Design, synthesis and biological activity of novel dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine as potent, selective, and orally-bioavailable 5-HT(1D) agonists

A novel series of highly potent human 5-HT_1D agonists, dimethyl-{2-[6-substituted-indol-1-yl]-ethyl}-amine, was synthesized. Structure–activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K_i=2.4 nM) agonist at the human 5-HT_1D receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F_po=51%).     

Vertebrate hosts of Ixodes pacificus (Acari: Ixodidae) in California.

The western black-legged tick, Ixodes pacificus Cooley & Kohls, is an important parasite and vector of disease agents that affect human and animal health in the western United States. This paper presents a review of all published California host records for I. pacificus. Unpublished data from public health, academic, and vector control agencies and researchers were reviewed as well. Host species were identified for each active life stage (larvae, nymph and adult). A total of 108 vertebrate species in three classes (Mammalia, Aves, and Reptilia) were identified as hosts for at least one life stage of I. pacificus. Adult I. pacificus were recorded from 29 species of mammals, 2 species of birds, and 1 reptile species. Nymphal I. pacificus were recorded from 30 species of mammals, 38 species of birds, and 8 reptile species. Larval I. pacificus were recorded from 29 species of mammals, 43 species of birds, and 8 species of reptiles. A table depicting the taxonomic classification of host species is provided. This review adds eight new host records to the California list of recognized vertebrate host species for I. pacificus.     

The minimum information required for reporting a molecular interaction experiment (MIMIx)

A wealth of molecular interaction data is available in the literature, ranging from large-scale datasets to a single interaction confirmed by several different techniques. These data are all too often reported either as free text or in tables of variable format, and are often missing key pieces of information essential for a full understanding of the experiment. Here we propose MIMIx, the minimum information required for reporting a molecular interaction experiment. Adherence to these reporting guidelines will result in publications of increased clarity and usefulness to the scientific community and will support the rapid, systematic capture of molecular interaction data in public databases, thereby improving access to valuable interaction data.     

Preparation and evaluation of glycosylated arginine-glycine-aspartate (RGD) derivatives for integrin targeting

Arginine-glycine-aspartate (RGD) derivatives were prepared by a combination of solid-phase and solution-phase synthesis for selective targeting of alpha vbeta 3 integrin expressed in tumors. In order to evaluate the value of a triazole moiety as a proposed amide isostere, the side chain glycosylated cyclic RGD ( cRGD) peptides were synthesized with either a natural amide linkage or a triazole. Affinity of the cRGD constructs for the alpha vbeta 3 integrin was determined in a solid-phase competitive binding assay, showing strong similarity in binding affinity for each of the compounds under evaluation. Furthermore, the in vivo tumor targeting potential of glycosylated cRGD peptides, linked via amide or triazole, was investigated by determining the biodistribution of (125)I-labeled derivatives in mice with tumors expressing alpha vbeta 3. All of the cyclic RGD derivatives showed preferential uptake in the subcutaneous tumors, with the highest tumor-to-blood ratio measured for the triazole-linked glycosylated derivative. The results of the present study are a clear indication of the value of the triazole moiety as a suitable amide isostere in the development of glycosylated peptides as pharmaceuticals.     

Sudden cardiac death thirty years ago and at present. The role of autonomic disturbances in acute myocardial infarction revisited

The most common cause of sudden cardiac death is ventricular fibrillation (VF). In addition to the status, size and location of the ventricular focus, a major pathogenic mechanism triggering VF is autonomic dysbalance (disturbance). This term refers to a wide range of reflex changes in the ratio of sympathetic to vagal ventricular activation over time, occurring immediately after coronary artery occlusion at the onset of acute myocardial infarction (AMI). Another trigger of VF is autonomic disturbance due to emotional stress. Experimental and clinical research into autonomic disturbances associated with coronary artery occlusion and emotional stress was given considerable attention as early as some 30 years ago when researchers were already searching for ways of inhibiting autonomic disturbances using predominant sympathetic and vagal activation by beta-blockers (BB) and atropine, respectively. The aim of our paper is to compare results obtained 30 years ago with current status of experimental and clinical research into SCD prevention. Another aim is to identify questions that have remained unanswered to date; answers to these outstanding questions could help further reduce the risk of SCD.     

Development of novel monoclonal antibodies that define differentiation stages of human stromal (mesenchymal) stem cells

Human mesenchymal stem cells (hMSC) are currently being introduced for cell therapy, yet, antibodies specific for native and differentiated MSCs are required for their identification prior to clinical use. Herein, high quality antibodies against MSC surface proteins were developed by immunizing mice with hMSC, and by using a panel of subsequent screening methods. Flow cytometry analysis revealed that 83.5, 1.1, and 8.5% of primary cultures of hMSC were double positive for STRO-1 and either of DJ 3, 9, and 18, respectively. However, none of the three DJ antibodies allowed enrichment of clonogenic hMSC from BMMNCs as single reagents. Using mass-spectrometric analysis, we identified the antigen recognised by DJ3 as CD44, whereas DJ9 and DJ18 recognized HLA-DRB1 and Collagen VI, respectively. The identified proteins were highly expressed throughout in vitro osteogenic- and adipogenic differentiation. Interestingly, undifferentiated cells revealed a sole cytoplasmic distribution pattern of Collagen VI, which however changed to an extracellular matrix appearance upon osteogenic- and adipogenic differentiation. In relation to this, we found that STRO-1^+/−/Collagen VI⁻ sorted hMSC contained fewer differentiated alkaline phosphatase⁺ cells compared to STRO-1^+/−/Collagen VI⁺ hMSC, suggesting that Collagen VI on the cell membrane exclusively defines differentiated MSCs. In conclusion, we have generated a panel of high quality antibodies to be used for characterization of MSCs, and in addition our results may suggest that the DJ18 generated antibody against Collagen VI can be used for negative selection of cultured undifferentiated MSCs.     

The heritability of multiple male mating in a promiscuous mammal

The tendency of females to mate with multiple males is often explained by direct and indirect benefits that could outweigh the many potential costs of multiple mating. However, behaviour can only evolve in response to costs and benefits if there is sufficient genetic variation on which selection can act. We followed 108 mating chases of 85 North American red squirrels (Tamiasciurus hudsonicus) during 4 years, to measure each female's degree of multiple male mating (MMM), and used an animal model analysis of our multi-generational pedigree to provide what we believe is the first estimate of the heritability of MMM in the wild. Female red squirrels were highly polyandrous, mating with an average of 7.0 ± 0.2 males on their day of oestrus. Although we found evidence for moderate levels of additive genetic variation (CV(A) = 5.1), environmental variation was very high (CV(E) = 32.3), which resulted in a very low heritability estimate (h(2) < 0.01). So, while there is genetic variation in this trait, the large environmental variation suggests that any costs or benefits associated with differences among females in MMM are primarily owing to environmental and not genetic differences, which could constrain the evolutionary response to natural selection on this trait.