Exploration of SAR features by modifications of thiazoleacetic acids as CRTH2 antagonists

The SAR features have been further explored for (2-benzhydryl-4-phenyl-thiazol-5-yl)acetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. The introduction of a nitrogen or a methyl substituent in the benzhydrylic position offer two alternative drugable scaffolds attractive for unsymmetrically substituted derivatives. An imidazole analogue lacks activity due to formation of a favored coplanar intramolecular hydrogen bond. The pyrimidine derivative 18 represents a potent and selective compound that will be subject to continued investigations.     

Notes on some species of Achasma (Zingiberaceae)

Six Indo–Chinese taxa of Achasma (Zingiberaceae) are discussed. Two new combinations are proposed: A. araneosum (Baker) K. Larsen and A. loroglossum (Gag–nep.) K. Larsen. Types have been selected for these and for A. pavieanum (Pierre ex Gagnep.) Loes.     

Slow Axonal Transport of Structural Polypeptides in Rat, Early Changes in Streptozocin Diabetes, and Effect of Insulin Treatment

The synthesis and transport of slowly transported polypeptides in sciatic nerves of rats was investigated by [35S]methionine pulse labeling and gel electrophoresis in control, diabetic, and insulin-treated diabetic rats. To detect very early changes diabetes was induced by streptozocin only 5 days prior to the labeling of the dorsal root ganglion cells. Fourteen days were allowed for axonal transport. In this experimental system, the neurofilament triplet is transported at an apparent velocity of 1.1 +/- 0.1 mm/day (mean +/- SD). The actin-related complex, including actin and two polypeptides of 87 kilodaltons and 37 kilodaltons, was transported at a velocity of 2.6 +/- 0.2 mm/day. For alpha- and beta-tubulin we found an apparent transport velocity of 2.2 +/- 0.1 mm/day, placing it between actin and the neurofilament triplet. The diabetic rats had a selective 32% decrease in the amount of the heaviest neurofilament subunit: 0.47 +/- 0.19% of trichloroacetic acid-insoluble radioactivity versus 0.69 +/- 0.17% in controls; 2p less than 0.05. This decrease was associated with a proximal accumulation of the two lighter neurofilament subunits. Insulin treatment of a diabetic group failed to normalize the changes of axonal transport and additional changes suggesting a hypoglycemic injury was observed.     

Protein kinase C activity in activated human T-lymphocytes stimulated by interleukin-2

Interleukin-2 and phorbol 12-myristate 13-acetate (PMA) are shown to induce DNA-synthesis in human T-lymphocytes activated with phytohaemagglutinin. However, whereas PMA induced a rapid and persistent translocation of protein kinase C from cytosol to particulate fraction, no translocation was observed upon stimulation with interleukin-2. Treatment with PMA for 72 h caused a slow down-regulation of protein kinase C activity to less than 10% of unstimulated T-lymphocytes and was mainly located in the particulate fraction. In contrast, stimulation with phytohaemagglutinin increased the total cellular protein kinase C activity by approx. 100% but with an unaltered subcellular distribution. However, interleukin-2-induced DNA synthesis in PMA- and phytohaemagglutinin-stimulated T-lymphocytes was comparable. Further, maximal DNA synthesis was shown to be dependent on the continuous presence of interleukin-2. These results indicate that interleukin-2-induced proliferation of activated human T-lymphocytes can occur without a translocation of protein kinase C from the cytosol to the particulate fraction and that interleukin-2 most likely functions as a progression factor.     

Tomato Thymidine Kinase Is Subject to Inefficient TTP Feedback Regulation

A promising suicide gene therapy system to treat gliomas has been reported: the thymidine kinase 1 from tomato (toTK1) combined with the nucleoside analog pro-drug zidovudine (azidothymidine, AZT), which is known to penetrate the blood–brain barrier. Transduction with toTK1 has been found to efficiently increase the sensitivity of human glioblastoma cells to AZT, and nude rats with intracranial glioblastoma grafts have shown significantly improved survival when treated with the toTK1/AZT system. We show in our paper that the strong suicidal effect of AZT together with toTK1 may be explained by reduced TTP-mediated feedback inhibition of the AZT phosphorylation.     

Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication

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Late Pleistocene and Holocene distribution of Mytilus edulis in the Barents Sea region and its palaeoclimatic implications

Aim For decades, subfossil shells of the bivalve Mytilus edulis Linnaeus, 1758 in Svalbard have been taken as evidence of higher surface temperatures during the early Holocene because the modern northern occurrence of this mollusc was, until recently, in the southern Barents Sea. Here, we elucidate and discuss the spatial and temporal Late Pleistocene and Holocene distribution of the species within the entire Barents Sea region. Location The Barents Sea region. Methods Radiocarbon dates of Mytilus shells from the Barents Sea region and information about the present distribution of the species were compiled, including two new radiocarbon dates from north‐eastern Spitsbergen. The dataset was divided into time slices, each covering 1000 years, and compared with Holocene temperature variations, ocean current systems and present‐day temperature patterns. Results Maps show the Late Pleistocene and Holocene spatial and temporal distribution of Mytilus edulis in the Barents Sea region. M. edulis was already present in northern Norway about 14,000 cal. yr bp . It appeared at western Spitsbergen about 11,000 cal. yr bp , and slowly spread to the rest of the archipelago. The maximum distribution in the region was reached 10,000–7000 cal. yr bp , coinciding with the Holocene climatic optimum. The species gradually disappeared in the late Holocene and became absent from the northern and eastern parts of the region 3000–1000 cal. yr bp . Today, M. edulis lives in the southern part and has begun to recolonize the northern parts. Main conclusions The time slices illustrate strong connections between the ocean current regimes, the climate and the distribution of M. edulis. The species settled in the southern part of the Barents Sea region several thousand years before it spread to the northern part during the Holocene climatic optimum. It may even have been completely absent from the region for a short time during the late Holocene cold period. The Holocene distribution of Mytilus implies that the underlying pattern of coastal sea surface temperatures in the region was very stable.     

Predicting greater sage‐grouse habitat selection at the southern periphery of their range

Mapping suitable habitat is an important process in wildlife conservation planning. Species distribution reflects habitat selection processes occurring across multiple spatio‐temporal scales. Because habitat selection may be driven by different factors at different scales, conservation planners require information at the scale of the intervention to plan effective management actions. Previous research has described habitat selection processes shaping the distribution of greater sage‐grouse (Centrocercus urophasianus; sage‐grouse) at the range‐wide scale. Finer‐scale information for applications within jurisdictional units inside the species range is lacking, yet necessary, because state wildlife agencies are the management authority for sage‐grouse in the United States. We quantified seasonal second‐order habitat selection for sage‐grouse across the state of Utah to produce spatio‐temporal predictions of their distribution at the southern periphery of the species range. We used location data obtained from sage‐grouse marked with very‐high‐frequency radio‐transmitters and lek location data collected between 1998 and 2013 to quantify species habitat selection in relation to a suite of topographic, edaphic, climatic, and anthropogenic variables using random forest algorithms. Sage‐grouse selected for greater sagebrush (Artemisia spp.) cover, higher elevations, and gentler slopes and avoided lower precipitations and higher temperatures. The strength of responses to habitat variables varied across seasons. Anthropogenic variables previously reported as affecting their range‐wide distribution (i.e., roads, powerlines, communication towers, and agricultural development) were not ranked as top predictors at our focal scale. Other than strong selection for sagebrush cover, the responses we observed differed from what has been reported at the range‐wide scale. These differences likely reflect the unique climatic, geographic, and topographic context found in the southern peripheral area of the species distribution compared to range‐wide environmental gradients. Our results highlight the importance of considering appropriateness of scale when planning conservation actions for wide‐ranging species.     

Basic N-interlinked imipramines show apoptotic activity against malignant cells including Burkitt’s lymphoma

We here report the synthesis of ethylene glycol N-interlinked imipramine dimers of various lengths from the tricyclic antidepressant desipramine via an amide coupling reaction followed by reduction with lithium aluminium hydride. The target molecules were found to be potent inhibitors of cellular viability while inducing cell type specific death mechanisms in three cancer cell lines including a highly chemoresistant Burkitt’s lymphoma cell line. Basic amine analogues were found to be important for increased potency. Imipramine and desipramine were also tested for apoptotic activity and were found to be much less active than the novel dimeric compounds. Imipramine dimers were only found to be moderate inhibitors of the human serotonin transporter (hSERT) having IC₅₀ values in the micromolar region whilst the induction of cell death occurred independently of hSERT expression. These results demonstrate the potential of newly designed and synthesised imipramines derivatives for use against malignant cells, including those resistant to standard chemotherapy.     

Incidence of embedded shotgun pellets and inferred hunting kill amongst Russian/Baltic barnacle geese Branta leucopsis

X-rays of wild caught barnacle geese from the Russian/Baltic population were taken in Denmark in the springs of 2009 and 2011 to determine the incidence of embedded shotgun pellets and to estimate the annual hunting kill. On average, 13 % of adult geese (n?=?212) and 6 % of first year geese (n?=?35) examined contained pellets in their tissue. Assuming that these birds represented a random sample, extrapolation to the entire population of c. 770,000 individuals indicates that 96,000 barnacle geese carry embedded pellets. Based on the assumption that the ratio between the number of birds with embedded shot and the total number of birds harvested per season is similar to that found in pink-footed geese Anser brachyrhynchus (recorded as 3.6:1 during 1990–1996 and 1.7:1 during 2009–2011), the annual kill of barnacle geese was estimated at 26,300–58,300 birds. The Russian/Baltic barnacle geese are protected from hunting on their winter quarters (The Netherlands, Germany and Denmark), but are quarry in Russia and are shot under license to protect agricultural crops in Estonia, Germany, Sweden and Denmark (amounting to a total of c. 1,800–3,000 geese shots per year). Barnacle geese are known to be shot illegally (accidentally and deliberately) along the migration route, but in the absence of Russian bag statistics, the contribution of illegal hunting to the overall harvest cannot be substantiated. Although the population is currently increasing at an annual rate of 8 %, the indirectly estimated hunting pressure (3–7 %) is not insubstantial and should be taken into account in future population management models.