Cloning and Functional Characterization of Dog OCT1 and OCT2: Another Step in Exploring Species Differences in Organic Cation Transporters

OCT1 and OCT2 are polyspecific membrane transporters that are involved in hepatic and renal drug clearance in humans and mice. In this study, we cloned dog OCT1 and OCT2 and compared their function to the human and mouse orthologs. We used liver and kidney RNA to clone dog OCT1 and OCT2. The cloned and the publicly available RNA-Seq sequences differed from the annotated exon-intron structure of OCT1 in the dog genome CanFam3.1. An additional exon between exons 2 and 3 was identified and confirmed by sequencing in six additional dog breeds. Next, dog OCT1 and OCT2 were stably overexpressed in HEK293 cells and the transport kinetics of five drugs were analyzed. We observed strong differences in the transport kinetics between dog and human orthologs. Dog OCT1 transported fenoterol with 12.9-fold higher capacity but 14.3-fold lower affinity (higher K_M) than human OCT1. Human OCT1 transported ipratropium with 5.2-fold higher capacity but 8.4-fold lower affinity than dog OCT1. Compared to human OCT2, dog OCT2 showed 10-fold lower transport of fenoterol and butylscopolamine. In conclusion, the functional characterization of dog OCT1 and OCT2 reported here may have implications when using dogs as pre-clinical models as well as for drug therapy in dogs.     

Cytopathological Outcomes of Knocking down Expression of Mitochondrial Complex II Subunits in Dictyostelium discoideum

Mitochondrial Complex II is composed of four core subunits and mutations to any of the subunits result in lowered Complex II activity. Surprisingly, although mutations in any of the subunits can yield similar clinical outcomes, there are distinct differences in the patterns of clinical disease most commonly associated with mutations in different subunits. Thus, mutations to the SdhA subunit most often result in mitochondrial disease phenotypes, whilst mutations to the other subunits SdhB-D more commonly result in tumour formation. The reason the clinical outcomes are so different is unknown. Here, we individually antisense-inhibited three of the Complex II subunits, SdhA, SdhB or SdhC, in the simple model organism Dictyostelium discoideum. Whilst SdhB and SdhC knockdown resulted in growth defects on bacterial lawns, antisense inhibition of SdhA expression resulted in a different pattern of phenotypic defects, including impairments of growth in liquid medium, enhanced intracellular proliferation of the bacterial pathogen Legionella pneumophila and phagocytosis. Knockdown of the individual subunits also produced different abnormalities in mitochondrial function with only SdhA knockdown resulting in broad mitochondrial dysfunction. Furthermore, these defects were shown to be mediated by the chronic activation of the cellular energy sensor AMP-activated protein kinase. Our results are in agreement with a role for loss of function of SdhA but not the other Complex II subunits in impairing mitochondrial oxidative phosphorylation and they suggest a role for AMP-activated protein kinase in mediating the cytopathological outcomes.     

Supplementation with SCFAs Re-Establishes Microbiota Composition and Attenuates Hyperalgesia and Pain in a Mouse Model of NTG-Induced Migraine

Migraine is a common brain-disorder that affects 15% of the population. Converging evidence shows that migraine is associated with gastrointestinal disorders. However, the mechanisms underlying the interaction between the gut and brain in patients with migraine are not clear. In this study, we evaluated the role of the short-chain fatty acids (SCFAs) as sodium propionate (SP) and sodium butyrate (SB) on microbiota profile and intestinal permeability in a mouse model of migraine induced by nitroglycerine (NTG). The mice were orally administered SB and SP at the dose of 10, 30 and 100 mg/kg, 5 min after NTG intraperitoneal injections. Behavioral tests were used to evaluate migraine-like pain. Histological and molecular analyses were performed on the intestine. The composition of the intestinal microbiota was extracted from frozen fecal samples and sequenced with an Illumina MiSeq System. Our results demonstrated that the SP and SB treatments attenuated hyperalgesia and pain following NTG injection. Moreover, SP and SB reduced histological damage in the intestine and restored intestinal permeability and the intestinal microbiota profile. These results provide corroborating evidence that SB and SP exert a protective effect on central sensitization induced by NTG through a modulation of intestinal microbiota, suggesting the potential application of SCFAs as novel supportive therapies for intestinal disfunction associated with migraine.     

Moderating effects of a craving intervention on the relation between negative mood and heavy drinking following treatment for alcohol dependence.

Objective: Negative affect is a significant predictor of alcohol relapse, and the relation between negative affect and drinking has been shown to be strongly mediated by alcohol craving. Thus, targeting craving during treatment could potentially attenuate the relation between negative affect and drinking. Method: The current study is a secondary analysis of data from the COMBINE study, a randomized clinical trial that combined pharmacotherapy with behavioral intervention in the treatment of alcohol dependence. Our goal in the current study was to examine whether a treatment module that targeted craving would predict changes in negative mood during the 16-week combined behavioral intervention (n = 776) and the relation among changes in mood, craving, and changes in heavy drinking during treatment and 1 year posttreatment. Results: Changes in negative mood were significantly associated with changes in heavy drinking during treatment (f2 = 0.78). Participants (n = 432) who received the craving module had significantly fewer heavy drinking days during treatment (d = 0.31), and receiving the module moderated the relation between negative mood and heavy drinking during treatment (f2 = 0.92) and 1 year posttreatment (f2 = 0.03). Moderating effects of the craving module were mediated by changes in craving during treatment. Within-subject analyses indicated significant pre- to postmodule reductions in negative mood. Additionally, postmodule craving significantly mediated the association between negative mood and heavy drinking during treatment and at posttreatment. Conclusions: The craving module of the combined behavioral intervention may weaken the relation between negative affect and heavy drinking by fostering greater decreases in craving during treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Predictors of supportive coparenting after relationship dissolution among at-risk parents.

