Zeitschriftenartikel: „CNOT3“

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Mittal, Saloni, Akhmed Aslam, Rachel Doidge, Rachel Medica und G. Sebastiaan Winkler. „The Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the human Ccr4–Not complex contribute to the prevention of cell death and senescence“. Molecular Biology of the Cell 22, Nr. 6 (15.03.2011): 748–58. http://dx.doi.org/10.1091/mbc.e10-11-0898.

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A key step in cytoplasmic mRNA degradation is the shortening of the poly(A) tail, which involves several deadenylase enzymes. Relatively little is known about the importance of these enzymes for the cellular physiology. Here we focused on the role of the highly similar Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the Ccr4–Not complex. In addition to a role in cell proliferation, Ccr4a and Ccr4b play a role in cell survival, in contrast to the Caf1a (CNOT7) and Caf1b (CNOT8) deadenylase subunits or the CNOT1 and CNOT3 noncatalytic subunits of the Ccr4–Not complex. Underscoring the differential contributions of the deadenylase subunits, we found that knockdown of Caf1a/Caf1b or Ccr4a/Ccr4b differentially affects the formation of cytoplasmic foci by processing-body components. Furthermore, we demonstrated that the amino-terminal leucine-rich repeat (LRR) domain of Ccr4b influenced its subcellular localization but was not required for the deadenylase activity of Ccr4b. Moreover, overexpression of Ccr4b lacking the LRR domain interfered with cell cycle progression but not with cell viability. Finally, gene expression profiling indicated that distinct gene sets are regulated by Caf1a/Caf1b and Ccr4a/Ccr4b and identified Ccr4a/Ccr4b as a key regulator of insulin-like growth factor–binding protein 5, which mediates cell cycle arrest and senescence via a p53-dependent pathway.

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Elmén, Lisa, Claudia B. Volpato, Anaïs Kervadec, Santiago Pineda, Sreehari Kalvakuri, Nakissa N. Alayari, Luisa Foco et al. „Silencing of CCR4-NOT complex subunits affects heart structure and function“. Disease Models & Mechanisms 13, Nr. 7 (29.05.2020): dmm044727. http://dx.doi.org/10.1242/dmm.044727.

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ABSTRACTThe identification of genetic variants that predispose individuals to cardiovascular disease and a better understanding of their targets would be highly advantageous. Genome-wide association studies have identified variants that associate with QT-interval length (a measure of myocardial repolarization). Three of the strongest associating variants (single-nucleotide polymorphisms) are located in the putative promotor region of CNOT1, a gene encoding the central CNOT1 subunit of CCR4-NOT: a multifunctional, conserved complex regulating gene expression and mRNA stability and turnover. We isolated the minimum fragment of the CNOT1 promoter containing all three variants from individuals homozygous for the QT risk alleles and demonstrated that the haplotype associating with longer QT interval caused reduced reporter expression in a cardiac cell line, suggesting that reduced CNOT1 expression might contribute to abnormal QT intervals. Systematic siRNA-mediated knockdown of CCR4-NOT components in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) revealed that silencing CNOT1 and other CCR4-NOT genes reduced their proliferative capacity. Silencing CNOT7 also shortened action potential duration. Furthermore, the cardiac-specific knockdown of Drosophila orthologs of CCR4-NOT genes in vivo (CNOT1/Not1 and CNOT7/8/Pop2) was either lethal or resulted in dilated cardiomyopathy, reduced contractility or a propensity for arrhythmia. Silencing CNOT2/Not2, CNOT4/Not4 and CNOT6/6L/twin also affected cardiac chamber size and contractility. Developmental studies suggested that CNOT1/Not1 and CNOT7/8/Pop2 are required during cardiac remodeling from larval to adult stages. To summarize, we have demonstrated how disease-associated genes identified by GWAS can be investigated by combining human cardiomyocyte cell-based and whole-organism in vivo heart models. Our results also suggest a potential link of CNOT1 and CNOT7/8 to QT alterations and further establish a crucial role of the CCR4-NOT complex in heart development and function.This article has an associated First Person interview with the first author of the paper.

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Zheng, Xiaofeng, Raluca Dumitru, Brad L. Lackford, Johannes M. Freudenberg, Ajeet P. Singh, Trevor K. Archer, Raja Jothi und Guang Hu. „Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation“. STEM CELLS 30, Nr. 5 (09.04.2012): 910–22. http://dx.doi.org/10.1002/stem.1070.

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McLenachan, Samuel, Dan Zhang, Janya Grainok, Xiao Zhang, Zhiqin Huang, Shang-Chih Chen, Khine Zaw et al. „Determinants of Disease Penetrance in PRPF31-Associated Retinopathy“. Genes 12, Nr. 10 (28.09.2021): 1542. http://dx.doi.org/10.3390/genes12101542.

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Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

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Banowska, Lidia. „Ironia, cnota i „strach śmieszności”. (Herbert – Norwid)“. Studia Norwidiana 40 (13.09.2022): 37–56. http://dx.doi.org/10.18290/sn2240.2.

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Artykuł dotyczy związku ironii oraz cnoty w poezji Cypriana Norwida oraz Zbigniewa Herberta jako pojęć kluczowych dla twórczości obu autorów i sytuuje się w obszarze badań nad tradycją norwidowską w pisarstwie autora Pana Cogito. Słynny wiersz Herberta Pan Cogito o cnocie zostaje potraktowany jako studium przypadku. Na podstawie interpretacji tego tekstu autorka stawia tezę, iż obrazową matrycą myślenia Herberta o cnocie była wyobraźnia ironiologiczna autora Quidama, a ironia odsłania się jako jedna z możliwych konkretyzacji cnoty. Podstawę dla budowania obrazowych przedstawień obu pojęć stanowią zabiegi personifikacji alegorii, którym nośność i oryginalność zapewnia dekonwencjonalizujący gest równoczesnej antropomorfizacji, prowadzący do ironizacji w ujęciu obu kobiecych bohaterek. Ważnym wątkiem rozważań jest związek między cnotą i ironią sytuowany w perspektywie kulturowej. Rodzaj relacji między obu pojęciami dobrze oddaje metafora siostrzeństwa: ironia jako siostra prawdy jest zarazem siostrą cnoty. Cnota jako aksjologiczna pamięć kultury warunkuje cywilizacyjny postęp; ironia sytuacji diagnozowanej przez obu twórców polega na odwróceniu znaczeń i wartości, w którym pod pręgierzem drwiny odrzucane jest to, co jedynie gwarantuje rozwój, a pojawiający się w związku z tym lęk przed wyśmianiem wywołuje u większości niechęć do praktykowania cnót – paradoksalnie uniemożliwiając rozwój. Związek między cnotą a ironią polega zatem tutaj na ujawnianiu niewłaściwości takiego biegu spraw; ironia odsłania się tym samym jako odpowiedź na nie-cnotę czasów i ludzi czasy te współtworzących, w degeneracji których istotnym czynnikiem okazuje się odrzucenie „myślenia według wartości”. Tym samym najgłębsza wartość związku obu omawianych pojęć zdaje się polegać na próbie przywrócenia aksjologicznego ładu.

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Díaz-Peña, Roberto, Ana M. Aransay, Beatriz Suárez-Álvarez, Jacome Bruges-Armas, Naiara Rodríguez-Ezpeleta, María Regueiro, Fernando M. Pimentel-Santos et al. „A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis“. Annals of the Rheumatic Diseases 71, Nr. 5 (31.01.2012): 714–17. http://dx.doi.org/10.1136/annrheumdis-2011-200661.

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ObjectiveTo identify genomic variants in the 19q13 chromosome region associated with ankylosing spondylitis (AS) in human leucocyte antigen (HLA)-B27-positive populations.MethodsHigh-throughput genotyping of 1536 haplotype-tag single nucleotide polymorphisms (SNPs) was performed in 249 patients with AS and 302 healthy controls. Some of the identified associations were validated by genotyping four SNPs in two additional cohorts consisting of 412 cases/301 controls and 144 cases/203 controls. All individuals selected (both cases and controls) were HLA-B27-positive.ResultsTwo markers in two different genes (CNOT3 and LAIR2) showed significant association (p<10−3) with AS. In addition, sliding windows analysis showed association of groups of adjacent SNPs in regions located around CNOT3 (Chr19: 59347459-59356564, p=2.43×10−4 to 6.54×10−4). The associations were validated by genotyping four SNPs from regions located near LAIR2 and CNOT3 genes (rs1055234, rs8111398, rs2287828 and rs4591276) in two additional cohorts. The CNOT3 polymorphism (rs1055234) remained associated with AS (combined p=9.73×10−6). One SNP, located downstream of KIR3DL1, was detected which, tested in combination with HLA-Bw4I80, was associated with AS.ConclusionA novel significant association was detected between SNP rs1055234 and AS susceptibility.

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Szram, Mariusz. „Can humility exist without poverty? A response by Cappadocian Fathers and John Chrysostom“. Vox Patrum 62 (04.09.2014): 505–10. http://dx.doi.org/10.31743/vp.3599.

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Greccy Ojcowie Kościoła IV w. uznawali zgodnie cnotę pokory za punkt wyjścia na drodze duchowego doskonalenia oraz za matkę wszystkich cnót. W duchu rozwijającego się monastycyzmu podkreślali przede wszystkim ścisły związek pokory z posłuszeństwem jako cnotą najbardziej jej pokrewną. Autor artykułu stara się znaleźć odpowiedź na pytanie, w jaki sposób postrzegali oni relację między pokorą i ubóstwem, mającą głęboką tradycję biblijną. Już w Starym Testamencie ludzie ubodzy (ptoco…) jako znajdujący się w potrzebie byli uważani za szczególnie skromnych i otwartych na pokorne szukanie pomocy u Boga i drugiego człowieka. Ojcowie Kapadoccy i Jan Chryzostom definiowali cnotę pokory jako przypisywanie wszelkiej chwały za dokonane dobre czyny samemu Bogu i niewywyższanie się ponad innych ludzi, nawet największych grzeszników. Zagadnienie związku ubóstwa z tak rozumianą pokorą poruszali komentując przede wszystkim pierwsze z ośmiu błogosławieństw Chrystusa na górze. Z analiz homilii poświęconych tej kwestii przez Grzegorza z Nyssy i Jana Chryzostoma wynikają następujące wnioski: (1) istnieją dwa rodzaje ubóstwa: duchowe i materialne, które są od siebie zależne; (2) istnieje także tzw. „złe ubóstwo”, które oznacza brak podstawowych cnót; jest ono przeszkodą do osiągnięcia cnoty pokory; (3) ubóstwo materialne ułatwia postawę pokory, ale nie wystarcza do osiągnięcia tej cnoty; (4) cnota pokory jest natomiast niemożliwa bez ubóstwa duchowego, które otwiera na Boga; (5) ludzie ubodzy w duchu, których dotyczy pierwsze błogosławieństwo, są synonimem ludzi pokornych.

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Inoue, Takeshi, Masahiro Morita, Atsushi Hijikata, Yoko Fukuda-Yuzawa, Shungo Adachi, Kyoichi Isono, Tomokatsu Ikawa et al. „CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability“. Journal of Experimental Medicine 212, Nr. 9 (03.08.2015): 1465–79. http://dx.doi.org/10.1084/jem.20150384.

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The CCR4–NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre–B cell transition. CNOT3 regulated generation of germline transcripts in the VH region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre-rearranged Igh transgene. Thus, our data suggest that the CCR4–NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA.

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Rodriguez-Gil, Alfonso, Olesja Ritter, Juliane Hornung, Hilda Stekman, Marcus Krüger, Thomas Braun, Elisabeth Kremmer, Michael Kracht und M. Lienhard Schmitz. „HIPK family kinases bind and regulate the function of the CCR4-NOT complex“. Molecular Biology of the Cell 27, Nr. 12 (15.06.2016): 1969–80. http://dx.doi.org/10.1091/mbc.e15-09-0629.

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The serine/threonine kinase HIPK2 functions as a regulator of developmental processes and as a signal integrator of a wide variety of stress signals, such as DNA damage, hypoxia, and reactive oxygen intermediates. Because the kinase is generated in a constitutively active form, its expression levels are restricted by a variety of different mechanisms. Here we identify the CCR4-NOT complex as a new regulator of HIPK2 abundance. Down-regulation or knockout of the CCR4-NOT complex member CNOT2 leads to reduced HIPK2 protein levels without affecting the expression level of HIPK1 or HIPK3. A fraction of all HIPK family members associates with the CCR4-NOT components CNOT2 and CNOT3. HIPKs also phosphorylate the CCR4-NOT complex, a feature that is shared with their yeast progenitor kinase, YAK1. Functional assays reveal that HIPK2 and HIPK1 restrict CNOT2-dependent mRNA decay. HIPKs are well known regulators of transcription, but the mutual regulation between CCR4-NOT and HIPKs extends the regulatory potential of these kinases by enabling posttranscriptional gene regulation.

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Głąb, Anna. „Cnota, charakter, dobroć. W nawiązaniu do powieści autobiograficznej Raimonda Gaity Mój ojciec Romulus“. Roczniki Filozoficzne 68, Nr. 1 (30.03.2020): 49–75. http://dx.doi.org/10.18290/rf20681-3.

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Przedmiotem tekstu jest rozróżnienie między dobrocią i cnotą oraz złem i występkiem, wprowadzone przez Hannah Arendt na podstawie lektury powieści Hermanna Melville’a Billy Budd. Rozróżnienie to analizuję, odnosząc się do historii życia Romulusa Gaity, bohatera powieści autobiograficznej Mój ojciec Romulus, której autorem jest australijski etyk Raimond Gaita. W paragrafie 1 zajmuję się ową dystynkcją, wskazując na przewartościowanie takich pojęć, jak cnota i występek w powieści Melville’a oraz jego rozumienie cnoty. Następnie (paragraf 2) staram się odpowiedzieć na pytanie, dlaczego Gaita pisze o swym ojcu, używając kategorii charakteru, a nie cnoty. Dalej (paragraf 3) podejmuję refleksję nad relacją między cnotą, charakterem, dobrocią a chorobą psychiczną Romulusa. Na koniec (paragraf 4) odpowiadam na pytanie, jaki jest metafizyczny fundament, na którym Gaita formułuje przekonanie o wyższości Dobra i dobroci nad cnotą oraz pokazuję, jakie konkrety składają się na przyjmowaną przez Romulusa etykę dobroci.

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Kaur, Ishwinder, Gopal P. Jadhav, Peter M. Fischer und Gerlof Sebastiaan Winkler. „The Discovery of Substituted 5-(2-Hydroxybenzoyl)-2-Pyridone Analogues as Inhibitors of the Human Caf1/CNOT7 Ribonuclease“. Molecules 29, Nr. 18 (13.09.2024): 4351. http://dx.doi.org/10.3390/molecules29184351.

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The Caf1/CNOT7 nuclease is a catalytic component of the Ccr4-Not deadenylase complex, which is a key regulator of post-transcriptional gene regulation. In addition to providing catalytic activity, Caf1/CNOT7 and its paralogue Caf1/CNOT8 also contribute a structural function by mediating interactions between the large, non-catalytic subunit CNOT1, which forms the backbone of the Ccr4-Not complex and the second nuclease subunit Ccr4 (CNOT6/CNOT6L). To facilitate investigations into the role of Caf1/CNOT7 in gene regulation, we aimed to discover and develop non-nucleoside inhibitors of the enzyme. Here, we disclose that the tri-substituted 2-pyridone compound 5-(5-bromo-2-hydroxy-benzoyl)-1-(4-chloro-2-methoxy-5-methyl-phenyl)-2-oxo-pyridine-3-carbonitrile is an inhibitor of the Caf1/CNOT7 nuclease. Using a fluorescence-based nuclease assay, the activity of 16 structural analogues was determined, which predominantly explored substituents on the 1-phenyl group. While no compound with higher potency was identified among this set of structural analogues, the lowest potency was observed with the analogue lacking substituents on the 1-phenyl group. This indicates that substituents on the 1-phenyl group contribute significantly to binding. To identify possible binding modes of the inhibitors, molecular docking was carried out. This analysis suggested that the binding modes of the five most potent inhibitors may display similar conformations upon binding active site residues. Possible interactions include π-π interactions with His225, hydrogen bonding with the backbone of Phe43 and Van der Waals interactions with His225, Leu209, Leu112 and Leu115.

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Zheng, Xiaofeng, Pengyi Yang, Brad Lackford, Brian D. Bennett, Li Wang, Hui Li, Yu Wang et al. „CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State“. Stem Cell Reports 7, Nr. 5 (November 2016): 897–910. http://dx.doi.org/10.1016/j.stemcr.2016.09.007.

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Abui, Abui Abraham. „The Vices against the Virtue of Temperance among the Atyap Cultural Heritage of Africa: A Philosophical Approach“. Roczniki Kulturoznawcze 10, Nr. 4 (23.06.2020): 161–77. http://dx.doi.org/10.18290/rkult.2019.10.4-8.

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Wady odpowiadające cnocie umiarkowania w kulturowym dziedzictwie szczepu Atyap: podejście filozoficzne W dyskursie moralnym cnoty wciąż zajmują centralne miejsce. Dzieje się tak, ponieważ dyskusje o moralności obracają się wokół pojęć cnoty i wady. Bierze się za pewnik, że wynikiem cnót są czyny dobre moralnie, natomiast wady prowadzą do czynów złych, powszechnie potępianych. Etycy cnót opierają swoje argumenty na założeniu, że czyny ludzkie są bezpośrednio połączone bądź to z cnotą, bądź z wadą. Każdej cnocie odpowiada nadmiar lub deficyt, którego przekroczenie wiąże się z przeciwną jej moralną dyspozycją, nazywaną wadą. W takim wypadku, powinna istnieć jakaś ustalona miara, na której podstawie rozróżniamy między cnotą a wadą. Jakie kryteria obowiązują w przypadku ustalania takiej miary? Co więcej, istnieje tradycyjny podział cnót na kardynalne i poboczne: jakie dokładnie cechy moralne winna mieć cnota, by być określona jako kardynalna? W artykule autor podejmuje próbę analizy jednej z tak zwanych cnót kardynalnych, mianowicie umiarkowania. Szczególny nacisk został położony na pojęciach wstydu i honoru, rozumianych w duchu dziedzictwa kulturowego szczepu Atyap. Celem autora jest znalezienie tych cech, które odpowiadają za ustanowienie umiarkowania cnotą kardynalną oraz podjęcie próby wyznaczenia miary, która odpowiada za wady związane z pojęciem umiarkowania.

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Manuela, Priolo, Radio Francesca Clementina, Pizzi Simone, Pintomalli Letizia, Pantaleoni Francesca, Mancini Cecilia, Cordeddu Viviana et al. „Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype“. Genes 12, Nr. 7 (30.06.2021): 1009. http://dx.doi.org/10.3390/genes12071009.

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Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.

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Cejas, Paloma, Alessia Cavazza, C. N. Yandava, Victor Moreno, David Horst, Juan Moreno-Rubio, Emilio Burgos et al. „Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype“. Cancer Research 77, Nr. 3 (29.11.2016): 766–79. http://dx.doi.org/10.1158/0008-5472.can-16-1346.

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Watanabe, C., M. Morita, T. Hayata, T. Nakamoto, C. Kikuguchi, X. Li, Y. Kobayashi et al. „Stability of mRNA influences osteoporotic bone mass via CNOT3“. Proceedings of the National Academy of Sciences 111, Nr. 7 (03.02.2014): 2692–97. http://dx.doi.org/10.1073/pnas.1316932111.

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Kieliszek, Zdzisław. „Męstwo a świętość“. Studia Warmińskie 49 (31.12.2012): 9–22. http://dx.doi.org/10.31648/sw.250.

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W artykule Męstwo a świętość autor, zainspirowany hasłem X Dnia Papieskiego „Odwaga świętości”, który był obchodzony w Polsce 10 października 2010 r., próbuje określić relację pomiędzy cnotą męstwa a świętością. W pierwszej części rozważań analizie poddana zostaje cnota męstwa. Zostaje ona ukazana jako cierpliwe, wytrwałe i ufne stawienie oporu złu, oraz długomyślne i wielkoduszne dążenie do prawdy, dobra i piękna. Część druga jest poświęcona refleksji nad świętością. W świetle prowadzonych badań jawi się ona jako wartość, którą człowiek realizuje, dążąc do doskonałości. W ostatniej części zostają wskazane punkty, w których cnota męstwa i dążenie człowieka do doskonałości wiążą się ze sobą. Na podstawie przeprowadzonych analiz autor dochodzi do przekonania, że kształtowanie w sobie przez człowieka cnoty męstwa należy uznać za strukturalnie konstytutywną część realizowania przez człowieka wartości świętości.

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Eskandarian, Samira, Roger J. Grand, Shiva Irani, Mohsen Saeedi und Reza Mirfakhraie. „Depletion of CNOT4 modulates the DNA damage responses following ionizing radiation (IR)“. Journal of Cancer Research and Therapeutics 20, Nr. 1 (08.04.2023): 126–32. http://dx.doi.org/10.4103/jcrt.jcrt_1723_22.

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Background: The Ccr4–Not complex (CNOT complex in mammals) is a unique and highly conserved complex with numerous cellular functions. Until now, there has been relatively little known about the importance of the CNOT complex subunits in the DNA damage response (DDR) in mammalian cells. CNOT4 is a subunit of the complex with E3 ubiquitin ligase activity that interacts transiently with the CNOT1 subunit. Here, we attempt to investigate the role of human CNOT4 subunit in the DDR in human cells. Material and Methods: In this study, cell viability in the absence of CNOT4 was assessed using a Cell Titer-Glo Luminescence assay up to 4 days post siRNA transfection. In a further experiment, CNOT4-depleted HeLa cells were exposed to 3Gy ionizing radiation (IR). Ataxia telangiectasia-mutated (ATM) and ATM Rad3-related (ATR) signaling pathways were then investigated by western blotting for phosphorylated substrates. In addition, foci formation of histone 2A family member X (γH2AX), replication protein A (RPA), TP53 binding protein 1 (53BP1), and DNA repair protein RAD51 homolog 1 was also determined by immunofluorescence microscopy comparing control and CNOT4-depleted HeLa cells 0, 8, and 24 h post IR treatment. Results: Our results from cell viability assays showed a significant reduction of cell growth activity at 24 (P value 0.02) and 48 h (P value 0.002) post siRNA. Western blot analysis showed slightly reduced or slightly delayed DDR signaling in CNOT4-depleted HeLa cells after IR. More significantly, we observed increased formation of γH2AX, RPA, 53BP1, and RAD51 foci after IR in CNOT4-depleted cells compared with the control cells. Conclusion: We conclude that depletion of CNOT4 affects various aspects of the cellular response to DNA damage.

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Chang, Nai-Wen, und Yi-Ping Huang. „The RNA degradation pathway is involved in PPARα-modulated anti-oral tumorigenesis“. BioMedicine 9, Nr. 4 (14.11.2019): 27. http://dx.doi.org/10.1051/bmdcn/2019090427.

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Background: The activation of peroxisome proliferator-activated receptor alpha (PPARα) has been shown to reprogram tumor metabolism and exhibits great potential for treating anti-oral tumorigenesis. Methods: In this study, we used a pathway-based strategy to explore possible functional pathways involved in the anticancer activity of PPARα in oral cancer cells through next-generation sequencing (NGS) and bioinformatic approaches. Results: We found that 3919 genes were upregulated and 1060 genes were downregulated through PPARα activation. These genes were mainly involved in the proteasomal, mRNA surveillance, spliceosomal, RNA transport, and RNA degradation pathways, as indicated by GO and KEGG enrichment analysis. Importantly, a total of 13 upregulated genes in the RNA degradation pathway were identified including 3 core exosome factor genes (RRP43, RRP42, and CSL4), 2 TRAMP complex genes (TRF4 and Mtr4), 2 exosome cofactor genes (RRP6 and MPP6), 2 CCR4-NOT complex genes (CNOT2 and CNOT3), 2 Ski complex genes (SKI2 and Ski3), 1 decapping complex gene (EDC4), and 1 gene involved in 5’ exoribonuclease activity (XRN1). Conclusion: Our findings suggest that the activation of PPARα to upregulate the RNA degradation pathway might provide a new strategy for oral cancer treatment.

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Martin, R., M. Splitt, D. Genevieve, E. Aten, A. Collins, C. I. de Bie, L. Faivre et al. „De novo variants in CNOT3 cause a variable neurodevelopmental disorder“. European Journal of Human Genetics 27, Nr. 11 (14.06.2019): 1677–82. http://dx.doi.org/10.1038/s41431-019-0413-6.

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Doidge, Rachel, Saloni Mittal, Akhmed Aslam und G. Sebastiaan Winkler. „Deadenylation of cytoplasmic mRNA by the mammalian Ccr4–Not complex“. Biochemical Society Transactions 40, Nr. 4 (20.07.2012): 896–901. http://dx.doi.org/10.1042/bst20120074.

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The Ccr4–Not complex is one of the major deadenylase factors present in eukaryotic cells. This multi-subunit protein complex is composed of at least seven stably associated subunits in mammalian cells including two enzymatic deadenylase subunits: one DEDD (Asp-Glu-Asp-Asp)-type deadenylase (either CNOT7/human Caf1/Caf1a or CNOT8/human Pop2/Caf1b/Calif) and one EEP (endonuclease–exonuclease–phosphatase)-type enzyme (either CNOT6/human Ccr4/Ccr4a or CNOT6L/human Ccr4-like/Ccr4b). Here, the role of the human Ccr4–Not complex in cytoplasmic deadenylation of mRNA is discussed, including the mechanism of its recruitment to mRNA and the role of the BTG/Tob proteins.

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Seki, Masafumi, Kenichi Yoshida, Yusuke Sato, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Motohiro Kato et al. „Genetic Landscapes Of Childhood T-Cell Acute Lymphoblastic Leukemia“. Blood 122, Nr. 21 (15.11.2013): 3786. http://dx.doi.org/10.1182/blood.v122.21.3786.3786.

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Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Generally, childhood T-ALL patients have a worse prognosis than B cell precursor ALL patients. Recent studies have identified a subtype of T-ALL termed “early T-cell precursor” (ETP) ALL, which is associated with a high risk of treatment failure. In spite of recent improvements of risk stratified multiagent chemotherapy, relapsed patients have a poor prognosis even if they were non-ETP ALL. Recent genome-wide approach revealed frequent NOTCH1 and FBXW7 oncogenic mutations mutations in T-ALL. In addition, previous whole-exome sequencing disclosed novel CNOT3 mutations in approximately 10% of adult T-ALL cases, and thus, CNOT3 was thought to be one of the novel tumor suppressor gene for adult T-ALL. CNOT3 is part of the CCR4-NOT complex that is the major deadenylase of mRNA. NT5C2, encoding a 5ʹ-nucleotidase was identified as relapse specific mutation, of which mutation is associated with the outgrowth of drug-resistant clones in ALL. However, these mutations have been found in a fraction of childhood T-ALL suggests that the existence of other genetic pathogenesis. To discover new oncogenic gene mutations which involved in the pathogenesis of relapsed T-ALL and to identify novel prognostic markers of childhood T-ALL, we performed genome-wide analysis using whole-exome sequencing and 250K SNP array analyses in 8 cases with relapsed T-ALL and 16 cases with non-relapsed T-ALL. The mean coverage in the whole-exome sequencing of tumor and germline samples was 108× and 100× for the 50-Mb target regions, respectively, by which more than 90% of the coding sequences were represented by more than 20 independent reads on average. A mean of nonsilent mutations per sample at presentation was 18, and sample at 1st relapsed was 19. There were only 16 recurrent mutations in 24 cases; however no shared mutation in 8 relapsed cases other than NOTCH1 and FBXW7. NOTCH1 mutations were found in 50% (12/24), and were frequently identified in relapsed cases (6/8). FBXW7 mutations were also frequently found in 6/24 cases, and 60 % (3/6) were compound heterozygous mutations. In those 6 cases, only one case with FBWX7 mutation had a NOTCH1 mutation. CNOT3 mutations were reported to be frequent in adult T-ALL, however we found only two cases with CNOT3 mutations (8.3%). In addition, PHF6 mutation, which is known as X-linked tumor suppressor gene in T-ALL, was recurrent in 3 cases. Other recurrent mutations were shared between 2 cases, respectively. NT5C2 mutation has been reported to a relapse-specific mutation, and we also found NT5C2 mutations in 2 relapsed cases, which detected in only relapsed samples. RPL5 and RPL10 mutations were reported to be found in 10 % of pediatric T-ALL; however there was one mutation in RPL related genes in our study. Furthermore, we found common mutations of acute myeloid leukemia such as TCF7, STAT5A, KIT, RUNX1, and EP300 mutations in a single case. On the other hand, although pediatric T-ALL showed largely normal genomic copy number profiles, homozygous deletions at chromosome 9p21 harboring CDKN2A were frequently detected in our study (17/24 71%). Especially, 9p21 deletions were found in all relapsed cases, suggesting that loss of CDKN2A locus was a critical genetic mechanism of relapsed T-ALL. In conclusion, our results revealed mutations in several known genes, but overall frequency of recurrent somatic mutations in childhood T-ALL is low, even in relapsed samples. Although loss of CDKN2A locus was detected in all relapsed cases, recurrent relapse-specific mutations could not be identified other than NT5C2. These findings suggest that the majority of relapsed T-ALL may be driven by aberrations of CDKN2A and minor clone variants and/or epigenetic modifications during tumor evolution. Disclosures: No relevant conflicts of interest to declare.

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Smółka, Lucyna. „O potrzebie umiaru w kulturze nadmiaru“. Horyzonty Wychowania 19, Nr. 52 (20.10.2020): 35–44. http://dx.doi.org/10.35765/hw.1858.

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CEL NAUKOWY: Celem artykułu jest konceptualizacja cnoty umiarkowania, wskazanie konsekwencji zaniedbania tej sprawności moralnej w kulturze konsumpcji, wyeksponowanie współczesnej etyki cnoty jako perspektywy rozważań nad konsumpcją etyczną. PROBLEM I METODY BADAWCZE: Przedstawiony problem badawczy dotyczy odpowiedzi na pytania: Czym jest umiarkowanie? Jak brak umiaru w kulturze konsumpcyjnej wpływa na życie ludzi? Jakich praktycznych wskazówek w kwestii etycznej konsumpcji może dostarczyć nam współczesna etyka cnót? Zastosowano metodę analityczno-syntetyczną literatury przedmiotu. PROCES WYWODU: Na podstawie opracowań naukowych dokonano charakterystyki cnoty umiarkowania, przedstawiono, jak brak umiaru ujawnia się w społeczeństwie konsumpcyjnym i jakie są tego konsekwencje dla rozwoju człowieka. Wykazano użyteczność etyki cnoty dla refleksji nad kształtowaniem cech odpowiedzialnego konsumenta. WYNIKI ANALIZY NAUKOWEJ: Z przeprowadzonych analiz wynika, że umiarkowanie to cnota kontrowersyjna, nie przez wszystkich akceptowana, mimo jej niewątpliwych walorów. Szczególne niezrozumienie dla niej wykazuje społeczeństwo konsumpcyjne, które płaci za to wysoką cenę. Konieczny jest zwrot ku wartościom, które muszą być urzeczywistniane w konkretnych czynach, czyli działaniach człowieka cnotliwego. WNIOSKI, INNOWACJE, REKOMENDACJE: Każdy, aby móc realizować się w człowieczeństwie, potrzebuje umiarkowania. Kierowanie się nim jest szczególnie trudne w dobie kultury konsumpcyjnej, gdzie cnotą stało się nabywanie i konsumowanie. Warto pomagać, zwłaszcza młodym, zrozumieć zależności między rozwojem własnym a przejawianymi zachowaniami konsumenckimi. Kluczowa jest zwłaszcza praca na swoim charakterem.

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Vattathil, Selina M., Yue Liu, Nadia V. Harerimana, Adriana Lori, Ekaterina S. Gerasimov, Thomas G. Beach, Eric M. Reiman et al. „A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with NTNG1 and CNOT3“. Genes 12, Nr. 6 (26.05.2021): 815. http://dx.doi.org/10.3390/genes12060815.

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Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in NTNG1. The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 (β = −0.27, 95% CI = (−0.35, −0.19), p = 1.29 × 10−10) and rs10881463 (β = −0.20, 95% CI = (−0.27, −0.13), p = 3.40 × 10−8). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4−NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.

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Delacruz, Richard Glenn C., Imelda T. Sandoval, Kyle Chang, Braden N. Miller, Laura Reyes-Uribe, Ester Borras, Patrick M. Lynch et al. „Functional characterization of CNOT3 variants identified in familial adenomatous polyposis adenomas“. Oncotarget 10, Nr. 39 (11.06.2019): 3939–51. http://dx.doi.org/10.18632/oncotarget.27003.

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Takahashi, Akinori, Chisato Kikuguchi, Masahiro Morita, Tetsuhiro Shimodaira, Noriko Tokai-Nishizumi, Kazumasa Yokoyama, Miho Ohsugi, Toru Suzuki und Tadashi Yamamoto. „Involvement of CNOT3 in mitotic progression through inhibition of MAD1 expression“. Biochemical and Biophysical Research Communications 419, Nr. 2 (März 2012): 268–73. http://dx.doi.org/10.1016/j.bbrc.2012.02.007.

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Lv, Jin, Wen-Jie Ming, Yang Zheng, Sha Xu, Gao-Li Fang, Qing Zhang, Yao Ding und Mei-Ping Ding. „A novel pathogenic variant in CNOT3 causing neurodevelopmental delay and epilepsy“. Seizure 107 (April 2023): 104–6. http://dx.doi.org/10.1016/j.seizure.2023.03.022.

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Lisbjerg, Kristian, Karen Grønskov, Mette Bertelsen, Lisbeth Birk Møller und Line Kessel. „Genetic Modifiers of Non-Penetrance and RNA Expression Levels in PRPF31-Associated Retinitis Pigmentosa in a Danish Cohort“. Genes 14, Nr. 2 (08.02.2023): 435. http://dx.doi.org/10.3390/genes14020435.

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(1) Background/aims: To examine potential genetic modifiers of disease penetrance in PRPF31-associated retinitis pigmentosa 11 (RP11). (2) Methods: Blood samples from individuals (n = 37) with PRPF31 variants believed to be disease-causing were used for molecular genetic testing and, in some cases (n = 23), also for mRNA expression analyses. Medical charts were used to establish if individuals were symptomatic (RP) or asymptomatic non-penetrant carriers (NPC). RNA expression levels of PRPF31 and CNOT3 were measured on peripheral whole blood using quantitative real-time PCR normalized to GAPDH. Copy number variation of minisatellite repeat element 1 (MSR1) was performed with DNA fragment analysis. (3) Results: mRNA expression analyses on 22 individuals (17 with RP and 5 non-penetrant carriers) revealed no statistically significant differences in PRPF31 or CNOT3 mRNA expression levels between individuals with RP and non-penetrant carriers. Among 37 individuals, we found that all three carriers of a 4-copy MSR1 sequence on their wild-type (WT) allele were non-penetrant carriers. However, copy number variation of MSR1 is not the sole determinant factor of non-penetrance, as not all non-penetrant carriers carried a 4-copy WT allele. A 4-copy MSR1 mutant allele was not associated with non-penetrance. (4) Conclusions: In this Danish cohort, a 4-copy MSR1 WT allele was associated with non-penetrance of retinitis pigmentosa caused by PRPF31 variants. The level of PRPF31 mRNA expression in peripheral whole blood was not a useful indicator of disease status.

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Seki, Masafumi, Kenichi Yoshida, Shiraishi Yuichi, Kenichi Chiba, Hiroko Tanaka, Motohiro Kato, Ryoji Hanada et al. „Whole Exome and Transcriptome Analyses in Pediatric T-Cell Acute Lymphoblastic Leukemia“. Blood 124, Nr. 21 (06.12.2014): 3527. http://dx.doi.org/10.1182/blood.v124.21.3527.3527.

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Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Recent genome-wide approach revealed frequent NOTCH1 and FBXW7 oncogenic mutations in T-ALL. In addition, previous whole-exome sequencing disclosed novel CNOT3 mutations in approximately 10% of adult T-ALL cases, and thus, CNOT3 is thought to be one of the novel tumor suppressor gene for adult T-ALL. However, somatic mutations in these genes have been found in a fraction of childhood T-ALL, suggesting that the existence of other genetic pathogenesis. Although chromosomal translocations are the most frequent genetic abnormalities detected in other types of leukemia, recurrent translocations except for SIL-TAL1 rearrangement have been poorly defined in T-ALL. To discover driver mutations or fusion genes which involved in the pathogenesis of pediatric T-ALL and to identify novel prognostic markers of childhood T-ALL, we performed whole-exome sequencing (WES) and transcriptome sequencing (WTS) in 25 cases with T-ALL. Diagnostic total DNA from 25 cases and RNA from 15 cases were analyzed for both WES and WTS, and 8 relapsed samples were also analyzed for WES. Median age at diagnosis was 9 years old (1–15), and male to female ratio was 20 to 5. Libraries for WES and WTS were generated using the SureSelect (Agilent) or TruSeq RNA Sample Preparation kit (Illumina), respectively. High throughput sequencing was performed using the Illumina HiSeq 2000 platform. To detect somatic mutations or fusion transcripts, we used our pipeline “Genomon-exome” and “Genomon-fusion” algorithm. Subsequently, somatic mutations were validated using deep amplicon sequencing. Candidate fusion transcripts were validated by reverse - transcription polymerase-chain-reaction (RT-PCR) and Sanger sequencing. Most frequent mutation was NOTCH1, which was detected in 52% (13/25) by WES. FBXW7 mutations were also frequently found in 28% (7/25), and 43 % (3/7) were compound heterozygous mutations. In those 6 cases, only one case with FBWX7 mutation had a NOTCH1 mutation. CNOT3 mutations were reported to be frequent in adult T-ALL; however we found only 2 cases with CNOT3 mutations (8.0%). In addition, PHF6 mutation, which is known as X-linked tumor suppressor gene in T-ALL, was recurrently detected in 4 cases (16%). Other recurrent mutations were shared between 2 cases, respectively. We identified previously known fusion genes, such as MLL-ENL and FGFROP1-FGFR1 in 2 cases. MLL-ENL is one of the frequent translocation for infant multilineage leukemia (MLL), but also reported in non-infant B cell precursor ALL or T-ALL. FGFR1OP is ubiquitously expressed, and the predicted chimeric FGFR1OP-FGFR1 protein contains the catalytic domain of FGFR1. It is thought to be promote hematopoietic stem cell proliferation and leukemogenesis through a constitutive phosphorylation and activation of the downstream pathway of FGFR1. In conclusion, although NOTCH1 and FBXW7 mutations were relatively frequently detected in our series, we could not detect frequent additional mutations in this study. Consistent with other reports, frequent translocations were not observed in T-ALL, suggesting the genetic differences between T-ALL and other hematological malignancies. Further studies will be necessary to unravel oncogenic mechanisms that implicated in new therapeutic strategy for pediatric T-ALL. Disclosures No relevant conflicts of interest to declare.

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Jing, Lin, Meng-En Zhai, Jian Cui, Xin-Yu Fan, Yuan-Yuan Cheng, Jian-Li Jiang und Zhi-Nan Chen. „CNOT3 contributes to cisplatin resistance in lung cancer through inhibiting RIPK3 expression“. Apoptosis 24, Nr. 7-8 (08.06.2019): 673–85. http://dx.doi.org/10.1007/s10495-019-01550-y.

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Pavanello, Lorenzo, Benjamin Hall, Blessing Airhihen und Gerlof Sebastiaan Winkler. „The central region of CNOT1 and CNOT9 stimulates deadenylation by the Ccr4–Not nuclease module“. Biochemical Journal 475, Nr. 21 (09.11.2018): 3437–50. http://dx.doi.org/10.1042/bcj20180456.

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Regulated degradation of cytoplasmic mRNA is important for the accurate execution of gene expression programmes in eukaryotic cells. A key step in this process is the shortening and removal of the mRNA poly(A) tail, which can be achieved by the recruitment of the multi-subunit Ccr4–Not nuclease complex via sequence-specific RNA-binding proteins or the microRNA machinery. The Ccr4–Not complex contains several modules that are attached to its large subunit CNOT1. Modules include the nuclease module, which associates with the MIF4G domain of CNOT1 and contains the catalytic subunits Caf1 and Ccr4, as well as the module containing the non-catalytic CNOT9 subunit, which binds to the DUF3819 domain of CNOT1. To understand the contributions of the individual modules to the activity of the complex, we have started to reconstitute sub-complexes of the human Ccr4–Not complex containing one or several functional modules. Here, we report the reconstitution of a pentameric complex including a BTG2–Caf1–Ccr4 nuclease module, CNOT9 and the central region of CNOT1 encompassing the MIF4G and DUF3819 domains. By comparing the biochemical activities of the pentameric complex and the nuclease module, we conclude that the CNOT1–CNOT9 components stimulate deadenylation by the nuclease module. In addition, we show that a pentameric complex containing the melanoma-associated CNOT9 P131L variant is able to support deadenylation similar to a complex containing the wild-type CNOT9 protein.

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Aslam, Akhmed, Saloni Mittal, Frederic Koch, Jean-Christophe Andrau und G. Sebastiaan Winkler. „The Ccr4–Not Deadenylase Subunits CNOT7 and CNOT8 Have Overlapping Roles and Modulate Cell Proliferation“. Molecular Biology of the Cell 20, Nr. 17 (September 2009): 3840–50. http://dx.doi.org/10.1091/mbc.e09-02-0146.

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Accurate gene expression requires the precise control of mRNA levels, which are determined by the relative rates of nuclear (pre-)mRNA synthesis and processing, and cytoplasmic mRNA turnover. A key step in mRNA degradation is the removal of the poly(A) tail, which involves several deadenylases including components of the Ccr4–Not complex. Here, we focused on the role of the human paralogues CNOT7 (hCaf1/Caf1a) and CNOT8 (hPop2/Caf1b/Calif), which possess deadenylase activity mediated by DEDD nuclease domains. We show that efficient proliferation requires both subunits, although combined knockdown of CNOT7 and CNOT8 further reduces cell proliferation indicating partial redundancy between these proteins. Interestingly, the function of CNOT7 in cell proliferation partly depends on its catalytic activity. On the other hand, the interaction between CNOT7 and BTG2, a member of the antiproliferative BTG/Tob family involved in transcription and mRNA decay appears less important for proliferation of MCF7 cells, suggesting that CNOT7 does not function solely in conjunction with BTG2. Further analysis of gene expression profiles of CNOT7 and/or CNOT8 knockdown cells underscores the partial redundancy between these subunits and suggests that regulation of several genes, including repression of the antiproliferative genes MSMB and PMP22, by the Ccr4–Not complex contributes to cell proliferation.

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Shirai, Yo-Taro, Anna Mizutani, Saori Nishijima, Masafumi Horie, Chisato Kikuguchi, Olga Elisseeva und Tadashi Yamamoto. „CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development“. Oncogene 38, Nr. 14 (10.12.2018): 2580–94. http://dx.doi.org/10.1038/s41388-018-0603-7.

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Venturini, Giulia, Anna M. Rose, Amna Z. Shah, Shomi S. Bhattacharya und Carlo Rivolta. „CNOT3 Is a Modifier of PRPF31 Mutations in Retinitis Pigmentosa with Incomplete Penetrance“. PLoS Genetics 8, Nr. 11 (08.11.2012): e1003040. http://dx.doi.org/10.1371/journal.pgen.1003040.

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Ghashghaei, Maryam, Marty Yue, Aaremish Arsalan, Giuseppe Bombaci, Sandra Spencer Miko, Haya Shaalan, Glenn Edin, Gregg Morin, Fabiana Perna und Ly P. Vu. „RNA Deadenylation Subunit CNOT3 Promotes Myeloid Leukemia By Driving Translation of Oncogenic Targets“. Blood 140, Supplement 1 (15.11.2022): 2962–63. http://dx.doi.org/10.1182/blood-2022-163026.

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Koszkało, Martyna. „Arystoteles, Tomasz z Akwinu, Jan Duns Szkot: Kilka uwag o różnicy między starożytnym i średniowiecznym pojmowaniem cnoty“. Roczniki Filozoficzne 72, Nr. 2 (28.06.2024): 489–510. http://dx.doi.org/10.18290/rf24722.24.

