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To determine whether there is a difference in orthopaedic trauma patient medication satisfaction and adherence using an oral versus subcutaneous injectable anticoagulant for venous thromboembolism chemoprophylaxis.Randomized controlled trial.Single academic Level 1 trauma center.One hundred twenty adult orthopaedic trauma patients with operative pelvic or lower extremity fractures were randomized and completed the study.Three weeks of either the service standard 40 mg once daily enoxaparin versus trial medication 10 mg once daily rivaroxaban postoperatively.Patient satisfaction as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM-9). Medication adherence as measured by the Morisky Medication Adherence Scale (MMAS-8).Medication adherence was similar in both groups. Medication satisfaction was significantly higher in the oral rivaroxaban group based on the TSQM-9 and patient-reported data. Secondary outcomes found no significant difference in the incidence of bleeding events or clinically relevant venous thromboembolism. The enoxaparin group experienced more adverse medication-related events. The rivaroxaban medication regimen costs 7.5-10× less out of pocket for uninsured patients.The results of this randomized controlled trial demonstrate that patients with surgical orthopaedic trauma prefer an oral anticoagulant for postoperative venous thromboembolism chemoprophylaxis and suggest that rivaroxaban may be a viable option. Furthermore, large-scale studies are needed to confirm safety and efficacy for rivaroxaban in this population as a potential alternative to enoxaparin and aspirin.Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

SummaryTheDrosophilabrain contains tens of thousands of distinct cell types. Thousands of different transgenic lines reproducibly target specific neuron subsets, yet most still express in several cell types. Furthermore, most lines were developed withouta prioriknowledge of where the transgenes would be expressed. To aid in the development of cell type-specific tools for neuronal identification and manipulation, we developed an iterative assay for transposase-accessible chromatin (ATAC) approach. Open chromatin regions (OCRs) enriched in neurons, compared to whole bodies, drove transgene expression preferentially in subsets of neurons. A second round of ATAC-seq from these specific neuron subsets revealed additional enriched OCR2s that further restricted transgene expression within the chosen neuron subset. This approach allows for continued refinement of transgene expression, and we used it to identify neurons relevant for sleep behavior. Furthermore, this approach is widely applicable to other cell types and to other organisms.

BACKGROUND: Despite improved survival rates, neurocognitive impairment persists in persons living with HIV (PLWH). An active lifestyle is linked to improved cognition among PLWH, yet the neural substrates remain unclear. Diffusion tensor imaging (DTI) and diffusion-basis spectrum imaging (DBSI) measure HIV-related changes in brain white matter integrity. We used these measures of structural brain integrity to assess white matter changes, physical fitness, and cognition in a cross-sectional study of PLWH. METHODS: Forty-four virologically well-controlled PLWH were recruited (average age of 56 years old, median recent CD4(+) count of 682 cells/mm(3)). DTI-derived fractional anisotropy (FA) and DBSI-derived axonal density were calculated. Cardiorespiratory fitness (maximal volume of oxygen consumption or VO(2) max) was measured by performing indirect calorimetry during exercise to volitional exhaustion. Cardiovascular risk was assessed by the Framingham risk score. Neuropsychological performance (NP) testing evaluated learning, memory, psychomotor/processing speed, and executive function. Partial correlations assessed the relationships among cardiorespiratory fitness, neuroimaging, NP, and HIV clinical metrics (CD4(+) count, time since diagnosis). RESULTS: Higher VO(2) max was associated with higher FA and higher axonal density in multiple white matter tracts including the corticospinal tract and superior longitudinal fasciculus. Better NP in the motor/psychomotor domain was positively associated with FA and axonal density in diverse tracts including those associated with motor and visuospatial processing. However, higher VO(2) max was not associated with NP or HIV clinical metrics. CONCLUSION: An active lifestyle promoting cardiorespiratory fitness may lead to better white matter integrity and decreased susceptibility to cognitive decline in virologically well-controlled PLWH.

As a general rule, plants defend against herbivores with multiple traits. The defense synergy hypothesis posits that some traits are more effective when co-expressed with others compared to their independent efficacy. However, this hypothesis has rarely been tested outside of phytochemical mixtures, and seldom under field conditions. We tested for synergies between multiple defense traits of common milkweed (Asclepias syriaca) by assaying the performance of two specialist chewing herbivores on plants in natural populations. We employed regression and a novel application of random forests to identify synergies and antagonisms between defense traits. We found the first direct empirical evidence for two previously hypothesized defense synergies in milkweed (latex by secondary metabolites, latex by trichomes) and identified numerous other potential synergies and antagonisms. Our strongest evidence for a defense synergy was between leaf mass per area and low nitrogen content; given that these "leaf economic" traits typically covary in milkweed, a defense synergy could reinforce their co-expression. We report that each of the plant defense traits showed context-dependent effects on herbivores, and increased trait expression could well be beneficial to herbivores for some ranges of observed expression. The novel methods and findings presented here complement more mechanistic approaches to the study of plant defense diversity and provide some of the best evidence to date that multiple classes of plant defense synergize in their impact on insects. Plant defense synergies against highly specialized herbivores, as shown here, are consistent with ongoing reciprocal evolution between these antagonists.

The US Endangered Species Act aims to recover threatened species and preserve their ecosystems, often through habitat management and restoration. In the face of climate change and phenological shifts, however, habitat management can seem futile. One of the most conspicuous effects of climate change is that many species are shifting in phenology, i.e., the timing of life history events. These shifts are assumed to have population-level effects on at-risk species, although it is less clear whether these effects are likely to be positive or negative. Here, we use a 27-year-long data set of Fender’s blue (Icaricia icarioides fenderi), an endangered butterfly, to investigate long-term changes in abundance and phenology at nine sites near Eugene, Oregon, USA. For Fender’s blue, day of peak flight activity consistently advanced at all sites from 1993 to 2019. At the same time, Fender’s blue populations increased at some sites and abundance was not changing at others. There was no association of population growth and advancement of peak flight activity. This suggests that although phenological shifts may be a “fingerprint” of climate change, they may not always be a cause for concern. Implications for insect conservation Lessons from Fender’s blue butterfly are likely applicable to conservation of other at-risk butterflies. Despite a rapidly changing climate, at least some rare species can be conserved and recovered with appropriate habitat management.

This Paper investigates the role of microcracks in Hall thruster wall erosion. The formation and growth of microcracks on the surface of M26 grade boron nitride composite due to repeated thermal sh...

Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is rapidly becoming the assay of choice to investigate chromatin-mediated gene regulation, largely because of low input requirements, a fast workflow, and the ability to interrogate the entire genome in an untargeted manner. Many studies using ATAC-seq use mammalian or human-derived tissues, and established protocols work well in these systems. However, ATAC-seq is not yet widely used in Drosophila. Vinegar flies present several advantages over mammalian systems that make them an excellent model for ATAC-seq studies, including abundant genetic tools that allow straightforward targeting, transgene expression, and genetic manipulation that are not available in mammalian models. Because current ATAC-seq protocols are not optimized to use flies, we developed an optimized workflow that accounts for several complicating factors present in Drosophila. We examined parameters affecting nuclei isolation, including input size, freezing time, washing, and possible confounds from retinal pigments. Then, we optimized the enzymatic steps of library construction to account for the smaller Drosophila genome size. Finally, we used our optimized protocol to generate ATAC-seq libraries that meet ENCODE quality metrics. Our optimized protocol enables extensive ATAC-seq experiments in Drosophila, thereby leveraging the advantages of this powerful model system to understand chromatin-mediated gene regulation.

Summary Experiments are often used to produce emulators of deterministic computer code. This article introduces composite grid experimental designs and a sequential method for building the designs for accurate emulation. Computational methods are developed that enable fast and exact Gaussian process inference even with large sample sizes. We demonstrate that the proposed approach can produce emulators that are orders of magnitude more accurate than current approximations at a comparable computational cost.

Liquids typically form droplets when exiting a nozzle. Jets––cylindrical streams of fluid—can form transiently at higher fluid velocities, yet interfacial tension rapidly drives jet breakup into droplets via the Rayleigh–Plateau instability. Liquid metal is an unlikely candidate to form stable jets since it has enormous interfacial tension and low viscosity. We report that electrochemical anodization significantly lowers the effective tension of a stream of metal, transitioning it from droplets to long (long lifetime and length) wires with 100- [Formula: see text] m diameters without the need for high velocities. Whereas surface minimization drives Rayleigh–Plateau instabilities, these streams of metal increase in surface area when laid flat upon a surface due to the low tension. The ability to tune interfacial tension over at least three orders of magnitude using modest potential (

Additional file 1. ATAC-seq quality control metrics.

Construction of the JT-60SA tokamak was completed on schedule in March 2020. Manufacture and assembly of all the main tokamak components satisfied technical requirements, including dimensional accuracy and functional performances. Development of the plasma heating systems and diagnostics have also progressed, including the demonstration of the favourable electron cyclotron range of frequency (ECRF) transmission at multiple frequencies and the achievement of long sustainment of a high-energy intense negative ion beam. Development of all the tokamak operation control systems has been completed, together with an improved plasma equilibrium control scheme suitable for superconducting tokamaks including ITER. For preparation of the tokamak operation, plasma discharge scenarios have been established using this advanced equilibrium controller. Individual commissioning of the cryogenic system and the power supply system confirmed that these systems satisfy design requirements including operational schemes contributing directly to ITER, such as active control of heat load fluctuation of the cryoplant, which is essential for dynamic operation in superconducting tokamaks. The integrated commissioning (IC) is started by vacuum pumping of the vacuum vessel and cryostat, and then moved to cool-down of the tokamak and coil excitation tests. Transition to the super-conducting state was confirmed for all the TF, EF and CS coils. The TF coil current successfully reached 25.7 kA, which is the nominal operating current of the TF coil. For this nominal toroidal field of 2.25 T, ECRF was applied and an ECRF plasma was created. The IC was, however, suspended by an incident of over current of one of the superconducting equilibrium field coil and He leakage caused by insufficient voltage holding capability at a terminal joint of the coil. The unique importance of JT-60SA for H-mode and high-β steady-state plasma research has been confirmed using advanced integrated modellings. These experiences of assembly, IC and plasma operation of JT-60SA contribute to ITER risk mitigation and efficient implementation of ITER operation.

Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is rapidly becoming the assay of choice to investigate chromatin-mediated gene regulation, largely because of low input requirements, a fast workflow, and the ability to interrogate the entire genome in an untargeted manner. Many studies using ATAC-seq use mammalian or human-derived tissues, and established protocols work well in these systems. However, ATAC-seq is not yet widely used in Drosophila. Vinegar flies present several advantages over mammalian systems that make them an excellent model for ATAC-seq studies, including abundant genetic tools that allow straightforward targeting, transgene expression, and genetic manipulation that are not available in mammalian models. Because current ATAC-seq protocols are not optimized to use flies, we developed an optimized workflow that accounts for several complicating factors present in Drosophila. We examined parameters affecting nuclei isolation, including input size, freezing time, washing, and possible confounds from retinal pigments. Then, we optimized the enzymatic steps of library construction to account for the smaller Drosophila genome size. Finally, we used our optimized protocol to generate ATAC-seq libraries that meet ENCODE quality metrics. Our optimized protocol enables extensive ATAC-seq experiments in Drosophila, thereby leveraging the advantages of this powerful model system to understand chromatin-mediated gene regulation.

Allee effects are processes that become disrupted at low population sizes, causing further declines to eventual extinction. Identifying Allee effects in natural populations is important for both ecological theory and conservation efforts but challenging because populations typically only experience them briefly before collapsing. In 2018, the Western monarch butterfly population fell below the threshold that scientists predicted would trigger Allee effects. Here we show that since 2018, the Western monarch population has expanded more slowly during spring and summer breeding and filled a smaller breeding range. Other aspects of the monarch life cycle (winter survival, fecundity, morphology) have not declined after the crash. However, winter survival is much lower and wing sizes of overwintering monarchs are larger now than in the 20th century, suggesting higher mortality and selection for increased dispersal in recent decades. Delayed arrival to parts of the Western monarch breeding range is a novel Allee effect, which could lead to temporal mismatches between monarchs and their and host plants.

Background Gene regulation is critical for proper cellular function. Next-generation sequencing technology has revealed the presence of regulatory networks that regulate gene expression and essential cellular functions. Studies investigating the epigenome have begun to uncover the complex mechanisms regulating transcription. Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is quickly becoming the assay of choice for many epigenomic investigations. However, whether intervention-mediated changes in accessible chromatin determined by ATAC-seq can be harnessed to generate intervention-inducible reporter constructs has not been systematically assayed. Results We used the insulin signaling pathway as a model to investigate chromatin regions and gene expression changes using ATAC- and RNA-seq in insulin-treated Drosophila S2 cells. We found correlations between ATAC- and RNA-seq data, especially when stratifying differentially-accessible chromatin regions by annotated feature type. In particular, our data demonstrated a weak but significant correlation between chromatin regions annotated to enhancers (1-2 kb from the transcription start site) and downstream gene expression. We cloned candidate enhancer regions upstream of luciferase and demonstrate insulin-inducibility of several of these reporters. Conclusions Insulin-induced chromatin accessibility determined by ATAC-seq reveals enhancer regions that drive insulin-inducible reporter gene expression.

Alcohol use is highly prevalent in the United States and across the world, and every year millions of people suffer from alcohol use disorders (AUDs). Although the genetic contribution to developing AUDs is estimated to be 50–60%, many of the underlying molecular mechanisms remain unclear. Previous studies from our laboratory revealed thatDrosophila melanogasterlacking RhoGAP18B and Ras Suppressor 1 (Rsu1) display reduced sensitivity to ethanol-induced sedation. Both Rsu1 and RhoGAP18B are negative regulators of the small Rho-family GTPase, Rac1, a modulator of actin dynamics. Here we investigate the role of Rac1 and its downstream target, the actin-severing protein cofilin, in alcohol consumption preference. We show that these two regulators of actin dynamics can alter male experience-dependent alcohol preference in a bidirectional manner: expressing either activated Rac1 or dominant-negative cofilin in the mushroom bodies (MBs) abolishes experience-dependent alcohol preference. Conversely, dominant-negative Rac1 or activated cofilin MB expression lead to faster acquisition of alcohol preference. Our data show that Rac1 and cofilin activity are key to determining the rate of acquisition of alcohol preference, revealing a critical role of actin dynamics regulation in the development of voluntary self-administration inDrosophila.SIGNIFICANCE STATEMENTThe risks for developing an alcohol use disorder (AUD) are strongly determined by genetic factors. Understanding the genes and molecular mechanisms that contribute to that risk is therefore a necessary first step for the development of targeted therapeutic intervention. Here we show that regulators of actin cytoskeleton dynamics can bidirectionally determine the acquisition rate of alcohol self-administration, highlighting this process as a key mechanism contributing to the risk of AUD development.

BackgroundGene regulation is critical for proper cellular function. Next-generation sequencing technology has revealed the presence of regulatory networks that regulate gene expression and essential cellular functions. Studies investigating the epigenome have begun to uncover the complex mechanisms regulating transcription. Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is quickly becoming the assay of choice for many epigenomic investigations. However, whether intervention-mediated changes in accessible chromatin determined by ATAC-seq can be harnessed to generate intervention-inducible reporter constructs has not been systematically assayed.ResultsWe used the insulin signaling pathway as a model to investigate chromatin regions and gene expression changes using ATAC- and RNA-seq in insulin-treated Drosophila S2 cells. We found correlations between ATAC- and RNA-seq data, especially when stratifying differentially-accessible chromatin regions by annotated feature type. In particular, our data demonstrated a strong correlation between chromatin regions annotated to distal promoters (1-2 kb from the transcription start site) and downstream gene expression. We cloned candidate distal promoter regions upstream of luciferase and demonstrate insulin-inducibility of several of these reporters.ConclusionsInsulin-induced chromatin accessibility determined by ATAC-seq reveals enhancer regions that drive insulin-inducible reporter gene expression.

Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is rapidly becoming the assay of choice to investigate chromatin-mediated gene regulation, largely because of low input requirements, a fast workflow, and the ability to interrogate the entire genome in an unbiased manner. Many studies using ATAC-seq use mammalian or human-derived tissues, and established protocols work well in these systems. However, ATAC-seq is not yet widely used in Drosophila. Vinegar flies present several advantages over mammalian systems that make them an excellent model for ATAC-seq studies, including abundant genetic tools that allow straightforward targeting, transgene expression, and genetic manipulation, and are not available in mammalian models. Because current ATAC-seq protocols are not optimized to use flies, we developed an optimized workflow that accounts for several complicating factors present in Drosophila. We examined parameters affecting nuclei isolation, including input size, freezing time, washing, and possible confounds from retinal pigments. Then, we optimized the enzymatic steps of library construction to account for the smaller Drosophila genome size. Finally, we used our optimized protocol to generate ATAC-seq libraries that meet ENCODE quality metrics. Our optimized protocol enables extensive ATAC-seq experiments in Drosophila, thereby leveraging the advantages of this powerful model system to understand chromatin-mediated gene regulation.

OBJECTIVE This study examined relationships between anticholinergic medication burden and brain integrity in people living with HIV (PLWH) and people without HIV (HIV-). METHODS Neuropsychological performance z-scores (learning, retention, executive function, motor/psychomotor speed, language domains, and global cognition), and neuroimaging measures (brain volumetrics and white matter fractional anisotropy) were analyzed in PLWH (n = 209) and HIV- (n = 95) grouped according to the Anticholinergic Cognitive Burden (ACB) scale (0 = no burden, 1-3 = low burden, >3 = high burden). Neuropsychological performance and neuroimaging outcomes were compared between HIV- and PLWH with high anticholinergic burden. Within a cohort of PLWH (n = 90), longitudinal change in ACB score over ∼2 years was correlated to the rate of change per month of study interval in neuropsychological performance and neuroimaging measures. RESULTS A higher number of anticholinergic medications and ACB was observed in PLWH compared with HIV- (P

Estimating population abundance is central to population ecology. With increasing concern over declining insect populations, estimating trends in abundance has become even more urgent. At the same time, there is an emerging in interest in quantifying phenological patterns, in part because phenological shifts are one of the most conspicuous signs of climate change. Existing techniques to fit activity curves (and thus both abundance and phenology) to repeated transect counts of insects (a common form of data for these taxa) frequently fail for sparse data, and often require advanced knowledge of statistical computing. These limitations prevent us from understanding both population trends and phenological shifts, especially in the at-risk species for which this understanding is most vital. Here we present a method to fit repeated transect count data with Gaussian curves using linear models, and show how robust abundance and phenological metrics can be obtained using standard regression tools. We then apply this method to eight years of Baltimore checkerspot data using generalized linear models (GLMs). This case study illustrates the ability of our method to fit even years with only a few non-zero survey counts, and identifies a significant negative relationship between population size and annual variation in thermal environment (in growing degree days). We believe our new method provides a key tool to unlock previously-unusable sparse data sets, and may provide a useful middle ground between ad hoc metrics of abundance and phenology and custom-coded mechanistic models.

This study tested a psychosocial model of suicide risk in a sample of 156 Latino college students. Specifically, depression and loneliness were hypothesized to be important predictors of suicide risk (namely, hopelessness and suicidal behaviors) in Latino students. Results of conducting regression analyses indicated that, independent of age and gender, depression and loneliness were significant predictors of both indices of suicide risk examined in the present study. It is noteworthy that within the psychosocial predictor set of depression and loneliness, depression was consistently found to be nearly twice as strong a predictor than was loneliness. Moreover, we found evidence for a significant depression-loneliness interaction effect in predicting suicide risk. That is, the highest level of suicide risk was found among dysphoric Latino students who were also socially isolated. Our findings indicate that depression and loneliness are important factors to consider in understanding suicide risk among Latino college students.

The article of record as published may be found at http://dx.doi.org/10.1109/WSC.2016.7822403 Proceedings of the 2016 Winter Simulation Conference, T. M. K. Roeder, P. I. Frazier, R. Szechtman, E. Zhou, T. Huschka, and S. E. Chick, eds. Gaussian process fitting, or kriging, is often used to create a model from a set of data. Many available software packages do this, but we show that very different results can be obtained from different packages even when using the same data and model. Seven different fitting packages that run on four different platforms are compared using various data functions and data sets that reveal there are stark differences between the packages. In addition to comparing the prediction accuracy, the predictive variance-which is important for evaluating precision of predictions and is often used in stopping criteria-is also evaluated.

An important part of landscape ecology is determining how the arrangement (aggregation or fragmentation) of patches in space influences the population dynamics of foraging organisms. One hypothesis in agricultural ecology is that fine-grain spatial heterogeneity in cropping (many small agricultural fields) should provide better pest control than coarse-grain heterogeneity (few large agricultural fields); this hypothesis has been proposed as an explanation for the increased pest abundance associated with agricultural intensification. However, empirical studies have found mixed support for this hypothesis, and some, surprisingly, demonstrate a strong decrease in pest abundance with increased crop aggregation. We developed a spatially explicit simulation model of pest movement across an agricultural landscape to uncover basic processes that could reduce pest abundance in landscapes with fewer, larger fields. This model focuses on herbivore movement and does not include predation effects or other biological interactions. We found that field aggregation in the model led to severely reduced pest densities and further discovered that this relationship was due to an increased distance between fields and a decreased “target area” in more aggregated landscapes. The features that create a negative relationship between aggregation and pest densities rely on crop rotation and limited dispersal capabilities of the pests. These findings help to explain seemingly counter-intuitive empirical studies and provide an expectation for when field aggregation may reduce pest populations in agro-ecosystems.

[ ]I was strictly forbidden from going there [ ]the state had to rely on the unpaid and undertrained labor of medical students and other volunteers From uncovering tenuous supply chains to necessitating reimbursement for telemedicine visits, COVID has exposed fault lines in our health care system and made us reevaluate our day-to-day practices

Objectives URB937, a peripheral fatty acid amide hydrolase (FAAH) inhibitor, exerts profound analgesic effects in animal models. We examined, in rats, (1) the pharmacokinetic profile of oral URB937; (2) the compound's ability to elevate levels of the representative FAAH substrate, oleoylethanolamide (OEA); and (3) the compound's tolerability after oral administration. Methods We developed a liquid chromatography/tandem mass spectrometry (LC/MS-MS) method to measure URB937 and used a pre-existing LC/MS-MS assay to quantify OEA. FAAH activity was measured using a radioactive substrate. The tolerability of single or repeated (once daily for 2 weeks) oral administration of supramaximal doses of URB937 (100, 300, 1000 mg/kg) was assessed by monitoring food intake, water intake and body weight, followed by post-mortem evaluation of organ structure. Key findings URB937 was orally available in male rats (F = 36%), but remained undetectable in brain when administered at doses that maximally inhibit FAAH activity and elevate OEA in plasma and liver. Acute and subchronic treatment with high doses of URB937 was well-tolerated and resulted in FAAH inhibition in brain. Conclusions Pain remains a major unmet medical need. The favourable pharmacokinetic and pharmacodynamic properties of URB937, along with its tolerability, encourage further development studies on this compound.

The response to drugs of abuse is a combination of aversive and reinforcing reactions. While much is known about the role of dopamine in mammalian drug reinforcement, we know little about the brain circuits mediating drug aversion. Here we show that two distinct dopaminergic circuits mediate reinforcing and acute aversive responses to alcohol consumption in Drosophila. Protocerebral anterior medial dopamine neurons projecting to the mushroom bodies are required for flies to acquire alcohol preference. Conversely, a bilateral pair of dopamine neurons projecting to the dorsal fan-shaped body (dFSB) mediates acute alcohol avoidance. Alcohol consumption can be reduced by decreasing the activity of the appetitive reinforcement-circuit to the mushroom bodies, or by increasing activity in the dopamine neurons projecting to the dFSB. Thus, distinct dopaminergic pathways can be targeted to reduce the intake of harmful drugs.

Alcohol use is highly prevalent in the United States and across the world, and every year millions of people suffer from alcohol use disorders (AUDs). While the genetic contribution to developing AUDs is estimated to be 50-60%, many of the underlying molecular mechanisms remain unclear. Previous studies from our lab revealed thatDrosophilalacking RhoGAP18B and Ras Suppressor 1 (Rsu1) display reduced sensitivity to ethanol-induced sedation. Both Rsu1 and RhoGAP18B are negative regulators of the small Rho-family GTPase, Rac1, a modulator of actin dynamics. Here we investigate the role of Rac1 and its downstream target, the actin-severing protein cofilin, in alcohol consumption preference. We show that these two regulators of actin dynamics can alter experience-dependent alcohol preference in a bidirectional manner: expressing either activated Rac1 or dominant-negative cofilin in the mushroom bodies (MB) abolishes experience-dependent alcohol preference. Conversely, dominant-negative Rac1 or activated cofilin MB expression lead to faster acquisition of alcohol preference. Our data show that Rac1 and cofilin activity are key to determining the rate of acquisition of alcohol preference, revealing a critical role of actin dynamics regulation in the development of voluntary self-administration inDrosophila.Significance StatementThe risks for developing an alcohol use disorder (AUD) are strongly determined by genetic factors. Understanding the genes and molecular mechanisms that contribute to that risk is therefore a necessary first step for the development of targeted therapeutic intervention. Here we show that regulators of actin cytoskeleton dynamics can bidirectionally determine the acquisition rate of alcohol self-administration, highlighting this process as a key mechanism contributing to the risk of AUD development.

Computer simulation experiments are commonly used as an inexpensive alternative to real-world experiments to form a metamodel that approximates the input-output relationship of the real-world experiment. While a user may want to understand the entire response surface, they may also want to focus on interesting regions of the design space, such as where the gradient is large. In this paper we present an algorithm that adaptively runs a simulation experiment that focuses on finding areas of the response surface with a large gradient while also gathering an understanding of the entire surface. We consider the scenario where small batches of points can be run simultaneously, such as with multi-core processors.