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Abstract Seasonal rhythms are gaining attention given their impact on metabolic disorders development such as obesity gut microbiota is emerging as a key factor in mediating this link. However, the underlying mechanisms are still poorly understood. In this regard, corticosterone may play a role as it has been shown to be affected by gut bacteria and seasonal rhythms, and has been linked to obesity. Thus, this study aimed to investigate if seasonal rhythms effects on corticosterone are influenced by gut microbiota in obese rats and whether this may be related to seasonal and clock genes expression in the pituitary gland and colon. Fischer 344 male rats fed with cafeteria diet (CAF) were housed under different photoperiods for 9 weeks and treated with an antibiotic cocktail (ABX) in drinking water during the last 4 weeks. Rats fed with standard chow and CAF-fed rats without ABX were included as controls. ABX altered gut microbiota, corticosterone levels and seasonal clock expression in the pituitary depending on photoperiod conditions. These results suggest a link between gut bacteria, seasonal rhythms and corticosterone and a novel nutrigenomic target for obesity.

Abstract Small and medium-sized reservoirs play an important role in water systems that need to cope with climate variability and various other man-made and natural challenges. Although reservoirs and dams are criticized for their negative social and environmental impacts by reducing natural flow variability and obstructing river connections, they are also recognized as important for social and economic development and climate change adaptation. Multiple studies map large dams and analyze the dynamics of water stored in the reservoirs behind these dams, but very few studies focus on small and medium-sized reservoirs on a global scale. In this research, we use multi-annual multi-sensor satellite data, combined with cloud analytics, to monitor the state of small (10–100 ha) to medium-sized (> 100 ha, excluding 479 large ones) artificial water reservoirs globally for the first time. These reservoirs are of crucial importance to the well-being of many societies, but regular monitoring records of their water dynamics are mostly missing. We combine the results of multiple studies to identify 71,208 small to medium-sized reservoirs, followed by reconstructing surface water area changes from satellite data using a novel method introduced in this study. The dataset is validated using 768 daily in-situ water level and storage measurements (r2 > 0.7 for 67% of the reservoirs used for the validation) demonstrating that the surface water area dynamics can be used as a proxy for water storage dynamics in many cases. Our analysis shows that for small reservoirs, the inter-annual and intra-annual variability is much higher than for medium-sized reservoirs worldwide. This implies that the communities reliant on small reservoirs are more vulnerable to climate extremes, both short-term (within seasons) and longer-term (across seasons). Our findings show that the long-term inter-annual and intra-annual changes in these reservoirs are not equally distributed geographically. Through several cases, we demonstrate that this technology can help monitor water scarcity conditions and emerging food insecurity, and facilitate transboundary cooperation. It has the potential to provide operational information on conditions in ungauged or upstream riparian countries that do not share such data with neighboring countries. This may help to create a more level playing field in water resource information globally.

BackgroundPrescription opioid use has increased steadily in many Western countries over the past two decades, most notably in the US, Canada, and most European countries, including the Netherlands. Especially the increasing use of prescription opioids for chronic non-cancer pain has raised concerns. Most opioids in the Netherlands are prescribed in general practices. However, little is known about variation in opioid prescribing between general practices. To better understand this, we investigated practice variation in opioid prescribing for non-cancer pain between Dutch general practices.MethodsData from 2017-2019 of approximately 10% of all Dutch general practices was used. Each year included approximately 1000000 patients distributed over approximately 380 practices. The primary outcome was the proportion of patients with chronic (>90 days) high-dose (≥90 oral morphine equivalents) opioid prescriptions. The secondary outcome was the proportion of patients with chronic (ResultsResults were similar across all years. The magnitude of variation for chronic high-dose opioid prescriptions in 2019 was 7.51-fold (95%/5% ratio), and 15.1-fold (top 10/bottom 10 ratio). The percentage of outliers in the funnel plots varied between 13.8% and 21.7%. Practices with high chronic high-dose opioid prescription proportions were larger, and had more patients from lower income and densely populated areas.ConclusionsThere might be unwarranted practice variation in chronic high-dose opioid prescriptions in primary care, pointing at possible inappropriate use of opioids. This appears to be related to socioeconomic status, urbanicity, and practice size. Further investigation of the factors driving practice variation can provide target points for quality improvement and reduce inappropriate care and unwarranted variation.

Background Prescription opioid use has increased steadily in many Western countries over the past two decades, most notably in the US, Canada, and most European countries, including the Netherlands. Especially the increasing use of prescription opioids for chronic non-cancer pain has raised concerns. Most opioids in the Netherlands are prescribed in general practices. However, little is known about variation in opioid prescribing between general practices. To better understand this, we investigated practice variation in opioid prescribing for non-cancer pain between Dutch general practices. Methods Data from 2017–2019 of approximately 10% of all Dutch general practices was used. Each year included approximately 1000000 patients distributed over approximately 380 practices. The primary outcome was the proportion of patients with chronic (>90 days) high-dose (≥90 oral morphine equivalents) opioid prescriptions. The secondary outcome was the proportion of patients with chronic (Results Results were similar across all years. The magnitude of variation for chronic high-dose opioid prescriptions in 2019 was 7.51-fold (95%/5% ratio), and 15.1-fold (top 10/bottom 10 ratio). The percentage of outliers in the funnel plots varied between 13.8% and 21.7%. Practices with high chronichigh-doseopioid prescription proportions were larger, and had more patients from lower income and densely populated areas. Conclusions There might be unwarranted practice variation in chronic high-dose opioid prescriptions in primary care, pointing at possible inappropriate use of opioids. This appears to be related to socioeconomic status, urbanicity, and practice size. Further investigation of the factors driving practice variation can provide target points for quality improvement and reduce inappropriate care and unwarranted variation.

The neurotransmitter γ-hydroxybutyric acid (GHB) is suggested to be involved in neuronal energy homeostasis processes, but the substance is also used as a recreational drug and as a prescription medication for narcolepsy. GHB has several high-affinity targets in the brain, commonly generalized as the GHB receptor. However, little is known about the structural and functional properties of GHB receptor subtypes. This opinion article discusses the literature on the putative structural and functional properties of the GHBh1 receptor subtype. GHBh1 contains 11 transmembrane helices and at least one intracellular intrinsically disordered region (IDR). Additionally, GHBh1 shows a 100% overlap in amino acid sequence with the Riboflavin (vitamin B2) transporter, which opens the possibility of a possible dual-function (transceptor) structure. Riboflavin and GHB also share specific neuroprotective properties. Further research into the GHBh1 receptor subtype may pave the way for future therapeutic possibilities for GHB.

Abstract There is increasing scientific interest in the potential association between mindfulness and romantic relationship wellbeing. To date, however, experimental studies using active control groups and testing dyadic effects (i.e. examining both actor and partner effects) are lacking. In the current study, romantically involved individuals engaged for 2 weeks daily in either guided mindfulness exercises, or guided relaxation exercises. Participants, and their partners, completed measures of relationship wellbeing at pre- and post-intervention, and at 1-month follow up. The mindfulness intervention significantly promoted relationship wellbeing, for both participants (i.e. actor effects) and their partners (i.e. partner effects). However, these findings did not significantly differ from changes in relationship wellbeing in the relaxation condition. Theoretical implications of these findings for understanding the association between mindfulness and romantic relationship wellbeing are discussed. Moreover, the findings are discussed in light of recent debates about the relative lack of proper control groups in mindfulness research.

BackgroundWe developed a jejunal and colonic experimental human ischemia-reperfusion (IR) model to study pathophysiological intestinal IR mechanisms and potential new intestinal ischemia biomarkers. Our objective was to evaluate the safety of these IR models by comparing patients undergoing surgery with and without in vivo intestinal IR.MethodsA retrospective study was performed comparing complication rates and severity, based on the Clavien-Dindo classification system, in patients undergoing pancreatoduodenectomy with (n = 10) and without (n = 20 matched controls) jejunal IR or colorectal surgery with (n = 10) and without (n = 20 matched controls) colon IR. Secondary outcome parameters were operative time, blood loss, 90-day mortality and length of hospital stay.ResultsFollowing pancreatic surgery, 63% of the patients experienced one or more postoperative complications. There was no significant difference in incidence or severity of complications between patients undergoing pancreatic surgery with (70%) or without (60%, P = 0.7) jejunal IR. Following colorectal surgery, 60% of the patients experienced one or more postoperative complication. Complication rate and severity were similar in patients with (50%) and without (65%, P = 0.46) colonic IR. Operative time, amount of blood loss, postoperative C-reactive protein, length of hospital stay or mortality were equal in both intervention and control groups for jejunal and colon IR.ConclusionThis study showed that human experimental intestinal IR models are safe in patients undergoing pancreatic or colorectal surgery.

