Putative chemosensory receptors are differentially expressed in the sensory organs of male and female crown-of-thorns starfish, Acanthaster planci.

BACKGROUND: Chemosensation is a critical signalling process for all organisms and is achieved through the interaction between chemosensory receptors and their ligands. The Crown-of-thorns starfish, Acanthaster planci species complex (COTS), is a predator of coral polyps and Acanthaster cf. solaris is currently considered to be one of the main drivers of coral loss on the Great Barrier Reef in Queensland, Australia. RESULTS: This study reveals the presence of putative variant Ionotropic Receptors (IRs) which are differentially expressed in the olfactory organs of COTS. Several other types of G protein-coupled receptors such as adrenergic, metabotropic glutamate, cholecystokinin, trace-amine associated, GRL101 and GPCR52 receptors have also been identified. Several receptors display male-biased expression within the sensory tentacles, indicating possible reproductive significance. CONCLUSIONS: Many of the receptors identified in this study may have a role in reproduction and are therefore key targets for further investigation. Based on their differential expression within the olfactory organs and presence in multiple tissues, it is possible that several of these receptor types have expanded within the Echinoderm lineage. Many are likely to be species-specific with novel ligand-binding affinity and a diverse range of functions. This study is the first to describe the presence of variant Ionotropic Glutamate Receptors in any Echinoderm, and is only the second study to investigate chemosensory receptors in any starfish or marine pest. These results represent a significant step forward in understanding the chemosensory abilities of COTS.

Influence of biases in numerical magnitude allocation on human prosocial decision making.

Over the past decade neuroscientific research has attempted to probe the neurobiological underpinnings of human prosocial decision making. Such research has almost ubiquitously employed tasks such as the dictator game or similar variations (i.e., ultimatum game). Considering the explicit numerical nature of such tasks, it is surprising that the influence of numerical cognition on decision making during task performance remains unknown. While performing these tasks, participants typically tend to anchor on a 50:50 split that necessitates an explicit numerical judgement (i.e., number-pair bisection). Accordingly, we hypothesize that the decision-making process during the dictator game recruits overlapping cognitive processes to those known to be engaged during number-pair bisection. We observed that biases in numerical magnitude allocation correlated with the formulation of decisions during the dictator game. That is, intrinsic biases toward smaller numerical magnitudes were associated with the formulation of less favorable decisions, whereas biases toward larger magnitudes were associated with more favorable choices. We proceeded to corroborate this relationship by subliminally and systematically inducing biases in numerical magnitude toward either higher or lower numbers using a visuo-vestibular stimulation paradigm. Such subliminal alterations in numerical magnitude allocation led to proportional and corresponding changes to an individual's decision making during the dictator game. Critically, no relationship was observed between neither intrinsic nor induced biases in numerical magnitude on decision making when assessed using a nonnumerical-based prosocial questionnaire. Our findings demonstrate numerical influences on decisions formulated during the dictator game and highlight the necessity to control for confounds associated with numerical cognition in human decision-making paradigms.NEW & NOTEWORTHY We demonstrate that intrinsic biases in numerical magnitude can directly predict the amount of money donated by an individual to an anonymous stranger during the dictator game. Furthermore, subliminally inducing perceptual biases in numerical-magnitude allocation can actively drive prosocial choices in the corresponding direction. Our findings provide evidence for numerical influences on decision making during performance of the dictator game. Accordingly, without the implementation of an adequate control for numerical influences, the dictator game and other tasks with an inherent numerical component (i.e., ultimatum game) should be employed with caution in the assessment of human behavior.

Bidirectional Modulation of Numerical Magnitude.

Numerical cognition is critical for modern life; however, the precise neural mechanisms underpinning numerical magnitude allocation in humans remain obscure. Based upon previous reports demonstrating the close behavioral and neuro-anatomical relationship between number allocation and spatial attention, we hypothesized that these systems would be subject to similar control mechanisms, namely dynamic interhemispheric competition. We employed a physiological paradigm, combining visual and vestibular stimulation, to induce interhemispheric conflict and subsequent unihemispheric inhibition, as confirmed by transcranial direct current stimulation (tDCS). This allowed us to demonstrate the first systematic bidirectional modulation of numerical magnitude toward either higher or lower numbers, independently of either eye movements or spatial attention mediated biases. We incorporated both our findings and those from the most widely accepted theoretical framework for numerical cognition to present a novel unifying computational model that describes how numerical magnitude allocation is subject to dynamic interhemispheric competition. That is, numerical allocation is continually updated in a contextual manner based upon relative magnitude, with the right hemisphere responsible for smaller magnitudes and the left hemisphere for larger magnitudes.

Perceived state of self during motion can differentially modulate numerical magnitude allocation.

Although a direct relationship between numerical allocation and spatial attention has been proposed, recent research suggests that these processes are not directly coupled. In keeping with this, spatial attention shifts induced either via visual or vestibular motion can modulate numerical allocation in some circumstances but not in others. In addition to shifting spatial attention, visual or vestibular motion paradigms also (i) elicit compensatory eye movements which themselves can influence numerical processing and (ii) alter the perceptual state of 'self', inducing changes in bodily self-consciousness impacting upon cognitive mechanisms. Thus, the precise mechanism by which motion modulates numerical allocation remains unknown. We sought to investigate the influence that different perceptual experiences of motion have upon numerical magnitude allocation while controlling for both eye movements and task-related effects. We first used optokinetic visual motion stimulation (OKS) to elicit the perceptual experience of either 'visual world' or 'self'-motion during which eye movements were identical. In a second experiment, we used a vestibular protocol examining the effects of perceived and subliminal angular rotations in darkness, which also provoked identical eye movements. We observed that during the perceptual experience of 'visual world' motion, rightward OKS-biased judgments towards smaller numbers, whereas leftward OKS-biased judgments towards larger numbers. During the perceptual experience of 'self-motion', judgments were biased towards larger numbers irrespective of the OKS direction. Contrastingly, vestibular motion perception was found not to modulate numerical magnitude allocation, nor was there any differential modulation when comparing 'perceived' vs. 'subliminal' rotations. We provide a novel demonstration that numerical magnitude allocation can be differentially modulated by the perceptual state of self during visual but not vestibular mediated motion.

Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria.

Statins induce acute vasorelaxation which may contribute to the overall benefits of statins in the treatment of cardiovascular disease. The mechanism underlying this relaxation is unknown. As statins have been shown to alter mitochondrial function, in this study we investigated the role of mitochondria in the relaxation to simvastatin. Relaxation of porcine coronary artery segments by statins was measured using isolated tissue baths. Mitochondrial activity was determined by measuring changes in rhodamine 123 fluorescence. Changes in intracellular calcium levels were determined in freshly isolated smooth muscle cells with Fluo-4 using standard epifluorescent imaging techniques. Simvastatin, but not pravastatin, produced a slow relaxation of the coronary artery, which was independent of the endothelium. The relaxation was attenuated by the mitochondrial complex I inhibitor rotenone (10µM) and the complex III inhibitor myxothiazol (10µM), or a combination of the two. The complex III inhibitor antimycin A (10µM) produced a similar time-dependent relaxation of the porcine coronary artery, which was attenuated by rotenone. Changes in rhodamine 123 fluorescence showed that simvastatin (10µM) depolarized the membrane potential of mitochondria in both isolated mitochondria and intact blood vessels. Simvastatin and antimycin A both inhibited calcium-induced contractions in isolated blood vessels and calcium influx in smooth muscle cells and this inhibition was prevented by rotenone. In conclusion, simvastatin produces an endothelium-independent relaxation of the porcine coronary artery which is dependent, in part, upon effects on the mitochondria. The effects on the mitochondria may lead to a reduction in calcium influx and hence relaxation of the blood vessel.

The endogenous cannabinoid anandamide increases human airway epithelial cell permeability through an arachidonic acid metabolite.

Injury to the bronchial epithelium in respiratory diseases such as asthma and COPD results in the loss of barrier function and an elevated sensitivity to environmental insults. An increased release of the endogenous cannabinoid, anandamide in response to inhalation of allergen in asthmatic patients has been reported. The aim of this study was, therefore, to determine the effects of endocannabinoids on bronchial epithelial cell permeability and to investigate the mechanisms involved. Calu-3 human bronchial epithelial cells were cultured at air-liquid interface to allow development of tight junctions. Changes in Transepithelial Electrical Resistance (TEER), a reflection of epithelial permeability, were measured at various time points post-treatment, and expression of the tight junction proteins, occludin and ZO-1, were determined using Western immunoblotting. Anandamide produced a significant reduction in TEER, which was unaffected by cannabinoid receptor antagonists, but attenuated by URB597, an inhibitor of fatty acid amide hydrolase, and by a combination of cyclooxygenase (COX) and lipoxygenase (LOX) blockade. The anandamide metabolite, arachidonic acid, showed similar TEER decrease that was also prevented in the presence of COX and LOX inhibitor. Expression of occludin and ZO-1 were also reduced by anandamide. These findings indicate a pro-inflammatory-like effect of anandamide on bronchial epithelial permeability, mediated by cyclooxygenase and lipoxygenase metabolites, and suggest that inhibition of anandamide degradation might provide a novel approach to treat airway inflammation.

Pituitary gland volume and psychosocial stress among children at elevated risk for schizophrenia.

BACKGROUND: Pituitary volume enlargements have been observed among individuals with first-episode psychosis. These abnormalities are suggestive of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, which may contribute to the development of psychosis. However, the extent to which these abnormalities characterize individuals at elevated risk for schizophrenia prior to illness onset is currently unclear, as volume increases, decreases and no volume differences have all been reported relative to controls. The current study aimed to determine whether antipsychotic-naive, putatively at-risk children who present multiple antecedents of schizophrenia (ASz) or a family history of illness (FHx) show pituitary volume abnormalities relative to typically developing (TD) children. An additional aim was to explore the association between pituitary volume and experiences of psychosocial stress. METHOD: ASz (n = 30), FHx (n = 22) and TD (n = 32) children were identified at age 9-12 years using a novel community-screening procedure or as relatives of individuals with schizophrenia. Measures of pituitary volume and psychosocial stress were obtained at age 11-14 years. RESULTS: Neither ASz nor FHx children showed differences in pituitary volume relative to TD children. Among FHx children only, pituitary volume was negatively associated with current distress relating to negative life events and exposure to physical punishment. CONCLUSIONS: The lack of pituitary volume abnormalities among ASz and FHx children is consistent with our previous work demonstrating that these children are not characterized by elevated diurnal cortisol levels. The findings imply that these biological markers of HPA axis hyperactivity, observed in some older samples of high-risk individuals, may emerge later, more proximally to disease onset.

A role for the sodium pump in H2O2-induced vasorelaxation in porcine isolated coronary arteries.

Hydrogen peroxide (H2O2) has been proposed to act as a factor for endothelium-derived hyperpolarization (EDH) and EDH may act as a 'back up' system to compensate the loss of the NO pathway. Here, the mechanism of action of H2O2 in porcine isolated coronary arteries (PCAs) was investigated. Distal PCAs were mounted in a wire myograph and pre-contracted with U46619 (1nM-50µM), a thromboxane A2-mimetic or KCl (60mM). Concentration-response curves to H2O2(1µM-1mM), bradykinin (0.01nM-1µM), sodium nitroprusside (SNP) (10nM-10µM), verapamil (1nM-10µM), KCl (0-20mM) or Ca(2+)-reintroduction (1µM-10mM) were constructed in the presence of various inhibitors. Activity of the Na(+)/K(+)-pump was measured through rubidium-uptake using atomic absorption spectrophotometry. H2O2 caused concentration-dependent vasorelaxations with a maximum relaxation (Rmax) of 100±16% (mean±SEM), pEC50=4.18±0.20 (n=4) which were significantly inhibited by PEG-catalase at 0.1-1.0mM H2O2 (P<0.05). 10mM TEA significantly inhibited the relaxation up to 100µM H2O2 (P<0.05). 60mM K(+) and 500nM ouabain significantly inhibited H2O2-induced vasorelaxation producing a relaxation of 40.8±8.5% (n=5) and 47.5±8.6% (n=6) respectively at 1mM H2O2 (P<0.0001). H2O2-induced vasorelaxation was unaffected by the removal of endothelium, inhibition of NO, cyclo-oxygenase, gap junctions, SKCa, IKCa, BKCa Kir, KV, KATP or cGMP. 100µM H2O2 had no effects on the KCl-induced vasorelaxation or Ca(2+)-reintroduction contraction. 1mM H2O2 inhibited both KCl-induced vasorelaxation and rubidium-uptake consistent with inhibition of the Na(+)/K(+)-pump activity. We have shown that the vascular actions of H2O2 are sensitive to ouabain and high concentrations of H2O2 are able to modulate the Na(+)/K(+)-pump. This may contribute towards its vascular actions.

Individual differences in expert motor coordination associated with white matter microstructure in the cerebellum.

Recent investigations into the neural basis of elite sporting performance have focused on whether cortical activity might characterize individual differences in ability. However, very little is understood about how changes in brain structure might contribute to individual differences in expert motor control. We compared the behavior and brain structure of healthy controls with a group of karate black belts, an expert group who are able to perform rapid, complex movements that require years of training. Using 3D motion tracking, we investigated whether the ability to control ballistic arm movements was associated with differences in white matter microstructure. We found that karate experts are better able than novices to coordinate the timing of inter-segmental joint velocities. Diffusion tensor imaging revealed significant differences between the groups in the microstructure of white matter in the superior cerebellar peduncles (SCPs) and primary motor cortex-brain regions that are critical to the voluntary control of movement. Motor coordination, the amount of experience, and the age at which training began were all associated with individual differences in white matter integrity in the cerebellum within the karate groups. These findings suggest a role for the white matter pathways of the SCPs in motor expertise.

Distinct mechanisms of relaxation to bioactive components from chamomile species in porcine isolated blood vessels.

German chamomile (Matricaria recutita L.), a widely-used herbal medicine, has been reported to have a wide range of biological effects, including smooth muscle relaxation. The aim of this study was to compare the effects of representative compounds from chamomile (apigenin, luteolin, (-)-α-bisabolol, farnesene, umbelliferone; 3-30 µM) on vascular tone using porcine coronary and splenic arteries mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane-mimetic U46619. Apigenin, luteolin, and (-)-α-bisabolol produced slow, concentration-dependent relaxations in both the coronary and splenic arteries that were not blocked by inhibition of nitric oxide synthase or potassium channels. Removal of extracellular calcium inhibited the relaxations to all three compounds, and these compounds also inhibited calcium re-addition-evoked contractions, indicating that the relaxation response may be mediated through inhibition of calcium influx. Apigenin and luteolin, but not (-)-α-bisabolol, enhanced the relaxation to the nitric oxide donor sodium nitroprusside, indicating that apigenin and luteolin may act to regulate cyclic GMP levels. Umbelliferone produced a rapid, transient relaxation in the splenic artery, but not the coronary artery, that was inhibited by L-NAME and removal of the endothelium, suggesting an influence on nitric oxide production. Farnesene, at concentrations up to 30 µM, was without effect in either blood vessel. In conclusion, hydroxylated compounds (apigenin, luteolin and (-)-α-bisabolol) found in chamomile all caused a slow relaxation of isolated blood vessels through an effect on calcium influx. Umbelliferone, on the other hand, produced a rapid, transient relaxation dependent upon release of nitric oxide from the endothelium.

Obese youths are not more likely to become depressed, but depressed youths are more likely to become obese.

BACKGROUND: Overweight/obesity and depression are both major public health problems among adolescents. However, the question of a link between overweight/obesity and depression remains unresolved in this age group. We examined whether obesity increases risk of depression, or depression increases risk of obesity, or whether there is a reciprocal effect. METHOD: A two-wave prospective cohort study of adolescents aged 11­17 years at baseline (n=4175) followed up a year later (n=3134) sampled from the Houston metropolitan area. Overweight was defined as 95th percentile >body mass index (BMI) < or = 85th percentile and obese as BMI >95th percentile. Three indicators of depression were examined: any DSM-IV mood disorder, major depression, and symptoms of depression. RESULTS: Data for the two-wave cohort indicated no evidence of reciprocal effects between weight and depression. Weight status predicted neither major depression nor depressive symptoms. However, mood disorders generally and major depression in particular increased risk of future obesity more than twofold. Depressed males had a sixfold increased risk of obesity. Females with depressive symptoms had a marginally increased risk of being overweight but not obese. CONCLUSIONS: Our findings, combined with those of recent meta-analyses, suggest that obese youths are not more likely to become depressed but that depressed youths are more likely to become obese.

Pre-contraction with the thromboxane-mimetic U46619 enhances P2X receptor-mediated contractions in isolated porcine splenic artery.

We have previously demonstrated that the thromboxane-mimetic U46619 enhances α(2)-adrenoceptor-mediated contractions through increased activation of extracellular signal-regulated kinase (ERK). In this study, we determined whether U46619 also enhances P2X-mediated contractions through the same pathway. Segments of porcine splenic artery were mounted in isolated tissue baths. Tissues were pre-contracted with U46619 to 10-20% of the response to 60 mM KCl prior to addition of α,ß-methylene ATP (P2X receptor agonist). The effect of inhibition of ERK activation with the mitogen-activated protein (MAP)/ERK kinase inhibitor PD98059 (50 µM), Rho kinase inhibition with Y27632 (10 µM), p38 MAP kinase with SB203580 (10 µM) or L-type calcium channels with nifedipine (1 µM) on both the direct and enhanced contractions was then determined. U46619 enhanced the contractions to α,ß-methylene ATP. Although PD98059 inhibited the direct contractions to α,ß-methylene ATP, it had no effect on the U46619-enhanced contractions. Similarly, Y27632 and SB203580 inhibited the direct contractions to α,ß-methylene ATP, but had no effect on the enhanced contractions. Nifedipine inhibited the responses to α,ß-methylene ATP in the absence and presence of U46619. This study demonstrates that pre-contraction with U46619 enhances P2X-mediated contractions in the porcine splenic artery through a mechanism independent of ERK, Rho kinase and p38 MAP kinase. Further studies are required to determine the exact mechanism involved.

The relationship between postprandial bile acid concentration, GLP-1, PYY and ghrelin.

BACKGROUND: Gut hormones peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) play an integral role in appetite control and energy homeostasis. Entero-endocrine L-cells can be stimulated by nutrients and or bile acids to co-secrete PYY and GLP-1. The aim of this study was to determine the response of bile acids, PYY, GLP-1 and ghrelin after a test meal. DESIGN: Twelve subjects with a BMI of 22·8 (0·52) kg/m² [mean (SEM)] received a 400 kcal test meal after which blood samples were taken every 30 min from 0 to 180 min. PYY, GLP-1 and ghrelin were measured by radioimmunoassays. Fractionated bile acids were measured by HPLC-MSMS. RESULTS: PYY positively correlated with glycochenodeoxycholic acid (GCDCA) (rs = 0·23, P = 0·03) and taurochenodeoxycholic acid (TCDCA) (rs = 0·26, P = 0·02). GLP-1 positively correlated with GCDCA (rs = 0·22, P = 0·047) and glycodeoxycholic acid (GDCA) (rs = 0·3, P = 0·005). Ghrelin negatively correlated with GDCA (rs = -0·45, P≤ 0·0001), TCDCA (rs = -0·23, P = 0·034) and taurodeoxycholic acid (TDCA) (rs = -0·44, P≤ 0·0001). CONCLUSION: PYY and GLP-1 responses correlated with chenodeoxycholic acid (CDCA) counterparts, whereas ghrelin negatively correlated with deoxycholic acid (DCA) counterparts. Specific bile acids may thus differentially affect entero-endocrine cells.

Co-morbidity between major depressive disorder and anxiety disorders: shared etiology or direct causation?

BACKGROUND: Major depressive disorder (MDD) and anxiety disorders (ANX) are debilitating and prevalent conditions that often co-occur in adolescence and young adulthood. The leading theoretical models of their co-morbidity include the direct causation model and the shared etiology model. The present study compared these etiological models of MDD-ANX co-morbidity in a large, prospective, non-clinical sample of adolescents tracked through age 30. METHOD: Logistic regression was used to examine cross-sectional associations between ANX and MDD at Time 1 (T1). In prospective analyses, Cox proportional hazards models were used to examine T1 predictors of subsequent disorder onset, including risk factors specific to each disorder or common to both disorders. Prospective predictive effect of a lifetime history of one disorder (e.g. MDD) on the subsequent onset of the second disorder (e.g. ANX) was then examined. This step was repeated while controlling for common risk factors. RESULTS: The findings supported relatively distinct profiles of risk between MDD and ANX depending on order of development. Whereas the shared etiology model best explained co-morbid cases in which MDD preceded ANX, direct causation was supported for co-morbid cases in which ANX preceded MDD. CONCLUSIONS: Consistent with previous research, significant cross-sectional and prospective associations were found between MDD and ANX. The results of the present study suggest that different etiological models may characterize the co-morbidity between MDD and ANX based upon the temporal order of onset. Implications for classification and prevention efforts are discussed.

An fMRI study of visuo-vestibular interactions following vestibular neuritis.

Vestibular neuritis (VN) is characterised by acute vertigo due to a sudden loss of unilateral vestibular function. A considerable proportion of VN patients proceed to develop chronic symptoms of dizziness, including visually induced dizziness, specifically during head turns. Here we investigated whether the development of such poor clinical outcomes following VN, is associated with abnormal visuo-vestibular cortical processing. Accordingly, we applied functional magnetic resonance imaging to assess brain responses of chronic VN patients and compared these to controls during both congruent (co-directional) and incongruent (opposite directions) visuo-vestibular stimulation (i.e. emulating situations that provoke symptoms in patients). We observed a focal significant difference in BOLD signal in the primary visual cortex V1 between patients and controls in the congruent condition (small volume corrected level of p < .05 FWE). Importantly, this reduced BOLD signal in V1 was negatively correlated with functional status measured with validated clinical questionnaires. Our findings suggest that central compensation and in turn clinical outcomes in VN are partly mediated by adaptive mechanisms associated with the early visual cortex.

Patients with chronic dizziness following traumatic head injury typically have multiple diagnoses involving combined peripheral and central vestibular dysfunction.

OBJECTIVE: We hypothesised that chronic vestibular symptoms (CVS) of imbalance and dizziness post-traumatic head injury (THI) may relate to: (i) the occurrence of multiple simultaneous vestibular diagnoses including both peripheral and central vestibular dysfunction in individual patients increasing the chance of missed diagnoses and suboptimal treatment; (ii) an impaired response to vestibular rehabilitation since the central mechanisms that mediate rehabilitation related brain plasticity may themselves be disrupted. METHODS: We report the results of a retrospective analysis of both the comprehensive clinical and vestibular laboratory testing of 20 consecutive THI patients with prominent and persisting vestibular symptoms still present at least 6months post THI. RESULTS: Individual THI patients typically had multiple vestibular diagnoses and unique to this group of vestibular patients, often displayed both peripheral and central vestibular dysfunction. Despite expert neuro-otological management, at two years 20% of patients still had persisting vestibular symptoms. CONCLUSION: In summary, chronic vestibular dysfunction in THI could relate to: (i) the presence of multiple vestibular diagnoses, increasing the risk of 'missed' vestibular diagnoses leading to persisting symptoms; (ii) the impact of brain trauma which may impair brain plasticity mediated repair mechanisms. Apart from alerting physicians to the potential for multiple vestibular diagnoses in THI, future work to identify the specific deficits in brain function mediating poor recovery from post-THI vestibular dysfunction could provide the rationale for developing new therapy for head injury patients whose vestibular symptoms are resistant to treatment.

A critical role for cystathionine-ß-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery.

Hypoxia-induced coronary artery vasodilatation protects the heart by increasing blood flow under ischemic conditions, however its mechanism is not fully elucidated. Hydrogen sulfide (H2S) is reported to be an oxygen sensor/transducer in the vasculature. The present study aimed to identify and characterise the role of H2S in the hypoxic response of the coronary artery, and to define the H2S synthetic enzymes involved. Immunoblotting and immunohistochemistry showed expression of all three H2S-producing enzymes, cystathionine-ß-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), in porcine coronary artery. Artery segments were mounted for isometric tension recording; hypoxia caused a transient endothelium-dependent contraction followed by prolonged endothelium-independent relaxation. The CBS inhibitor amino-oxyacetate (AOAA) reduced both phases of the hypoxic response. The CSE inhibitor dl-propargylglycine (PPG) and aspartate (limits MPST) had no effect alone, but when applied together with AOAA the hypoxic relaxation response was further reduced. Exogenous H2S (Na2S and NaHS) produced concentration-dependent contraction followed by prolonged relaxation. Responses to both hypoxia and exogenous H2S were dependent on the endothelium, NO, cGMP, K+ channels and Cl-/HCO3- exchange. H2S production in coronary arteries was blocked by CBS inhibition (AOAA), but not by CSE inhibition (PPG). These data show that H2S is an endogenous mediator of the hypoxic response in coronary arteries. Of the three H2S-producing enzymes, CBS, expressed in the vascular smooth muscle, appears to be the most important for H2S generated during hypoxic relaxation of the coronary artery. A contribution from other H2S-producing enzymes only becomes apparent when CBS activity is inhibited.

Functional neuroimaging of visuo-vestibular interaction.

The brain combines visual, vestibular and proprioceptive information to distinguish between self- and world motion. Often these signals are complementary and indicate that the individual is moving or stationary with respect to the surroundings. However, conflicting visual motion and vestibular cues can lead to ambiguous or false sensations of motion. In this study, we used functional magnetic resonance imaging to explore human brain activation when visual and vestibular cues were either complementary or in conflict. We combined a horizontally moving optokinetic stimulus with caloric irrigation of the right ear to produce conditions where the vestibular activation and visual motion indicated the same (congruent) or opposite directions of self-motion (incongruent). Visuo-vestibular conflict was associated with increased activation in a network of brain regions including posterior insular and transverse temporal areas, cerebellar tonsil, cingulate and medial frontal gyri. In the congruent condition, there was increased activation in primary and secondary visual cortex. These findings suggest that when sensory information regarding self-motion is contradictory, there is preferential activation of multisensory vestibular areas to resolve this ambiguity. When cues are congruent, there is a bias towards visual cortical activation. The data support the view that a network of brain areas including the posterior insular cortex may play an important role in integrating and disambiguating visual and vestibular cues.

Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder.

Bipolar disorder (BD) is characterized by emotional dysregulation and cognitive deficits associated with abnormal connectivity between subcortical-primarily emotional processing regions-and prefrontal regulatory areas. Given the significant contribution of genetic factors to BD, studies in unaffected first-degree relatives can identify neural mechanisms of genetic risk but also resilience, thus paving the way for preventive interventions. Dynamic causal modeling (DCM) and random-effects Bayesian model selection were used to define and assess connectomic phenotypes linked to facial affect processing and working memory in a demographically matched sample of first-degree relatives carefully selected for resilience (n=25), euthymic patients with BD (n=41) and unrelated healthy controls (n=46). During facial affect processing, patients and relatives showed similarly increased frontolimbic connectivity; resilient relatives, however, evidenced additional adaptive hyperconnectivity within the ventral visual stream. During working memory processing, patients displayed widespread hypoconnectivity within the corresponding network. In contrast, working memory network connectivity in resilient relatives was comparable to that of controls. Our results indicate that frontolimbic dysfunction during affect processing could represent a marker of genetic risk to BD, and diffuse hypoconnectivity within the working memory network a marker of disease expression. The association of hyperconnectivity within the affect-processing network with resilience to BD suggests adaptive plasticity that allows for compensatory changes and encourages further investigation of this phenotype in genetic and early intervention studies.

Altered GAP-43 immunoreactivity in regenerating sciatic nerve of diabetic rats.

Experimental diabetes in the rat is associated with impaired axon regeneration. Successful regeneration depends on the construction of axonal growth cones and establishment of appropriate target connections. The growth-associated protein (GAP)-43 is a major component of the axonal growth cone, and its synthesis and axonal transport are markedly increased during regeneration. The purpose of this study was to determine the effect of experimental diabetes on the synthesis and axonal transport of GAP-43 in regenerating sciatic nerves. Rats were rendered diabetic with 50 mg/kg streptozotocin i.p. Four weeks later, the rats were anesthetized, and one sciatic nerve was crushed to induce regeneration. After 2 weeks, nerves were ligated, and 6 h later, nerve pieces proximal to the ligature and dorsal root ganglia were removed, and proteins were separated by PAGE. Western blots of gels were probed with antibody 10E8/E7 against GAP-43. The presence of GAP-43 was confirmed by immunohistochemistry of nerve sections. Densitometric analysis of the blots showed a 45% reduction in native GAP-43 immunoreactivity in nerve pieces proximal to the ligature (P < 0.05; n = 7). Northern blots of total RNA extracted from pooled dorsal root ganglia were probed with a 32P-radiolabeled cDNA probe for GAP-43. There was no significant difference in the amount of GAP-43 mRNA between diabetic and nondiabetic rats. Immunohistochemistry of sciatic nerve confirmed the reduction in GAP-43 immunoreactivity. We conclude that a defect in turnover or axonal transport of GAP-43 may contribute to the impaired peripheral nerve regeneration in diabetes.