Antimicrobial effects of inhaled sphingosine against Pseudomonas aeruginosa in isolated ventilated and perfused pig lungs

Background Ex-vivo lung perfusion (EVLP) is a save way to verify performance of donor lungs prior to implantation. A major problem of lung transplantation is a donor-to-recipient-transmission of bacterial cultures. Thus, a broadspectrum anti-infective treatment with sphingosine in EVLP might be a novel way to prevent such infections. Sphingosine inhalation might provide a reliable anti-infective treatment option in EVLP. Here, antimicrobial potency of inhalative sphingosine in an infection EVLP model was tested. Methods A 3-hour EVLP run using pig lungs was performed. Bacterial infection was initiated 1-hour before sphingosine inhalation. Biopsies were obtained 60 and 120 min after infection with Pseudomonas aeruginosa. Aliquots of broncho-alveolar lavage (BAL) before and after inhalation of sphingosine were plated and counted, tissue samples were fixed in paraformaldehyde, embedded in paraffin and sectioned. Immunostainings were performed. Results Sphingosine inhalation in the setting of EVLP rapidly resulted in a 6-fold decrease of P. aeruginosa CFU in the lung (p = 0.016). We did not observe any negative side effects of sphingosine. Conclusion Inhalation of sphingosine induced a significant decrease of Pseudomonas aeruginosa at the epithelial layer of tracheal and bronchial cells. The inhalation has no local side effects in ex-vivo perfused and ventilated pig lungs

Uncertainty in Natural Language Generation: From Theory to Applications

Recent advances of powerful Language Models have allowed Natural Language Generation (NLG) to emerge as an important technology that can not only perform traditional tasks like summarisation or translation, but also serve as a natural language interface to a variety of applications. As such, it is crucial that NLG systems are trustworthy and reliable, for example by indicating when they are likely to be wrong; and supporting multiple views, backgrounds and writing styles -- reflecting diverse human sub-populations. In this paper, we argue that a principled treatment of uncertainty can assist in creating systems and evaluation protocols better aligned with these goals. We first present the fundamental theory, frameworks and vocabulary required to represent uncertainty. We then characterise the main sources of uncertainty in NLG from a linguistic perspective, and propose a two-dimensional taxonomy that is more informative and faithful than the popular aleatoric/epistemic dichotomy. Finally, we move from theory to applications and highlight exciting research directions that exploit uncertainty to power decoding, controllable generation, self-assessment, selective answering, active learning and more

Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD

A RELAÇÃO ENTRE NÚMEROS E QUANTIDADES: um relato de experiência de atividade realizada com pré-escolares

This work consists of an experience report resulting from extension activities, experienced by volunteers from the Early Childhood Stimulation Project (PEPPI/UFAL), carried out in a Municipal Child Education Center, located in a suburb of the city of Maceió, capital. of the State of Alagoas, in the month of August of the year 2018. The activity developed by the volunteers was entitled “Relating numbers and quantities”, which aimed to stimulate the cognitive development of children, through mathematics. The activity carried out with an average of 15 students, consisted of two stages, in the first stage the students were asked to place the number of characters according to the number that was written on a poster, in the second stage, the writing of the numerals. Through the application of the activity, it was possible to stimulate learning based on playfulness, where through games and games, children can learn various subjects, such as mathematics.Este trabalho consiste em um relato de experiência resultante de atividades extensionistas, vivenciadas por voluntários do Projeto de Estimulação Precoce na Primeira Infância (PEPPI/UFAL), realizadas em um Centro Municipal de Educação Infantil, localizado em um bairro periférico da cidade de Maceió, capital do Estado de Alagoas, no mês de agosto do ano de 2018. A atividade desenvolvida pelos voluntários foi intitulada de “Relacionando números e quantidades”, esta objetivou estimular o desenvolvimento cognitivo das crianças, através da matemática. A atividade realizada com uma média de 15 alunos, consistiu em duas etapas, na primeira etapa foi solicitado que os alunos colocassem a quantidade de personagens de acordo com o número que estava escrito em um cartaz, já na segunda etapa, foi desenvolvido a escrita dos numerais. Através da aplicação da atividade foi possível estimular a aprendizagem a partir da ludicidade, onde por meio de jogos e brincadeiras, as crianças podem aprender diversos assuntos, como a matemática

A RELAÇÃO ENTRE NÚMEROS E QUANTIDADES: um relato de experiência de atividade realizada com pré-escolares

