Sum of ranking differences (SRD) to ensemble multivariate calibration model merits for tuning parameter selection and comparing calibration methods

Most multivariate calibration methods require selection of tuning parameters, such as partial least squares (PLS) or the Tikhonov regularization variant ridge regression (RR). Tuning parameter values determine the direction and magnitude of respective model vectors thereby setting the resultant predication abilities of the model vectors. Simultaneously, tuning parameter values establish the corresponding bias/variance and the underlying selectivity/sensitivity tradeoffs. Selection of the final tuning parameter is often accomplished through some form of cross-validation and the resultant root mean square error of cross-validation (RMSECV) values are evaluated. However, selection of a "good" tuning parameter with this one model evaluation merit is almost impossible. Including additional model merits assists tuning parameter selection to provide better balanced models as well as allowing for a reasonable comparison between calibration methods. Using multiple merits requires decisions to be made on how to combine and weight the merits into an information criterion. An abundance of options are possible. Presented in this paper is the sum of ranking differences (SRD) to ensemble a collection of model evaluation merits varying across tuning parameters. It is shown that the SRD consensus ranking of model tuning parameters allows automatic selection of the final model, or a collection of models if so desired. Essentially, the user's preference for the degree of balance between bias and variance ultimately decides the merits used in SRD and hence, the tuning parameter values ranked lowest by SRD for automatic selection. The SRD process is also shown to allow simultaneous comparison of different calibration methods for a particular data set in conjunction with tuning parameter selection. Because SRD evaluates consistency across multiple merits, decisions on how to combine and weight merits are avoided. To demonstrate the utility of SRD, a near infrared spectral data set and a quantitative structure activity relationship (QSAR) data set are evaluated using PLS and RR

Origin and Neuronal Function of in Vivo Nonsynaptic Glutamate

Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known. This report reveals that blockade of glutamate release from the cystine–glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na and Ca2 channels produced relatively minimal changes (0– 30%). This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine–glutamate antiporter. By measuring [ 35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine–glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5- phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4- aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporterderived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicular release from the cystine–glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission. Key words: microdialysis;glutamate;cystine;striatum;nonvesicular;cystine–glutamate antiporter;system xc

Regulation of locomotor activity by metabotropic glutamate receptors in the nucleus accumbens and ventral tegmental

ABSTRACT Glutamatergic innervation of the ventral tegmental area (VTA) and the nucleus accumbens (NA) regulates locomotor activity. The present study was designed to evaluate the involvement of metabotropic glutamate receptors (mGluRs) in motor activity. Agonists selective for each of the three subgroups of mGluRs were microinjected into the VTA or NA, and motor activity was monitored. The group I agonist (S)-3,5-dihydroxyphenylglycine elicited a dose-dependent elevation in motor activity after microinjection into either the VTA or NA. The effect in the NA was blocked by the mGluR1-specific antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The group II agonist (2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine also elicited a short-duration motor activation after microinjection into either structure. The dose response in the VTA was biphasic, and the coadministration of the group II/III-specific antagonist (RS)-␣-methyl-4-phosphonophenylglycine partially blocked motor activation in both the NA and VTA. Although the group III agonist L-(ϩ)-2-amino-4-phosphonobutyric acid produced a relatively modest behavioral stimulation after microinjection into the NA, it was without effect in the VTA. These data indicate a role for mGluR subgroups in the regulation of motor activity in the VTA and NA

Pancytopenia due to Restrictive Food Intake in an Autistic Adult

Autism spectrum disorder (ASD) is a neuro-behavioral syndrome that develops in childhood and can be comorbid with restrictive and avoidant food intake disorder. This case details a young man who was hospitalized with pancytopenia due to restrictive nutritional intake related to his severe ASD. He was found to have undetectable vitamin B12 levels. His blood counts improved with transfusion, nutritional supplementation, and dental care. This report illustrates the importance of understanding ASD and potential medical complications of related behaviors

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

Stressor- and Corticotropin releasing Factor-induced Reinstatement and Active Stress-related Behavioral Responses are Augmented Following Long-access Cocaine Self-administration by Rats

Rationale Stressful events during periods of drug abstinence likely contribute to relapse in cocaine-dependent individuals. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) responsiveness. Objectives This study examined stressor- and CRF-induced cocaine seeking and other stress-related behaviors in rats with different histories of cocaine self-administration (SA). Materials and methods Rats self-administered cocaine under short-access (ShA; 2 h daily) or long-access (LgA; 6 h daily) conditions for 14 days or were provided access to saline and were tested for reinstatement by a stressor (electric footshock), cocaine or an icv injection of CRF and for behavioral responsiveness on the elevated plus maze, in a novel environment and in the light–dark box after a 14- to 17-day extinction/withdrawal period. Results LgA rats showed escalating patterns of cocaine SA and were more susceptible to reinstatement by cocaine, EFS, or icv CRF than ShA rats. Overall, cocaine SA increased activity in the center field of a novel environment, on the open arms of the elevated plus maze, and in the light compartment of a light–dark box. In most cases, the effects of cocaine SA were dependent on the pattern/amount of cocaine intake with statistically significant differences from saline self-administering controls only observed in LgA rats. Conclusions When examined after several weeks of extinction/ withdrawal, cocaine SA promotes a more active pattern of behavior during times of stress that is associated with a heightened susceptibility to stressor-induced cocaine-seeking behavior and may be the consequence of augmented CRF regulation of addiction-related neurocircuitry

Altered Ratio of D1 and D2 Dopamine Receptors in Mouse Striatum Is Associated with Behavioral Sensitization to Cocaine

BACKGROUND: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R) availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. METHODS AND FINDINGS: ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT) and G protein coupled receptor associated sorting protein-1 (GASP-1) knock out (KO) mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. CONCLUSIONS: Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization

Repeated Exposure to Methamphetamine, Cocaine or Morphine Induces Augmentation of Dopamine Release in Rat Mesocorticolimbic Slice Co-Cultures

Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1–1000 µM), cocaine (0.1–300 µM) or morphine (0.1–100 µM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1–1000 µM) had little effect. Following repeated exposure to methamphetamine (10 µM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1–300 µM) or morphine (10 and 100 µM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 µM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA receptors and the medial prefrontal cortex play an essential role in the dopaminergic sensitization. This in vitro sensitization model provides a unique approach for studying mechanisms underlying behavioral sensitization to drugs of abuse

Detection of adulterations with different grains in wheat products based on the hyperspectral image technique: The specific cases of flour and bread

[EN] The objective of this study was to test the capability of a SW-NIR hyperspectral image technique to detect adulterations in wheat flour and bread with cheap grains, such us sorghum, oats and corn, and to compare the hyperspectral information with the physicochemical alterations in the properties of products. Wheat flour was adulterated at four different degrees (2.5, 5, 7.5 and 10%) with sorghum, oat and corn flours. Flours were prepared and used to make bread. Flours and breads were characterized according to several physicochemical parameters (pasting properties, water activity, mass loss during the baking process and texture profile analysis). Crumbs were extracted from breads and conditioned. Hyperspectral image captures were taken of both flours and conditioned crumbs. The data analysis was based on multivariate statistical process control method (MSPC), where the differentiation of adulterated samples was observed in all cases for both flours and crumbs. Finally, in order to relate the image analysis results and the adulterated sample properties, a correlation significance map was created between the physicochemical properties of samples and the multivariate statistical parameters. The SW-NIR image technique was capable of detecting adulterations in each case and high correlation significances were observed (alpha = 0.01) between wavelengths from specific spectra zones and the physicochemical properties of samples.Verdú Amat, S.; Vásquez, F.; Grau Meló, R.; Ivorra Martínez, E.; Sánchez Salmerón, AJ.; Barat Baviera, JM. (2016). Detection of adulterations with different grains in wheat products based on the hyperspectral image technique: The specific cases of flour and bread. Food Control. 62:373-380. doi:10.1016/j.foodcont.2015.11.002S3733806