Vascular endothelial growth factor B-role in metabolism, lipotoxicity and disease

Vascular Endothelial Growth Factor B (VEGF-B) was previously shown to control lipid uptake from the bloodstream via the endothelium into tissue cells, and when ablating Vegfb, intra-tissue lipid accumulation was reduced. However, very little is known regarding the metabolic role of VEGF-B in physiologic, or pathophysiologic conditions. In paper I, we characterized the upstream regulatory mechanism controlling VEGF-B expression. We showed in vitro and in vivo that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a major regulator of mitochondrial biogenesis, controls the expression of VEGF-B. The tight regulation of VEGF-B via PGC-1α enables the coordination of lipid uptake with mitochondrial biogenesis and β-oxidation, and hence the prevention of lipotoxicity. Lipotoxicity and insulin resistance are suggested as key pathologies in type 2 diabetes (T2D). In paper II we analysed the effects of reduced VEGF-B signalling on lipotoxicty and disease progression in different rodent models of T2D. VEGF-B signalling was reduced by either genetic, or pharmaceutical means, and this reduced lipotoxicity, increased glucose uptake into peripheral tissues, improved dyslipidaemia and enhanced sensitivity to insulin, in rodent models of T2D. Therefore, targeting VEGF-B signalling is a promising therapeutic method for the treatment of T2D. Lipotoxicity has also lately been attributed a larger role in the pathogenesis of diabetic nephropathy (DN), a comorbidity of both type 1 diabetes (T1D) and T2D. Therefore, in paper III, we investigated the effects of reducing VEGF-B signalling in mouse models of DN. We showed that renal lipotoxicity was an important element of DN in these models, and by reducing VEGF-B signalling renal lipotoxicity was ameliorated. Also, renal function, morphology and the filtration capacity were enhanced. Furthermore, VEGF-B signalling was present and activated in patients with DN in comparison to healthy individuals. Thus, targeting VEGF-B signalling represents a novel therapeutic approach for DN. Finally, in paper IV, a protocol for detecting and imaging of intra-tissue neutral lipids is presented. This protocol enables the exact quantification of neutral lipids and was crucial for all papers discussed above. To conclude, our data show that lipotoxicity is a major driving force for the development and progression of T2D and DN. Hence, VEGF-B could be a novel target for the treatment of both T2D and DN

Risk analysis and guidelines for selecting PPE against the thermal hazards of electric fault arcs

Electric fault arcs occurring with short-circuits in electric power equipment and installations are enormous sources of power. There are particularly thermal effects (radiation and convective heat flux, metal splash) with high risks for persons especially in case of direct exposure, e.g. during live working or working in the vicinity of live parts. Personal protective equipment (PPE) can essentially contribute to increase the personal safety. The selection of protective measures or the assessment of their efficiency requires a risk analysis. Since the thermal arc hazards are proportional to the electric arc energy as well as the incident energy in the exposure distance, the risk assessment has to be based on the energy conditions. The electric arc energies to be expected in the electric power systems (working places) under consideration have to be determined as well as the equivalent energetic protection levels of the PPE. The paper gives an algorithm for analyzing the thermal arc risks for finding the necessary protection class of PPE according to the box test levels for protective clothing (IEC or EN 61482-1-2). Interconnections to the influence of the electric protection devices are shown

Testing of PPE for eye and face protection

The performance of personal protective equipment (PPE) and its contribution to increase personal safety in usual work places has to be proven by tests. One potential hazard for people are electric fault arcs occurring with short-circuits in electric power installations. There are very high risks for persons especially in case of direct exposure, e.g. during live working or working in the vicinity to live parts. Particularly radiation and convective heat is converted. With the box test according to IEC or EN 61482-1-2 a method for testing protection textiles and clothing against the thermal hazards of electric fault arcs has already been existing and used in certification for several years. But as shown by arc accidents the face is also particularly affected by severe damages. Protective equipment for eye and face protection which is also tested for arc resistance and protection is necessary. Based on basic investigations test principles for eye and face protection equipment against the thermal hazards of electric fault arcs have been developed and laid down in a new German test guide. The test set-up of the box test is suitable. It has been adapted and modified by a test head where test samples such as visors, visorhelmet combinations, face shields etc. are placed. The tests are carried out in accordance to the box test method of protective clothing (IEC/EN 61482-1-2). The paper gives information on tests made according to this test guide. Furthermore general conclusions are drawn on how to test and how to standardize tests of PPE for eye and face protection. The principles will be introduced in E DIN 58118 becoming a supplementation to the German edition of EN 166. It can also be the base for an international or European standard later on

