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In real-world situations, marine fish farms accommodate multiple fish species and cohorts within the farm, leading to diverse farm layouts influenced by cage dimensions, configurations, and intricate arrangements. These cage management practices are essential to meet production demands, however, farm-level complexities can impact model predictions of waste deposition and benthic impact near fish cages. This is of particular importance when the cages are used for integrated multi-trophic aquaculture (IMTA) with benthic feeders, where this waste not only affects environmental conditions but also provides a potential food source. The Cage Aquaculture Particulate Output and Transport (CAPOT) model incorporated multiple species, cohorts, and cage arrangements to estimate waste distribution from a commercial fish farm in the Mediterranean between October 2018 and July 2019. This spreadsheet model estimated dispersion for individual fish cages using a grid resolution of 5 m x 5 m. The study categorized discrete production periods for each fish cage every month, aligning with intermittent changes in biomass and food inputs due to different cage management practices throughout production. This approach facilitated the use of detailed input data and enhanced model representativeness by considering variations in cage biomass, food types, settling velocities, and configurations. Model outputs, represented in contour plots, indicated higher deposition directly below fish cages that varied monthly throughout fish production cycles. Deposition footprints reflected changes in cage biomass, food inputs, and farm-level practices reflecting this real-world scenario where aquaculture does not follow a production continuum. Moreover, cohort dynamics and cage movements associated with the cage management practices of the fish farm influenced the quantity and fate of wastes distributed around fish cages, revealing variability in deposition footprints. Clearly, these findings have important implications for the design of benthic IMTA systems, with species such as sea cucumber and polychaetes. Variability in waste deposition creates challenges in identifying where the benthic organisms should be placed to allow optimal uptake of waste to meet their food requirements and increase survivability. Evidently, models have an important role to play and this study emphasizes the need for representative input data to describe actual food inputs, cage biomass changes, and management practices for more representative farm-scale modelling and essentially to improve particulate waste management. To effectively mitigate benthic impacts through IMTA, models must quantify and resolve particulate waste distribution and impact around fish farms to maintain a balanced system with net removal of wastes. Resolving farm-level complexities provides vital information about the variability of food availability and quality for extractive organisms that helps improve recycling of organic wastes in integrated systems, demanding a more representative modelling approach.

Evidence about the relationship between lighting and crime is mixed. Although a review of evidence found that improved road / street lighting was associated with reductions in crime, these reductions occurred in daylight as well as after dark, suggesting any effect was not due only to changes in visual conditions. One limitation of previous studies is that crime data are reported in aggregate and thus previous analyses were required to make simplifications concerning types of crimes or locations. We will overcome that by working with a UK police force to access records of individual crimes. We will use these data to determine whether the risk of crime at a specific time of day is greater after dark than during daylight. If no difference is found, this would suggest improvements to visual conditions after dark through lighting would have no effect. If however the risk of crime occurring after dark was greater than during daylight, quantifying this effect would provide a measure to assess the potential effectiveness of lighting in reducing crime risk after dark. We will use a case and control approach to analyse ten years of crime data. We will compare counts of crimes in 'case' hours, that are in daylight and darkness at different times of the year, and 'control' hours, that are in daylight throughout the year. From these counts we will calculate odds ratios as a measure of the effect of darkness on risk of crime, using these to answer three questions: 1) Is the risk of overall crime occurring greater after dark than during daylight? 2) Does the risk of crime occurring after dark vary depending on the category of crime? 3) Does the risk of crime occurring after dark vary depending on the geographical area?

