Podcasts about 26s

En nuestro especial de San Valentin iremos a través de una narrativa que juega con el tiempo:Carta Blanca de Jordi Lafebre donde exploramos la historia de un amor que se resiste a ser olvidado Ana y Zeno, a pesar de todo, seguirán amándose.Discusión 0:00Patrocinador 22:51Noticias 24:26Síguenos enFacebook,Instagram yTikTok y escúchanos en las diferentes plataformas:https://linktr.ee/nerdifymx¡Crea tupodcast hoy! #madeonzencastr. Utiliza nuestro link especialhttps://zencastr.com?via=nerdifymx⁠ y obten un descuento de Zencastr.Hackers por Karl Casey @ White Bat Audio | Donations (Sting) por Riot

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.05.535705v1?rss=1 Authors: Yang, L., Parajuli, N., Wu, P., Liu, J., Wang, X. Abstract: Background: A better understanding of the regulation of proteasome activities can facilitate the search for new therapeutic strategies. A cell culture study shows that cAMP-dependent protein kinase (PKA) activates the 26S proteasome by phosphorylating Ser14 of RPN6 (pS14-RPN6), but this discovery and its physiological significance remain to be established in vivo. Methods: Male and female mice with Ser14 of Rpn6 mutated to Ala (S14A) or Asp (S14D) to respectively block or mimic pS14-Rpn6 were created and used along with cells derived from them. cAMP/PKA were manipulated pharmacologically. Ubiquitin-proteasome system (UPS) functioning was evaluated with the GFPdgn reporter mouse and proteasomal activity assays. Impact of S14A and S14D on proteotoxicity was tested in mice and cardiomyocytes overexpressing the misfolded protein R120G-CryAB (R120G). Results: PKA activation increased pS14-Rpn6 and 26S proteasome activities in wild-type (WT) but not S14A embryonic fibroblasts (MEFs), adult cardiomyocytes (AMCMs), and mouse hearts. Basal 26S proteasome activities were significantly greater in S14D myocardium and AMCMs than in WT counterparts. S14D::GFPdgn mice displayed significantly lower myocardial GFPdgn protein but not mRNA levels than GFPdgn mice. In R120G mice, a classic model of cardiac proteotoxicity, basal myocardial pS14-Rpn6 was significantly lower compared with non-transgenic littermates, which was not always associated with reduction of other phosphorylated PKA substrates. Cultured S14D neonatal cardiomyocytes displayed significantly faster proteasomal degradation of R120G than WT neonatal cardiomyocytes. Compared with R120G mice, S14D/S14D::R120G mice showed significantly greater myocardial proteasome activities, lower levels of total and K48-linked ubiquitin conjugates and of aberrant CryAB protein aggregates, less reactivation of fetal genes and cardiac hypertrophy, and delays in cardiac malfunction. Conclusions: This study establishes in animals that pS14-Rpn6 mediates the activation of 26S proteasomes by PKA and that the reduced pS14-Rpn6 is a key pathogenic factor in cardiac proteinopathy, thereby identifies a new therapeutic target to reduce cardiac proteotoxicity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

SEMANA habla con la senadora del Centro Democrático María Fernanda Cabal, quien reacciona a la nueva reunión entre Petro y Uribe, y hace un vehemente pronunciamiento tras las marchas del 26S en Colombia: "Un estallido de patria, amamos a Colombia".

FDA 批准治疗慢性免疫性血小板减少症的新药BMJ 术后血栓预防中，加压袜并不能提供额外的获益Nature子刊 白血病治疗性疫苗的研制阿凡波帕（avatrombopag）阿凡波帕（avatrombopag）血小板生成素受体激动剂。在上周三《消化科星期三 Episode 23》中已经给介绍了阿凡波帕用于治疗慢性肝病合并血小板减少患者的手术前用药，可以改善血小板计数、减少出血和输血。2019年6月，该药的适应症被扩展至慢性免疫性血小板减少。《随机对照研究：阿凡波帕治疗慢性免疫血小板减少症的3期临床研究》British Journal of Haematology，2018年11月 (1)这个安慰剂对照、多中心、随机、双盲的3阶段的研究，目的是评估阿凡波帕20mg qd治疗成人慢性、免疫性血小板减少症的疗效。研究纳入49位患者，入组时血小板计数

FDA 批准治疗慢性免疫性血小板减少症的新药BMJ 术后血栓预防中，加压袜并不能提供额外的获益Nature子刊 白血病治疗性疫苗的研制阿凡波帕（avatrombopag）阿凡波帕（avatrombopag）血小板生成素受体激动剂。在上周三《消化科星期三 Episode 23》中已经给介绍了阿凡波帕用于治疗慢性肝病合并血小板减少患者的手术前用药，可以改善血小板计数、减少出血和输血。2019年6月，该药的适应症被扩展至慢性免疫性血小板减少。《随机对照研究：阿凡波帕治疗慢性免疫血小板减少症的3期临床研究》British Journal of Haematology，2018年11月 (1)这个安慰剂对照、多中心、随机、双盲的3阶段的研究，目的是评估阿凡波帕20mg qd治疗成人慢性、免疫性血小板减少症的疗效。研究纳入49位患者，入组时血小板计数

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.13.381962v1?rss=1 Authors: Cheng, C. L., Wong, M. K., Li, Y., Hochstrasser, M. Abstract: The proteasome is a large protease complex that degrades both misfolded and regulatory proteins. In eukaryotes, the 26S proteasome contains six different AAA+ ATPase subunits, Rpt1-Rpt6, which form a hexameric ring as part of the base subcomplex that drives unfolding and translocation of substrates into the proteasome core. Archaeal proteasomes contain only a single type of ATPase subunit, the proteasome-activating nucleotidase (PAN), which forms a trimer-of-dimers and is homologous to the eukaryotic Rpt subunits. A key PAN proline residue (P91) forms cis and trans peptide bonds in successive subunits around the ring, allowing efficient dimerization through upstream coiled coils. The importance of the equivalent Rpt prolines in eukaryotic proteasome assembly was unknown. We show an equivalent proline is strictly conserved in Rpt3 (in S. cerevisiae, P93) and Rpt5 (P76), well conserved in Rpt2 (P103), and loosely conserved in Rpt1 (P96) in deeply divergent eukaryotes, but in no case is its mutation strongly deleterious to yeast growth. However, the rpt2-P103A, rpt3-P93A, and rpt5-P76A mutations all cause synthetic defects with specific base assembly chaperone deletions. The Rpt5-P76A mutation decreases the levels of the protein and induces a mild proteasome assembly defect. The yeast rpt2-P103A rpt5-P76A double mutant has strong growth defects attributable to defects in proteasome base formation. Several Rpt subunits in this mutant form aggregates that are cleared, at least in part, by the Hsp42-mediated protein quality control (PQC) machinery. We propose that the conserved Rpt linker prolines promote efficient 26S proteasome base assembly by facilitating specific ATPase heterodimerization. Copy rights belong to original authors. Visit the link for more info

Regulation of cholesterol synthesis is very important: cholesterol is a component of cell membranes and a precursor of steroid hormones and bile acids, yet high levels of cholesterol can be toxic to cells and can contribute to heart disease. Cells in our body obtain cholesterol one of two ways – by taking it up from the bloodstream (via low-density lipoprotein or LDL) or by synthesizing it intracellularly. In Part 1 of his iBioSeminar, Dr. Russell DeBose-Boyd provides an overview of cholesterol regulation with a focus on HMG CoA reductase, the rate-limiting enzyme of cholesterol synthesis. He describes how the effects of statins, drugs prescribed to lower LDL in the blood, are blunted due to the disruption of feedback control of HMG CoA reductase. In the presence of sterols, HMG CoA reductase protein stability is decreased. This sterol-accelerated degradation of HMG CoA reductase is dependent on the enzyme’s membrane domain in a process known as ER-associated degradation (ERAD). DeBose-Boyd describes his lab’s contributions to a model of HMG CoA reductase ERAD in which polyubiquitination of the enzyme in response to sterols is mediated by two proteins, Insig-1 and Insig-2, leading to its ERAD by the 26S proteasome.

Regulation of cholesterol synthesis is very important: cholesterol is a component of cell membranes and a precursor of steroid hormones and bile acids, yet high levels of cholesterol can be toxic to cells and can contribute to heart disease. Cells in our body obtain cholesterol one of two ways – by taking it up from the bloodstream (via low-density lipoprotein or LDL) or by synthesizing it intracellularly. In Part 1 of his iBioSeminar, Dr. Russell DeBose-Boyd provides an overview of cholesterol regulation with a focus on HMG CoA reductase, the rate-limiting enzyme of cholesterol synthesis. He describes how the effects of statins, drugs prescribed to lower LDL in the blood, are blunted due to the disruption of feedback control of HMG CoA reductase. In the presence of sterols, HMG CoA reductase protein stability is decreased. This sterol-accelerated degradation of HMG CoA reductase is dependent on the enzyme's membrane domain in a process known as ER-associated degradation (ERAD). DeBose-Boyd describes his lab's contributions to a model of HMG CoA reductase ERAD in which polyubiquitination of the enzyme in response to sterols is mediated by two proteins, Insig-1 and Insig-2, leading to its ERAD by the 26S proteasome.