Kategoriensystem zur Kodierung der interaktiven Einbettung sprachlicher Beiträge von Kindern in schulischen und vorschulischen Sprachförderaktivitäten

Der Beitrag nimmt die Ebene der Kinder im Kita- und Grundschulalltag in den Blick. Mit Hilfe des Kategoriensystems zur Erfassung der Einbettung kindlicher Sprachbeiträge in Dialoge wird auf der Basis von transkribierten Videografien von Kleingruppensituationen analysiert, wie die Redebeiträge der Kinder entstehen bzw. in den Interaktionsverlauf eingebettet sind (z.B. selbstinitiierter Beitrag, Zugzwang nach Frage der Fachkraft, Nachsprechen). (DIPF/Orig.

A novel Dual Amylin and Calcitonin Receptor Agonist (DACRA), KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

BACKGROUND AND PURPOSE: Obesity and associated co‐morbidities, such as type 2 diabetes and non‐alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co‐morbidities. EXPERIMENTAL APPROACH: The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP‐089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight‐independent effects of KBP‐089 using a weight‐matched group. KEY RESULTS: Rats fed a high‐fat diet were treated, s.c., with KBP‐089 0.625, 1.25, 2.5 μg·kg(−1) or vehicle. KB‐089 induced in a dose‐dependent and sustained weight loss (~17% by 2.5 μg·kg(−1)). Moreover, KBP‐089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP‐089 improved glucose homeostasis through improved insulin action. To obtain a weight‐matched group, significantly less food was offered (9% less than in the KBP‐089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP‐089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP‐089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. CONCLUSIONS AND IMPLICATIONS: The novel DACRA, KBP‐089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet‐induced weight loss

Interpersonal neural synchrony and mental disorders: unlocking potential pathways for clinical interventions

Introduction: Interpersonal synchronization involves the alignment of behavioral, affective, physiological, and brain states during social interactions. It facilitates empathy, emotion regulation, and prosocial commitment. Mental disorders characterized by social interaction dysfunction, such as Autism Spectrum Disorder (ASD), Reactive Attachment Disorder (RAD), and Social Anxiety Disorder (SAD), often exhibit atypical synchronization with others across multiple levels. With the introduction of the “second-person” neuroscience perspective, our understanding of interpersonal neural synchronization (INS) has improved, however, so far, it has hardly impacted the development of novel therapeutic interventions. Methods: To evaluate the potential of INS-based treatments for mental disorders, we performed two systematic literature searches identifying studies that directly target INS through neurofeedback (12 publications; 9 independent studies) or brain stimulation techniques (7 studies), following PRISMA guidelines. In addition, we narratively review indirect INS manipulations through behavioral, biofeedback, or hormonal interventions. We discuss the potential of such treatments for ASD, RAD, and SAD and using a systematic database search assess the acceptability of neurofeedback (4 studies) and neurostimulation (4 studies) in patients with social dysfunction. Results: Although behavioral approaches, such as engaging in eye contact or cooperative actions, have been shown to be associated with increased INS, little is known about potential long-term consequences of such interventions. Few proof-of-concept studies have utilized brain stimulation techniques, like transcranial direct current stimulation or INS-based neurofeedback, showing feasibility and preliminary evidence that such interventions can boost behavioral synchrony and social connectedness. Yet, optimal brain stimulation protocols and neurofeedback parameters are still undefined. For ASD, RAD, or SAD, so far no randomized controlled trial has proven the efficacy of direct INS-based intervention techniques, although in general brain stimulation and neurofeedback methods seem to be well accepted in these patient groups. Discussion: Significant work remains to translate INS-based manipulations into effective treatments for social interaction disorders. Future research should focus on mechanistic insights into INS, technological advancements, and rigorous design standards. Furthermore, it will be key to compare interventions directly targeting INS to those targeting other modalities of synchrony as well as to define optimal target dyads and target synchrony states in clinical interventions

