Phenotype-dependent Ca2+ dynamics in single boutons of various anatomically identified GABAergic interneurons in the rat hippocampus

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Refrakter pyoderma gangraenosum sikeres visilizumabkezelése colitis ulcerosás betegben = Pyoderma gangrenosum treated successfully with visilizumab in patients with ulcerative colitis

A pyoderma gangraenosum a legismertebb IBD-vel asszociált bőrbetegség, leggyakrabban az IBD aktív fázisában alakul ki. A visilizumab (Nuvion, PDL Bio Pharma, Amerikai Egyesült Államok) egy IgG2 típusú monoklonális antitest, amely a T-lymphocyták felszíni CD3 receptorának epszilon-láncához kötődik, csökkenti a perifériás vérben lévő nyugvó T-sejteken a CXCR-3-mediált kemotaxist, valamint az aktivált T-sejtek gyors apoptózisát idézi elő. Esetismertetés: a 40 éves férfi beteget az utóbbi közel 20 évben több mint 30 alkalommal kezelték bőrgyógyászaton ekzemának, illetve mycosisnak vélt alsó végtagi bőrelváltozások miatt. 1996 óta ismert colitis ulcerosája. Orális vagy szisztémás szteroidkezelésben 1997 óta részesül, amelynek az évek során számos szövődménye alakult ki. A pyoderma gangraenosum diagnózisát 2005-ben állították fel. 2006-ban a beteg egy gyógyszervizsgálatban vett részt, amelynek során két alkalommal 375 mcg visilizumabot kapott (5 mcg/ttkg) intravénásan. Hat hónappal a kezelés után a bőrelváltozások csaknem teljesen behámosodtak. Pyodermás bőrtünetek azóta sem jelentkeztek. Következtetés: az eset alapján felmerül, hogy a pyoderma gangraenosum etiológiájában kóros T-sejt-válasz játszhat szerepet. Súlyos colitis ulcerosa kezelésében a visilizumab nem váltotta be a hozzá fűzött reményeket, azonban a pyoderma gangraenosum esetében egy új terápiás lehetőséget jelenthet. | Pyoderma gangrenosum is a misleading designation for an idiopathic ulcerating cutaneous disease. The activity of pyoderma gangrenosum may or may not follow the activity of the inflammatory bowel disease. Visilizumab (Nuvion, PDL Bio Pharma, USA), a humanized IgG2 monoclonal antibody that binds to the human CD3 epsilon chain expressed on human T cells, induces the rapid production of selective chemokines, and reduces the CXCR3-mediated chemotaxis of the resting peripheral blood lymphocytes. In activated, but not resting T cells, visilizumab leads to rapid apoptosis. Case report: During a period of 20 years, a 40-year-old male took part in more than 30 courses of treatment for a dermatological condition misdiagnosed as crural eczema, mycosis and infected wounds. This ulcerative process was very severe in both crural regions. Ulcerative colitis was diagnosed a decade ago. He has been steroid-dependent since 1997. In 2005, pyoderma gangrenosum was diagnosed. In 2006, the patient participated in the visilizumab study and received 2x375 mcg study drug (5 mcg/kg/dose) intravenously. Six months after visilizumab administration, his leg ulcers healed. After the administration of visilizumab, pyoderma gangrenosum had not relapsed. Conclusion: In this severe pyoderma case, visilizumab also treated the skin disease. Although the colitis later worsened, the pyoderma gangrenosum has not recurred to date in this steroid-dependent patient. Pyoderma gangrenosum may be a T cell-mediated disease. The fact that biological therapy proved dramatically effective in this patient may suggest the use of these agents as first line of therapy in such cases

Digital & Cognitive Corporate Reality

As part of the most recent developments in human co-evolution with information and communication technologies, the increasing complexity of our digital realities, as well as the expanding capabilities of omni-present artificial intelligence, are having profound implications. This transformative shift leads to a new era in many fields, including corporate management and business. Newly co-evolved cognitive capabilities, both natural and artificial, are emerging, necessitating a paradigm shift in our understanding and approaches to corporate management and business science. This paper introduces the concept of Digital and Cognitive Corporate Reality (DCR) to establish a new broader view for higher-level conceptual discussion, adopting a holistic perspective that encompasses related scientific fields. Following this definition, the paper briefly explores how different scientific disciplines can be expected to contribute to the development of DCR. Use case examples are also provided to demonstrate the benefits of the holistic perspective adopted in DCR

A nemszinaptikus nikotinikus acetilkolin és NMDA receptorok szerepe élettani körülmények között és pathológiás állapotokban = Role of nonsynaptic nicotinic acetylcholine receptors and NMDA receptors in physiological and pathophysiological conditions

A szélütés (stroke) utáni neurodegeneráció a jelenlegi morbiditási és mortalitási mutatók egyik legfontosabb tényezője. Az iszkémiás stroke kezelésében számos ígéretes gyógyszerjelölt molekula vallott kudarcot a klinikai vizsgálatokban. Ennek valószínűleg az az oka, hogy hiányosak ismereteink az iszkémiás kórképek kialakulásának mechanizmusaira vonatkozólag. A legtöbb központi idegrendszerre ható gyógyszert szinaptikusan elhelyezkedő receptorokra vagy transzporterekre fejlesztik annak érdekében, hogy igazán hatékony gyógyszereket tudjunk fejleszteni, figyelembe kell venni, hogy az extraszinaptikus receptorok és transzporterek száma jóval meghaladja a szinaptikusakét, illetve hogy nagyon sok központi idegrendszeri megbetegedés alapja a nemszinaptikus rendszer malfunkciója. Például, a szinaptikus NMDA receptorok aktivációja neuroprotektív hatást fejt ki, míg az extraszinaptikus NMDA receptor aktiváció excitotoxikus hatású. Konkrét javaslataink a gyógyszerfejlesztést illetően: Az NR2B alegységet tartalmazó NMDA receptorok szelektív gátlói (mint például a fluoxetine), és a nátriumcsatorna gátlók egyes típusai; mint neuroprotektív szerek. A nikotinikus agonisták pozitív modulátorai, amelyek a kognitív problémák kezelésében, ill. a dohányzásról való leszokás segítésében lehetnek hasznosak. | Neurodegeneration after a stroke is one of the major causes of present-day morbidity and mortality. There is a long list of neuroprotective compounds that have failed to be clinically useful in the treatment of ischaemic stroke. This is likely due, at least in part, to our inadequate knowledge regarding the core mechanisms of ischaemic diseases. Most “novel” drugs that target the CNS are designed to act on neurotransmitter receptors or transporters that are localised within synapses. To develop the most effective drugs, it is important to remember that there are extrasynaptic receptors and transporters that may outnumber those located within synapses and that, when malfunctioning, may be responsible for several symptoms of CNS disorders. For example, activation of synaptic NMDA receptors is neuroprotective, whereas stimulation of extrasynaptic NMDA receptors causes excitotoxicity. We suggest that future drug development research consider the following: Compounds that are able to selectively inhibit non-synaptic NR2B Glu receptors (such as Fluoxetine), and specific subtypes of sodium channel inhibitors as neuroprotective compounds. Positive modulators of nicotinic acetylcholine receptors. They would be potential drugs in the treatment of memory problems and in smoking cessation

Condition-Dependent Functional Shift of Two Drosophila Mtmr Lipid Phosphatases in Autophagy Control

Myotubularin (MTM) and myotubularin-related (MTMR) lipid phosphatases catalyze the removal of a phosphate group from certain phosphatidylinositol derivatives. Because some of these substrates are required for macroautophagy/autophagy, during which unwanted cytoplasmic constituents are delivered into lysosomes for degradation, MTM and MTMRs function as important regulators of the autophagic process. Despite its physiological and medical significance, the specific role of individual MTMR paralogs in autophagy control remains largely unexplored. Here we examined two Drosophila MTMRs, EDTP and Mtmr6, the fly orthologs of mammalian MTMR14 and MTMR6 to MTMR8, respectively, and found that these enzymes affect the autophagic process in a complex, condition-dependent way. EDTP inhibited basal autophagy, but did not influence stress-induced autophagy. In contrast, Mtmr6 promoted the process under nutrient-rich settings, but effectively blocked its hyperactivation in response to stress. Thus, Mtmr6 is the first identified MTMR phosphatase with dual, antagonistic roles in the regulation of autophagy, and shows conditional antagonism/synergism with EDTP in modulating autophagic breakdown. These results provide a deeper insight into the adjustment of autophagy. Abbreviations: Atg, autophagy-related; BDSC, Bloomington Drosophila Stock Center; DGRC, Drosophila Genetic Resource Center; EDTP, Egg-derived tyrosine phosphatase; FYVE, zinc finger domain from Fab1 (yeast ortholog of PIKfyve), YOTB, Vac1 (vesicle transport protein) and EEA1 cysteine-rich proteins; LTR, LysoTracker Red; MTM, myotubularin; MTMR, myotubularin-related; PI, phosphatidylinositol; Pi3K59F, Phosphotidylinositol 3 kinase 59F; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns(3,5)P(2), phosphatidylinositol-3,5-bisphosphate; PtdIns5P, phosphatidylinositol-5-phosphate; ref(2)P, refractory to sigma P; Syx17, Syntaxin 17; TEM, transmission electron microscopy; UAS, upstream activating sequence; Uvrag, UV-resistance associated gene; VDRC, Vienna Drosophila RNAi Center; Vps34, Vacuolar protein sorting 34

Developmentally regulated autophagy is required for eye formation in Drosophila

The compound eye of the fruit fly Drosophila melanogaster is one of the most intensively studied and best understood model organs in the field of developmental genetics. Herein we demonstrate that autophagy, an evolutionarily conserved selfdegradation process of eukaryotic cells, is essential for eye development in this organism. Autophagic structures accumulate in a specific pattern in the developing eye disc, predominantly in the morphogenetic furrow (MF) and differentiation zone. Silencing of several autophagy genes (Atg) in the eye primordium severely affects the morphology of the adult eye through triggering ectopic cell death. In Atg mutant genetic backgrounds however genetic compensatory mechanisms largely rescue autophagic activity in, and thereby normal morphogenesis of, this organ. We also show that in the eye disc the expression of a key autophagy gene, Atg8a, is controlled in a complex manner by the anterior Hox paralog lab (labial), a master regulator of early development. Atg8a transcription is repressed in front of, while activated along, the MF by lab. The amount of autophagic structures then remains elevated behind the moving MF. These results indicate that eye development in Drosophila depends on the cell death-suppressing and differentiating effects of the autophagic process. This novel, developmentally regulated function of autophagy in the morphogenesis of the compound eye may shed light on a more fundamental role for cellular self-digestion in differentiation and organ formation than previously thought

Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress

NF-E2-related factor 2 (NRF2) transcription factor has a fundamental role in cell homeostasis maintenance as one of the master regulators of oxidative and electrophilic stress responses. Previous studies have shown that a regulatory connection exists between NRF2 and autophagy during reactive oxygen species-generated oxidative stress. The aim of the present study was to investigate how autophagy is turned off during prolonged oxidative stress, to avoid overeating and destruction of essential cellular components. AMPK is a key cellular energy sensor highly conserved in eukaryotic organisms, and it has an essential role in autophagy activation at various stress events. Here the role of human AMPK and its Caenorhabditis elegans counterpart AAK-2 was explored upon oxidative stress. We investigated the regulatory connection between NRF2 and AMPK during oxidative stress induced by tert-butyl hydroperoxide (TBHP) in HEK293T cells and C. elegans. Putative conserved NRF2/protein skinhead-1 binding sites were found in AMPK/aak-2 genes by in silico analysis and were later confirmed experimentally by using EMSA. After addition of TBHP, NRF2 and AMPK showed a quick activation; AMPK was later down-regulated, however, while NRF2 level remained high. Autophagosome formation and Unc-51-like autophagy activating kinase 1 phosphorylation were initially stimulated, but they returned to basal values after 4 h of TBHP treatment. The silencing of NRF2 resulted in a constant activation of AMPK leading to hyperactivation of autophagy during oxidative stress. We observed the same effects in C. elegans demonstrating the conservation of this self-defense mechanism to save cells from hyperactivated autophagy upon prolonged oxidative stress. We conclude that NRF2 negatively regulates autophagy through delayed down-regulation of the expression of AMPK upon prolonged oxidative stress. This regulatory connection between NRF2 and AMPK may have an important role in understanding how autophagy is regulated in chronic human morbidities characterized by oxidative stress, such as neurodegenerative diseases, certain cancer types, and in metabolic diseases.-Kosztelnik, M., Kurucz, A., Papp, D., Jones, E., Sigmond, T., Barna, J., Traka, M. H., Lorincz, T., Szarka, A., Banhegyi, G., Vellai, T., Korcsmaros, T., Kapuy, O. Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress