Search

An axion insulator is a correlated topological phase, which is predicted to arise from the formation of a charge-density wave in a Weyl semimetal1,2—that is, a material in which electrons behave as massless chiral fermions. The accompanying sliding mode in the charge-density-wave phase—the phason—is an axion3,4and is expected to cause anomalous magnetoelectric transport effects. However, this axionic charge-density wave has not yet been experimentally detected. Here we report the observation of a large positive contribution to the magnetoconductance in the sliding mode of the charge-density-wave Weyl semimetal (TaSe4)2I for collinear electric and magnetic fields. The positive contribution to the magnetoconductance originates from the anomalous axionic contribution of the chiral anomaly to the phason current, and is locked to the parallel alignment of the electric and magnetic fields. By rotating the magnetic field, we show that the angular dependence of the magnetoconductance is consistent with the anomalous transport of an axionic charge-density wave. Our results show that it is possible to find experimental evidence for axions in strongly correlated topological condensed matter systems, which have so far been elusive in any other context.

Abstract Study objective--To examine whether changes in environmental housing quality influence the wellbeing of movers taking into account other dimensions of housing quality and sociodemographic factors. Design--Cross sectional telephone survey. [...]

Neurodegeneration is now accepted as a pathologic hallmark of multiple sclerosis (MS). We sought to discover whether CSF levels of neurofilament heavy chain protein (NfHSMI35) correlate with disability, disease activity, or specific stages of MS.

Cu/Ge0.3Se0.7/Pt cells were prepared and bipolar resistive switching in Ge0.3Se0.7films by means of copper ion migration was examined. The cell was switched from the high to the low resistance state at about -50mV, and it was switched back to the high resistance state at about 100mV. The resistance ratio between the high and the low state was up to 200. Up to approximately 104switching cycles were achieved. Pulse measurements showed that the two resistance states were tuneable by varying the applied voltage and the pulse length. Therefore, it is possible to store more than one bit per cell. The current density is independent of the electrode diameter, indicating that the cell can be scaled down to the range of nanometers. Due to the low switching voltages, non-destructive read out operation, high storage density, and scalability, such cells are promising for future memory applications.

Assessment of drug‐induced venodilation by the dorsal hand vein compliance method requires stable constriction of the vein. This study was designed to investigate intra‐ and intersubject reproducibility of the venous preconstriction technique in response to phenylephrine and prostaglandin F2αand to determine the influence of basal vein size. Twelve healthy male nonsmokers participated in a prospective crossover study. Inter‐ and intrasubject variability was tested in response to phenylephrine and PGF2αon different study days in the same hand vein. The dose of the respective constrictor causing approximately 80% constriction of the vein (ED80) was determined and infused for another 100 minutes. Actual vein size was measured every 5 minutes. Coefficient of variation and regression analyses were performed to analyze influence of vessel size on ED80of the respective constrictor. Adjusted constriction levels were stable and well reproducible in all subjects. The intersubject coefficient of variation of ED80ranged from 0.9% to 6.7% for phenylephrine and from 0.9% to 6.9% for PGF2α. Whereas responses to phenylephrine were independent of basal vein diameter, there was a positive correlation between ED80of PGF2αand basal vein size. Thus, the hand vein compliance method is a suitable method to study dilatory responses in phenylephrine‐ or PGF2α‐constricted veins with considerable interindividual but small intraindividual variability. However, in such studies, phenylephrine appears to be a more reliable tool than PGF2α.

Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.

Between 1955 and 1963, millions of children and adults were exposed to SV40‐contaminated poliovirus vaccines. The oncogenic potential of this polyomavirus was revealed when intracerebral inoculation of SV40 into newborn hamsters resulted in the development of ependymomas and choroid plexus papillomas. Subsequently, SV40‐like sequences were repeatedly detected in human ependymomas with broadly ranging incidence rates of 7–90%. Most epidemiological studies, however, have not described an increased occurrence of ependymomas. To gain more data on this controversial issue, this study examined 62 archived ependymal tumours from 31 children and 31 adults who underwent surgery between 1990 and 1999. Only three (5%) of the tumours – including 24 classical, 20 anaplastic, and 12 myxopapillary ependymomas; one subependymoma; and five ependymoblastomas – revealed subgenomic SV40 sequences. None of the ependymomas in patients born between 1920 and 1960 demonstrated SV40‐like sequences. The positive tumours represent 7% of grade II and III ependymomas (two paediatric and one adult tumour). DNA sequencing of the PCR product revealed identical sequences of SV40 in the positive ependymal tumours. Compared with the results from other countries, this incidence rate is relatively low. Therefore, it seems likely that significant differences between individual countries exist regarding the prevalence of SV40‐positive ependymomas. These differences may reflect different degrees of exposure to SV40‐contaminated polio vaccine. Copyright © 2001 John Wiley & Sons, Ltd.

While evoked potentials are sensitive tools for diagnosing multiple sclerosis, little is known about their prognostic value and their role in determining the course of the disease. To validate the visual and motor evoked potentials (VEP and MEP) as measures for the course of multiple sclerosis, we examined prospectively 30 patients with relapsing-remitting or secondary progressive multiple sclerosis. The Expanded Disability Status Scale (EDSS), VEP and MEP were measured at entry and after 6, 12 and 24 months. The Spearman rank correlation was used for statistical analysis. Applying multiple regression in 15 randomized patients allowed derivation of a formula for predicting changes in EDSS score based on changes in MEP and VEP. Validation was done by comparing the predicted with the real changes in EDSS in the other 15 patients. The number of pathological VEP and MEP results correlated at all four measurement points with the EDSS (rho > or = 0.6, P < or = 0.01). When the latencies of VEP and MEP were combined using the sum of their Z scores, correlation with the EDSS was even more significant (rho > or = 0.6, P < 0.001). Changes over time of electrophysiological data and EDSS were also correlated (rho = 0.43, P < 0.05). Moreover, VEP and MEP at baseline correlated with the EDSS after 2 years (rho = 0.43,P = 0.03). Reliable prediction of the course of multiple sclerosis for individual patients is not possible from VEP and MEP data. However, we conclude that, for groups of patients with secondary progressive or relapsing-remitting multiple sclerosis the combined testing of VEP and MEP yields numerical data that allow objective estimation of the course and prognosis of the disease.

The influence of potassium (K) removal on dialysis efficiency as measured by urea elimination is not clear. In this prospective, randomized, cross-over study we investigated the magnitude of K removal and its effect on urea (u) elimination during high-flux haemodialysis (HD).

Butyrylcholinesterase (BChE) is known to metabolize cocaine in humans. In the present study, three different experiments were performed to determine whether the addition of horse serum-derived BChE would accelerate the metabolism of cocaine. In the first experiment, the addition of BChE to squirrel monkey plasma in vitro reduced the half-life of cocaine by over 80%, decreased the production of the metabolic product benzoylecgonine, and increased ecgonine methyl ester formation. The effect of BChE on cocaine metabolism was reversed by a specific BChE inhibitor. In the second, in vivo, experiment, exogenously administered BChE reduced peak cocaine concentrations when given to anesthetized squirrel monkeys. Finally, incubation of cocaine with added BChE in human plasma in vitro resulted in a decrease in cocaine half-life similar to that observed with squirrel monkey plasma. The magnitude of the decrease in cocaine half-life was proportional to the amount of added BChE. Together, these results indicate that exogenously administered BChE can accelerate cocaine metabolism in such a way as to potentially lessen the behavioral and toxic effects of cocaine. Therefore, BChE may be useful as a treatment for cocaine addiction and toxicity.

In glioblastoma-derived cell lines, PTEN does not significantly alter apoptotic sensitivity or cause complete inhibition of DNA synthesis. However, in these cell lines PTEN regulates hypoxia- and IGF-1-induced angiogenic gene expression by regulating Akt activation of HIF-1 activity. Restoration of wild-type PTEN to glioblastoma cell lines lacking functional PTEN ablates hypoxia and IGF-1 induction of HIF-1-regulated genes. In addition, Akt activation leads to HIF-1alpha stabilization, whereas PTEN attenuates hypoxia-mediated HIF-1alpha stabilization. We propose that loss of PTEN during malignant progression contributes to tumor expansion through the deregulation of Akt activity and HIF-1-regulated gene expression.

The interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-α/β)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-γ) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-γ stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-α/β and -γ, can commonly elicit antiviral activities.

Abstract.: Characterization of the ability of interferons to induce immediate early genes led to the identification of the signal transducer and activators of transcription (STAT) signaling paradigm, where a single protein transduces signals directly from the receptor to the nucleus. Subsequent studies have determined that all cytokines transduce pivotal signals through at least one of the seven members of this STAT family. Notably, cytokines can be placed in functional subgroups based on the STATs they activate.

Characterization of the ability of human interferons (IFNs) to rapidly induce genes led to the identification of the first two members of the STAT (signal transducers and activators of transcription) family, Stat1 and Stat2. To study the unique role of this transcription factor in IFN signaling under more physiological conditions, murine Stat2 was isolated and found to be surprisingly divergent. This divergence was most striking in the C-terminal transcriptional activation domain. Studies on murine Stat2 indicate that it functions in IFN signaling. This includes IFN-alpha-dependent activation, nuclear translocation, DNA binding and activation of reporter genes. However, the profound divergence at the C-terminus suggests that murine Stat2 may have evolved to mediate some unique functions as well. To explore this possibility, proteins that interact with the C-termini of murine and human Stat2 were examined. These studies indicate that the murine and human C-termini interact with an overlapping, but distinct set of proteins.

Immature myeloid cells have been shown to transduce signals through a carboxyl-terminally truncated isoform of Stat5. This functionally distinct signal transducer and activator of transcription isoform is generated through a unique protein-processing event. Evaluation of numerous cell lines has determined that there is a direct correlation between the expression of truncated Stat5 and protease activity. Moreover, protease activity is found only in the myeloid and not in lymphoid progenitors. To further characterize the protease small quantities have been purified to near homogeneity. Studies on this purified material indicate that the protease has an apparent molecular mass of approximately 25 kDa and is active over a wide range of pH values. The protease will also cleave both activated (i.e. tyrosine-phosphorylated) and inactivate Stat5. Although this activity is sensitive to phenylmethylsulfonyl fluoride, it is notably not sensitive to several other serine protease inhibitors. Additional studies have led to the identification of the unique site where the protease cleaves Stat5. Mutagenesis of this site renders Stat5 resistant to cleavage. Consistent with the model that Stat5 cleavage is important for early myeloid development, introduction of a "non-cleavable" isoform of Stat5 into FDC-P1 cells (a myeloid progenitor line) leads to significant phenotypic changes.

Background: Clinical and population studies have shown that exposure and sensitization to allergens derived from furred pets, particularly cats, represent an important risk factor of allergic respiratory disease and also a significant risk factor for asthma. Objective: In the framework of the multicenter European Community Respiratory Health Survey an analysis of the association of current and childhood exposure to cat with atopic sensitization to cat was conducted. Methods: This study included cross-sectional data from 35 centers representing 16 countries. Altogether, 18,097 subjects were included, of whom 13,509 (75%) provided a blood sample for the measurement of specific IgE. Exposure data and data for potential confounders were extracted from an interviewer-led questionnaire. Results: The prevalence of sensitization to cat (serum specific IgE >0.35 kU/L) was 9%. Among those who did not report allergic symptoms in the presence of pets or house dust, those who owned cats were significantly more likely to be sensitized to cats than were those who did not (odds ratio [95% confidence interval] 1.57 [1.20-2.06]. Childhood exposure to pets including cats was associated with lower sensitization to cats in adulthood, particularly among those with a positive family history of atopy (odds ratio [95% confidence interval] 0.68 [0.51-0.93]. Positive correlations were found between the community prevalence of cat and the prevalences of sensitization to cat, respiratory symptoms, physician-diagnosed asthma, and current asthma medication. Conclusions: Current cat ownership represents a significant risk for sensitization to cat if cats are allowed indoors. Our results support the hypothesis that childhood exposure to pets, including cats, might modulate immunologic mechanisms and reduce sensitization to cat in adulthood. The significant correlation found between the community prevalence of cat ownership and community prevalence of specific sensitization to cat represents the first documentation of such a relationship. (J Allergy Clin Immunol 1999;104:941-7.)

Analysis of the ability of IFN‐alpha to rapidly stimulate genes has led to the identification of a new family of signal transducing factors (STFs). The STF activated by IFN‐alpha consists of two members of the STAT (Signal Transducers and Activators of Transcription) family of signaling proteins, Stat1 and Stat2. Sequence comparison of these STATs has determined that they share several conserved domains, the most notable of which is an SH2 domain. Recently, studies have determined that these SH2 domains can mediate a specific association between a STAT and the cytoplasmic domain of the appropriate receptor. Once associated with the receptor, the STATs become activated by an associated tyrosine kinase, whereupon they dissociate from the receptor and dimerize to form active STFs. The SH2 domain has also been implicated in the formation of STAT dimers found in STFs, suggesting it may play multiple roles in signaling. We have carried out a detailed analysis on the role of the Stat1 and Stat2 SH2 domains in the mediation of IFN‐alpha stimulated signals. These studies, which have determined that the SH2 domain of Stat1 and Stat2 can mediate homo‐ as well as heterodimerization, suggest that a single SH2 domain‐phosphotyrosyl interaction is sufficient for dimerization. Moreover, they provide the first direct evidence that the target of the SH2 domain is the STAT tyrosine activation site. In addition, these studies implicate the SH2 domain in another step in the signaling cascade, namely mediation of the interaction between STATs and their activating kinases (i.e. the JAKs).

Interferon‐alpha (IFN alpha) induces rapid tyrosine phosphorylation of its receptors, two JAK kinases and three STAT transcription factors. One kinase, p135tyk2, is complexed with the IFNaR1 receptor, and may catalyze some of these phosphorylation events. We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH‐2‐dependent manner. Furthermore, only latent, non‐phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha‐dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2. These observations are consistent with a model in which IFNaR1 mediates the interaction between JAK kinases and the STAT transcription factors.

Mutants in complementation group U3, completely defective in the response of all genes tested to interferons (IFNs) alpha and gamma, do not express the 91 and 84 kDa polypeptide components of interferon‐stimulated gene factor 3 (ISGF3), a transcription factor known to play a primary role in the IFN‐alpha response pathway. The 91 and 84 kDa polypeptides are products of a single gene. They result from differential splicing and differ only in a 38 amino acid extension at the C‐terminus of the 91 kDa polypeptide. Complementation of U3 mutants with cDNA constructs expressing the 91 kDa product at levels comparable to those observed in induced wild‐type cells completely restored the response to both IFN‐alpha and ‐gamma and the ability to form ISGF3. Complementation with the 84 kDa component similarly restored the ability to form ISGF3 and, albeit to a lower level, the IFN‐alpha response of all genes tested so far. It failed, however, to restore the IFN‐gamma response of any gene analysed. The precise nature of the DNA motifs and combination of factors required for the transcriptional response of all genes inducible by IFN‐alpha and ‐gamma remains to be established. The results presented here, however, emphasize the apparent general requirement of the 91 kDa polypeptide in the primary transcriptional response to both types of IFN.

The interleukin (IL)‐3 family of cytokines mediates its numerous effects on myeloid growth and maturation by binding a family of related receptors. It has been shown recently that IL‐3 induces the activation of two distinct cytoplasmic signal transducing factors (STFs) that are likely to mediate the induction of immediate early genes. In immature myeloid cells, IL‐3 activates STF‐IL‐3a, which comprises two tyrosine‐phosphorylated DNA binding proteins of 77 and 80 kDa. In mature myeloid cells, IL‐3 and granulocyte‐macrophage colony‐stimulating factor activate STF‐IL‐3b, which consists of a 94 and 96 kDa tyrosine‐phosphorylated DNA binding protein. Peptide sequence data obtained from the purified 77 and 80 kDa proteins (p77 and p80) indicate that they are closely related but are encoded by distinct genes. Both peptide and nucleotide sequence data demonstrate that these two proteins are the murine homologs of ovine mammary gland factor (MGF)/Stat5. The peptide data also indicate that p77 and p80 are phosphorylated on tyrosine 699, a position analogous to the tyrosine that is phosphorylated in Stat1 and Stat2 in response to interferon. Additionally, antiserum raised against bacterially expressed p77/p80 recognizes the 94 and 96 kDa protein components of STF‐IL‐3b, suggesting that these may be additional isoforms of Stat5. These studies indicate that the IL‐3 family of ligands is able to activate multiple isoforms of the signal transducing protein Stat5.

The mechanism by which interleukin‐4 (IL‐4) regulates the expression of particular genes is unknown. We have determined that IL‐4 induces a DNA binding factor (termed STF‐IL‐4) which has a strong affinity for an IFN‐gamma activation site (GAS). Interestingly, STF‐IL‐4 also binds to the IL‐4 responsive promoter for the Ig heavy chain germline epsilon transcript. The IL‐4 dependent activation of STF‐IL‐4 is rapid, does not require protein synthesis and results in the sequential appearance of binding activity first in the cytoplasm and then later in the nucleus. Activation of STF‐IL‐4 is sensitive to tyrosine kinase inhibitors and the active factor is tyrosine phosphorylated. This pattern of activation is similar to the activation of interferon‐induced transcription factors. STF‐IL‐4 appears to be a new member of a growing family of cytokine‐induced transcriptional regulators.

ISGF2 was initially identified, purified and cloned as an interferon‐alpha (IFN alpha) induced transcription factor that binds to the IFN‐stimulated response element (ISRE) of IFN alpha/beta‐stimulated genes (ISGs). It was reported to be transcriptionally regulated by several cytokines including IFN alpha and IFN gamma. IFN alpha and IFN gamma inducibility is mediated by a single element: a high affinity, nearly palindromic version of the IFN gamma activation site (GAS). The ISGF2 GAS is bound specifically by p91, which was previously identified as a subunit of the ISG activator ISGF3, and shown to mediate IFN gamma induction of the GBP gene via a GAS. Tyrosine phosphorylation and DNA binding activity of p91 parallel transcription of ISGF2 in response to IFN alpha and/or IFN gamma, consistent with induction mediated by only a GAS. Transcription of the genes that encode p91 and p113, another subunit of ISGF3, is activated only by IFN alpha. This result suggests induction mediated by an ISRE, and implies autoregulation, requiring the products of both genes. Specificity of the ISRE is the basis for the previous conclusion. In contrast, it appears likely that the ISGF2 GAS, and p91 or related factors, also mediate induction of ISGF2 by IL‐6 and prolactin. Convergence of signalling pathways from at least four cytokines on this single site would thus be a key aspect of a general role for ISGF2 in cellular growth control.

The effects of cocaine alone and in combination with the calcium channel blockers nimodipine, verapamil and diltiazem were determined for different groups of squirrel monkeys on cardiovascular function, schedule-controlled behavior and drug self-administration. Cocaine alone (0.3 mg/kg) produced increases in both blood pressure and heart rate. All three calcium channel blockers antagonized the pressor effect, but were ineffective against the tachycardiac effect of cocaine. Nimodipine was the most potent agent in antagonizing the pressor effect of cocaine. Response rates for monkeys responding on a second-order schedule of food presentation were increased by intermediate doses of cocaine (0.1-1.0 mg/kg) and were primarily decreased at a higher dose (3.0 mg/kg). Quarter-life values, an index of response patterning, were only decreased by cocaine. None of the calcium channel blockers altered cocaine's effects on either response rate or response patterning. In the self-administration experiments, the training dose of 56 micrograms/kg cocaine maintained high rates of responding on a simple fixed-ratio schedule. As with schedule-controlled behavior, none of the calcium channel blockers altered cocaine self-administration even when administered before self-administration sessions during 5 consecutive days. These results suggest that the calcium channel blockers may be useful in treating cardiovascular-related complications after cocaine use, but they would not be effective as long-term treatment agents for cocaine abuse.

A series of five experiments examined the effects of mu and kappa opioid agonists on acquisition of conditioned responses in the rabbit and the antagonism of their effects by naloxone. Extension of the nictitating membrane was classically conditioned to a tone stimulus presented before delivery of an electric shock unconditioned stimulus to the skin over the paraorbital region of the head. Morphine, ethylketocyclazocine and U-50,488H retarded the acquisition of conditioned responses to the tone conditioned stimulus with ethylketocyclazocine being twice as potent as the more specific kappa agonist U-50,488H, and 40 times more potent than the prototypic mu agonist morphine. Control experiments indicated that the retarded acquisition produced by the three opioids was due to an action on associative learning. Doses of 0.1 and 1.0 mg/kg of naloxone alone did not affect acquisition of conditioned responses, but did significantly antagonize the retardant effects of all three opioid agonists. On the basis of the parallelism of the dose-effect curves for the three opioid agonists, their order of potency which was remarkably different from potency ratios observed for other measures, e.g. analgesia, and on the finding that all three opioids demonstrated approximately equivalent sensitivity to antagonism by naloxone, it was concluded that the effects of all three opioid agonists on the acquisition of conditioned responses may be mediated by a common receptor.

It is shown that the cone of positive normal functionals on a hypergraphA may be substantially larger than the cone of positive weights onA. For a semiclassical hypergraphA the two cones coincide if and only if the number of edges ofA of cardinality =2 is finite. This disproves an earlier statement of T. A. Cook.

Transcription of tissue-specific genes in mammary gland requires signals from both prolactin and basement membrane. Here we address the mechanism by which this specialized extracellular matrix regulates transcription. Using mammary cell cultures derived from transgenic mice harboring the ovine beta-lactoglobulin gene, we show that either a basement membrane extract, or purified laminin-1, induced high levels of beta-lactoglobulin synthesis. It is known that prolactin signals through Stat5 (signal transducer and activator of transcription). This transcription factor interacts with gamma-interferon activation site-related motifs within the beta-lactoglobulin promoter, which we show are required for matrix dependence of beta-lactoglobulin expression. The DNA binding activity of Stat5 was present only in extracts of mammary cells cultured on basement membrane, indicating that the activation state of Stat5 is regulated by the type of substratum the cell encounters. Thus, basement membrane controls transcription of milk protein genes through the Stat5-mediated prolactin signaling pathway, providing a molecular explanation for previous studies implicating extracellular matrix in the control of mammary differentiation.

Presenting independently established discriminative stimuli in compound can substantially increase response rates under food and shock-avoidance schedules. To determine whether this effect extends to drug self-administration, rats were trained to press a lever to receive cocaine intravenously. A tone and a light were independently established as discriminative stimuli for cocaine self-administration, then presented in combination in a stimulus-compounding test. Compared to tone and light alone, the tone-plus-light compound stimulus increased responding approximately three-fold when cocaine was withheld during testing, and it increased drug intake approximately two-fold when cocaine was made available during testing. Compounding did not increase responding after training in a truly random control condition where tone and light were presented uncorrelated with the availability of cocaine. The results obtained with this animal model of drug abuse define conditions under which combinations of environmental stimuli might substantially increase human drug use.

Rats treated weekly with cumulative doses (1–100 mg/kg, IP) of naltrexone develop an enhanced sensitivity to the operant response-rate decreasing effect of naltrexone. In the present experiment the pharmacological specificity of that enhanced sensitivity was determined by testing a variety of drugs for cross-sensitivity to naltrexone. Cross-sensitivity was evaluated with two procedures. In one, dose-effect functions were determined for each of the test compounds before and after the development of enhanced sensitivity to naltrexone in a single group of rats. In the second procedure, one group of rats was made sensitive to naltrexone, while a second was not. Test compounds were then evaluated in both groups. For both procedures, a shift to the left in the dose-effect functions similar to naltrexone was considered evidence of cross-sensitivity. Of the opioid antagonists tested, only naloxone showed clear cross-sensitivity to naltrexone, although MR 2266 and diprenorphine also showed evidence of cross-sensitivity. The opioid antagonist quadazocine did not show cross-sensitivity to naltrexone on the day of testing, although some evidence of cross-sensitivity was evident 24 h later. In addition, the dose-effect function ford-amphetamine was significantly changed following naltrexone treatment. No evidence of cross-sensitivity was observed for the optical isomer of naloxone,d-naloxone, or for naloxone's quaternary derivative, naloxone methiodide. None of the opioid agonists or agonist-antagonists tested showed cross-sensitivity to naltrexone (i.e. morphine, U-50, 488H, ethylketocyclazocine,N-allylnormetazocine and pentazocine). The non-opioid drugs chlordiazepoxide and phencyclidine also failed to show evidence of cross-sensitivity. However, the dose-effect curves for chlordiazepoxide were shifted significantly to the right following naltrexone treatment. The results of the present experiment indicate that the enhanced sensitivity which develops to naltrexone in rats is stereospecific and centrally mediated. The effect is specific, in that it does not appear to confer changes in the behavioral effects of non-opioids or even opioid agonists.

Male food-restricted hooded rats were trained to respond on a two-component multiple schedule. Reinforcement density was several times higher in one component than in the other. However, responses were intermittently punished with shock in the richer reinforcement component (conflict situation). Shock intensities were adjusted to produce mild and strong suppression of responding in two separate phases. Half of the rats controlled which component was operating (Preference group) and half did not (Yoked group). The effect of chlordiazepoxide (CDZ; 0, 1, 3, and 10 mg/kg; IP) was measured on component preference and response rate. Chlordiazepoxide increased both time spent in the conflict situation and response rate in that component. This is the first study employing a schedule that permitted these two behavioral indices to be measured independently in a conflict paradigm. Response rates were also increased in the unpunished response alternative, but to a lesser degree than in the conflict situation. The effects of CDZ were at least partially mediated by the benzodiazepine receptor because CDZ's effects were diminished by flumanezil (10 mg/kg; IP), a benzodiazepine antagonist.

Locomotor activity was studied in the rabbit following injections of morphine, ethylketocyclazocine andN-allylnormetazocine. All three drugs produced only depression of activity. The opioid antagonist naloxone antagonized the effects of both morphine and ethylketocyclazocine. Naloxone (0.1 mg/kg) did not antagonize the effects ofN-allylnormetazocine. Naloxone alone depressed locomotor activity at doses above 0.3 mg/kg. This effect of naloxone was partially antagonized by 0.1 mg/kg ethylketocyclazocine, but not by 0.1 mg/kg morphine. The GABA agonist muscimol (0.1 and 1.0 mg/kg) also did not antagonize the effect of naloxone on locomotor activity. Finally, amphetamine did not produce a great deal of locomotor activation in the rabbit, which may indicate that increasing activity in the rabbit by drug intervention may be inherently difficult. These results indicate that the opioids have effects in the rabbit that are clearly different from those observed in rodents, where morphine andN-allylnormetazocine have been reported to produce locomotor activation, and naloxone typically has little effect. In addition, the effects of the opioids on locomotor activity were clearly distinguishable from their effects on learning in the rabbit. While morphine and ethylketocyclazocine were approximately equipotent in depressing locomotor activity, morphine is much less potent than ethylketocyclazocine in retarding acquisition of the classically conditioned nictitating membrane response in the rabbit.

Hemodynamic and cardiac-electrophysiologic effects of cocaine and its metabolites were measured in 18 groups (n = 6 each) of anesthetized, artificially ventilated rats during continuous intravenous (i.v.) infusions at three different doses (0.15, 0.45, and 1.5 mg/kg/min). At the highest dose, cocaine decreased blood pressure (BP) and heart rate (HR), while QRS duration, an index of cocaine's local anesthetic effect, was increased. Cocaethylene, a metabolite produced after coadministration of cocaine and ethanol, had effects comparable to those of cocaine. The cocaine metabolite norcocaine produced a decrease in BP at the lower dose that reversed to a small increase at the higher dose. The highest dose of norcocaine clearly decreased HR and increased QRS duration. The increases in QRS duration observed for cocaine, co-caethylene, and norcocaine were reversed by sodium bicarbonate. The cocaine metabolites benzoylecgonine and ecgonine methyl ester increased BP at the higher doses without affecting either HR or QRS duration. These results suggest that the spectrum of effects produced by cocaine are not necessarily mimicked by its metabolites. In particular, accumulation of the persistent, active metabolites benzoylecgonine and ecgonine methyl ester may contribute to delayed-onset, cocaine-related toxicity.

The abscission zone in tomato (Lycopersicon esculentum (L.) Mill. flower pedicels is morphologically distinguishable prior to separation and is delineated by an indentation of the epidermis. Exposure of excised pedicels with the flower attached to ethylene results in abscission within 12 h and this can be accelerated by flower removal. Abscission of excised pedicels with the flower removed takes place in the absence of exogenous ethylene but this is delayed by pretreatment with aminoethoxyvinyl glycine, an inhibitor of ethylene biosynthesis. The data presented support the hypothesis that flower tissue is the source of an abscission inhibitor.