Optical creation of a supercrystal with three-dimensional nanoscale periodicity.

Stimulation with ultrafast light pulses can realize and manipulate states of matter with emergent structural, electronic and magnetic phenomena. However, these non-equilibrium phases are often transient and the challenge is to stabilize them as persistent states. Here, we show that atomic-scale PbTiO3/SrTiO3 superlattices, counterpoising strain and polarization states in alternate layers, are converted by sub-picosecond optical pulses to a supercrystal phase. This phase persists indefinitely under ambient conditions, has not been created via equilibrium routes, and can be erased by heating. X-ray scattering and microscopy show this unusual phase consists of a coherent three-dimensional structure with polar, strain and charge-ordering periodicities of up to 30 nm. By adjusting only dielectric properties, the phase-field model describes this emergent phase as a photo-induced charge-stabilized supercrystal formed from a two-phase equilibrium state. Our results demonstrate opportunities for light-activated pathways to thermally inaccessible and emergent metastable states.

2H-[1]benzopyrano[3,4-b]pyridines: synthesis and activity at central monoamine receptors.

Two general synthetic approaches to a novel series of 2H-[1]benzopyrano[3,4-b]pyridines are described together with their receptor binding profile at a variety of monoamine receptors in mammalian brain tissue. The biologically active members of this series fall into into one of two broad classes: 3,4,4a,5-tetrahydro-2H-[1]benzopyrano[3,4-b]pyridines or trans-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[3,4-b]pyridines. By appropriate pharmacophoric modification potent selective ligands for D2, alpha-2, 5HT1A, and 5HT2 receptors may be obtained. The previously published in vivo data on certain key representatives of these series are also summarized.

2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands.

The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.

HLA-DR expression in macaque neuroendothelial cells in vitro and during SIV encephalitis.

HLA-DR expression in neuroendothelial cells (NEC) was studied during the course of SIV encephalitis in rhesus monkeys. HLA-DR determinants were detected on NEC in monkeys with SIV encephalitis, but not in control animals. In situ hybridization with an SIV probe indicated that HLA-DR expression was not a consequence of SIV replication within NEC. Cultured rhesus NEC stimulated with gamma interferon expressed HLA-DR to a higher degree than cultured brain fibroblasts or astrocytes. These data support the contention that NEC participate in retrovirus-induced inflammation and autoimmunity within the central nervous system.

Long-term observations of human immunodeficiency virus-infected chimpanzees.

Twenty-seven chimpanzees inoculated with material presumed to contain human immunodeficiency virus (HIV) between June 1983 and February 1985 were studied. The animals were examined on four to six occasions between 1989 and 1992 for serologic, virologic, hematologic, immunophenotypic, as well as clinical signs of HIV infection and compared to five uninfected control animals. The 19 animals that had seroconverted within 244 days of inoculation remained antibody positive, whereas those that did not seroconvert within 244 days of inoculation remained antibody negative 6 to 8 years later. HIV antigen was demonstrated at least once in lymphocyte cultures from 12 of the 19 antibody positive chimpanzees during this period. Nested polymerase chain reaction amplified proviral DNA in lymphocytes from 14 of the 19 animals. No proviral DNA was detected in antibody-negative animals. Antibody titers were generally higher in animals from which virus was recovered in lymphocyte cultures [granulocyte-macrophage (GM) titer, 1:8427] compared to virus-negative animals (GM titer, 1:3608). Mean total white blood cell and lymphocyte subtype counts were similar in the HIV-infected animals and uninfected controls. The high antibody levels and Western blot profiles, over periods as long as 9 years in these chimpanzees, suggest continuous stimulation of the immune system by HIV antigen although virus was detected only sporadically in the peripheral blood. No illness suggestive of immunodeficiency was seen.

Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist.

CGS 12066B is a novel pyrroloquinoxaline with selectivity for the serotonin-1B (5HT1B) recognition site as assessed by binding, biochemical and electrophysiological studies. The compound had an IC50 value of 51 nM at the 5HT1B recognition site as determined using the binding of [3H]5HT in the presence of 1 microM spiperone. At the 5HT1A receptor the compound had an IC50 value of 876 nM, providing a 5HT1A/5HT1B ratio of 17 in contrast to the putative 5HT1B selective agent trifluoromethylphenylpiperazine (TFMPP) which had a corresponding ratio of 3.6. The compound had minimal affinity for alpha 1-, alpha 2- and beta-adrenoceptors and for dopamine D-1 and D-2 receptors. CGS 12066B, in contrast to TFMPP, which was inactive, was found to inhibit dorsal raphe cell firing with an ED50 value of 358 nmol/kg i.v. The corresponding values for the 5HT1A selective agonists 8-OH-DPAT and ipsapirone were 1.3 and 33 nmol/kg. CGS 12066B was also effective in decreasing rat brain 5-HTP concentrations and inhibiting in vitro 5HT release. The data obtained indicate that CGS 12066B is a reasonably active 5HT1B site agonist, which due to its selectivity as compared to compounds such as TFMPP, will be a useful tool for evaluating the physiological role of such receptors in the mammalian CNS.

Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain.

In thin sections of rat brain, [3H]spiperone binds to D2 sites in the basal ganglia (caudate-putamen, nucleus accumbens, olfactory tubercle) and S2 sites in the claustrum and motor cortex. The in vitro displacement of [3H]spiperone from these regions was quantified autoradiographically with the "atypical" neuroleptics clozapine and thioridazine, which ameliorate psychosis, a "typical" neuroleptic, haloperidol, which also induces extrapyramidal side effects, or with metoclopramide, which induces extrapyramidal side effects but is an ineffective antipsychotic. Whereas metoclopramide was equipotent at D2 sites, haloperidol was less potent and clozapine and thioridazine more potent by 2- to 3-fold at competing for D2 sites in the nucleus accumbens or olfactory tubercle than in the caudate-putamen. As measured autoradiographically or with tissue homogenates, clozapine, thioridazine, and five other atypical neuroleptics were 4- to 800-times more potent at competing for S2 sites in the frontal cortex than for D2 sites in the basal ganglia. A preference of atypical antipsychotics for D2 receptors in the nucleus accumbens and olfactory tubercle and for the S2 receptor may explain the relative lack of extrapyramidal side effects produced by these compounds.

CGS 9343B, a novel, potent, and selective inhibitor of calmodulin activity.

1,3-Dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]- benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-o ne (1:1) maleate was synthesized in six steps from methyl anthranilate and designated CGS 9343B. CGS 9343B inhibited calmodulin-stimulated cAMP phosphodiesterase activity with an IC50 value of 3.3 microM. CGS 9343B was 3.8 times more potent than trifluoperazine (IC50 = 12.7 microM) as an inhibitor of calmodulin activity. CGS 9343B did not inhibit protein kinase C activity at concentrations up to 100 microM, whereas trifluoperazine inhibited protein kinase C activity with an IC50 value of 43.9 microM. CGS 9343B weakly displaced [3H]spiperone from postsynaptic dopamine receptors with an IC50 value of 4.8 microM while the value for trifluoperazine, a potent antipsychotic agent, was 0.018 microM. It is concluded that CGS 9343B is a novel, potent, and selective inhibitor of calmodulin activity. Unlike trifluoperazine, CGS 9343B does not inhibit protein kinase C activity and does not possess potential antidopaminergic activity.

Immunophenotyping of peripheral blood, ranges of serum chemistries and clinical hematology values of healthy chimpanzees (Pan troglodytes).

This paper presents clinical chemistry, hematology and immunophenotyping data from 102 chimpanzees over a 2-year period. The groupings were: 3 years or less, 4-7 years, and 8 + years. These data are intended to augment formerly published information on these parameters and to serve as a concise reference guide for primate veterinarians and researchers for whom these data may be useful. This study has larger samplings than previously published data and more panel constituents by immunophenotyping.

Transmission of human T-cell leukemia virus type I from a patient with HTLV-I associated myelopathy/tropical spastic paraparesis and an asymptomatic carrier to rabbits.

Rabbits were infected successfully with two strains of human T-cell leukemia virus type I (HTLV-I), one isolated from a Colombian patient with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and the other from an asymptomatic carrier. HTLV-I was repeatedly demonstrated in peripheral blood mononuclear cells (PBMNC) of infected rabbits, and the rabbits had elevated antibodies against the various structural proteins of HTLV-I. Four rabbits inoculated with HTLV-I-infected autologous lymphoid cells intravenously (i.v.) and intracerebrally (i.c.) had virus present in their PBMNC for more than 40 weeks, while those that were inoculated either with HTLV-I-infected human lymphoid cells or with autologous rabbit lymphoid cells intraperitoneally (i.p.) had episodes during which virus was not recovered from their PBMNC. The one rabbit inoculated i.p. developed antibodies to viral envelope glycoproteins earlier than did those inoculated i.v. and i.c. Rabbit lymphoid cell lines persistently infected with HTLV-I were established by cocultivating the rabbit PBMNC with HTLV-I-infected human lymphoid cells that had been irradiated or by inoculation with cell-free supernatant fluids of HTLV-I infected non-irradiated lymphoid cell cultures. HTLV-I-infected rabbit cell lines were of T-cell origin and expressed HTLV-I antigens by immunofluorescence. Electron microscopy revealed type-C retrovirus particles.

Biochemical characterization of the triazoloquinazoline, CGS 15943, a novel, non-xanthine adenosine antagonist.

CGS 15943A, a triazoloquinazoline, is a potent and selective adenosine receptor antagonist as assessed by its effects on radioligand binding and adenosine-stimulated adenylate cyclase activity in guinea pig synaptoneurosomes. At the adenosine A-1 receptor labeled with [3H]cyclohexyladenosine, CGS 15943A had an IC50 value of 20 nM. At the striatal A-2 receptor labeled with [3H]5'-N-ethylcarboxamidoadenosine in the presence of a low concentration of cyclopentyladenosine to block A-1 receptors labeled by this nonselective adenosine agonist, CGS 15943A had an IC50 value of 3 nM, indicating that the compound had some degree of selectivity for the A-2 receptor. Analysis of the effect of the compound on the saturation isotherms for each of the receptors indicated that it was a competitive antagonist at the brain A-1 receptor but that it was noncompetitive at the striatal A-2 receptor. CGS 15943A was a potent adenosine antagonist in the adenosine-stimulated adenylate cyclase system in guinea pig synaptoneurosomes, where the compound was found to have an IC50 value of 30 to 70 nM against the increase in cyclic AMP evoked by 5 microM adenosine. CGS 15943A had no effect on the binding of [3H]nitrobenzylthioinosine, a ligand thought to bind to adenosine uptake sites, and, at a concentration of 10 microM, had no effect on beef heart type III phosphodiesterase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between binding affinities for brain A1 and A2 receptors of adenosine agonists and antagonists and their effects on heart rate and coronary vascular tone.

The activities of a series of A1 and A2 adenosine receptor agonists and antagonists were determined using radioligand binding techniques in rat brain tissues. The potencies of these agonists on heart rate and coronary vascular tone were also assessed in the perfused working rat heart preparation. The order of potency of these agonists in producing negative chronotropic effects was similar to the rank order for their A1 receptor binding activities [6-N-cyclohexyladenosine (CHA) = 6-N-(R-phenylisopropyl)-adenosine greater than 5'-N-ethylcarboxamideadenosine (NECA) = 2-chloroadenosine greater than 2-phenylaminoadenosine] with a correlation coefficient of 0.97. Their order of potency in reducing coronary vascular tone followed the same rank order as their A2 receptor binding activities with a correlation coefficient of 0.97 (NECA greater than 2-chloroadenosine = 6-N-(R-phenylisopropyl)-adenosine = 2-phenylaminoadenosine greater than CHA). In addition, the antagonists 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]ox]phenyl-1,3- dipropylxanthine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) and 8-phenyltheophylline (8-PT) blocked the negative chronotropic effect of CHA and the vasodilatory effect of NECA in a concentration-dependent manner. The same order of potency of the antagonists was noted in blocking CHA-induced bradycardia and A1 receptor binding activities (XAC = PACPX greater than 8-PT). A similar correlation was observed for their effects in blocking NECA-induced vasodilation and A2 receptor binding activity (XAC greater than PACPX greater than 8-PT).(ABSTRACT TRUNCATED AT 250 WORDS)

Retroviruses and schizophrenia in Jamaica.

Reports of an 18-fold higher incidence of schizophrenia among second-generation Afro-Caribbeans, and especially Jamaican migrants in the United Kingdom were soon called "an epidemic of schizophrenia," with the inference that a novel virus, likely to be perinatally transmitted, was a possible etiological agent. This intriguing observation led us to explore a possible link with human T-cell lymphotropic virus type one (HTLV-I), because it is a virus that is endemic in the Caribbean Island, is perinatally transmitted, known to be neuropathogenic, and the cause of a chronic myelopathy (tropical spastic paraparesis/HTLV-I associated myelopathy. We therefore examined inpatients as the Bellevue Mental Hospital, Kingston, Jamaica and did standard serological tests for retroviruses HTLV-I and HTLV-II and HIV-I and HIV-II on 201 inpatients who fulfilled ICD-9 and DSM III-R criteria for schizophrenia. Our results produced important negative data, since the seropositivity rates for HTLV-I, the most likely pathogen, were no greater than the seropositivity range for HTLV-I carriers in this island population, indicating the HTLV-1 and the other retroviruses tested do not play a primary etiological role in Jamaican schizophrenics.

Phylogenetic analysis of simian T-lymphotropic virus Type I (STLV-I) in common chimpanzees (Pan troglodytes): evidence for interspecies transmission of the virus between chimpanzees and humans in Central Africa.

Serum and peripheral blood leukocytes from the chimpanzees (Pan troglodytes) of the colony of the Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, NIH, were tested for the presence of STLV-I-specific antibodies and proviral DNA. Antibodies were determined by gelatin particle agglutination and Western blot (WB) assays utilizing HTLV-I antigens. Proviral DNA was detected by four PCR assays targeting three different regions of STLV-I genome: the fragments of the env and pol genes and LTR. Twenty of twenty-two DNA samples from WB-positive animals were PCR positive. None of the DNA samples from WB-negative (n = 5) and WB-indeterminate (n = 4) animals was PCR positive. The results of the nested and double nested env PCR tests were fully concordant; the seminested LTR PCR test was much less sensitive. The DNA sequences from the env (483 bp) and the pol (200 bp) genes and LTR (705 bp) were determined for six, two, and two chimpanzee STLV-I isolates, respectively. Phylogenetic analysis revealed that chimpanzee STLV-I isolates can be attributed to three clades. The first of these clades (SS-PTR1/CSA) included STLV-I isolates from the chimpanzees and West African subspecies of African green monkeys (Cercopithecus a. sabaeus). The other clades (S-PTR2 and S-PTR3) included STLV-I isolates only from chimpanzees. However, both S-PTR2 and S-PTR3 clustered together with Central African HTLV-I comprising the human/simian clade (HS-HSA/PTR). This pattern of phylogenetic clustering suggests that interspecies transmission of STLV-I occurred between chimpanzees and African green monkey subspecies as well between chimpanzees and human populations in Central Africa.