Supportive coparenting after relationship dissolution is associated with increased father involvement which can buffer against the negative effects of parental relationship dissolution. Low-income, at-risk families are much more likely to experience relationship dissolutions; hence, supportive coparenting after dissolution is particularly important in these families. We examined whether relationship (commitment and quality) and child (difficult temperament and gender) characteristics predicted initial levels of, and change in, supportive coparenting after relationship dissolution in the Fragile Families and Child Wellbeing Study (N = 1,603). We used structural equation modeling of latent growth curves to examine four time points collected at the focal child's birth and first, third, and fifth birthdays. Ninety-percent of the mothers had nonmarital births, and about three-quarters had a high school diploma or less education. Overall, supportive coparenting decreased over time. Mothers in more committed relationships prior to the dissolution initially had significantly lower supportive coparenting. But over time, mothers who had been in more committed relationships increased in supportive coparenting. Mothers who had been in higher quality relationships prior to dissolution initially reported more supportive coparenting. At each time point, if a mother was romantically involved with a new partner, she reported significantly lower supportive coparenting compared to mothers who were single. With regard to child characteristics, mothers who reported their child as more difficult had significantly lower initial supportive coparenting. Similar results for fathers are discussed. Overall, the relationship characteristics of parents were important predictors of supportive coparenting both initially and over time. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Web-conference supervision for advanced psychotherapy training: A practical guide.

The advent of readily accessible, inexpensive Web-conferencing applications has opened the door for distance psychotherapy supervision, using video recordings of treated clients. Although relatively new, this method of supervision is advantageous given the ease of use and low cost of various Internet applications. This method allows periodic supervision from point to point around the world, with no travel costs and no long gaps between direct training contacts. Web-conferencing permits face-to-face training so that the learner and supervisor can read each other's emotional responses while reviewing case material. It allows group learning from direct supervision to complement local peer-to-peer learning methods. In this article, we describe the relevant literature on this type of learning method, the practical points in its utilization, its limitations, and its benefits. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Implicit and explicit preferences for physical attractiveness in a romantic partner: A double dissociation in predictive validity.

Five studies develop and examine the predictive validity of an implicit measure of the preference for physical attractiveness in a romantic partner. Three hypotheses were generally supported. First, 2 variants of the go/no-go association task revealed that participants, on average, demonstrate an implicit preference (i.e., a positive spontaneous affective reaction) for physical attractiveness in a romantic partner. Second, these implicit measures were not redundant with a traditional explicit measure: The correlation between these constructs was .00 on average, and the implicit measures revealed no reliable sex differences, unlike the explicit measure. Third, explicit and implicit measures exhibited a double dissociation in predictive validity. Specifically, explicit preferences predicted the extent to which attractiveness was associated with participants' romantic interest in opposite-sex photographs but not their romantic interest in real-life opposite-sex speed-daters or confederates. Implicit preferences showed the opposite pattern. This research extends prior work on implicit processes in romantic relationships and offers the first demonstration that any measure of a preference for a particular characteristic in a romantic partner (an implicit measure of physical attractiveness, in this case) predicts individuals' evaluation of live potential romantic partners. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

The influence of delaying judgments of learning on metacognitive accuracy: A meta-analytic review.

Many studies have examined the accuracy of predictions of future memory performance solicited through judgments of learning (JOLs). Among the most robust findings in this literature is that delaying predictions serves to substantially increase the relative accuracy of JOLs compared with soliciting JOLs immediately after study, a finding termed the delayed JOL effect. The meta-analyses reported in the current study examined the predominant theoretical accounts as well as potential moderators of the delayed JOL effect. The first meta-analysis examined the relative accuracy of delayed compared with immediate JOLs across 4,554 participants (112 effect sizes) through gamma correlations between JOLs and memory accuracy. Those data showed that delaying JOLs leads to robust benefits to relative accuracy (g = 0.93). The second meta-analysis examined memory performance for delayed compared with immediate JOLs across 3,807 participants (98 effect sizes). Those data showed that delayed JOLs result in a modest but reliable benefit for memory performance relative to immediate JOLs (g = 0.08). Findings from these meta-analyses are well accommodated by theories suggesting that delayed JOL accuracy reflects access to more diagnostic information from long-term memory rather than being a by-product of a retrieval opportunity. However, these data also suggest that theories proposing that the delayed JOL effect results from a memorial benefit or the match between the cues available for JOLs and those available at test may also provide viable explanatory mechanisms necessary for a comprehensive account. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurocognitive signs in prodromal Huntington disease.

Objective: PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. Method: For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be ≤9 years; MID, between 9 and 15 years; and FAR, ≥15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory–perceptual functions, and executive functions. Results: Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohen's d NEAR as large as ?1.17, MID as large as ?0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = ?0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntington's Disease Rating Scale motor score accounted for 11.7%. Conclusions: Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)