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Artykuł przedstawia grecki ideał człowieka cnotliwego prezentowany w koncepcji Arystotelesa w kontraście do odpowiednika tego ideału obecnego w kulturze chrześcijańskiej (Tomasz z Akwinu, Jan Duns Szkot). Pewne elementy etyki Arystotelesa wzbudzały bowiem kontrowersje, szczególnie elitaryzm oraz model megalópsychos i musiały zostać w etyce chrześcijańskiej przekształcone. Ze względu na nowy model antropologiczny (człowieka jako istoty grzesznej) pojęcie cnoty uległo pewnej modyfikacji zwłaszcza w nurtach woluntarystycznych, gdyż cnotliwy człowiek, mimo posiadania dobrego charakteru, jest w ramach takiej wizji podatny na upadek. Artykuł prezentuje koncepcję relacji przyczynowej między cnotą a wolną wolą, odnosząc się do uwag Tomasza z Akwinu i Jana Dunsa Szkota. Ponieważ nie ma miejsca na libertariańsko pojętą wolną wolę w etyce Arystotelesa jego cnotliwy ideał moralny jest w pewnym sensie ideałem zamkniętym w swojej doskonałości. Różnica pomiędzy perspektywą chrześcijańskiej i greckiej etyki polega na tym, że w etyce chrześcijańskiej podmiotowość realizuje się bardziej w wolnych aktach podmiotu niż w praktycznej racjonalności. Tym samym cnota nie może determinować wolnej woli w sposób, który odbierałby woli liberatriańsko pojętą wolność.

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Vu, Ly, Aaremish Arsalan, Guiseppe Bombaci, Glenn Edin, Lina Garawany, Maryam Ghashghaei, Sandi Miko, Gregg Morin, Fabiana Perna und Marty Yue. „3219 – RNA DEADENYLATION SUBUNIT CNOT3 PROMOTES MYELOID LEUKEMIA BY DRIVING TRANSLATION OF ONCOGENIC TARGETS“. Experimental Hematology 111 (2022): S154. http://dx.doi.org/10.1016/j.exphem.2022.07.275.

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Meyer, Robert, Matthias Begemann, Stephanie Demuth, Florian Kraft, Daniela Dey, Herdit Schüler, Sabine Busse et al. „Inherited cases of CNOT3 ‐associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies“. Clinical Genetics 98, Nr. 4 (19.08.2020): 408–12. http://dx.doi.org/10.1111/cge.13819.

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Celary, Ireneusz. „Pastoraltheologische Vorschläge von Papst Franziskus für Ältere Priester und Ordensleute“. Warszawskie Studia Pastoralne 1, Nr. 34 (01.01.2018): 169. http://dx.doi.org/10.21697/wsp.2017.12.1.34.09.

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Niniejszy artykuł, oparty na analizie nauczania papieża Franciszka, dotyczy sytuacji starszych kapłanów i osób zakonnych w dzisiejszym świecie. Zawiera pastoralno-teologiczne propozycje względem nich. Papież mówił o nich w wielu swoich przemówieniach i innych dokumentach. Czynił to, analizując trzy ewangeliczne cnoty: ubóstwo, bezżeństwo i posłuszeństwo. Publikacja składa się z trzech rozdziałów. Pierwszy zawiera rozważania pa-pieża na temat realizacji cnoty ubóstwa w życiu starszych kapłanów i osób zakonnych. Drugi ukazuje przemyślenia papieża na temat realizacji – w ich posłudze – cnoty bezżeństwa. Trzeci zaś zawiera refleksje związane z cnotą posłuszeństwa w ostatnich latach ich doczesnej egzystencji.

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Łojek, Stanisław. „Kim jest megalopsychos?“ Etyka 40 (01.12.2007): 115–29. http://dx.doi.org/10.14394/etyka.435.

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Celem niniejszego artykułu jest przybliżenie tajemniczej i kontrowersyjnej cnoty megalopsychii („wielkoduszności”), którą Arystoteles opisuje w czwartej księdze Etyki nikomachejskiej. Badając jej rodowód (sięgający ethosu starohelleńskiej szlachty) oraz etyczny kontekst, w jakim może ona mieć doniosłość, staram się wykazać, iż dostarcza ona alternatywnego ujęcia cnoty w porównaniu z jej rozumieniem „klasycznym”. A ponieważ to ostatnie opiera się na metafizycznych założeniach, które w dzisiejszych czasach utraciły wiarygodność, właśnie cnota „wielkoduszności” — odwołująca się do znacznie nam bliższych poglądów na naturę rzeczywistości i naturę ludzką — może okazać się pomocna przy rozważaniu możliwości przywrócenia pojęciu cnoty jej etycznego znaczenia.

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Pinard, Amélie, Stéphanie Guey, Dongchuan Guo, Alana C. Cecchi, Natasha Kharas, Stephanie Wallace, Ellen S. Regalado et al. „The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy“. Genetics in Medicine 22, Nr. 2 (02.09.2019): 427–31. http://dx.doi.org/10.1038/s41436-019-0639-2.

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Braun, Rachel M., Max Ferretti, Jesse Miller, Lauren Castellana, Jae Seung Lee, Kristen W. Lynch und Sara Cherry. „Host mRNA deadenylation machinery selectively targets interferon mRNAs, regulating antiviral immunity“. Journal of Immunology 210, Nr. 1_Supplement (01.05.2023): 236.08. http://dx.doi.org/10.4049/jimmunol.210.supp.236.08.

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Abstract Elucidating host-mediated regulation of viral infection is critical in the development of antivirals and in understanding viral pathogenesis. Here, through high-throughput RNA interference screening, we determine that CNOT2 promotes SARS-CoV-2 infection in human respiratory epithelial cells. CNOT2 is a non-enzymatic subunit of the CCR4-NOT complex, which plays conserved roles in the control of gene expression by deadenylating the poly(A) tails of host mRNAs, thus targeting them for decay. CCR4-NOT can selectively degrade cohorts of mRNAs that are delivered by RNA Binding Proteins. Tristetraprolin (TTP) is among the best characterized of such cargo adapters and is known to recruit mRNAs containing AU-rich elements in their 3′ UTR to CCR4-NOT for deadenylation and decay. We found that in addition to CNOT2, another non-catalytic subunit of CCR4-NOT, CNOT1, in addition to the selectivity factor, TTP, also promote SARS-CoV-2 infection. Global transcriptomics revealed that CNOT2, CNOT1, and TTP specifically regulate interferons (IFNs) and interferon stimulated genes (ISGs) and that depletion of these mRNA decay factors leads to increased levels of IFNs and ISGs. Moreover, the pro-viral activity of CCR4-NOT components and TTP is dependent on IFN signaling: the CCR4-NOT complex has no effect on SARS-CoV-2 infection when IFN signaling is blocked. This led us to discover that CNOT2 promotes the selective deadenylation of IFN mRNAs, and that depletion of CNOT2 leads to increased poly(A) tail lengths of IFN mRNAs. Therefore, we found that the basal levels of IFNs, and thus IFN signaling, are post-transcriptionally regulated by deadenylation machinery, which in turn impacts susceptibility to viral infections including SARS-CoV-2. Supported by grants from NIH (T32-AI-007324)

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Jung, Ji Hoon, Duckgue Lee, Hyun Min Ko und Hyeung-Jin Jang. „Inhibition of CNOT2 Induces Apoptosis via MID1IP1 in Colorectal Cancer Cells by Activating p53“. Biomolecules 11, Nr. 10 (10.10.2021): 1492. http://dx.doi.org/10.3390/biom11101492.

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CCR4-NOT transcription complex subunit 2 (CNOT2), a subunit of the CCR4-NOT complex, has been described in cancer progression. The CNOT complex plays an important role in multiple cellular functions. Recent studies in our laboratory showed that CNOT2 promotes breast cancer cell proliferation and angiogenesis. In addition, CNOT2 signals are critically related to apoptosis induced by atorvastatin in lung cancer cells. Furthermore, depletion of CNOT2 was shown to enhance the antitumor effect of midline 1 interacting protein 1 (MID1IP1) depletion, thus inhibiting c-Myc expression in liver cancer cells. However, the molecular mechanisms related to its oncogenic role remain unclear. Herein, for the first time, we report that CNOT2 inhibition can induce apoptosis in colorectal cancer cells by activating p53. Inhibition of CNOT2 markedly induced apoptosis in various cancer cells like that of the wild-type p53. Furthermore, inhibition of CNOT2 elongated p53 s half-life. Previously, our laboratory demonstrated that MID1IP1 promoted colocalization with c-Myc mediated by CNOT2. Interestingly, inhibition of CNOT2 cannot induce p53 expression without MID1IP1 or apoptosis in cancer cells. In conclusion, our results demonstrate that CNOT2 inhibition induces apoptosis through MID1IP1 by activating p53.

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De Keersmaecker, Kim, Zeynep Kalender Atak, Ning Li, Carmen Vicente, Stephanie Patchett, Tiziana Girardi, Valentina Gianfelici et al. „Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia“. Nature Genetics 45, Nr. 2 (23.12.2012): 186–90. http://dx.doi.org/10.1038/ng.2508.

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Raszewska-Żurek, Beata. „Kobieca cnota. Próba zrozumienia ewolucji znaczenia cnoty na przestrzeni wieków“. Studia z Filologii Polskiej i Słowiańskiej 46 (25.09.2015): 83–102. http://dx.doi.org/10.11649/sfps.2011.006.

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Feminine virtue. An attempt at understanding the evolution of the meaning of cnota (virtue) over the centuriesThe article is devoted to the evolution of the meaning of the Polish lexeme cnota (virtue) starting from the Old Polish to the present time. The starting point is the change in the meaning of the lexeme virtue from the ‘complex of ethical qualities’ in the Old Polish language to the ‘hymen’ in the twentieth century. From the beginning of the Polish language, the lexeme virtue contained a different catalogue of values in relation to men and women. Analysis concerned these meanings which referred to a woman and were related to the valuation not only of the virtue, but also of a woman in general, taking into consideration non-linguistic, social and cultural determinants. The material comes from historical and contemporary Polish language dictionaries. The studies also included the use of lexemes related to the lexem cnota (virtue), such as an adjective cnotliwy (virtuous) or a noun cnotka (would-be virgin, goody-goody), if they concerned the woman‘s virtue. The meaning of the lexeme virtue in relation to a woman was associated with virginity, chastity, considered as a key factor for determining the value of a woman. Such meaning, associated with a positive valuation of virtue persisted until the nineteenth century. In the twentieth century, the broad importance of the lexeme virtue has fallen into disuse, the meaning has been narrowed to ‘virginity’. Following this, in connection with social and customary changes, the virtue, already as ‘virginity’, lost its traditional high rating in the category of moral values.

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Mao, Qingyan, Qianfeng Zhuang, Jie Shen, Zhen Chen, Dong Xue, Tao Ding und Xiaozhou He. „MiRNA-124 regulates the sensitivity of renal cancer cells to cisplatin-induced necroptosis by targeting the CAPN4-CNOT3 axis“. Translational Andrology and Urology 10, Nr. 9 (September 2021): 3669–83. http://dx.doi.org/10.21037/tau-21-777.

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Meijer, Hedda A., Tobias Schmidt, Sarah L. Gillen, Claudia Langlais, Rebekah Jukes-Jones, Cornelia H. de Moor, Kelvin Cain, Ania Wilczynska und Martin Bushell. „DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity“. Nucleic Acids Research 47, Nr. 15 (10.06.2019): 8224–38. http://dx.doi.org/10.1093/nar/gkz509.

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Abstract The CCR4–NOT complex plays an important role in the translational repression and deadenylation of mRNAs. However, little is known about the specific roles of interacting factors. We demonstrate that the DEAD-box helicases eIF4A2 and DDX6 interact directly with the MA3 and MIF domains of CNOT1 and compete for binding. Furthermore, we now show that incorporation of eIF4A2 into the CCR4–NOT complex inhibits CNOT7 deadenylation activity in contrast to DDX6 which enhances CNOT7 activity. Polyadenylation tests (PAT) on endogenous mRNAs determined that eIF4A2 bound mRNAs have longer poly(A) tails than DDX6 bound mRNAs. Immunoprecipitation experiments show that eIF4A2 does not inhibit CNOT7 association with the CCR4–NOT complex but instead inhibits CNOT7 activity. We identified a CCR4–NOT interacting factor, TAB182, that modulates helicase recruitment into the CCR4–NOT complex, potentially affecting the outcome for the targeted mRNA. Together, these data show that the fate of an mRNA is dependent on the specific recruitment of either eIF4A2 or DDX6 to the CCR4–NOT complex which results in different pathways for translational repression and mRNA deadenylation.

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Yamaguchi, Tomokazu, Ryo Ozawa, Takafumi Minato, Midori Hoshizaki, Yutaro Kammura, Kazuma Okawara, Yousef Khalil et al. „Haploinsufficiency of Cnot3 Aggravates Acid-Induced Acute Lung Injury Likely Through Transcriptional and Post-Transcriptional Upregulation of Pro-Inflammatory Genes“. Journal of Inflammation Research Volume 17 (August 2024): 5415–25. http://dx.doi.org/10.2147/jir.s468612.

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Gliniecki, Wojciech. „„DOBRZE DZIAŁAĆ” I „DOBRZE ŻYĆ” – CNOTY JAKO TRWAŁY FUNDAMENT LUDZKIEGO DZIAŁANIA“. Studia Pelplińskie 57 (31.12.2023): 83–98. http://dx.doi.org/10.12775/splp.2023.006.

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Człowiek kieruje się w stronę jakiegoś dobra − cel działania. W naszej pracy skupimy się na stronie praktycznej ludzkiej egzystencji analizując następującą problematyką: w jaki sposób można kierować owym działaniem, aby realizować dobro właściwe tylko człowiekowi? Jakie warunki pozwalają człowiekowi możliwie najpełniej żyć zgodnie z wymaganiami prawa moralnego? W tym celu analizujemy cnoty rozumiane jako konkretne dyspozycje, które ukierunkowują człowieka na dobro i wyznaczają pewne imperatywy działania ludzkiego. Dochodzimy do wniosku, że cnoty pozwalają się człowiekowi rozwijać i afirmować jego specyfikę pośród innych stworzeń. Jest ona stałą sprawnością, która kieruje działanie i angażuje władze typowe dla człowieka: świadomości, rozumu i wolnej woli. Pozwala nie tylko dobrze działać, ale również dobrze żyć. W oparciu o personalistyczne ujęcie bytu człowieka stwierdzamy, iż cnota utożsamia się z dobrem moralnym i w ten sposób pomaga określić sens obiektywny tego działania.

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Stoney, Patrick N., Akiko Yanagiya, Saori Nishijima und Tadashi Yamamoto. „CNOT7 Outcompetes Its Paralog CNOT8 for Integration into The CCR4-NOT Complex“. Journal of Molecular Biology 434, Nr. 9 (Mai 2022): 167523. http://dx.doi.org/10.1016/j.jmb.2022.167523.

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