Intensive farming practices can increase exposure of animals to infectious agents against which antibiotics are used. Orally administered antibiotics are well known to cause dysbiosis. To counteract dysbiotic effects, numerous studies in the past two decades sought to understand whether probiotics are a valid tool to help re-establish a healthy gut microbial community after antibiotic treatment. Although dysbiotic effects of antibiotics are well investigated, little is known about the effects of intramuscular antibiotic treatment on the gut microbiome and a few studies attempted to study treatment effects using phylogenetic diversity analysis techniques. In this study we sought to determine the effects of two probiotic- and one intramuscularly administered antibiotic treatment on the developing gut microbiome of post-weaning piglets between their 3rd and 9th week of life. Shotgun metagenomic sequences from over 800 faecal time-series samples derived from 126 post-weaning piglets and 42 sows were analysed in a phylogenetic framework. Differences between individual hosts such as breed, litter, and age, were found to be important contributors to variation in the community composition. Host age was the dominant factor in shaping the gut microbiota of piglets after weaning. The post-weaning pig gut microbiome appeared to follow a highly structured developmental program with characteristic post-weaning changes that can distinguish hosts that were born as little as two days apart in the second month of life. Treatment effects of the antibiotic and probiotic treatments were found but were subtle and included a higher representation of Mollicutes associated with intramuscular antibiotic treatment, and an increase of Lactobacillus associated with probiotic treatment. The discovery of correlations between experimental factors and microbial community composition is more commonly addressed with OTU-based methods and rarely analysed via phylogenetic diversity measures. The latter method, although less intuitive than the former, suffers less from library size normalization biases, and it proved to be instrumental in this study for the discovery of correlations between microbiome composition and host-, and treatment factors.

BackgroundCholera continues to pose a problem for low-resource, fragile and humanitarian contexts. Evidence suggests that 2.86 million cholera cases and 95,000 deaths due to cholera are reported annually. Without quick and effective diagnosis and treatment, case-fatality may be 50%. In line with the priorities of the Global Task Force on Cholera Control, we undertook a systematic review and meta-analysis of diagnostic test accuracy and other test characteristics of current tests for cholera detection in stool and water.MethodsWe searched 11 bibliographic and grey literature databases. Data was extracted on test sensitivity, specificity and other product information. Meta-analyses of sensitivity and specificity were conducted for tests reported in three or more studies. Where fewer studies reported a test, estimates were summarised through narrative synthesis. Risk of Bias was assessed using QUADAS-2.ResultsSearches identified 6,637 records; 41 studies reporting on 28 tests were included. Twenty-two tests had both sensitivities and specificities reported above 95% by at least one study, but there was, overall, wide variation in reported diagnostic accuracy across studies. For the three tests where meta-analyses were possible the highest sensitivity meta-estimate was found in the Cholera Screen test (98.6%, CI: 94.7%-99.7%) and the highest specificity meta-estimate in the Crystal VC on enriched samples (98.3%, CI: 92.8%-99.6%). There was a general lack of evidence regarding field use of tests, but where presented this indicated trends for lower diagnostic accuracy in field settings, with lesser-trained staff, and without the additional process of sample enrichment. Where reported, mean test turnaround times ranged from over 50% to 130% longer than manufacturer's specification. Most studies had a low to unclear risk of bias.ConclusionsCurrently available Rapid Diagnostic Tests can potentially provide high diagnostic and detection capability for cholera. However, stronger evidence is required regarding the conditions required to secure these levels of accuracy in field use, particularly in low-resource settings.RegistrationPROSPERO (CRD42016048428).

The negative effect of sedentary behaviour on type 2 diabetes markers is established, but the interaction with measures of physical activity is still largely unknown. Previous studies have analysed associations with single-activity models, which ignore the interaction with other behaviours. By including results from various analytical approaches, this review critically summarises the effects of sedentary behaviour on diabetes markers and the benefits of substitutions and compositions of physical activity. Ovid Medline, Embase and Cochrane Library databases were systematically searched. Studies were selected if sedentary behaviour and physical activity were measured by accelerometer in the general population, and if associations were reported with glucose, insulin, HOMA-IR, insulin sensitivity, HbA1c, diabetes incidence, CRP and IL-6. Forty-five studies were included in the review. Conclusive detrimental associations with sedentary behaviour were determined for 2-h insulin (6/12 studies found associations), fasting insulin (15/19 studies), insulin sensitivity (4/6 studies), diabetes (3/4 studies) and IL-6 (2/3 studies). Reallocating sedentary behaviour to light or moderate-to-vigorous activity has a beneficial effect for 2-h glucose (1/1 studies), fasting insulin (3/3 studies), HOMA-IR (1/1 studies) and insulin sensitivity (1/1 studies). Compositional measures of sedentary behaviour were found to affect 2-h glucose (1/1 studies), fasting insulin (2/3 studies), 2-h insulin (1/1 studies), HOMA-IR (2/2 studies) and CRP (1/1 studies). Different analytical methods produced conflicting results for fasting glucose, 2-h glucose, 2-h insulin, insulin sensitivity, HOMA-IR, diabetes, hbA1c, CRP and IL-6. Studies analysing data by quartiles report independent associations between sedentary behaviour and fasting insulin, HOMA-IR and diabetes only for high duration of sedentary time (7–9 hours/day). However, this review could not provide sufficient evidence for a time-specific cut-off of sedentary behaviour for diabetes biomarkers. While substituting sedentary behaviour with moderate-to-vigorous activity brings greater improvements for health, light activity also benefits metabolic health. Future research should elucidate the effects of substituting and combining different activity durations and modalities.

The Bronze Age village of Politiko-Troullia, located in the foothills of the copper-bearing Troodos mountains of central Cyprus, was occupied ~2050-1850 cal BCE. Excavated evidence shows that community activities included copper metallurgy (ore processing, smelting and casting), crop cultivation, and rearing of livestock. Faunal analysis reveals day-to-day subsistence practices that included consumption of sheep, goat, cattle, and pig, as well as community-scale ritual feasting focused on fallow deer, Dama dama mesopotamica. In this paper, we present bone collagen stable isotope data from these taxa to infer how these animals were managed. We incorporate stable isotope baselines calculated from modern cereal grains and compare these to archaeological seeds from Politiko-Troullia. Mean values of δ13C and δ15N cluster for livestock consistent with a diet of C3 plants, with a wider range in goats that suggests free-browsing herds. Higher δ15N values in cattle may reflect supplemental feeding or grazing in manured fields. Plant isotope values suggest livestock diets were predominantly composed of cultivated taxa. In contrast, deer and pig bones produce more negative mean δ13C and δ15N values suggesting that the villagers of Politiko-Troullia complemented their management of domesticated animals with hunting of wild deer and feral pigs in the woodlands surrounding their village.

We conducted a cross sectional survey in Zimbabwe to describe urban-rural disparity in socio-demographic characteristics and sexual behaviors of HIV-positive adolescent girls and young women (AGYW) and their male sexual partners. Between September and November 2016, we interviewed 360 sexually active HIV positive AGYW, aged 15--24 years attending ART and PMTCT clinics in urban and rural health facilities in Harare and Mazowe district respectively. HIV positive AGYW in rural areas as compared to those in urban areas were older, less educated, more frequently married or cohabiting, had lower number of male sexual partners in their lifetime and in the last 12 months preceding the survey. They were mostly heterosexually infected, more likely to disclose their status to a family member and to be more adherent to ART (OR = 2.5-95% CI = 1.1-5.5). Most recent male sexual partners of HIV positive AGYW in urban areas as compared to those from rural areas were mainly current or former boyfriends, single, more educated, less likely to have a child with them and to engage in couple voluntary counseling and testing (CVCT). They were more likely to patronize dancing and drinking venues and involved in transactional sex (OR = 2.2-95% CI: 1.2-4). They were also more likely to be circumcised (OR = 2.3-95% CI: 1.3-4.1) and to use condom more consistently in the last 12 months preceding the survey. Our study findings called for the strengthening of HIV prevention interventions in urban areas among HIV positive AGYW who had more than one partner in their lifetime or are patronizing dancing and drinking venues. In Zimbabwe, promotion of CVCT, index testing, male circumcision and condom use should be sustained to engage male sexual partners of both urban and rural HIV positive AGYW in HIV prevention.

