Melanocortin receptors in rat liver cells: change of gene expression and intracellular localization during acute-phase response

MCRs are known to be expressed predominantly in the brain where they mediate metabolic and anti-inflammatory functions. Leptin plays an important role in appetite and energy regulation via signaling through melanocortin receptors (MCRs) in the brain. As serum levels of MCR ligands are elevated in a clinical situation [acute-phase response (APR)] to tissue damage, where the liver is responsible for the metabolic changes, we studied hepatic gene expression of MCRs in a model of muscle tissue damage induced by turpentine oil (TO) injection in rats. A significant increase in gene expression of all five MCRs (MC4R was the highest) in liver at the RNA and protein level was detected after TO injection. A similar pattern of increase was also found in the brain. Immunohistology showed MC4R in the cytoplasm, but also in the nucleus of parenchymal and non-parenchymal liver cells, whereas MC3R-positivity was mainly cytoplasmic. A time-dependent migration of MC4R protein from the cytoplasm into the nucleus was observed during APR, in parallel with an increase in α-MSH and leptin serum levels. An increase of MC4R was detected at the protein level in wild-type mice, while such an increase was not observed in IL-6ko mice during APR. Moreover, treatment of isolated liver cells with melanocortin agonists (α-MSH and THIQ) inhibited the endotoxin-induced upregulation of the acute-phase cytokine (IL-6, IL1β and TNF-α) gene expression in Kupffer cells and of chemokine gene expression in hepatocytes. MCRs are expressed not only in the brain, but also in liver cells and their gene expression in liver and brain tissue is upregulated during APR. Due to the presence of specific ligands in the serum, they may mediate metabolic changes and exert a protective effect on liver cells

A survey of uncertainty in deep neural networks

Over the last decade, neural networks have reached almost every field of science and become a crucial part of various real world applications. Due to the increasing spread, confidence in neural network predictions has become more and more important. However, basic neural networks do not deliver certainty estimates or suffer from over- or under-confidence, i.e. are badly calibrated. To overcome this, many researchers have been working on understanding and quantifying uncertainty in a neural network's prediction. As a result, different types and sources of uncertainty have been identified and various approaches to measure and quantify uncertainty in neural networks have been proposed. This work gives a comprehensive overview of uncertainty estimation in neural networks, reviews recent advances in the field, highlights current challenges, and identifies potential research opportunities. It is intended to give anyone interested in uncertainty estimation in neural networks a broad overview and introduction, without presupposing prior knowledge in this field. For that, a comprehensive introduction to the most crucial sources of uncertainty is given and their separation into reducible model uncertainty and irreducible data uncertainty is presented. The modeling of these uncertainties based on deterministic neural networks, Bayesian neural networks (BNNs), ensemble of neural networks, and test-time data augmentation approaches is introduced and different branches of these fields as well as the latest developments are discussed. For a practical application, we discuss different measures of uncertainty, approaches for calibrating neural networks, and give an overview of existing baselines and available implementations. Different examples from the wide spectrum of challenges in the fields of medical image analysis, robotics, and earth observation give an idea of the needs and challenges regarding uncertainties in the practical applications of neural networks. Additionally, the practical limitations of uncertainty quantification methods in neural networks for mission- and safety-critical real world applications are discussed and an outlook on the next steps towards a broader usage of such methods is given

The HGR motif is the antiangiogenic determinant of vasoinhibin : implications for a therapeutic orally active oligopeptide

The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.“Consejo Nacional de Ciencia y Tecnología” (CONACYT) and UNAM grant.http://link.springer.com/journal/10456ImmunologyNeurolog

Untersuchung von Prolactin-related Vasoinhibin in Sera von Patienten mit diabetischer Retinopathie

Wissenschaftlicher Hintergrund: In-vitro-Experimente und in-vivo-Studien mit Nagetieren zeigten, dass die N-terminalen 14,15, 16, 17 und 18 kDa-Fragmente (prolactin-related vasoinhibin, PRL-V) des menschlichen Prolaktins natürliche Inhibitoren der Neovaskularisation in der Retina sind. Diese N-terminalen PRL-Fragmente gehören zur Familie der Vasoinhibine, einer Gruppe von Peptiden, die aufgrund ihrer Eigenschaften als endogene Regulatoren der Angiogenese bekannt geworden sind. Diese Beobachtungen führten zu der Hypothese, dass PRL-V eine Rolle in der Pathophysiologie der diabetischen Retinopathie im Menschen spielen könnte. Das Ziel dieser Studie war es, zu untersuchen, ob Patienten mit Diabetes Mellitus und diabetischer Retinopathie eine von der Normalpopulation abweichende Konzentration von PRL-V im zirkulierenden Blut aufweisen. Studiendesign: Wir führten eine Fall-Kontroll-Studie durch und entwickelten eine neue Technik zur semiquantitativen Bestimmung von PRL-V in Serum-Proben von 48 männlichen Individuen. Die Fallgruppe bestand aus 21 Patienten mit Diabetes Mellitus und proliferativer oder nicht-proliferativer diabetischer Retinopathie. Die Kontroll-Gruppe bestand aus 27 gesunden Individuen ohne einen Diabetes Mellitus in der Vorgeschichte. Methoden: Zur Detektion von PRL-V entwickelten wir eine neue analytische Methode, bestehend aus immunologischen Methoden und einer Technik, die auf laser-induzierter Fluoreszenz basiert. Resultate: Die Fallgruppe wies eine signifikant niedrigere PRL-V-Konzentration im Serum als die Kontrollgruppe (P=0.041) auf. Es gab keine signifikanten Unterschiede zwischen Patienten mit proliferativer oder nicht-proliferativer diabetischer Retinopathie. Schlussfolgerung: Wir schlussfolgern, berücksichtigt man die antiangiogenen Eigenschaften des PRL-V, dass die erniedrigten Konzentrationen von PRL-V im Serum von Patienten mit Diabetes Mellitus zur Entstehung und Progression der diabetischen Retinopathie beitragen könnten.Objective: In vitro experiments and in vivo studies on rodents demonstrate that N-terminal 14, 15, 16, 17, and 18 kDa fragments (prolactin-related vasoinhibin, PRL-V) of human PRL are natural inhibitors of neovascularization in the retina and elsewhere. These N-terminal PRL fragments belong to a family of peptides named vasoinhibins, which act as endogenous regulators of angiogenesis and vascular function. These observations led to the hypothesis that PRL-V could play a role in the pathophysiology of diabetic retinopathy in humans. The purpose of this study was to investigate whether patients with diabetes mellitus and diabetic retinopathy have aberrant concentrations of PRL-V in the circulating blood. Research design: We performed a case control study and developed a new technique to semiquantitatively determine PRL-V in serum samples from 48 male subjects. The case group consisted of 21 patients with diabetes mellitus and proliferative or non-proliferative diabetic retinopathy. The control group consisted of 27 healthy subjects with no history of diabetes mellitus. Methods: For the detection of PRL-V, we developed a new analytical method, consisting of immunologic and laser-induced fluorescence techniques. Results: The case group had significantly lower PRL-V serum concentrations than the control group (P=0.041). There was no significant difference between patients with proliferative and those with non-proliferative diabetic retinopathy. Conclusion: We conclude that given the antiangiogenic and antivasopermeability actions of PRL-V, the decreased serum levels of PRL-V in patients with diabetes mellitus could contribute to the development and progression of diabetic retinopathy

High Resolution Images of "Matrix Metalloproteases and Cathepsin D in Human Serum do not Cleave Prolactin to Generate Vasoinhibin"

The dataset contains high resolution image files of Western Blots in JPG and TIFF-file format

Der Eckerlin- und Geierschen Ehe-Verbindung widmete dieses Gedicht einer von Des würdigsten Bräutigams Freunden Jakob Lorenz Triebel

Hochzeitsgedicht auf Salomo August Eckerlin und Johanna Sabina Elisabeth Geier, 1771Vorlageform des Erscheinungsvermerks: Jm Herbste des 1771sten Jahres