Neutral Intramolecular Hydrogen-Bonded Bases

B3LYP/aug-cc-pVDZ computations were carried out on polyamines with up to seven amino groups. The gas-phase proton affinities of these compounds are 219.6 (1-BuNH2), 238.6 (H2NCH2CH2CH2CH2NH2), 252.8 [(H2NCH2CH2CH2)2CHNH2], 261.3 [(H2NCH2CH2CH2)2CNH2 (1)], and 288.5 kcal mol−1 [(H2NCH2CH2CH(NH2)CH2CH2)2CNH2]. These results indicate that the tetraamine is near the top of the basicity scale and the heptaamine is more basic than any neutral organic compound which has been measured to date. A gas-phase equilibrium acidity determination between 1 and DBU also was carried out, and PA(1) = 256.2 ± 2.1 kcal mol−1 was obtained. This demonstrates that multiple intramolecular hydrogen bonds can greatly increase basicities, and represents a new motif for designing super bases

Specific Inhibition of p97/VCP ATPase and Kinetic Analysis Demonstrate Interaction between D1 and D2 ATPase domains

The p97 AAA (ATPase associated with diverse cellular activities), also called VCP (valosin-containing protein), is an important therapeutic target for cancer and neurodegenerative diseases. p97 forms a hexamer composed of two AAA domains (D1 and D2) that form two stacked rings, and an N-terminal domain that binds numerous cofactor proteins. The interplay between the three domains in p97 is complex, and a deeper biochemical understanding is needed in order to design selective p97 inhibitors as therapeutic agents. It is clear that the D2 ATPase domain hydrolyzes ATP in vitro, but whether D1 contributes to ATPase activity is controversial. Here, we use Walker A and B mutants to demonstrate that D1 is capable of hydrolyzing ATP, and show for the first time that nucleotide binding in the D2 domain increases the catalytic efficiency (kcat/Km) of D1 ATP hydrolysis 280-fold, by increasing kcat 7-fold and decreasing Km about 40-fold. We further show that an ND1 construct lacking D2 but including the linker between D1 and D2 is catalytically active, resolving a conflict in the literature. Applying enzymatic observations to small-molecule inhibitors, we show that four p97 inhibitors (DBeQ, ML240, ML241, and NMS-873) have differential responses to Walker A and B mutations, to disease-causing IBMPFD mutations, and to the presence of the N-domain binding cofactor protein p47. These differential effects provide the first evidence that p97 cofactors and disease mutations can alter p97 inhibitor potency and suggest the possibility of developing context-dependent inhibitors of p97

Specific Inhibition of p97/VCP ATPase and Kinetic Analysis Demonstrate Interaction between D1 and D2 ATPase domains

The p97 AAA (ATPase associated with diverse cellular activities), also called VCP (valosin-containing protein), is an important therapeutic target for cancer and neurodegenerative diseases. p97 forms a hexamer composed of two AAA domains (D1 and D2) that form two stacked rings, and an N-terminal domain that binds numerous cofactor proteins. The interplay between the three domains in p97 is complex, and a deeper biochemical understanding is needed in order to design selective p97 inhibitors as therapeutic agents. It is clear that the D2 ATPase domain hydrolyzes ATP in vitro, but whether D1 contributes to ATPase activity is controversial. Here, we use Walker A and B mutants to demonstrate that D1 is capable of hydrolyzing ATP, and show for the first time that nucleotide binding in the D2 domain increases the catalytic efficiency (k_(cat)/K_m) of D1 ATP hydrolysis 280-fold, by increasing k_(cat) 7-fold and decreasing K_m about 40-fold. We further show that an ND1 construct lacking D2 but including the linker between D1 and D2 is catalytically active, resolving a conflict in the literature. Applying enzymatic observations to small-molecule inhibitors, we show that four p97 inhibitors (DBeQ, ML240, ML241, and NMS-873) have differential responses to Walker A and B mutations, to disease-causing IBMPFD mutations, and to the presence of the N-domain binding cofactor protein p47. These differential effects provide the first evidence that p97 cofactors and disease mutations can alter p97 inhibitor potency and suggest the possibility of developing context-dependent inhibitors of p97

The expression of creativity in learning how to read and write : a case study

O presente artigo tem por objetivo destacar as formas em que a criatividade se expressa na aprendizagem da leitura e da escrita da criança. Assume-se como referencial teórico a concepção de aprendizagem criativa desenvolvida por Mitjáns Martínez. Segundo essa concepção, os processos criativos emergem nos contextos de ação do sujeito, mediante recursos subjetivos constituídos historicamente e que se organizam no momento da ação concreta. A expressão desse tipo de aprendizagem tem se configurado pela personalização da informação, confrontação com o dado e pela geração, produção de ideias novas que vão além do que está posto. Adota-se como eixo norteador a pesquisa qualitativa, apoiada nos princípios da epistemologia qualitativa desenvolvida por González Rey, com opção pelo estudo de caso utilizando instrumentos abertos e semiabertos, tais como: dinâmicas conversacionais, observações, entrevistas como processo e diário de ideias. A investigação foi desenvolvida em uma escola da rede pública, com alunos dos primeiros e segundos anos do ensino fundamental, na qual acompanhamos os aprendizes por dois anos consecutivos. Como conclusão, considera-se que a expressão da criatividade na aprendizagem da leitura e da escrita foi significativamente apresentada pelas características destacadas por Mitjáns Martínez, bem como pela relação lúdica da criança com sua aprendizagem.This paper has the purpose of highlighting the ways through which creativity is expressed in the child´s learning of how to read and write. The theoretical assumption taken is the concept of creative learning developed by Mitjáns Martínez. According to such conception, the creative processes emerge in the context of the individual´s action, through subjective resources that are historically constructed and are organized in the moment of concrete action. The expression of this type of learning has been configured by the personalization of information, confrontation with the data, and by the generation and production of new ideas that go beyond what is taken for granted. The guiding axis adopted is qualitative research, supported by the principles of thequalitative epistemology developed by González Rey, with the option of conducting a case study utilizing open and semi-open tools, such as: conversational dynamics, observations, interviews as a process and a diary of ideas. The investigation took place in a public school, among 1st and 2nd graders, in which we monitored the learners for two years in a row. As a conclusion, we consider that the expression of creativity in learning how to read and write was significantly presented by the characteristics emphasized by the author mentioned above, as well as by the playful relationship of the child with his/her learning

Neutral Intramolecular Hydrogen-Bonded Bases

B3LYP/aug-cc-pVDZ computations were carried out on polyamines with up to seven amino groups. The gas-phase proton affinities of these compounds are 219.6 (1-BuNH2), 238.6 (H2NCH2CH2CH2CH2NH2), 252.8 [(H2NCH2CH2CH2)2CHNH2], 261.3 [(H2NCH2CH2CH2)2CNH2 (1)], and 288.5 kcal mol−1 [(H2NCH2CH2CH(NH2)CH2CH2)2CNH2]. These results indicate that the tetraamine is near the top of the basicity scale and the heptaamine is more basic than any neutral organic compound which has been measured to date. A gas-phase equilibrium acidity determination between 1 and DBU also was carried out, and PA(1) = 256.2 ± 2.1 kcal mol−1 was obtained. This demonstrates that multiple intramolecular hydrogen bonds can greatly increase basicities, and represents a new motif for designing super bases

Phenylcyclopropane Energetics and Characterization of Its Conjugate Base: Phenyl Substituent Effects and the C–H Bond Dissociation Energy of Cyclopropane

The α-C–H bond dissociation energy (BDE) of phenylcyclo­propane (<b>1</b>) was experimentally determined using Hess’ law. An equilibrium acidity determination of <b>1</b> afforded Δ<i>H</i>°_acid = 389.1 ± 0.8 kcal mol^–1, and isotopic labeling established that the α-position of the three-membered ring is the favored deprotonation site. Interestingly, the structure of the base proved to be a key factor in correctly determining the proper ionization site (i.e., secondary amide ions are needed, and primary ones and OH^– lead to incorrect conclusions since they scramble the deuterium label). An experimental measurement of the electron affinity of 1-phenylcyclopropyl radical (EA = 17.5 ± 2.8 kcal mol^–1) was combined with the ionization energy of hydrogen (313.6 kcal mol^–1) to afford BDE = 93.0 ± 2.9 kcal mol^–1. This enabled the effect of the phenyl substituent to be evaluated and compared to other situations where it is attached to an sp³- or sp²-hybridized carbon center. M06-2X, CCSD­(T), G4, and W1BD computations were also carried out, and a revised C–H BDE for cyclopropane of 108.9 ± 1.0 kcal mol^–1 is recommended

Carbon–Hydrogen Bond Dissociation Energies: The Curious Case of Cyclopropene

The ionization energy (IE) of the 3-cyclopropenyl radical (6.00 ± 0.17 eV) was measured in the gas phase by reacting 3-cyclopropenium cation (<i>c</i>-C₃H₃⁺) with a series of reference reagents of known IEs. This result was combined in a thermodynamic cycle to obtain the heat of formation of <i>c</i>–C₃H₃^• (118.9 ± 4.0 kcal mol^–1) and the allylic C–H bond dissociation energy (BDE) of cyclopropene (104.4 ± 4.0 kcal mol^–1). These experimental values are well reproduced by high level G3 and W1 computations and reveal that the BDE is similar to that for cyclopropane and the vinyl position of cyclopropene. This is unprecedented and is a reflection of the unusual nature of cyclopropene