Carboxymethylated-κ-casein: A convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation

Reduced and carboxymethylated-κ-casein (RCM-κ-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Aβ), which is associated with Alzheimer’s disease. In this study, a series of flavonoids, many known to be inhibitors of Aβ fibril formation, were screened for their ability to inhibit RCM-κ-CN fibrilisation, and the results were compared with literature data on Aβ inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-κ-CN fibril formation. IC₅₀ values were between 10- and 200-fold higher with RCM-κ-CN than literature results for Aβ fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-κ-CN assay make it an economic alternative first screen for Aβ inhibitory activity, especially for use with large compound libraries.     

Genetic and historic evidence for climate-driven population fragmentation in a top cetacean predator: the harbour porpoises in European water

Recent climate change has triggered profound reorganization in northeast Atlantic ecosystems, with substantial impact on the distribution of marine assemblages from plankton to fishes. However, assessing the repercussions on apex marine predators remains a challenging issue, especially for pelagic species. In this study, we use Bayesian coalescent modelling of microsatellite variation to track the population demographic history of one of the smallest temperate cetaceans, the harbour porpoise (Phocoena phocoena) in European waters. Combining genetic inferences with palaeo-oceanographic and historical records provides strong evidence that populations of harbour porpoises have responded markedly to the recent climate-driven reorganization in the eastern North Atlantic food web. This response includes the isolation of porpoises in Iberian waters from those further north only approximately 300 years ago with a predominant northward migration, contemporaneous with the warming trend underway since the ‘Little Ice Age’ period and with the ongoing retreat of cold-water fishes from the Bay of Biscay. The extinction or exodus of harbour porpoises from the Mediterranean Sea (leaving an isolated relict population in the Black Sea) has lacked a coherent explanation. The present results suggest that the fragmentation of harbour distribution range in the Mediterranean Sea was triggered during the warm ‘Mid-Holocene Optimum’ period (approx. 5000 years ago), by the end of the post-glacial nutrient-rich ‘Sapropel’ conditions that prevailed before that time.     

Local regulation of human breast xenograft models

Breast cancer studies implant human cancer cells under the renal capsule, subcutaneously, or orthotopically and often use estrogen supplementation and immune suppressants (etoposide) in xenograft mouse models. However, cell behavior is significantly impacted by signals from the local microenvironment. Therefore, we investigated how the combinatorial effect of the location of injection and procedural differences affected xenograft characteristics. Patient‐derived breast cancer cells were injected into mouse abdominal or thoracic mammary glands ± estrogen and/or etoposide pretreatment. Abdominal xenografts had increased tumor incidence and volume, and decreased latency (P < 0.001) compared to thoracic tumors. No statistically significant difference in tumor volume was found in abdominal xenografts treated ± estrogen or etoposide; however, etoposide suppressed tumor volume in thoracic xenografts (P < 0.02). The combination of estrogen and etoposide significantly decreased tumor incidence in both sites. In addition, mice treated ± estradiol were injected orthotopically or subcutaneously with well‐characterized breast cancer cell lines (MCF7, ZR75‐1, MDA MB‐231, or MCF10Ca1h). Orthotopic injection increased tumor volume; growth varied with estrogen supplementation. Location also altered methylation status of several breast cancer‐related gene promoters. Lastly, vascularization of orthotopic tumors was significantly enhanced compared to subcutaneous tumors. These data suggest that optimal xenograft success occurs with orthotopic abdominal injections and illustrate molecular details of the compelling influence of the local microenvironment on in vivo models. J. Cell. Physiol. 224: 795–806, 2010. Published 2010 Wiley‐Liss, Inc.     

Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity

T cell Ig-like mucin-like-1 (TIM-1) is an important asthma susceptibility gene, but the immunological mechanisms by which TIM-1 functions remain uncertain. TIM-1 is also a receptor for phosphatidylserine (PtdSer), an important marker of cells undergoing programmed cell death, or apoptosis. We now demonstrate that NKT cells constitutively express TIM-1 and become activated by apoptotic cells expressing PtdSer. TIM-1 recognition of PtdSer induced NKT cell activation, proliferation, and cytokine production. Moreover, the induction of apoptosis in airway epithelial cells activated pulmonary NKT cells and unexpectedly resulted in airway hyperreactivity, a cardinal feature of asthma, in an NKT cell-dependent and TIM-1-dependent fashion. These results suggest that TIM-1 serves as a pattern recognition receptor on NKT cells that senses PtdSer on apoptotic cells as a damage-associated molecular pattern. Furthermore, these results provide evidence for a novel innate pathway that results in airway hyperreactivity and may help to explain how TIM-1 and NKT cells regulate asthma.     

Testosterone may increase selective attention to threat in young male macaques

Animal studies indicate that sex hormones have widespread effects on the brain, cognition and emotion, but findings in humans are inconsistent. Well-controlled studies in nonhuman primates are crucial to resolve these discrepancies. In this study, we examined the effects of testosterone (T) on emotion in male rhesus monkeys. Six young adult males were tested on two emotional tasks during three hormonal conditions in a crossover design: when intact at baseline and when pharmacologically hypogonadal with add-back of T or placebo. The emotional tasks were the Approach–Avoidance task, which tested behavioral responses to three categories of objects (familiar, novel, and negative) and a Social Playback task which tested behavioral responses to scenes of unfamiliar conspecifics engaged in three types of social activities (neutral, positive, or negative). Following a 4-week baseline period, monkeys were treated with Depot Lupron, 200 μg/kg before being randomly assigned to one of two treatment groups: Depot Lupron + Testosterone Enanthate (TE, 20 mg/kg) or Depot Lupron + oil vehicle. In each treatment group, monkeys received one injection of Lupron and one injection of TE or one injection of Lupron and one injection of oil at the onset of a 4-week testing period, before crossing over to the alternate treatment for an additional 4 weeks of testing. TE treatment had no effect on behavioral measures in the Approach–Avoidance task. For the Social Playback task, however, TE significantly increased watching time of video clips which depicted fights between unfamiliar conspecifics. The enhancing effect of T on watching time for negative social scenes is consistent with human data suggesting that T decreases aversion or facilitates approach to threatening social stimuli. Further studies are needed to understand the mechanisms by which T may mediate responsiveness to social threat in male primates.     

Binuclear manganese(III) complexes of an unsymmetric pyrazolate-based compartmental ligand with hard donor set

The synthesis, crystal structure and magnetic properties of manganese(III) binuclear complexes [Mn^III₂(L-3Н)₂(CH₃ОH)₄]·2CH₃ОH (1) and [Mn^III₂(L-3Н)₂(Py)₄]·2Py (2) (L = 3-[(1E)-N-hydroxyethanimidoyl]-4-methyl-1H-pyrazole-5-carboxylic acid) are reported. The ligand contains two distinct donor compartments formed by the pyrazolate-N and the oxime or the carboxylic groups. The complexes were characterized by X-ray single crystal diffraction, revealing that both 1 and 2 consist of dinuclear units in which the two metal ions are linked by double pyrazolate bridges with a planar {Mn₂N₄} core. Cryomagnetic measurements show antiferromagnetic interaction with g = 1.99, J = −3.6 cm⁻¹, Θ = −2.02 K for 1 and g = 2.00, J = −3.7 cm⁻¹, Θ = 1.43 K for 2.     

Invasive Temperate Species are a Threat to Tropical Island Biodiversity

To protect the remaining biodiversity on tropical islands it is important to predict the elevational ranges of non-native species. We evaluated two hypotheses by examining land snail faunas on the eastern (windward) side of the island of Hawaii: (1) the latitude of a species' native region can be used to predict its potential elevational range and (2) non-native temperate species, which experience greater climatic fluctuations in their native range, are more likely to become established at higher elevations and to extend over larger elevational ranges than non-native tropical species. All non-native tropical species were distributed patchily among sites ≤500 m and occupied small elevational ranges, whereas species introduced from temperate regions occupied wide elevational ranges and formed a distinct fauna spanning elevations 500–2000 m. Most native land snail species and ecosystems occur >500 m in areas dominated by temperate non-native snail and slug species. Therefore, knowing the native latitudinal region of a non-native species is important for conservation of tropical island ecosystems because it can be translated into potential elevational range if those species are introduced. Because temperate species will survive in tropical locales particularly at high elevation, on many tropical islands the last refuges of the native species, preventing introduction of temperate species should be a conservation priority.     

Anthropogenic Vegetation Contributions to Polynesia’s Social Heritage: The Legacy of Candlenut Tree (<Emphasis Type="Italic">Aleurites moluccana</Emphasis>) Forests and Bamboo (<Emphasis Type="Italic">Schizostachyum glaucifolium</Emphasis>) Groves on the Island of Tahiti

Anthropogenic Vegetation Contributions to Polynesia’s Social Heritage: The Legacy of Candlenut Tree ( Aleurites moluccana ) Forests and Bamboo ( Schizostachyum glaucifolium ) Groves on the Island of Tahiti. In the tropical oceanic islands of the Pacific, vegetation patterns and dynamics are the result of plant dispersal capacities, the physical characteristics of the islands’ ecosystems, and natural disturbances. However, humans have profoundly modified native landscapes through habitat destruction and the introduction of animal and plant species. The candlenut tree Aleurites moluccana (Euphorbiaceae) and the Polynesian bamboo Schizostachyum glaucifolium (Poaceae), intentionally introduced as useful plants by the first Polynesian migrants at least 1,000 years ago, are now widely naturalized in the high volcanic islands of the Society archipelago (French Polynesia), but with an intriguing patchy distribution. The present study consists of a comparative analysis between the most recent existing vegetation map and the known archeological sites on the island of Tahiti. Thirty-nine bamboo groves and 30 candlenut forests were identified and located using GIS and a Digital Elevation Model. The results show that the dispersal and distribution patterns of these two plant taxa are related to the presence and location of ancient sites of Polynesian occupation. The bamboo groves can be used as a bio-indicator of the presence of potential archeological sites. Their currently restricted distribution might reflect habitat requirements and poor dispersal capacities. The candlenut tree and the Polynesian bamboo are relicts of ancient Polynesian society that have persisted and remain integrated in the modern landscape. They can therefore be viewed as introduced species of high cultural heritage value.