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Changes in the organization and structure of the fibronectin matrix are believed to contribute to dysregulated wound healing and subsequent tissue inflammation and tissue fibrosis. These changes include an increase in the EDA isoform of fibronectin as well as the mechanical unfolding of fibronectin type III domains. In previous studies using embryonic foreskin fibroblasts, we have shown that fibronectin’s EDA domain (FnEDA) and the partially unfolded first Type III domain (FnIII-1c) function as Damage Associated Molecular Pattern (DAMP) molecules to stimulate the induction of inflammatory cytokines by serving as agonists for Toll-Like Receptor-4 (TLR4). However, the role of signaling molecules downstream of TLR-4 such as TGF-β Activated Kinase 1 (TAK1) and Mitogen activated protein kinases (MAPK) in regulating the expression of fibronectin DAMP induced inflammatory genes in specific cell types is not known. In the current study, we evaluate the molecular steps regulating the fibronectin driven induction of inflammatory genes in three human fibroblast cell lines: embryonic foreskin, adult dermal, and adult kidney. The fibronectin derived DAMPs each induce the phosphorylation and activation of TAK1 which results in the activation of two downstream signaling arms, IKK/NF-κB and MAPK. Using the specific inhibitor 5Z-(7)-Oxozeanol as well as siRNA, we show TAK1 to be a crucial signaling mediator in the release of cytokines in response to fibronectin DAMPs in all three cell types. Finally, we show that FnEDA and FnIII-1c induce several pro-inflammatory cytokines whose expression is dependent on both TAK1 and JNK MAPK and highlight cell-type specific differences in the gene-expression profiles of the fibroblast cell-lines.

Plasmodium falciparum is a parasite that causes asymptomatic or symptomatic malaria infections in humans depending on various factors. These infections are also a major cause of anemia in intertropical countries such as Gabon. Past studies have clearly demonstrated that inflammatory markers such as cytokines play a key role in the pathogenesis of malaria disease. However, the clinical manifestations of severe malaria vary according to the level of transmission and more information is needed to gain a better understanding of the factors involved. As such, the objective of this study was to investigate the circulating levels of nine cytokines in asymptomatic and symptomatic P. falciparum infections in Gabonese children and their roles in the pathogenesis of anemia. Blood samples were collected from 241 children aged 3 to 180 months in Lastourville, south-eastern Gabon. Diagnosis of P. falciparum infection was performed using Rapid Diagnosis Tests, microscopy and nested PCR. Levels in the plasma of the Th1 (IFN-γ, TNF-α, IL-6 and IL-12p70), Th17 (IL-17A and IL-22) and Th2 (IL-10, IL-4 and IL-13) cytokines were measured by ELISA. Data showed that IL-6, IFN-γ, IL-12p70, IL-10, and IL-13 levels were significantly higher in children with symptomatic P. falciparum infection compared to uninfected children. IL-10 levels were significantly higher in symptomatic children than in asymptomatic children, who had moderately increased levels compared to uninfected controls. Moreover, only IL-10 and IL-6 levels were significantly higher in children with severe malarial anemia compared to children with uncomplicated malaria who had significantly lower IL-10 levels than children with moderate malarial anemia. These data indicate that the progression of P. falciparum infection towards an advanced stage in children is accompanied by a significant increase in type Th1 and/or Th2 cytokines. These inflammatory mediators could serve as potential predictors of anemia for malaria patients.

Management regimes of marine resources that rely on spatial boundaries might be poorly adapted to climate change shifts in species distributions. This is of specific concern for the management of fish stocks that cross management jurisdictions, known as shared stocks. Transitioning to dynamic rules in spatial management has been suggested as a solution for mismatches between species distributions and the spatial boundaries. However, in many cases spatial boundaries are not clearly drawn, hampering such transitions. Here, we use black sea bass (Centropristis striata), summer flounder (Paralichthys dentatus) and scup (Stenotomus chrysops) as case studies to explore different approaches to designing spatial regulatory units to facilitate the adaptation of fisheries management to shifting distributions of shared stocks. First, we determine the yearly distribution of each stock within the United States Exclusive Economic Zone from 1951 to 2019 during Fall and Spring sampling seasons. Second, we explore two approaches for drawing regulatory units based on state waters and historical landings. Finally, we estimate each state’s proportion of the stock’s distribution and compare historical and recent values. We show that the distribution of all three stocks has changed relative to the years used to determine the current quota allocation across states, with an overall gain for central-northern states at the expense of the southernmost states. In terms of the distribution of allocation, we find that, while seasonal differences exist, the biggest differences in the proportion of the stock spatial distribution attributed to each state come from the method for designing regulatory units. Here, we show that the method used to define allocation units can have meaningful impacts on resulting adaptive policy. As climate change-driven conflicts in fishing resource allocation are expected to increase and deepen around the world, we provide a replicable approach to make an informed and transparent choice to support data-driven decision-making.

The current study aimed to verify whether or not passive static stretching affects balance control capacity. Thirty-eight participants (19 women and 19 men) underwent a passive static stretching session, involving the knee extensor/flexor and dorsi/plantarflexor muscles, and a control session (no stretching, CTRL). Before (PRE), immediately after (POST), after 15 (POST15) and 30 min (POST30) from stretching (or rest in CTRL), balance control was evaluated under static and dynamic conditions, with open/closed eyes, and with/without somatosensory perturbation (foam under the feet). During tests, centre of pressure (CoP) sway area and perimeter and antero-posterior and medio-lateral sway mean speed were computed. Surface electromyography root mean square (sEMG RMS) was calculated from the vastus lateralis, biceps femoris, gastrocnemius medialis, and tibialis anterior muscles during MVC and during the balance tests. Hip flexion/extension and dorsi/plantarflexion range of motion (ROM), maximum voluntary contraction (MVC) and sEMG RMS during MVC were measured at the same time points. After stretching, ROM increased (≈6.5%; P

Advanced ovarian cancer is one of the most lethal gynecological tumor, mainly due to late diagnoses and acquired drug resistance. MicroRNAs (miRNAs) are small-non coding RNA acting as tumor suppressor/oncogenes differentially expressed in normal and epithelial ovarian cancer and has been recognized as a new class of tumor early detection biomarkers as they are released in blood fluids since tumor initiation process. Here, we evaluated by droplet digital PCR (ddPCR) circulating miRNAs in serum samples from healthy (N = 105) and untreated ovarian cancer patients (stages I to IV) (N = 72), grouped into a discovery/training and clinical validation set with the goal to identify the best classifier allowing the discrimination between earlier ovarian tumors from health controls women. The selection of 45 candidate miRNAs to be evaluated in the discovery set was based on miRNAs represented in ovarian cancer explorative commercial panels. We found six miRNAs showing increased levels in the blood of early or late-stage ovarian cancer groups compared to healthy controls. The serum levels of miR-320b and miR-141-3p were considered independent markers of malignancy in a multivariate logistic regression analysis. These markers were used to train diagnostic classifiers comprising miRNAs (miR-320b and miR-141-3p) and miRNAs combined with well-established ovarian cancer protein markers (miR-320b, miR-141-3p, CA-125 and HE4). The miRNA-based classifier was able to accurately discriminate early-stage ovarian cancer patients from health-controls in an independent sample set (Sensitivity = 80.0%, Specificity = 70.3%, AUC = 0.789). In addition, the integration of the serum proteins in the model markedly improved the performance (Sensitivity = 88.9%, Specificity = 100%, AUC = 1.000). A cross-study validation was carried out using four data series obtained from Gene Expression Omnibus (GEO), corroborating the performance of the miRNA-based classifier (AUCs ranging from 0.637 to 0.979). The clinical utility of the miRNA model should be validated in a prospective cohort in order to investigate their feasibility as an ovarian cancer early detection tool.

BackgroundBipolar Transurethral Enucleation of the Prostate (B-TUEP) is recommended as a first-choice treatment for benign prostatic obstruction in prostates >80 ml. Differently, B-TUEP is only considered as an alternative option after TURP for smaller prostates (30-80 ml). The aim of our study is to assess the relation between prostate size and surgical outcomes after B-TUEP.MethodsWe performed a retrospective analysis of data collected from 172 patients submitted to B-TUEP. Patients were segregated according to tertiles of prostate volume (PV) (≤60 ml, 61-110 ml, >110 ml). For each group we evaluated enucleation efficacy (enucleated weight/enucleation time), complication rates, urinary and sexual function parameters. Functional and sexual parameters were compared between groups at baseline, 1 and 3 months follow up. Descriptive statistics and linear and logistic regression models tested the association between PV and postoperative complications/outcomes.ResultsOperative time and weight of enucleated adenomas increased along with prostate volumes (all p≤0.01). Enucleation efficacy was higher in men with PV >110 ml compared to other groups (p≤0.001). Length of hospital stay, catheterization time and rates of postoperative complications, such as transfusion and clot evacuation rates and bladder neck/urethral strictures, were comparable between groups. Urinary symptoms improved at 1-and 3-months in each group as compared to baseline evaluation (all pConclusionAccording to our findings, B-TUEP should be considered a "size independent procedure" as it can provide symptom relief in men with prostates of all sizes with the same efficacy and safety profile.

