Publication date: Available online 7 October 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Markus Christmann, Bernd Kaina
DNA repair represents the first barrier against genotoxic stress causing metabolic changes, inflammation and cancer. Besides its role in preventing cancer, DNA repair needs also to be considered during cancer treatment with radiation and DNA damaging drugs as it impacts therapy outcome. The DNA repair capacity is mainly governed by the expression level of repair genes. Alterations in the expression of repair genes can occur due to mutations in their coding or promoter region, changes in the expression of transcription factors activating or repressing these genes, and/or epigenetic factors changing histone modifications and CpG promoter methylation or demethylation levels. In this review we provide an overview on the epigenetic regulation of DNA repair genes. We summarize the mechanisms underlying CpG methylation and demethylation, with de novo methyltransferases and DNA repair involved in gain and loss of CpG methylation, respectively. We discuss the role of components of the DNA damage response, p53, PARP-1 and GADD45a on the regulation of the DNA (cytosine-5)-methyltransferase DNMT1, the key enzyme responsible for gene silencing. We stress the relevance of epigenetic silencing of DNA repair genes for tumor formation and tumor therapy. A paradigmatic example is provided by the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), which is silenced in up to 40% of various cancers through CpG promoter methylation. The CpG methylation status of the MGMT promoter strongly correlates with clinical outcome and, therefore, is used as prognostic marker during glioblastoma therapy. Mismatch repair genes are also subject of epigenetic silencing, which was shown to correlate with colorectal cancer formation. For many other repair genes shown to be epigenetically regulated the clinical outcome is not yet clear. We also address the question of whether genotoxic stress itself can lead to epigenetic alterations of genes encoding proteins involved in the defense against genotoxic stress.
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Κυριακή 8 Οκτωβρίου 2017
Epigenetic regulation of DNA repair genes and implications for tumor therapy
Fast in situ gamma spectroscopy using hand-held spectrometer with NaI probe
Source:Journal of Environmental Radioactivity
Author(s): Szymon Guguła, Krzysztof Kozak, Jadwiga Mazur, Dominik Grządziel, Mariusz Mroczek
In this work a hand-held spectrometer InSpector 1000 with NaI (Tl) 2″ x 2″ detector has been adapted to fast in situ gamma-ray spectroscopy. Two specially designed mounting stands with shielding have been built, allowing conducting measurements in different geometries. Three particular geometries (NW, IS50, IS00) have been chosen for efficiency calibration and further study. The first one (NW) is intended for small environmental samples (volume ca 140 cm3) collected on site. IS50 geometry is a typical in situ geometry meant for radioactivity measurements in soil with detector pointed towards the ground. In this geometry the probe is shielded and mounted 50 cm above the soil surface. The new proposed geometry IS00 is designed in the way that the detector is inserted directly into the soil in order to increase the counting efficiency. The methods of efficiency calibration involved using calibration standards (in NW geometry) and the results obtained in previous in situ measurements with InSpector 2000 portable spectrometer with HPGe detector and ISOCS™ Shield Systems, which is routinely used in environmental measurements.NW geometry turned out to be useful for natural radioisotopes concentrations (K-40, U-238 and Th-232), which significantly exceed typical values of those concentrations observed in Poland. Both IS50 and IS00 geometries are applicative for quick (2 h long measurement) evaluation of typical concentrations of K, U and Th in soils. The newly proposed geometry IS00 is superior as it showed lower detection limits and uncertainties as well as its handling was far easier than of IS50. Authors have proven that hand-held spectrometer InSpector 1000, together with mounting stands and shielding, can be successfully used for fast in situ gamma-spectroscopy. Its relatively small weight and good mobility are additional assets. Moreover, detailed procedures for measurements in each geometry have been developed to conduct such analyses properly.
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Eyes have ears: Indexing the orienting response to sound using pupillometry
Source:International Journal of Psychophysiology
Author(s): Alexandre Marois, Katherine Labonté, Mark Parent, François Vachon
The rare occurrence of a sound deviating from the auditory background tends to trigger attentional orienting. While some sympathetic physiological responses can be used to index this orienting response, findings surrounding the pupillary dilation response (PDR) as a proxy for the orienting response are conflicting. The current study was tailor-designed to examine whether the PDR satisfies specific criteria of an orienting response index, namely the classic habituation pattern and a sensitivity to the size of the deviation. The PDR decrement to a repeated standard sound, recovery to a deviant sound, and dishabituation to the re-presentation of the standard were assessed for small and large deviations embedded in irrelevant auditory sequences. The PDR not only showed habituation and dishabituation, but also recovered in correspondence with the magnitude of the acoustic deviation. This consistency between variations of the PDR and orienting response's properties indicates that the PDR is a valid index of the auditory orienting response.
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Using theta and alpha band power to assess cognitive workload in multitasking environments
Source:International Journal of Psychophysiology
Author(s): Sébastien Puma, Nadine Matton, Pierre-V. Paubel, Éric Raufaste, Radouane El-Yagoubi
Cognitive workload is of central importance in the fields of human factors and ergonomics. A reliable measurement of cognitive workload could allow for improvements in human machine interface designs and increase safety in several domains. At present, numerous studies have used electroencephalography (EEG) to assess cognitive workload, reporting the rise in cognitive workload to be associated with increases in theta band power and decreases in alpha band power. However, results have been inconsistent with some failing to reach the required level of significance. We hypothesized that the lack of consistency could be related to individual differences in task performance and/or to the small sample sizes in most EEG studies. In the present study we used EEG to assess the increase in cognitive workload occurring in a multitasking environment while taking into account differences in performance. Twenty participants completed a task commonly used in airline pilot recruitment, which included an increasing number of concurrent sub-tasks to be processed from one to four. Subjective ratings, performances scores, pupil size and EEG signals were recorded. Results showed that increases in EEG alpha and theta band power reflected increases in the involvement of cognitive resources for the completion of one to three subtasks in a multitasking environment. These values reached a ceiling when performances dropped. Consistent differences in levels of alpha and theta band power were associated to levels of task performance: highest performance was related to lowest band power.
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Homozygous indel mutation in CDH11 as the probable cause of Elsahy–Waters syndrome
Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy–Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell–cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).
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Pitfalls and errors in measuring jitter
Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): Erik Stålberg, Donald B. Sanders, João Aris Kouyoumdjian
The safety factor of neuromuscular transmission can be assessed by measuring the neuromuscular jitter, which reflects the time variability of processes in the motor end-plate. Jitter is increased in any condition with disturbed end-plate function, such as myasthenic conditions and ongoing reinnervation. Jitter is increasingly being measured with concentric needle (CN) electrodes, which are more prone to artefacts than single fiber EMG recordings.The objective of this review is to identify and demonstrate pitfalls that can be seen with CN jitter measurements, made with both voluntary activation and electrical stimulation.With voluntary activation, errors are caused by poor signal quality; inappropriate time reference points on the signal; an irregular firing rate; and signals with dual latencies, i.e., "flip-flop." With electrical stimulation, additional errors result from insufficient stimulation intensity; from abrupt change in firing rate; and from axon reflexes.Many pitfalls cannot be avoided during recording and can only be detected during post-processing.It is critical to be aware of these artefacts when measuring jitter with CN electrodes.
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Eye movements in genetic parkinsonisms affecting the α-synuclein, PARK9, and manganese network
Source:Clinical Neurophysiology
Author(s): Elena Pretegiani, Francesca Rosini, Antonio Federico, Lance M. Optican, Alessandra Rufa
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