Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide

In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones and \u1d6fc-pyones. The incorporation of the key bridge methyl group and subsequent control of its stereochemistry is also outlined

Structures of New Alkaloids from Rain Forest Trees Galbulimima belgraveana and Galbulimima baccata in Papua New Guinea, Indonesia, and Northern Australia

Following on our 60-year research on the chemical constituents of the rain forest trees Galbulimima belgraveana and Galbulimima baccata, we report the isolation of seven new alkaloids: GB14 (14), GB22 (15), GB25 (16), GB21 (17), GB23 (18), GB24 (19), and GB26 (20). Their structures were elucidated by a combination of spectroscopic analyses and single-crystal X-ray crystallography, as well as structure degradation and interconversion. The newly isolated alkaloids are precursors or derivatives of the known family members from our early studies and could be intermediates in the biosynthesis of the Galbulimima alkaloids. Therefore, the present study has expanded the range of structures in this family of alkaloids and provided some missing links in the biosynthetic sequences.This study was supported by the Fundamental Research Funds for the Central Universities, Chin

The total synthesis of dl-rimuene

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32176/1/0000232.pd

The total synthesis of (+/-)-hibaene

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32076/1/0000120.pd

Selective deactivation of gibberellins below the shoot apex is critical to flowering but not to stem elongation of Lolium

Gibberellins (GAs) cause dramatic increases in plant height and a genetic block in the synthesis of GA1 explains the dwarfing of Mendel's pea. For flowering, it is GA5 which is important in the long-day (LD) responsive grass, Lolium. As we show here, GA

ISOLATION AND STRUCTURE DETERMINATION OF BISDEMTHYLAAPTAMINE FROM BUNAKEN MARINE PARK SPONGE <i>Aaptos, sp.</i>

Bisdemethylaaptamine, an alkaloid naphtyridine with molecular weight 200 and formulae molecule C11H8N2O2 has been isolated from Bunaken Marine Park sponge Aaptos sp. Isolation was done by using several stages of column chromatography and high performance liquid chromatography. Molecular weight of this naphtyridine alkaloid was determined by electron ionization (EI) and electrospray ionization (ESI) mass spectroscopies and its structure assigned to be 8,9-dihydroxy-1H-benzo[d,e][1,6]naphtyridine by proton and carbon nuclear magnetic resonances (1H and 13C-NMR).   Keywords: Sponge, Aaptos sp., naphtyridine alkaloid, bisdemethylaaptami

Women's experiences of coping with pain during childbirth: A critical review of qualitative research

Objective To identify and analyse qualitative literature exploring women׳s experiences of coping with pain during childbirth. Design Critical review of qualitative research. Findings Ten studies were included, conducted in Australia, England, Finland, Iceland, Indonesia, Iran and Sweden. Eight of the studies employed a phenomenological perspective with the remaining two without a specific qualitative methodological perspective. Thematic analysis was used as the approach for synthesising the data in this review. Two main themes emerged as the most significant influences upon a woman׳s ability to cope with pain: (i) the importance of individualised, continuous support and (ii) an acceptance of pain during childbirth. This review found that women felt vulnerable during childbirth and valued the relationships they had with health professionals. Many of the women perceived childbirth pain as challenging, however, they described the inherent paradox for the need for pain to birth their child. This allowed them to embrace the pain subsequently enhancing their coping ability. Key conclusions Women׳s experience of coping with pain during childbirth is complex and multifaceted. Many women felt the need for effective support throughout childbirth and described the potential implications where this support failed to be provided. Feeling safe through the concept of continuous support was a key element of care to enhance the coping ability and avoid feelings of loneliness and fear. A positive outlook and acceptance of pain was acknowledged by many of the women, demonstrating the beneficial implications for coping ability. These findings were consistent despite the socio-economic, cultural and contextual differences observed within the studies suggesting that experiences of coping with pain during childbirth are universal. Implications for practice The findings suggest there is a dissonance between what women want in order to enhance their ability to cope with pain and the reality of clinical practice. This review found women would like health professionals to maintain a continuous presence throughout childbirth and support a social model of care that promotes continuity of care and an increasing acceptance of pain as part of normal childbirth. It is suggested future research regarding the role of antenatal provision for instilling such a viewpoint in preparation of birth be undertaken to inform policy makers. The need for a shift in societal norms is also suggested to disseminate expectations and positive or negative views of what the role of pain during childbirth should be to empower women to cope with childbirth and embrace this transition to motherhood as part of a normal process

Improving a Natural Enzyme Activity through Incorporation of Unnatural Amino Acids

The bacterial phosphotriesterases catalyze hydrolysis of the pesticide paraoxon with very fast turnover rates and are thought to be near to their evolutionary limit for this activity. To test whether the naturally evolved turnover rate could be improved through the incorporation of unnatural amino acids and to probe the role of peripheral active site residues in nonchemical steps of the catalytic cycle (substrate binding and product release), we replaced the naturally occurring tyrosine amino acid at position 309 with unnatural L-(7-hydroxycoumarin-4-yl)ethylglycine (Hco) and L-(7-methylcoumarin-4-yl)ethylglycine amino acids, as well as leucine, phenylalanine, and tryptophan. Kinetic analysis suggests that the 7-hydroxyl group of Hco, particularly in its deprotonated state, contributes to an increase in the rate-limiting product release step of substrate turnover as a result of its electrostatic repulsion of the negatively charged 4-nitrophenolate product of paraoxon hydrolysis. The 8-11-fold improvement of this already highly efficient catalyst through a single rationally designed mutation using an unnatural amino acid stands in contrast to the difficulty in improving this native activity through screening hundreds of thousands of mutants with natural amino acids. These results demonstrate that designer amino acids provide easy access to new and valuable sequence and functional space for the engineering and evolution of existing enzyme functions

Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis

Monocytes and macrophages are key drivers in the pathogenesis of inflammatory diseases. Epigenetic targets have been shown to control the transcriptional profile and phenotype of these cells. Since histone deacetylase protein inhibitors demonstrate profound anti-inflammatory activity, we wanted to test whether HDAC inhibition within monocytes and macrophages could be applied to suppress inflammation in vivo. ESM technology conjugates an esterase-sensitive motif (ESM) onto small molecules to allow targeting of cells that express carboxylesterase 1 (CES1), such as mononuclear myeloid cells. This study utilized an ESM-HDAC inhibitor to target monocytes and macrophages in mice in both an acute response model and an atherosclerosis model. We demonstrate that the molecule blocks the maturation of peritoneal macrophages and inhibits pro-inflammatory cytokine production in both models but to a lesser extent in the atherosclerosis model. Despite regulating the inflammatory response, ESM-HDAC528 did not significantly affect plaque size or phenotype, although histological classification of the plaques demonstrated a significant shift to a less severe phenotype. We hereby show that HDAC inhibition in myeloid cells impairs the maturation and activation of peritoneal macrophages but shows limited efficacy in a model of atherosclerosis

Tumor-Associated Macrophages (TAMs) Form an Interconnected Cellular Supportive Network in Anaplastic Thyroid Carcinoma

BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined