Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains.

Cyclic AMP (cAMP)-dependent signaling is highly implicated in the pathophysiology of alcohol use disorder (AUD), with evidence supporting the efficacy of inhibiting the cAMP hydrolyzing enzyme phosphodiesterase 4 (PDE4) as a therapeutic strategy for drinking reduction. Off-target emetic effects associated with non-selective PDE4 inhibitors has prompted the development of selective PDE4 isozyme inhibitors for treating neuropsychiatric conditions. Herein, we examined the effect of a selective PDE4B inhibitor A33 (0-1.0 mg/kg) on alcohol drinking in both female and male mice from two genetically distinct C57BL/6 substrains. Under two different binge-drinking procedures, A33 pretreatment reduced alcohol intake in male and female mice of both substrains. In both drinking studies, there was no evidence for carry-over effects the next day; however, we did observe some sign of tolerance to A33's effect on alcohol intake upon repeated, intermittent, treatment (5 injections of 1.0 mg/kg, every other day). Pretreatment with 1.0 mg/kg of A33 augmented sucrose intake by C57BL/6NJ, but not C57BL/6J, mice. In mice with a prior history of A33 pretreatment during alcohol-drinking, A33 (1.0 mg/kg) did not alter spontaneous locomotor activity or basal motor coordination, nor did it alter alcohol's effects on motor activity, coordination or sedation. In a distinct cohort of alcohol-naïve mice, acute pretreatment with 1.0 mg/kg of A33 did not alter motor performance on a rotarod and reduced sensitivity to the acute intoxicating effects of alcohol. These data provide the first evidence that selective PDE4B inhibition is an effective strategy for reducing excessive alcohol intake in murine models of binge drinking, with minimal off-target effects. Despite reducing sensitivity to acute alcohol intoxication, PDE4B inhibition reduces binge alcohol drinking, without influencing behavioral sensitivity to alcohol in alcohol-experienced mice. Furthermore, A33 is equally effective in males and females and exerts a quantitatively similar reduction in alcohol intake in mice with a genetic predisposition for high versus moderate alcohol preference. Such findings further support the safety and potential clinical utility of targeting PDE4 for treating AUD.

Increased Alcohol-Drinking Induced by Manipulations of mGlu5 Phosphorylation within the Bed Nucleus of the Stria Terminalis.

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.

How long do people stick to a diet resolution? A digital epidemiological estimation of weight loss diet persistence.

OBJECTIVE: To use Internet search data to compare duration of compliance for various diets. DESIGN: Using a passive surveillance digital epidemiological approach, we estimated the average duration of diet compliance by examining monthly Internet searches for recipes related to popular diets. We fit a mathematical model to these data to estimate the time spent on a diet by new January dieters (NJD) and to estimate the percentage of dieters dropping out during the American winter holiday season between Thanksgiving and the end of December. SETTING: Internet searches in the USA for recipes related to popular diets over a 15-year period from 2004 to 2019. PARTICIPANTS: Individuals in the USA performing Internet searches for recipes related to popular diets. RESULTS: All diets exhibited significant seasonality in recipe-related Internet searches, with sharp spikes every January followed by a decline in the number of searches and a further decline in the winter holiday season. The Paleo diet had the longest average compliance times among NJD (5.32 ± 0.68 weeks) and the lowest dropout during the winter holiday season (only 14 ± 3 % dropping out in December). The South Beach diet had the shortest compliance time among NJD (3.12 ± 0.64 weeks) and the highest dropout during the holiday season (33 ± 7 % dropping out in December). CONCLUSIONS: The current study is the first of its kind to use passive surveillance data to compare the duration of adherence with different diets and underscores the potential usefulness of digital epidemiological approaches to understanding health behaviours.

Silver nanoparticles are lethal to the ciliate model Tetrahymena and safe to the pike silverside Chirostoma estor.

Ciliate ectoparasites are one of the most important groups of pathogens in fish culture, and the traditional treatments are sometimes harmful to the fish and the environment. Thus, the search for novel compounds that are effective at low concentrations and safe for fish are necessary to optimise treatments in aquaculture. The antiprotozoal capacity of silver nanoparticles (AgNPs) against the ciliate Tetrahymena has been documented; however, their toxicity may vary with the synthesis methodology and nanoparticle size. The objectives of this study were a) to evaluate the acute toxicity in vitro of two AgNPs (Argovit™ and UTSA) on Tetrahymena sp., a biological model for ciliated ectoparasites of fish and b) to test the safety of lethal and higher doses of UTSA AgNPs for ciliates on the fish C. estor. Light microscopy and scanning electron microscopy (SEM) were used to determine whether AgNPs affected the structure of the cell surface of Tetrahymena. The mortality, histopathological alterations and metagenomics of the fish were used to determine the major effects of UTSA AgNPs. In Tetrahymena, the median lethal concentration (LC50) for Argovit™ was 2501 ± 1717 ng/L at 15 min and 796 ± 510 ng/L at 60 min, while the LC50 for UTSA AgNPs was 4 ± 2 and 1 ± 0.6 ng/L at 15 min and 60 min, respectively. A concentration of 3300 ng/L Argovit™ and 10.6 ng/L UTSA AgNPs for 15 and 60 min, respectively, was 100% effective against Tetrahymena. After 60 min of exposure to 0.25 and 0.50 ng/L UTSA AgNPs, the number of cilia significantly reduced, there were small holes on the cell surface, and the cellular membrane was ruptured. In fish exposed to lethal (10.6 ng/L) and higher (31.8 and 95.4 ng/L) doses of UTSA, the AgNPs did not affect fish survival after 96 h, and there were no signs of histopathological damage or gut microbial changes. This study is the first report on microscopic and ultrastructural changes in Tetrahymena after exposure to significantly low concentrations of UTSA AgNPs with antiprotozoal efficacy without evidence of harmful effects on fish. These results provide the basis for further studies of both pet aquarium and commercial fish that may validate these findings at a larger experimental scale, taking into account AgNPs bioaccumulation, safety for human consumption and environmental impact.

Discontinuous spirals of stability in an optically injected semiconductor laser.

We report a new kind of discontinuous spiral with stable periodic orbits in the parameter space of an optically injected semiconductor laser model, which is a combination of the intercalation of fish-like and cuspidal-like structures (the two normal forms of complex cubic dynamics). The spiral has a tridimensional structure that rolls up in at least three directions. A turn of approximately 2π radians along the spiral and toward the center increases the number of peaks in the laser intensity by one, which does not occur when traversing the discontinuities. We show that as we vary the linewidth enhancement factor (α), discontinuities are created (destroyed) through disaggregation (collapses) from (into) the so-called shrimp-like structures. Future experimental verification and applications, as well as theoretical studies to explain its origin and relation with homoclinic spirals that exist in its neighborhood, are needed.

Tricorn-like structures in an optically injected semiconductor laser.

This study reports the existence of tricorn-like structures of stable periodic orbits in the parameter plane of an optically injected semiconductor laser model (a continuous-time dynamical system). These tricorns appear inside tongue-like structures that are created through simple Shi'lnikov bifurcations. As the linewidth enhancement factor-α of the laser increases, these tongues invade the laser locking zone and extends over the zone of stable period-1 orbits. This invasion provokes a rich overlap dynamics of the parameter planes that produces an abundant multistability. As α increases, the tricorn exhibits a phenomenon of codimension-3 rotating in the clockwise and counterclockwise directions in the plane of the injected field rate K vs its detuning ω. We hope that the numerical evidence of the tricorns presented herein motivates the study of mathematical conditions for their genesis. We also encourage the experimental verification of these tricorn-like structures because our results also open new possibilities for optical switching between several different laser outputs in the neighborhood of these structures.

First Direct-Detection Constraints on eV-Scale Hidden-Photon Dark Matter with DAMIC at SNOLAB.

We present direct detection constraints on the absorption of hidden-photon dark matter with particle masses in the range 1.2-30 eV c^{-2} with the DAMIC experiment at SNOLAB. Under the assumption that the local dark matter is entirely constituted of hidden photons, the sensitivity to the kinetic mixing parameter κ is competitive with constraints from solar emission, reaching a minimum value of 2.2×10^{-14} at 17 eV c^{-2}. These results are the most stringent direct detection constraints on hidden-photon dark matter in the galactic halo with masses 3-12 eV c^{-2} and the first demonstration of direct experimental sensitivity to ionization signals <12 eV from dark matter interactions.

The Progetto Nazionale Emorragia Digestiva (PNED) system vs. the Rockall score as mortality predictors in patients with nonvariceal upper gastrointestinal bleeding: A multicenter prospective study. / Sistema Progetto Nazionale Emorragia Digestiva (PNED) vs. escala de Rockall como predictores de mortalidad en pacientes con hemorragia de tubo digestivo alto no variceal: un estudio multicéntrico prospectivo.

BACKGROUND: The predictive scale for mortality risk in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) proposed by Italy's PNED (Progetto Nazionale Emorragia Digestiva) group has not been validated in Latin America since its original publication. AIM: To compare the PNED system and the Rockall score as mortality predictors in patients hospitalized for NVUGIB. MATERIAL AND METHODS: A multicenter, prospective, cross-sectional, analytic study was conducted that recruited patients diagnosed with nonvariceal upper gastrointestinal bleeding within the time frame of 2011 to 2015. Six Mexican hospital centers participated in the study. The Rockall and PNED system scores were calculated, classifying the patients as having mild, moderate, or severe disease. The association between mortality and risk was determined through the chi-square test and relative risk (RR) calculation. Statistical significance was set at a P<.05. RESULTS: Information on 198 patients was collected. Only 8 patients (4%) died from causes directly associated with bleeding. According to the Rockall score, 46 patients had severe disease (23.2%), 5 of whom died, with a RR of 5.5 (CI 1.35-22.02, P=.006). In relation to the PNED, only 8 patients had severe disease (4%), 5 of whom died, with a RR of 38.7 (CI 11.4-137.3, P=.001). CONCLUSIONS: The PNED system was more selective for classifying a case as severe, but it had a greater predictive capacity for mortality, compared with the Rockall score.

Molecular thrombophilic profile in Mexican patients with idiopathic recurrent pregnancy loss.

Idiopathic recurrent pregnancy loss (IRPL) is defined by three or more consecutive miscarriages occurring before the twentieth week of gestation as a result of unidentified etiological factors. The results of previous studies have indicated that prothrombotic factors play a pathogenic role in early and late pregnancy. This study aimed to identify inherited prothrombotic and hypofibrinolytic risk factors in Mexican-Mestizo patients with IRPL. Fifty-six women with IRPL and 50 control women with at least two full-term pregnancies and no history of RPL were included in this case-control study. Four prothrombotic (F5 G1691A, F2 G20210A, MTHFR C677T-A1298C) and one hypofibrinolytic (PAI1 4G/5G) restricted fragment length polymorphisms were subjected to molecular analysis. In the case of hypofibrinolytic ACE Ins/Del (I/D), identification was performed by direct PCR. The independent risk correlated with the presence of polymorphisms in IRPL patients was estimated using odds ratio (OR) with a 95% confidence interval (CI). MTHFR 677TT was the most frequent prothrombotic factor in the IRPL group (23%), followed by the compound-heterozygous C677T-A1298C (16%) and heterozygous F2 20210GA (3.6%). The heterozygous ACE I/D (62%) was the main hypofibrinolytic risk factor of IRPL, followed by the homozygote PAI1 4G/4G (18%). The ACE I/D polymorphism was the only significantly different factor among the cases and controls. The dominant genetic model D/D+I/D vs I/I showed an OR (95%CI) of 2.89 (1.22-6.89) and P = 0.019 in Mexican-Mestizo women. The results of this study support an association between the ACE I/D polymorphism and IRPL risk in a Mexican population.

Legislative and regulatory aspects of molluscan health management.

The world population is growing quickly and there is a need to make sustainable protein available through an integrated approach that includes marine aquaculture. Seafood is already a highly traded commodity but the production from capture fisheries is rarely sustainable, which makes mollusc culture more important. However, an important constraint to its continued expansion is the potential for trade movements to disseminate pathogens that can cause disease problems and loss of production. Therefore, this review considers legislative and regulatory aspects of molluscan health management that have historically attempted to control the spread of mollusc pathogens. It is argued that the legislation has been slow to react to emerging diseases and the appearance of exotic pathogens in new areas. In addition, illegal trade movements are taken into account and possible future developments related to improvements in areas such as data collection and diagnostic techniques, as well as epidemiology, traceability and risk analysis, are outlined.

Photoperiodic growth enhancement in a tropical batch spawning atherinopsid, pike silverside Chirostoma estor.

The effect of photoperiod on growth and survival in early life was determined in the tropical batch spawning atherinopsid, pike silverside Chirostoma estor. The results demonstrate high sensitivity of newly hatched C. estor to photoperiod treatments up to 90 days post hatch shown by improved growth in mass (43%) under continuous illumination. This is accompanied by increased fat deposition, which suggests a critical interaction between different photoperiod-mediated mechanisms. A thorough understanding of these mechanisms can help to optimize the development of aquaculture of C. estor and similar species.

Hidden sources of mercury in clinical laboratories.

The healthcare sector is an important contributor to mercury (Hg) pollution because of the potential presence of mercury in thermometers, blood pressure cuffs, amalgams, etc. There are also other potential sources of mercury in this sector which are used frequently and in high volumes where the presence of the metal is not obvious and which might be collectively contributing to pollution. For instance, some chemicals used for the clinical diagnosis of illness may contain mercury. The goal of this study was to investigate potential sources of mercury pollution, which originate from clinical laboratory discharges, using an exploratory approach. The focus was on the residue generated during automatic analysis of patients' bodily fluids at a medical center in Hermosillo, Sonora, Mexico. This study shows an overview of what might be happening in the region or the country related to non-obvious sources of mercury in the healthcare sector. The results showed measurable levels of mercury in the residues coming from urine sediment analysis. These amounts do not exceed the maximum allowed by Mexican environmental regulations; nevertheless, the frequency and cumulative volume of residues generated, combined with the potential for persistence and the bioaccumulation of mercury in the environment, warrant attention. The work carried out in this study is being taken as a model for future studies for pollution prevention in the healthcare sector with the goal of measuring mercury emissions to the environment from clinical laboratory wastewater, including identifying sources which--while not obvious--could be important given the frequency and volume of their use in the clinical diagnosis.

[Intraoperative choledochoscopy usefulness in the treatment of difficult biliary stones]. / Utilidad de la coledocoscopia transquirúrgica en el tratamiento de litos biliares difíciles.

BACKGROUND: Choledocholithiasis presents in 5-10% of the patients with biliary lithiasis. Numerous treatment algorithms have been considered for this disease, however, up to 10% of these therapeutic procedures may fail. Intraoperative choledochoscopy has become a useful tool in the treatment of patients with difficult-to-manage choledocholithiasis. OBJECTIVES: To determine the usefulness of intraoperative choledochoscopy in the laparoendoscopic treatment of difficult stones that was carried out in our service. PATIENTS AND METHODS: A cross-sectional study was conducted. The case records were reviewed of the patients that underwent intraoperative choledochoscopy during biliary tree exploration plus laparoscopic choledochoduodenal anastomosis within the time frame of March 1, 2011 and May 31, 2012, at the Hospital General Dr. Manuel Gea González. Transabdominal choledochoscopies were performed with active stone extraction when necessary, followed by peroral choledochoscopies through the recently formed bilioenteric anastomosis. The data were analyzed with descriptive statistics and measures of central tendency. RESULTS: The mean age was 71 years, 57% of the patients were women, and the ASA III score predominated. Active extraction of stones with 7 to 35mm diameters was carried out in 4 of the cases and the absence of stones in the biliary tract was corroborated in all the patients. The mean surgery duration was 18 minutes (range: 4 to 45min). CONCLUSIONS: Choledochoscopy is a safe and effective minimally invasive procedure for the definitive treatment of difficult stones.

Modulation of marble-burying behavior in adult versus adolescent C57BL/6J mice of both sexes by ethologically relevant chemosensory stimuli.

The marble-burying test is a pharmacologically validated paradigm used to study anxiety-like behaviors in laboratory rodents. Our laboratory has employed this assay as part of a behavioral screen to examine drug-induced negative affective states. Historically, the majority of our prior binge alcohol-drinking studies employed male subjects exclusively and reliably detected adolescent-adult differences in both basal and alcohol withdrawal-induced negative affect. However, age-related differences in marble-burying behavior were either absent or opposite those observed in our prior work when female subjects were included in the experimental design. As chemosensory cues from females are reported to be anxiolytic in males, the present study examined how odors from adult members of the opposite and same sex (obtained from soiled bedding) influence marble-burying behavior in adult, as well as adolescent, mice. Control studies examined the responsiveness of mice in the presence of novel neutral (vanilla) and aversive (tea tree) odors. Adult males exhibited reduced signs of anxiety-like behavior in the presence of female-soiled bedding, while adult females and adolescent mice of both sexes increased marble-burying behavior in the presence of both male- and female-soiled bedding. All mice exhibited increased burying in the presence of an aversive odor, while only adolescents increased marble-burying in response to the novel neutral odor. These data indicate sex by age interactions in the effects of volatile and nonvolatile odors from sexually-naive adult conspecifics on indices of anxiety-like behavior in the marble-burying test of relevance to the experimental design and procedural timing of experiments including sex as a biological variable.

Expression of non-replicating persistence associated genes of Mycobacterium bovis in lymph nodes from skin test-reactor cattle.

Upon oxygen shift-down, Mycobacterium tuberculosis complex bacteria can induce a genetic program characterized by halted duplication, which is called Non-replicating persistence (NRP). During this phase, at least 48 genes, collectively named Dormancy survival regulator (DosR) regulon, are important for the long-term survival of bacilli under a non-respiring state, a condition that bacilli encounter inside granulomatous lesions. It remains unclear whether expression of NRP genes occurs within the tissue of Mycobacterium bovis naturally infected cattle. In order to start dissecting this question, total RNA from bovine lymph node tissues of sacrificed tuberculin reacting animals was isolated and transcription of genes required for in vivo duplication (esxB and fbpB) and in vitro NRP (hspX, pfkB, and mb2660c) were analyzed by RT-PCR approaches. Detection of transcripts was positive in bovine tissue samples for genes hspX, pfkB, and mb2660c in 84, 32, and 21%, respectively. NRP genes were upregulated even in animals with a negative IFN-γ in vitro test, and the expression of NRP genes occurred more often than expression of the esxB gene.

Measurement of 2D density profiles using a second-harmonic, dispersion interferometer.

A second-harmonic, dispersion interferometer is used to image large-area (≃5 cm2) plasma-jet and gas-jet density profiles. Achromatic telescopes magnify the diameters of the primary-laser beam (1064 nm) and its second-harmonic (532 nm) before probing the sample and de-magnify the beam diameters after the sample, where the primary beam transfers its phase change to a second, second-harmonic beam, allowing the sample's dispersive-phase change to be measured between two, orthogonally polarized second harmonic beams. The telescopes produce an azimuthally symmetric, dispersive-phase shift in the sample + background phase-change image and in the background phase-change image, which is removed by digital subtraction. The interferometer's performance was verified using standard-optical components as dispersive elements (BK7 lenses and wedge plates), resolving a minimum, phase-change sensitivity of Δϕmin ≳ 15 mrad and spatial resolution of Δxres ≃ 100 µm. The phase change produced by unknown-density objects (a pulsed-plasma-jet and a pulsed-gas-jet) was measured, and their data were used to recover the original, 2D density profiles using an inverse Abel transform: peak-number density, Ngas ≃ 6 × 1020 cm-3 and Ne ≃ 5 × 1016 cm-3; line-integrated density, ∫Ngasdl ∼ 2 × 1019cm-2 and ∫Nedl ∼ 1 × 1016cm-2. The techniques and methods developed here are scalable to even larger probe-beam diameters and frame-capture rates, leading to a diagnostic capability that is well-suited for applications involving the real-time measurement of density.

A subchronic history of binge-drinking elicits mild, age- and sex-selective, affective, and cognitive anomalies in C57BL/6J mice.

Introduction: Alcohol abuse is a risk factor for affective and cognitive disorders, with evidence indicating that adolescent-onset excessive drinking can result in long-term deficiencies in emotional regulation and cognition, with females more susceptible to the negative emotional and cognitive consequences of excessive alcohol consumption. However, our prior examination of the interactions between sex and the age of drinking-onset indicated minimal signs of anxiety-like behavior during alcohol withdrawal, which may have related to the concurrent anxiety testing of male and female subjects. Methods: The present study addressed this potential confound by assaying for alcohol withdrawal-induced negative affect separately in males and females and expanded our investigation to include measures of spatial and working memory. Results: Following 14 days of drinking under modified Drinking-in-the-Dark procedures (10, 20, and 40% alcohol v/v; 2 h/day), adolescent and adult binge-drinking mice of both sexes exhibited, respectively, fewer and more signs of negative affect in the light-dark shuttle-box and forced swim tests than their water-drinking counterparts. Adolescent-onset binge-drinking mice also exhibited signs of impaired working memory early during radial arm maze training during early alcohol withdrawal. When tested in late (30 days) withdrawal, only adult female binge-drinking mice buried more marbles than their water-drinking counterparts. However, adolescent-onset binge-drinking mice exhibited poorer spatial memory recall in a Morris water maze. Discussion: These findings indicate that a subchronic (14-day) binge-drinking history induces mild, age- and sex-selective, changes in negative affect and cognition of potential relevance to understanding individual variability in the etiology and treatment of alcohol abuse and alcohol use disorder.

Evidence for Phosphorylation-Dependent, Dynamic, Regulation of mGlu5 and Homer2 in Expression of Cocaine Aversion in Mice.

Cocaine-induced changes in the expression of the glutamate-related scaffolding protein Homer2 influence this drug's psychostimulant and rewarding properties. In response to neuronal activity, Homer2 is phosphorylated on S117/S216 by calcium-calmodulin kinase IIα (CaMKIIα), which induces a rapid dissociation of mGlu5-Homer2 scaffolds. Herein, we examined the requirement for Homer2 phosphorylation in cocaine-induced changes in mGlu5-Homer2 coupling, to include behavioral sensitivity to cocaine. For this, mice with alanine point mutations at (S117/216)-Homer2 (Homer2AA/AA ) were generated, and we determined their affective, cognitive and sensorimotor phenotypes, as well as cocaine-induced changes in conditioned reward and motor hyperactivity. The Homer2AA/AA mutation prevented activity-dependent phosphorylation of S216 Homer2 in cortical neurons, but Homer2AA/AA mice did not differ from wild-type (WT) controls with respect to Morris maze performance, acoustic startle, spontaneous or cocaine-induced locomotion. Homer2AA/AA mice exhibited signs of hypoanxiety similar to the phenotype of transgenic mice with a deficit in signal-regulated mGluR5 phosphorylation (Grm5AA/AA ). However, opposite of Grm5AA/AA mice, Homer2AA/AA mice were less sensitive to the aversive properties of high-dose cocaine under both place-conditioning and taste-conditioning procedures. Acute injection with cocaine caused dissociation of mGluR5 and Homer2 in striatal lysates from WT, but not Homer2AA/AA mice, suggesting a molecular basis for the deficit in cocaine aversion. These findings indicate that CaMKIIα-dependent phosphorylation of Homer2 gates the negative motivational valence of high-dose cocaine via regulation of mGlu5 binding, furthering an important role for dynamic changes in mGlu5-Homer interactions in addiction vulnerability.

CH bond activation in aromatic ketones mediated by iridium-tris(pyrazolyl)borate complexes.

Reaction of complex [TpMe2Ir(η4-CH2C(Me)C(Me)C2)] (1) with a series of aromatic ketones at 130 °C renders, by means of a selective ortho-CH activation, Ir(III)-metallacycles 2-5, which display an Ir-H bond. When [TpMe2Ir(C6H5)2N2] (6) is treated with 2-(trifluoromethyl)acetophenone and 2-fluoroacetophenone at 80 °C, the formation of dimeric (7) and trimeric architectures (8) is achieved through the meta- and para-CH activation of the aromatic ketone, respectively. The generation of complexes 2-5 is proposed to occur by the initial formation of Ir(III) η1-ketone adducts as key intermediates, followed by aromatic CH activations and the release of a butadiene ligand. The formation of complexes 7 and 8 involves an assisted process in which a metal center activation of the less sterically hindered C-H bond of the aromatic ketone takes place (releasing a benzene molecule), followed by the coordination of the carbonyl group, which generates the respective dimeric and trimeric structures. Complexes 7 and 8 are efficient catalysts for the transfer hydrogenation of ketones and aldehydes using isopropanol as the hydrogen source. All complexes have been fully characterized by NMR spectroscopy, FT-IR, elemental analysis and, in the cases of 7 and 8, X-ray crystallography. Details of the reaction conditions, isolation of the products, and proposals for the pathways of formation of complexes 2-5 and 7-8 are discussed.