Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Status of Intraductal Therapy for Ductal Carcinoma in Situ

The intraductal approach is particularly appealing in the setting of ductal carcinoma in situ (DCIS), a preinvasive breast neoplasm that is thought to be entirely intraductal in its extent. Based on an emerging understanding of the anatomy of the ductal system as well as novel techniques to leverage the access accorded by the intraductal approach, researchers are actively exploring how ductal lavage, ductoscopy, and intraductal infusion of therapeutic agents may enhance breast cancer treatment. Both cytologic and molecular diagnostics continue to improve, and work is ongoing to identify the most effective diagnostic biomarkers for DCIS and cancer, although optimal targeting of the diseased duct remains an important consideration. Ductoscopy holds potential in detection of occult intraductal lesions, and ductoscopically guided lumpectomy could increase the likelihood of a more comprehensive surgical excision. Exciting pilot studies are in progress to determine the safety and feasibility of intraductal chemotherapy infusion. These studies are an important starting point for future investigations of intraductal ablative therapy for DCIS, because as our knowledge and techniques evolve, it is likely that DCIS may be the target most amenable to treatment by intraductal therapy. If such studies are successful, these approaches will allow an important and meaningful transformation in treatment options for women diagnosed with DCIS

Recent Shift in Climate Relationship Enables Prediction of the Timing of Bird Breeding

Large-scale climate processes influence many aspects of ecology including breeding phenology, reproductive success and survival across a wide range of taxa. Some effects are direct, for example, in temperate-zone birds, ambient temperature is an important cue enabling breeding effort to coincide with maximum food availability, and earlier breeding in response to warmer springs has been documented in many species. In other cases, time-lags of up to several years in ecological responses have been reported, with effects mediated through biotic mechanisms such as growth rates or abundance of food supplies. Here we use 23 years of data for a temperate woodland bird species, the great tit (Parus major), breeding in deciduous woodland in eastern England to demonstrate a time-lagged linear relationship between the on-set of egg laying and the winter index of the North Atlantic Oscillation such that timing can be predicted from the winter index for the previous year. Thus the timing of bird breeding (and, by inference, the timing of spring events in general) can be predicted one year in advance. We also show that the relationship with the winter index appears to arise through an abiotic time-lag with local spring warmth in our study area. Examining this link between local conditions and larger-scale processes in the longer-term showed that, in the past, significant relationships with the immediately preceding winter index were more common than those with the time-lagged index, and especially so from the late 1930s to the early 1970s. However, from the mid 1970s onwards, the time-lagged relationship has become the most significant, suggesting a recent change in climate patterns. The strength of the current time-lagged relationship suggests that it might have relevance for other temperature-dependent ecological relationships

Ordinal-Level Phylogenomics of the Arthropod Class Diplopoda (Millipedes) Based on an Analysis of 221 Nuclear Protein-Coding Loci Generated Using Next-Generation Sequence Analyses

Background The ancient and diverse, yet understudied arthropod class Diplopoda, the millipedes, has a muddled taxonomic history. Despite having a cosmopolitan distribution and a number of unique and interesting characteristics, the group has received relatively little attention; interest in millipede systematics is low compared to taxa of comparable diversity. The existing classification of the group comprises 16 orders. Past attempts to reconstruct millipede phylogenies have suffered from a paucity of characters and included too few taxa to confidently resolve relationships and make formal nomenclatural changes. Herein, we reconstruct an ordinal-level phylogeny for the class Diplopoda using the largest character set ever assembled for the group. Methods Transcriptomic sequences were obtained from exemplar taxa representing much of the diversity of millipede orders using second-generation (i.e., next-generation or high-throughput) sequencing. These data were subject to rigorous orthology selection and phylogenetic dataset optimization and then used to reconstruct phylogenies employing Bayesian inference and maximum likelihood optimality criteria. Ancestral reconstructions of sperm transfer appendage development (gonopods), presence of lateral defense secretion pores (ozopores), and presence of spinnerets were considered. The timings of major millipede lineage divergence points were estimated. Results The resulting phylogeny differed from the existing classifications in a number of fundamental ways. Our phylogeny includes a grouping that has never been described (Juliformia+Merocheta+Stemmiulida), and the ancestral reconstructions suggest caution with respect to using spinnerets as a unifying characteristic for the Nematophora. Our results are shown to have significantly stronger support than previous hypotheses given our data. Our efforts represent the first step toward obtaining a well-supported and robust phylogeny of the Diplopoda that can be used to answer many questions concerning the evolution of this ancient and diverse animal group

The effect of linking community health centers to a state-level smoker's quitline on rates of cessation assistance

<p>Abstract</p> <p>Background</p> <p>Smoking cessation quitlines are an effective yet largely untapped resource for clinician referrals. The aim of this study was to assess the effect of a fax referral system that links community health centers (CHCs) with the New York State Quitline on rates of provider cessation assistance.</p> <p>Methods</p> <p>This study was conducted in four CHCs using a quasi experimental study design. Two comparison sites offered usual care (expanded vital sign chart stamp that prompted providers to ask about tobacco use, advice smokers to quit, assess readiness, and offer assistance (4As)) and two intervention sites received the chart stamp plus an office-based fax referral link to the New York State Quitline. The fax referral system links patients to a free proactive telephone counseling service. Provider adherence to the 4 As was assessed with 263 pre and 165 post cross sectional patient exit interviews at all four sites.</p> <p>Results</p> <p>Adherence to the 4As increased significantly over time in the intervention sites with no change from baseline in the comparison sites. Intervention sites were 2.4 (p < .008) times more likely to provide referrals to the state Quitline over time than the comparison sites and 1.8 (p < .001) times more likely to offer medication counseling and/or a prescription.</p> <p>Conclusions</p> <p>Referral links between CHCs and state level telephone quitlines may facilitate the provision of cessation assistance by offering clinicians a practical method for referring smokers to this effective service. Further studies are needed to confirm the efficacy of fax referral systems and to identify implementation strategies that work to facilitate the utilization of these systems across a wide range of clinical settings.</p

A comprehensive introduction to the genetic basis of non-syndromic hearing loss in the Saudi Arabian population

<p>Abstract</p> <p>Background</p> <p>Hearing loss is a clinically and genetically heterogeneous disorder. Mutations in the <it>DFNB1 </it>locus have been reported to be the most common cause of autosomal recessive non-syndromic hearing loss worldwide. Apart from <it>DFNB1</it>, many other loci and their underlying genes have also been identified and the basis of our study was to provide a comprehensive introduction to the delineation of the molecular basis of non-syndromic hearing loss in the Saudi Arabian population. This was performed by screening <it>DFNB1 </it>and to initiate prioritized linkage analysis or homozygosity mapping for a pilot number of families in which <it>DFNB1 </it>has been excluded.</p> <p>Methods</p> <p>Individuals from 130 families of Saudi Arabian tribal origin diagnosed with an autosomal recessive non-syndromic sensorineural hearing loss were screened for mutations at the <it>DFNB1 </it>locus by direct sequencing. If negative, genome wide linkage analysis or homozygosity mapping were performed using Affymetrix GeneChip^®Human Mapping 250K/6.0 Arrays to identify regions containing any known-deafness causing genes that were subsequently sequenced.</p> <p>Results</p> <p>Our results strongly indicate that <it>DFNB1 </it>only accounts for 3% of non-syndromic hearing loss in the Saudi Arabian population of ethnic ancestry. Prioritized linkage analysis or homozygosity mapping in five separate families established that their hearing loss was caused by five different known-deafness causing genes thus confirming the genetic heterogeneity of this disorder in the kingdom.</p> <p>Conclusion</p> <p>The overall results of this study are highly suggestive that underlying molecular basis of autosomal recessive non-syndromic deafness in Saudi Arabia is very genetically heterogeneous. In addition, we report that the preliminary results indicate that there does not seem to be any common or more prevalent loci, genes or mutations in patients with autosomal recessive non-syndromic hearing loss in patients of Saudi Arabian tribal origin.</p

Assessing childhood maltreatment and mental health correlates of disordered eating profiles in a nationally representative sample of English females

PURPOSE: Previous research suggests that childhood maltreatment is associated with the onset of eating disorders (ED). In turn, EDs are associated with alternative psychopathologies such as depression and posttraumatic stress disorder (PTSD), and with suicidality. Moreover, it has been reported that various ED profiles may exist. The aim of the current study was to examine the profiles of disordered eating and the associations of these with childhood maltreatment and with mental health psychopathology. METHODS: The current study utilised a representative sample of English females (N = 4206) and assessed for the presence of disordered eating profiles using Latent Class Analysis. Multinomial logistic regression was implemented to examine the associations of childhood sexual and physical abuse with the disordered eating profiles and the associations of these with PTSD, depression and suicidality. RESULTS: Results supported those of previous findings in that we found five latent classes of which three were regarded as disordered eating classes. Significant relationships were found between these and measures of childhood trauma and mental health outcomes. CONCLUSIONS: Childhood sexual and physical abuse increased the likelihood of membership in disordered eating classes and these in turn increased the likelihood of adverse mental health and suicidal outcomes

Constraint-based modeling analysis of the metabolism of two Pelobacter species

BACKGROUND: Pelobacter species are commonly found in a number of subsurface environments, and are unique members of the Geobacteraceae family. They are phylogenetically intertwined with both Geobacter and Desulfuromonas species. Pelobacter species likely play important roles in the fermentative degradation of unusual organic matters and syntrophic metabolism in the natural environments, and are of interest for applications in bioremediation and microbial fuel cells. RESULTS: In order to better understand the physiology of Pelobacter species, genome-scale metabolic models for Pelobacter carbinolicus and Pelobacter propionicus were developed. Model development was greatly aided by the availability of models of the closely related Geobacter sulfurreducens and G. metallireducens. The reconstructed P. carbinolicus model contains 741 genes and 708 reactions, whereas the reconstructed P. propionicus model contains 661 genes and 650 reactions. A total of 470 reactions are shared among the two Pelobacter models and the two Geobacter models. The different reactions between the Pelobacter and Geobacter models reflect some unique metabolic capabilities such as fermentative growth for both Pelobacter species. The reconstructed Pelobacter models were validated by simulating published growth conditions including fermentations, hydrogen production in syntrophic co-culture conditions, hydrogen utilization, and Fe(III) reduction. Simulation results matched well with experimental data and indicated the accuracy of the models. CONCLUSIONS: We have developed genome-scale metabolic models of P. carbinolicus and P. propionicus. These models of Pelobacter metabolism can now be incorporated into the growing repertoire of genome scale models of the Geobacteraceae family to aid in describing the growth and activity of these organisms in anoxic environments and in the study of their roles and interactions in the subsurface microbial community