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onsdag 26 juli 2017

öylätti sisältää edelleen gluteenia Rooman kirkossa

https://www.thelocal.it/20170710/vatican-bans-gluten-free-bread-wine-doubtful-provenance-from-holy-communion-catholic-mass-eucharist

 Suomen luterilaisessa kirkossa on mahdollsita saada ehtoollialeipä gluteenittomana ja ehkä viinikin alkoholittomana pyynnöstä.

Keliaakikon on kuitenkin syytä välttää liian tiheitä ehtoollisia, jos  seurakunta jossa hän käy ehtoollisella,lla ei tunnsuta olevankaan tarvetta gluteenittomaan ehtoollisleipään. 
vaikka samassa hengenvedossa kirkossa rukoillaan:
 Anna meille meidän jokapäiväinen leipämme, siis  meille individeille meidän individuellisti  sovellutettu  jokapäiväinen leipämme.
eikä esim "anna meille  meidän pappimme jokapäiväinen leipä".

Toinen tapa millä voi alentaa gluteenialtistusta  sakramenttiin osallistumisen frekvenssin vähentämisen ohella,   lipämäärän vähentämisellä.  Esim  ison 8 keliakikon silmisäs jättimäisen gluteenipalan9 asemasta  voi ottaa mikromurun, niin pinenn murun että se vain tarttuu sormenpäähän kiinni. siinä ei mahdu olemaan päivän  sallitun gliadiinimäärän ylittävää  gluteenimäärä.

Pitää selvittää, että hyvin tarkasti dieettiä noudattavillakin on lymfoomavaara 17 vuoden jälkeen, sillä T-solut  rasittuvat ja voivat ottaa malignin linjan. Ne havaitsevat  toksiset peptidit.   Italiassa on paljon  ongelmaa juuri siitä, että katolilaiset oat kuin miljoonat  juutalaiset Auschwitsissa menevät  apaattisesti kuooleman junaan vastustamatta  pakkoa.

Kuolemaa tulee vastustaa.

  Luonnollsiesti  tietämättömyys on suuri este,  siinä että  tämä asia vielä  sata vuotta sen jälkeen kun on alettu nähdä jotain  elintarviketekijää , joka vaikuttaa  terveyteen.

Tietysti pappien tahotla voi  esittää puolustuksen: Eivät keliakikot kuitenkaan noudata mitään tarkkaa dieettiä, joten öylätin osuus kaikessa inkomplianssissa on statistisesti merkityksetön.

Mene ja tiedä! Se joka  noudattaa huonosti  dieettiä,  tuskin välittää siitä onko öylätissä  gluteenia vai ei, jos hän saattuu olemaan kristitty ja  sattuu käymään ehtoollisella.  Ja on uskon suuntia jotka puolustavat vehnäöylättiä   Raamatun sanalla..
Jopa papit  kuolevat keliakiaan ja sen komplikaatioihin  ja  siinä tapauksessa jopa muista nopeammin. 
Toisalta keliakiian ja lymfoomaan kuolee myös niitä, jotka eivät edes käy ehtoollisella, joten ehtollissakramenttiin  sinänsä liittyvät  tervehdyttävät siunaukset ja niiden poisjääminen ovat uncertainty factor , kun asiaa punnitsee.





tisdag 11 juli 2017

Mitä kansanvalistaja Wikipedia näistä polykombiproteiineista kertoo

 Englanninkielestä selviää seuraavaa valoa:
PRC2 , polykombinen repressiivinen kompleksi  on toinen polykombisen ryhmän proteiiniluokista 1 ja 2 .Tämän rymän toinen komponenti on PRC1, polykombinen repressiivinen kompleksi 1.

Mitä tällaiset proteiinit tekevät?

Tämä kompleksi PRC2 omaa  histonimetyylitransferaasin kyvyt ja se pystyy trimetyloimaan H3- histonia  aminohappoon lysiini, joka on  peptidiketjun jäjestyksesä numero 27.  eli lyhennyksenä on tuotetta H3K27me3 ( histoni 3, lysiini numero 27, metyyliryhmiä 3). Tällainen molekyylirakenne ilmoittaa, että kromatiini on  transkriptionaalisesti hiljaisessa vaiheessa ( siitä siis ei kopioida koodeja sillä hetkellä: eli "Kopiokonetta  printteriä ei käytetä").

 PRC2  tarvitaan  genomisen kohdealueensa   hiljentamisen alkuunpanemiseen, mutta PRC1 taas vaaditaan stabiloimaan tämä  hiljaisuustila.  Tämä järjestelmä on  solujen erilaistumisen jälkeen hiljennetyn alueen  solumuistin  perusta.
  •  PRC2 is required for initial targeting of genomic region (PRC Response Elements or PRE) to be silenced, while PRC1 is required for stabilizing this silencing and underlies cellular memory of silenced region after cellular differentiation.
 PRC1 myöskin monoubikitinisoi  Histonia H2A sen lysiinin numero 119. ( Tästä on merkkinä molekyyliä H2AK119Ub1) .
  •  PRC1 also mono-ubiquitinates histone H2A on lysine 119 (H2AK119Ub1). 
 Näitä proteiineja tarvitaan kromatiinin pitkäaikaiseen epigeneettiseen hiljentämsieen. ja niillä on tärkeää osuutta kantasolun erikoistumisessa ja varahisesa alkiokehityksessä. PRC2 ilmenee kaikissa monisoluisissa organismeissa.
 Hiiren PRC2 omaa neljä alayksikköä: Suz12 ( zinc finger) , Eed, Ezh1 tai Ezh2 (SET domeeni jolla on histonimetyylitransderaasin aktiivisuutta ) ja RbAp48 (histonia sitova domeeni).
https://en.wikipedia.org/wiki/SUZ12
 PRC2 omaa myös osaa X-kromosomin hiljentämisessä, kantasolulinjan ylläpidossa. On myö shavaittu poikkeavaa PRC2 iolmenem istä syövässä.
  • PRC2 has a role in X chromosome inactivation, in maintenance of stem cell fate, and in imprinting. Aberrant expression of PRC2 has been observed in cancer.[1][2]
Evolutionaalisti tämä geeni on konservoitunut ja sitä löytyy imettäväisissä, hyönteisissä  ja kasveissa
 

Käsite " polycomb group proteins"


Näyttää olevan kantasolututkimusaluetta.
Stem Cell Res. 2014 Jan;12(1):296-308. doi: 10.1016/j.scr.2013.11.007. Epub 2013 Nov 16.

Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells.

Abstract

The aryl hydrocarbon receptor (AHR) is a transcription factor and environmental sensor that regulates expression of genes involved in drug-metabolism and cell cycle regulation.
Chromatin immunoprecipitation (ChIP)   analyses, Ahr ablation in mice and studies with orthologous genes in invertebrates suggest that AHR may also play a significant role in embryonic development.

To address this hypothesis, we studied the regulation of Ahr expression in mouse embryonic stem cells  (ESC)  and their differentiated progeny. In ES cells, interactions between OCT3/4, NANOG, SOX2 and Polycomb Group  (PcG) proteins at the Ahr promoter repress AHR expression, which can also be repressed by ectopic expression of reprogramming factors in hepatoma cells.

 In ES cells, unproductive RNA polymerase II (RNAPII)  binds at the Ahr transcription start site (TSS) and drives the synthesis of short abortive transcripts. Activation of Ahr expression during differentiation follows from reversal of repressive marks in Ahr promoter chromatin, release of pluripotency factors and PcG proteins, binding of Sp factors, establishment of histone marks of open chromatin, and engagement of active RNAPII to drive full-length RNA transcript elongation.

Our results suggest that reversible Ahr repression in ES cells holds the gene poised for expression and allows for a quick switch to activation during embryonic development.

KEYWORDS:

 AHR, aryl hydrocarbon receptor; ( transkriptiotekijä ja miljöösensori)
ARNT; Ah receptor nuclear translocator;
 AhRE,AHR response element;
 CTD,  carboxyl-terminal repeat domain;
 ChIP, chromatin immunoprecipitation;
 EB, embryoid bodies;
 EMT, epithelial-to-mesenchymal transition;
 ESC, embryonic stem cells;
 EZH2,  enhancer of zeste homolog 2;
H3K27ac; acetylated lysine-27 of histone H3;
H3K27me3/2/1, tri/di/mono-methylated lysine-27 of histone H3;
H3K36me3;  tri-methylated lysine-36 of histone H3;
H3K4me3/2/,  ;tri/di/mono-methylated lysine-4 of histone H3;
H3K9ac,  acetylated lysine-9 of histone H3;
H3K9me3/2/1,   tri/di/mono-methylated lysine-9 of histone H3
H3ac, acetylated histone H3;
HMT, histone methyltransferase;
ICMm inner-cell-mass;
 KDM6A/B,  lysine demethylase 6A and 6B;
KO,  knock out;
MET, mesenchymal-to-epithelial transition;
 MLL, myeloid/lymphoid or mix-lineage leukemia;
 OCT3/4,
 SOX2,
 KLF4,
MYC;
 OSKM;
PRC1/2, Polycomb repressive complexes 1 and 2;
 PcG; Polycomb Group proteins;
 RING1B,  ring finger protein 1B;
RNAPII,  RNA polymerase II;
RNAPII (S5p(+)S2p(+)),  RNA polymerase II hyperphosphorylated in CTD serine-5 and serine-2;
RNAPII (S5p(+)S2p(−)),  RNA polymerase II phosphorylated in CTD serine-5 but not serine-2;
SUZ12,  suppressor of zeste 12 homolog;
TCDD,  2,3,7,8-tetrachlorodibenzo-p-dioxin;
TES. transcription end site;
 TSS, transcription start site;
 TxG, Trithorax Group proteins;
 bHLH/PAS,  basic helix–loop–helix/Per-ARNT-Sim;
 iPSC,  induced pluripotent stem cells;

Kommentti: Otin tämäna rtikkelin  sitaatina, näiden termisanojen takia, ksoka  Suomen keliakiatutkimus on  tällä tasolla  asian syvillä juurilla ja näitä termejä käytetään. Jätetään tämä asia hautumaan. ja seurataan mitä tuloksia Tempereelta ilmenee.
Muistiin 11.7. 2017



PRC2 geenistä

Katson lisätietoa tästä geenistä
https://en.wikipedia.org/wiki/PRC2

Käynnissä olevia tutkimustöitä Tampereella

University of Tampere: Taculty of Medicine and Life Sciences:

The Research Council for Health of the Academy of Finland granted five-year research fellowships to project director Ilkka Junttila and university researcher Keijo Viiri from the University of Tampere. Twelve fellowships were granted to eighty-five applicants, i.e. to fourteen percent of the applicants.

  • Ilkka Junttila’s study is investigating how cytokines, especially Interleukin(IL)-4, regulates allergic inflammation. Immune response protects people against invading pathogens such as viruses, bacteria, parasites and yeasts. Inappropriately activated immune response can result in an autoimmune reaction or an allergic reaction. Humoral mediators, cytokines, are critical regulators of various immune responses. By understanding how IL-4 and its cell surface receptors function, its therapeutic utilisation, for example in autoimmune diseases to redirect immune response to less inflammatory direction, may become possible. The study will be conducted in cooperation between the University of Tampere, Tampere University Hospital, Fimlab Ltd and National Institutes of Health (United States) and it is based on Junttila’s previous studies.

  • Keijo Viiri’s project will study the function of epigenetically dysregulated genes in coeliac disease. The main hallmark of the coeliac disease is the defectively differentiated intestinal epithelium, which leads to food malabsorption. The project previously discovered that an epigenetic gene-silencer called the polycomb controls the intestinal homeostasis between intestinal stem cells in crypts and mature epithelium in villi. In response to gluten ingestion, consequent aberrant polycomb activity was found to cause imbalance in intestinal homeostasis. The results are anticipated to reveal novel pathogenetic mechanisms and improve the diagnosis of the early coealiac disease.
Keijo Viiri’s Intestinal Signalling and Epigenetics group
http://www.uta.fi/tacc/research/signallingepigenetics/index.html

 Information in the genome is written in the bases of DNA and misspellings (mutations) in this code have sometimes profound effects leading to diseases. Yet, genome is not a static entity where information is only stored but it needs mechanisms to regulate the usage of this information i.e. gene activation and repression. Scientific advances in couple of last decades have taught us that there is a rather plastic interface between genome and environment. These epigenetic mechanisms include DNA methylation and plethora of different histone modifications which in turn regulate gene expression and a given gene expression state is inherited to the daughter cells. Perturbations in epigenetic mechanisms can also contribute to diseases such as cancer. One epigenetic regulator called ‘Polycomb’ has been shown to be overexpressed in endometrial-, breast-, colon-, lung-, and skin cancer. Cell type specific expression programs are orchestrated through regulated access to chromatin. Polycomb proteins regulate developmental gene expression. Polycombs are essential for embryonic stem cell self-renewal and pluripotency but they are also necessary for the maintenance of cell identity and cell differentiation throughout life. It has been shown that overexpressed polycomb keeps cells in more proliferative and lower differentiation state, which inevitably is one of the hallmarks of cancer.

Reminiscent to hyper-proliferative state in cancer the main manifestation of Celiac disease is also more proliferative and lower differentiation state, namely of the epithelium of the small intestine leading to food malabsorption. We’ve found that polycomb maintains the homeostasis between intestinal stem cells and mature epithelium. Moreover this homeostasis is broken when celiac patients are on gluten containing diet.

As celiac disease is an ailment with the strong autoimmune component in its pathogenesis we strive to understand how intestinal barrier (epithelium, immune cells and lamina propria cells) is dysregulated in the disease.  In our projects we use human and mouse primary cell cultures (intestinal organoids, primary myofibroblasts etc) and genome-wide techniques (such as ChIP-Seq) in endeavours to understand how signalling is reigned in intestinal barrier and how epigenetic mechanisms are running the errands of the signalling.

Figure 1. (A) Schematic representation of the role of Polycomb Repressive Complex 2 (PRC2) on enacting the Wnt/beta-catenin signaling and regulating the homeostasis of intestinal stem cell self-renewal and differentiation. At transit amplifying (TA) region PRC2 selectively set an epigenomic identity by labelling genes with repressive H3K27me3 mark and therefore enforce and maintain the dichotomy for crypt and villus identities. Scatter blot on the right demonstrates the genome-wide change in H3K27me3 occupancy during the differentiation of crypt/Intestinal stem cells to mature enterocytes. Blue dots represents all normalized differential H3K27me3 ChIP-Seq peaks near protein coding genes of the mouse genome (above genes silenced in crypts and below genes silenced in villi). Red coloured triangles denote the genes having significant gene expression difference measured by GRO-Seq and green arrows quantitatively illustrate the gene expression difference in enterocytes relative to crypts/ISCs (up=activation, down=repression). (B) PRC2 is out-of-bounds expressed and its enterocytic target genes are repressed in celiac patients on gluten-containing diet.

Figure 2. Growing ‘minigut’ organoids from intestinal stem cells harvested from mouse intestinal crypts. We use organoids as a model for intestinal differentiation. 24h after harvesting intestinal stem cells proliferate and visible spheres can be seen in three-dimensional matrigel cultures. Same spheroidal organoid after six days of culturing (Pictures in the same scale). With specific inhibitor and/or growth factor cocktails organoids can be differentiated virtually to any intestinal epithelial cell type ex vivo.

Group members

Keijo Viiri, Group leader
PhD
Mikko Oittinen (MSc, PhD student)
Joel George (MSc, PhD student
Jorma Kulmala (Laboratory technician, part-time)

Selected Publications

    Oittinen M, Popp A, Kurppa K, Lindfors K, Mäki M, Kaikkonen MU & Viiri K. ”PRC2 enacts Wnt signaling in intestinal homeostasis and contributes to the instigation of stemness in disease entailing epithelial hyperplasia or neoplasia” Stem Cells 2017 Feb; 35(2):445-457

    Teppo S, Laukkanen S, Liuksiala T, Nordlund J, Oittinen M, Teittinen K, Grönroos T, Syvänen AC, Nykter M, Viiri K, Heinäniemi M, Lohi O. Genome-wide repression of eRNA and target gene loci by the TEL-AML1 fusion in acute leukemia” Genome Research 2016 Nov;26(11):1468-1477

    Beltran M, Yates CM, Skalska L, Dawson M, Reis FP, Viiri K, Fisher CL, Sibley CR, Foster BM, Bartke T, Ule J & Jenner RG. “The interaction of PRC2 with RNA or chromatins is mutually antagonistic” Genome Research 2016 Jul; 26(7):896-907.

    Mäntylä E, Salokas K, Oittinen M, Aho V, Mäntysaari P, Palmujoki L, Kalliolinna O, Ihalainen TO, Niskanen EA, Timonen J, Viiri K, Vihinen-Ranta M. ”Promoter-Targeted histone acetylation of chromatinized parvoviral genome is essential for the progress of infection” Journal of Virology 2016 Mar 28;90(8):4059-66.

    Hervonen K, Salmi TT, Ilus T, Paasikivi K, Vornanen M, Laurila K, Lindfors K, Viiri K, Saavalainen P, Collin P, Kaukinen K, Reunala T. ”Dermatitis herpetiformis refractory to gluten-free dietary treatment.” ActaDermato-Venereologica. 2016 Jan; 96(1):82-6.

    Vlachogiannis G, Niederhuth CE, Tuna S, Stathopoulou A, Viiri K, de Rooij DG, Jenner RG, Schmitz RJ, Ooi SK. “The Dnmt3L ADD domain Controls cytosine methylation establishment during spermatogenesis.” Cell Reports. 2015 Feb 12.

    Viiri K, Mäki M, Lohi O. “Phosphoinositides as regulators of protein-chromatin interactions.” Science Signaling. 2012 May 1; 5(222):pe19.

    Kanhere AS, Viiri K, Araújo CC, Rasaiyaah J, Bouwman RD, Whyte W, Pereira CF, Brookes E, Walker K, Bell GW, Pombo A, Fisher AG, Young RA , Jenner RG “Short RNAs are transcribed from repressed Polycomb target genes and interact with Polycomb Repressive Complex-2”. Molecular Cell 2010 Jun 11;38(5):675-88


Funding

Academy of Finland
TEKES – the Finnish Funding Agency for Technology and Innovation
Sigrid Jusélius Foundation
IASR – Institute for Advanced Social Research
Sohlberg Foundation

onsdag 7 juni 2017

candesartan, hm

 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007307

Volume-sensitive chloride current in human cardiac fibroblasts

The current with outward rectification shown in Fig. 1D was insensitive to inhibition of K+ channel blockers including 5 mM tetraethylammonium (TEA), 5 mM 4-AP, or 0.5 mM Ba2+ (n = 4−6), suggesting that the outwardly-rectifying current is not carried by K+ ion. We then employed the Cl channel inhibitor DIDS to determine whether the current is carried by chloride ions. Figure 5A shows the current traces recorded in a representative cell with the protocol shown in the inset; DIDS (150 µM) suppressed the current. The I-V relationship (Fig. 5B) of the DIDS-sensitive current obtained by subtracting control currents by the current recorded after DIDS application displayed outward rectification and had a reversal potential at −35 mV, which is close to Cl equilibrium potential (ECl, −46.8 mV). Similar results were obtained in a total of 6 cells. This result suggests that the recorded current under isotonic conditions is carried by Cl ions.
To investigate whether the Cl channel is volume sensitive in human cardiac fibroblasts, we employed a 0.7T tonic solution and recorded membrane current using a K+-free pipette solution, symmetrical Cl ion in pipette and bath medium as described in the Methods section. The membrane conductance was remarkably enhanced by exposure to 0.7T (20 min), and the increased current was highly suppressed by the Cl channel blocker NPPB (Fig. 5C). The I-V relationship of 0.7T-induced Cl current is linear under symmetrical Cl conditions Fig. 5D), similar to the previous report [21]. These results indicate that volume-sensitive Cl channel (ICl.vol) is present in human cardiac fibroblasts

Angiotensin II, EGF receptors, and reactive oxygen species

Stretch of cardiac myocytes has long been known to release angiotensin II (AngII) [81], which acts on myocytes in an autocrine-paracrine loop and signals via Src and EGFR kinase in a multistep pathway ultimately leading to the formation of reactive oxygen species (ROS) [47, 90, 99]. AngII and ROS are implicated in cardiac remodelling and the development of heart failure, where ICl,swell is chronically activated [22, 23], and in hypertrophy of vascular smooth muscle [5, 14, 47, 90, 91, 99].

This raised a question: Does activation of the AngII signalling cascade modulate ICl,swell?
The role of AngII signalling was investigated for ICl,swell elicited both by stretching β1 integrins [10, 12] and by osmotic swelling [75, 76]. 
 Block of AT1 receptors by losartan prevents activation of ICl,swell by either stimulus, and exogenous AngII activates a comparable Cl- current. Thus, activation of ICl,swell appears likely to result from the autocrine-paracrine action of AngII. AngII release may not be required, however. Native cardiac and heterologously expressed AT1 receptors are activated by stretch both in the presence of AngII neutralizing antibodies that block responses to exogenous AngII and in the absence of AngII in an expression system [113]. While AT1 receptors are not activated by AngII in these studies, stretch-induced signalling still is blocked by candesartan, an AT1 antagonist.

Other components of the AngII signalling cascade [14, 47, 90, 91] are also implicated in the upregulation of ICl,swell in response to both stretch and swelling [10, 12, 33, 75, 76], and the signalling scheme is shown in Figure 4.
 Figure 4. Simplified diagram of autocrine-paracrine signalling cascade that controls ICl,swell.

 Simplified diagram of autocrine-paracrine signalling cascade that controls ICl,swell. Swelling and stretch initiate the cascade via integrins and one or more downstream molecules. Exogenous AngII and EGF also active ICl,swell. Src family PTK and ROS are likely to interact at additional sites. It is unclear whether ROS activates ICl,swell directly or via intermediates.

AT1 receptor activation causes transactivation of EGF receptors, which possess intrinsic EGFR kinase activity. ICl,swell is blocked by EGFR kinase inhibitors in human atria and rabbit ventricle [12, 33, 75, 76] and is activated by exogenous EGF [12]. EGFR kinase signals via PI-3K, and PI-3K inhibitors wortmannin and LY294002 block ICl,swell. Ultimately this signalling cascade stimulates sarcolemmal NAD(P)H oxidase, which produces ·O2-, and ·O2- rapidly undergoes dismutation to H2O2 a longer-lived, membrane permeant ROS.

Cardiac muscle expresses two NAD(P)H oxidase isoforms, NOX2, the classical phagocyte isoform, and NOX4 [13, 52, 106]. As expected, ICl,swell is blocked by organic inhibitors of NAD(P)H oxidase, including DPI (diphenylene iodinium),

CaT alternans

https://www.ncbi.nlm.nih.gov/pubmed/27356267
Channels (Austin). 2016 Nov;10(6):507-17. doi: 10.1080/19336950.2016.1207020. Epub 2016 Jun 29.

Ca(2+)-activated chloride channel activity during Ca(2+) alternans in ventricular myocytes. Kanaporis G1, Blatter LA1.

Cardiac alternans, defined beat-to-beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias.

 We investigated mechanisms of cardiac alternans in single rabbit ventricular myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. A strong correlation between beat-to-beat alternations of AP morphology and CaT alternans was observed.

During CaT alternans application of voltage clamp protocols in form of pre-recorded APs revealed a prominent Ca(2+)-dependent membrane current consisting of a large outward component coinciding with AP phases 1 and 2, followed by an inward current during AP repolarization.

Approximately 85% of the initial outward current was blocked by Cl(-) channel blocker DIDS or lowering external Cl(-) concentration identifying it as a Ca(2+)-activated Cl(-) current (ICaCC).
The data suggest that ICaCC plays a critical role in shaping beat-to-beat alternations in AP morphology during alternans.

KEYWORDS:

action potential; alternans; arrhythmias; calcium; calcium-activated chloride channels; excitation-contraction coupling; heart