Divergent Manner Research Articles

Synthesis of Ganbajunins D and E and the Proposed Structure of Thelephantin D

AbstractThe syntheses of ganbajunins D and E and of the structure proposed for thelephantin D, as well as its regioisomer, were achieved in a divergent manner via a common monoester intermediate. The proposed structure of thelephantin D had NMR chemical shifts different from those of natural thelephantin D. This supported Takahashi's suggestion that the true structure of natural thelephantin D should be the same as that of terrestrin C, as was deduced from the similarities in their NMR spectra. The presence of isomerization equilibria between 2′,5′‐ and 2′,6′‐diacyloxy‐p‐terphenyl derivatives in solution, which are the cause of the inseparability of these derivatives, was also demonstrated by monitoring the dynamic transition from a 2′,6′‐diacyloxy‐p‐terphenyl‐rich mixture of the derivatives to an equilibrium mixture. The results of biological and chemical property tests – such as cytotoxicity against cancer cells, affinity towards Fe2+ ion, and antioxidative activity – with the synthesized compounds are also described.

Problem-solving and decision-making in translation revision: Two case studies

This project investigates two young professional translators’ problem-solving and decision-making behaviour during revision processes. It sets out to qualitatively describe the complexity of interplay involved in problem-solving and decision-making in translation revision, using think-aloud protocols as a research method. The data I elicited suggest that, for a revision point to occur, the translator first has to find a translation problem. However, the translation problem itself can evolve over time in the revision process in either a divergent or convergent manner. In other words, a single translation problem can be subdivided into several smaller problems and be tackled individually. Meanwhile, the translator may choose to merge several problems into a single problem that requires a holistic problem-solving approach. In terms of decision-making, the translator does not generally verbalise his/her reasons for choosing a translation solution. Nevertheless, s/he has an appropriateness threshold in mind, so that s/he can judge and compare the appropriateness of translation choices and make a decision accordingly. A tentative model of end-revision problem-solving and decision-making has been produced to summarise the findings of this project.

Synthesis and characterisation of two new tripodal metalloligands incorporating zinc(II)

The in situ Schiff base condensation of 2-acetylpyrazine with tris(2-aminoethyl)amine in the presence of zinc(II) perchlorate was carried out in absolute ethanol and 95 % ethanol, respectively. Two new tripodal metalloligands, 1 and 2, were isolated. The formation of complexes 1 and 2 has been verified by NMR, mass spectral studies and X-ray (for 2), with the evidence indicating that a zinc ion is incorporated in the tripodal cavity defined by the tren backbone in each case. However the products differed in the number of Schiff base condensation reactions that had occurred. While the use of absolute ethanol resulted in condensation at all three primary amine sites of tris(2-aminoethyl)amine, employing 95 % ethanol yielded condensation at only one of the primary amine sites. These different outcomes can be ascribed, at least in part, to the effect of the different water contents in the respective reaction solvents resulting in a shift of the dynamic equilibrium involving imine formation towards the precursor amine and ketone reagents. In 1, steric considerations dictate that the three uncoordinated pyrazine nitrogen donors will have their coordination vectors oriented in a mutually divergent manner suitable for coordination to three different metal centres when acting as a metalloligand while for 2, the X-ray structure confirms that the single uncoordinated (pendent) pyrazine nitrogen is also oriented for ready coordination to a second metal centre.

Sphingosine 1-phosphate counteracts insulin signaling in pancreatic β-cells via the sphingosine 1-phosphate receptor subtype 2.

Glucolipotoxic stress has been identified as a key player in the progression of pancreatic β-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic β-cells but also regulate β-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in β-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by β-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued β-cell damage clearly indicating an important role of the S1P2 in β-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β-cell dysfunction and the development of T2D.

Total synthesis of cryptomoscatones D1 and D2: stereochemical assignment of cryptomoscatone D1

The first total synthesis and structural elucidation of cryptomoscatone D1, and a novel synthetic approach for cryptomoscatone D2 were achieved in 30% and 29% overall yield, respectively. The synthesis relied on the use of a key Mukaiyama aldol reaction followed by a diastereoselective carbonyl reduction that allowed the preparation of four cryptomoscatone isomers in a stereochemically divergent manner. Comparison of NMR data and CD curves of the synthetic stereoisomers and natural products confirmed the stereochemical nature of cryptomoscatone D2, and led to establishing the absolute configuration of cryptomoscatone D1.

Welfare Performance in Southern Europe: Employment Crisis and Poverty Risk

The Great Recession has had a deep impact on employment levels and on income inequality in the Southern European countries (Greece, Spain, Portugal and Italy). It has given rise to a new stage in the discussion on the distinctiveness of a possible ‘Mediterranean’ variant of welfare capitalism. This paper analyses the performance of the Mediterranean cluster during the Great Recession period in its two main dimensions, labour market participation and poverty risk, and to what extent that performance has evolved in a divergent or convergent manner. Firstly, it portrays the main changes in this variant of welfare capitalism during the last two decades. The second and third sections, respectively, provide a comparative profile of the employment crisis suffered by these countries and of its impact on poverty risks. Finally, the main institutional traits are discussed, explaining the relative performance of welfare capitalism in this cluster of countries.

Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy

We sought to determine whether acute resistance exercise (RE)-induced gene expression is modified by RE training. We studied the expression patterns of a select group of genes following an acute bout of RE in naïve and hypertrophying muscle. Thirteen untrained subjects underwent supervised RE training for 12 wk of the nondominant arm and performed an acute bout of RE 1 wk after the last bout of the training program (training+acute). The dominant arm was either unexercised (control) or subjected to the same acute exercise bout as the trained arm (acute RE). Following training, men (14.8 ± 2.8%; P < 0.05) and women (12.6 ± 2.4%; P < 0.05) underwent muscle hypertrophy with increases in dynamic strength in the trained arm (48.2 ± 5.4% and 72.1 ± 9.1%, respectively; P < 0.01). RE training resulted in attenuated anabolic signaling as reflected by a reduction in rpS6 phosphorylation following acute RE. Changes in mRNA levels of genes involved in hypertrophic growth, protein degradation, angiogenesis, and metabolism commonly expressed in both men and women was determined 4 h following acute RE. We show that RE training can modify acute RE-induced gene expression in a divergent and gene-specific manner even in genes belonging to the same ontology. Changes in gene expression following acute RE are multidimensional, and may not necessarily reflect the actual adaptive response taking place during the training process. Thus RE training can selectively modify the acute response to RE, thereby challenging the use of gene expression as a marker of exercise-induced adaptations.

“Differently normal” and “normally different”: Negotiations of female embodiment in women's accounts of ‘atypical’ sex development

During recent decades numerous feminist scholars have scrutinized the two-sex model and questioned its status in Western societies and medicine. Along the same line, increased attention has been paid to individuals' experiences of atypical sex development, also known as intersex or ‘disorders of sex development’ (DSD). Yet research on individuals' experiences of finding out about their atypical sex development in adolescence has been scarce. Against this backdrop, the present article analyses 23 in-depth interviews with women who in their teens found out about their atypical sex development. The interviews were conducted during 2009–2012 and the interviewees were all Swedish. Drawing on feminist research on female embodiment and social scientific studies on diagnosis, I examine how the women make sense of their bodies and situations. First, I aim to explore how the women construe normality as they negotiate female embodiment. Second, I aim to investigate how the divergent manners in which these negotiations are expressed can be further understood via the women's different access to a diagnosis. Through a thematic and interpretative analysis, I outline two negotiation strategies: the “differently normal” and the “normally different” strategy. In the former, the women present themselves as just slightly different from ‘normal’ women. In the latter, they stress that everyone is different in some manner and thereby claim normalcy. The analysis shows that access to diagnosis corresponds to the ways in which the women present themselves as “differently normal” and “normally different”, thus shedding light on the complex role of diagnosis in their negotiations of female embodiment. It also reveals that the women make use of what they do have and how alignments with and work on norms interplay as normality is construed.

PCSK9 and the Road Less Traveled: How an Unconventional Approach Led to a Major Discovery

A gene with a remarkable translational research story is leading the way in becoming potentially the next blockbuster drug in heart disease. This “gene of rare effect,” proprotein convertase subtilisin/kexin type 9 ( PCSK9 ),2 was found to be a contributing factor to profoundly low cholesterol concentrations in some individuals and has made its way from unknown factor to headline grabber, as detailed in a recent Nature news feature (1). In the postgenome era, the prevailing “common variant hypothesis” was that genetic variants present at approximately 5% frequencies were expected to contribute importantly to complex disease (such as heart disease). However, subsequent genome-wide association studies proved disappointing, finding that common variants actually have a very small effect on disease. On the contrary, a decade before the Human Genome Project, Helen Hobbs and Jonathan Cohen and their colleagues from the University of Texas Southwestern approached this problem in a divergent manner, by hypothesizing that many different rare variants were likely to have a big effect in complex disorders. They reasoned that common variants with a major impact on complex disorders would be weeded out by natural selection. The Dallas Heart Study (DHS) was a large multiethnic (>50% …

Cryptocaryols A and B: total syntheses, stereochemical revision, structure elucidation, and structure-activity relationship.

The first total syntheses and structural elucidation of cryptocaryol A and cryptocaryol B were achieved in 23 and 25 linear steps, respectively. The synthesis relied on the use of a key pseudo-Cs symmetric pentaol intermediate, which in a stereochemically divergent manner was converted into either enantiomer as well as diastereomers. This synthetic effort enabled the first structure-activity relationships of this class of PDCD4 stabilizing natural products.

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

The purpose of this study was to evaluate the role of sirtuin 1 (SirT1) in exercise- and resveratrol (RSV)-induced skeletal muscle mitochondrial biogenesis. Using muscle-specific SirT1-deficient (KO) mice and a cell culture model of differentiated myotubes, we compared the treatment of resveratrol, an activator of SirT1, with that of exercise in inducing mitochondrial biogenesis. These experiments demonstrated that SirT1 plays a modest role in maintaining basal mitochondrial content and a larger role in preserving mitochondrial function. Furthermore, voluntary exercise and RSV treatment induced mitochondrial biogenesis in a SirT1-independent manner. However, when RSV and exercise were combined, a SirT1-dependent synergistic effect was evident, leading to enhanced translocation of PGC-1α and SirT1 to the nucleus and stimulation of mitochondrial biogenesis. Thus, the magnitude of the effect of RSV on muscle mitochondrial biogenesis is reliant on SirT1, as well as the cellular environment, such as that produced by repeated bouts of exercise.

Divergent Synthesis of Trans-Fused Polycyclic Ethers by a Convergent Oxiranyl Anion Strategy

Octacyclic polyethers that correspond to the CDEFGHIJ-ring system of yessotoxin as well as G- and/or I-ring-modified analogues were synthesized in a divergent manner, starting from a common intermediate, using an [X + 2 + Y]-type convergent method. Reaction of a triflate with the oxiranyl anion generated from an epoxy sulfone, followed by ring expansion, allowed for the incorporation of medium-sized ring ethers into the key intermediate. Subsequent acetal formation and reductive etherification afforded various octacycles containing seven- and eight-membered ether rings.

Divergent total synthesis of (−)-aspidophytine and its congeners via Fischer indole synthesis

A total synthesis of (−)-aspidophytine and the first total syntheses of its congeners, (+)-cimicidine and (+)-cimicine, were accomplished in a divergent manner. Construction of the aspidosperma skeleton was executed by Fischer indole synthesis between substituted phenylhydrazines and tricyclic aminoketone. The regiochemistry of the Fischer indole synthesis was strongly dependent on the choice of acid, and a weak acid, such as acetic acid provided the desired indolenine isomer in high selectivity.

STAT5 activity downstream of IgE and IgG receptors in mast cells (177.8)

Abstract Removal of STAT5 impairs mast cell development, survival, and IgE-mediated cytokine production, justifying a need to closely investigate its activity downstream of Fc receptors. We found that STAT5 tyrosine phosphorylation occurs shortly after FcϵRI crosslinking in a Fyn-dependent manner, while the suppression of Lyn, and other negative regulators of IgE signaling, appears to enhance STAT5 activation. Tyrosine phosphorylation of STAT5 also occured during IgG-mediated activity, suggesting some overlap in the signaling proximal to different Fc receptors in mast cells. Additionally, IgE- and IgG-mediated signaling elicited serine phosphorylation of both STAT5A and STAT5B, possibly in a divergent manner. Inhibition of Syk ablated IgE-mediated pS-STAT5, but affected to a lesser extent, if at all, pS-STAT5B and IgG-mediated total pS-STAT5. Furthermore, inhibition of JNK reduced pS-STAT5 during FcγR crosslinking. Collectively, these data highlight similarities and differences from variable receptor inputs as well as the different STAT5 proteins, supporting their essential roles in mast cell biology.

Discovery of Potential piRNAs from Next Generation Sequences of the Sexually Mature Porcine Testes

Piwi- interacting RNAs (piRNAs), a new class of small RNAs discovered from mammalian testes, are involved in transcriptional silencing of retrotransposons and other genetic elements in germ line cells. In order to identify a full transcriptome set of piRNAs expressed in the sexually mature porcine testes, small RNA fractions were extracted and were subjected to a Solexa deep sequencing. We cloned 6,913,561 clean reads of Sus Scrofa small RNAs (18–30 nt) and performed functional characterization. Sus Scrofa small RNAs showed a bimodal length distribution with two peaks at 21 nt and 29 nt. Then from 938,328 deep-sequenced small RNAs (26–30 nt), 375,195 piRNAs were identified by a k-mer scheme and 326 piRNAs were identified by homology searches. All piRNAs predicted by the k-mer scheme were then mapped to swine genome by Short Oligonucleotide Analysis Package (SOAP), and 81.61% of all uniquely mapping piRNAs (197,673) were located to 1124 defined genomic regions (5.85 Mb). Within these regions, 536 and 501 piRNA clusters generally distributed across only minus or plus genomic strand, 48 piRNA clusters distributed on two strands but in a divergent manner, and 39 piRNA clusters distributed on two strands in an overlapping manner. Furthermore, expression pattern of 7 piRNAs identified by homology searches showed 5 piRNAs displayed a ubiquitous expression pattern, although 2 piRNAs were specifically expressed in the testes. Overall, our results provide new information of porcine piRNAs and their specific expression pattern in porcine testes suggests that piRNAs have a role in regulating spermatogenesis.

Synthesis of variously sulfated biotinylated oligosaccharides from the linkage region of proteoglycans

The synthesis of a collection, as biotinylated conjugates, of various sulfoforms of the trisaccharide β-d-GlcpA-(1→3)-β-d-Galp-(1→3)-β-d-Galp, structures encountered in the linkage region of proteoglycans, is reported herein for the first time. An efficient and stereocontrolled preparation was achieved using common key intermediates in a divergent manner. These molecules should be useful probes to study the substrate specificity of the glycosyltransferases involved at the bifurcation point in the biosynthesis of proteoglycans.

Responses of Arabidopsis thaliana plant lines differing in hydroxylation of aliphatic glucosinolate side chains to feeding of a generalist and specialist caterpillar

Plants contain variable chemical compositions which play a role in direct defense against phytophagous insects. Glucosinolates (GSs) are the predominant secondary metabolites and defense compounds in brassicaceous species. As a consequence of co-evolution between adapted crucifer-feeding specialists and their associated host-plants, specific plant-insect interactions have developed in a divergent manner from non-adapted generalists. Therefore, generalist and specialist insects may provoke different insect-inducible plant responses. Here, we have investigated the specific biochemical and molecular plant responses of Arabidopsis thaliana (L.) induced by the generalist Spodoptera exigua (Hübner) and the specialist Pieris brassicae L. To get more detailed information about herbivore-mediated-specific plant responses in different chemotypes within one species, we used multiple plant lines with either the non-hydroxylated 3-methylsulfinylpropyl GS or the hydroxylated 3-hydroxypropyl GS in a comparable genetic background. Caterpillar feeding induced a stronger GS accumulation in the 3-hydroxypropyl GS chemotype than the 3-methylsulfinylpropyl GS chemotype, considering the overall insect-mediated changes in aliphatic and indole GS levels in all lines. Herbivory by the generalist S.exigua and the specialist P.brassicae had similar effects on biochemical and transcriptional response pattern. Contrary to the paradigm that specialists may minimize the induction of chemical defenses, we observed a higher elicitation of GSs by the specialist species. The accumulation of especially 1-methoxy-indol-3-ylmethyl GS and the induced gene transcripts by the two species point to an insect-mediated activation of the jasmonic acid signaling pathway in the plant lines.

Sex Differences in the Metabolic Effects of Testosterone in Sheep

Adiposity is regulated in a sexually divergent manner. This is partly due to sex steroids, but the differential effects of androgens in males and females are unclear. We investigated effects of testosterone on energy balance in castrated male (n = 6) and female sheep (n = 4), which received 3 × 200 mg testosterone implants for 2 wk or blank implants (controls). Temperature probes were implanted into retroperitoneal fat and skeletal muscle. Blood samples were taken to measure metabolites and insulin. In males, muscle and fat biopsies were collected to measure uncoupling protein (UCP) mRNA and phosphorylation of AMP-activated protein kinase and Akt. Testosterone did not change food intake in either sex. Temperature in muscle was higher in males than females, and testosterone reduced heat production in males only. In fat, however, temperature was higher in the castrate males compared with females, and there was no effect of testosterone treatment in either sex. Preprandial glucose levels were lower, but nonesterified fatty acids were higher in females compared with males, irrespective of testosterone. In males, the onset of feeding increased UCP1 and UCP3 mRNA levels in skeletal muscle, without an effect of testosterone. During feeding, testosterone reduced glucose levels in males only but did not alter the phosphorylation of AMP-activated protein kinase or Akt in muscle. Thus, testosterone maintains lower muscle and fat temperatures in males but not females. The mechanism underlying this sex-specific effect of testosterone is unknown but may be due to sexual differentiation of the brain centers controlling energy expenditure.

Total Synthesis of Norcembrenolide B and Scabrolide D

An efficient stereoselective synthesis of norcembrenolide B (8) and scabrolide D (9) is reported. The strategy is inspired by biogenetic relationships of related cembrenoids. Central to this approach is the construction of norbipinnatin J which upon selective C2 deoxygenation and C8 oxygenation produces norrubifolide and norcoralloidolide A. A sequence of site-selective oxidations and skeletal reorganizations then yields, in a divergent manner, compounds 8 and 9. The studies allow revision of the proposed structure of scabrolide D (9), which is identical to norcembrenolide C.

ChemInform Abstract: Preactivation‐Based, One‐Pot Combinatorial Synthesis of Heparin‐Like Hexasaccharides for the Analysis of Heparin—Protein Interactions.

Heparin (HP) and heparan sulfate (HS) play important roles in many biological events. Increasing evidence has shown that the biological functions of HP and HS can be critically dependent upon their precise structures, including the position of the iduronic acids and sulfation patterns. However, unraveling the HP code has been extremely challenging due to the enormous structural variations. To overcome this hurdle, we investigated the possibility of assembling a library of HP/HS oligosaccharides using a preactivation-based, one-pot glycosylation method. A major challenge in HP/HS oligosaccharide synthesis is stereoselectivity in the formation of the cis-1,4-linkages between glucosamine and the uronic acid. Through screening, suitable protective groups were identified on the matching glycosyl donor and acceptor, leading to stereospecific formation of both the cis-1,4- and trans-1,4-linkages present in HP. The protective group chemistry designed was also very flexible. From two advanced thioglycosyl disaccharide intermediates, all of the required disaccharide modules for library preparation could be generated in a divergent manner, which greatly simplified building-block preparation. Furthermore, the reactivity-independent nature of the preactivation-based, one-pot approach enabled us to mix the building blocks. This allowed rapid assembly of twelve HP/HS hexasaccharides with systematically varied and precisely controlled backbone structures in a combinatorial fashion. The speed and the high yields achieved in glycoassembly without the need to use a large excess of building blocks highlighted the advantages of our approach, which can be of general use to facilitate the study of HP/HS biology. As a proof of principle, this panel of hexasaccharides was used to probe the effect of backbone sequence on binding with the fibroblast growth factor-2 (FGF-2). A trisaccharide sequence of 2-O-sulfated iduronic acid flanked by N-sulfated glucosamines was identified to be the minimum binding motif and N-sulfation was found to be critical. This provides useful information for further development of more potent compounds towards FGF-2 binding, which can have potential applications in wound healing and anticancer therapy.