Mateo 11.25–30 Reina Valera Revisada (1960) Venid a mí y descansad 25En aquel tiempo, respondiendo Jesús, dijo: Te alabo, Padre, Señor del cielo y de la tierra, porque escondiste estas cosas de los sabios y de los entendidos, y las revelaste a los niños. 26Sí, Padre, porque así te agradó. 27Todas las cosas me fueron entregadas por mi Padre;j y nadie conoce al Hijo, sino el Padre, ni al Padre conoce alguno, sino el Hijo,k y aquel a quien el Hijo lo quiera revelar. 28Venid a mí todos los que estáis trabajados y cargados, y yo os haré descansar. 29Llevad mi yugo sobre vosotros, y aprended de mí, que soy manso y humilde de corazón; y hallaréis descanso para vuestras almas;l 30porque mi yugo es fácil, y ligera mi carga.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.20.305532v1?rss=1 Authors: Chen, L., Shu, X., Chen, Q., Wei, T., Wang, X., Wu, Q., Wang, H., Zhang, X., Liu, X., Zhang, Y., Zheng, S., Huang, L., Xiao, J., Jiang, C., Wang, Z., Yang, B., Guo, X. Abstract: Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine (pTyr) sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here we show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, we found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptor tyrosine kinases (RTKs) can trigger Rpt2-Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2-Y439 in vitro and negatively regulates 26S proteasome integrity and activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase non-receptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anti-cancer therapies. Copy rights belong to original authors. Visit the link for more info

Christian, Dabul e Esperon descobrem novos vícios no YouTube, fazem chover anime e veem uns Bagulhos Sinistros pela terceira vez!O Semana dos 10 é o nosso podcast semanal no qual toda segunda nos juntamos para falar sobre o que assistimos e jogamos nos últimos 7 dias, contar histórias e comentar as últimas notícias.Torne-se uma PATROA ou PATRÃO do 10de10!> apoia.se/10de10> picpay.me/10de10Acesse o site pra a lista completa de assuntos comentados:> bit.ly/Sd10-172Segue nós no Twitter!!11!!onze!> @10de10> @bedabul> @kiwistian> @mtesperon> @gangeleas***********DLC > 00:05:02Filmes > 00:28:26Séries > 00:28:37Jogos > 00:50:35Diversos > 00:53:02Notícias > 00:59:41**********Christian » Broforce; Evangelion; One Punch Man; Attack On Titan; Stranger Things; The Great British Baking Show;Dabul » One Punch Man S02; Apex Legends; Mahō Shōjo Madoka Magika; Stranger Things 3Esperon » Booksmart (Fora de Série); Comrade Detective; Katana Zero. See acast.com/privacy for privacy and opt-out information.

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Even though platelets are the smallest cells in circulating blood, they play an integral role in blood clotting where they are activated, adhere to the vessel wall, and contribute to hemostasis. But over the years it was discovered that those anucleate cells have more extended functions. They organize their cellular vitality similar to nucleated cells and have an active protein metabolism performing protein de novo synthesis as well as protein degradation. One of the main degradation systems in cells is the proteasome. Besides protein quality control, the proteasome is involved in important cellular processes like cell survival, transcription, development, selective elimination of abnormal proteins and antigen processing. A dysregulation of this multicatalytic protein complex leads to various disease developments. Proteasome inhibitors, for instance, have been studied for treating cancer. Platelets like nucleated cells contain a proteasome. However, the impact of the proteasome on platelet functions remains poorly investigated until today. A better knowledge of signaling pathways in platelets aids in understanding how alterations in proteasome functions affect platelet-mediated processes and diseases. This study confirms the existence of a functional proteasome in human platelets and illustrates an important role in platelet biology, as well as sepsis. With this study the role of the proteasome in anucleate platelets is demonstrated in more detail and a signaling pathway regulating its activity was observed. Here, the proteasome in platelets is linked to platelet aggregation. First, proteasome inhibitors epoxomicin and bortezomib reduce ADP- and collagen-induced aggregation. Furthermore, the 26S chymotrypsin-like activity of the proteasome is enhanced when platelets are incubated with the platelet agonist collagen. Additionally, cytoskeletal proteins Filamin A and Talin-1, which are crucial for platelet activation, were identified as proteasome substrates and increased cleavage of these proteins occurs with proteasome activation. To investigate possible mechanisms of regulating the proteasome, the signaling pathway related to NFκB was analyzed under platelet agonist treatment. The NFκB pathway, that mediates aggregation, is initiated when platelets are treated with collagen and the inhibitory protein of NFκB, IκBα, is degraded in collagen-stimulated platelets. More interestingly, NFκB inhibitors prevent collagen-stimulated enhancement of the proteasome activity. In return the connection of the proteasome and the NFκB pathway is further demonstrated as NFκB inhibitors restrict cleavage of the proteasome substrate Talin-1. These results propose a novel pathway that involves the proteasome and that is in return connected with non-genomic functions of NFκB in regulating platelet aggregation. In a second part this work shows for the first time that mitochondrial membrane depolarization in platelets correlates with the disease course and disease severity in patients with sepsis. Additionally, during these studies increased proteasome activity was observed in sepsis patients compared to control patients and pathogenic bacteria intensified the 26S trypsin-like activity of human platelets. Therefore, molecular markers of platelet vitality may be valuable parameters to help evaluating the clinical outcome of sepsis patients. In summary, the study confirms the existence of a functional proteasome in human platelets, contributes to our understanding how the proteasome affects platelet functions such as aggregation and how this may be regulated on a molecular basis. Furthermore, it allows for new insights in the disease course of sepsis and identifies new molecular markers for assessing the disease severity and clinical outcome of sepsis patients.

Oxidative stress induces separation of the catalytic and regulatory portions of the yeast 26S proteasome, enabling the catalytic core to degrade toxic oxidized proteins.

Preface This study is focussed on the structural investigation of large molecular assemblies such as the 26S proteasome and the translocation machinery of the outer mitochondrial membrane. It is divided in two chapters and in both parts the structural and further functional analysis is based on X-ray crystallography. Chapter 1: Structural investigation of Rpn13, the multifunctional adaptor protein of the 26S proteasome The results in chapter 1 reveal that the multifunctional adaptor protein Rpn13 acts as a novel ubiquitin receptor of the 26S proteasome and deliver structural and biophysical details of its interaction with ubiquitin and with other proteasomal subunits. The crystal structure of the ubiquitin binding domain of Rpn13 reveals the molecular architecture of a Pleckstrin Homology (PH) domain and the NMR structure of the complex with ubiquitin shows a novel ubiquitin-binding mode. Additional NMR studies and domain mapping by truncation analysis provide further insights in the domain architecture of Rpn13 and the interaction with its partners Rpn2 and Uch37. Chapter 2: Crystallographic studies of the TOM core complex Chapter 2 presents the purification and crystallization of the mitochondrial protein translocase, the TOM core complex, from Neurospora crassa. Preliminary crystallographic data lead to the determination of space group and cell dimensions. This chapter also describes various experiments to improve the diffraction quality of the crystals and the co-crystallization of TOM core complex with specific monoclonal antibody fragments. Furthermore, expression and refolding of the main component Tom40 is raised as an alternative approach in structural investigation of the TOM complex.

Late mitotic events are chiefly controlled by proteolysis of key regulatory proteins via the ubiquitin-proteasome pathway. In this pathway ubiquitin ligases modify substrates by attachment of ubiquitin (“ubiquitylation”), which usually results in their subsequent degradation by the 26S proteasome. The crucial ubiquitin ligase involved in late mitosis is the anaphase-promoting complex or cyclosome (APC/C). Among the many substrates of the APC/C is the anaphase inhibitor securin, whose destruction leads to activation of separase, which in turn triggers sister chromatid separation by proteolytic cleavage of cohesin. The APC/C also targets cyclin B1, an activating subunit of Cdk1 kinase, whose inactivation is a prerequisite for mitotic exit. The unstable APC/C substrates are often found in association with stable partner proteins. How single subunits of multi-protein complexes are selectively extracted and eventually degraded is largely unknown, but there is increasing evidence that additional factors assist to extract ubiquitin-carrying subunits from stable binding partners. One such factor is vertebrate p97 (Cdc48 in yeast), an abundant and highly conserved member of the AAA-ATPase family. It is involved in such diverse processes as transcriptional regulation, membrane fusion, and ER-associated protein degradation (ERAD). The unifying scheme in these seemingly unrelated functions is that p97 is able to “extract” preferentially ubiquitylated proteins from their environment. Roles of p97 in mitosis have recently emerged: p97 was reported to be required for spindle disassembly and for nuclear envelope reformation during mitotic exit in Xenopus. Furthermore, a genetic interaction between p97, separase and securin, as well as a requirement of p97 for separase stability, were discovered in fission yeast. Given these hints and the importance of ubiquitylation in both mitosis and p97 pathways, this study intended to elucidate additional mitotic roles of p97 in vertebrates. Towards this end, tools to interfere with p97 function in Xenopus egg extracts were developed. These included immunodepletion of the p97 adaptors Npl4, Ufd1 and p47 and addition of recombinant dominant-negative p97-mutants. ERAD, which could be established here for the first time in Xenopus egg extracts, was greatly impaired in the absence of p97 function. However, many aspects of mitosis were found to be unaffected. Importantly, p97’s proposed role in spindle disassembly was clearly falsified within this thesis. Furthermore, p97 was shown to be dispensable for activity and stability of vertebrate separase. Disassembly of the mitotic checkpoint complex, which prevents premature APC/C activation by sequestering its activator Cdc20, did also not require functional p97 despite its dependence on ubiquitylation of Cdc20. However, a novel function of p97 at fertilization was discovered. p97 was found to interact with nucleoplasmin, a histone-binding chaperone that catalyzes the exchange of sperm-specific basic proteins (SBPs) to histones. Indeed, interference with p97 function delayed sperm decondensation in Xenopus egg extracts, thereby confirming a novel role of this AAA-ATPase in sperm chromatin remodelling. In another project the role of securin in human cells was investigated. Human cells lacking securin had been reported to suffer from massive chromosome missegregation, which was in sharp contrast to the mild phenotype of securin knockout mice. In collaboration with the group of M. Speicher it could be demonstrated that chromosome losses in securin-/- cells are transient and give way to a stable segregation pattern after just a few passages. This was despite persisting biochemical defects such as reduced level and activity of separase. These data demonstrate that securin is dispensable for chromosomal stability in human cells.

The majority of eukaryotic proteins are degraded by the ubiquitin-proteasome system. In this pathway, cytosolic substrates are first earmarked for degradation by modification with ubiquitin ('ubiquitylation') and subsequently degraded by the 26S pro-teasome, a large protease residing in both the cytosol and the nucleus. ER-resident proteins are similarly degraded but take the route of a specialized pathway coined ER-associated degradation (ERAD). In order to reach the cytosolic ubiquitin/proteasome system, these substrates must first relocate from the ER to the cytosol, possibly with the help of protein conducting membrane channels. Previous work has shown that specific ubiquitin-conjugating enzymes (e.g. Ubc6, Ubc7) and ubiquitin ligases (e.g. Hrd1) con-tribute to ERAD, but how the substrates reach the proteasome remained to be clarified. Besides its function as a quality control system in recognizing and eliminating aberrant proteins, ERAD appears also to play a part in regulatory pathways. This study focuses on the identification of novel components contributing to ERAD. It could be demonstrated that the yeast protein Cdc48 (p97 in mammals), to-gether with its co-factors Ufd1 and Npl4, plays a key role in this process. Cdc48 belongs to the large family of AAA-type ATPases and is believed to function as a chaperone-like enzyme. Previous work has shown that the Cdc48 complex specifically acts on ubiquitylated substrates. This study indicates that the Cdc48 complex takes part in mo-bilization of ERAD substrates from the ER membrane for proteasomal targeting. Fur-thermore, degradation of some ERAD substrates involves the multiubiquitylation factor E4/Ufd2 and proteasome targeting factors of the Rad23 protein family. Another aspect of this work addresses the regulatory functions of ERAD. The fatty acid desaturase Ole1, an integral membrane protein of the ER, was identified as a novel ERAD substrate. Intriguingly, ERAD of Ole1 is specifically regulated since the protein is particularly short lived in the presence of high levels of unsaturated fatty acids, the products of Ole1. Thus, this feedback loop provides an additional mechanism, by which the cell regulates the amount of unsaturated fatty acids. The t-SNARE (syntaxin) protein Ufe1 was characterized as another substrate of ERAD. This protein is required for homotypic membrane fusion of ER vesicles. Notably, Ufe1 degradation is negatively controlled by its binding partner Sly1, a member of the SM (Sec1/Munc18) protein fam-ily. Reciprocal mutations in the Ufe1-Sly1 interaction face result in rapid degradation of Ufe1 by ERAD. Conversely, strong overproduction of Ufe1 was found to be detrimental for cellular growth. These findings suggest that one important function of Sly1 is to con-trol Ufe1 SNARE levels in order to ensure cellular homeostasis. In conclusion, analysis of the degradation of Ole1 and Ufe1 revealed an important contribution of ERAD to es-sential regulatory pathways.