Corpo, linguagem e linguagem do corpo

After pointing on how language cuts the atualworld and how words listened in certain situations-of anguish, forinstance - may mark the subject's body, behaviors and thoughts,the author develops the Lacanian thesis that "the unconcious isstructured as a language". Following, he develops another Lacanianthesis, that which states, acording to the analytical experiencebasis, the narrow interdependence of the subject's actual, imaginaryand symbolic bodies.Depois de ter indicado como a linguagem recorta o reale como as palavras escutadas em certas condições - de angústia por exemplo - podem marcar o corpo do sujeito, seus comportamentos e seus pensamentos, o autor desenvolve a tese lacaniana que "o inconsciente é estruturado como uma linguagem". Ele desenvolve em seguida uma outra tese lacaniana, aquela que, segundo a base da experiência analítica, afirma a estreita interdependência dos corpos real, imaginário e simbólico de um sujeito

The selectivity filter is involved in the U-type inactivation process of Kv2.1 and Kv3.1 channels

Voltage-gated potassium (Kv) channels display several types of inactivation processes, including N-, C-, and U-types. C-type inactivation is attributed to a nonconductive conformation of the selectivity filter (SF). It has been proposed that the activation gate and the channel's SF are allosterically coupled because the conformational changes of the former affect the structure of the latter and vice versa. The second threonine of the SF signature sequence (e.g., TTVGYG) has been proven to be essential for this allosteric coupling. To further study the role of the SF in U-type inactivation, we substituted the second threonine of the TTVGYG sequence by an alanine in the hKv2.1 and hKv3.1 channels, which are known to display U-type inactivation. Both hKv2.1-T377A and hKv3.1-T400A yielded channels that were resistant to inactivation, and as a result, they displayed noninactivating currents upon channel opening; i.e., hKv2.1-T377A and hKv3.1-T400A remained fully conductive upon prolonged moderate depolarizations, whereas in wild-type hKv2.1 and hKv3.1, the current amplitude typically reduces because of U-type inactivation. Interestingly, increasing the extracellular K+ concentration increased the macroscopic current amplitude of both hKv2.1-T377A and hKv3.1-T400A, which is similar to the response of the homologous T to A mutation in Shaker and hKv1.5 channels that display C-type inactivation. Our data support an important role for the second threonine of the SF signature sequence in the U-type inactivation gating of hKv2.1 and hKv3.1. SIGNIFICANCE Voltage-dependent K+ (Kv) channels generate cells' repolarizing power, which is consequently regulated by the channel's conductance. Aside from the opening or closure, Kv channels undergo inactivation that drives them into a lower or nonconductive state. Among the different inactivation processes described in Kv channels, the U-type process develops from a preopen but activated state. The molecular determinants of this process are, in contrast to the Ctype mechanism, not well characterized. Our data show that the intracellular part of the K+ selectivity filter within the pore domain is involved. An alanine for threonine substitution results in channels that do not inactivate upon opening, suggesting that an allosteric coupling between the activation gate and selectivity filter exists in U-type inactivation

Covalent Cysteine Targeting of Bruton's Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

Simple Summary Glucocorticoid therapy resistance in B-cell malignancies is often associated with constitutive activation of tyrosine kinases. Novel anticancer drugs targeting hyperactivated tyrosine kinases, such as Bruton's tyrosine kinase (BTK), have, therefore, gained much interest over the past few decades and have already been approved for clinical use. In this study, we compared the therapeutic efficacy of the phytochemical kinase inhibitor withaferin A with the clinically approved BTK inhibitor ibrutinib to target hyperactivated tyrosine kinase signaling in glucocorticoid-resistant multiple myeloma cells. Our results demonstrate that withaferin A-induced cell death of glucocorticoid-resistant MM1R cells involves covalent cysteine targeting of multiple Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including BTK. Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells' uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA's promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM

L'avenir du psychologue clinicien. Hommage à Léon Cassiers

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Que serait une institution "suffisamment bonne" ?

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Funciones paternas y nacimientos del sujeto

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