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.     

Ras regulatory interactions: Novel targets for anti-cancer intervention?

Advances in the understanding of Ras oncoprotein function suggest novel points for anti-tumor intervention. First, upstream-acting guanine nucleotide exchange factors and SH2/SH3 domain-containing adaptor proteins that link Ras with growth factor receptor tyrosine kinases have recently been characterized. Second, work on downstream-acting Ras effector functions including the Ras GTPase-activating protein (p120^GAP) and the Raf kinase has revealed direct biochemical interactions that are functionally required for oncogenic Ras signalling. We summarize progress in these areas and discuss the potential for novel applications to anti-cancer chemotherapy.     

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.     

DBA/2J Genetic Background Exacerbates Spontaneous Lethal Seizures but Lessens Amyloid Deposition in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APP^swe and PSEN1^de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1^de9 has not been tested. Our study shows that DBA/2J.APP^swePSEN1^de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APP^swePSEN1^de9 mice—70% of DBA/2J.APP^swePSEN1^de9 mice die between 2-3 months of age. Of the DBA/2J.APP^swePSEN1^de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APP^swePSEN1^de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.     

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.     

Structure-function analysis of the rat prolactin promoter: phasing requirements of proximal cell-specific elements

Expression of PRL, a member of the GH family of genes, is restricted to the lactotroph cells of the anterior pituitary. The proximal promoter of the rat PRL (rPRL) gene contains four factor-binding sites. Three nonadjacent elements, footprints (FP) I, III, and IV, are separated by an integral number of helical turns and bind a pituitary-specific factor, LSF-1. FP II binds another factor present in pituitary and nonpituitary cells. The mechanisms by which DNA-bound proteins influence RNA polymerase-II activity over large distances are not fully understood, but protein-protein interactions, with looping of intervening DNA, may bring distant sites into close proximity. Here, we demonstrate, using protein titration studies, that LSF-1 binds to the most proximal FP I element with the highest affinity, whereas it binds the more distal elements, FP III and FP IV, with progressively lower affinities. Time-course and salt-sensitivity studies reveal that binding of LSF-1 to all three pituitary-specific rPRL promoter sites occurs rapidly (less than or equal to 1 min) and requires fairly high salt concentrations (greater than or equal to 300 mM KCl) to destabilize protein-DNA interactions. Moreover, once bound, the pituitary nuclear factor(s) induces a conformational change in rPRL DNA structure with greatly delayed kinetics (greater than 15 min) and at a different salt concentration than are required for simply factor binding. Taken together, these data suggest a model in which LSF-1 initially binds fairly rapidly to multiple nonadjacent elements and then interacts with itself or other DNA-bound proteins much more slowly, possibly looping or bending the rPRL promoter.(ABSTRACT TRUNCATED AT 250 WORDS)