Analysis of the small chromosomal Prionium serratum (Cyperid) demonstrates the importance of reliable methods to differentiate between mono- and holocentricity.

For a long time, the Cyperid clade (Thurniceae-Juncaceae-Cyperaceae) was considered a group of species possessing holocentromeres exclusively. The basal phylogenetic position of Prionium serratum (Thunb.) Drège (Thurniceae) within Cyperids makes this species an important specimen to understand the centromere evolution within this clade. In contrast to the expectation, the chromosomal distribution of the centromere-specific histone H3 (CENH3), alpha-tubulin and different centromere-associated post-translational histone modifications (H3S10ph, H3S28ph and H2AT120ph) demonstrate a monocentromeric organisation of P. serratum chromosomes. Analysis of the high-copy repeat composition resulted in the identification of two centromere-localised satellite repeats. Hence, monocentricity was the ancestral condition for the Juncaceae-Cyperaceae-Thurniaceae Cyperid clade, and holocentricity in this clade has independently arisen at least twice after differentiation of the three families, once in Juncaceae and the other one in Cyperaceae. In this context, methods suitable for the identification of holocentromeres are discussed.

Implementation of nearly arbitrary spatially varying polarization transformations: an in-principle lossless approach using spatial light modulators.

A fast and automated scheme for general polarization transformations holds great value in adaptive optics, quantum information, and virtually all applications involving light-matter and light-light interactions. We present an experiment that uses a liquid crystal on silicon spatial light modulator to perform polarization transformations on a light field. We experimentally demonstrate the point-by-point conversion of uniformly polarized light fields across the wavefront to realize arbitrary, spatially varying polarization states. Additionally, we demonstrate that a light field with an arbitrary spatially varying polarization can be transformed to a spatially invariant (i.e., uniform) polarization.

Heart rate variability in type 2 spinocerebellar ataxia.

OBJECTIVES: To explore cardiovascular autonomic regulation in Spinocerebellar ataxia type 2 (SCA2) patients, using heart rate variability (HRV) analysis and neurophysiologic autonomic reflex tests, and determine relations and causal related factors of dysautonomia in SCA2. MATERIALS AND METHODS: Heart rate variability indices for 5 min series of RR intervals were analyzed in 97 SCA2 patients, assessed quantitatively for somatic and autonomic nervous system complaints applying the International Cooperative Ataxia Rating Scale and Scales for Outcomes in Parkinson's disease (SCOPA-AUT), respectively. Autonomic testing included: resting control, standing, Valsalva maneuver and deep breathing. RESULTS: Mean RR, long- and short-term variability indices and spectral density power (LF, HF) indices were lower in the patients group, whereas LF/HF ratio and LF (nu) were higher. Highly differences between groups were observed for seven diagnostic autonomic test indices. Significant correlations were found between different clinical and demographic indices and between clinical indices and some HRV indices. CONCLUSIONS: We confirm the presence of cardiovascular autonomic dysfunction in a large group of SCA2 patients.

[Screening and congenital transmission of Chagas Disease in the user population of the Dr. Félix Bulnes Cerda Hospital and Primary Health Care Services of the Metropolitan Health Service West of Santiago, Chile]. / Cribado y transmisión congénita de la enfermedad de Chagas en población usuaria del Hospital Dr. Félix Bulnes Cerda y Atención Primaria de Salud del Servicio de Salud Metropolitano Occidente de Santiago, Chile.

BACKGROUND: In 2016, the Hospital Dr. Félix Bulnes Cerda (HDFBC) implemented the mandatory screening of anti Trypanosoma cruzi antibodies in pregnant women, thus complying with national regulations to detect new Chagas disease cases (CHD) in mother and child, whose early detection mediates timely pharmacological treatment. This, because the congenital transmission continues the main active transmission mechanisms of T. cruzi and a major public health problem for the country. AIM: To present the epidemiological information generated after the implementation of the ECH screening in the SSFCC HFBC, two years after its operation began. METHODS: Screening test: inmunequimioluminiscence (IQLU), certification by IFI, ELISA and/or western blot. Follow up of newborn infants with PCR, IFI, ELISA and IQLU. RESULTS: Between April 2016 and July 2018, 14.012 subject's samples were examined of which 62 resulted reactive (0.53% seropositivity) in the total studied population where 28 patients resulted positive for CHD, which corresponds to a 0.2% prevalence. Of the total population, 11.780 were pregnant women, of these 41 were reactive and 10 were confirmed with CHD thus showing a prevalence of 0.085%. The other 18 positive cases of non-pregnant patients corresponded a prevalence of 0.81%. Also, 10 newborn and infant children of mothers with CHD were followed up. In all, congenital transmission (0%) was ruled out. Nifurtimox treatment of the mothers were completed in 30% of them. It is concluded that the implementation of the program in the HDFBC fulfills the objectives of screening, detection and diagnosis of CHD, so as the timely follow-up and pharmacologic treatment of the newborn. The 0.085% prevalence of CHD in pregnant women as the 0.20% in total population are significantly lower (p-valor < 0.01) than the 0.7% reported in 2016 for the Metropolitan Region (MR), a fact that we suggest is a consequence of the national program implementation. Likewise, the 0% transplacental transmission is accorded to the rate of 0.91 x 10.000 live births reported in 2017 for the MR. Based on the learning acquired during the development of the research, recommendations are given to contribute to the operation of the program.

Evidence for a cultivar and a chronology from patterned wetlands in central veracruz, Mexico.

The patterning found in certain wetlands of lowland Mesoamerica has added an important element to the subsistence system that may be attributed to pre-Hispanic inhabitants of the region. The form of the remains, largely expressed in terms of surface vegetation, suggests agriculture on planting platforms, separated by canals. The physical and chemical aspects of the stratigraphy have clarified depositional environments but have not indicated agricultural horizons. Maize phytoliths at about 1 meter below the surface in two Central Veracruzan wetlands do confirm the practice of agriculture. Associated ceramics indicate wetlands agriculture was practiced by A.D. 500 and perhaps earlier.

Adsorption of glyphosate on variable-charge, volcanic ash-derived soils.

Glyphosate (N-phosphonometylglycine) is widely used due to its broad spectrum of activity and nonselective mode of action. In Chile it is the most used herbicide, but its adsorption behavior in the abundant and widespread variable charge soils is not well understood. In this study, three volcanic ash-derived soils were selected, including Andisols (Nueva Braunau and Diguillin) and Ultisols (Collipulli), to evaluate the adsorption kinetics, equilibrium isotherms, and the effect of pH in glyphosate adsorption. The influence of glyphosate on soil phosphorus retention was also studied. Glyphosate was rapidly and strongly adsorbed on the selected soils, and adsorption isotherms were well described by the Freundlich relationship with strong nonlinearity (n(fads) < 0.5). The n(fads) values were consistently higher than n(fdes) values, suggesting strong hysteresis. Adsorption (K(ads)) increased strongly when pH decreased. The presence of glyphosate (3200 mug mL(-1)) changed the adsorption behavior of phosphate at its maximum adsorption capacity. Andisol soils without the addition of glyphosate had similar mean K(ads) values for Nueva Braunau (5.68) and Diguillin (7.38). Collipulli had a mean K(ads) value of 31.58. During the successive desorption steps, glyphosate at the highest level increased K(ads) values for phosphate in the Andisol soils but had little effect in the Ultisol soil. This different behavior was probably due to the irreversible occupation of some adsorption sites by glyphosate in the Ultisol soil attributed to the dominant Kaolinite mineral. Results from this study suggest that in the two types of volcanic soils, different mechanisms are involved in glyphosate and phosphate adsorption and that long-term use of glyphosate may impose different effects on the retention and availability of phosphorus. Volcanic ash-derived soils have a particular environmental behavior in relation to the retention of organic contaminants, representing an environmental substrate that may become highly polluted over time due to intensive agronomic uses.

The 3D Kasteleyn transition in dipolar spin ice: a numerical study with the conserved monopoles algorithm.

We study the three-dimensional Kasteleyn transition in both nearest neighbours and dipolar spin ice models using an algorithm that conserves the number of excitations. We first limit the interactions range to nearest neighbours to test the method in the presence of a field applied along [Formula: see text], and then focus on the dipolar spin ice model. The effect of dipolar interactions, which is known to be greatly self screened at zero field, is particularly strong near full polarization. It shifts the Kasteleyn transition to lower temperatures, which decreases ≈0.4 K for the parameters corresponding to the best known spin ice materials, [Formula: see text] and [Formula: see text]. This shift implies effective dipolar fields as big as 0.05 T opposing the applied field, and thus favouring the creation of 'strings' of reversed spins. We compare the reduction in the transition temperature with results in previous experiments, and study the phenomenon quantitatively using a simple molecular field approach. Finally, we relate the presence of the effective residual field to the appearance of string-ordered phases at low fields and temperatures, and we check numerically that for fields applied along [Formula: see text] there are only three different stable phases at zero temperature.

Tuning the electronic hybridization in the heavy fermion cage compound YbFe2Zn20 with Cd doping.

The tuning of the electronic properties of heavy fermion compounds by chemical substitution provides excellent opportunities for further understanding the physics of hybridized ions in crystal lattices. Here we present an investigation on the effects of Cd doping in flux-grown single crystals of the complex intermetallic cage compound YbFe2Zn20, which has been described as a heavy fermion with a Sommerfeld coefficient of 535 mJ mol(-1) · K(-2). The substitution of Cd for Zn disturbs the system by expanding the unit cell and, in this case, the size of the Zn cages that surround the Yb and Fe. With an increasing amount of Cd, the hybridization between the Yb 4f electrons and the conduction electrons is weakened, as shown by a decrease in the Sommerfeld coefficient, which should be accompanied by a valence shift of the Yb(3+) due to the negative chemical pressure effect. This scenario is also supported by the low temperature DC magnetic susceptibility, which is gradually suppressed and shows an increment of the Kondo temperature, based on a shift to higher temperatures of the characteristic broad susceptibility peak. Furthermore, the DC resistivity decreases with the isoelectronic substitution of Cd for Zn, contrary to expectations in an increasingly disordered system, and implying that the valence shift is not related to charge carrier doping. The combined results demonstrate the excellent complementarity between positive physical pressure and negative chemical pressure, and point to a rich playground for exploring the physics and chemistry of strongly correlated electron systems in the general family of Zn20 compounds, despite their structural complexity.

Species differences in 5-HT2A receptors: cloned pig and rhesus monkey 5-HT2A receptors reveal conserved transmembrane homology to the human rather than rat sequence.

Pig and rhesus monkey 5-HT2A receptor cDNA clones were isolated. The pig and rhesus monkey clones encode proteins that share a 94% and 95% homology, respectively, with the rat 5-HT2A receptor, and a 97% and > 99% homology, respectively, with the human 5-HT2A receptor. Within the transmembrane regions of the pig and monkey receptors, the deduced amino acid shows only three differences compared to that of the rat and are identical to the human 5-HT2A receptor clone.

Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice.

RATIONALE: (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a potent and selective agonist for group II metabotropic glutamate (mGlu2 and mGlu3) receptors, with anxiolytic-like activity in animal and human models, and efficacy in anxiety patients. However, the lack of mGlu2 or mGlu3 receptor specific agonists has prevented in vivo characterization of individual functions of these two receptors in mediating the anxiolytic-like effects of LY354740. OBJECTIVE: To utilize mGlu2 receptor and mGlu3 receptor knockout animals and the mGlu2/3 selective antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495) to further investigate the roles of mGlu2 and mGlu3 receptors in mediating the anxiolytic-like actions of LY354740 in a mouse model of anxiety [elevated plus maze (EPM) test]. METHODS: To confirm that mGlu2/3 receptors are responsible for anxiolytic-like activity in the EPM under these test conditions, mice were pretreated with LY341495 at 30 min prior to s.c. administered LY354740. Subsequently, saline vehicle or LY354740 was administered (s.c.) 30 min before the EPM testing in wild-type, mGlu2 receptor knockout, and mGlu3 receptor knockout mice. RESULTS: LY354740 reduced in a dose-dependent manner anxiety-related behavior on the EPM in wild-type mice with a maximally effective dose of 10--20 mg/kg s.c. Pretreatment with LY341495 potently prevented the anxiolytic-like effects of LY354740 (20 mg/kg, s.c.) in mice. Although the mGlu2 receptor knockout and mGlu3 receptor knockout mice were grossly normal, the anxiolytic-like activity of LY354740 (20 mg/kg, s.c.) was not evident in either mGlu2 or mGlu3 receptor knockout mice, when compared to their wild-type controls. CONCLUSIONS: The activation of both mGlu2 and mGlu3 receptors by LY354740 appears to be required for anxiolytic-like activity in the EPM test in mice. These studies serve as a foundation for additional studies on underlying circuits, brain structures, and receptor subtypes involved in the anxiolytic-like actions of mGlu receptor active agents, and the design of future drugs for anxiety disorders in humans.

Cribado y transmisión congénita de la enfermedad de Chagas en población usuaria del Hospital Dr. Félix Bulnes Cerda y Atención Primaria de Salud del Servicio de Salud Metropolitano Occidente de Santiago, Chile / Screening and congenital transmission of Chagas Disease in the user population of the Dr. Félix Bulnes Cerda Hospital and Primary Health Care Services of the Metropolitan Health Service West of Santiago, Chile

Resumen Introducción: El año 2016, el Hospital Dr. Félix Bulnes Cerda (HDFBC) implementó el tamizaje obligatorio de anticuerpos anti Trypanosoma cruzi, para pesquisar nuevos casos de la enfermedad de Chagas (ECH) en mujeres embarazadas y recién nacidos (RN) y brindar tratamiento antiparasitario oportuno. Ello, porque la transmisión transplacentaria de T. cruzi continúa siendo un importante problema de salud pública. Objetivo: Presentar la información epidemiológica generada luego de la implementación del cribado de la ECH en el HDFBC del SSMOCC, al cabo de dos años de iniciada su operación. Material y Métodos: Cribado por inmunoquimioluminiscencia (IQLU), confirmación por IFI, ELISA y/o western blot. Seguimiento de RN: mediante RPC, IFI, ELISA e IQLU. Resultados: Entre abril de 2016 y julio de 2018 se analizó un total de 14.012 muestras de pacientes; 62 resultaron reactivas (0,53% seropositividad) y 28 fueron confirmadas positivas (prevalencia de 0,2%). Del total, 11.780 fueron de mujeres gestantes (n: 41 casos reactivos y 10 confirmadas con ECH), con prevalencia de 0,085%. Los restantes 18 casos positivos fueron usuarios no gestantes, con sospecha clínica de ECH y casos de estudios familiares, mostrando una prevalencia de 0,81%. El seguimiento a 10 RN y lactantes hijos de madres chagásicas descartó la transmisión transplacentaria Completaron tratamiento con nifurtimox 30% de las madres. Discusión: La implementación del programa en el HDFBC cumple los objetivos de cribado, pesquisa y diagnóstico de la ECH así como el seguimiento y tratamiento oportuno del RN. La prevalencia de 0,085% de la ECH en la población gestante como la de 0,2% en población total son significativamente menores (p-valor < 0,01) que la prevalencia de 0,7% reportada (año 2016) para la Región Metropolitana (RM); sugerimos que es consecuencia de la implementación del programa nacional y local. La transmisión congénita de 0% es acorde a la tasa de [0,91 x 10.000] reportada el 2017 para la RM. En base al aprendizaje adquirido, durante el desarrollo de la investigación, se entrega sugerencias para aportar al funcionamiento del programa.

Abstract Background: In 2016, the Hospital Dr. Félix Bulnes Cerda (HDFBC) implemented the mandatory screening of anti Trypanosoma cruzi antibodies in pregnant women, thus complying with national regulations to detect new Chagas disease cases (CHD) in mother and child, whose early detection mediates timely pharmacological treatment. This, because the congenital transmission continues the main active transmission mechanisms of T. cruzi and a major public health problem for the country. Aim: To present the epidemiological information generated after the implementation of the ECH screening in the SSFCC HFBC, two years after its operation began. Methods: Screening test: inmunequimioluminiscence (IQLU), certification by IFI, ELISA and/or western blot. Follow up of newborn infants with PCR, IFI, ELISA and IQLU. Results: Between April 2016 and July 2018, 14.012 subject's samples were examined of which 62 resulted reactive (0.53% seropositivity) in the total studied population where 28 patients resulted positive for CHD, which corresponds to a 0.2% prevalence. Of the total population, 11.780 were pregnant women, of these 41 were reactive and 10 were confirmed with CHD thus showing a prevalence of 0.085%. The other 18 positive cases of non-pregnant patients corresponded a prevalence of 0.81%. Also, 10 newborn and infant children of mothers with CHD were followed up. In all, congenital transmission (0%) was ruled out. Nifurtimox treatment of the mothers were completed in 30% of them. It is concluded that the implementation of the program in the HDFBC fulfills the objectives of screening, detection and diagnosis of CHD, so as the timely follow-up and pharmacologic treatment of the newborn. The 0.085% prevalence of CHD in pregnant women as the 0.20% in total population are significantly lower (p-valor < 0.01) than the 0.7% reported in 2016 for the Metropolitan Region (MR), a fact that we suggest is a consequence of the national program implementation. Likewise, the 0% transplacental transmission is accorded to the rate of 0.91 x 10.000 live births reported in 2017 for the MR. Based on the learning acquired during the development of the research, recommendations are given to contribute to the operation of the program.

Performance deficits of mGluR8 knockout mice in learning tasks: the effects of null mutation and the background genotype.

mGluR8 is a G-protein coupled metabotropic glutamate receptor expressed in the mammalian brain. Members of the mGluR family have been shown to be modulators of neural plasticity and learning and memory. Here we analyze the consequences of a null mutation at the mGluR8 gene locus generated using homologous recombination in embryonic stem cells by comparing the learning performance of the mutants with that of wild type controls in the Morris water maze (MWM) and the context and cue dependent fear conditioning (CFC). Our results revealed robust performance deficits associated with the genetic background, the ICR outbred strain, in both mGluR8 null mutant and the wild type control mice. Mice of this strain origin suffered from impaired vision as compared to CD1 or C57BL/6 mice, a significant impediment in MWM, a visuo-spatial learning task. The CFC task, being less dependent on visual cues, allowed us to reveal subtle performance deficits in the mGluR8 mutants: novelty induced hyperactivity and temporally delayed and blunted responding to shocks and temporally delayed responding to contextual stimuli were detected. The role of mGluR8 as a presynaptic autoreceptor and its contribution to cognitive processes are hypothesized and the utility of gene targeting as compared to pharmacological methods is discussed.

Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor.

Pre-synaptic metabotropic glutamate (mGlu) receptors modulate neuronal excitability by controlling glutamate and gamma-aminobutyric acid (GABA) release. The mGlu8 receptor is predominantly found in pre-synaptic terminals and its expression is highly restricted. To study the role of this receptor, mGlu8 receptor-deficient mice were generated. Here we report that naïve mGlu8 receptor-deficient mice showed increased anxiety-related behavior in the elevated plus maze in low illumination conditions (red light). Open arm avoidance and risk assessment behavior were both significantly increased in mutant mice. Increased stressfulness of the testing conditions abolished this behavioral difference. Fluorescent light or prior restraint stress decreased the open arm activity of wild-type mice, while the open arm activity of mutant mice was essentially unaffected, leading to similar values in both strains. The total number of arm entries or closed arm entries was not significantly different between strains, indicating that the lack of mGlu8 receptor does not affect locomotor activity. No gross behavioral changes, or changes in the function of the autonomic nervous system or somatomotor systems were observed in mutant mice. Moreover, no significant differences in seizure susceptibility were detected between strains. Our results suggest that mGlu8 receptor may play a role in responses to novel stressful environment.

Increased c-Fos expression in the centromedial nucleus of the thalamus in metabotropic glutamate 8 receptor knockout mice following the elevated plus maze test.

Ligands for metabotropic glutamate 8 (mGlu8) receptors, such as (S)-2-amino-4-phosphonobutanoic acid and (S)-3,4-dicarboxyphenylglycine suppress CNS excitability via presynaptic regulation of glutamate release and are anticonvulsant in mice. These observations suggest that mGlu8 receptors play a role in the regulation of neuronal excitability. To further characterize the role of mGlu8 receptors in vivo, the mGlu8 receptor knockout mouse was generated. Recently, we reported that mGlu8 receptor knockout mice showed increased anxiety in the elevated plus maze (EPM). Here, the pattern of c-Fos expression was studied in mGlu8 receptor knockout and wild-type mice after exposure to the EPM test for 5 min. The present study shows that the increased anxiety-related behavior of mGlu8 receptor knockout mice in the EPM was associated with a 2.3-fold higher (P<0.05) number of c-Fos positive cells in the centromedial nucleus of the thalamus compared with wild-type mice (when prehandled mice were used). The increased neuronal activity in the centromedial nucleus of the thalamus in the mGlu8 receptor knockout mouse was also observed in a separate experiment with naive mice (no prehandling). In these naive mGlu8 receptor knockouts, c-Fos expression was significantly induced by the EPM in the centrolateral nucleus of the thalamus, paraventricular nucleus of the hypothalamus, and granular cell layer of the dentate gyrus, but in naive wild-type mice c-Fos was significantly increased only in the piriform cortex. Basal c-Fos expression in the absence of EPM exposure did not differ between wild-type and mGlu8 receptor knockout mice in any brain region we examined. As the centromedial nucleus of the thalamus is important in regulating sensory information to higher brain regions, these results support the hypothesis that mGlu8 receptors are involved in the response to certain novel, aversive environments. In particular, the deletion of the mGlu8 receptor reduced the threshold of neuronal activation in stress-related brain regions such as the centromedial nucleus of the thalamus.

Mutations of transmembrane IV and V serines indicate that all tryptamines do not bind to the rat 5-HT2A receptor in the same manner.

Two mutations of the rat serotonin 5-HT2A receptor were made, expressed and examined for their ability to bind and be stimulated by certain tryptamines as well as their ability to bind antagonists. Mutation of Ser207 to an Ala (S207A) resulted in no substantial changes in binding of either 5-HT2A antagonists or agonists. In contrast, mutation of Ser239 to an Ala (S239A) resulted in significant changes in the 5-HT2A receptor with some but not all agonists and antagonists examined. Specifically, 5-HT had decreased affinity for the S239A mutated 5-HT2A receptor, showing over a 10-fold decrease in receptor-binding displacement, while still being capable of stimulating IP3 formation. However, the agonists tryptamine, 5-methoxytryptamine (5-MeOT), and N-1-isopropyl-5-methoxytryptamine; and the antagonists ketanserin, LY 86057, and LY 53857 were significantly less affected by a S239A mutation. These results suggest that while 5-HT might have a direct interaction with the Ser239 of the 5-HT2A receptor, tryptamine and 5-MeOT interact with this receptor in a different manner.

5-hydroxytryptamine2A, 5-hydroxytryptamine2B, and 5-hydroxytryptamine2C receptor mRNA expression in the spinal cord of rat, cat, monkey and human.

Currently three subtypes of the 5-HT2 receptor have been identified through binding studies and/or molecular biology studies, 5-HT2A, 5-HT2B, and 5-HT2C. The identification of these receptor subtypes in the spinal cord of humans and experimental animal species is incomplete. In the present study, polymerase chain reaction with Southern hybridization analysis was used to determine whether the mRNA for the 5-HT2A, 5-HT2B and 5-HT2C receptors could be detected in spinal cord tissue from rats, cats, monkeys and humans. Brain tissue from rat, cat and monkey were also examined for comparison. 5-HT2A and 5-HT2B receptor mRNAs were amplified and localized with rat 5-HT2A and 5-HT2B primers and probes, respectively, in tissue from all species. In rats, 5-HT2C receptor mRNA was amplified and localized with rat 5-HT2C primer and mouse 5-HT2C probe, respectively, while in cat, monkey, and human tissue, human 5-HT2C primers and probes were used. Spinal cord from all four species contained mRNA for the 5-HT2A receptor. Brain tissue from rat, cat and monkey also contained 5-HT2A mRNA. Spinal cord tissue from all four species contained 5-HT2B message. Brain tissue from cat and monkey contained 5-HT2B mRNA, but this was not detected in rat brain. 5-HT2C mRNA was detected in spinal cord and brain tissue from rat, monkey and human, but was only detected in brain tissue of the cat (i.e. no 5-HT2C mRNA was detected in cat spinal cord).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-ranging study to delineate the additive antihypertensive effect of guanabenz and captopril.

This open crossover study in eight hypertensive patients defined a possible additive effect of oral guanabenz and captopril and determined a safe and effective dose range. Each group of four patients received placebo followed by ascending doses (on alternate days) of either guanabenz (2, 4, 8 mg) or captopril (6.25, 12.5, 25 mg) as initial monotherapy and were subsequently crossed over to the alternate monotherapy. Guanabenz and captopril were given concomitantly in increasing doses--the highest dose for both groups being 8 mg guanabenz/25 mg captopril. When guanabenz and captopril were given concomitantly, blood pressure decreased, both from the values during placebo administration and from the lead-in values recorded before each dose. Mean supine systolic and diastolic blood pressures after combination therapy decreased significantly (P less than .05) in a dose-related manner at most evaluations. The authors conclude that guanabenz and captopril have an additive effect when administered in combination to patients with hypertension.

Cloning and characterization of Rhesus monkey neuropeptide Y receptor subtypes.

Neuropeptide Y (NPY) is a 36 amino acid peptide that is abundant in the brain and peripheral nervous system. NPY has a variety of effects when administered into the brain including a pronounced feeding effect, anxiolysis, regulation of neuroendocrine axes and inhibition of neurotransmitter release. These effects are mediated by up to 6 G protein coupled receptors designated Y1, Y2, Y3, Y4, Y5 and y6. To better understand the phylogeny and pharmacology of NPY in non-human primates, we have cloned and expressed the NPY Y1, Y2 and Y5 receptor subtypes from the Rhesus monkey. No cDNA sequence encoding a Y4 receptor was found suggesting substantial sequence differences when compared to the human sequence. Comparison of these sequences with those from human indicated strong sequence conservation of Y1, Y2 and Y5 between the two species. The displacement of (125)I-PYY binding to the Rhesus monkey and human receptors by various peptides was compared to evaluate the pharmacology of the two species. Similar pharmacologies were noted across the species at the various receptor subtypes. These results indicate the Rhesus monkey and human NPY receptor subtypes have a close amino acid sequence conservation and that the peptide recognition domains are conserved as well.

Functional coupling of the 5-HT2C serotonin receptor to G proteins in Xenopus oocytes.

The serotonin 2c (5-HT2C) receptor mediates its cellular effects by interacting with heterotrimeric guanine nucleotide binding proteins (G proteins). To characterize which G proteins are involved in functional coupling to the receptor, a mouse 5-HT2C receptor was expressed in Xenopus oocytes, and antisense oligoncleotides complementary to the mRNA sequence of the endogenous Xenopus G protein alpha subunits were used to inhibit G protein synthesis. Antisense oligonucleotide against the Xenopus G(o) alpha subunit inhibited the 5-HT2C receptor function, and coexpression of a rat G(o) alpha subunit reversed the inhibition by the anti-Xenopus G(o) oligonucleotide. Furthermore, antisense oligonucleotides against both the G(o) and Gi1 alpha subunits inhibited the electrophysiologic response induced by stimulation of the 5-HT2C receptor. These data suggest that both G(o) and Gi1 are involved in functional coupling of the 5-HT2C receptor to phospholipase C in Xenopus oocytes.

Tropane alkaloids from the leaves and stem bark of Erythroxylon alaternifolium and Erythroxylon rotundifolium.

A novel 3alpha,6beta,7beta-triol tropane alkaloid esterified by two benzoyl residues was isolated from the leaves of the endemic cuban species, Erythroxylon alaternifolium. Another novel 3alpha,6alpha,7beta-triol tropane alkaloid esterified by trimethoxycinnamoyl and trimethoxybenzoyl residues was isolated from the leaves and stem bark of a second endemic cuban species, Erythroxylon rotundifolium. Their structures were elucidated as 3alpha,7beta-dibenzoyloxy-6beta-hydroxy-tropane and 3alpha-(3,4,5-trimethoxycinnamoyloxy)-7beta-(3,4,5- trimethoxybenzoyloxy)-6alpha-hydroxy-tropane by spectroscopic methods including 2D-NMR techniques.