INTRODUCTION:Substance use disorders (SUD) in physicians often remain concealed for a long time. Peer monitoring and open discussions with colleagues are essential for identifying SUD. However, physicians often feel uncomfortable discussing substance use with a colleague. We explored physicians' attitudes and norms about substance use (disorders) and their (intended) approach upon a presumption of substance use in a colleague. MATERIALS AND METHODS:An online cross-sectional survey concerning "Addiction in physicians" was administered by the Royal Dutch Medical Association physician panel. Overall, 1685 physicians (47%) responded. Data were analyzed by logistic regression to explore factors associated with taking action upon a substance use presumption. RESULTS:Most physicians agreed that SUD can happen to anyone (67%), is not a sign of weakness (78%) and that it is a disease that can be treated (83%). Substance use in a working context was perceived as unacceptable (alcohol at work: 99%, alcohol during a standby duty: 91%, alcohol in the eight hours before work: 77%, and illicit drugs in the eight hours before work: 97%). Almost all respondents (97%) intend to act upon a substance use presumption in a colleague. Of the 29% who ever had this presumption, 65% took actual action. Actual action was associated with male gender and older age (OR = 1.81; 95% CI = 1.20-2.74 and OR = 1.03; 95% CI = 1.01-1.05, respectively). CONCLUSIONS:About one-third of physicians reported experience with a presumption of substance use in a colleague. Whilst most physicians intend to take action upon such a presumption, two-thirds actually do act upon a presumption. To bridge this intention-behavior gap continued medical education on signs and symptoms of SUD and instructions on how to enter a supportive dialogue with a colleague about personal issues, may enhance physicians' knowledge, confidence, and ethical responsibility to act upon a presumption of substance use or other concerns in a colleague.

HIV, hepatitis B and C, and syphilis share common transmission routes of which primarily unsafe sexual contact and injecting drug use are important. Impulsivity is a major factor contributing to this transmission risk behavior; however comprehensive studies within female, prison, and Asian populations are scarce. This cross-sectional study aims to delineate the contributions of different aspects of impulsivity to risk behavior, among female inmates living in a prison in Jakarta (N = 214). The relationships between various aspects of impulsivity, risk behaviors and seropositivity were tested using analyses of variance and logistic regression analyses. Motor impulsivity was related to alcohol use, reward-related impulsivity to drug use, and cognitive/goal-directed impulsivity to sexual risk behavior. Finally, goal-directed impulsivity was also directly associated with seropositivity. Specific aspects of impulsivity are associated with different types of risk behavior in Indonesian female prisoners, which can be relevant for future studies on infection prevention strategies for such a population.

IntroductionPoor translation of efficacy data derived from animal models can lead to clinical trials unlikely to benefit patients-or even put them at risk-and is a potential contributor to costly and unnecessary attrition in drug development.ObjectivesTo develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy.Design and resultsWe performed a scoping review to identify the key aspects used to validate animal models. Eight domains (Epidemiology, Symptomatology and Natural History-SNH, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified. We drafted questions to evaluate the different facets of human disease simulation. We designed the Framework to Identify Models of Disease (FIMD) to include standardised instructions, a weighting and scoring system to compare models as well as factors to help interpret model similarity and evidence uncertainty. We also added a reporting quality and risk of bias assessment of drug intervention studies in the Pharmacological Validation domain. A web-based survey was conducted with experts from different stakeholders to gather input on the framework. We conducted a pilot study of the validation in two models for Type 2 Diabetes (T2D)-the ZDF rat and db/db mouse. Finally, we present a full validation and comparison of two animal models for Duchenne Muscular Dystrophy (DMD): the mdx mouse and GRMD dog. We show that there are significant differences between the mdx mouse and the GRMD dog, the latter mimicking the human epidemiological, SNH, and histological aspects to a greater extent than the mouse despite the overall lack of published data.ConclusionsFIMD facilitates drug development by serving as the basis to select the most relevant model that can provide meaningful data and is more likely to generate translatable results to progress drug candidates to the clinic.

[This corrects the article DOI: 10.1371/journal.pone.0218014.].

Many biopharmaceuticals exhibit mixed heterogeneity in their post-translational modifications (PTMs) that are essential for their function. Here the authors use a combination of mass spectrometry techniques to analyse human erythropoietin (EPO) and properdin to discover new PTMs on properdin and derive a biosimilarity score for various sources of EPO.

Precipitation is one of the most important components of the water cycle and its accurate spatial and temporal representation is fundamental for hydrological modeling. In the present study, we investigated the impact of spatial resolution of various precipitation datasets on discharge estimates. First, a new precipitation spatial downscaling procedure was developed and applied to four gridded global precipitation datasets based on (i) solely satellite observations: CMORPH and PERSIANN, (ii) satellite and in situ observations: TRMM, and (iii) satellite and in situ observations and reanalysis data: MSWEP. The here presented downscaling methodology blended global precipitation datasets with data on vegetation and topography to improve the representation of precipitation spatial variability. Second, interpolated in situ, non-downscaled (25 km) and downscaled (1 km) precipitation data were used to force a grid-distributed version of the HBV-96 rainfall-runoff model for the Magdalena River basin in Colombia. Results showed that MSWEP and TRMM outperformed CMORPH and PERSIANN precipitation datasets. The downscaling procedure resulted in considerable improvements in coefficient of determination, root mean square error and bias in comparison with in situ precipitation observations. Discharge model estimates were also in better agreement with the observations when the model was forced with the downscaled precipitation. Model performance was improved with Kling Gupta efficiency increases in the order of 0.1 to 0.5. Moreover, better discharge simulations were obtained using downscaled precipitation compared to using only in situ precipitation data when using less than 100 stations.

Addiction, or substance dependence, is nowadays considered a chronic relapsing condition. However, perceptions of addiction vary widely, also among healthcare professionals. Perceptions of addiction are thought to contribute to attitude and stigma towards patients with addiction. However, studies into perceptions of addiction among healthcare professionals are limited and instruments for reliable assessment of their perceptions are lacking. The Illness Perception Questionnaire (IPQ) is widely used to evaluate perceptions of illness. The aim of this study was to evaluate the psychometric properties of the IPQ: factor structure, internal consistency, and discriminant validity, when applied to evaluate healthcare professionals' perceptions of addiction.Participants were 1072 healthcare professionals in training and master students from the Netherlands and Indonesia, recruited from various addiction-training programs. The revised version of the IPQ was adapted to measure perceptions of addiction (IPQ-A). Maximum likelihood method was used to explore the best-fit IPQ factor structure. Internal consistency was evaluated for the final factors. The final factor structure was used to assess discriminant validity of the IPQ, by comparing illness perceptions of addiction between 1) medical students from the Netherlands and Indonesia, 2) medical students psychology students and educational science students from the Netherlands, and 3) participants with different training levels: medical students versus medical doctors.Factor analysis revealed an eight-factor structure for the perception subscale (demoralization, timeline chronic, consequences, personal control, treatment control, illness coherence, timeline cyclical emotional representations) and a four-factor structure for the attribution subscale (psychological attributions, risk factors, smoking/alcohol, overwork). Internal reliability was acceptable to good. The IPQ-A was able to detect differences in perceptions between healthcare professionals from different cultural and educational background and level of training.The IPQ-A is a valid and reliable instrument to assess healthcare professionals' perceptions of addiction.

Operational flood forecasting systems share a fundamental challenge: forecast uncertainty which needs to be considered when making a flood warning decision. One way of representing this uncertainty is through employing an ensemble approach. This paper presents research funded by the Environment Agency in which ensemble rainfall forecasts are utilised and tested for operational use. The form of ensemble rainfall forecast used is the Met Office short-range product called MOGREPS. It is tested for operational use within the Environment Agency's National Flood Forecasting System (NFFS) for England and Wales. Currently, the NFFS uses deterministic forecasts only. The operational configuration of the NFFS for Thames Region is extended to trial the use of the new ensemble rainfall forecasts in support of probabilistic flood forecasting. Evaluation includes considering issues of model performance, configuration (how to fit the ensemble forecasts within the current configurations), data volumes, run times and options for displaying probabilistic forecasts. Although ensemble rainfall forecasts available from MOGREPS are not extensive enough to fully verify product performance, it is concluded that their use within current Environment Agency regional flood forecasting systems can provide better information to the forecaster than use of the deterministic forecasts alone. Of note are the small number of false alarms of river flow exceedance generated when using MOGREPS as input and that small flow events are also forecasted rather well, notwithstanding the rather coarse resolution of the MOGREPS grid (24 km) compared to the studied catchments. In addition, it is concluded that, with careful configuration in NFFS, MOGREPS can be used in existing systems without a significant increase in system load.

ColoPulse tablets are an innovative development in the field of oral dosage forms characterized by a distal ileum and colon-specific release. Previous studies in humans showed release in the ileo-colonic region, but the relationship between gastrointestinal pH and release was not experimentally proven in vivo. This information will complete the in vivo release-profile of ColoPulse tablets.Release from ColoPulse tablets was studied in 16 healthy volunteers using the dual label isotope strategy. To determine gastrointestinal pH profiles and transit times the IntelliCap system was used. A ColoPulse tablet containing 13C-urea and an uncoated, immediate release tablet containing 15N2-urea were taken simultaneously followed by a standardized breakfast after three hours. Five minutes after intake of the tablets the IntelliCap capsule was swallowed and pH was measured until excretion in the feces. Breath and urine samples were collected for isotope analysis.Full analysis could be performed in 12 subjects. Median bioavailability of 13C -urea was 82% (95% CI 74-94%, range 61-114%). The median lag time (5% release of 13C) was 5:42 h (95% CI 5:18-6:18 h, range 2:36-6:36 h,) There was no statistically significant difference between lag time based on isotope signal and colon arrival time (CAT) based on pH (median 5:42 vs 5:31 h p = 0.903). In all subjects an intestinal pH value of 7.0 was reached before release of 13C from the ColoPulse tablet occurred.From the combined data from the IntelliCap system and the 13C -isotope signal it can be concluded that release from a ColoPulse tablet in vivo is not related to transit times but occurs in the ileo-colonic region after pH 7.0 is reached. This supports our earlier findings and confirms that the ColoPulse system is a promising delivery system for targeting the distal ileum and colon.ISRCTN Registry 18301880.

Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a). Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits.

Protein aggregates are a major risk factor for immunogenicity. Until now most studies on aggregate-driven immunogenicity have focused on linking physicochemical features of the aggregates to the formation of anti-drug antibodies. Lacking is however, basic knowledge on the effect of aggregation on the biodistribution and clearance of therapeutic proteins in vivo. The aim of current study was to get insight into the effect of aggregation on biodistribution in mice using different routes of administration. Fluorescently labeled stressed and unstressed mouse serum albumin was injected via different routes in mice and detected via in vivo fluorescence imaging up to 48 hrs post-injection. We found that biodistribution of stressed MSA significantly differed from its unstressed counterpart. Subcutaneous and intramuscular administration resulted in accumulation of protein at the site of injection, from which clearance of stressed MSA was considerably slower than clearance of unstressed MSA. Upon intravenous and intraperitoneal injection of stressed MSA, fluorescent "hotspots" were observed in the spleens, livers and lungs. Further and more detailed examination of biodistribution after intraperitoneal injection showed higher fluorescence in most of tested organs suggesting more efficient diffusion and/or lymphatic uptake from peritoneum of unstressed MSA than the stressed formulation.

Recent imaging studies have reported directional motion biases in human visual cortex when perceiving moving random dot patterns. It has been hypothesized that these biases occur as a result of the integration of motion detector activation along the path of motion in visual cortex. In this study we investigate the nature of such motion integration with functional MRI (fMRI) using different motion stimuli. Three types of moving random dot stimuli were presented, showing either coherent motion, motion with spatial decorrelations or motion with temporal decorrelations. The results from the coherent motion stimulus reproduced the centripetal and centrifugal directional motion biases in V1, V2 and V3 as previously reported. The temporally decorrelated motion stimulus resulted in both centripetal and centrifugal biases similar to coherent motion. In contrast, the spatially decorrelated motion stimulus resulted in small directional motion biases that were only present in parts of visual cortex coding for higher eccentricities of the visual field. In combination with previous results, these findings indicate that biased motion responses in early visual cortical areas most likely depend on the spatial integration of a simultaneously activated motion detector chain.

Accurate maps of surface water are essential for many environmental applications. Surface water maps can be generated by combining measurements from multiple sources. Precise estimation of surface water using satellite imagery remains a challenging task due to the sensor limitations, complex land cover, topography, and atmospheric conditions. As a complementary dataset, in the case of hilly landscapes, a drainage network can be extracted from high-resolution digital elevation models. Additionally, Volunteered Geographic Information (VGI) initiatives, such as OpenStreetMap, can also be used to produce high-resolution surface water masks. In this study, we derive a high-resolution water mask using Landsat 8 imagery and OpenStreetMap as well as (potential) a drainage network using 30 m SRTM. Our approach to derive a surface water mask from Landsat 8 imagery comprises the use of a lower 15% percentile of Landsat 8 Top of Atmosphere (TOA) reflectance from 2013 to 2015. We introduce a new non-parametric unsupervised method based on the Canny edge filter and Otsu thresholding to detect water in flat areas. For hilly areas, the method is extended with an additional supervised classification step used to refine the water mask. We applied the method across the Murray-Darling basin, Australia. Differences between our new Landsat-based water mask and the OpenStreetMap water mask regarding positional differences along the rivers and overall coverage were analyzed. Our results show that about 50% of the OpenStreetMap linear water features can be confirmed using the water mask extracted from Landsat 8 imagery and the drainage network derived from SRTM. We also show that the observed distances between river features derived from OpenStreetMap and Landsat 8 are mostly smaller than 60 m. The differences between the new water mask and SRTM-based linear features and hilly areas are slightly larger (110 m). The overall agreement between OpenStreetMap and Landsat 8 water masks is about 30%.

The central serotonergic signalling system has been shown to play an important role in appetite control and the regulation of food intake. Serotonin exerts its anorectic effects mainly through the 5-HT(1B), 5-HT(2C) and 5-HT(6) receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT(2C) receptor has the distinctive ability to be modified by posttranscriptional RNA editing on 5 nucleotide positions (A, B, C, D, E), having an overall decreased receptor function. Recently, it has been shown that feeding behaviour and fat mass are altered when the 5-HT(2C) receptor RNA is fully edited, suggesting a potential role for 5-HT(2C) editing in obesity. The present studies investigate the expression of serotonin receptors involved in central regulation of food intake, appetite and energy expenditure, with particular focus on the level of 5-HT(2C) receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob), we show increased hypothalamic 5-HT(1A) receptor expression as well as increased hippocampal 5-HT(1A), 5-HT(1B), and 5-HT(6) receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT(2C) expression, depending on time of day, as well as differences in 5-HT(2C) receptor editing were found, independent of changes in total 5-HT(2C) receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite-suppressing effects of the 5-HT(2C) receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT(1A), 5-HT(1B) and 5-HT(6) receptor expression and altered 5-HT(2C) receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies.

In many fisheries multiple species are simultaneously caught while stock assessments and fishing quota are defined at species level. Yet species caught together often share habitat and resources, resulting in interspecific resource competition. The consequences of resource competition on population dynamics and revenue of simultaneously harvested species has received little attention due to the historical single stock approach in fisheries management. Here we present the results of a modelling study on the interaction between resource competition of sole (Solea solea) and slaice (Pleuronectus platessa) and simultaneous harvesting of these species, using a stage-structured population model. Three resources were included of which one is shared with a varied competition intensity. We find that plaice is the better competitor of the two species and adult plaice are more abundant than adult sole. When competition is high sole population biomass increases with increasing fishing effort prior to plaice extinction. As a result of this increase in the sole population, the revenue of the stocks combined as function of effort becomes bimodal with increasing resource competition. When considering a single stock quota for sole, its recovery with increasing effort may result in even more fishing effort that would drive the plaice population to extinction. When sole and plaice compete for resources the highest revenue is obtained at effort levels at which plaice is extinct. Ignoring resource competition promotes overfishing due to increasing stock of one species prior to extinction of the other species. Consequently, efforts to mitigate the decline in one species will not be effective if increased stock in the other species leads to increased quota. If a species is to be protected against extinction, management should not only be directed at this one species, but all species that compete with it for resource as well.

BACKGROUND: Despite widespread immunization programs, a clear increase in pertussis incidence is apparent in many developed countries during the last decades. Consequently, additional immunization strategies are considered to reduce the burden of disease. The aim of this study is to design an individual-based stochastic dynamic framework to model pertussis transmission in the population in order to predict the epidemiologic and economic consequences of the implementation of universal booster vaccination programs. Using this framework, we estimate the cost-effectiveness of universal adolescent pertussis booster vaccination at the age of 12 years in the Netherlands. METHODS/PRINCIPAL FINDINGS: We designed a discrete event simulation (DES) model to predict the epidemiological and economic consequences of implementing universal adolescent booster vaccination. We used national age-specific notification data over the period 1996-2000--corrected for underreporting--to calibrate the model assuming a steady state situation. Subsequently, booster vaccination was introduced. Input parameters of the model were derived from literature, national data sources (e.g. costing data, incidence and hospitalization data) and expert opinions. As there is no consensus on the duration of immunity acquired by natural infection, we considered two scenarios for this duration of protection (i.e. 8 and 15 years). In both scenarios, total pertussis incidence decreased as a result of adolescent vaccination. From a societal perspective, the cost-effectiveness was estimated at €4418/QALY (range: 3205-6364 € per QALY) and €6371/QALY (range: 4139-9549 € per QALY) for the 8- and 15-year protection scenarios, respectively. Sensitivity analyses revealed that the outcomes are most sensitive to the quality of life weights used for pertussis disease. CONCLUSIONS/SIGNIFICANCE: To our knowledge we designed the first individual-based dynamic framework to model pertussis transmission in the population. This study indicates that adolescent pertussis vaccination is likely to be a cost-effective intervention for The Netherlands. The model is suited to investigate further pertussis booster vaccination strategies.

BACKGROUND: In many countries, the reported pertussis has increased despite high vaccination coverage. However, accurate determination of the burden of disease is hampered by reporting artifacts. The infection frequency is more reliably estimated on the basis of the prevalence of high IgG concentrations against pertussis toxin (IgG-Ptx). We determined whether the increase in reported pertussis in the last decade is associated with an increase in the number of infections. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional population-based serosurveillance study conducted in 2006-07, from a randomly selected age-stratified sample of 7,903 persons, serum IgG-Ptx concentrations were analyzed using a fluorescent bead-based multiplex immuno assay. In 2006-07, 9.3% (95%CI 8.5-10.1) of the population above 9 years of age had an IgG-Ptx concentration above 62.5 EU/ml (suggestive for pertussis infection in the past year), which was more than double compared to 1995-96 (4.0%; 95%CI 3.3-4.7). The reported incidence showed a similar increase as the seroprevalence between both periods. CONCLUSIONS: Although changes in the vaccination program have reduced pertussis morbidity in childhood, they have not affected the increased infection rate in adolescent and adult pertussis. Indeed, the high circulation of B. pertussis in the latter age-categories may limit the effectiveness of pediatric vaccination.

Climate scenarios are used to explore impacts of possible future climates and to assess the robustness of adaptation actions across a range of futures. Time-dependent climate scenarios are commonly used in mitigation studies. However, despite the dynamic nature of adaptation, most scenarios for local or regional decision making on climate adaptation are static ‘endpoint’ projections. This paper describes the development and use of transient (time-dependent) scenarios by means of a case on water management in the Netherlands. Relevant boundary conditions (sea level, precipitation and evaporation) were constructed by generating an ensemble of synthetic time-series with a rainfall generator and a transient delta change method. Climate change impacted river flows were then generated with a hydrological simulation model for the Rhine basin. The transient scenarios were applied in model simulations and game experiments. We argue that there are at least three important assets of using transient scenarios for supporting robust climate adaptation: (1) raise awareness about (a) the implications of climate variability and climate change for decision making and (b) the difficulty of finding proof of climate change in relevant variables for water management; (2) assessment of when to adapt by identifying adaptation tipping points which can then be used to explore adaptation pathways, and (3) identification of triggers for climate adaptation.

Accurate investigations of quantum-level energies in molecular systems are shown to provide a testing ground to constrain the size of compactified extra dimensions. This is made possible by recent progress in precision metrology with ultrastable lasers on energy levels in neutral molecular hydrogen (H _2 , HD, and D _2 ) and molecular hydrogen ions (H _2 ^+ , HD ^+ , and D _2 ^+ ). Comparisons between experiment and quantum electrodynamics calculations for these molecular systems can be interpreted in terms of probing large extra dimensions, under which conditions gravity will become much stronger. Molecules are a probe of spacetime geometry at typical distances where chemical bonds are effective (i.e., at length scales of an Å). Constraints on compactification radii for extra dimensions are derived within the Arkani-Hamed-Dimopoulos-Dvali framework, while constraints for curvature or brane separation are derived within the Randall-Sundrum framework. Based on the molecular spectroscopy of D _2 molecules and HD ^+ ions, the compactification size for seven extra dimensions (in connection to M-theory defined in 11 dimensions) of equal size is shown to be limited to ${{R}_{7}}\lt 0.6\;\mu {\rm m}$ . While limits on compactification sizes of extra dimensions based on other branches of physics are compared, the prospect of further tightening constraints from the molecular method is discussed.