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Jean tears through today's crossword, as, allowing for heteronyms, does Mike. There were quite a few teaching moments in today's crossword:57A, Fashion designer associated with the item spelled out by the starts of 17-, 26- and 42-Across, COCOCHANEL -- alluding to the Little Black Dress that apparently is a staple of most women's wardrobes. 26A, Bicolor cookies also called half-moons, BLACKANDWHITES, not OREOOOOOOOOOOOS (that's an OREO being eaten while falling off a cliff).32D, ________ Rutter, "Jeopardy!" contestant with the all-time highest winnings ($4.9+ million)To get the details on all of the above, and more, download and listen up.
Today's crossword was a bit of a slog, although we were happy to see the return of AMONRA - the god of tricky spelling -- and several Star Wars references (21A, Hoth, in "Star Wars", ICEPLANET, and 27A, Sci-fi enemy collective, perhaps, EVILEMPIRE). Jean struggled in the northwest corner, and both Jean & Mike had to grit their teeth in the southeast, where the dubious 49D, Hit on the head, in slang, DONK, and the clever but obscure 32D, "100 Years ... 100 Stars" and others, in brief, AFILISTS, caused difficulty. Still, any crossword that includes 47A, Portmanteau coinage for the uneducated and uncultured, BOOBOISIE, can't be all bad -- we give this a 4 squares on the JAMCR scale.
Primeira Leitura: Atos 5,27-33 Leitura dos Atos dos Apóstolos – Naqueles dias, os guardas 27levaram os apóstolos e os apresentaram ao sinédrio. O sumo sacerdote começou a interrogá-los, 28dizendo: “Nós tínhamos proibido expressamente que vós ensinásseis em nome de Jesus. Apesar disso, enchestes a cidade de Jerusalém com a vossa doutrina. E ainda nos quereis tornar responsáveis pela morte desse homem!” 29Então Pedro e os outros apóstolos responderam: “É preciso obedecer a Deus antes que aos homens. 30O Deus de nossos pais ressuscitou Jesus, a quem vós matastes, pregando-o numa cruz. 31Deus, por seu poder, o exaltou, tornando-o guia supremo e salvador, para dar ao povo de Israel a conversão e o perdão dos seus pecados. 32E disso somos testemunhas, nós e o Espírito Santo, que Deus concedeu àqueles que lhe obedecem”. 33Quando ouviram isso, ficaram furiosos e queriam matá-los. – Palavra do Senhor. Salmo Responsorial: 33(34) Este infeliz gritou a Deus e foi ouvido. 1. Bendirei o Senhor Deus em todo o tempo, / seu louvor estará sempre em minha boca. / Provai e vede quão suave é o Senhor! / Feliz o homem que tem nele o seu refúgio! – R. 2. Mas ele volta a sua face contra os maus / para da terra apagar sua lembrança. / Clamam os justos, e o Senhor bondoso escuta / e de todas as angústias os liberta. – R. 3. Do coração atribulado ele está perto / e conforta os de espírito abatido. / Muitos males se abatem sobre os justos, / mas o Senhor de todos eles os liberta. – R. Evangelho: João 3,31-36 Aleluia, aleluia, aleluia. Acreditaste, Tomé, porque me viste. / Felizes os que creem sem ter visto (Jo 20,29). – R. Proclamação do Evangelho de Jesus Cristo segundo João – 31“Aquele que vem do alto está acima de todos. O que é da terra pertence à terra e fala das coisas da terra. Aquele que vem do céu está acima de todos. 32Dá testemunho daquilo que viu e ouviu, mas ninguém aceita o seu testemunho. 33Quem aceita o seu testemunho atesta que Deus é verdadeiro. 34De fato, aquele que Deus enviou fala as palavras de Deus, porque Deus lhe dá o Espírito sem medida. 35O Pai ama o Filho e entregou tudo em sua mão. 36Aquele que acredita no Filho possui a vida eterna. Aquele, porém, que rejeita o Filho não verá a vida, pois a ira de Deus permanece sobre ele”. – Palavra da salvação.
Evangelho (Jo 3,31-36) — O Senhor esteja convosco. — Ele está no meio de nós. — Proclamação do Evangelho de Jesus Cristo + segundo João. — Glória a vós, Senhor. 31“Aquele que vem do alto está acima de todos. O que é da terra, pertence à terra e fala das coisas da terra. Aquele que vem do céu está acima de todos. 32Dá testemunho daquilo que viu e ouviu, mas ninguém aceita o seu testemunho. 33Quem aceita o seu testemunho atesta que Deus é verdadeiro. 34De fato, aquele que Deus enviou fala as palavras de Deus, porque Deus lhe dá o espírito sem medida. 35O Pai ama o Filho e entregou tudo em sua mão. 36Aquele que acredita no Filho possui a vida eterna. Aquele, porém, que rejeita o Filho não verá a vida, pois a ira de Deus permanece sobre ele”. — Palavra da Salvação. — Glória a vós, Senhor.
2ª Semana da Páscoa | Quinta-feiraEvangelho do dia (Jo 3,31-36)31“Aquele que vem do alto está acima de todos. O que é da terra, pertence à terra e fala das coisas da terra. Aquele que vem do céu está acima de todos. 32Dá testemunho daquilo que viu e ouviu, mas ninguém aceita o seu testemunho. 33Quem aceita o seu testemunho atesta que Deus é verdadeiro. 34De fato, aquele que Deus enviou fala as palavras de Deus, porque Deus lhe dá o espírito sem medida.35O Pai ama o Filho e entregou tudo em sua mão. 36Aquele que acredita no Filho possui a vida eterna. Aquele, porém, que rejeita o Filho não verá a vida, pois a ira de Deus permanece sobre ele”.Palavra da Salvação.Glória a vós, Senhor.
31“Aquele que vem do alto está acima de todos. O que é da terra, pertence à terra e fala das coisas da terra. Aquele que vem do céu está acima de todos. 32Dá testemunho daquilo que viu e ouviu, mas ninguém aceita o seu testemunho. 33Quem aceita o seu testemunho atesta que Deus é verdadeiro. 34De fato, aquele que Deus enviou fala as palavras de Deus, porque Deus lhe dá o espírito sem medida. 35O Pai ama o Filho e entregou tudo em sua mão. 36Aquele que acredita no Filho possui a vida eterna. Aquele, porém, que rejeita o Filho não verá a vida, pois a ira de Deus permanece sobre ele”.
Evangelho (Jo 3,31-36) - 2ª Semana da Páscoa | Quinta-feira 31“Aquele que vem do alto está acima de todos. O que é da terra, pertence à terra e fala das coisas da terra. Aquele que vem do céu está acima de todos. 32Dá testemunho daquilo que viu e ouviu, mas ninguém aceita o seu testemunho. 33Quem aceita o seu testemunho atesta que Deus é verdadeiro. 34De fato, aquele que Deus enviou fala as palavras de Deus, porque Deus lhe dá o espírito sem medida. 35O Pai ama o Filho e entregou tudo em sua mão. 36Aquele que acredita no Filho possui a vida eterna. Aquele, porém, que rejeita o Filho não verá a vida, pois a ira de Deus permanece sobre ele”. — Palavra da Salvação. --- Send in a voice message: https://anchor.fm/pe-jose-vicente/message
A punny Wednesday, with multiple clues, based on PARADOX, that happened to contain, DOX, um, make that Docs as in Dr. EVIL, Dr. OZ, Dr. WHO, Dr. RUTH, Dr. DRE and Dr. NO -- clearly the makings of a great medical clinic!There were a few grin-inducing clues -- 53A, Elbows and such, PASTA, and 32D, Togs for sawing logs?, PJS -- offset by one sad clue -- 61D, Number of season's played by baseball's Seattle Pilots, ONE. Clearly there is a story to be told ...
An ARTFULLY constructed Saturday, with plenty of tough clues to RUMINATE over, from 14A, Wait here!, RESTAURANT (very nice), to the slightly less arcane 32D, Main course?, SEAROUTE. Jean had some difficulty with 33D, Nickname for the White House Correspondents' Dinner, NERDPROM, while Mike was temporarily flummoxed by 43A, Bottom lines, SUMS (as opposed to BUMS), crossing with 43D, It's not a good look, SNEER (as opposed to his original guess, based of suspension of disbelief and the basics of spelling, BLEER).
