Effects of repeated cocaine on medial prefrontal cortical GABAB receptor modulation of neurotransmission in the mesocorticolimbic dopamine system

Increased excitatory output from medial prefrontal cortex is an important component in the development of cocaine sensitization. Activation of GABAergic systems in the prefrontal cortex can decrease glutamatergic activity. A recent study suggested that sensitization might be associated with a decrease in GABAB receptor responsiveness in the medial prefrontal cortex. Therefore, the present study examined whether repeated exposure to cocaine-modified neurochemical changes in the mesocorticolimbic dopamine system induced by infusion of baclofen into the medial prefrontal cortex. In vivo microdialysis studies were conducted to monitor dopamine, glutamate and GABA levels in the medial prefrontal cortex and glutamate levels in the ipsilateral nucleus accumbens and ventral tegmental area during the infusion of baclofen into medial prefrontal cortex. Baclofen minimally affected glutamate levels in the medial prefrontal cortex, nucleus accumbens or ventral tegmental area of control animals, but dose-dependently increased glutamate levels in each of these regions in animals sensitized to cocaine. This effect was not the result of changes in GABAB receptor-mediated modulation of dopamine or GABA in the medial prefrontal cortex. The data suggest that alterations in GABAB receptor modulation of medial prefrontal cortical excitatory output may play an important role in the development of sensitization to cocaine.     

Resolution of tethered antiparallel and parallel holliday junctions by the Flp site-specific recombinase

Members of the integrase family site-specific recombinases (also called the tyrosine family) bring about recombination in two steps by exchanging pairs of single strands at a time. The product of the first exchange reaction is a four-way DNA junction, the Holliday intermediate. The conformational dynamics by which the recombination complex "isomerizes" from the Holliday-forming to the Holliday-resolving mode are not well understood. Experiments with the lambda Int and Escherichia coli XerC/XerD systems imply that the strand configurations at the branch point of the protein-free junction dictate the resolution mode in the protein-bound junction. We have examined the question of strand bias during resolution for the Flp system by using a series of synthetic Holliday junctions that are conformationally constrained by local sequences or by strand tethering. We have not observed a strong resolution bias in favor of the strands designed to assume the "crossed" configuration within the unbound junction. The resolution patterns with antiparallel junctions in a variety of substrate contexts reveal either parity in strand choice, or only modest disparity. On the other hand, the highly biased resolutions observed in the case of tethered parallel junctions can be explained by the non-equivalence in protein occupancy of the DNA arms of these substrates and/or inefficient conversion of cleavage events to recombinants at the tethered ends.     

Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2'-MeAD (1) and T-3'-MeAD (2) containing, respectively, a methyl group at the ribose 2'-C-, and 3'-C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2'-C-methyl- or 3'-C-methyl-adenosine 5'-monophosphate with 2',3'-O-isopropylidene-tiazofurin 5'-monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2'-MeAD and T-3'-MeAD was noncompetitive with respect to NAD substrate. Binding of T-3'-MeAD was comparable to that of parent compound TAD, while T-2'-MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2'-MeAD and T-3'-MeAD were found to inhibit the growth of K562 cells (IC(50) 30.7 and 65.0muM, respectively).     

A molecular dynamics study based post facto free energy analysis of the binding of bovine angiogenin with UMP and CMP ligands

Angiogenin is a protein belonging to the superfamily of RNase A. The RNase activity of this protein is essential for its angiogenic activity. Although members of the RNase A family carry out RNase activity, they differ markedly in their strength and specificity. In this paper, we address the problem of higher specificity of angiogenin towards cytosine against uracil in the first base binding position. We have carried out extensive nano-second level molecular dynamics(MD) computer simulations on the native bovine angiogenin and on the CMP and UMP complexes of this protein in aqueous medium with explicit molecular solvent. The structures thus generated were subjected to a rigorous free energy component analysis to arrive at a plausible molecular thermodynamic explanation for the substrate specificity of angiogenin.     

Cytologic appearances in invasive lobular carcinoma of the breast. A study of 21 cases

OBJECTIVE: To examine the fine needle aspiration cytologic features of invasive lobular carcinoma of breast and to discuss problems that may occur in cytodiagnosis. STUDY DESIGN: Fine needle aspiration cytologic smears from 21 cases of invasive lobular carcinoma (ILC) of breast were subjected to detailed cytomorphologic analysis. Features studied included pattern of cells, size of cells, nuclear placement, pleomorphism, presence of intracytoplasmic lumina (ICL) and signet ring cells. RESULTS: Cellularity was generally moderate or high, and the pattern was predominantly or partly dissociated in 86% of cases. Rosettelike pattern was discerned in alveolar-type ILC. Cell size was usually small or intermediate, with nuclei placed eccentrically in most cases. ICLs with or without signet ring cells were present in 12 cases (57%). CONCLUSION: A cytologic picture consisting of predominantly dissociated small or intermediate-sized tumor cells with eccentric nuclei, with some of the cells showing ICLs, is highly suggestive of ILC. Indian file pattern, another characteristic feature of ILC, is, however, focal and inconsistent. Variant patterns of ILC may show other cytologic features, such as rosettelike pattern (alveolar variant of ILC) or large cell pattern (pleomorphic variant of ILC) and may consequently be difficult to categorize on cytologic smears.     

Fine needle aspiration cytology of lymph nodes in HIV-infected individuals

OBJECTIVE: To assess the role of fine needle aspiration cytology (FNAC) in lymphadenopathy in human immunodeficiency virus-infected individuals (HIVII). STUDY DESIGN: Thirty-nine HIVII presenting with lymphadenopathy at University Hospital, Kuala Lumpur, were subjected to FNAC. Cytologic smears were routinely stained with May-Grünwald-Giemsa stain. Special stains and immunostains were used when necessary. RESULTS: In nine cases, the cytologic appearance was compatible with HIV type A and in one case with HIV type C lymphadenopathy. In 21 cases, acid-fast bacilli (AFB) were demonstrated in the cytologic smears, enabling a diagnosis of mycobacterial lymphadenitis. In one of these cases there was a concomitant infection with Penicillium marneffei that was overlooked on initial cytologic examination. The cause of granulomatous lymphadenitis could not be ascertained in one case, where neither AFB nor any other organisms were demonstrable. Two cases of histoplasma and one of cryptococcal lymphadenitis were diagnosed, as was one high grade non-Hodgkin's lymphoma that could be immunophenotyped on cytologic material. In three cases the aspirates were inadequate for a cytologic diagnosis. CONCLUSION: Lymph node FNAC is a valuable investigative modality in HIVII. Most opportunistic infections (bacterial and fungal) can be correctly identified, and high grade lymphoma can be diagnosed and phenotyped.     

Gust J, a salt-insensitive mutant ofDrosophila melanogaster

A set of 340 P insert lines on the X chromosome and the autosomes were screened for altered responses of the labellar chemoreceptors to salts and sucrose. A mutant linegustJ was isolated in which the electrophysiological response of the salt-sensitive neuron to Na⁺ in the sensilla of the proboscis is reduced. The responses to KC1 and sucrose are unaffected. In feeding tests,gustJ flies have Na⁺-specific defects. Heterozygotes ofgustJ with two other salt mutantsgustE andBE1323 are normal. Multiple alleles ofgustJ have been obtained by excision of the original P element. All mutants have defects in Na⁺ sensing specifically, thus defining a new gene that affects Na⁺ response of the fly.     

Cytology of hemangioendothelioma

The cytologic appearance is described of hemangioendothelioma in fine needle aspiration smears from a young male who presented with recurring bilateral lesions within two years. The cytomorphologic pattern was extremely cellular, with a monomorphic population of cells, some of which showed a tendency to form rosettelike or pseudoacinar formations.     

Aqueous Hydration of Nucleic Acid Constituents: Monte Carlo Computer Simulation Studies

Abstract

Monte Carlo computer simulations were performed on dilute aqueous solutions of thymine, cytosine, uracil, adenine, guanine, the dimethyl phosphate anion in the gauche-gauche conformation and a ribose and deoxyribose derivative. The aqueous hydration of each molecule was analysed in terms of quasi-component distribution functions based on the Proximity Criterion, and partitioned into hydrophobic, hydrophilic and ionic contributions. Color stereo views of selected hydration complexes are also presented. A preliminary discussion of the transferability of functional group coordination numbers is given. The results enable to comment on two current problems related to the hydration of nucleic acids: a) the theory of Dickerson and coworkers on the role of water in the relative stability of the A and B forms of DNA and b) the idea of water bridges and filaments emerging from the computer simulation results on the hydration of DNA fragments by Clementi.