Drosophila melanogaster as a model to study drug addiction

Animal studies have been instrumental in providing knowledge about the molecular and neural mechanisms underlying drug addiction. Recently, the fruit fly Drosophilamelanogaster has become a valuable system to model not only the acute stimulating and sedating effects of drugs but also their more complex rewarding properties. In this review, we describe the advantages of using the fly to study drug-related behavior, provide a brief overview of the behavioral assays used, and review the molecular mechanisms and neural circuits underlying drug-induced behavior in flies. Many of these mechanisms have been validated in mammals, suggesting that the fly is a useful model to understand the mechanisms underlying addiction

A Tree-Ring-Based Reconstruction of Delaware River Basin Streamflow Using Hierarchical Bayesian Regression

A hierarchical Bayesian regression model is presented for reconstructing the average summer streamflow at five gauges in the Delaware River basin using eight regional tree-ring chronologies. The model provides estimates of the posterior probability distribution of each reconstructed streamflow series considering parameter uncertainty. The vectors of regression coefficients are modeled as draws from a common multivariate normal distribution with unknown parameters estimated as part of the analysis. This leads to a multilevel structure. The covariance structure of the streamflow residuals across sites is explicitly modeled. The resulting partial pooling of information across multiple stations leads to a reduction in parameter uncertainty. The effect of no pooling and full pooling of station information, as end points of the method, is explored. The no-pooling model considers independent estimation of the regression coefficients for each streamflow gauge with respect to each tree-ring chronology. The full-pooling model considers that the same regression coefficients apply across all streamflow sites for a particular tree-ring chronology. The cross-site correlation of residuals is modeled in all cases. Performance on metrics typically used by tree-ring reconstruction experts, such as reduction of error, coefficient of efficiency, and coverage rates under credible intervals is comparable to, or better, for the partial-pooling model relative to the no-pooling model, and streamflow estimation uncertainty is reduced. Long record simulations from reconstructions are used to develop estimates of the probability of duration and severity of droughts in the region. Analysis of monotonic trends in the reconstructed drought events do not reject the null hypothesis of no trend at the 90% significance over 1754–2000

Is an Epic Pluvial Masking the Water Insecurity of the Greater New York City Region?

Six water emergencies have occurred since 1981 for the New York City (NYC) region despite the following: 1) its perhumid climate, 2) substantial conservation of water since 1979, and 3) meteorological data showing little severe or extreme drought since 1970. This study reconstructs 472 years of moisture availability for the NYC watershed to place these emergencies in long-term hydroclimatic context. Using nested reconstruction techniques, 32 tree-ring chronologies comprised of 12 species account for up to 66.2% of the average May–August Palmer drought severity index. Verification statistics indicate good statistical skill from 1531 to 2003. The use of multiple tree species, including rarely used species that can sometimes occur on mesic sites like Liriodendron tulipifera, Betula lenta, and Carya spp., seems to aid reconstruction skill. Importantly, the reconstruction captures pluvial events in the instrumental record nearly as well as drought events and is significantly correlated to precipitation over much of the northeastern United States. While the mid-1960s drought is a severe drought in the context of the new reconstruction, the region experienced repeated droughts of similar intensity, but greater duration during the sixteenth and seventeenth centuries. The full record reveals a trend toward more pluvial conditions since ca. 1800 that is accentuated by an unprecedented 43-yr pluvial event that continues through 2011. In the context of the current pluvial, decreasing water usage, but increasing extra-urban pressures, it appears that the water supply system for the greater NYC region could be severely stressed if the current water boom shifts toward hydroclimatic regimes like the sixteenth and seventeenth centuries

Summary of the 2012 Inductive Pulsed Plasma Thruster Development and Testing Program

Inductive pulsed plasma thrusters are spacecraft propulsion devices in which energy is capacitively stored and then discharged through an inductive coil. While these devices have shown promise for operation at high efficiency on a range of propellants, many technical issues remain before they can be used in flight applications. A conical theta-pinch thruster geometry was fabricated and tested to investigate potential improvements in propellant utilization relative to more common, flat-plate planar coil designs. A capacitor charging system is used to permit repetitive discharging of thrusters at multiple cycles per second, with successful testing accomplished at a repetition-rate of 5 Hz at power levels of 0.9, 1.6, and 2.5 kW. The conical theta-pinch thruster geometry was tested at cone angles of 20deg, 38deg, and 60deg, with single-pulse operation at 500 J/pulse and repetitionrate operation with the 38deg model quantified through direct thrust measurement using a hanging pendulum thrust stand. A long-lifetime valve was designed and fabricated, and initial testing was performed to measure the valve response and quantify the leak rate at beginning-of-life. Subscale design and testing of a capacitor charging system required for operation on a spacecraft is reported, providing insights into the types of components needed in the circuit topology employed. On a spacecraft, this system would accept as input a lower voltage from the spacecraft DC bus and boost the output to the high voltage required to charge the capacitors of the thruster

Microneedle assisted transdermal delivery of zolmitriptan: effect of microneedle geometry, in vitro permeation experiments, scaling analyses and numerical simulations

Objective: The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of Zolmitriptan (ZMT). Methods: Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 0.9, 1.2 and 1.5mm lengths) and laboratory fabricated polymeric MNs (PM) of 0.6mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77cm2 skin area (PM-3) to maintain the MN density closer to 0.6mm ADM. Scaling analyses was done using dimensionless parameters like concentration of ZMT (Ct/Cs), thickness (h/L) and surface area of the skin (Sa/L2). Results: Micro-injection moulding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 3.17 and 3.65 fold increase in ZMT flux values were observed with 1.5mm ADM and PM-3 applications when compared to the passive studies. Good correlations were observed between different dimensionless parameters with scaling analyses. Numerical simulations, using MATLAB and COMSOL software, based on experimental data and histological images provided information regarding the ZMT skin distribution after MN application. Discussion: Both from experimental studies and simulations, it was inferred that PM were more effective in enhancing the transdermal delivery of ZMT when compared to ADM. Conclusion: The study suggests that MN application enhances the ZMT transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement

Barriers encountered during enrollment in an internet-mediated randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Online technology is a promising resource for conducting clinical research. While the internet may improve a study's reach, as well as the efficiency of data collection, it may also introduce a number of challenges for participants and investigators. The objective of this research was to determine the challenges that potential participants faced during the enrollment phase of a randomized controlled intervention trial of Stepping Up to Health, an internet-mediated walking program that utilized a multi-step online enrollment process.</p> <p>Methods</p> <p>We conducted a quantitative content analysis of 623 help tickets logged in a participant management database during the enrollment phase of a clinical trial investigating the effect of an automated internet-mediated walking intervention. Qualitative coding was performed by two trained coders, and 10% of the sample was coded by both coders to determine inter-coder reliability. Quantitative analyses included standard descriptive statistics on ticket characteristics and theme frequency, and a Poisson regression analysis identified characteristics of potential participants who reported more frequent problems during enrollment.</p> <p>Results</p> <p>In total, 880 potential participants visited the study website and 80% completed the enrollment screening. Of the potential participants who visited the study website, 38% had help tickets logged in the participant management database. The total number of help tickets associated with individual potential participants ranged from 0 to 7 (M = .71). Overall, 46% of help tickets were initiated by email and 54% were initiated by phone. The most common help ticket theme was issues related to the study process (48%). The next most prominent theme was discussion related to obtaining medical clearance (34%), followed by issues related to pedometers and uploading (31%). Older individuals, women, and those with lower self-rated internet ability were more likely to report problems during the enrollment process.</p> <p>Conclusion</p> <p>Prospective participants in an online clinical trial encountered a number of barriers to enrollment that led them to request help from study staff. Questions about the complex enrollment process itself were common. In a complex multi-step enrollment process, providing personalized feedback to potential participants indicating their status within the enrollment process may be beneficial.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00729040</p

Six Centuries of Upper Indus Basin Streamflow Variability and Its Climatic Drivers

Our understanding of the full range of natural variability in streamflow, including how modern flow compares to the past, is poorly understood for the Upper Indus Basin because of short instrumental gauge records. To help address this challenge, we use Hierarchical Bayesian Regression with partial pooling to develop six centuries long (1394–2008 CE) streamflow reconstructions at three Upper Indus Basin gauges (Doyian, Gilgit, and Kachora), concurrently demonstrating that Hierarchical Bayesian Regression can be used to reconstruct short records with interspersed missing data. At one gauge (Partab Bridge), with a longer instrumental record (47 years), we develop reconstructions using both Bayesian regression and the more conventionally used principal components regression. The reconstructions produced by principal components regression and Bayesian regression at Partab Bridge are nearly identical and yield comparable reconstruction skill statistics, highlighting that the resulting tree ring reconstruction of streamflow is not dependent on the choice of statistical method. Reconstructions at all four reconstructions indicate that flow levels in the 1990s were higher than mean flow for the past six centuries. While streamflow appears most sensitive to accumulated winter (January–March) precipitation and summer (May–September) temperature, with warm summers contributing to high flow through increased melt of snow and glaciers, shifts in winter precipitation and summer temperatures cannot explain the anomalously high flow during the 1990s. Regardless, the sensitivity of streamflow to summer temperatures suggests that projected warming may increase streamflow in coming decades, though long-term water risk will additionally depend on changes in snowfall and glacial mass balance

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Multimodal behavioral treatment of migraine: An Internet-administered, randomized, controlled trial

Introduction. Multimodal approaches in behavioral treatment have gained recent interest, with proven efficacy for migraine. The utility of the Internet has been demonstrated for behavioral treatment of headache disorders, but not specifically for migraine. The aim of the study was to develop and evaluate an Internet-based multimodal behavior treatment (MBT) program for migraine and to test hand massage treatment as an adjunct. Methods. Eighty-three adults, 58 women and 25 men, with at least two migraine attacks a month were recruited via advertisements. An MBT program aiming at improvements in life-style and stress coping was developed for this study and, together with a diary, adapted for use over the Internet. Participants were randomized to MBT with and without hand massage and to a control group, and were followed for 11 months. Questionnaires addressing issues of quality of life (PQ23) and depressive symptoms (MADRS-S) were used. Results. A 50%, or greater, reduction in migraine frequency was found in 40% and 42% of participants of the two groups receiving MBT (with and without hand massage, respectively), who statistically were significantly more improved than participants in the control group. No effect of hand massage was detected, and gender did not show any independent contribution to the effect in a multivariate analysis. Conclusions. MBT administered over the Internet appears feasible and effective in the treatment of migraine, but no effect of hand massage was found. For increased knowledge on long-term effects and the modes of action of the present MBT program, further studies are needed

Use of Spatial Information and Search Strategies in a Water Maze Analog in Drosophila melanogaster

Learning the spatial organization of the environment is crucial to fitness in most animal species. Understanding proximate and ultimate factors underpinning spatial memory is thus a major goal in the study of animal behavior. Despite considerable interest in various aspects of its behavior and biology, the model species Drosophila melanogaster lacks a standardized apparatus to investigate spatial learning and memory. We propose here a novel apparatus, the heat maze, conceptually based on the Morris water maze used in rodents. Using the heat maze, we demonstrate that D. melanogaster flies are able to use either proximal or distal visual cues to increase their performance in navigating to a safe zone. We also show that flies are actively using the orientation of distal visual cues when relevant in targeting the safe zone, i.e., Drosophila display spatial learning. Parameter-based classification of search strategies demonstrated the progressive use of spatially precise search strategies during learning. We discuss the opportunity to unravel the mechanistic and evolutionary bases of spatial learning in Drosophila using the heat maze