We weren't quite PASTED by Nam Jin Yoon's Saturday spectacular, but it definitely took a while for us to GETGOING on this one, as there were a lot of tricky (and fascinating) clues. The winner in that category was surely 32D, Amphibian that Ogden Nash once rhymed with "bottle", AXOLOTL, with honorable mention going to 19D, Holding up the line for?, CUING. There were quite a few new-to-us names -- 46D, Actress Rowlands, GENA, 19A, "Between the World and Me" author, 2015, COATES, and 34D, Milan _______, author of 1984's "The Unbearable Lightness of Being", KUNDERA. So it definitely took a bit of ROCKETSCIENCE to get through today's puzzle, and if you did, well -- MOREPOWERTOYOU!
A few challenges for the spelling-challenged -- DIDGERIDOO and MATZOH, to name two -- but other than that, ITLLDO (quite WELL, in fact). It did feature Jean's favorite musketeer, ARAMIS, as well as Mike's favorite prime minister, PIERRE (48D, Justin Trudeau's father). There was also a (possibly intentional) acoustical tie-in to yesterday's crossword -- that featured 48A, Wished (BADE), whereas today's included the clue 32D, Sounded like sheep (BAAED).Tomorrow is Tip Tuesday, and remember, if you have some tips that you'd like to share with our burgeoning listening audience, drop us a line at crosswordpodcast@icloud.com.
Evangelho – João 3,31-36 Proclamação do evangelho de Jesus Cristo segundo João – 31“Aquele que vem do alto está acima de todos. O que é da terra pertence à terra e fala das coisas da terra. Aquele que vem do céu está acima de todos. 32Dá testemunho daquilo que viu e ouviu, mas ninguém aceita o seu testemunho. 33Quem aceita o seu testemunho atesta que Deus é verdadeiro. 34De fato, aquele que Deus enviou fala as palavras de Deus, porque Deus lhe dá o Espírito sem medida. 35O Pai ama o Filho e entregou tudo em sua mão. 36Aquele que acredita no Filho possui a vida eterna. Aquele, porém, que rejeita o Filho não verá a vida, pois a ira de Deus permanece sobre ele”. – Palavra da salvação.
32D الحديد تفسیر 29-26
Gestern der Post bei Facebook mit dem Aufruf, dass die Freaks aufstehen sollen und sich outen. (Der Text geht sowas von durch die Decke, dass ich mit dem Staunen nicht mehr hinterher komme!!!!) Heute das erste Interview mit einem dieser "Freaks". ;) Auf eigenen Wunsch, wohlgemerkt! Wow! Maja Siebel - so oft hab ich sie schon in meinen Texten markiert und hier erwähnt. Eine Soulsister, einer meiner Sparringspartner in Sachen Bewusstseinsforschung und -erweiterung, ein Ruhepol in diesen aufgewühlten Zeiten, ein Fels in der Brandung. Maja ist nicht 5D, Maja ist 32D! ;) Das war bei Weitem nicht immer so. Mit 19 Jahren die erste Psychose, nie so wirklich reingepasst in diese Welt, nie angekommen im Arbeitsleben, Psychopharmaka als Dauerlösung verordnet bekommen und immer das Gefühl, falsch zu sein. Doch das Leben musste mehr zu bieten haben, als das. Sie machte sich auf den eigenen Weg, auf die eigene Suche nach sich selbst und ihrer Wahrheit. Und ist fündig geworden. Heimat in sich selbst. Tiefer Frieden und eine Anbindung an die göttliche Quelle. Heute ahnt sie immer mehr, dass ihre Wahrnehmungen in Psychosen wundervolle Einweihungen waren, Vermittlung von spirituellem Wissen. Sie erzählt uns ihre Geschichte und glaubt mir, das ist erst der Anfang. ;) Dieser Leuchtturm wird immer heller leuchten und gaaaaanz weit sichtbar sein. ♥ Maja, ich liebe dich so sehr und bin einfach nur arschfroh, dass wir uns gefunden haben!!!!! #freakouting #herzradikal #majasiebel #anjareiche #leuchtturm #bigshift #allin #neuewelt #vompsychozumfelsinderbrandung
Prästen Berth Löndahl och jag samtalar om evangeliet, om att öppna oss för Gud, om Jesu ande och skaparkraften i det levande ordet. Vi talar om att vara öppen för att lyssna till Gud, vara mottagare av den helige ande och låta Gud lägga orden i munnen på oss.Dagens text:Sedan lämnade han trakten kring Tyros och gick över Sidon till Galileiska sjön, i Dekapolisområdet. 32Där kom de till honom med en man som var döv och knappt kunde tala, och de bad Jesus lägga sin hand på honom. 33Han tog honom avsides från folket och stack fingrarna i hans öron och spottade och rörde vid hans tunga. 34Sedan såg han upp mot himlen, andades djupt och sade till honom: ”Effata!” (det betyder: Öppna dig!). 35Med ens öppnades mannens öron och hans tunga löstes och han talade riktigt. 36Jesus förbjöd dem att berätta det för någon. Men ju mer han förbjöd dem, desto ivrigare spred de ut det. 37Och alla blev överväldigade och sade: ”Allt han har gjort är bra: de döva får han att höra och de stumma att tala.”Mark /.31-37 (Bibel 2000)Marie Ek Lipanovska, författare och illustratörhttp://www.marieeklipanovska.se
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 05/19
The BCR/ABL1 fusion protein is found in virtually all cases chronic myeloid leukemia (CML) and a large proportion of acute lymphoblastic leukemia (ALL). The fact that the BCR/ABL1 fusion protein is crucial for the development of leukemia makes this fusion protein an attractive target for therapy development. We have developed a strategy for the in vivo detection of the BCR/ABL1 fusion protein, in which the presence of the BCR/ABL1 fusion protein is detected intracellularly and if the fusion protein is present an arbitrary action is initiated in the cell (e.g. mark the cells or selectively kill the cells). Our BCR/ABL1 detection strategy is based on protein-protein interactions. Two detection proteins are expressed in the cells: 1) protein A, a GAL4-DNA binding domain/BCR interacting protein fusion protein (GAL4DBD-BAP-1) and 2) protein B, a GAL4-activation domain/ABL interacting protein fusion protein (GAL4AD-CRKL). Only when BCR/ABL1 is present in the cell, do protein A, protein B, and BCR/ABL1 form a trimeric complex which activates the transcription of reporter genes under the control of GAL4-upstream activating sequence (UAS). A proof of principle for the strategy was implemented in the yeast system. We did not use full length BAP-1 or CRKL but only those portions of the proteins that directly interacted with BCR or ABL, respectively. We showed in the yeast two hybrid system, that the C-terminus of BAP-1(amino acids 617-879) binds to full length BCR. The site of interaction of CRKL and ABL was confirmed to be the N-terminal SH3 domain (SH3n) of CRKL as described in the literature. Yeast cells (strain CG1945) transformed with a protein A expressing plasmid (pGBT9-BAP), a protein B expressing plasmid (pGAD424-CRKLSH3n), and a BCR/ABL expressing plasmid (pES1/BCR-ABL) showed expression of the reporter genes HIS3 and LACZ. The expression of the HIS3 reporter gene was assayed by growth of the yeast cells on medium lacking histidine. The expression of the LACZ gene was verified by a beta-galactosidase filter assay. Yeast cells that were transformed with the pES1 plasmid without the BCR/ABL1 coding region did not show activation of the reporter genes. Several other negative controls demonstrated the specificity of the assay. Thus the method was able to clearly distinguish between BCR/ABL expressing cells and cells did not express BCR/ABL1. We then adapted this system for use in mammalian cells. The open-reading frames encoding the proteins A and B were recloned into mammalian expression vectors. The human embryonal kidney cell line HEK293 and the murine myeloid progenitor cell line 32D which had been stably transfected with a BCR/ABL expressing plasmid were tested. The firefly luciferase gene and the yellow fluorescent protein (eYFP) were used to evaluate the whole cell population and single cell, respectively. Unfortunately, the system failed to work in the mammalian cell lines tested. Even though the detection system did not work in mammalian cells, most likely due to the cytoplasmic localization of the BCR/ABL1 fusion protein, it should still be a viable strategy for the detection of leukemia-associated fusion protein, which localize to the nucleus (i.e AML-ETO). This strategy could be adapted for purging the bone marrow of leukemia patients using therapeutically more useful effector genes like suicide genes, which encode pro-drug converting enzymes (e.g. HSV thymidine kinase), or markers that can easily be assayed (e.g. YFP).
