gmxapi: A GROMACS-native Python interface for molecular dynamics with ensemble and plugin support.

Gmxapi provides an integrated, native Python API for both standard and advanced molecular dynamics simulations in GROMACS. The Python interface permits multiple levels of integration with the core GROMACS libraries, and legacy support is provided via an interface that mimics the command-line syntax, so that all GROMACS commands are fully available. Gmxapi has been officially supported since the GROMACS 2019 release and is enabled by default in current versions of the software. Here we describe gmxapi 0.3 and later. Beyond simply wrapping GROMACS library operations, the API permits several advanced operations that are not feasible using the prior command-line interface. First, the API allows custom user plugin code within the molecular dynamics force calculations, so users can execute custom algorithms without modifying the GROMACS source. Second, the Python interface allows tasks to be dynamically defined, so high-level algorithms for molecular dynamics simulation and analysis can be coordinated with loop and conditional operations. Gmxapi makes GROMACS more accessible to custom Python scripting while also providing support for high-level data-flow simulation algorithms that were previously feasible only in external packages.

Matrix Effects in GC-MS Profiling of Common Metabolites after Trimethylsilyl Derivatization.

Metabolite profiling using gas chromatography coupled to mass spectrometry (GC-MS) is one of the most frequently applied and standardized methods in research projects using metabolomics to analyze complex samples. However, more than 20 years after the introduction of non-targeted approaches using GC-MS, there are still unsolved challenges to accurate quantification in such investigations. One particularly difficult aspect in this respect is the occurrence of sample-dependent matrix effects. In this project, we used model compound mixtures of different compositions to simplify the study of the complex interactions between common constituents of biological samples in more detail and subjected those to a frequently applied derivatization protocol for GC-MS analysis, namely trimethylsilylation. We found matrix effects as signal suppression and enhancement of carbohydrates and organic acids not to exceed a factor of ~2, while amino acids can be more affected. Our results suggest that the main reason for our observations may be an incomplete transfer of carbohydrate and organic acid derivatives during the injection process and compound interaction at the start of the separation process. The observed effects were reduced at higher target compound concentrations and by using a more suitable injection-liner geometry.

ER-GCaMP6f: An Endoplasmic Reticulum-Targeted Genetic Probe to Measure Calcium Activity in Astrocytic Processes.

Ca2+ is a major second messenger involved in cellular and subcellular signaling in a wide range of cells, including astrocytes, which use calcium ions to communicate with other cells in the brain. Even though a variety of genetically encoded Ca2+ indicators have been developed to study astrocyte calcium signaling, understanding the dynamics of endoplasmic reticulum calcium signaling is greatly limited by the currently available tools. To address this, we developed an endoplasmic reticulum-targeted calcium indicator, ER-GCaMP6f, which is anchored to the cytosolic side of the organelle and measures signaling that occurs in close proximity to the endoplasmic reticulum of astrocytes. Using a combination of confocal and super-resolution microscopy techniques, we demonstrate the localization of the indicator in the endoplasmic reticulum in both cell soma and processes of astrocytes. Combining ER-GCaMP6f with total internal reflection fluorescence microscopy, we show that Ca2+ fluctuations in small astrocytic processes can be detected, which are otherwise not observable with existing indicators and standard wide-field and confocal techniques. We also compared the ER-GCaMP6f indicator against currently used plasma membrane-tethered and cytosolic GCaMP6f indicators. ER-GCaMP6f identifies dynamics in calcium signaling of endoplasmic reticulum resident receptors that are missed by plasma membrane-anchored indicators. We also generated an adeno-associated virus (AAV5) and demonstrate that ER-GCaMP6f can be expressed in vivo and by measured calcium activity in brain slices. ER-GCaMP6f provides a powerful tool to study calcium signaling in close proximity to the endoplasmic reticulum in astrocyte cell soma and processes both in culture and in brain slices.

The feasibility of a personality targeted intervention for addictive overeating: FoodFix.

Recent reviews have identified potential treatment targets for addictive overeating. These include: motivational interviewing, development of specific coping strategies for emotional regulation and the use of harm minimisation strategies based on interventions for substance use disorders. However, there is very little experiential evidence. The aim of this study was to determine the feasibility of a personality-targeted motivational interviewing intervention in adults above the healthy-weight range with symptoms of addictive eating, to reduce symptoms of addictive overeating and improve dietary profiles. Individuals with overweight and obesity (BMI >25 kg/m2) with addictive eating as defined by the modified Yale Food Addiction Scale (mYFAS) were recruited to a three-session intervention held over 3 months. Sessions were conducted by telehealth and facilitated by dietitians. Fifty-two individuals were randomised to either intervention or control (mean age 43.6 ± 12.2yrs, mean BMI 36.7 ± 6.8 kg/m2, 96% female). At three month follow up, there were significant reductions from baseline (BL) for both groups in total YFAS 2.0 symptoms, however, these changes were not significantly different between groups (intervention BL 8.0 ± 2.7; 3-months 6.5 ± 3.8, control BL 8.1 ± 2.5; 3-months 6.9 ± 3.9, p > 0.05). At 3 months the intervention group significantly reduced their energy from non-core foods compared with control (intervention BL 48% energy/day; 3-months 38%, control BL 41% energy/day; 3-months 38%, p < 0.01). The FoodFix intervention provides insight to the development of future management interventions for addictive eating.

The Efficacy of eHealth Interventions for the Treatment of Adults Diagnosed With Full or Subthreshold Binge Eating Disorder: Systematic Review and Meta-analysis.

BACKGROUND: There has been a recent rise in the use of eHealth treatments for a variety of psychological disorders, including eating disorders. OBJECTIVE: This meta-analysis of randomized controlled trials is the first to evaluate the efficacy of eHealth interventions specifically for the treatment of binge eating disorder (characterized by compulsive overconsumption of food, in a relatively short period, and without compensatory behaviors such as purging or fasting). METHODS: A search on the electronic databases PubMed, Web of Science, Embase, MEDLINE, and CINAHL was conducted for randomized controlled trials that compared the efficacy of eHealth treatment interventions with waitlist controls. RESULTS: From the databases searched, 3 studies (298 participants in total) met the inclusion criteria. All interventions were forms of internet-based guided cognitive behavioral therapy. The results of the analysis demonstrated that when compared with waitlist controls, individuals enrolled in eHealth interventions experienced a reduction in objective binge episodes (standardized mean difference [SMD] -0.77, 95% CI -1.38 to -0.16) and eating disorder psychopathology (SMD -0.71, 95% CI -1.20 to -0.22), which included shape (SMD -0.61, 95% CI -1.01 to -0.22) and weight concerns (SMD -0.91, 95% CI -1.33 to -0.48). There was no significant difference in BMI between the eHealth interventions and controls (SMD -0.01, 95% CI -0.40 to 0.39). CONCLUSIONS: These findings provide promising results for the use of internet-based cognitive behavioral therapy for binge eating disorder treatment and support the need for future research to explore the efficacy of these eHealth interventions.

Use of Multiple Ion Fragmentation Methods to Identify Protein Cross-Links and Facilitate Comparison of Data Interpretation Algorithms.

Multiple ion fragmentation methods involving collision-induced dissociation (CID), higher-energy collisional dissociation (HCD) with regular and very high energy settings, and electron-transfer dissociation with supplementary HCD (EThcD) are implemented to improve the confidence of cross-link identifications. Three different S. cerevisiae proteasome samples cross-linked by diethyl suberthioimidate (DEST) or bis(sulfosuccinimidyl)suberate (BS3) are analyzed. Two approaches are introduced to combine interpretations from the above four methods. Working with cleavable cross-linkers such as DEST, the first approach searches for cross-link diagnostic ions and consistency among the best interpretations derived from all four MS2 spectra associated with each precursor ion. Better agreement leads to a more definitive identification. Compatible with both cleavable and noncleavable cross-linkers such as BS3, the second approach multiplies scoring metrics from a number of fragmentation experiments to derive an overall best match. This significantly increases the scoring gap between the target and decoy matches. The validity of cross-links fragmented by HCD alone and identified by Kojak, MeroX, pLink, and Xi was evaluated using multiple fragmentation data. Possible ways to improve the identification credibility are discussed. Data are available via ProteomeXchange with identifier PXD018310.

Non-Singlet Oxygen Kinetic Solvent Isotope Effects in Aquatic Photochemistry.

The kinetic solvent isotope effect (KSIE) is typically utilized in environmental photochemistry to elucidate whether a compound is susceptible to photooxidation by singlet oxygen (1O2), due to its known difference in lifetime in water (H2O) versus heavy water (D2O). Here, the overall indirect photodegradation rates of diarylamines in the presence of dissolved organic matter (DOM) were enhanced in D2O to a greater extent than expected based on their reactivity with 1O2. For each diarylamine, the relative contribution of reaction with 1O2 to the observed KSIE was determined from high resolution data of 1O2 lifetimes by time-resolved infrared luminescence spectroscopy. The additional enhancement in D2O beyond reaction with 1O2 contributed significantly to the observed KSIE for diarylamines (8-65%) and diclofenac (100%). The enhancement was ascribed to slower reduction of transient radical species of the diarylamines due to H/D exchange at DOM's phenolic antioxidant moieties. A slower second-order reaction rate constant with a model antioxidant was verified for mefenamic acid radicals using transient absorption spectroscopy. Changes in lifetime and reactivity with triplet sensitizers were not responsible for the additional KSIE. Other pollutants with quenchable radical intermediates may also be susceptible to such an additional KSIE, which has to be considered when using the KSIE as a diagnostic tool.

Compulsive "grazing" and addictive tendencies towards food.

Evidence suggests that palatable foods can promote an addictive process akin to drugs of abuse. To date, research in the field of food addiction has focused largely on binge eating as a symptom of this condition. The present study investigated relationships between food addiction and other patterns of overeating, such as compulsive grazing-a behaviour with high relevance to bariatric surgery outcomes. Adults between the ages of 20 and 50 years (n = 232) were recruited for the study. Participants completed questionnaires to assess various eating behaviours and related personality measures. Regression analysis employed the Yale Food Addiction Scale (YFAS) as the dependent variable. Results indicated that addictive personality traits, reward-driven eating, and compulsive grazing each contributed unique variance to the YFAS symptom score. These findings provide novel insight into the association between a grazing pattern of overeating and food addiction, and emphasize that similar to traditional addiction disorders such as alcoholism, binge consumption is not the only pattern of compulsive intake.

Nitrate uptake in an agricultural stream estimated from high-frequency, in-situ sensors.

Real-time, continuous, in situ water quality sensors were deployed on a fourth-order Iowa (U.S.) stream draining an agricultural watershed to evaluate key in-stream processes affecting concentrations of nitrate during a 24-day late summer (Aug-Sep) period. Overall, nitrate-nitrogen (NO3-N) concentrations declined 0.11 mg L-1 km-1, or about 1.9% km-1 and 35% in total across 18 km. We also calculated stream metabolic rates using in situ dissolved oxygen data and determined stream biotic N demand to be 108-117 mg m-2 day-1. From this, we estimate that 11% of the NO3-N concentration decline measured between two in-situ sensors separated by 2 km was a result of biotic NO3-N demand, while groundwater NO3-N data and estimates of groundwater flow contributions indicate that dilution was responsible for 53%. Because the concentration decline extends linearly across the entire 18 km of stream length, these processes seem consistent throughout the basin downstream of the most upstream sensor site. The nitrate-dissolved oxygen relationship between the two sites separated by 2 km, calculations of biotic NO3-N demand, and diurnal variations in NO3-N concentration all indicate that denitrification by anaerobes is removing less NO3-N than that assimilated by aquatic organisms unable to fix nitrogen for their life processes, and thus the large majority of the NO3-N entering this stream is not retained or removed, but rather transported downstream.

A commentary on the associations among 'food addiction', binge eating disorder, and obesity: Overlapping conditions with idiosyncratic clinical features.

This commentary discusses the evidence linking patterns of compulsive overeating, such as binge eating and grazing, with a putative psychopathological condition known commonly as 'food addiction'. It also addresses their distinctiveness as independent - albeit overlapping - clinical entities. Discussions focus largely on their respective clinical features and neuropsychobiological associations. Despite semantic issues about the appropriateness of the food-addiction label, there is accumulating evidence that some vulnerable individuals display addictive symptoms in relation to their consumption of certain highly rewarding foods. It is also argued in this paper that despite a positive relationship between obesity and addictive tendencies towards food, it is over-inclusive to model obesity as an addiction disorder, especially given the multi-faceted etiology and current pervasiveness of weight gain worldwide.

Is decision-making ability related to food choice and facets of eating behaviour in adolescents?

PURPOSE: To test the prediction that poor decision-making would predict poor eating-related behaviours, which in turn would relate to elevated body mass index (BMI) percentile. METHODS: Associations among decision-making ability, eating behaviours, and BMI percentile were examined in a sample of 311 healthy male and female adolescents, aged 14-18 years. Structural equation modelling was used to test the proposed relationships. RESULTS: The predicted model was a good fit to the data and all paths between latent and indicator variables were significant. Impulsive responding significantly predicted poor food choice and overeating. No significant relationships emerged between eating-related variables and BMI percentile. CONCLUSIONS: Findings from this study extend the existing research in adults and offer a more comprehensive understanding of factors that may contribute to eating behaviours and weight status in teenagers.

Validation of the German Version of the Commitment to Exercise Scale.

Pathological forms of exercising are a topic of debate in terms of classification, etiology, and treatment. Validated instruments are a precondition for research in this field. The aim of this study was to validate the German version of the Commitment to Exercise Scale (CES-de). A confirmatory factor analysis was conducted using data from a large community sample (n = 571). In a second study, 100 eating disordered patients, 107 elite athletes and 100 individuals engaged in leisure time sporting activities were compared to assess discriminant validity and psychological correlates. A 1-factor solution showed the best fit to the data. The CES-de differentiated between the eating disordered group and individuals engaged in leisure time sporting activities, but not between those with an eating disorder and competitive athletes. The total score was significantly correlated with drive for thinness, perfectionism, and overall psychopathology. The CES-de can be considered a valid instrument for measuring problematic behavioral and attitudinal aspects of the commitment to exercise. The use of the CES-de total score is recommended. However, a more specific instrument should be used for athletes. A limitation of the study is that the samples were not stratified by age and gender.

Optimizing Sampling Strategies for Riverine Nitrate Using High-Frequency Data in Agricultural Watersheds.

Understanding linked hydrologic and biogeochemical processes such as nitrate loading to agricultural streams requires that the sampling bias and precision of monitoring strategies be known. An existing spatially distributed, high-frequency nitrate monitoring network covering ∼40% of Iowa provided direct observations of in situ nitrate concentrations at a temporal resolution of 15 min. Systematic subsampling of nitrate records allowed for quantification of uncertainties (bias and precision) associated with estimates of various nitrate parameters, including: mean nitrate concentration, proportion of samples exceeding the nitrate drinking water standard (DWS), peak (>90th quantile) nitrate concentration, and nitrate flux. We subsampled continuous records for 47 site-year combinations mimicking common, but labor-intensive, water-sampling regimes (e.g., time-interval, stage-triggered, and dynamic-discharge storm sampling). Our results suggest that time-interval sampling most efficiently characterized all nitrate parameters, except at coarse frequencies for nitrate flux. Stage-triggered storm sampling most precisely captured nitrate flux when less than 0.19% of possible 15 min observations for a site-year were used. The time-interval strategy had the greatest return on sampling investment by most precisely and accurately quantifying nitrate parameters per sampling effort. These uncertainty estimates can aid in designing sampling strategies focused on nitrate monitoring in the tile-drained Midwest or similar agricultural regions.

Neuromuscular electrical stimulation-assisted gait increases muscle strength and volume in children with unilateral spastic cerebral palsy.

AIM: To determine if neuromuscular electrical stimulation (NMES) applied to the ankle dorsiflexors during gait improves muscle volume and strength in children with unilateral spastic cerebral palsy (CP). METHOD: Thirty-two children (15 females, 17 males; mean age 10y 8mo, age range 5y 5mo-18y 1mo) with unilateral spastic CP and a Gross Motor Function Classification System of level I or level II were randomly assigned to either the 8-week daily NMES treatment group or control group (usual or conventional treatments). Outcomes at week 8 (post-NMES) and week 14 (carryover) included magnetic resonance imaging for muscle volumes (tibialis anterior, anterior compartment, and gastrocnemius), strength (hand-held dynamometry for isometric dorsiflexion strength and heel raises for functional strength), and clinical measures for lower limb selective motor control. RESULTS: At week 8, the treatment group demonstrated significantly (p<0.05) increased muscle volumes for tibialis anterior, anterior compartment, medial and lateral gastrocnemius, and dorsiflexion strength not only when compared to their baseline values but also when compared to the control group at week 8. At week 14, both tibialis anterior and lateral gastrocnemius volumes in the treatment group remained significantly increased when compared to their baseline values. However, only lateral gastrocnemius volumes had significantly greater values when compared to the control group at week 14. There were no between group differences in the clinical measures for lower limb selective motor control at week 8 and 14. INTERPRETATION: Eight weeks of daily NMES-assisted gait increases muscle volume and strength of the stimulated ankle dorsiflexors in children with unilateral spastic CP. These changes are use-dependent and do not carry over after the 8-week treatment period. Gastrocnemius volume also increased post-treatment with carryover at week 14.

Sex differences in subjective and objective responses to a stimulant medication (methylphenidate): Comparisons between overweight/obese adults with and without binge-eating disorder.

OBJECTIVE: The purpose of this study was to examine sex differences in response to a single dose of a psychomotor-stimulant medication (methylphenidate: MP) and to assess whether expected differences were moderated by binge-eating disorder (BED) status. It is anticipated that findings will shed light on factors that contribute to response variation in the use of stimulant pharmacotherapy to treat BED. METHOD: The study employed a double-blind, drug-placebo, cross-over design in overweight/obese adults with BED (n = 90) and without BED (n = 108). Emotional/mood ratings were assessed every 15 minutes after oral administration of the drug/placebo, and appetite, cravings, and consumption were assessed during a laboratory-based snack-food challenge. RESULTS: Women reported earlier and more sustained "overall" effects of the drug-including "feeling high"-than the men. There was also a significantly greater suppression in appetite ratings, food cravings, and food consumption from the placebo to the drug condition among the women. Indeed, among men there were no significant differences between the two conditions on any of the food-related variables. BED status also did not moderate any of the drug-placebo differences. DISCUSSION: These findings are relevant to the use of stimulant pharmacotherapy for BED, and raise the possibility that overweight/obese men may be relatively less responsive to this form of treatment. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:473-481).

An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor.

Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and (15)N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins-a heretofore untapped reservoir for antibiotic agents.

Genetic Similarities between Compulsive Overeating and Addiction Phenotypes: A Case for "Food Addiction"?

There exists a continuous spectrum of overeating, where at the extremes there are casual overindulgences and at the other a 'pathological' drive to consume palatable foods. It has been proposed that pathological eating behaviors may be the result of addictive appetitive behavior and loss of ability to regulate the consumption of highly processed foods containing refined carbohydrates, fats, salt, and caffeine. In this review, we highlight the genetic similarities underlying substance addiction phenotypes and overeating compulsions seen in individuals with binge eating disorder. We relate these similarities to findings from neuroimaging studies on reward processing and clinical diagnostic criteria based on addiction phenotypes. The abundance of similarities between compulsive overeating and substance addictions puts forth a case for a 'food addiction' phenotype as a valid, diagnosable disorder.

The epidemiology and genetics of binge eating disorder (BED).

This narrative review provides an overview of the epidemiology of binge eating disorder (BED), highlighting the medical history of this disorder and its entry as an independent condition in the Feeding and Eating Disorders section of the recently published Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Estimates of prevalence are provided, as well as recognition that the female to male ratio is lower in BED than in other eating disorders. Evidence is also provided of the most common comorbidities of BED, including mood and anxiety disorders and a range of addiction disorders. In addition, discussion of the viewpoint that BED itself may be an addiction - at least in severe cases - is presented. Although the genetic study of BED is still in its infancy, current research is reviewed with a focus on certain neurotransmitter genes that regulate brain reward mechanisms. To date, a focal point of this research has been on the dopamine and the µ-opioid receptor genes. Preliminary evidence suggests that a predisposing risk factor for BED may be a heightened sensitivity to reward, which could manifest as a strong dopamine signal in the brain's striatal region. Caution is encouraged, however, in the interpretation of current findings, since samples are relatively small in much of the research. To date, no genome-wide association studies have focused exclusively on BED.