Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, ...resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.
Streamwood accumulation at bridges exerts additional forces to bridge structures and may aggravate flooding, local scouring, and eventually may lead to bridge collapse. However, the important ...ecological role of streamwood in fluvial systems calls for a compromise between preservation of river ecosystems and prevention of streamwood‐related hazards (e.g., bridge clogging). This study evaluates the effect of bridge pier shape on wood accumulation or blockage, probability in lowland type of rivers. We conducted laboratory experiments in a flume testing various pier shapes and wood transport mechanisms under two different flow conditions, complemented with numerical modelling. Results revealed that the flow field immediately upstream from the pier has a significant influence on the blockage probability. The pier shape is controlling the flow field, thus, it has a significant influence on wood accumulation. In particular, a squared pier shape, higher Froude number and semi‐congested wood transport resulted in the highest blockage probability under the tested conditions. Our results may help to better design infrastructures to mitigate streamwood‐related hazards in rivers.
Urea transporters (UTs) facilitate urea diffusion across cell membranes and play an important role in the urinary concentration mechanisms in the kidney. Herein, we injected cRNAs encoding for ...c-Myc-tagged murine UT-B, UT-A2 or UT-A3 (versus water-injected control) in
oocytes and evaluated oocyte surface protein expression with biotinylation and immunoblotting, urea uptake using
C counts and water permeability (P
) by video microscopy. Immunoblots of UT-injected oocyte membranes revealed bands with a molecular weight consistent with that of a UT monomer (34 kDa), and UT-injected oocytes displayed significantly increased and phloretin-sensitive urea uptake and P
when compared to day-matched control oocytes. Subtracting the water-injected urea uptake or P
values from those of UT-injected oocytes yielded UT-dependent values*. We demonstrate for the first time that UT-A2 and UT-A3 can transport water, and we confirm that UT-B is permeable to water. Moreover, the
C urea*/P
* ratios fell in the sequence mUT-B>mUT-A2>mUT-A3, indicating that UTs can exhibit selectivity to urea and/or water. It is likely that specific kidney regions with high levels of UTs will exhibit increased urea and/or water permeabilities, directly influencing urine concentration. Furthermore, UT-mediated water transport activity must be considered when developing UT-inhibitors as novel diuretics.This article has an associated First Person interview with the first author of the paper.
Road traffic is recognized as a significant source of particulate matter (PM), especially in urban areas, where exceedances of the legislation PM limit values is one of the main environmental ...concerns. Therefore, the development and implementation of methodologies allowing detailed characterization of PM within urban areas are required to find potential solutions to decrease PM levels. This work aims to provide a detailed characterization of traffic-related PM concentrations at urban scale by using an integrated modelling approach and insitu aerosol measurements. For this purpose, a modelling cascade based on transportation-emission-dispersion approach was implemented for a medium-sized Portuguese city (Coimbra). Moreover, optical aerosol measurements were obtained from an experimental field monitoring campaign (June 2017) implemented at a city ‘hot-spot’ to provide relevant in-situ data on number, surface and mass concentrations distribution into 31 size ranges from 0.25 to 32 μm. The spatial distribution of the exhaust and non-exhaust traffic-related emissions is analysed and discussed addressing their contribution to the PM pollution. The current study evidences the importance of road traffic non-exhaust emissions and demonstrates the usefulness of the integrated modelling approach in the mobility policy relevant context.
Cold start emissions, which are released during the first minutes of driving after the vehicle engine is started, may contribute significantly to the urban road traffic emissions. Implementation of ...bottom-up approaches for emission quantification in urban context is crucial to address the distribution of pollution with fine temporal and spatial resolution and to establish local mitigation measures and plans. In this research a modeling approach to quantify cold start excess emissions from road transport with fine spatial resolution is proposed and applied. In combination with transportation modeling, a new module has been developed to estimate cold start emissions at road segment level and for a trip, while preserving information on Origin-Destination of the trips contributing to those emissions. The methodology was applied to Coimbra case study allowing spatial analysis of cold start emissions in the urban context. The frequency distribution and summary statistics for road segments are provided focusing on different types of roads and seasonal variations. High contribution of cold start emissions is demonstrated with median values above 70% for carbon monoxide and hydrocarbons at local roads, where most people leave or work. The methodology applied in this work highlights the importance of cold start emission quantification for traffic pollution studies.
Infliximab is therapeutic monoclonal antibody (mAb) against TNF-α employed in the treatment of immunoinflammatory diseases. The development of biosimilar mAbs is a global strategy to increase drug ...accessibility and reduce therapy-associated costs. Herein we compared key physicochemical characteristics and biological activities produced by infliximab and infliximab-Probiomed in order to identify functionally relevant differences between the mAbs. Binding of infliximab-Probiomed to TNF-α was specific and had kinetics comparable to that of the reference product. Both mAbs had highly similar neutralizing efficacy in HUVEC cell cultures stimulated with TNF-α. In vitro induction of CDC and ADCC were also similar between the evaluated products. In vivo comparability was assessed using a transgenic mouse model of arthritis that expresses human TNF-α in a 13-week multiple-administration study. Infliximab and infliximab-Probiomed showed comparable efficacy, safety, and pharmacokinetic profiles. Our results indicate that infliximab-Probiomed has highly similar activities to infliximab in preclinical models, warranting a clinical evaluation of its biosimilarity.
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European harbours are known to contribute to air quality degradation. While most of the literature focuses on emissions from stacks or logistics operations, ship refit and repair activities are also ...relevant aerosol sources in EU harbour areas. Main activities include abrasive removal of filler and spray painting with antifouling coatings/primers/topcoats. This work aimed to assess ultrafine particle (UFP) emissions from ship maintenance activities and their links with exposure, toxicity and health risks for humans and the aquatic environment. Aerosol emissions were monitored during mechanical abrasion of surface coatings under real-world operating conditions in two scenarios in the Mallorca harbour (Spain). Different types of UFPs were observed: (1) highly regular (triangular, hexagonal) engineered nanoparticles (Ti-, Zr-, Fe-based), embedded as nano-additives in the coatings, and (2) irregular, incidental particles emitted directly or formed during abrasion. Particle number concentrations monitored were in the range of industrial activities such as drilling or welding (up to 5 ∗ 105/cm3, mean diameters <30 nm). The chemical composition of PM4 aerosols was dominated by metallic tracers in the coatings (Ti, Al, Ba, Zn). In vitro toxicity of PM2 aerosols evidenced reduced cell viability and a moderate potential for cytotoxic effects. While best practices (exhaust ventilation, personal protective equipment, dust removal) were in place, it is unlikely that exposures and environmental release can be fully avoided at all times. Thus, it is advisable that health and safety protocols should be comprehensive to minimise exposures in all types of locations (near- and far-field) and periods (activity and non-activity). Potential release to coastal surface waters of metallic engineered and incidental nanomaterials, as well as fine and coarse particles (in the case of settled dust), should be assessed and avoided.
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•Ship refit activities emit ultrafine and engineered nanoparticles in harbour areas.•Ultrafine and engineered nanoparticles impact human exposure.•In vitro assays evidenced moderate particle toxicity.•There is high potential for impacts to the aquatic coastal environment.•Improvements to safety protocols may minimise exposure and environmental release.
Abstract
Objectives
Heister valves are mucosal folds located on the endoluminal surface of the cystic duct (CD) and were first described by Lorenz Heister in 1732. Their presence could represent an ...obstacle that impedes transcystic exploration. It has been suggested that the distribution of Heister valves follows a steady rhythmic pattern in a spiral disposition; however, there is no conclusive data to support this claim. The aim of this study was to describe the main characteristics of the CD and Heister valves in adult human cadavers.
Methods
A descriptive cross-sectional study was performed on 46 extrahepatic biliary tracts.
Results
The CD has an average length of 25.37 mm and diameter of 4.53 mm. The most frequent level of junction was the middle union. Heister valves were present on 32 CDs; in most cases, they were distributed uniformly on the duct and presented an oblique disposition. A nonreticular pattern was the most frequent reticular pattern. The most frequent type of the nonreticular type was the B1 subtype. The most frequent type of distribution was the nonreticular type, particularly the B1 type.
Conclusions
The cystic fold could hinder transcystic exploration. The cysticotomy incision should not be determined by the distribution of the fold on the CD. The morphology of the Heister valves does not show evidence of a steady systematic pattern.
Se han clasificado diversas porciones del conducto colédoco, desde su origen en la unión cistohepática, hasta la segunda porción del duodeno. No se puede lograr un consenso al momento de segmentarlo, ...debido a que algunos autores sostienen la existencia de 3 o 4 porciones.
El objetivo fue establecer la prevalencia de cada una de las porciones del conducto colédoco, determinar sus características morfológicas y analizar su asociación quirúrgica.
Estudio analítico de corte transversal en el que se diseccionaron 40 vías biliares.
Se evidenció 85% de porción retroduodenal, 20% retropancreática, 80% intrapancreática y 45% intramural. No se evidenció la porción supraduodenal debido a las relaciones anatómicas regionales, al tabique cistohepático o a una unión cistohepática baja. La combinación secuencial más frecuente fue la retroduodenal e intrapancreática. El conducto colédoco tuvo una longitud de 66,19mm y un diámetro de 6,31mm.
La segmentación biliar establecida tendría implicancias tanto teóricas, al justificar las teorías etiopatogénicas vigentes de la pancreatitis biliar, como prácticas, redefiniendo la coledocotomía supraduodenal y los cuadros clínicos de ictericia obstructiva.
Several portions of the bile duct have been classified from its origin in the cystohepatic junction to its outfall in the second portion of the duodenum. An agreement could not be reached among the authors at the time of segmenting it, since some of them claim that there are three or four portions.
To establish the prevalence of each of the bile duct portions, determine its morphological characteristics and to analyze its surgical associations.
A cross-sectional study. 40 biliary tracks were dissected.
Retroduodenal portion 85%, retropancreatic 20%, intrapancreatic 80%, intramural 45%. The supraduodenal portion was not made evident because of the regional anatomic relations, the cystohepatic septum or a cystohepatic lower junction. The bile duct had an average lenght of 66.19mm and a diameter of 6.31mm.
The biliary segmentation would have a theoretical explanation to justify the etiopathogenic theories of the biliary pancreatitis, and a practical implication by redefining the choledochotomy supraduodenal and clinical pictures of obstructive jaundice.
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