A high-throughput polymer microarray approach for identifying defined substrates for mesenchymal stem cells

Mesenchymal stem cells (MSCs) hold great promise in regenerative medicine due to their wide multilineage potential as well as their ability to suppress/modulate the immune response. Maintaining these cells in vitro and expanding them on a clinically relevant scale remains a challenge that needs to be addressed to realise their full potential. Current culture methods for MSCs typically rely on animal sourced substrates and often result in a heterogeneous population of cells with varying degrees of differentiation capacity. Here, a high-throughput platform was used to identify synthetic substrates for MSC culture that not only facilitated growth but also maintained the MSC phenotype. Two polymers, PU157 (synthesised from poly(butyleneglycol) and 4,4′-methylenediphenyldiisocyanate with 3-(dimethylamino)-1,2-propanediol as a chain extender) and PA338 (N-methylaniline modified poly(methylmethacrylate-co-glycidylmethacrylate)) were able to maintain the growth and phenotype of human embryonic derived mesenchymal progenitors (hES-MPs) and adipose derived MSCs (ADMSCs) for five and ten passages, respectively. Cell phenotype and multipotency were confirmed by flow cytometry analysis of ten MSC markers and differentiation analysis. These new polymer substrates provide a chemically defined synthetic surface for efficient, long-term MSC culture

Maternal hyperleptinemia is associated with male offspring’s altered vascular function and structure in mice

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Lepr db/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under astandard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post-natal environments to contribute to altered vascular function in offspring of diabetic pregnancie

The lived experience of schooling the child with cognitive late effects of cancer treatment

The purpose of this secondary analysis study was to explore the lived experience of schooling a child with cognitive deficits as a result of late effects of central nervous system cancer therapy. The sample consisted of seven female participants who provided a rich description of their experience. Audiotaped interviews were analyzed using an adaptation of Colaizzi's seven-step procedure. Eleven major themes emerged: Watching the Academic Downslide, Dealing with the Academic Downslide, Teachers Setting the Tone, Parent-Teacher Interactions, Working the (School) System, Specific Strategies to Address the Academic Problem, Homework, Ways of Caring for Oneself, Hopes and Fears, Living with the Cure, and Hope Continues. An essential structure was derived from the data.Digitized from a paper copy provided by the Arizona Health Sciences Library

Literate und narrative Textgestaltung in der Zweitsprache zwischen Mündlichkeit und Schriftlichkeit - Grundschüler türkischer Herkunftssprache erzählen einen Stummfilm auf Deutsch

Während die Entwicklung narrativer Kompetenze in gesprochener Sprache häufig als Voraussetzung literaler Kompetenzen gesehen wird, stellt der Beitrag die strukturelle Verschiedenheit beider Kompetenzbereiche heraus. Dabei wird an der mehrfach kritisierten Vorstellung eines Kontinuums zwischen einem oraten und einem literaten Pol sprachstruktureller Mittel ebenso festgehalten wie an der analytischen Trennung zwischen einer medialen und einer sprachstrukturellen Dimension. Am Beispiel mündlicher und schriftlicher Erzählungen eines Stummfilms durch Erstklässler türkischer Herkunft in ihrer Zweitsprache Deutsch werden zunächst interaktive Prozesse der Textproduktion unter den Bedingungen des Diktierens und des kooperierenden Schreibens rekonstruiert, aus denen sich zwei unterschiedliche Formen eines Scaffolding durch erwachsene Interaktionspartner ergeben. Es schließen sich eine orat-literat-Analyse des Gebrauchs von Nominalphrasen in den Texten sowie narrative Analysen an, die die Realisierung globaler Erzählstrukturen, die sprachliche Gestaltung der Wiederaufnahme und den Gebrauch direkter und indirekter Figurenrede untersuchen. Die Verteilung der Texte entlang der beiden Kontinua zeigt ein partielles Auseinandertreten der narrativen und literaten Indikatoren, die jeweils stärker in den mündlichen bzw. schriftlichen Texten in Erscheinung treten. Im Fazit wird der Beitrag medialer Strukturierungshilfen für die konzeptuelle Schreibaufgabe herausgearbeitet