Background and purposeHemorrhagic transformation (HT) after cerebral infarction is a complex and multifactorial phenomenon in the acute stage of ischemic stroke, and often results in a poor prognosis. Thus, identifying risk factors and making an early prediction of HT in acute cerebral infarction contributes not only to the selections of therapeutic regimen but also, more importantly, to the improvement of prognosis of acute cerebral infarction. The purpose of this study was to develop and validate a model to predict a patient's risk of HT within 30 days of initial ischemic stroke.MethodsWe utilized a retrospective multicenter observational cohort study design to develop a Lasso Logistic Regression prediction model with a large, US Electronic Health Record dataset which structured to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). To examine clinical transportability, the model was externally validated across 10 additional real-world healthcare datasets include EHR records for patients from America, Europe and Asia.ResultsIn the database the model was developed, the target population cohort contained 621,178 patients with ischemic stroke, of which 5,624 patients had HT within 30 days following initial ischemic stroke. 612 risk predictors, including the distance a patient travels in an ambulance to get to care for a HT, were identified. An area under the receiver operating characteristic curve (AUC) of 0.75 was achieved in the internal validation of the risk model. External validation was performed across 10 databases totaling 5,515,508 patients with ischemic stroke, of which 86,401 patients had HT within 30 days following initial ischemic stroke. The mean external AUC was 0.71 and ranged between 0.60-0.78.ConclusionsA HT prognostic predict model was developed with Lasso Logistic Regression based on routinely collected EMR data. This model can identify patients who have a higher risk of HT than the population average with an AUC of 0.78. It shows the OMOP CDM is an appropriate data standard for EMR secondary use in clinical multicenter research for prognostic prediction model development and validation. In the future, combining this model with clinical information systems will assist clinicians to make the right therapy decision for patients with acute ischemic stroke.

Interpreting discourses among implementers of what is termed a "landscape approach" enables us to learn from their experience to improve conservation and development outcomes. We use Q-methodology to explore the perspectives of a group of experts in the landscape approach, both from academic and implementation fields, on what hinderances are in place to the realisation of achieving sustainable landscape management in Indonesia. The results show that, at a generic level, "corruption" and "lack of transparency and accountability" rank as the greatest constraints on landscape functionality. Biophysical factors, such as topography and climate change, rank as the least constraining factors. When participants considered a landscape with which they were most familiar, the results changed: the rapid change of regulations, limited local human capacity and inaccessible data on economic risks increased, while the inadequacy of democratic institutions, "overlapping laws" and "corruption" decreased. The difference indicates some fine-tuning of generic perceptions to the local context and may also reflect different views on what is achievable for landscape approach practitioners. Overall, approximately 55% of variance is accounted for by five discourse factors for each trial. Four overlapped and two discourses were discrete enough to merit different discourse labels. We labelled the discourses (1) social exclusionists, (2) state view, (3) community view, (4) integrationists, (5) democrats, and (6) neoliberals. Each discourse contains elements actionable at the landscape scale, as well as exogenous issues that originate at national and global scales. Actionable elements that could contribute to improving governance included trust building, clarified resource rights and responsibilities, and inclusive representation in management. The landscape sustainability discourses studied here suggests that landscape approach "learners" must focus on ways to remedy poor governance if they are to achieve sustainability and multi-functionality.

Compassion is a complex cognitive, emotional and behavioural process that has important real-world consequences for the self and others. Considering this, it is important to understand how compassion is communicated. The current research investigated the expression and perception of compassion via the face. We generated exemplar images of two compassionate facial expressions induced from two mental imagery tasks with different compassionate motivations (Study 1). Our kind- and empathic compassion faces were perceived differently and the empathic-compassion expression was perceived as best depicting the general definition of compassion (Study 2). Our two composite faces differed in their perceived happiness, kindness, sadness, fear and concern, which speak to their underling motivation and emotional resonance. Finally, both faces were accurately discriminated when presented along a compassion continuum (Study 3). Our results demonstrate two perceptually and functionally distinct facial expressions of compassion, with potentially different consequences for the suffering of others.

Many catabolic stimuli, including interleukin-1 (IL-1) in combination with oncostatin M (OSM), promote cartilage breakdown via the induction of collagen-degrading collagenases such as matrix metalloproteinase 1 (MMP1) and MMP13 in human articular chondrocytes. Indeed, joint diseases with an inflammatory component are characterised by excessive extracellular matrix (ECM) catabolism. Importantly, protein kinase C (PKC) signalling has a primary role in cytokine-induced MMP1/13 expression, and is known to regulate cellular functions associated with pathologies involving ECM remodelling. At present, substrates downstream of PKC remain undefined. Herein, we show that both IL-1- and OSM-induced phosphorylation of protein kinase D (PKD) in human chondrocytes is strongly associated with signalling via the atypical PKCι isoform. Consequently, inhibiting PKD activation with a pan-PKD inhibitor significantly reduced the expression of MMP1/13. Specific gene silencing of the PKD isoforms revealed that only PKD3 (PRKD3) depletion mirrored the observed MMP repression, indicative of the pharmacological inhibitor specifically affecting only this isoform. PRKD3 silencing was also shown to reduce serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) as well as phosphorylation of all three mitogen-activated protein kinase groups. This altered signalling following PRKD3 silencing led to a significant reduction in the expression of the activator protein-1 (AP-1) genes FOS and JUN, critical for the induction of many MMPs including MMP1/13. Furthermore, the AP-1 factor activating transcription factor 3 (ATF3) was also reduced concomitant with the observed reduction in MMP13 expression. Taken together, we highlight an important role for PKD3 in the pro-inflammatory signalling that promotes cartilage destruction.

The structures of non-human antibodies are largely unstudied despite the potential for the identification of alternative structural motifs and physical properties that will benefit a basic understanding of protein and immune system evolution as well as highlight unexplored motifs to improve therapeutic monoclonal antibody. Here we probe the structure and receptor-binding properties of the mouse IgG2c crystallizable fragment (Fc) to compare to mouse IgG2b and human IgG1 Fcs. Models of mIgG2c Fc determined by x-ray crystallography with a complex-type biantennary (to 2.05 Å) or a truncated (1)GlcNAc asparagine-linked (N)-glycan attached (to 2.04 Å) show differences in key regions related to mouse Fc γ receptor IV (mFcγRIV) binding. Mouse IgG2c forms different non-bonded interactions between the BC, DE and FG loops than the highly-conserved mIgG2b and binds to FcγRIV with 4.7-fold greater affinity in the complex-type glycoform. Secondary structural elements surrounding the Asn297 site of glycosylation form longer beta strands in the truncated mIgG2c Fc glycoform when compared to mIgG2c with the complex-type N-glycan. Solution NMR spectroscopy of the N-linked (1)GlcNAc residues show differences between mIgG2b, 2c and hIgG1 Fc that correlate to receptor binding affinity. Mutations targeting differences in mIgG2 DE and FG loops decreased affinity of mIgG2c for FcγRIV and increased affinity of mIgG2b. Changes in NMR spectra of the mutant Fc proteins mirrored these changes in affinity. Our studies identified structural and functional differences in highly conserved molecules that were not predicted from primary sequence comparison.

Irreversible cartilage collagen breakdown by the collagenolytic matrix metalloproteinases (MMPs)-1 and MMP-13 represents a key event in pathologies associated with tissue destruction such as arthritis. Inflammation is closely associated with such pathology and occurs in both rheumatoid and osteoarthritis making it highly relevant to the prevailing tissue damage that characterises these diseases. The inflammation-induced activating protein-1 (AP-1) transcription factor is an important regulator of both MMP1 and MMP13 genes with interplay between signalling pathways contributing to their expression. Here, we have examined the regulation of MMP1 expression, and using in vivo chromatin immunoprecipitation analyses we have demonstrated that cFos bound to the AP-1 cis element within the proximal MMP1 promoter only when the gene was transcriptionally silent as previously observed for MMP13. Subsequent small interfering RNA-mediated silencing confirmed however, that cFos significantly contributes to MMP1 expression. In contrast, silencing of ATF3 (a prime MMP13 modulator) did not affect MMP1 expression whilst silencing of the Wnt-associated regulator cysteine- serine-rich nuclear protein-1 (CSRNP1) resulted in substantial repression of MMP1 but not MMP13. Furthermore, following an early transient peak in expression of CSRNP1 at the mRNA and protein levels similar to that seen for cFOS, CSRNP1 expression subsequently persisted unlike cFOS. Finally, DNA binding assays indicated that the binding of CSRNP1 to the AP-1 consensus-like sequences within the proximal promoter regions of MMP1 and MMP13 was preferentially selective for MMP1 whilst activating transcription factor 3 (ATF3) binding was exclusive to MMP13. These data further extend our understanding of the previously reported differential regulation of these MMP genes, and strongly indicate that although cFos modulates the expression of MMP1/13, downstream factors such as CSRNP1 and ATF3 ultimately serve as transcriptional regulators in the context of an inflammatory stimulus for these potent collagenolytic MMPs.

