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Type 2 diabetes (T2D) represents a multifactorial metabolic disease with a strong genetic predisposition. Despite elaborate efforts in identifying the genetic variants determining individual susceptibility towards T2D, the majority of genetic factors driving disease development remain poorly understood. With the aim to identify novel T2D risk genes we previously generated an N2 outcross population using the two inbred mouse strains New Zealand obese (NZO) and C3HeB/FeJ (C3H). A linkage study performed in this population led to the identification of the novel T2D-associated quantitative trait locus (QTL)

Realization of all-solid-state batteries combined with metallic Li/Na is still hindered due to the unstable interface between the alkali metal and solid electrolytes, especially for highly promising thiophosphate materials. Artificial and uniform solid-electrolyte interphases (SEIs), serving as thin ion-conducting films, have been considered as a strategy to overcome the issues of such reactive interfaces. Here, we synthesized sulfide-based artificial SEIs (Li

Besides a therapeutic target for type 2 diabetes, dipeptidyl peptidase 4 (DPP4) is an adipokine potentially upregulated in human obesity. We aimed to explore the role of adipocyte-derived DPP4 in diet-induced obesity and insulin resistance with an adipose tissue-specific knockout (AT-DPP4-KO) mouse. Wild-type and AT-DPP4-KO mice were fed for 24 wk with a high fat diet (HFD) and characterized for body weight, glucose tolerance, insulin sensitivity by hyperinsulinemic-euglycemic clamp, and body composition and hepatic fat content. Image and molecular biology analysis of inflammation, as well as adipokine secretion, was performed in AT by immunohistochemistry, Western blot, real-time-PCR, and ELISA. Incretin levels were determined by Luminex kits. Under HFD, AT-DPP4-KO displayed markedly reduced circulating DPP4 concentrations, proving AT as a relevant source. Independently of glucose-stimulated incretin hormones, AT-DPP4-KO had improved glucose tolerance and hepatic insulin sensitivity. AT-DPP4-KO displayed smaller adipocytes and increased anti-inflammatory markers. IGF binding protein 3 (IGFBP3) levels were lower in AT and serum, whereas free IGF1 was increased. The absence of adipose DPP4 triggers beneficial AT remodeling with decreased production of IGFBP3 during HFD, likely contributing to the observed, improved hepatic insulin sensitivity.

Aims We aimed to unravel the genetic, molecular and cellular pathomechanisms of DSC2 truncation variants leading to arrhythmogenic cardiomyopathy (ACM). Methods and results We report a homozygous 4-bp DSC2 deletion variant c.1913_1916delAGAA, p.Q638LfsX647hom causing a frameshift carried by an ACM patient. Whole exome sequencing and comparative genomic hybridization analysis support a loss of heterozygosity in a large segment of chromosome 18 indicating segmental interstitial uniparental isodisomy (UPD). Ultrastructural analysis of the explanted myocardium from a mutation carrier using transmission electron microscopy revealed a partially widening of the intercalated disc. Using qRT-PCR we demonstrated that DSC2 mRNA expression was substantially decreased in the explanted myocardial tissue of the homozygous carrier compared to controls. Western blot analysis revealed absence of both full-length desmocollin-2 isoforms. Only a weak expression of the truncated form of desmocollin-2 was detectable. Immunohistochemistry showed that the truncated form of desmocollin-2 did not localize at the intercalated discs. In vitro, transfection experiments using induced pluripotent stem cell derived cardiomyocytes and HT-1080 cells demonstrated an obvious absence of the mutant truncated desmocollin-2 at the plasma membrane. Immunoprecipitation in combination with fluorescence measurements and Western blot analyses revealed an abnormal secretion of the truncated desmocollin-2. Conclusion In summary, we unraveled segmental UPD as the likely genetic reason for a small homozygous DSC2 deletion. We conclude that a combination of nonsense mediated mRNA decay and extracellular secretion is involved in DSC2 related ACM.

OBJECTIVE Individuals with type 2 diabetes are at higher risk of progression of nonalcoholic fatty liver (steatosis) to steatohepatitis (NASH), fibrosis, and cirrhosis. The hepatic metabolism of obese individuals adapts by upregulation of mitochondrial capacity, which may be lost during the progression of steatosis. However, the role of type 2 diabetes with regard to hepatic mitochondrial function in NASH remains unclear. RESEARCH DESIGN AND METHODS We therefore examined obese individuals with histologically proven NASH without (OBE) (n = 30; BMI 52 ± 9 kg/m2) or with type 2 diabetes (T2D) (n = 15; 51 ± 7 kg/m2) as well as healthy individuals without liver disease (CON) (n = 14; 25 ± 2 kg/m2). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose. Liver biopsies were used for assessing mitochondrial capacity by high-resolution respirometry and protein expression. RESULTS T2D and OBE had comparable hepatic fat content, lobular inflammation, and fibrosis. Oxidative capacity in liver tissue normalized for citrate synthase activity was 59% greater in OBE than in CON, whereas T2D presented with 33% lower complex II–linked oxidative capacity than OBE and higher H2O2 production than CON. Interestingly, those with NASH and hepatic fibrosis score ≥1 had lower oxidative capacity and antioxidant defense than those without fibrosis. CONCLUSIONS Loss of hepatic mitochondrial adaptation characterizes NASH and type 2 diabetes or hepatic fibrosis and may thereby favor accelerated disease progression.

Objective Insulin action in the brain controls metabolism and brain function, which is linked to proper mitochondrial function. Conversely, brain insulin resistance associates with mitochondrial stress and metabolic and neurodegenerative diseases. In the present study, we aimed to decipher the impact of hypothalamic insulin action on mitochondrial stress responses, function and metabolism. Methods To investigate the crosstalk of insulin action and mitochondrial stress responses (MSR), namely the mitochondrial unfolded protein response (UPRmt) and integrated stress response (ISR), qPCR, western blotting, and mitochondrial activity assays were performed. These methods were used to analyze the hypothalamic cell line CLU183 treated with insulin in the presence or absence of the insulin receptor as well as in mice fed a high fat diet (HFD) for three days and STZ-treated mice without or with insulin therapy. Intranasal insulin treatment was used to investigate the effect of acute brain insulin action on metabolism and mitochondrial stress responses. Results Acute HFD feeding reduces hypothalamic mitochondrial stress responsive gene expression of Atf4, Chop, Hsp60, Hsp10, ClpP, and Lonp1 in C57BL/6N mice. We show that insulin via ERK activation increases the expression of MSR genes in vitro as well as in the hypothalamus of streptozotocin-treated mice. This regulation propagates mitochondrial function by controlling mitochondrial proteostasis and prevents excessive autophagy under serum deprivation. Finally, short-term intranasal insulin treatment activates MSR gene expression in the hypothalamus of HFD-fed C57BL/6N mice and reduces food intake and body weight development. Conclusions We define hypothalamic insulin action as a novel master regulator of MSR, ensuring proper mitochondrial function by controlling mitochondrial proteostasis and regulating metabolism., Graphical abstract Image 1, Highlights • Hypothalamic insulin regulates mitochondrial stress responses. • Insulin controls mitochondrial function by regulating mitochondrial proteostasis. • Insulin via ERK signaling regulates MSR activation and prevents starvation-induced autophagy. • Intranasal insulin reduces HFD-induced food intake and activates the MSR.

The Rab guanosine triphosphatase-activating protein (RabGAP) TBC1D1 has been shown to be a key regulator of glucose and lipid metabolism in skeletal muscle. Its function in pancreatic islets, however, is not yet fully understood. Here, we aimed to clarify the specific impact of TBC1D1 on insulin secretion and substrate use in pancreatic islets. We analyzed the dynamics of glucose-stimulated insulin secretion (GSIS) and lipid metabolism in isolated islets from Tbc1d1-deficient (D1KO) mice. To further investigate the underlying cellular mechanisms, we conducted pharmacological studies in these islets. In addition, we determined morphology and number of both pancreatic islets and insulin vesicles in β-cells using light and transmission electron microscopy. Isolated pancreatic islets from D1KO mice exhibited substantially increased GSIS compared with wild-type (WT) controls. This was attributed to both enhanced first and second phase of insulin secretion, and this enhanced secretion persisted during repetitive glucose stimuli. Studies with sulfonylureas or KCl in isolated islets demonstrated that TBC1D1 exerts its function via a signaling pathway at the level of membrane depolarization. In line, ultrastructural analysis of isolated pancreatic islets revealed both higher insulin-granule density and number of docked granules in β-cells from D1KO mice compared with WT controls. Like in skeletal muscle, lipid use in isolated islets was enhanced upon D1KO, presumably as a result of a higher mitochondrial fission rate and/or higher mitochondrial activity. Our results clearly demonstrate a dual role of TBC1D1 in controlling substrate metabolism of the pancreatic islet.

The increasing importance of zebrafish as a biomedical model organism is reflected by the steadily growing number of publications and laboratories working with this species. Regulatory recommendations for euthanasia as issued in Directive 2010/63/EU are, however, based on experience with fish species used for food production and do not take the small size and specific physiology of zebrafish into account. Consequently, the currently recommended methods of euthanasia in the Directive 2010/63/EU are either not applicable or may interfere with research goals. An international workshop was held in Karlsruhe, Germany, March 9, 2017, to discuss and propose alternative methods for euthanasia of zebrafish. The aim was to identify methods that adequately address the physiology of zebrafish and its use as a biomedical research model, follow the principles of the 3Rs (Replacement, Reduction, and Refinement) in animal experimentation and consider animal welfare during anesthesia and euthanasia. The results of the workshop are summarized here in the form of a white paper.

Durch die vorangegangene Untersuchung lassen sich nun – erganzend zu den in Teil II, Kapitel 1.2 festgelegten Minimalmerkmalen – eine Reihe zusatzlicher Eigenschaften der Gattung Postmortaler Narrationen bestimmen. Dabei ist es hilfreich zwischen k ons t i tut iv en Merkmalen und f akul t a t i ven Merkmalen zu unterscheiden, wobei erstere die Eigenschaften bezeichnen, die der Gattung a priori zuzuschreiben sind, und die zweiteren solche, die auffallig haufig auftreten, sich somit also als fur die Gattung typisch auszeichnen, jedoch nicht in der Grundstruktur Postmortaler Narrationen angelegt ist.

The mitochondrial chaperones heat shock protein 10 (HSP10) and 60 enable proper protein folding and thereby facilitate mitochondrial function. Previously, we demonstrated a reduction of hypothalamic Hsp60 gene expression in type 2 diabetic mice and patients which caused mitochondrial dysfunction and central insulin resistance. Mitochondrial HSP10 is also reduced in brains of db/db mice. However, the effects of reduced HSP10 expression in brain on metabolism and insulin sensitivity are unknown. Thus, we generated a shRNA-mediated knockdown (KD) of Hsp10 in the hypothalamic murine cell line Clu183 and investigated cellular stress responses, mitochondrial function and insulin signaling. 50% KD of HSP10 in vitro causes impaired mitochondrial dynamics and reduced mitochondrial count, but increases mitochondria-endoplasmatic reticulum (ER) contact sites. These cells exhibit reduced mitochondrial respiration and mild oxidative stress represented by a 35% decrease of protein amount of SOD2 along with about 20% decreased protein amounts of subunits of the electron transport chain complexes IV and II. Notably, HSP10 KD induces ER stress shown by the increased gene expression of Chop and increased phosphorylation of IRE1(S724). Most importantly, KD of HSP10 induces acute insulin resistance shown by reduced phosphorylation of IRS-1(Y612) and AKT/PKB(S473) after 5 min of 10 nM insulin stimulation. Preliminary data of a lentiviral-mediated KD approach of Hsp10 in the mediobasal hypothalamus in C57BL/6N mice revealed an unexpected 11% reduction in liver weight partly due to reduced hepatic glycogen content compared to control mice. Consistently, hepatic gene expression of Pepck, which is suppressed by insulin, was increased in Hsp10 KD mice by 60%. In conclusion, we identified an unexpected role of Hsp10 in regulating hypothalamic mitochondrial function, insulin sensitivity and liver function. Thus, hypothalamic Hsp10 may present a novel regulator of the brain-liver crosstalk. Disclosure K. Wardelmann: None. J. Castro: None. M. Rath: None. J. Weiß: None. A. Schuermann: None. A. Kleinridders: None.

Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides and c-Jun N-terminal kinase activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C θ activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.

In the past few years we investigated effects of perception of combined acoustical and optical stimuli. These investigations were triggered by the quest for coherence effects in artificially illuminated environment in conjunction with acoustic immissions. Further, harmonies and chords transposed down to frequencies near flicker perception carried by power modulated light in combination with the coherent acoustic stimuli in audible range were subject to research. A deeper discussion is found in previous SPIE papers. These chord experiments showed that - depending on the spatial distribution of light sources and their spots - rhythmic patterns in time and space are generated by the beat frequencies occurring between the chord components. While these results might have consequences in problems of occupational medicine - the original intention of such studies - there might be applications in music and entertainment. The recent paper deals with a deeper discussion of the interference process in power domain and the limits of perception. The resulting rhythm patterns show a fine structure beside the main beat resulting from the frequency differences of the components, which was not considered in earlier works, but obviously depends on phase and signal shape of the components. A basic framework for the design of optical rhythm pattern corresponding to certain sounds is derived. Especially interesting is the question of perception of static phase of the components of chords in both acoustical and optical domains. The paper will give some practical examples, which are part of the talk and the multimedia attachment.

To evaluate the outcome of frozen-thawed embryo transfer (FET) when freezing takes place at the pronuclear stage, a retrospective analysis was performed comparing spontaneous and artificial cycles.148 women received FET in a spontaneous cycle (Group A) and 55 women received FET in an artificial cycle (Group B) induced by administering estrogen (E2) and progesterone (P). Pregnancy rates, endometrial thickness and serum levels of E2, P and luteinizing hormone (LH) were measured. Statistical analysis included the mean, the standard deviation, the Chi-squared test and the T-test.The clinical pregnancy rate was 34.5% for Group A and 21.8% for Group B (p = 0.084), with a live birth rate of 20.9% and 12.7% respectively (p = 0.15). There was no difference in endometrial thickness or the P levels, while LH and E2 levels were significantly higher in group B (p 0.0001).Our retrospective study shows a trend towards higher pregnancy rates and live birth rates with the administration of FET during a spontaneous cycle compared to FET during an artificial cycle. Large randomized controlled trials are needed to confirm this trend.

Die Mediennutzung und Medienkompetenz von Menschen mit Migrationshintergrund ist Gegenstand einer breiten gesellschaftspolitischen und wissenschaftlichen Debatte. Neben positiven Erwartungen an die Bildungs-, Kommunikationsund Partizipationspotenziale insbesondere der digitalen Medien fur junge Migranten steht dahinter auch die Befurchtung, diese konnten die genannten Potenziale nicht in voller Bandbreite erschliesen. Allerdings liegen zur Mediennutzung und Medienkompetenz junger Migranten in Deutschland bislang kaum reprasentative Basisdaten vor. Vor diesem Hintergrund prasentiert der Beitrag Ergebnisse einer reprasentativen Telefonbefragung zur Mediennutzung und Medienkompetenz von jungen russischen Aussiedlern im Alter von 12 bis 19 Jahren in Nordrhein-Westfalen und vergleicht diese mit Befunden fur die gesamte Altersgruppe der in Deutschland lebenden 12bis 19-Jahrigen. Im Ergebnis verweist dieser Vergleich vor allem auf die Gemeinsamkeiten, die junge Menschen im Umgang mit den alten und den neuen Medien verbinden. Der Medienumgang der jungen russischen Aussiedler wird weniger durch ihren Migrationsstatus als vielmehr durch Lebensalter, Geschlecht und insbesondere Schulbildung bestimmt.

Diabetes mellitus is characterized by hyperglycemia that plays an important role in the pathogenesis of diabetic complications including cardiovascular diseases. Moreover, hyperglycemia induces increased generation of advanced glycation end products (AGEs). The activation of platelets is associated with the development of cardiovascular diseases. The question whether AGEs acutely induce platelet activation as a response to exogenous stimulus is addressed. The effect of AGEs derived from food and human serum being purified by lysozyme affinity chromatography was examined by incubating in vitro freshly isolated blood platelets from fasted subjects at various concentrations and different time points. Platelet activation, determined as expression of surface markers CD62 and CD63, and the presence of the receptor for AGEs (RAGE) in platelet membranes was measured by flow cytometric analysis using specific antibodies. Incubation with food-derived as well as serum-derived AGEs stimulated significantly the expression of CD62 up to 7.1-fold and CD63 up to 2.2-fold at the platelet surface membrane as a function of concentration and time. Incubation with thrombin or AGEs significantly increased RAGE expression twofold at the platelet surface membrane. The increase in surface activation marker and RAGE expression in platelets, resulting from concentrations of AGEs that occur in vivo after a meal or a drink as a source of exogenous AGEs, points to signaling mechanisms for food AGEs that could favor the precipitation of acute postprandial ischemic events.

The use of 3d printing technology seems to be a promising way for low cost prototyping, not only of mechanical, but also of optical components or systems. It is especially useful in applications where customized equipment repeatedly is subject to immediate destruction, as in experimental detonics and the like. Due to the nature of the 3D-printing process, there is a certain inner texture and therefore inhomogeneous optical behaviour to be taken into account, which also indicates mechanical anisotropy. Recent investigations are dedicated to quantification of optical properties of such printed bodies and derivation of corresponding optimization strategies for the printing process. Beside mounting, alignment and illumination means, also refractive and reflective elements are subject to investigation. The proposed measurement methods are based on an imaging nearfield scatterometer for combined volume and surface scatter measurements as proposed in previous papers. In continuation of last year’s paper on the use of near field imaging, which basically is a reflective shadowgraph method, for characterization of glossy surfaces like printed matter or laminated material, further developments are discussed. The device has been extended for observation of photoelasticity effects and therefore homogeneity of polarization behaviour. A refined experimental set-up is introduced. Variation of plane of focus and incident angle are used for separation of various the images of the layers of the surface under test, cross and parallel polarization techniques are applied. Practical examples from current research studies are included.

The paper is understood as a continuation of a series of papers on surface metrology for application in quality control of printed matter. A stereoscopic device for extremely rugged applications, especially in quality control in printing industry, is presented. The device developed is based on variable tilted delay elements, which allow the use of a single imaging sensor and robust definition of parallax shift. Variable orthogonal delay elements were already used for variation of plane of focus in surface inspection, as described in previous papers. The method can be applied for macroscopical as well as for microscopic imaging. Beside mechanical design issues, the theoretical description, geometrical-optical approaches, and the treatment of the dispersion problem are discussed. Experimental results are included.

A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.

Tunneling cracks driven by drying in a ceramic precursor confined between two glass plates represent a simple type of three-dimensional (3D) crack pattern. They arrange themselves via mutual unloading which causes some cracks to stop whereby the remaining ones get the right spacing for further propagation. By extending a 2D-model of self-driven propagation of crack arrays, a fracture mechanical bifurcation analysis for 3D-crack patterns based on calculating the post-critical contour of the alternating bifurcation mode has been developed. Shrinkage due to drying is replaced here by a simplified thermo-mechanical model based on an effective heat flow whose related temperature field and thermal stresses drive crack propagation. By means of the finite element method, the propagation velocity and the minimum spacing between the steady-state parallel tunnelling cracks are determined. Comparison of theory and experiment suggests that propagation may be non-stationary in these experiments. The observed relation between crack spacing and layer thickness, p ~ e2/3, follows from a scaling analysis.

Market power is a prominent issue in the current debate about electricity industry restructuring. Market experiments I conducted with industry subjects via the Internet show the impact of seller concentration, demand-side bidding, and transmission constraints on competition in simulated electricity markets. Realistic modeling of the transmission grid revealed opportunities to exercise market power not found in simpler experimental designs. In particular, increasing the number of sellers in a market did not necessarily reduce market power as standard theory suggests. Rather, locational advantages allowed some players to maintain profits near monopoly levels even when seller concentration was at levels generally considered competitive. The implication is that divestiture of existing local monopolies may not be enough to make electricity markets competitive. I confirm the positive impact of demand-side bidding on competition.

The present paper is a follow up of a paper presented in 2013 at the Novel Optical Systems conference in the session on Optics and Music. It is derived from an ongoing study on the human perception of combined optical and acoustical periodical stimuli. Originating from problems concerning artificial illumination and certain machinery with coherent optical and acoustical emissions there are effects to be observed which are interesting in the context of occupational medicine. It seems, that acoustic stimuli in the frequency range of the flicker fusion and below might lead to unexpected perceptible effects beyond those of the single stimuli. The effect of infrasound stimuli as a whole body perception seems to be boosted. Because of the difficulties in evaluation of physical and psychological effects of such coherent stimuli in a first step we question if such coherence is perceivable at all. Further, the problem of modulation of optical signals by acoustical signal is concerned. A catalogue of scenarios and ’effects to look for’ including measurement concepts is presented and discussed.

Mutations of the tumour-suppressor gene NF1 (neurofibromatosis 1) have been observed in neurofibromas and neurofibrosarcomas of patients with von Recklinghausen's disease and in sporadic nerve sheath tumours. In contrast, melanoma, another tumour type of neuroectodermal origin, rarely shows NF1 alterations. Desmoplastic neurotropic melanoma (DNM) is an uncommon melanoma subtype that shares morphological characteristics with nerve sheath tumours. Therefore, we analysed 15 DNM and 20 melanomas without morphological features of desmoplasia or neuroid differentiation (common melanomas) for loss of heterozygosity (LOH) at the NF1 locus and flanking regions. Allelic loss was detected in 10/15 (67%) DNM but only in 1/20 (5%) common melanomas. LOH was most frequently observed at marker IVS38, located in intron 38 of NF1. These data suggest a role for NF1 in the pathogenesis of DNM and support an earlier hypothesis that exon 37 might encode a functional domain. DNM may represent an interesting tumour model tor the further elucidation of the cellular functions and tumour-suppressive potential of neurofibromin.

In der letzten Dekade wurde bei insgesamt 16 Patientinnen, die an einer Autoimmunerkrankung litten, eine ungewohnliche amikrobielle intertriginose Dermatose beschrieben. Das klinische Charakteristikum war eine sterile pustulose Dermatitis v.a. in intertriginosen Regionen, die durch lokale oder meist systemische Steroidtherapie gebessert werden konnte. Histologisch imponierten subkorneale teilweise spongiforme neutrophile Pustulationen. Die vorliegende Arbeit beschreibt eine weitere Patientin mit dieser ungewohnlichen Dermatose. In einer Literaturubersicht soll anhand der bislang beschriebenen Falle versucht werden, eine Abgrenzung von bekannten pustulosen Dermatitiden durchzufuhren.

A large number of benign melanocytic nevi is the major risk factor for malignant melanoma (MM). In a multicenter case-control study, the number of common (CN) and clinically atypical (AN) nevi were counted separately at individual sites in 278 melanoma patients and 278 age- and gender-matched non-melanoma controls. Relative risk (RR) adjusted for age and sex was calculated. In men as well as women, the number of CN on the legs was the best predictor of overall melanoma risk. In men, RR for developing MM when > or = 1 AN were present on the trunk was 4-fold (vs. none). In women, presence of AN on the arms increased RR 9.5-fold. For men and women combined, after adjusting for age and gender, the RR for developing MM on the trunk and on the legs was best predicted by counts of CN at the respective body region. However, high counts of CN on the arms were associated with high melanoma risk on the legs (somewhat lower on the trunk). For AN, no site-specificity of melanoma risk was found. Our data suggest that nevus counts of the legs are the best predictor of overall melanoma risk if total body nevus counts are not feasible. Although high counts of CN on the trunk and legs are associated with a higher risk of developing MM at the respective site than at another site, our data do not unequivocally support a direct site-specific melanoma risk.

An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor ‘empty sleeves’ of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue., Nature Communications, 7, ISSN:2041-1723

Obesity is closely associated with muscle insulin resistance and is a major risk factor for the pathogenesis of type 2 diabetes. Regular physical activity not only prevents obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. We sought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. Contracting human skeletal muscle cell cultures were established by applying electrical pulse stimulation. To induce insulin resistance, skeletal muscle cells were incubated with human adipocyte-derived conditioned medium, monocyte chemotactic protein (MCP)-1 and chemerin. Similarly to in exercising skeletal muscle in vivo, electrical pulse stimulation induced contractile activity in human skeletal muscle cells, combined with the formation of sarcomeres, activation of AMP-activated protein kinase (AMPK) and increased IL-6 secretion. Insulin-stimulated glucose uptake was substantially elevated in contracting cells compared with control. The incubation of skeletal muscle cells with adipocyte-conditioned media, chemerin and MCP-1 significantly reduced the insulin-stimulated phosphorylation of Akt. This effect was abrogated by concomitant pulse stimulation of the cells. Additionally, pro-inflammatory signalling by adipocyte-derived factors was completely prevented by electrical pulse stimulation of the myotubes. We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion. In our model, muscle contractile activity eliminates insulin resistance by blocking pro-inflammatory signalling pathways. This novel model therefore provides a unique tool for investigating the molecular mechanisms that mediate the beneficial effects of muscle contraction.