Direct and Propagated Effects of Small Molecules on Protein-Protein Interaction Networks.

Networks of protein-protein interactions (PPIs) link all aspects of cellular biology. Dysfunction in the assembly or dynamics of PPI networks is a hallmark of human disease, and as such, there is growing interest in the discovery of small molecules that e

H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids

Genotoxic DNA double-strand breaks (DSBs) can be repaired by error-free homologous recombination (HR) or mutagenic non-homologous end-joining1. HR supresses tumorigenesis1, but is restricted to the S and G2 phases of the cell cycle when a sister chromatid is present2. Breast cancer type 1 susceptibility protein (BRCA1) promotes HR by antagonizing the anti-resection factor TP53-binding protein 1(53BP1) (refs. 2,3,4,5), but it remains unknown how BRCA1 function is limited to the S and G2 phases. We show that BRCA1 recruitment requires recognition of histone H4 unmethylated at lysine 20 (H4K20me0), linking DSB repair pathway choice directly to sister chromatid availability. We identify the ankyrin repeat domain of BRCA1-associated RING domain protein 1 (BARD1)—the obligate BRCA1 binding partner3—as a reader of H4K20me0 present on new histones in post-replicative chromatin6. BARD1 ankyrin repeat domain mutations disabling H4K20me0 recognition abrogate accumulation of BRCA1 at DSBs, causing aberrant build-up of 53BP1, and allowing anti-resection activity to prevail in S and G2. Consequently, BARD1 recognition of H4K20me0 is required for HR and resistance to poly (ADP-ribose) polymerase inhibitors. Collectively, this reveals that BRCA1–BARD1 monitors the replicative state of the genome to oppose 53BP1 function, routing only DSBs within sister chromatids to HR

Backbone and methyl resonance assignments of the 42 kDa human Hsc70 nucleotide binding domain in the ADP state

Hsc70 is the constitutively expressed mammalian heat shock 70 kDa (Hsp70) cytosolic chaperone. It plays a central role in cellular proteostasis and protein trafficking. Here, we present the backbone and methyl group assignments for the 386-residue nucleotide binding domain of the human protein. This domain controls the chaperone’s allostery, binds multiple co-chaperones and is the target of several classes of known chemical Hsp70 inhibitors. The NMR assignments are based on common triple resonance experiments with triple labeled protein, and on several (15)N and (13)C-resolved 3D NOE experiments with methyl-reprotonated samples. A combination of computer and manual data interpretation was used

Intersubjetividade mãe-filho na experiência com comunicação ampliada e alternativa Mother-child intersubjectivity in alternative and augmentative communication experience

OBJETIVO: escutar a percepção materna sobre a introdução e uso da prancha de comunicação ampliada e alternativa na clínica de linguagem da paralisia cerebral. MÉTODOS: foram realizadas entrevistas com um roteiro semi-dirigido e através da coletânea de narrativas foram criadas categorias de análise a partir de três pontos norteadores: a) a constituição da função materna e seu exercício junto ao sujeito com paralisia cerebral; b) a interação dialogal sob a ótica bakhtiniana; e c) os efeitos da clínica de linguagem na função materna e no diálogo das mães com seus filhos. RESULTADOS: os resultados indicam diferentes tipos de uso do recurso na díade mãe-filho, tendo relação com a qualidade do exercício da função materna e a forma de apresentação do recurso ao usuário e a sua família. Quando a concepção de linguagem com a qual é implementado o recurso não inclui a família, nem considera o exercício da função materna, os resultados na sua generalização e manutenção são precários. Nos casos em que houve o debate sobre o uso familiar da prancha, o processo de intersubjetividade do sujeito sem oralidade foi favorecido o uso e a generalização foram ampliados. CONCLUSÃO: conclui-se que a concepção de linguagem dialógica de Bakhtin, atravessada pela psicanálise, permite uma abordagem mais eficaz do recurso comunicativo investigado.<br>PURPOSE: to analyze the maternal perception on the introduction and use of alternative and augmentative communication boards in cerebral palsy language clinic. METHODS: semi-structured interviews were conducted and used to created analysis categories based on three guiding aspects: a) the constitution of maternal function and its execution with individuals with cerebral palsy; b) dialogic interaction under Bakhtinian perspective; and c) the effects of language clinic on the maternal role and on the dialogue between mothers and their children. RESULTS: the results indicate different types of resource usage in the mother-child dyad, which are related to the quality of the maternal role and to the form of presenting the resource to users and their family. When the conception of language with which the resource is implemented does not include the family or consider the exercise of maternal role, the results in its generalization and maintenance are precarious. In cases where there was a debate on family use of the communication board, favoring the process of intersubjectivity between subjects without orality and their family, use and generalization were increased. CONCLUSIONS: it may be concluded that Bakhtin conception on dialogic language crossed by psychoanalysis allows for a more efficacious approach as for the probed communicative device