Introducing the MiniPONS: A Short Multichannel Version of the Profile of Nonverbal Sensitivity (PONS)

Despite extensive research activity on the recognition of emotional expression, there are only few validated tests of individual differences in this competence (generally considered as part of nonverbal sensitivity and emotional intelligence). This paper reports the development of a short, multichannel, version (MiniPONS) of the established Profile of Nonverbal Sensitivity (PONS) test. The full test has been extensively validated in many different cultures, showing substantial correlations with a large range of outcome variables. The short multichannel version (64 items) described here correlates very highly with the full version and shows reasonable construct validity through significant correlations with other tests of emotion recognition ability. Based on these results, the role of nonverbal sensitivity as part of a latent trait of emotional competence is discussed and the MiniPONS is suggested as a convenient method to perform a rapid screening of this central socioemotional competenc

The Role of Perceived Voice and Speech Characteristics in Vocal Emotion Communication

Aiming at a more comprehensive assessment of nonverbal vocal emotion communication, this article presents the development and validation of a new rating instrument for the assessment of perceived voice and speech features. In two studies, using two different sets of emotion portrayals by German and French actors, ratings of perceived voice and speech characteristics (loudness, pitch, intonation, sharpness, articulation, roughness, instability, and speech rate) were obtained from non-expert (untrained) listeners. In addition, standard acoustic parameters were extracted from the voice samples. Overall, highly similar patterns of results were found in both studies. Rater agreement (reliability) reached highly satisfactory levels for most features. Multiple discriminant analysis results reveal that both perceived vocal features and acoustic parameters allow a high degree of differentiation of the actor-portrayed emotions. Positive emotions can be classified with a higher hit rate on the basis of perceived vocal features, confirming suggestions in the literature that it is difficult to find acoustic valence indicators. The results show that the suggested scales (Geneva Voice Perception Scales) can be reliably measured and make a substantial contribution to a more comprehensive assessment of the process of emotion inferences from vocal expression

Effects of Plant Diversity, Functional Group Composition, and Fertilization on Soil Microbial Properties in Experimental Grassland

Background: Loss of biodiversity and increased nutrient inputs are two of the most crucial anthropogenic factors driving ecosystem change. Although both received considerable attention in previous studies, information on their interactive effects on ecosystem functioning is scarce. In particular, little is known on how soil biota and their functions are affected by combined changes in plant diversity and fertilization. Methodology/principal findings: We investigated the effects of plant diversity, functional community composition, and fertilization on the biomass and respiration of soil microbial communities in a long-term biodiversity experiment in semi-natural grassland (Jena Experiment). Plant species richness enhanced microbial basal respiration and microbial biomass, but did not significantly affect microbial specific respiration. In contrast, the presence of legumes and fertilization significantly decreased microbial specific respiration, without altering microbial biomass. The effect of legumes was superimposed by fertilization as indicated by a significant interaction between the presence of legumes and fertilization. Further, changes in microbial stoichiometry (C-to-N ratio) and specific respiration suggest the presence of legumes to reduce N limitation of soil microorganisms and to modify microbial C use efficiency. Conclusions/significance: Our study highlights the role of plant species and functional group diversity as well as interactions between plant community composition and fertilizer application for soil microbial functions. Our results suggest soil microbial stoichiometry to be a powerful indicator of microbial functioning under N limited conditions. Although our results support the notion that plant diversity and fertilizer application independently affect microbial functioning, legume effects on microbial N limitation were superimposed by fertilization, indicating significant interactions between the functional composition of plant communities and nutrient inputs for soil processes

Automated Sizing Process of a complete Aircraft Structure for the Usage within a MDO Process

The paper gives an overview of an automated sizing process of a complete aircraft structure which is part of a multidisciplinary optimization process that has been developed at the German Aerospace Center (DLR). It covers all aspects of aircraft model generation, model analysis and the implemented sizing concepts. Where the main focus concentrates on metallic based sizing within the global optimization process, an alternative composite sizing concept is also described in detail. Furthermore, exemplary results of the automated sizing process will be illustrated

Modeling the cognitive effects of diet discontinuation in adults with phenylketonuria (PKU) using pegvaliase therapy in PAH-deficient mice

Existing phenylalanine hydroxylase (PAH)-deficient mice strains are useful models of untreated or late-treated human phenylketonuria (PKU), as most contemporary therapies can only be initiated after weaning and the pups have already suffered irreversible consequences of chronic hyperphenylalaninemia (HPA) during early brain development. Therefore, we sought to evaluate whether enzyme substitution therapy with pegvaliase initiated near birth and administered repetitively to C57Bl/6-Pahenu2/enu2 mice would prevent HPA-related behavioral and cognitive deficits and form a model for early-treated PKU. The main results of three reported experiments are: 1) lifelong weekly pegvaliase treatment prevented the cognitive deficits associated with HPA in contrast to persisting deficits in mice treated with pegvaliase only as adults. 2) Cognitive deficits reappear in mice treated with weekly pegvaliase from birth but in which pegvaliase is discontinued at 3 months age. 3) Twice weekly pegvaliase injection also prevented cognitive deficits but again cognitive deficits emerged in early-treated animals following discontinuation of pegvaliase treatment during adulthood, particularly in females. In all studies, pegvaliase treatment was associated with complete correction of brain monoamine neurotransmitter content and with improved overall growth of the mice as measured by body weight. Mean total brain weight however remained low in all PAH deficient mice regardless of treatment. Application of enzyme substitution therapy with pegvaliase, initiated near birth and continued into adulthood, to PAH-deficient Pahenu2/enu2 mice models contemporary early-treated human PKU. This model will be useful for exploring the differential pathophysiologic effects of HPA at different developmental stages of the murine brain. Keywords: Behavior; Cognition; Dopamine; Hyperphenylalaninemia; Pegvaliase; Phenylalanine hydroxylase; Phenylketonuria; Serotonin; Tryptophan; Tryptophan hydroxylase; Tyrosine; Tyrosine hydroxylase

The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.publishedVersio

Intrabiliary infusion of naked DNA vectors targets periportal hepatocytes in mice

Hydrodynamic tail vein injection (HTV) is the "gold standard" for delivering naked DNA vectors to mouse liver, thereby transfecting predominately perivenous hepatocytes. While HTV corrects metabolic liver defects such as phenylketonuria or cystathionine β-synthase deficiency, correction of spf ash mice with ornithine transcarbamylase (OTC) deficiency was not possible despite overexpression in the liver, as the OTC enzyme is primarily expressed in periportal hepatocytes. To target periportal hepatocytes, we established hydrodynamic retrograde intrabiliary injection (HRII) in mice and optimized minicircle (MC) vector delivery using luciferase as a marker gene. HRII resulted in a transfection efficiency below 1%, 100-fold lower than HTV. While HRII induced minimal liver toxicity compared with HTV, overexpression of luciferase by both methods, but not of a natural liver-specific enzyme, elicited an immune response that led to the elimination of luciferase expression. Further testing of MC vectors delivered via HRII in spf ash mice did not result in sufficient therapeutic efficacy and needs further optimization and/or selection of the corrected cells. This study reveals that luciferase expression is toxic for the liver. Furthermore, physical delivery of MC vectors via the bile duct has the potential to treat defects restricted to periportal hepatocytes, which opens new doors for non-viral liver-directed gene therapy. Keywords: FLAG-tagged OTC; OTC deficiency; hydrodynamic retrograde intrabiliary injection; hydrodynamic tail vein injection; immune response; liver toxicity; liver-directed gene therapy; luciferase expression; naked DNA minicircle vector; non-viral; urea cycle disorder

Delivery of non-viral naked DNA vectors to liver in small weaned pigs by hydrodynamic retrograde intrabiliary injection

Hepatic gene therapy by delivering non-integrating therapeutic vectors in newborns remains challenging due to the risk of dilution and loss of efficacy in the growing liver. Previously we reported on hepatocyte transfection in piglets by intraportal injection of naked DNA vectors. Here, we established delivery of naked DNA vectors to target periportal hepatocytes in weaned pigs by hydrodynamic retrograde intrabiliary injection (HRII). The surgical procedure involved laparotomy and transient isolation of the liver. For vector delivery, a catheter was placed within the common bile duct by enterotomy. Under optimal conditions, no histological abnormalities were observed in liver tissue upon pressurized injections. The transfection of hepatocytes in all tested liver samples was observed with vectors expressing luciferase from a liver-specific promoter. However, vector copy number and luciferase expression were low compared to hydrodynamic intraportal injection. A 10-fold higher number of vector genomes and luciferase expression was observed in pigs using a non-integrating naked DNA vector with the potential for replication. In summary, the HRII application was less efficient (i.e., lower luciferase activity and vector copy numbers) than the intraportal delivery method but was significantly less distressful for the piglets and has the potential for injection (or re-injection) of vector DNA by endoscopic retrograde cholangiopancreatography

Serious infection risk of tofacitinib compared to biologics in patients with rheumatoid arthritis treated in routine clinical care

Recently, serious infections related to the use of tofacitinib (TOF) for treatment of rheumatoid arthritis (RA) have raised considerable interest. This study aimed to compare the risk for serious infections in patients with RA upon receiving TOF versus biologic disease-modifying antirheumatic drugs (bDMARDs) by age at treatment initiation. We identified adult RA patients exposed to TOF or bDMARDs using data collected by the Swiss registry for inflammatory rheumatic diseases (SCQM) from 2015 to 2018. The event of interest was the first non-fatal serious infection (SI) during drug exposure. Missing or incomplete SI dates were imputed as either the lower (left) or upper (right) limit of the known occurrence interval. The ratio of SI hazards (HR) of TOF versus bDMARDs was estimated as a function of age using covariate-adjusted Cox regression applied to each type of imputed time-to-SI. A total of 1687 patients provided time at risk for a first SI during study participation and drug exposure for 2238 different treatment courses, 345 for TOF and 1893 for bDMARDs. We identified 44 (left imputation) or 43 (right imputation), respectively, first SIs (12/12 on TOF versus 32/31 on bDMARDs). Left and right imputation produced similar results. For patients aged ≥ 69 years, the treatment HR started to be increased (lower limit of 95% confidence intervals (LLCIs) > 1). By the age of 76, the difference between TOF and bDMARDs started to be clinically relevant (LLCIs > 1.25). For patients aged < 65 years, the data were insufficient to draw conclusions. Our results suggest that we should expect an increased risk for SIs in older patients treated with TOF compared to bDMARDs supporting a cautious use of TOF in these patients

Serious infection risk of tofacitinib compared to biologics in patients with rheumatoid arthritis treated in routine clinical care.

Recently, serious infections related to the use of tofacitinib (TOF) for treatment of rheumatoid arthritis (RA) have raised considerable interest. This study aimed to compare the risk for serious infections in patients with RA upon receiving TOF versus biologic disease-modifying antirheumatic drugs (bDMARDs) by age at treatment initiation. We identified adult RA patients exposed to TOF or bDMARDs using data collected by the Swiss registry for inflammatory rheumatic diseases (SCQM) from 2015 to 2018. The event of interest was the first non-fatal serious infection (SI) during drug exposure. Missing or incomplete SI dates were imputed as either the lower (left) or upper (right) limit of the known occurrence interval. The ratio of SI hazards (HR) of TOF versus bDMARDs was estimated as a function of age using covariate-adjusted Cox regression applied to each type of imputed time-to-SI. A total of 1687 patients provided time at risk for a first SI during study participation and drug exposure for 2238 different treatment courses, 345 for TOF and 1893 for bDMARDs. We identified 44 (left imputation) or 43 (right imputation), respectively, first SIs (12/12 on TOF versus 32/31 on bDMARDs). Left and right imputation produced similar results. For patients aged ≥ 69 years, the treatment HR started to be increased (lower limit of 95% confidence intervals (LLCIs) > 1). By the age of 76, the difference between TOF and bDMARDs started to be clinically relevant (LLCIs > 1.25). For patients aged < 65 years, the data were insufficient to draw conclusions. Our results suggest that we should expect an increased risk for SIs in older patients treated with TOF compared to bDMARDs supporting a cautious use of TOF in these patients