Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization

Epothilones are macrocyclic bacterial natural products with potent microtubule-stabilizing and antiproliferative activity. They have served as successful lead structures for the development of several clinical candidates for anticancer therapy. However, the structural diversity of this group of clinical compounds is rather limited, as their structures show little divergence from the original natural product leads. Our own research has explored the question of whether epothilones can serve as a basis for the development of new structural scaffolds, or chemotypes, for microtubule stabilization that might serve as a basis for the discovery of new generations of anticancer drugs. We have elaborated a series of epothilone-derived macrolactones whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of a conformationally constrained side chain, the removal of the C3-hydroxyl group, and the replacement of C12 with nitrogen. So far, this approach has yielded analogs 30 and 40 that are the most advanced, the most rigorously modified, structures, both of which are potent antiproliferative agents with low nanomolar activity against several human cancer cell lines in vitro. The synthesis was achieved through a macrolactone-based strategy or a high-yielding RCM reaction. The 12-aza-epothilone ("azathilone" 40) may be considered a "non-natural" natural product that still retains most of the overall structural characteristics of a true natural product but is structurally unique, because it lies outside of the general scope of Nature's biosynthetic machinery for polyketide synthesis. Like natural epothilones, both 30 and 40 promote tubulin polymerization in vitro and at the cellular level induce cell cycle arrest in mitosis. These facts indicate that cancer cell growth inhibition by these compounds is based on the same mechanistic underpinnings as those for natural epothilones. Interestingly, the 9,10-dehydro analog of 40 is significantly less active than the saturated parent compound, which is contrary to observations for natural epothilones B or D. This may point to differences in the bioactive conformations of N-acyl-12-aza-epothilones like 40 and natural epothilones. In light of their distinct structural features, combined with an epothilone-like (and taxol-like) in vitro biological profile, 30 and 40 can be considered as representative examples of new chemotypes for microtubule stabilization. As such, they may offer the same potential for pharmacological differentiation from the original epothilone leads as various newly discovered microtubule-stabilizing natural products with macrolactone structures, such as laulimalide, peloruside, or dictyostatin.

Percutaneous transluminal angioplasty and stent placement in acute vessel occlusion: evaluation of new methods for interventional stroke treatment

BACKGROUND AND PURPOSE: The major goal of acute ischemic stroke treatment is fast and sufficient recanalization. Percutaneous transluminal balloon angioplasty (PTA) and/or placement of a stent might achieve both by compressing the thrombus at the occlusion site. This study assesses the feasibility, recanalization rate, and complications of the 2 techniques in an animal model. MATERIALS AND METHODS: Thirty cranial vessels of 7 swine were occluded by injection of radiopaque thrombi. Fifteen vessel occlusions were treated by PTA alone and 15, by placement of a stent and postdilation. Recanalization was documented immediately after treatment and after 1, 2, and 3 hours. Thromboembolic events and dissections were documented. RESULTS: PTA was significantly faster to perform (mean, 16.6 minutes versus 33.0 minutes for stent placement; P < .001), but the mean recanalization rate after 1 hour was significantly better after stent placement compared with PTA alone (67.5% versus 14.6%, P < .001). Due to the self-expanding force of the stent, vessel diameter further increased with time, whereas the recanalization result after PTA was prone to reocclusion. Besides thromboembolic events related to the passing maneuvers at the occlusion site, no thrombus fragmentation and embolization occurred during balloon inflation or stent deployment. Flow to side branches could also be restored at the occlusion site because it was possible to direct thrombus compression. CONCLUSIONS: Stent placement and postdilation proved to be much more efficient in terms of acute and short-term vessel recanalization compared with PTA alone.

The past ecology of Abies alba provides new perspectives on future responses of silver fir forests to global warming

Paleoecology can provide valuable insights into the ecology of species that complement observation and experiment-based assessments of climate impact dynamics. New paleoecological records (e.g., pollen, macrofossils) from the Italian Peninsula suggest a much wider climatic niche of the important European tree species Abies alba (silver fir) than observed in its present spatial range. To explore this discrepancy between current and past distribution of the species, we analyzed climatic data (temperature, precipitation, frost, humidity, sunshine) and vegetation-independent paleoclimatic reconstructions (e.g., lake levels, chironomids) and use global coupled carbon-cycle climate (NCAR CSM1.4) and dynamic vegetation (LandClim) modeling. The combined evidence suggests that during the mid-Holocene (6000 years ago), prior to humanization of vegetation, A. alba formed forests under conditions that exceeded the modern (1961-1990) upper temperature limit of the species by 5-7°C (July means). Annual precipitation during this natural period was comparable to today (>700-800 mm), with drier summers and wetter winters. In the meso-Mediterranean to sub-Mediterranean forests A. alba co-occurred with thermophilous taxa such as Quercus ilex, Q. pubescens, Olea europaea, Phillyrea, Arbutus, Cistus, Tilia, Ulmus, Acer, Hedera helix, Ilex aquifolium, Taxus, and Vitis. Results from the last interglacial (ca. 130 000-115 000 BP), when human impact was negligible, corroborate the Holocene evidence. Thermophilous Mediterranean A. alba stands became extinct during the last 5000 years when land-use pressure and specifically excessive anthropogenic fire and browsing disturbance increased. Our results imply that the ecology of this key European tree species is not yet well understood. On the basis of the reconstructed realized climatic niche of the species, we anticipate that the future geographic range of A. alba may not contract regardless of migration success, even if climate should become significantly warmer than today with summer temperatures increasing by up to 5-7°C, as long as precipitation does not fall below 700-800 mm/yr, and anthropogenic disturbance (e.g., fire, browsing) does not become excessive. Our finding contradicts recent studies that projected range contractions under global-warming scenarios, but did not factor how millennia of human impacts reduced the realized climatic niche of A. alba.

Direct male-male competition can facilitate invasion of new colour types in Lake Victoria cichlids

The possibility that disruptive sexual selection alone can cause sympatric speciation is currently a subject of much debate. The initial difficulty for new and rare ornament phenotypes to invade a population, and the stabilisation of the resulting polymorphism in trait and preference make this hypothesis problematic. Recent theoretical work indicates that the invasion is facilitated if males with the new phenotype have an initial advantage in male-male competition. We studied a pair of sympatric incipient species of cichlids from Lake Victoria, in which the red (Pundamilia nyererei) and blue males (P. pundamilia) vigorously defend territories. Other studies suggested that red phenotypes may have repeatedly invaded blue populations in independent episodes of speciation. We hypothesised that red coloration confers an advantage in male-male competition, assisting red phenotypes to invade. To test this hypothesis, we staged contests between red and blue males from a population where the phenotypes are interbreeding morphs or incipient species. We staged contests under both white and green light condition. Green light effectively masks the difference between red and blue coloration. Red males dominated blue males under white light, but their competitive advantage was significantly diminished under green light. Contests were shorter when colour differences were visible. Experience of blue males with red males did not affect the outcome of a contest. The advantage of red over blue in combats may assist the red phenotype to invade blue populations. The apparently stable co-existence of red and blue incipient species in many populations of Lake Victoria cichlids is discussed.

Contemplating a ‘public service navigator’: In search of new (and better) functioning public service media

This is a paper contemplating a tool of public editorial intelligence, so that key media policy objectives can be attained in the complex and multi-faceted environment of digital media. The paper is meant to be an article of a special issue of the International Journal of Communication on "Public Media and Exposure Diversity", co-edited by Natali Helberger and Mira Burri.

Language ideologies: the formation and legitimisation of New Zealand English

New Zealand English first emerged at the beginning of the 19th century as a result of the dialect contact of British (51%), Scottish (27.3%) and Irish (22%) migrants (Hay and Gordon 2008:6). This variety has subsequently developed into an autonomous and legitimised national variety and enjoys a distinct socio-political status, recognition and codification. In fact, a number of dictionaries of New Zealand English have been published1 and the variety is routinely used as the official medium on TV, radio and other media. This however, has not always been the case, as for long only British standard norms were deemed suitable for media broadcasting. While there is some work already on lay commentary about New Zealand English (see for example Gordon 1983, 1994; Hundt 1998), there is much more to be done especially concerning more recent periods of the history of this variety and the ideologies underlying its development and legitimisation. Consequently, the current project aims at investigating the metalinguistic discourses during the period of transition from a British norm to a New Zealand norm in the media context, this will be done by focusing on debates about language in light of the advent of radio and television. The main purpose of this investigation is thus to examine the (language) ideologies that have shaped and underlain these discourses (e.g. discussions about the appropriateness of New Zealand English vis à vis external, British models of language) and their related practices in these media (e.g. broadcasting norms). The sociolinguistic and pragmatic effects of these ideologies will also be taken into account. Furthermore, a comparison will be carried out, at a later stage in the project, between New Zealand English and a more problematic and less legitimised variety: Estuary English. Despite plenty of evidence of media and other public discourses on Estuary English, in fact, there has been very little metalinguistic analysis of this evidence, nor examinations of the underlying ideologies in these discourses. The comparison will seek to discover whether similar themes emerge in the ideologies played out in publish discourses about these varieties, themes which serve to legitimise one variety, whilst denying such legitimacy to the other.

Bacterial meningitis: insights into pathogenesis and evaluation of new treatment options: a perspective from experimental studies.

ABSTRACT  Bacterial meningitis is associated with high mortality and morbidity rates. Bacterial components induce an overshooting inflammatory reaction, eventually leading to brain damage. Pathological correlates of neurofunctional deficits include cortical necrosis, damage of the inner ear and hippocampal apoptosis. The hippocampal dentate gyrus is important for memory acquisition and harbors a neuronal stem cell niche, thus being potentially well equipped for regeneration. Adjuvant therapies aimed at decreasing the inflammatory reaction, for example, dexamethasone, and those protecting the brain from injury have been evaluated in animal models of the disease. They include nonbacteriolytic antibiotics (e.g., daptomycin), metalloproteinase inhibitors and modulators of the immunological response, for example, granulocyte colony-stimulating factor. Increasing research interest has recently been focused on interventions aimed at supporting regenerative processes.

The Role of Corruption in Explaining the Electoral Success of New Political Parties in Central and Eastern Europe

More than 20 years after the collapse of the Soviet Union, the electoral volatility in Central and Eastern Europe (CEE) is still remarkably high. A considerable part of the volatility derives from the votes for new political parties, since they are very often on the winning side of elections. This paper examines corruption as potential determinant of their electoral success. It argues that the effect of corruption is twofold: On the onehand, the historically-grown corruption level reduces the electoral success of new political parties due to strong clientelist structures that bind the electorate to the established parties. On the other hand, an increase of the perceived corruption above the traditional corruption level leads to a loss of trust in the political elite and therefore boosts the electoral success of new competitors. A statistical analysis of all democratic elections in CEE between 1996 and 2011 confirms these two counteracting effects.

Synthesis and Structural Characterizations of New Coordination Polymers Generated by the Interaction Between the Trinuclear Triangular SBU [Cu 3 (μ 3 -OH)(μ-pz) 3 ] 2+ and 4,4′-Bipyridine. 3°

The reactions of 4,4′-bipyridine with selected trinuclear triangular copper(II) complexes, [Cu3(μ3-OH)(μ-pz)3(RCOO)2Lx], [pz = pyrazolate anion, R = CH3(CH2)n (2 ≤ n ≤ 5); L = H2O, MeOH, EtOH] yielded a series of 1D coordination polymers (CPs) based on the repetition of [Cu3(μ3-OH)(μ-pz)3] secondary building units joined by bipyridine. The CPs were characterized by conventional analytical methods (elemental analyses, ESI-MS, IR spectra) and single crystal XRD determinations. An unprecedented 1D CP, generated through the bipyridine bridging hexanuclear copper clusters moieties, two 1D CPs presenting structural analogies, and two monodimensional tapes having almost exactly superimposable structures, were obtained. In one case, the crystal packing makes evident the presence of small, not-connected pores, accounting for ca. 6% of free cell volume.

Corruption and the Electoral Support of New Political Parties in Central and Eastern Europe

More than 20 years after the collapse of the Soviet Union, the electoral volatility in Central and Eastern Europe (CEE) is still remarkably high. A considerable part of the volatility derives from the votes for new political parties, since they are very often on the winning side of elections. This article examines corruption as a potential determinant of their electoral support. It argues that the effect of corruption is twofold: on the one hand, the historically derived corruption level reduces the electoral support for new political parties due to strong clientelist structures that bind the electorate to the established parties. On the other hand, an increase in perceived corruption above the traditional corruption level leads to a loss of trust in the political elite and therefore boosts the electoral support for new competitors. A statistical analysis of all democratic elections in CEE between 1996 and 2013 confirms these two counteracting effects.