We explore what researchers can gain or lose by using three widely used models for the analysis of discrete choice experiment data—the random parameter logit (RPL) with correlated parameters, the RPL with uncorrelated parameters and the hybrid choice model. Specifically, we analyze three data sets focused on measuring preferences to support a renewable energy programme to grow seaweed for biogas production. In spite of the fact that all three models can converge to very similar median WTP values, they cannot be used indistinguishably. Each model is based on different assumptions, which should be tested before their use. The fact that standard sample sizes usually applied in environmental valuation are generally unable to capture the outcome differences between the models cannot be used as a justification for their indistinct application.

BackgroundThis study investigated the associations between socio-economic deprivation and tuberculosis (TB) treatment outcomes, alongside well-known TB risk factors. The effects of healthcare expenditures and their growth on trends in TB incidence from 2009 to 2013 were also assessed.MethodsSecondary data analysis was performed on data obtained from various sources including governmental, non-governmental and research institutions. Indicators for TB treatment outcomes included TB death rate, TB rate among the household contacts of the Index TB cases, TB treatment failure, HIV associated TB death rate, TB defaulter rate, and new TB smear positive cases. Analysis of variance (ANOVA) and Turkey’s tests for post-hoc analysis were used to compare means of variables of interest considering a type I error rate of 0.05. Regression models and canonical discriminant analysis (CDA) were used to explore the associations between trends in TB incidence and independent TB predictors. During CDA, Fischer’s linear functions, Eigen values, and Mahalanobis distances were determined with values of Wilk’s Lambda closer to zero being the evidence for well discriminated patient groups. Data analysis was performed using SPSS® statistical software version 23.0 (Chicago, IL).ResultsIn total, 62 400 records of TB notification were analyzed for the period 2009–2013. The average TB incidence rate over a 5-year period was 298 cases per 100,000 inhabitants per year. The incidence of TB was reduced by 79.70% at the end of the evaluation as compared to the baseline data in 2009. Multiple linear regression analysis showed that the Expenditure per patient day equivalent (PDE) and PHC expenditure per capita were significantly and independently associated with the decline of TB incidence (adjusted R2= 60%; ρ = 0.002) following the equation:Y = (- 209× Expenditure per PDE) + (- 0.191 × PHC expenditure per capita). CDA showed that in the most socio-economically deprived communities (quintile 1), HIV associated TB death rates were significantly more likely to be higher as compared to the least socio-economically deprived group (quintile 5) [Eigen value (12.95), function coefficient (1.49) > (.77); Wilk’s Lambda = .019, p < .0001].ConclusionsAlthough TB control programs in OR Tambo district have averted thousands of TB incident cases, their effects on HIV associated TB deaths among the most deprived communities remain insignificant. There is an urgent need for strengthening integration of TB/HIV services in most deprived settings.

BackgroundThough several procedures of IOL implantation have been described (sutured scleral fixation, intra-scleral fixation, angle-supported anterior chamber, and anterior chamber or retropupillary iris-claw IOLs), there are no randomized trials which are comparing different techniques. Hence, the surgical treatment of aphakia still remains controversial and challenging. The purpose of this study was to compare the long-term efficacy and the rate of complications of anterior versus posterior Iris-claw intraocular lenses (IOL) implantation to correct for the treatment of aphakia without sufficient capsule support.Methods and findingsConsecutive eyes having secondary implantation of aphakic iris-fixated IOLs with a follow-up of at least 5 years were considered. Mean correct distance visual acuity (CDVA) changes, percentage of eyes with CDVA improvement, mean corneal endothelial cell density (CECD) loss and the rate of other complications were used for statistical analysis. The study evaluated a total of 180 eyes (Group A: 87 anterior chamber iris-claw fixation, Group B: 93 retropupillary iris-claw implantation) of 180 consecutive different patients, with aphakia of various reasons. CDVA improved significantly in both groups after surgery (PConclusionsFive-year follow-up shows that secondary implantation of aphakic IOLs is effective and safe for the correction treatment of aphakia in eyes without capsule support.

In the present study, we evaluate the effect of acute restraint stress (15 min) of male Wistar rats on social interaction measurements and c-Fos immunoreactivity (c-Fos-ir) expression, a marker of neuronal activity, in areas involved with the modulation of acute physical restraint in rats, i.e., the paraventricular nucleus of the hypothalamus (PVN), median raphe nucleus (MnR), medial prefrontal cortex (mPFC), cingulate prefrontal cortex (cPFC), nucleus accumbens (NaC), hippocampus (CA3), lateral septum (LS) and medial amygdala (MeA). We considered the hypothesis that restraint stress exposure could promote social withdrawal induced by the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, and increase c-Fos expression in these limbic forebrain areas investigated. In addition, we investigated whether pretreatment with the atypical antipsychotic clozapine (5 mg/kg; I.P.) could attenuate or block the effects of restraint on these responses. We found that restraint stress induced social withdrawal, and increased c-Fos-ir in these areas, demonstrating that a single 15 min session of physical restraint of rats effectively activated the HPA axis, representing an effective tool for the investigation of neuronal activity in brain regions sensitive to stress. Conversely, pretreatment with clozapine, prevented social withdrawal and reduced c-Fos expression. We suggest that treatment with clozapine exerted a preventive effect in the social interaction deficit, at least in part, by blocking the effect of restraint stress in brain regions that are known to regulate the HPA-axis, including the cerebral cortex, hippocampus, hypothalamus, septum and amygdala. Further experiments will be done to confirm this hypothesis.

Oceans absorb a huge part of the atmospheric heat, leading to the rise in water temperature. Reefs are among the most affected ecosystems, where the complex behavioral repertoire of fishes is usually an indicator of environmental impacts. Here, we examined whether temperature (28 and 34°C) and habitat complexity (high and low) interact to affect the agonistic behavior (mirror test) of the dusky damselfish (Stegastes fuscus), a key species in Brazilian reefs because of its gardening capacity and territorial behavior. Higher temperatures altered basal behavior in both high and low-complexity conditions. Fish kept at 28°C under the high-complexity condition were more aggressive than those at a higher temperature (34°C) and in a low-complexity condition, which also exhibited lower dispersion. Our data show that changes in behavior of coral reef fish is associated to fluctuations in environmental conditions. Thus, it is important to implement management or conservation strategies that could mitigate global change effects.

Alongside government driven management initiatives to achieve sustainable fisheries management, there remains a role for market-based mechanisms to improve fisheries outcomes. Market-based mechanisms are intended to create positive economic incentives that improve the status and management of fisheries. Research to understand consumer demand for certified fish is central but needs to be mirrored by supply side understanding including why fisheries decide to gain or retain certification and the impact of certification on them and other stakeholders involved. We apply semi-structured interviews in seven different Marine Stewardship Council (MSC) certified fisheries that operate in (or from) Western Australia with the aim of better understanding fisheries sector participation in certification schemes (the supply side) and the impacts and unintended benefits and costs of certification. We find that any positive economic impacts of certification were only realised in a limited number of MSC fisheries in Western Australia, which may be explained by the fact that only a small proportion of Western Australian state-managed fisheries are sold with the MSC label and ex-vessel or consumer market price premiums are therefore mostly not obtained. Positive impacts of certification in these Western Australian fisheries are more of a social and institutional nature, for example, greater social acceptability and increased efficiency in the governance process respectively. However, opinion is divided on whether the combined non-monetary and monetary benefits outweigh the costs.

During experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis associated with blood-brain barrier (BBB) disruption, oligodendrocyte precursor cells (OPCs) overexpress proteoglycan nerve/glial antigen 2 (NG2), proliferate, and make contacts with the microvessel wall. To explore whether OPCs may actually be recruited within the neurovascular unit (NVU), de facto intervening in its cellular and molecular composition, we quantified by immunoconfocal morphometry the presence of OPCs in contact with brain microvessels, during postnatal cerebral cortex vascularization at postnatal day 6, in wild-type (WT) and NG2 knock-out (NG2KO) mice, and in the cortex of adult naïve and EAE-affected WT and NG2KO mice. As observed in WT mice during postnatal development, a higher number of juxtavascular and perivascular OPCs was revealed in adult WT mice during EAE compared to adult naïve WT mice. In EAE-affected mice, OPCs were mostly associated with microvessels that showed altered claudin-5 and occludin tight junction (TJ) staining patterns and barrier leakage. In contrast, EAE-affected NG2KO mice, which did not show any significant increase in vessel-associated OPCs, seemed to retain better preserved TJs and BBB integrity. As expected, absence of NG2, in both OPCs and pericytes, led to a reduced content of vessel basal lamina molecules, laminin, collagen VI, and collagen IV. In addition, analysis of the major ligand/receptor systems known to promote OPC proliferation and migration indicated that vascular endothelial growth factor A (VEGF-A), platelet-derived growth factor-AA (PDGF-AA), and the transforming growth factor-β (TGF-β) were the molecules most likely involved in proliferation and recruitment of vascular OPCs during EAE. These results were confirmed by real time-PCR that showed Fgf2, Pdgfa and Tgfb expression on isolated cerebral cortex microvessels and by dual RNAscope-immunohistochemistry/in situ hybridization (IHC/ISH), which detected Vegfa and Vegfr2 transcripts on cerebral cortex sections. Overall, this study suggests that vascular OPCs, in virtue of their developmental arrangement and response to neuroinflammation and growth factors, could be integrated among the classical NVU cell components. Moreover, the synchronized activation of vascular OPCs and pericytes during both BBB development and dysfunction, points to NG2 as a key regulator of vascular interactions.