NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase β and Potentiate Temozolomide-Induced DNA Damage,Senescence and Apoptosis in Colorectal Cancer Cells

Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC₅₀ of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients.     

Air Pollution in China: Mapping of Concentrations and Sources

China has recently made available hourly air pollution data from over 1500 sites, including airborne particulate matter (PM), SO₂, NO₂, and O₃. We apply Kriging interpolation to four months of data to derive pollution maps for eastern China. Consistent with prior findings, the greatest pollution occurs in the east, but significant levels are widespread across northern and central China and are not limited to major cities or geologic basins. Sources of pollution are widespread, but are particularly intense in a northeast corridor that extends from near Shanghai to north of Beijing. During our analysis period, 92% of the population of China experienced >120 hours of unhealthy air (US EPA standard), and 38% experienced average concentrations that were unhealthy. China’s population-weighted average exposure to PM_2.5 was 52 μg/m³. The observed air pollution is calculated to contribute to 1.6 million deaths/year in China [0.7–2.2 million deaths/year at 95% confidence], roughly 17% of all deaths in China.     

Mechanistic studies on aromatase and related C---C bond cleaving P-450 enzymes

Some P-450 systems, notably aromatase and 14-demethylase catalyse not only the hydroxylate reaction but also the oxidation of an alcohol into a carbonyl compound as well as a C---C bond cleavage process. All these reactions occur at the same active site. A somewhat analogous situation is noted with 17-hydroxylase-17,20-lyase that participates in hydroxylation as well as C---C bond cleavage process. The C---C bond cleavage reactions catalysed by the above enzymes conform to the general equation:

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It is argued that all three types of reaction catalyzed by these enzymes may be viewed as variations on a common theme. In P-450 dependent hydroxylation the initially formed Fe^III---O---O^. species is converted into Fe^III---O---OH and the heterolysis of the oxygen—oxygen bond of the latter then gives the oxo-derivative for which a number of canonical structures are possible; for example Fe^V = O ↔ (+^.)Fe^IV = O ↔ Fe^IV---O^.. One of these, Fe^IV---O^. behaves like an alkoxyl radical and participates in hydrogen abstraction from C---H bond to produce Fe^IV---OH and carbon radical. The latter is then quenched by the delivery of hydroxyl radical from Fe^IV---OH. The latter species may thus be regarded as a carrier of hydroxyl radical. We have proposed that the C---C bond cleavage reaction occurs through the participation of the Fe^III---O---OH species that is trapped by the electrophilic property of the carbonyl compound giving a peroxide adduct that fragments to produce an acyl—carbon cleavage. Scientific developments leading up to this conclusion are considered. In the first author's views,

“The study of mechanisms is not a scientific but a cultural activity. Mechanisms do not aim at an absolute truth but are intended to be a “running” commentary on the status of knowledge in a field. As the structural knowledge in a field advances Mechanisms evolve to take note of the new findings. Just as a constructive “running” commentary provides the stimulus for higher standards of performance, so Mechanisms call for better and firmer structural information from their practitioners”.     

White-Matter Development is Different in Bilingual and Monolingual Children: A Longitudinal DTI Study

Although numerous people grow up speaking more than one language, the impact of bilingualism on brain developing neuroanatomy is still poorly understood. This study aimed to determine whether the changes in the mean fractional-anisotropy (MFA) of language pathways are different between bilingual and monolingual children. Simultaneous-bilinguals, sequential-bilinguals and monolingual, male and female 10–13 years old children participated in this longitudinal study over a period of two years. We used diffusion tensor tractography to obtain mean fractional-anisotropy values of four language related pathways and one control bundle: 1-left-inferior-occipitofrontal fasciculus/lIFOF, 2-left-arcuate fasciculus/lAF/lSLF, 3-bundle arising from the anterior part of corpus-callosum and projecting to orbital lobe/AC-OL, 4-fibres emerging from anterior-midbody of corpus-callosum (CC) to motor cortices/AMB-PMC, 5- right-inferior-occipitofrontal fasciculus rIFOF as the control pathway unrelated to language. These values and their rate of change were compared between 3 groups. FA-values did not change significantly over two years for lAF/lSLF and AC-OL. Sequential-bilinguals had the highest degree of change in the MFA value of lIFOF, and AMB-PMC did not present significant group differences. The comparison of MFA of lIFOF yielded a significantly higher FA-value in simultaneous bilinguals compared to monolinguals. These findings acknowledge the existing difference of the development of the semantic processing specific pathway between children with different semantic processing procedure. These also support the hypothesis that age of second language acquisition affects the maturation and myelination of some language specific white-matter pathways.     

Hierarchical Novelty-Familiarity Representation in the Visual System by Modular Predictive Coding

Predictive coding has been previously introduced as a hierarchical coding framework for the visual system. At each level, activity predicted by the higher level is dynamically subtracted from the input, while the difference in activity continuously propagates further. Here we introduce modular predictive coding as a feedforward hierarchy of prediction modules without back-projections from higher to lower levels. Within each level, recurrent dynamics optimally segregates the input into novelty and familiarity components. Although the anatomical feedforward connectivity passes through the novelty-representing neurons, it is nevertheless the familiarity information which is propagated to higher levels. This modularity results in a twofold advantage compared to the original predictive coding scheme: the familiarity-novelty representation forms quickly, and at each level the full representational power is exploited for an optimized readout. As we show, natural images are successfully compressed and can be reconstructed by the familiarity neurons at each level. Missing information on different spatial scales is identified by novelty neurons and complements the familiarity representation. Furthermore, by virtue of the recurrent connectivity within each level, non-classical receptive field properties still emerge. Hence, modular predictive coding is a biologically realistic metaphor for the visual system that dynamically extracts novelty at various scales while propagating the familiarity information.