Immunocompromised individuals are at high risk of developing Clostridium difficile-associated disease (CDAD). Fecal microbiota transplantation (FMT) is a highly effective therapy for refractory or recurrent CDAD and, despite safety concerns, has recently been offered to immunocompromised patients. We investigated the genomics of bacterial composition following FMT in immunocompromised patients over a 1-year period. Metagenomic, strain and gene-level bacterial dynamics were characterized in two CDAD-affected hematopoietic stem cell (HCT) recipients following FMT. We found alterations in gene content, including loss of virulence and antibiotic resistance genes. These alterations were accompanied by long-term bacterial divergence at the species and strain levels. Our findings suggest limited durability of the specific bacterial consortium introduced with FMT and indicate that alterations of the functional potential of the microbiome are more complex than can be inferred by taxonomic information alone. Our observation that FMT alone cannot induce long-term donor-like alterations of the microbiota of HCT recipients suggests that FMT cannot indefinitely supersede environmental and/or host factors in shaping bacterial composition.

Community health workers (CHWs) provide critical services to underserved populations in low and middle-income countries, but maintaining CHW's clinical knowledge through formal continuing medical education (CME) activities is challenging and rarely occurs. We tested whether a Short Message Service (SMS)-based mobile CME (mCME) intervention could improve medical knowledge among a cadre of Vietnamese CHWs (Community Based Physician's Assistants-CBPAs) who are the leading providers of primary medical care for rural underserved populations.The mCME Project was a three arm randomized controlled trial. Group 1 served as controls while Groups 2 and 3 experienced two models of the mCME intervention. Group 2 (passive model) participants received a daily SMS bullet point, and were required to reply to the text to acknowledge receipt; Group 3 (interactive model) participants received an SMS in multiple choice question format addressing the same thematic area as Group 2, entering an answer (A, B, C or D) in their response. The server provided feedback immediately informing the participant whether the answer was correct. Effectiveness was based on standardized examination scores measured at baseline and endline (six months later). Secondary outcomes included job satisfaction and self-efficacy.638 CBPAs were enrolled, randomized, and tested at baseline, with 592 returning at endline (93.7%). Baseline scores were similar across all three groups. Over the next six months, participation of Groups 2 and 3 remained high; they responded to >75% of messages. Group 3 participants answered 43% of the daily SMS questions correctly, but their performance did not improve over time. At endline, the CBPAs reported high satisfaction with the mCME intervention, and deemed the SMS messages highly relevant. However, endline exam scores did not increase over baseline, and did not differ between the three groups. Job satisfaction and self-efficacy scores also did not improve. Average times spent on self-study per week did not increase, and the kinds of knowledge resources used by the CBPAs did not differ between the three groups; textbooks, while widely available, were seldom used.The SMS-based mCME intervention, while feasible and acceptable, did not result in increased medical knowledge. We hypothesize that this was because the intervention failed to stimulate lateral learning. For an intervention of this kind to be effective, it will be essential to find more effective ways to couple SMS as a stimulus to promote increased self-study behaviors.ClinicalTrials.gov NCT02381743.

Soil respiration represents the second largest CO2 flux from terrestrial ecosystems to the atmosphere, and a small rise could significantly contribute to further increase in atmospheric CO2. Unfortunately, the extent of this effect cannot be quantified reliably, and the outcomes of experiments designed to study soil respiration remain notoriously unpredictable. In this context, the mathematical simulations described in this article suggest that assumptions of linearity and presumed irrelevance of micro-scale heterogeneity, commonly made in quantitative models of microbial growth in subsurface environments and used in carbon stock models, do not appear warranted. Results indicate that microbial growth is non-linear and, at given average nutrient concentrations, strongly dependent on the microscale distribution of both nutrients and microbes. These observations have far-reaching consequences, in terms of both experiments and theory. They indicate that traditional, macroscopic soil measurements are inadequate to predict microbial responses, in particular to rising temperature conditions, and that an explicit account is required of microscale heterogeneity. Furthermore, models should evolve beyond traditional, but overly simplistic, assumptions of linearity of microbial responses to bulk nutrient concentrations. The development of a new generation of models along these lines, and in particular incorporating upscaled information about microscale processes, will undoubtedly be challenging, but appears to be key to understanding the extent to which soil carbon mineralization could further accelerate climate change.

There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1) individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2) that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral) faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing.

Virtual reality has been successfully used to study and treat psychological disorders such as phobias and posttraumatic stress disorder but has rarely been applied to clinically-relevant emotions other than fear and anxiety. Self-criticism is a ubiquitous feature of psychopathology and can be treated by increasing levels of self-compassion. We exploited the known effects of identification with a virtual body to arrange for healthy female volunteers high in self-criticism to experience self-compassion from an embodied first-person perspective within immersive virtual reality. Whereas observation and practice of compassionate responses reduced self-criticism, the additional experience of embodiment also increased self-compassion and feelings of being safe. The results suggest potential new uses for immersive virtual reality in a range of clinical conditions.

Skeletal muscles of myostatin null (Mstn(-/-)) mice are more susceptible to atrophy during hind limb suspension (HS) than are muscles of wild-type mice. Here we sought to elucidate the mechanism for this susceptibility and to determine if Mstn(-/-) mice can regain muscle mass after HS. Male Mstn(-/-) and wild-type mice were subjected to 0, 2 or 7 days of HS or 7 days of HS followed by 1, 3 or 7 days of reloading (n = 6 per group). Mstn(-/-) mice lost more mass from muscles expressing the fast type IIb myofibres during HS and muscle mass was recovered in both genotypes after reloading for 7 days. Concentrations of MAFbx and MuRF1 mRNA, crucial ligases regulating the ubiquitin-proteasome system, but not MUSA1, a BMP-regulated ubiquitin ligase, were increased more in muscles of Mstn(-/-) mice, compared with wild-type mice, during HS and concentrations decreased in both genotypes during reloading. Similarly, concentrations of LC3b, Gabarapl1 and Atg4b, key effectors of the autophagy-lysosomal system, were increased further in muscles of Mstn(-/-) mice, compared with wild-type mice, during HS and decreased in both genotypes during reloading. There was a greater abundance of 4E-BP1 and more bound to eIF4E in muscles of Mstn(-/-) compared with wild-type mice (P

Soluble CD14 (sCD14) and IL-18 are markers and mediators of the innate immune response, and their plasma levels candidate biomarkers of HCV treatment effects and outcome. Here, we retrospectively studied sCD14 and IL-18 over the course of interferon-based treatment of HCV genotype 1 infection, with the aim to investigate the impact of direct-acting antivirals (DAAs) on the dynamics and relationships between these biomarkers and treatment effects and outcome. Two cohorts were followed longitudinally; one treated with standard dual therapy of pegylated IFNα and ribavirin, and one cohort receiving triple therapy including Telaprevir. sCD14 and IL-18 were measured before and during treatment and analyzed in relation to treatment effects. The initial analysis confirmed two patterns previously observed in patients with HCV/HIV-1 co-infection: Baseline levels of sCD14 were significantly lower in patients that went on to clear HCV infection in response to IFNα and ribavirin, and sCD14 levels were strongly induced during the course of this treatment. Interestingly, baseline levels of sCD14 and IL-18 in combination predicted treatment outcome in dual therapy better than either marker alone. Notably, these associations were weaker with the addition of Telaprevir to the treatment regimen, suggesting that the relationships between innate immune activation and outcome were altered and diminished by inclusion of a DAA in the treatment. In triple therapy, the dynamic increase of sCD14 in response to treatment was higher in patients clearing the virus, suggesting that the innate response to interferon is still significantly associated with outcome in patients treated with DAA-containing regimens. These results support the notion that levels of innate immune activation before and during treatment are associated with interferon-based treatment outcome. Furthermore, the addition of Telaprevir significantly alters the dynamics and relationships between innate immune biomarkers and treatment effects and outcome.

Polysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated post-translational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (K i = 10 µM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.

