Ghrelin and the brain-gut axis as a pharmacological target for appetite control

Appetite regulation is highly complex and involves a large number of orexigenic and anorexigenic peptide hormones. These are small, processed, secreted peptides derived from larger prepropeptide precursors. These peptides are important targets for the development of therapeutics for obesity, a global health epidemic. As a case study, we consider the ghrelin axis. The ghrelin axis is likely to be a particularly useful drug target, as it also plays a role in energy homeostasis, adipogenesis, insulin regulation and reward associated with food intake. Ghrelin is the only known circulating gut orexigenic peptide hormone. As it appears to play a role in diet-induced obesity, blocking the action of ghrelin is likely to be effective for treating and preventing obesity. The ghrelin peptide has been targeted using a number of approaches, with ghrelin mirror-image oligonucleotides (Spiegelmers) and immunotherapy showing some promise. The ghrelin receptor, the growth hormone secretagogue receptor, may also provide a useful target and a number of antagonists and inverse agonists have been developed. A particularly promising new target is the enzyme which octanoylates ghrelin, ghrelin O-acyltransferase (GOAT), and drugs that inhibit GOAT are likely to circumvent pharmacological issues associated with approaches that directly target ghrelin or its receptor.

Systematic differences in membrane acyl composition associated with varying body mass in mammals occur in all phospholipid classes : an analysis of kidney and brain

The acyl composition of membrane phospholipids in kidney and brain of mammals of different body mass was examined. It was hypothesized that reduction in unsaturation index (number of double bonds per 100 acyl chains) of membrane phospholipids with increasing body mass in mammals would be made-up of similar changes in acyl composition across all phospholipid classes and that phospholipid class distribution would be regulated and similar in the same tissues of the different-sized mammals. The results of this study supported both hypotheses. Differences in membrane phospholipid acyl composition (i. e. decreased omega-3 fats, increased monounsaturated fats and decreased unsaturation index with increasing body size) were not restricted to any specific phospholipid molecule or to any specific phospholipid class but were observed in all phospholipid classes. With increase in body mass of mammals both monounsaturates and use of less unsaturated polyunsaturates increases at the expense of the long-chain highly unsaturated omega-3 and omega-6 polyunsaturates, producing decreases in membrane unsaturation. The distribution of membrane phospholipid classes was essentially the same in the different-sized mammals with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) together constituting similar to 91% and similar to 88% of all phospholipids in kidney and brain, respectively. The lack of sphingomyelin in the mouse tissues and higher levels in larger mammals suggests an increased presence of membrane lipid rafts in larger mammals. The results of this study support the proposal that the physical properties of membranes are likely to be involved in changing metabolic rate.

Validity of accelerometry for measurement of activity in people with brain injury

Purpose To evaluate the validity of a uniaxial accelerometer (MTI Actigraph) for measuring physical activity in people with acquired brain injury (ABI) using portable indirect calorimetry (Cosmed K4b(2)) as a criterion measure. Methods Fourteen people with ABI and related gait pattern impairment (age 32 +/- 8 yr) wore an MTI Actigraph that measured activity (counts(.)min-(1)) and a Cosmed K4b(2) that measured oxygen consumption (mL(.)kg(-1.)min(-1)) during four activities: quiet sitting (QS) and comfortable paced (CP), brisk paced (BP), and fast paced (FP) walking. MET levels were predicted from Actigraph counts using a published equation and compared with Cosmed measures. Predicted METs for each of the 56 activity bouts (14 participants X 4 bouts) were classified (light, moderate, vigorous, or very vigorous intensity) and compared with Cosmed-based classifications. Results Repeated-measures ANOVA indicated that walking condition intensities were significantly different (P < 0.05) and the Actigraph detected the differences. Overall correlation between measured and predicted METs was positive, moderate, and significant (r = 0.74). Mean predicted METs were not significantly different from measured for CP and BP, but for FP walking, predicted METs were significantly less than measured (P < 0.05). The Actigraph correctly classified intensity for 76.8% of all activity bouts and 91.5% of light- and moderate-intensity bouts. Conclusions Actigraph counts provide a valid index of activity across the intensities investigated in this study. For light to moderate activity, Actigraph-based estimates of METs are acceptable for group-level analysis and are a valid means of classifying activity intensity. The Actigraph significantly underestimated higher intensity activity, although, in practice, this limitation will have minimal impact on activity measurement of most community-dwelling people with ABI.

International hermelin brain tumor symposium on matricellular proteins in normal and cancer cell-matrix interactions

The second of the Hermelin Brain Tumor Center Symposia was held once again at Henry Ford Hospital in Detroit, Michigan on October 24th and 25th, 2003. A public conference was held on the 24th while a closed-door session took place on the 25th. The purpose of these symposia is to bring together experts in a particular field of study with the aim to share information with each other and the public, but then to meet privately to present novel data, hold discussions, and share concepts. While the interaction is intended to benefit all involved, the incentive is the expectation that the shared information will aid researchers at the Hermelin Brain Tumor Center in their quest to identify potential therapeutic targets and explore translational therapeutic strategies for the treatment of patients suffering nervous system tumors...

Brain decoding based on functional magnetic resonance imaging using machine learning : a comparative study

Brain decoding of functional Magnetic Resonance Imaging data is a pattern analysis task that links brain activity patterns to the experimental conditions. Classifiers predict the neural states from the spatial and temporal pattern of brain activity extracted from multiple voxels in the functional images in a certain period of time. The prediction results offer insight into the nature of neural representations and cognitive mechanisms and the classification accuracy determines our confidence in understanding the relationship between brain activity and stimuli. In this paper, we compared the efficacy of three machine learning algorithms: neural network, support vector machines, and conditional random field to decode the visual stimuli or neural cognitive states from functional Magnetic Resonance data. Leave-one-out cross validation was performed to quantify the generalization accuracy of each algorithm on unseen data. The results indicated support vector machine and conditional random field have comparable performance and the potential of the latter is worthy of further investigation.

The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

MicroRNAs are small non-coding RNAs that mediate post-transcriptional gene silencing. Fear-extinction learning in C57/Bl6J mice led to increased expression of the brain-specific microRNA miR-128b, which disrupted stability of several plasticity-related target genes and regulated formation of fear-extinction memory. Increased miR-128b activity may therefore facilitate the transition from retrieval of the original fear memory toward the formation of a new fear-extinction memory.

Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.

Soil-pile interaction of pile embedded in deep layered marine sediment under seismic excitation

This research provides validated Finite Element techniques to analyse pile foundations under seismic loads. The results show that the capability of the technique to capture the important pile response which includes kinematic and inertial interaction effects, effects of soil stiffness and depth on pile deflection patterns and permanent deformations.

Brain networks subserving the evaluation of static and dynamic facial expressions

Because moving depictions of face emotion have greater ecological validity than their static counterparts, it has been suggested that still photographs may not engage ‘authentic’ mechanisms used to recognize facial expressions in everyday life. To date, however, no neuroimaging studies have adequately addressed the question of whether the processing of static and dynamic expressions rely upon different brain substrates. To address this, we performed an functional magnetic resonance imaging (fMRI) experiment wherein participants made emotional expression discrimination and Sex discrimination judgements to static and moving face images. Compared to Sex discrimination, Emotion discrimination was associated with widespread increased activation in regions of occipito-temporal, parietal and frontal cortex. These regions were activated both by moving and by static emotional stimuli, indicating a general role in the interpretation of emotion. However, portions of the inferior frontal gyri and supplementary/pre-supplementary motor area showed task by motion interaction. These regions were most active during emotion judgements to static faces. Our results demonstrate a common neural substrate for recognizing static and moving facial expressions, but suggest a role for the inferior frontal gyrus in supporting simulation processes that are invoked more strongly to disambiguate static emotional cues.

Identification of novel antigens in blood vessels in rectovaginal endometriosis

To identify specific markers of rectovaginal endometriotic nodule vasculature, highly enriched preparations of vascular endothelial cells and pericytes were obtained from endometriotic nodules and control endometrial and myometrial tissue by laser capture microdissection (LCM), and gene expression profiles were screened by microarray analysis. Of the 18 400 transcripts on the arrays, 734 were significantly overexpressed in vessels from fibromuscular tissue and 923 in vessels from stromal tissue of endometriotic nodules, compared with vessels dissected from control tissues. The most frequently expressed transcripts included known endothelial cell-associated genes, as well as transcripts with little or no previous association with vascular cells. The higher expression in blood vessels was further corroborated by immunohistochemical staining of six potential markers, five of which showed strong expression in pericytes. The most promising marker was matrix Gla protein, which was found to be present in both glandular epithelial cells and vascular endothelial cells of endometriotic lesions, although it was barely expressed at all in normal endometrium. LCM, combined with microarray analysis, constitutes a powerful tool for mapping the transcriptome of vascular cells. After immunohistochemical validation, markers of vascular endothelial and perivascular cells from endometriotic nodules could be identified, which may provide targets to improve early diagnosis or to selectively deliver therapeutic agents.

The N170 observed ‘in the wild’: robust event-related potentials to faces in cluttered dynamic visual scenes

As a social species in a constantly changing environment, humans rely heavily on the informational richness and communicative capacity of the face. Thus, understanding how the brain processes information about faces in real-time is of paramount importance. The N170 is a high temporal resolution electrophysiological index of the brain's early response to visual stimuli that is reliably elicited in carefully controlled laboratory-based studies. Although the N170 has often been reported to be of greatest amplitude to faces, there has been debate regarding whether this effect might be an artifact of certain aspects of the controlled experimental stimulation schedules and materials. To investigate whether the N170 can be identified in more realistic conditions with highly variable and cluttered visual images and accompanying auditory stimuli we recorded EEG 'in the wild', while participants watched pop videos. Scene-cuts to faces generated a clear N170 response, and this was larger than the N170 to transitions where the videos cut to non-face stimuli. Within participants, wild-type face N170 amplitudes were moderately correlated to those observed in a typical laboratory experiment. Thus, we demonstrate that the face N170 is a robust and ecologically valid phenomenon and not an artifact arising as an unintended consequence of some property of the more typical laboratory paradigm.

Functional magnetic resonance brain imaging of executive cognitive performance in young first-episode schizophrenia patients and age-matched long-term cannabis users

Converging evidence from epidemiological, clinical and neuropsychological research suggests a link between cannabis use and increased risk of psychosis. Long-term cannabis use has also been related to deficit-like “negative” symptoms and cognitive impairment that resemble some of the clinical and cognitive features of schizophrenia. The current functional brain imaging study investigated the impact of a history of heavy cannabis use on impaired executive function in first-episode schizophrenia patients. Whilst performing the Tower of London task in a magnetic resonance imaging scanner, event-related blood oxygenation level-dependent (BOLD) brain activation was compared between four age and gender-matched groups: 12 first-episode schizophrenia patients; 17 long-term cannabis users; seven cannabis using first-episode schizophrenia patients; and 17 healthy control subjects. BOLD activation was assessed as a function of increasing task difficulty within and between groups as well as the main effects of cannabis use and the diagnosis of schizophrenia. Cannabis users and non-drug using first-episode schizophrenia patients exhibited equivalently reduced dorsolateral prefrontal activation in response to task difficulty. A trend towards additional prefrontal and left superior parietal cortical activation deficits was observed in cannabis-using first-episode schizophrenia patients while a history of cannabis use accounted for increased activation in the visual cortex. Cannabis users and schizophrenia patients fail to adequately activate the dorsolateral prefrontal cortex, thus pointing to a common working memory impairment which is particularly evident in cannabis-using first-episode schizophrenia patients. A history of heavy cannabis use, on the other hand, accounted for increased primary visual processing, suggesting compensatory imagery processing of the task.