Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53

In-situ cosmogenic ³⁶Cl denudation rates of carbonates in Guizhou karst area

This study quantifies surface denudation of carbonate rocks by the first application of in-situ cosmogenic <sup>36</sup>Cl in China. Concentrations of natural Cl and in-situ cosmogenic <sup>36</sup>Cl in bare carbonates from Guizhou karst areas were measured with isotope dilution by accelerator mass spectrometer. The Cl concentration varied from 16 to 206 ppm. The <sup>36</sup>Cl concentrations were in range of (0.8–2.4)×106 atom g−1, resulting in total denudation rates of 20–50 mm ka−1 that averaged over a 104–105 a timescale. The <sup>36</sup>Cl-denudation rates showed roughly a negative correlation with the local mean temperature. This preliminary observation may suggest the variations of proportions of chemical weathering and physical erosion in denudation process, depending upon local climatic conditions

Nova praga exótica no ecossistema florestal.

O país está convivendo desde de junho de 2003 com mais uma séria praga de florestas de eucalipto, o psilídeode- concha, Glycaspis brimblecombei (Hemiptera: Psyllidae). Este inseto, de tamanho reduzido, é semelhante a uma cigarrinha que suga a seiva das folhas novas das árvores. A praga tem provocado danos às florestas de eucaliptos, e atualmente se encontra distribuída em mais de 140 municípios do Estado de São Paulo, em pelo menos 20 municípios de Minas Gerais, um de Goiás, dois de Mato Grosso do Sul e seis do Paraná.bitstream/CNPMA/5837/1/comunicado_18.pd

Towards biological control strategies for the bronze bug, Thaumastocoris peregrinus, on eucalyptus plantations in South America.

Edição dos abstracts do 24º IUFRO World Congress, 2014, Salt Lake City. Sustaining forests, sustaining people: the role of research

Improving mass rearing techniques for Cleruchoides noackae (Hymenoptera: Mymaridae).

Edição dos abstracts do 24º IUFRO World Congress, 2014, Salt Lake City. Sustaining forests, sustaining people: the role of research

Righteousness and Peace: A Cantata of Reconciliation

Righteousness and Peace, a new cantata, uses the composer’s own assemblage of Christian biblical texts to illustrate the meeting and reconciliation between moral law and mutual love. It is scored for mixed chorus with soprano and tenor soloist, accompanied by chamber orchestra; a version with piano accompaniment is also provided to facilitate rehearsal and expand the possibilities of performance. Its performance duration of 40-45 minutes makes it suitable for a special concert or community event. A system of key relationships is used to delineate the core concepts of righteousness (moral law) and peace (mutual love and cooperation), and to create shadings of meaning both to distinguish these core topical areas and to delineate connections and deeper unities between them as articulated in the source texts. Motivic links between all movements are also used to emphasize the continuity between apparently opposite ideas