Myostatin plays a fundamental role in regulating the size of skeletal muscles. To date, only a single myostatin gene and no splice variants have been identified in mammals. Here we describe the splicing of a cryptic intron that removes the coding sequence for the receptor binding moiety of sheep myostatin. The deduced polypeptide sequence of the myostatin splice variant (MSV) contains a 256 amino acid N-terminal domain, which is common to myostatin, and a unique C-terminus of 65 amino acids. Western immunoblotting demonstrated that MSV mRNA is translated into protein, which is present in skeletal muscles. To determine the biological role of MSV, we developed an MSV over-expressing C2C12 myoblast line and showed that it proliferated faster than that of the control line in association with an increased abundance of the CDK2/Cyclin E complex in the nucleus. Recombinant protein made for the novel C-terminus of MSV also stimulated myoblast proliferation and bound to myostatin with high affinity as determined by surface plasmon resonance assay. Therefore, we postulated that MSV functions as a binding protein and antagonist of myostatin. Consistent with our postulate, myostatin protein was co-immunoprecipitated from skeletal muscle extracts with an MSV-specific antibody. MSV over-expression in C2C12 myoblasts blocked myostatin-induced Smad2/3-dependent signaling, thereby confirming that MSV antagonizes the canonical myostatin pathway. Furthermore, MSV over-expression increased the abundance of MyoD, Myogenin and MRF4 proteins (P

BACKGROUND: The observation of conspecifics influences our bodily perceptions and actions: Contagious yawning, contagious itching, or empathy for pain, are all examples of mechanisms based on resonance between our own body and others. While there is evidence for the involvement of the mirror neuron system in the processing of motor, auditory and tactile information, it has not yet been associated with the perception of self-motion. METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether viewing our own body, the body of another, and an object in motion influences self-motion perception. We found a visual-vestibular congruency effect for self-motion perception when observing self and object motion, and a reduction in this effect when observing someone else's body motion. The congruency effect was correlated with empathy scores, revealing the importance of empathy in mirroring mechanisms. CONCLUSIONS/SIGNIFICANCE: The data show that vestibular perception is modulated by agent-specific mirroring mechanisms. The observation of conspecifics in motion is an essential component of social life, and self-motion perception is crucial for the distinction between the self and the other. Finally, our results hint at the presence of a "vestibular mirror neuron system".

BackgroundProcess evaluation is essential in developing, piloting and evaluating complex interventions. This often involves observation of intervention delivery and interviews with study participants. Mobile telephone interventions involve no face to face contact, making conventional process evaluation difficult. This study assesses the utility of novel techniques for process evaluation involving no face to face contact.MethodsText messages were delivered to 34 disadvantaged men as part of a feasibility study of a brief alcohol intervention. Process evaluation focused on delivery of the text messages and responses received from study participants. The computerized delivery system captured data on receipt of the messages. The text messages, delivered over 28 days, included nine which asked questions. Responses to these questions served as one technique for process evaluation by ascertaining the nature of engagement with the study and with steps on the causal chain to behavior change.ResultsA total of 646 SMS text messages were sent to participants. Of these, 613 messages (95%) were recorded as delivered to participants' telephones. 88% of participants responded to messages that asked questions. There was little attenuation in responses to the questions across the intervention period. Content analysis of the responses revealed that participants engaged with text messages, thought deeply about their content and provided carefully considered personal responses to the questions.ConclusionsSocially disadvantaged men, a hard to reach population, engaged in a meaningful way over a sustained period with an interactive intervention delivered by text message. The novel process measures used in the study are unobtrusive, low cost and collect real-time data on all participants. They assessed the fidelity of delivery of the intervention and monitored retention in the study. They measured levels of engagement and identified participants' reactions to components of the intervention. These methods provide a valuable addition to conventional process evaluation techniques.

Continued suboptimal measles-mumps-rubella (MMR) vaccine uptake has re-established measles epidemic risk, prompting a UK catch-up campaign in 2008-09 for children who missed MMR doses at scheduled age. Predictors of vaccine uptake during catch-ups are poorly understood, however evidence from routine schedule uptake suggests demographics and attitudes may be central. This work explored this hypothesis using a robust evidence-based measure.Cross-sectional self-administered questionnaire with objective behavioural outcome.365 UK parents, whose children were aged 5-18 years and had received