Combining Near Infrared Spectroscopy and functional MRI during Continuous Performance Test in healthy subjects

Proceedings of the 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS'06: pp. 1944-1947.The study of cognitive functions is a major challenge of the modern functional imaging. Activation of specific cerebral area is obtained from the observation of physic characteristic affected by changes occurring in the blood flow resulting from an increased metabolic consumption. In this work two imaging techniques are used, the functional magnetic resonance (fMRI) and the Near Infrared Spectroscopy (NIRS), in order to assess cerebral performance during the execution of a well known sustained attention task, the Conners’ Continuous Performance Test (CPT). With fMRI analysis were found activations in the frontal, parietal and supplementary motor areas, whereas NIRS system showed a region-wise difference in the variations of parameters and different activation trend localized in the middle-right frontal area. The combined analysis of the two techniques allows to obtain more detailed information and places itself as a first step toward a result of multimodal image integration

Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models

Purpose: DNA polymerase theta (Polθ, encoded by the POLQ gene) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. In this study we evaluate whether targeting Polθ with novel small-molecule inhibitors is a feasible strategy to improve the efficacy of radiotherapy. Experimental Design: We characterized the response to Polθ inhibition in combination with ionizing radiation in different cancer cell models in vitro and in vivo. Results: Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, noncancerous cells were not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared with radiation alone. Conclusions: These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy

Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication

The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints. \ua92014 Macmillan Publishers Limited. All rights reserved

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella

Multimodal analysis of a sustained attention protocol: Continuous performance test assessed with near infrared spectroscopy and EEG

The aim of this work is to describe, using functional imaging techniques, the spatial and temporal distribution of neural activations ensuing from execution of cognitive functions and to rind correlation in data coming from analysis modalities related to different physical properties. A 10-min continuous performance test (CPT) was administered to a group of healthy subjects as measure of sustained attention. Images of Electroencephalography (EEG) and of Near Infrared Spectroscopy (NIRS) were recorded during the task. Cerebral activation's measure is obtained from the recording of quantities linked with electrical neural activity for the EEG and with change in blood oxygenation for the NIRS system. Good agreement was found between the two modalities, both showing higher activation in the middle upper frontal region and similar temporal trend. A further understanding of the superior central nervous system behavior can be achieved from combined use of both imaging modalities

Combining near infrared spectroscopy and functional MRI during continuous performance test in healthy subjects

The study of cognitive functions is a major challenge of the modern functional imaging. Activation of specific cerebral area is obtained from the observation of physic characteristic affected by changes occurring in the blood flow resulting from an increased metabolic consumption. In this work two imaging techniques are used, the functional magnetic resonance (fMRI) and the Near Infrared Spectroscopy (NIRS), in order to assess cerebral performance during the execution of a well known sustained attention task, the Conners' Continuous Performance Test (CPT). With fMRI analysis were found activations in the frontal, parietal and supplementary motor areas, whereas NIRS system showed a region-wise difference in the variations of parameters and different activation trend localized in the middle-right frontal area. The combined analysis of the two techniques allows to obtain more detailed information and places itself as a first step toward a result of multimodal image integration

The use of siderophores for improving the control of postharvest diseases in stored fruits and vegetables

Penicillium expansum and Botrytis cinerea are well-known postharvest pathogens. They produce blue rot and gray rot, respectively. Biocontrol, an alternative to fungicides for the control of these phytopathogens, employs saprophytic microorganisms that protect fruits and vegetables from infection. However, it appears that control of postharvest diseases with antagonistic microorganisms is not often as consistent as control with synthetic fungicides. At this point, microbial metabolites may help improve control of plant pathogens either by enhancing the action of antagonistic microorganisms or by providing tools to develop healthier alternatives than synthetic chemical fungicides. Particularly, the siderophores, ferric chelating agents of low molecular weight, produced by yeasts and bacteria can significantly improve control by antagonistic microorganisms especially if their mechanism of action is the competition for nutrients. Also, the siderophores can interfere with the action of the pathogens because may inhibit enzymes important for their installation in the wounds of post-harvest fruit. Rhodotorulic acid produced by Rhodotorula glutinis and Enterochelin produced by Rahnella aquatilis, siderophores of different chemical nature, can be applied with success in the control of P. expansum and B. cinerea. This chapter describes the production and application of siderophores, and also shows as these metabolites allow the design of new and improved strategies for the control of postharvest pathogens.Fil: Sanz Ferramola, Maria Isabel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Benuzzi, Delia Aurora. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Calvente, Viviana Edith. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Calvo, Juan Armando. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Sansone, María Gabriela. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; ArgentinaFil: Cerutti, Estela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Raba, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; Argentin

Telomerase abrogates aneuploidy‐induced telomere replication stress, senescence and cell depletion

The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy‐controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb‐dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase‐deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy‐induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction