Two novel and potent 3-[(o-methoxyphenyl)piperazinylethyl]-5-phenylthien

The synthesis and in vitro characterization of A-119637 and A-123189, two novel, selective and potent alpha1D antagonists, are described.     

The Organization of Local and Distant Functional Connectivity in the Human Brain

Information processing in the human brain arises from both interactions between adjacent areas and from distant projections that form distributed brain systems. Here we map interactions across different spatial scales by estimating the degree of intrinsic functional connectivity for the local (≤14 mm) neighborhood directly surrounding brain regions as contrasted with distant (>14 mm) interactions. The balance between local and distant functional interactions measured at rest forms a map that separates sensorimotor cortices from heteromodal association areas and further identifies regions that possess both high local and distant cortical-cortical interactions. Map estimates of network measures demonstrate that high local connectivity is most often associated with a high clustering coefficient, long path length, and low physical cost. Task performance changed the balance between local and distant functional coupling in a subset of regions, particularly, increasing local functional coupling in regions engaged by the task. The observed properties suggest that the brain has evolved a balance that optimizes information-processing efficiency across different classes of specialized areas as well as mechanisms to modulate coupling in support of dynamically changing processing demands. We discuss the implications of these observations and applications of the present method for exploring normal and atypical brain function.     

Taxonomic review of the New World tamarins (Primates: Callitrichidae)

Twelve generic names have been ascribed to the New World tamarins but all are currently placed in just one: Saguinus Hoffmannsegg, 1807. Based on geographical distributions, morphology, and pelage patterns and coloration, they have been divided into six species groups: (1) nigricollis, (2) mystax, (3) midas, (4) inustus, (5) bicolor and (6) oedipus. Molecular phylogenetic studies have validated five of these groups; each are distinct clades. Saguinus inustus is embedded in the mystax group. Genetic studies show that tamarins are sister to all other callitrichids, diverging 15?13 Ma. The small‐bodied nigricollis group diverged from the remaining, larger tamarins 11?8 Ma, and the mystax group diverged 7?6 Ma; these radiations are older than those of the marmosets (Callithrix, Cebuella, Mico), which began to diversify 6?5 Ma. The oedipus group diverged from the midas and bicolor groups 5?4 Ma. We review recent taxonomic changes and summarize the history of the generic names. Taking into account the Late Miocene divergence time (11?8 Ma) between the large‐ and small‐bodied tamarin lineages, the small size of the nigricollis group species when compared with other tamarins, and the sympatry of the nigricollis group species with the larger mystax group species, we argue that the nigricollis group be recognized as a distinct genus: Leontocebus Wagner, 1839.     

In search of balance: a review of Povinelli’s world without weight

Povinelli and colleagues ask whether chimpanzees can understand the concept of weight, answering with a resounding “no”. They justify their answer by appeal to over thirty previously unpublished experiments. I here evaluate in detail Povinelli’s arguments against his targets, questioning the assumption that such comparative questions will be resolved with an unequivocal “yes” or “no”.     

Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC₅₀ <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate.     

The dielectrophoresis of blood platelets as affected by hemophilic traits

We find that there are moderate differences in the electrical polarizabilities of normal and various hemophilic canine blood platelets. The technique of dielectrophoresis, using the effect of nonuniform fields on neutral bodies, was used to perform rapid assays of the platelets. At present the dielectrophoretic test can only distinguish reliably between relatively large groups of animals on a statistical basis. The present technique shows a unique ability however, to distinguish even between normal canine platelets and the transmitter female canine platelets. In studies of the effects of various chemical agents upon the dielectrophoresis of platelets, inhibitors such as NaF, sodium iodacetate, NaCN, and NaN₃ had marked effects at low concentration. Ions such as Na⁺ K⁺, Mg⁺⁺, and La⁺⁺⁺, as well as NO₃ ⁻, SO₄ ⁼, and mellitic ion had lesser effects. In some cases the presence of trace quantities of the chemical agent “stabilizes” the cellular dielectrophoretic response, enabling the platelet to continue to be attracted by the nonuniform field for longer than usual. The CN⁻ and F⁻ ions appear to do this. This may have useful application. From the shape of the frequency spectrum of the dielectrophoretic response we suggest that the peaks at about 0.1 to 10 MHz imply a Maxwell-Wagner type of response, typical of an interface between bulk regions of differing conductivity, as at the cell boundary. From a lack of low frequency response, we suggest that the platelet interface with the surrounding aqueous medium must be singularly free of ionic double layers — or at least that the ionic double layers present must be of unusually low charge density. The technique of dielectrophoresis has been used in comparative study of canine blood platelets, from (1) normal dogs, (2) female dogs that transmit Factor VIII deficiency to their offspring, (3) male dogs with Factor VIII deficiency, and (4) female dogs with Factor VIII deficiency. The study showed that differences exist between the 4 groups of dogs in the average dielectrophoretic responses at 1 MHz. The effect of several chemical agents, i.e., NaCN and NaF on normal canine platelets was to effectively stabilize the platelets against deteriorationin vitro.     

Reconfigurable task-dependent functional coupling modes cluster around a core functional architecture

Functional coupling across distributed brain regions varies across task contexts, yet there are stable features. To better understand the range and central tendencies of network configurations, coupling patterns were explored using functional MRI (fMRI) across 14 distinct continuously performed task states ranging from passive fixation to increasingly demanding classification tasks. Mean global correlation profiles across the cortex ranged from 0.69 to 0.82 between task states. Network configurations from both passive fixation and classification tasks similarly predicted task coactivation patterns estimated from meta-analysis of the literature. Thus, even across markedly different task states, central tendencies dominate the coupling configurations. Beyond these shared components, distinct task states displayed significant differences in coupling patterns in response to their varied demands. One possibility is that anatomical connectivity provides constraints that act as attractors pulling network configurations towards a limited number of robust states. Reconfigurable coupling modes emerge as significant modifications to a core functional architecture.