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 04/19
Zelllinienentscheidungen in der Hämatopoese werden eingeleitet und sind abhängig von der Aktivierung von Transkriptionsfaktoren. Es ist allerdings bisher nicht geklärt, ob die initiale Aktivierung früher hämatopoetischer Transkriptionsfaktoren durch bisher unbekannte extrinsische Signale oder durch ein zellinternes autonomes Programm erfolgt. Notch Rezeptoren sind evolutionär hoch konservierte Transmembranrezeptoren, die an der Regulation von Zelllinienentscheidungen, Differenzierung und Proliferation in verschiedenen embryonalen und adulten Geweben beteiligt sind. Die Expression von Notch Rezeptoren auf hämatopoetischen Zellen und der dazugehörigen Liganden wie Jagged1 auf Knochenmarksstromazellen deutet auf eine Bedeutung von Notch in der Regulation der Hämatopoese. Vor Kurzem konnte die Induktion der myeloischen Differenzierung von hämatopoetischen Stamm- und Vorläuferzellen durch Notch nachgewiesen werden. Die molekularen Mechanismen dieses Prozesses sind dabei noch völlig unklar. Darin Einblick zu gewinnen wurde im Rahmen dieser Doktorarbeit durch die Suche nach Zielgenen von Notch in der Myelopoese versucht. Dazu wurden die multipotente myeloische Stammzelllinie FDCP-mix und die granulozytäre Vorläuferzelllinie 32D mit einem durch Tamoxifen aktivierbarem Notch als Zellsysteme gewählt. In dieser Arbeit durchgeführte zytokingesteuerte Differenzierungskinetiken konnten bestätigen, dass die verwendeten FDCP-mix Zellen während ihrer Differenzierung in reife Granulozyten, Makrophagen und Erythrozyten auf RNA-Ebene charakteristische Regulationen von wichtigen myeloischen Transkriptionsfaktoren, Zytokinrezeptoren sowie differenzierungsabhängigen Funktionsproteinen durchlaufen. Sie stellen somit ein optimales Zellsystem zur Analyse von Notch-Zielgenen in der Myelopoese dar. Mit dem Tamoxifen induzierbaren System der Notchaktivierung wurden zuerst bekannte, zentrale Regulationsfaktoren der Myelopoese auf eine Induktion durch Notch im Northern Blot untersucht. Dabei stellte sich als entscheidendes Ergebnis sowohl in 32D als auch FDCP-mix Zellen die direkte, spezifische Induktion des frühen myeloischen Transkriptionsfaktors PU.1 heraus, von dem bekannt ist, dass er myeloische Differenzierung initiiert. Außerdem kam es zu einer indirekten Hochregulation des M-CSF-Rezeptors, der als wichtiges Zielgen von PU.1 bekannt ist. Diese Ergebnisse zeigen, dass ein extrinsisches Signal, im Organismus durch den Jagged / Notch Signalweg vermittelt, zu einer Aktivierung eines frühen hämatopoetischen Transkriptionsfaktors führt, welcher Zelllinienentscheidungen in der Hämatopoese bestimmt. In Zusammenschau mit den biologischen Wirkungen von Notch in der Hämatopoese weist dies darauf hin, dass extrinsische Mechanismen eine wichtige Rolle in der Regulation der Hämatopoese spielen dürften. Durch ein neu zu etablierendes cDNA-Filter (cDNA-Microarray) Screening-Verfahren konnten dann als weitere wichtige Zielgene von Notch in der Hämatopoese u.a. der Interferon Regulatory Factor-1 (IRF-1), der Interleukin1-Rezeptor-Antagonist (IL1RA), der Tumornekrosefaktor-Rezeptor 2 (TNFR2), sowie c-myc und myb identifiziert werden.
Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06
Flt3 is the most recently discovered member of the platelet-derived growth factor receptor (PDGFR) subfamily of receptor tyrosine kinases (RTKs). It is expressed on early hematopoietic progenitor cells and is involved in their growth. Activating mutations of Flt3, such as internal tandem duplications (ITD) in the juxtamembrane (JM) region of Flt3, are among the most common genetic alterations found in patients with acute myeloid leukemia (AML). For this reason Flt3 is an attractive target for specific tyrosine kinase inhibitors, and a number of such compounds are currently being tested in clinical trials. However, the mechanisms of Flt3-mediated signal transduction are poorly understood. Src family tyrosine kinases (SFKs) are involved in the signaling processes of various RTKs, including those of the PDGFR subfamily . Most SFKs are expressed predominantly or exclusively in hematopoietic cells, and at least Hck and Lyn were found to be activated in AML patients. These observations indicate that SFKs could also be involved in Flt3 signaling. In this work the role of SFKs in signal transduction of the Flt3 receptor was investigated. A panel of Hck and Flt3 mutants was used in biochemical and biological assays to deduce the contribution of kinase activity, SH2 and SH3 binding domains and tyrosine phosphorylation status to Flt3-SFK interaction. The work presented shows that SFKs interfere with the maturation of wild type and Flt3 ITD receptors in human embryonic kidney 293 (HEK- 293) cells in a kinase-dependent manner. The SFK-mediated effect on receptor maturation is reflected by accumulation of the immature, intracellular form of Flt3 at the expense of the mature, plasma membrane-inserted form of the receptor. This effect of SFK kinase activity on receptor maturation is not limited to Flt3, because analogous results were also obtained for the Kit receptor, another member of the PDGFR subfamily. The demonstration of the role of SFKs in regulation of receptor maturation is novel and the exact mechanism underlying this effect requires further investigation. Using the HEK-293 cells it was also shown that Hck is able to phosphorylate Flt3 on tyrosine residues and to associate with autophosphorylated Flt3 in an SH2 domain-dependent manner. Hck-mediated tyrosine phosphorylation occurs in the JM region of Flt3. Tyrosine residues 589 and 591 in the JM region, when phosphorylated, were also identified as the docking sites for Hck. Although Hck phosphorylation and binding sites on Flt3 overlap, Hck-mediated phosphorylation of Flt3 is not sufficient for Flt3-Hck association. In contrast to the situation in HEK-293 cells, Hck neither interferes with Flt3 maturation nor phosphorylates Flt3 on tyrosine residues, and does not detectably associate with the Flt3 receptor in the hematopoietic murine cell line 32D clone 3 (32D cl.3). However, the level of the ectopic expression of Hck in 32D cl.3 cells was lower than in HEK-293 cells. This difference in Hck expression level probably accounts for both the lack of the Hck-mediated phosphorylation of Flt3 and the interference with its maturation in 32D cl.3 cells. The lower Hck expression level, however, does not account for the lack of detectable association of Hck with Flt3 in 32D cl.3 cells. Using biological assays in which activation of Flt3 can partially overcome the requirement for cytokine stimulation in 32D cl.3 survival and proliferation, it was shown that Hck is not involved in Flt3 signal transduction leading to Flt3-mediated cell survival and Flt3 ITD-dependent cell growth. Therefore, biological relevance of SFKs in Flt3 signaling remains unclear. In summary, although the binding and phosphorylation of Flt3 by Hck can be shown, the biological relevance of Hck in Flt3 signaling remains to be formally demonstrated. This research led to the novel finding that, at least when over-expressed or hyperactivated, SFKs interfere with the maturation process of RTKs. Various studies have shown that the ligandindependent activation of RTKs as well as their premature phosphorylation can interfere with maturation of RTKs. This study reveals that, by virtue of their phosphorylating of Flt3, Kit and possibly other RTKs, SFKs can regulate maturation of these RTKs and consequently alter their transport to the plasma membrane. Further studies are required to investigate the biological relevance of this function of SFKs.