Synthesis of 1′-C-Cyano Pyrimidine Nucleosides and Characterization as HCV Polymerase Inhibitors

Ribose modified 1′-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.     

Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome

Mutations in the hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma (MB), one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study, we found that a specific isoform PDE4D3 is tethered to the centrosome by Myomegalin (Mmg), a centrosome/Golgi-associated protein. Mmg loss dislocates PDE4D3 from the centrosome, leading to local PKA overactivation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Mmg loss suppresses the proliferation of granule neuron precursors and blocks the growth of MB in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.     

Description of Alpheus cedrici sp. n., a strikingly coloured snapping shrimp (Crustacea, Decapoda, Alpheidae) from Ascension Island, central Atlantic Ocean

Alpheus cedricisp. n. is described based on two specimens collected under rocks while scuba diving off the coast of Ascension Island, central Atlantic Ocean. The new species belongs to the Alpheus macrocheles (Hailstone, 1835) species complex and appears to be most closely related to the eastern-central Atlantic Alpheus macrocheles, the western Atlantic Alpheus amblyonyx Chace, 1972, and the eastern Pacific Alpheus bellimanus Lockington, 1877 and Alpheus rectus Kim & Abele, 1988. However, it differs from all these species by a combination of morphological characters and by a diagnostic and striking colour pattern.     

Molecular systematics of caridean shrimps based on five nuclear genes: Implications for superfamily classification

Caridean shrimps are the second most diverse group of Decapoda. Over the years, several different systematic classifications, exclusively based on morphology, have been proposed, but the classification of the infraorder Caridea remains unresolved. In this study, five nuclear genes, 18S rRNA, enolase, histone 3, phosphoenolpyruvate carboxykinase and sodium–potassium ATPase α-subunit, were used to examine the systematic status of caridean families and superfamilies. We constructed gene trees based on a combined dataset of 3819 bp, containing 35 caridean species from 19 families in 11 superfamilies. At the family level, and based on our restricted representation, our molecular data support monophyly of the families Glyphocrangonidae, Crangonidae, Pandalidae, Alpheidae, Rhynchocinetidae, Nematocarcinidae, Pasiphaeidae, Atyidae and Stylodactylidae. In contrast, both the Hippolytidae and Palaemonidae are polyphyletic in our analysis. Two major clades are revealed. The Alpheidae, Hippolytidae, Crangonidae, Glyphocrangonidae, Barbouriidae, Pandalidae, Hymenoceridae, Gnathophyllidae and Palaemonidae make up the first clade, while the second clade comprises the Rhynchocinetidae, Oplophoridae, Nematocarcinidae, Alvinocarididae, Campylonotidae, Pasiphaeidae and Eugonatonotidae. Two families, Bathypalaemonellidae and Stylodactylidae, are shown to be basal groups in our tree. At the superfamily level, our results do not support the currently accepted superfamily classification, although there is support for a superfamily Palaemonoidea, though only three out of its eight families are included. The results suggest that the currently accepted superfamily classification of the Caridea does not reflect their evolutionary relationships. A major revision of the higher systematics of Caridea appears thus to be vital, ideally incorporating both molecular and morphological evidence.     

EFFECT OF TEMPERATURE AND IRRADIANCE ON GROWTH OF HAEMATOCOCCUS PLUVIALIS (CHLOROPHYCEAE)1

The growth characteristics of Haematococcus pluvialis Flotow were determined in batch culture. Optimal temperature for growth of the alga was between 25° and 28°C, at which the specific growth rate was 0.054 h^?1. At higher temperatures, no cell division was observed, and cell diameter increased from 5 to 25 μm. The saturated irradiance for growth of the alga was 90 μmol quanta · m^?2·s^?1; under higher irradiances (e.g. 400 μmol quanta·m^?2·s^?1) astaxanthin accumulation was induced. Growth rate, cell cycle, and astaxanthin accumulation were significantly affected by growth conditions. Careful attention should be given to the use of optimal growth conditions when studying these processes.     

The endothelial cell-produced antiangiogenic cytokine vascular endothelial growth inhibitor induces dendritic cell maturation

Angiogenesis is an essential component of chronic inflammation that is linked to carcinogenesis. In this study, we report that human vascular endothelial growth inhibitor (VEGI, TNF superfamily 15), an endothelial cell-produced antiangiogenic cytokine, induces mouse dendritic cell (DC) maturation, a critical event in inflammation-initiated immunity. VEGI-stimulated bone marrow-derived immature DCs display early activation of maturation signaling molecules NF-kappaB, STAT3, p38, and JNK, and cytoskeleton reorganization and dendrite formation. The activation signals are partially inhibited by using a neutralizing Ab against death domain-containing receptor-3 (DR3) or a truncated form of DR3 consisting of the extracellular domain, indicating an involvement of DR3 in the transmission of VEGI activity. A VEGI isoform, TL1A, does not induce similar activities under otherwise identical experimental conditions. Additionally, the cells reveal significantly enhanced expression of mature DC-specific marker CD83, secondary lymphoid tissue-directing chemokine receptor CCR7, the MHC class-II protein (MHC-II), and costimulatory molecules CD40, CD80, and CD86. Functionally, the cells exhibit decreased Ag endocytosis, increased cell surface distribution of MHC-II, and increased secretion of IL-12 and TNF. Moreover, VEGI-stimulated DCs are able to facilitate the differentiation of CD4+ naive T cells in cocultures. These findings suggest that the anticancer activity of VEGI arises from coupling the inhibition of endothelial cell growth with the promotion of the adaptive immune mechanisms through the stimulation of DC maturation.     

Structure–activity relationships of dinucleotides: Potent and selective agonists of P2Y receptors

Dinucleoside polyphosphates act as agonists on purinergic P2Y receptors to mediate a variety of cellular processes. Symmetrical, naturally occurring purine dinucleotides are found in most living cells and their actions are generally known. Unsymmetrical purine dinucleotides and all pyrimidine containing dinucleotides, however, are not as common and therefore their actions are not well understood. To carry out a thorough examination of the activities and specificities of these dinucleotides, a robust method of synthesis was developed to allow manipulation of either nucleoside of the dinucleotide as well as the phosphate chain lengths. Adenosine containing dinucleotides exhibit some level of activity on P2Y₁ while uridine containing dinucleotides have some level of agonist response on P2Y₂ and P2Y₆. The length of the linking phosphate chain determines a different specificity; diphosphates are most accurately mimicked by dinucleoside triphosphates and triphosphates most resemble dinucleoside tetraphosphates. The pharmacological activities and relative metabolic stabilities of these dinucleotides are reported with their potential therapeutic applications being discussed.     

Quantifying killing of orangutans and human-orangutan conflict in Kalimantan, Indonesia

Human-orangutan conflict and hunting are thought to pose a serious threat to orangutan existence in Kalimantan, the Indonesian part of Borneo. No data existed prior to the present study to substantiate these threats. We investigated the rates, spatial distribution and causes of conflict and hunting through an interview-based survey in the orangutan's range in Kalimantan, Indonesia. Between April 2008 and September 2009, we interviewed 6983 respondents in 687 villages to obtain socio-economic information, assess knowledge of local wildlife in general and orangutan encounters specifically, and to query respondents about their knowledge on orangutan conflicts and killing, and relevant laws. This survey revealed estimated killing rates of between 750 and 1800 animals killed in the last year, and between 1950 and 3100 animals killed per year on average within the lifetime of the survey respondents. These killing rates are higher than previously thought and are high enough to pose a serious threat to the continued existence of orangutans in Kalimantan. Importantly, the study contributes to our understanding of the spatial variation in threats, and the underlying causes of those threats, which can be used to facilitate the development of targeted conservation management.     

尼日利亚西南部奥孙河沿线黑蝇Simulium damnosum Theobald complex的形态分类研究(双翅目: 蚋科)（英文）

黑蝇Simulium damnosum sensu lato是由多个姊妹种组成的复合体,这些种在生态学和盘尾丝虫病的传播方面各不相同。本文对奥孙河沿线的尼日利亚西南部森林区域的黑蝇S. damnosum s.l.复合体的组成以及成虫的形态学特征进行了研究。本研究所用的黑蝇S. damnosum s.l.成虫标本来源于奥孙河沿线的3个区,分别是Osun Eleja, Osun Ogbere和Osun Budepo。标本采集通过人体诱捕的方式,采集时间从2008年2月至2009年6月上午7:00到下午6:00,每两周采集1次。通过观察成虫的翅毛簇（wing tufts）和其他形态特征,对其进行分类研究。结果表明：存在同域分布的森林种和稀树草原种。在奥孙河沿线3个区内,森林种为优势种,占总捕获量的99.18%,而稀树草原种仅占0.82%;森林种和稀树草原种在多度上存在显著差异(P<0.05)。所捕获的所有稀树草原种的翅毛簇均为灰白色,而捕获的森林种的翅毛簇颜色存在显著差异(P<0.05)。为了更清楚地揭示该地区黑蝇S. damnosum s.l.的物种组成,建议进行更深入的研究。     

Cradle to gate: life cycle impact of primary aluminium production

Purpose

The International Aluminium Institute’s (IAI) aim was to publish life cycle inventory (LCI) data for use by life cycle assessment (LCA) practitioners through professional databases. The need to provide robust data stems from the increasing application of LCA as a tool for making material and design choices and the importance for representative, up-to-date information to underpin such studies. In addition to this, the institute aimed to evaluate the significance of potential environmental impacts, based on the LCI results, against a defined set of impact categories which can be tracked over time.

Methods

Key environmental data collected as part of the IAI’s long-running industry surveys provided the foundation for the life cycle inventory. In order to evaluate the environmental impact, direct input and output data for primary aluminium production were supplemented with background data for indirect processes available in GaBi version 6 (PE International, 2013b). A cradle-to-gate model was constructed with two distinct datasets, global (GLO) and global minus China (rest of world (RoW)). A partial life cycle impact assessment (LCIA) was completed using the models, and the following six CML (2001–Nov 2010) midpoint environmental impact categories were reported: acidification potential, depletion of fossil energy resources, eutrophication potential, global warming potential, ozone depletion potential and photo-oxidant creation potential. Water scarcity footprint of primary aluminium (Buxmann et al. in this issue) was also included.

Results and discussion

The results indicated that the largest greenhouse gas contributions were attributed to the alumina refining and electrolysis unit processes in both datasets, with electricity and thermal energy, being the major contributing factors to these higher values. The energy intensive nature of primary aluminium production means energy supply can significantly influence the overall environmental impact. Electricity production was found to contribute between 25 % and 80 % to all impact category indicator results, with higher values in the global dataset, a result of the inclusion of Chinese energy data and the increased share of coal-based electricity consumption that it represents.

Conclusions

The global aluminium industry remains dedicated to transparent reporting of its environmental impacts and ensuring that up-to-date, representative LCI data is available. Development of suitable methodologies for new indicators will be required to ensure that the industry continues to report accurately all its relevant impacts. Additionally, with the increased importance of Chinese aluminium production, inclusion of foreground data from Chinese production would further enhance the dataset from which the global impacts of aluminium production are assessed from cradle to gate.