Hidden Gibbs random fields model selection using Block Likelihood Information Criterion

Performing model selection between Gibbs random fields is a very challenging task. Indeed, due to the Markovian dependence structure, the normalizing constant of the fields cannot be computed using standard analytical or numerical methods. Furthermore, such unobserved fields cannot be integrated out and the likelihood evaluztion is a doubly intractable problem. This forms a central issue to pick the model that best fits an observed data. We introduce a new approximate version of the Bayesian Information Criterion. We partition the lattice into continuous rectangular blocks and we approximate the probability measure of the hidden Gibbs field by the product of some Gibbs distributions over the blocks. On that basis, we estimate the likelihood and derive the Block Likelihood Information Criterion (BLIC) that answers model choice questions such as the selection of the dependency structure or the number of latent states. We study the performances of BLIC for those questions. In addition, we present a comparison with ABC algorithms to point out that the novel criterion offers a better trade-off between time efficiency and reliable results

A tutorial on pilot studies: the what, why and how

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format

Dietary magnesium, not calcium, prevents vascular calcification in a mouse model for pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic calcification of connective tissue in skin, Bruch’s membrane of the eye, and walls of blood vessels. PXE is caused by mutations in the ABCC6 gene, but the exact etiology is still unknown. While observations on patients suggest that high calcium intake worsens the clinical symptoms, the patient organization PXE International has published the dietary advice to increase calcium intake in combination with increased magnesium intake. To obtain more data on this controversial issue, we examined the effect of dietary calcium and magnesium in the Abcc6−/− mouse, a PXE mouse model which mimics the clinical features of PXE. Abcc6−/− mice were placed on specific diets for 3, 7, and 12 months. Disease severity was measured by quantifying calcification of blood vessels in the kidney. Raising the calcium content in the diet from 0.5% to 2% did not change disease severity. In contrast, simultaneous increase of both calcium (from 0.5% to 2.0%) and magnesium (from 0.05% to 0.2%) slowed down the calcification significantly. Our present findings that increase in dietary magnesium reduces vascular calcification in a mouse model for PXE should stimulate further studies to establish a dietary intervention for PXE

Dopamine in the dorsal hippocampus impairs the late-consolidation of cocaine-associated memory

Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.Fil: Kramar, Cecilia Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Chefer, Vladimir I.. National Institutes of Health; Estados UnidosFil: Wise, Roy A.. National Institutes of Health; Estados UnidosFil: Medina, Jorge Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Barbano, María Flavia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentin

Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence

We recently introduced an animal model to study incubation of drug craving after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Here we studied the role of the nucleus accumbens (NAc) in this model. We trained rats to self-administer a palatable solution (sucrose+maltodextrin 1%, 6 h/day, 6 days) and methamphetamine (6 h/day, 12 days). We then evaluated relapse to methamphetamine seeking after 1 and 15 days of voluntary abstinence, achieved via a discrete choice procedure between the palatable solution and methamphetamine (14 days). We used RNAscope in-situ hybridization to quantify the co-labeling of the neuronal activity marker Fos, and dopamine Drd1- and Drd2-expressing medium spiny neurons (MSNs) in NAc core and shell during the incubation tests. Next, we determined the effect of pharmacological inactivation of NAc core and shell by either GABAA and GABAB agonists (muscimol+baclofen, 50+50 ng/side), Drd1-Drd2 antagonist (flupenthixol, 10 µg/side) or the selective Drd1 or Drd2 antagonists (SCH39166 1.0 µg/side or raclopride 1.0 µg/side) during the relapse tests. Incubated methamphetamine seeking after voluntary abstinence was associated with a selective increase of Fos expression in the NAc core, but not shell, and Fos was co-labeled with both Drd1- and Drd2-MSNs. NAc core, but not shell, injections of muscimol+baclofen, flupenthixol, SCH39166, and raclopride reduced methamphetamine seeking after 15 days of abstinence. Together, our results suggest that dopamine transmission through Drd1 and Drd2 in NAc core is critical to the incubation of methamphetamine craving after voluntary abstinence

Convergent Processing of Both Positive and Negative Motivational Signals by the VTA Dopamine Neuronal Populations

Dopamine neurons in the ventral tegmental area (VTA) have been traditionally studied for their roles in reward-related motivation or drug addiction. Here we study how the VTA dopamine neuron population may process fearful and negative experiences as well as reward information in freely behaving mice. Using multi-tetrode recording, we find that up to 89% of the putative dopamine neurons in the VTA exhibit significant activation in response to the conditioned tone that predict food reward, while the same dopamine neuron population also respond to the fearful experiences such as free fall and shake events. The majority of these VTA putative dopamine neurons exhibit suppression and offset-rebound excitation, whereas ∼25% of the recorded putative dopamine neurons show excitation by the fearful events. Importantly, VTA putative dopamine neurons exhibit parametric encoding properties: their firing change durations are proportional to the fearful event durations. In addition, we demonstrate that the contextual information is crucial for these neurons to respectively elicit positive or negative motivational responses by the same conditioned tone. Taken together, our findings suggest that VTA dopamine neurons may employ the convergent encoding strategy for processing both positive and negative experiences, intimately integrating with cues and environmental context

Biological effects of naturally occurring and man-made fibres: in vitro cytotoxicity and mutagenesis in mammalian cells

Cytotoxicity and mutagenicity of tremolite, erionite and the man-made ceramic (RCF-1) fibre were studied using the human– hamster hybrid A L cells. Results from these fibres were compared with those of UICC Rhodesian chrysotile fibres. The A L cell mutation assay, based on the S1 gene marker located on human chromosome 11, the only human chromosome contained in the hybrid cell, has been shown to be more sensitive than conventional assays in detecting deletion mutations. Tremolite, erionite and RCF-1 fibres were significantly less cytotoxic to A L cells than chrysotile. Mutagenesis studies at the HPRT locus revealed no significant mutant yield with any of these fibres. In contrast, both erionite and tremolite induced dose-dependent S1− mutations in fibre-exposed cells, with the former inducing a significantly higher mutant yield than the latter fibre type. On the other hand, RCF-1 fibres were largely non-mutagenic. At equitoxic doses (cell survival at ∼ 0.7), erionite was found to be the most potent mutagen among the three fibres tested and at a level comparable to that of chrysotile fibres. These results indicate that RCF-1 fibres are non-genotoxic under the conditions used in the studies and suggest that the high mesothelioma incidence previously observed in hamster may either be a result of selective sensitivity of hamster pleura to fibre-induced chronic irritation or as a result of prolonged fibre treatment. Furthermore, the relatively high mutagenic potential for erionite is consistent with its documented carcinogenicity. © 1999 Cancer Research Campaig

Hippocampus Leads Ventral Striatum in Replay of Place-Reward Information

While the brain is asleep, the hippocampus plays first fiddle in the orchestra of memory; spatial information is reactivated in the hippocampus shortly in advance of emotional memory traces in the vental striatum

Maize Inbreds Exhibit High Levels of Copy Number Variation (CNV) and Presence/Absence Variation (PAV) in Genome Content

Following the domestication of maize over the past ∼10,000 years, breeders have exploited the extensive genetic diversity of this species to mold its phenotype to meet human needs. The extent of structural variation, including copy number variation (CNV) and presence/absence variation (PAV), which are thought to contribute to the extraordinary phenotypic diversity and plasticity of this important crop, have not been elucidated. Whole-genome, array-based, comparative genomic hybridization (CGH) revealed a level of structural diversity between the inbred lines B73 and Mo17 that is unprecedented among higher eukaryotes. A detailed analysis of altered segments of DNA conservatively estimates that there are several hundred CNV sequences among the two genotypes, as well as several thousand PAV sequences that are present in B73 but not Mo17. Haplotype-specific PAVs contain hundreds of single-copy, expressed genes that may contribute to heterosis and to the extraordinary phenotypic diversity of this important crop