This work consists of an experience report resulting from extension activities, experienced by volunteers from the Early Childhood Stimulation Project (PEPPI/UFAL), carried out in a Municipal Child Education Center, located in a suburb of the city of Maceió, capital. of the State of Alagoas, in the month of August of the year 2018. The activity developed by the volunteers was entitled “Relating numbers and quantities”, which aimed to stimulate the cognitive development of children, through mathematics. The activity carried out with an average of 15 students, consisted of two stages, in the first stage the students were asked to place the number of characters according to the number that was written on a poster, in the second stage, the writing of the numerals. Through the application of the activity, it was possible to stimulate learning based on playfulness, where through games and games, children can learn various subjects, such as mathematics.Este trabalho consiste em um relato de experiência resultante de atividades extensionistas, vivenciadas por voluntários do Projeto de Estimulação Precoce na Primeira Infância (PEPPI/UFAL), realizadas em um Centro Municipal de Educação Infantil, localizado em um bairro periférico da cidade de Maceió, capital do Estado de Alagoas, no mês de agosto do ano de 2018. A atividade desenvolvida pelos voluntários foi intitulada de “Relacionando números e quantidades”, esta objetivou estimular o desenvolvimento cognitivo das crianças, através da matemática. A atividade realizada com uma média de 15 alunos, consistiu em duas etapas, na primeira etapa foi solicitado que os alunos colocassem a quantidade de personagens de acordo com o número que estava escrito em um cartaz, já na segunda etapa, foi desenvolvido a escrita dos numerais. Através da aplicação da atividade foi possível estimular a aprendizagem a partir da ludicidade, onde por meio de jogos e brincadeiras, as crianças podem aprender diversos assuntos, como a matemática

Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma

Major depressive disorder (MDD) is a very common, severe disease with a lifetime prevalence of ~ 10%. The pathogenesis of MDD is unknown and, unfortunately, therapy is often insufficient. We have previously reported that ceramide levels are increased in the blood plasma of patients with MDD and in mice with experimental MDD. Here, we demonstrate that ceramide-enriched exosomes in the blood plasma are increased in mice with stress-induced MDD. Genetic studies reveal that neutral sphingomyelinase 2 is required for the formation of ceramide-enriched exosomes in the blood plasma. Accordingly, induced deficiency of neutral sphingomyelinase 2 prevented mice from the development of stress-induced MDD. Intravenous injection of microparticles from mice with MDD or injection of ceramide-loaded exosomes induced MDD-like behavior in untreated mice, which was abrogated by ex vivo pre-incubation of purified exosomes with anti-ceramide antibodies or ceramidase. Mechanistically, injection of exosomes from mice with MDD or injection of ex vivo ceramide-loaded microparticles inhibited phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus, which has been previously shown to mediate MDD by plasma ceramide. In summary, our data indicate that ceramide-enriched exosomes are released by neutral sphingomyelinase 2 into the blood plasma upon stress and mediate stress-induced MDD

Response to responsible research assessment I and II from the perspective of the DGPs working group on open science in clinical psychology

We comment on the papers by Schönbrodt et al. (2022) and Gärtner et al. (2022) on responsible research assessment from the perspective of clinical psychology and psychotherapy research. Schönbrodt et al. (2022) propose four principles to guide hiring and promotion in psychology: (1) In addition to publications in scientific journals, data sets and the development of research software should be considered. (2) Quantitative metrics can be useful, but they should be valid and applied responsibly. (3) Methodological rigor, research impact, and work quantity should be considered as three separate dimensions for evaluating research contributions. (4) The quality of work should be prioritized over the number of citations or the quantity of research output. From the perspective of clinical psychology, we endorse the initiative to update current practice by establishing a matrix for comprehensive, transparent and fair evaluation criteria. In the following, we will both comment on and complement these criteria from a clinical-psychological perspective

Inhibition of PI-3-K and AKT Amplifies Kv1.3 Inhibitor-Induced Death of Human T Leukemia Cells

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Potential involvement of the bone marrow in experimental Graves’ disease and thyroid eye disease

IntroductionGraves’ disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves’ disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves’ disease and TED is unknown. Here, we investigated whether induction of experimental Graves’ disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation.ResultsImmunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells in vitro prevented immune-inhibition by linsitinib.ConclusionCollectively, these data indicate that the bone marrow is activated in experimental Graves’ disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition