Design and synthesis of novel 2',3'-dideoxy-4'-selenonucleosides as potential antiviral agents

On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closure reaction of the dimesylate with Se(2-) and Pummerer type condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated that 4'-seleno-ddNs adopted the same C2'-endo/C3'-exo (South) conformation as anti-HIV active ddNs, but did not show anti-HIV activity, indicating that RT seems to prefer the C2'-exo/C3'-endo (North) conformation on binding with their triphosphates.     

Liver specification: a new role for Wnts in liver development

Secreted Wnt proteins control a diverse array of developmental decisions. A recent analysis of the zebrafish mutant prometheus points to a previously unknown role for Wnts during liver specification.     

Which conditions promote negative density dependent selection on prey aggregations?

Negative density dependent selection on individuals in prey aggregations (negative DDS, the preferential selection by predators of spatially isolated prey) is assumed to contribute in many cases to the evolution and maintenance of aggregation. Both positive and negative DDS on prey groups have been documented in nature but there is no existing framework to predict when each of these forms of natural selection is most likely. By exploiting the tendency of artificial neural networks to exhibit consumer-like emergent behaviours, I isolate at least two environmental factors impinging on the consumer organism that may determine which form of density dependent natural selection is shown: the distribution of prey group size attacked by the predator and the spatial conformation (dispersed or compacted) of the prey group. Numerous forms of DDS on artificial prey (positive, negative, and non-DDS) are displayed through different combinations of these factors. I discuss in detail how the predictions of the model may be tested by empiricists in order to assess the usefulness of the framework presented. I stress the importance of understanding DDS on prey groups given the recent emergence of these systems as test beds for ideas on biological self-organisation.     

Hollow fibre membrane bioreactors for tissue engineering applications

Hollow fibre membrane bioreactors (HFB) provide a novel approach towards tissue engineering applications in the field of regenerative medicine. For adherent cell types, HFBs offer an in vivo-like microenvironment as each fibre replicates a blood capillary and the mass transfer rate across the wall is independent from the shear stresses experienced by the cell. HFB also possesses the highest surface area to volume ratio of all bioreactor configurations. In theory, these factors enable a high quantity of the desired cellular product with less population variation, and favourable operating costs. Experimental analyses of different cell types and bioreactor designs show encouraging steps towards producing a clinically relevant device. This review discusses the basic HFB design for cell expansion and in vitro models; compares data produced on commercially available systems and addresses the operational differences between theory and practice. HFBs are showing some potential for mammalian cell culture but further work is needed to fully understand the complexities of cell culture in HFBs and how best to achieve the high theoretical cell yields.     

Panethnicity revisited: contested group boundaries in the post-9/11 era

Existing theories of panethnicity in the USA concentrate on Asian Americans and Latinos, two umbrella groups that originally coalesced during the 1960s civil rights era. Although the role played by the state is recognized as central to panethnic development, we argue that the influence of this pivotal variable is contingent on historical context. Through a case study of emerging minority groups (Middle Eastern and South Asian Americans in the post-9/11 era), we re-examine the existing conceptualization of panethnicity at a time when the state plays a more punitive than compensatory role. Using a methodology that draws on a range of novel sources, we document the way that pre-existing ethnic, religious and national-origin labels have been reinforced instead of panethnic labels for the populations under study. Accordingly, we develop an updated conceptualization of group formation that incorporates historical context and the role of the state in the post-9/11 era.     

Ecological and epidemiological studies of histoplasmosis in the United States of America

Histoplasmosis is a disease that is transmitted from nature to man. The causative agent,Histoplasma capsulatum, grows freely in the soil and the infection is spread by inhalation of the infectious spores. The infection is highly endemic in the central United States. Soil contaminated with fecal droppings of chickens, starlings, blackbirds, and other avian species is a principal source of infection.Paper read at the Eighth International Congresses for Tropical Medicine and Malaria, September 1968, Teheran (Iran).     

High pressure volumetric measurements in dipalmitoylphosphatidylcholine bilayers

The one previously reported high pressure volumetric experiment on a phospholipid bilayer investigated a region of pressure between 0 and 25 MPa and obtained isothermal compressibility values for the liquid crystal and intermediate phases which differed by more than a factor of ten. We report new volumetric measurements around the main transition in dipalmitoylphosphatidylcholine (DPPC) from 0 to 100 MPa. The isothermal compressibility data for the two phases are of the same order of magnitude, and the experimentally determined coexistence curve, specific volume dependence, and volume discontinuity values are compared with the predictions of the phenomenological theory according to Sugar and Tarjan ((1982) Sov. Phys. Crystallogr. 27, 4-5). Significant discrepancies between this theory and experiment are found. Finally, the data indicate that steric interactions play a more dominant role in the main transition of phospholipid bilayers than in transitions in most thermotropic liquid crystals.     

Efficient,large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain

We reported that 2-(3,4-difluorophenylethynyl)-N⁶-3-chlorobenzyl (N)-methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A₃ adenosine receptors (A₃ARs, K_i 3 nM). It is becoming an important pharmacological tool for defining A₃AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from d-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t_1/2 of 1.09 h and plasma C_max of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.

Electronic supplementary material

The online version of this article (doi:10.1007/s11302-015-9459-2) contains supplementary material, which is available to authorized users.     

Inter-population differences in diving behaviour of adult male southern elephant seals (Mirounga leonina)

Access to different environments may lead to inter-population behavioural changes within a species that allow populations to exploit their immediate environments. Elephant seals from Marion Island (MI) and King George Island (KGI) (Isla 25 de Mayo) forage in different oceanic environments and evidently employ different foraging strategies. This study elucidates some of the factors influencing the diving behaviour of male southern elephant seals from these populations tracked between 1999 and 2002. Mixed-effects models were used to determine the influence of bathymetry, population of origin, body length (as a proxy for size) and individual variation on the diving behaviour of adult male elephant seals from the two populations. Males from KGI and MI showed differences in all dive parameters. MI males dived deeper and longer (median: 652.0?m and 34.00?min) than KGI males (median: 359.1?m and 25.50?min). KGI males appeared to forage both benthically and pelagically while MI males in this study rarely reached depths close to the seafloor and appeared to forage pelagically. Model outputs indicate that males from the two populations showed substantial differences in their dive depths, even when foraging in areas of similar water depth. Whereas dive depths were not significantly influenced by the size of the animals, size played a significant role in dive durations, though this was also influenced by the population that elephant seals originated from. This study provides some support for inter-population differences in dive behaviour of male southern elephant seals.