); esomeprazole 20 mg, 29.3% (22.3% to 36.2%) (p = 0.006 versus placebo); and esomeprazole 40 mg, 26.1% (19.4% to 32.9%) (p = 0.001 versus placebo). Patients on either non-selective NSAIDs or selective COX-2 inhibitors appeared to benefit. The frequency of adverse events was similar in the three groups. Esomeprazole maintains relief of NSAID-associated upper GI symptoms in patients taking continuous NSAIDs, including selective COX-2 inhibitors.     

Validation of daily increments and a marine‐entry check in the otoliths of sockeye salmon Oncorhynchus nerka post‐smolts

Juvenile sockeye salmon Oncorhynchus nerka that were reared and smolted in laboratory conditions were found to produce otolith daily increments, as well as a consistently visible marine‐entry check formed during their transition to salt water. Field‐collected O. nerka post‐smolts of an equivalent age also displayed visible checks; however, microchemistry estimates of marine‐entry date using Sr:Ca ratios differed from visual estimates by c. 9 days suggesting that microstructural and microchemical processes occur on different time scales.     

Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptase

Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI’s.     

A high-throughput screen for directed evolution of the natural product sulfotransferase LipB

In this article, the authors describe a colorimetric, high-throughput assay suitable for optimizing the activity of the recently discovered sulfotransferase LipB, by directed evolution. Crucially, LipB uses para-nitrophenol sulfate as donor in the sulfation of the nucleoside antibiotic liposidomycin B-I and other acceptor surrogates. Thus, using a robotic liquid-handling device, crude cell extracts were prepared from an Escherichia coli strain that overproduced LipB in wells of a microplate, and production of para-nitrophenol at 405 nm was monitored spectrophotometrically. Enzyme activity could be detected only in the presence of both LipB substrates and overexpressed LipB. The screen displays a suitable standard deviation for directed evolution and importantly is not limited to the natural desulfo-liposidomycin acceptor. The authors plan to use the screen to identify LipB variants with altered acceptor specificity and promiscuity for use in sulfation of natural products and other small-molecule therapeutics.     

Alien flora of mountains: global comparisons for the development of local preventive measures against plant invasions

Aim We use data from 13 mountain regions and surrounding lowland areas to identify (1) the origins, traits and cultural uses of alien plant species that establish in mountains, (2) the alien species that are most likely to be a threat and (3) how managers might use this information to prevent further invasions. Location Australia, Canada, Chile, India, New Zealand, South Africa, Spain, Switzerland, USA. Methods Lists of alien species were compiled for mountains and their surrounding or nearby lowlands. Principal co‐ordinates analysis was performed on a matrix of similarities created using presence/absence data for alien species. The significance of differences between means for (1) similarity metrics of lowland and mountain groups and (2) species traits of lowland and mountain alien floras was determined using t‐tests. In seven of the 13 mountain regions, lists of alien species undergoing management were compiled. The significance of differences between proportions of traits for species requiring and not requiring management input was determined with chi‐square tests. Results We found that the proximal lowland alien flora is the main determinant of a mountain region’s alien species composition. The highest similarities between mountain floras were in the Americas/Pacific Region. The majority of alien species commonly found in mountains have agricultural origins and are of little concern to land managers. Woody species and those used for ornamental purposes will often pose the greatest threat. Main conclusions Given the documented potential threat of alien species invading mountains, we advise natural resource managers to take preventive measures against the risk of alien plant invasion in mountains. A strategy for prevention should extend to the surrounding lowland areas and in particular regulate the introduction of species that are already of management concern in other mountains as well as climatically pre‐adapted alien mountain plants. These may well become more problematic than the majority of alien plants currently in mountains.