Automatic and Controlled Information Processing in Alzheimer\u27s Disease

This research investigation explored the cognitive processing operations of 18 healthy elderly (HE) subjects and 12 Alzheimer\u27s Disease (AD) subjects in the mild clinical stage of the disease in their performance on a semantic priming task involving semantic lexical activations of both automatic and controlled processing natures. Relatively little conclusive evidence has been documented regarding the relative roles of attention and memory processing in the lexical-semantic impairment of Alzheimer\u27s Disease. A lexical decision processing task was implemented to investigate the effects of normal aging and neuropathological damage of Alzheimer\u27s Disease on subjects\u27 semantic priming abilities. The research design was based on the growing body of literature reporting successful procedural use of priming techniques with HE and AD subjects, as well as the fact that temporal boundaries reflecting attention-dependent and non-attention dependent processing have been suggested, particularly with healthy young populations. Findings of this investigation revealed that healthy elderly subjects demonstrate priming of a facilitative nature, at both automatic and controlled temporal processing boundaries, whereas AD subjects demonstrated priming due to inhibition at long controlled temporal processing boundaries. Implications of these findings relative to normal age-related changes in language function and progressive lexical semantic impairment in AD are addressed

Two-photon luminescence of gold nanorods: applications to single-particle tracking and spectroscopy

Gold nanorods are biocompatible nanoparticles that present an excellent two-photon signal that can be used to get high spatial resolution inside living cells. Gold nanorods are photostable and therefore can be followed inside cells for long time, with possible applications as trackers in live cells. We explored the use of gold nanorods as labels for single-particle tracking in live cells, both not functionalized and functionalized with nuclear localization signal for nuclear targeting. For single-particle tracking we used mean square displacement analysis, after characterizing the limitations of this analysis with simulations. We also tested the acquisition of excitation spectra of single gold nanorods for sensing applications.FOMBiological and Soft Matter Physic

Testing the metal of ERCC2 in predicting the response to platinum-based therapy

DNA repair has been shown to affect the cellular response to platinum-based therapy in a variety of cancers; however, translating this knowledge to the clinic has proven difficult and yielded mixed results. In this issue of Cancer Discovery, Van Allen and colleagues have analyzed responders and nonresponders to neoadjuvant platinum-based therapy with locally advanced urothelial cancer and identified a series of mutations in the nucleotide excision repair (NER) gene ERCC2 that correlate with the response to platinum-based therapy. This work provides evidence that defects in NER can be exploited to maximize the efficacy of conventional platinum-based chemotherapy

Accuracy of the detection of binding events using 3d single particle tracking

Biological and Soft Matter Physic

DNA repair targeted therapy: The past or future of cancer treatment?

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy

Unraveling the Complexities of DNA-Dependent Protein Kinase Autophosphorylation

DNA-dependent protein kinase (DNA-PK) orchestrates DNA repair by regulating access to breaks through autophosphorylations within two clusters of sites (ABCDE and PQR). Blocking ABCDE phosphorylation (by alanine mutation) imparts a dominant negative effect, rendering cells hypersensitive to agents that cause DNA double-strand breaks. Here, a mutational approach is used to address the mechanistic basis of this dominant negative effect. Blocking ABCDE phosphorylation hypersensitizes cells to most types of DNA damage (base damage, cross-links, breaks, and damage induced by replication stress), suggesting that DNA-PK binds DNA ends that result from many DNA lesions and that blocking ABCDE phosphorylation sequesters these DNA ends from other repair pathways. This dominant negative effect requires DNA-PK's catalytic activity, as well as phosphorylation of multiple (non-ABCDE) DNA-PK catalytic subunit (DNA-PKcs) sites. PSIPRED analysis indicates that the ABCDE sites are located in the only contiguous extended region of this huge protein that is predicted to be disordered, suggesting a regulatory role(s) and perhaps explaining the large impact ABCDE phosphorylation has on the enzyme's function. Moreover, additional sites in this disordered region contribute to the ABCDE cluster. These data, coupled with recent structural data, suggest a model whereby early phosphorylations promote initiation of nonhomologous end joining (NHEJ), whereas ABCDE phosphorylations, potentially located in a “hinge” region between the two domains, lead to regulated conformational changes that initially promote NHEJ and eventually disengage NHEJ

La rivière et sa mise en paysage dans les parcs et jardins : étude de cas dans l'Ouest français

L\u27objectif de cet article est d\u27étudier les formes de mobilisation de la ressource en eau (énergétique, esthétique) dans les parcs et jardins. Deux hypothèses seront examinées : les parcs et jardins sont des motifs paysagers pertinents pour observer les trajectoires d\u27usage de la ressource en eau et ses conséquences hydrodynamiques ; l\u27artificialisation des hydrosystèmes n\u27est pas toujours synonyme de dégradation mais peut au contraire être génératrice de diversité paysagère et d\u27ingéniosité hydraulique (Baridon, 2007). Il s\u27agit d\u27aborder ces espaces sous l\u27angle géo-historique enrichi de l\u27histoire de l\u27art des parcs et jardins. Dans un premier temps, nous proposerons une description des sites d\u27étude avant d’analyser les projets et les intentions hydrauliques. Les paysages construits sont ensuite analysés afin de mettre en exergue les transformations des formes et les dynamiques fluviales entre la Renaissance et le XXIe siècle. La recherche se fonde sur deux études de cas choisies dans le bassin versant du Couasnon (265 km²), rivière angevine tributaire de la Loire. La démarche retenue associe : une lecture systémique de la trajectoire des paysages fluviaux où les formes fluviales mises en projet sont abordées comme l\u27expression d\u27une interaction nature/société ; une caractérisation des aménagements hydrauliques du parc dans le contexte de la vallée. L\u27étude s\u27appuie sur l\u27analyse diachronique de séries de cartes et de plans, de photographies et d\u27observations de terrain

The Need for a Specific Risk Prediction System in Native Valve Infective Endocarditis Surgery

The need for a specific risk score system for infective endocarditis (IE) surgery has been previously claimed. In a single-center pilot study, preliminary to future multicentric development and validation, bivariate and multivariate (logistic regression) analysis of early postoperative mortality predictors in 440 native valve IE patients were performed. Mathematical procedures assigned scores to the independent predictors emerged (AUC of the ROC curve: 0.88). Overall mortality was 9.1%. Six predictors were identified and assigned scores, including age (5–13 points), renal failure (5), NYHA class IV (9), critical preoperative state (11), lack of preoperative attainment of blood culture negativity (5), perivalvular involvement (5). Four risk classes were drawn ranging from “very low risk” (≤5 points, mean predicted mortality 1%), and to “very high risk” (≥20 points, 43% mortality). IE-specific risk stratification models are both needed, as disease-specific factors (e.g., cultures, abscess), beside the generic ones (e.g., age, renal impairment) affect mortality, and feasible

Structure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors

Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA–DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents