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farkas tamás Eötvös Loránd Tudományegyetem Bíró Ferenc 70 éves * Kedves Ünnepelt, tisztelt Kollégák! ... koromPay klára Eötvös Loránd Tudományegyetem T Á R S A S Á G I Ü G Y E K Végső búcsú Ördög Ferenctől * Ördög Ördög tanár úr nyelvészként, névkutatóként páratlan munkabírással és szorgalommal kutatta ...doi:10.18349/magyarnyelv.2016.1.115 fatcat:gccysybdm5cbfguajybvo3dbuy
Ordog, Zörnig, Hayashi 703 www.StemCellsTM.com ©AlphaMed Press 2015 Ordog, Zörnig, Hayashi 705 www.StemCellsTM.com ©AlphaMed Press 2015 www.StemCellsTM.com ©AlphaMed Press 2015 ...doi:10.5966/sctm.2014-0298 pmid:25934947 pmcid:PMC4479627 fatcat:jyhc2wo5mbf7tajmkz3krmkfoe
Journal of Gastrointestinal Cancer
The revolution of epigenetics has revitalized cancer research, shifting focus away from somatic mutation toward a more holistic perspective involving the dynamic states of chromatin. Disruption of chromatin organization can directly and indirectly precipitate genomic instability and transformation. One group of epigenetic mediators, the Polycomb group (PcG) proteins, establishes heritable gene repression through methylation of histone tails. Although classically considered regulators ofdoi:10.1007/s12029-011-9262-4 pmid:21336826 pmcid:PMC3678558 fatcat:vuceopjhhngkvaao2ujskusv24
more »... ent and cellular differentiation, PcG proteins engage in a variety of neoplastic processes, including cellular proliferation and invasion. Due to their multifaceted potential, PcG proteins rest at the intersection of transcriptional memory and malignancy. Expression levels of PcG proteins hold enormous diagnostic and prognostic value in breast, prostate, and more recently, gastrointestinal cancers. In this review, we briefly summarize the function of PcG proteins and report the latest developments in understanding their role in pancreatic cancer.
Intrinsic β-cell circadian clocks are a prerequisite for the control of glucose homeostasis through regulation of β-cell function and turnover. However, little is known about the contributions of circadian clock disruption to the natural progression of β-cell failure in diabetes. To address this, we examined the effects of cytokine-mediated inflammation, common to the pathophysiology of Type 1 and Type 2 diabetes, on the physiological, molecular, and epigenetic regulation of circadian clocks indoi:10.1101/705210 fatcat:xpszrbkaj5egladpjkkw3ou6yu
more »... β-cells. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β-cell circadian clock and circadian regulation of insulin secretion through impaired expression of the key transcription factor Bmal1, evident at the level of promoter activation, mRNA, and protein expression. Additionally, IL-1β-mediated inflammation was shown to augment genome-wide DNA-binding patterns of Bmal1 (and its heterodimer, Clock) in β-cells towards binding sites in the proximity of genes annotated to pathways regulating β-cell apoptosis, inflammation, and dedifferentiation. Finally, we identified that the development of hyperglycemia in humans is associated with compromised β-cell BMAL1 expression suggestive of a causative link between circadian clock disruption and β-cell failure in diabetes.
& Aims-Maintaining the integrity of networks of interstitial cells of Cajal (ICC) is essential to preserve orderly contractile activity and neuroregulation in the gastrointestinal tract and to restore these functions after tissue damage or surgeries. Maintenance of ICC requires insulin-or insulin-like growth factor-I (IGF-I)-dependent production of membrane-bound stem cell factor (SCF) and may involve regeneration from local progenitors. Our goal was to identify ICC precursors in postnataldoi:10.1053/j.gastro.2008.01.036 pmid:18395089 pmcid:PMC2435491 fatcat:54blelbd3ngxfgkinze7r6mn3a
more »... e gastric muscles. Methods-We used flow cytometry and immunohistochemistry to examine freshly dissected and cultured muscles for cells expressing CD34, an adhesion molecule expressed by stromal tumors; CD44, which occurs on mesenchymal stem cells; and receptors for SCF (Kit), insulin (Insr) and IGF-I (Igf1r). Slow waves were studied by intracellular recording. Results-In gastric muscles we identified rare, Kit low CD44 + CD34 + Insr + Igf1r + cells resembling common embryonic precursors of ICC and smooth muscle. These putative progenitors were absent from organotypic cultures lacking mature ICC (Kit + CD44 + CD34 − Insr − Igf1r − ) due to prolonged insulin/IGF-I deprivation but were rescued by IGF-I that also prevented ICC loss. Soluble SCF failed to prevent the loss of mature ICC but dramatically expanded the putative progenitors, which supported robust slow wave activity despite retaining an immature, Kit + CD44 + CD34 + Insr + Igf1r + phenotype. Differentiation of these cells into mature, network-forming ICC required IGF-I. Conversely, restoration of ICC networks by IGF-I after prolonged insulin and IGF-I deprivation required the survival of the presumed progenitors. Conclusions-Kit low CD44 + CD34 + Insr + Igf1r + cells may be local progenitors for gastric ICC and stromal tumors. Loss of these cells may contribute to gastrointestinal dysmotilities.
Genes & Development
Results Depletion of USP51 results in increased DNA damage foci In a shRNA screen for the regulators of nucleosome assembly (H Zhang, H Gan, Z Wang, J Lee, T Ordog, M Wold, M Ljungman, and Z Zhang, ...doi:10.1101/gad.271841.115 pmid:27083998 pmcid:PMC4840300 fatcat:mxsoae4la5hwrdpyglmuczzy4m
relative electron transport rate through PSII; F o , minimal fluorescence level in dark-adapted leaves; F o ', minimal fluorescence level in light-adapted leaves; F m , maximal fluorescence level in dark-adapted leaves; F m ', maximal fluorescence level in light-adapted leaves; F v , maximum variable fluorescence level in dark-adapted leaves; F v ', maximum variable fluorescence level in light-adapted leaves; F v /F m , maximal efficiency of PSII photochemistry; F v '/F m ', efficiency ofdoi:10.1093/jxb/ers397 pmid:23364939 fatcat:au5vt4lj6nbpnffamhc45k7h3i
more »... tion energy capture by open PSII reaction centres; Φ PSII , photochemical efficiency of PSII measured in the light; GSNO, S-nitrosoglutathione; GSSG, glutathione disulphide; NO, nitric oxide; NPQ, non-photochemical quenching; PAM, pulse amplitude modulation; PPFD, photosynthetically active photon flux density; PSII, photosystem II; qE, energy-dependent quenching component; qI, photoinhibitory quenching component; qL, coefficient of photochemical fluorescence quenching assuming interconnected PSII antennae; qP, coefficient of photochemical fluorescence quenching assuming non-interconnected PSII antennae; Rubisco, ribulose-1,5-bisphosphate carboxylase⁄oxygenase. Abstract Nitric oxide (NO) is one of the key elements in the complex signalling pathway leading to stomatal closure by inducing reversible protein phosphorylation and Ca 2+ release from intracellular stores. As photosynthesis in guard cells also contributes to stomatal function, the aim of this study was to explore the potential role of NO as a photosynthetic regulator. This work provides the first description of the reversible inhibition of the effect of NO on guard cell photosynthetic electron transport. Pulse amplitude modulation (PAM) chlorophyll fluorescence measurements on individual stomata of peeled abaxial epidermal strips indicated that exogenously applied 450 nM NO rapidly increases the relative fluorescence yield, followed by a slow and constant decline. It was found that NO instantly decreases photochemical fluorescence quenching coefficients (qP and qL), the operating quantum efficiency of photosystem II (Φ PSII ), and non-photochemical quenching (NPQ) to close to zero with different kinetics. NO caused a decrease in NPQ, which is followed by a slow and continuous rise. The removal of NO from the medium surrounding the epidermal strips using a rapid liquid perfusion system showed that the effect of NO on qP and Φ PSII , and thus on the linear electron transport rate through PSII (ETR), is reversible, and the constant rise in NPQ disappears, resulting in a near steady-state value. The reversible inhibition by NO of the ETR could be restored by bicarbonate, a compound known to compete with NO for one of the two coordination sites of the non-haem iron (II) in the Q A Fe 2+ Q B complex.
ruptions of networks of interstitial cells of Cajal (ICC), gastrointestinal pacemakers and mediators of neurotransmission, can lead to disordered phasic contractions and peristalsis by reducing and uncoupling electrical slow waves. However, detailed analysis of the ICC network behavior has been hampered by their scarcity, limited accessibility in intact tissues, and contamination with other cell types in culture. Our goal was to develop a simple technique to purify ICC from murinedoi:10.1152/ajpgi.00281.2003 pmid:14563669 fatcat:kqjyzqug7bgpbhf6gy6egdxcfq
more »... al muscles for functional studies. We identified ICC in live small intestinal muscles or primary cell cultures by Kit immunoreactivity using fluorescent antibodies. Because this technique also labels resident macrophages nonspecifically, parallel studies were performed in which nonfluorescent Kit antibodies and macrophages labeled with fluorescent dextran were used for subtractive analysis of ICC. In both groups, Kit-positive cells were tagged with superparamagnetic antibodies and sorted on magnetic columns. Efficacy was assessed by flow cytometry. ICC enrichment from primary cultures and freshly dissociated tissues was ϳ63-fold and ϳ8-fold, respectively. Unlike the cells derived directly from tissues, cells sorted from cultures frequently yielded extensive, nearly homogenous ICC networks on reseeding. Monitoring oscillations in mitochondrial Ca 2ϩ or membrane potential by imaging revealed spontaneous rhythmicity in these networks. Cells that did not bind to the columns yielded cultures that were depleted of ICC and dominated by smooth muscle cells. In conclusion, immunomagnetic sorting of primary cultures of ICC results in relatively homogenous, functional ICC networks. This technique is less suitable for obtaining ICC from freshly dispersed cells. mouse; Kit; macrophage; pacemaking; fluorescent imaging
Chromatin immunoprecipitation-sequencing (ChIP-seq) is a widely used epigenetic approach for investigating genome-wide protein-DNA interactions in cells and tissues. The approach has been relatively well established but several key steps still require further improvement. As a part of the procedure, immnoprecipitated DNA must undergo purification and library preparation for subsequent high-throughput sequencing. Current ChIP protocols typically yield nanogram quantities of immunoprecipitateddoi:10.1186/s12864-017-4371-5 pmid:29268714 pmcid:PMC5740926 fatcat:2qsxno26kneinejuw63ir5u5ge
more »... mainly depending on the target of interest and starting chromatin input amount. However, little information exists on the performance of reagents used for the purification of such minute amounts of immunoprecipitated DNA in ChIP elution buffer and their effects on ChIP-seq data. Here, we compared DNA recovery, library preparation efficiency, and ChIP-seq results obtained with several commercial DNA purification reagents applied to 1 ng ChIP DNA and also investigated the impact of conditions under which ChIP DNA is stored. Results: We compared DNA recovery of ten commercial DNA purification reagents and phenol/chloroform extraction from 1 to 50 ng of immunopreciptated DNA in ChIP elution buffer. The recovery yield was significantly different with 1 ng of DNA while similar in higher DNA amounts. We also observed that the low nanogram range of purified DNA is prone to loss during storage depending on the type of polypropylene tube used. The immunoprecipitated DNA equivalent to 1 ng of purified DNA was subject to DNA purification and library preparation to evaluate the performance of four better performing purification reagents in ChIP-seq applications. Quantification of library DNAs indicated the selected purification kits have a negligible impact on the efficiency of library preparation. The resulting ChIP-seq data were comparable with the dataset generated by ENCODE consortium and were highly correlated between the data from different purification reagents. Conclusions: This study provides comparative data on commercial DNA purification reagents applied to nanogram-range immunopreciptated ChIP DNA and evidence for the importance of storage conditions of low nanogram-range purified DNA. We verified consistent high performance of a subset of the tested reagents. These results will facilitate the improvement of ChIP-seq methodology for low-input applications.
AS ITS NAME SUGGESTS, the tunica muscularis of the gastrointestinal tract is dominated by smooth muscle cells, which perform all the mechanical work required for digestion, absorption, and waste removal. The muscle layers also contain several other cell types, which, despite representing a much smaller percentage of the total cellular content, also contribute to gastrointestinal motility by regulating smooth muscle contractions. In this group belong interstitial cells of Cajal (named afterdoi:10.1152/ajpgi.00530.2007 pmid:18270367 fatcat:qdvrb3ss5zeela22igrq5n26ri
more »... ago Ramón y Cajal and commonly referred to as ICC), which represent ϳ5% of cells within the muscular coat. ICC are mesenchymal cells that have been described throughout the gastrointestinal tract of all vertebrates studied to date (15). They can be distinguished from other cell types on the basis of their light microscopic and ultrastructural morphology (16), gene expression pattern, and surface markers (2). Until the discovery of Kit, a type III receptor tyrosine kinase, as a light microscopic marker for ICC (10), investigators could only speculate on the function of these cells on the basis of less specific histochemical staining techniques and electron microscopy and by relying on relatively crude approaches to separate them from the rest of the tissues for physiological analyses. The identification of the interaction between Kit and stem cell factor (SCF or Kitl), its natural ligand, as the most specific target for genetic and pharmacological manipulation of ICC also paved the way for further, more mechanistic investigations. The first part of the "post-Kit era" culminated in the concept that functions previously attributed solely to smooth muscle cells and the extrinsic and intrinsic innervation of the gut may be performed, mediated, or aided by ICC (16). These include the generation and propagation of electrical slow waves underlying rhythmic contractile activity in the phasic parts of the gastrointestinal tract and mediation of communication between the smooth muscle and the autonomic (systemic and enteric) nerves. Later a role in mechanoreception was added (4), and the notion that changes in ICC populations likely play a role in the pathogenesis of various diseases also emerged (19). An exponential rise in interest and studies followed, which further enriched and refined these concepts and broadened the horizon by looking beyond the gut in search of ICC-like cells to explain functions shared by tubular, smooth muscle-lined organs. From these studies emerged a more integrative and nuanced view of the physiology and pathophysiology of gastrointestinal motility and of the role of ICC therein (5, 6, 13, 16). However, significant gaps in our knowledge remain, and it could be argued that filling those gaps and devising more rational therapeutic strategies for disorders involving ICC will require critical reevaluation of the existing data and the development and application of novel concepts and methodology to gastrointestinal motility research (13, 16) . In this issue of American Journal of Physiology Gastrointestinal and Liver Physiology, Dr. Sushil Sarna takes a critical look at the evidence supporting various roles of ICC in gastrointestinal motor functions and concludes that besides setting the membrane potential of smooth muscle cells by releasing the inhibitory gaseous neurotransmitter carbon monoxide, ICC play little, if any, physiological role (17) . This concept is based on earlier views of the control of gastrointestinal motility that only assigned major roles to the smooth muscle and the autonomic (systemic and enteric) nervous system. In this paradigm, smooth muscle cells would produce electrical slow waves, perform mechanical work, and serve as the only relevant recipient and source of information needed for enteric reflexes and motor patterns. Is such a dramatic return to an old paradigm really justified? In his review, Dr. Sarna points out data in the literature that he uses as an argument to refute the current concepts on the roles of ICC in slow-wave generation, mediation of neuromuscular neurotransmission, and mechanoreception. Reexamining concepts from a new aspect is always important for furthering scientific research, and this provocative review will certainly force many in the research community to reassess the literature. It is ultimately up to the informed reader to decide about the proper course of action in response to the issues raised. Are the new data strong enough to justify shutting down efforts in a particular direction? Is the alternative concept presented compelling enough to replace the one in question, or, rather, should we consider the highlighted inconsistencies as unsolved problems requiring that we "raise our game" and employ innovative approaches to get answers? The purpose of this editorial is to jump-start this process by examining Dr. Sarna's hypothesis and by discussing whether the right action in response to the raised issues is to abandon and ignore ICC and resuscitate old paradigms or, alternatively, to give serious consideration to the remaining inconsistencies and then attempt to resolve them by applying novel, state-of-the-art concepts and methods of the postgenomic era to gastrointestinal motility research. Which Cell has the Clock for Timing the Slow Waves? Manifestations of electrical slow waves can be simultaneously recorded from both smooth muscle cells and ICC (5, 8), but which of these two cell types times their periodicity? There is no controversy that ICC possess an electrical pacemaker mechanism that is robust and capable of producing large-amplitude oscillations even in isolation. However, according to the hypothesis advanced in Sarna's review, this clock is not the physiological source of slow waves and is
., Tamás Ö rdög, and Kenton M. Sanders. Neural regulation of slow-wave frequency in the murine gastric antrum. ...doi:10.1152/ajpgi.00349.2005 pmid:16166340 fatcat:jpuxnzfkebduvkef5waieismea
Cellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture over multiple distance scales [nucleosomes (~10^2 bp), topologically-associated domains (TADs;doi:10.1101/2020.10.23.350892 fatcat:s4odz2yzgzd3ph6htv7ows7geu
more »... ~10^5 - 10^6 bp), and chromatin compartments (10^6 - 10^8 bp)]. Metabolically-driven hyperacylation of histones led to weakened nucleosome positioning in multiple types of chromatin, and we further demonstrate that lysine acylation directly destabilizes histone octamer-DNA interactions. Hyperacylation of cohesin subunits correlated with decreased mobility on interphase chromatin and increased TAD boundary strength, suggesting that cohesin is metabolically regulated. Erosion of chromatin compartment distinctions reveals metabolic regulation of chromatin liquid-liquid phase separation. The TCA cycle and ETC thus modulate chromatin structure over multiple distance scales.
SeungilFigure 1 . 1 Ro, Sung Jin Hwang, Tamás Ördög, and Kenton M. ...doi:10.2144/05384rn01 pmid:15884680 fatcat:k35jhhkb3vcwxnxh7ygrkbrtly
Knobil. On the mechanism of lactational anovulation in the rhesus monkey. Am. J. Physiol. 274 (Endocrinol. Metab. 37): E665-E676, 1998.-The relative roles of infant suckling and of maternal prolactin (PRL) secretion in lactational anovulation were studied in ovaryintact and ovariectomized rhesus monkeys nursing young that had been removed from their natural mothers. Hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator activity was monitored electrophysiologically in freelydoi:10.1152/ajpendo.1998.274.4.e665 fatcat:laa43ship5g47epewgbcclgjmy
more »... animals by radiotelemetry. Serum luteinizing hormone, PRL, estradiol, and progesterone were also measured. Suckling inhibited GnRH pulse generator activity and ovarian cyclicity in all ovary-intact females but had no such effect on the pulse generator in long-term ovariectomized animals. When PRL secretion was suppressed by daily bromocriptine administration, GnRH pulse generator activity remained significantly inhibited and ovulation was prevented in four monkeys (6 trials), whereas in two females (6 trials) a rapid increase in pulse generator frequency and the resumption of ovarian cyclicity were observed although suckling activity was maintained. One monkey displayed both response types. Although these results indicate that suckling per se is able to restrain GnRH pulse generator activity in the absence of PRL, they also suggest that the relative importance of these determinants is variable depending on factors that remain to be determined. The present study also confirms the permissive role of the ovary in the lactational suppression of GnRH pulse generator activity.
& Aims-Vascular endothelial growth factor (VEGF)-induced angiogenesis is implicated in fibrogenesis and portal hypertension. However, the function of VEGF in fibrosis resolution has not been explored. Methods-We developed a cholecystojejunostomy procedure to reconstruct biliary flow after bile duct ligation in C57BL/6 mice to generate a model of fibrosis resolution. These mice were then given injections of VEGF-neutralizing (mcr84) or control antibodies, and other mice received an adenovirusdoi:10.1053/j.gastro.2014.01.061 pmid:24503129 pmcid:PMC4001704 fatcat:q7qvzogkk5fadjjxkwpsa3lbf4
more »... t expressed mouse VEGF or a control vector. The procedure was also performed on macro-phage fas-induced apoptosis mice, in which macrophages can be selectively depleted. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, vascular permeability, real-time polymerase chain reaction, and flow cytometry assays.
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