The Fanconi anemia pathway and ubiquitin

Fanconi anemia (FA) is a rare genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin. To date, 12 FA gene products have been identified, which cooperate in a common DNA damage-activated signaling pathway regulating DNA repair (the FA pathway). Eight FA proteins form a nuclear complex harboring E3 ubiquitin ligase activity (the FA core complex) that, in response to DNA damage, mediates the monoubiquitylation of the FA protein FANCD2. Monoubiquitylated FANCD2 colocalizes in nuclear foci with proteins involved in DNA repair, including BRCA1, FANCD1/BRCA2, FANCN/PALB2 and RAD51. All these factors are required for cellular resistance to DNA crosslinking agents. The inactivation of the FA pathway has also been observed in a wide variety of human cancers and is implicated in the sensitivity of cancer cells to DNA crosslinking agents. Drugs that inhibit the FA pathway may be useful chemosensitizers in the treatment of cancer

Correct your Text with Google

to appear in the Proceedings of the International Conference on Web Intelligence, IEEE 2007.International audienceWith the increasing amount of text files that are produced nowadays, spell checkers have become essential tools for everyday tasks of millions of end users. Among the years, several tools have been designed that show decent performances. Of course, grammatical checkers may improve corrections of texts, nevertheless, this requires large resources. We think that basic spell checking may be improved (a step towards) using the Web as a corpus and taking into account the context of words that are identified as potential misspellings. We propose to use the Google search engine and some machine learning techniques, in order to design a flexible and dynamic spell checker that may evolve among the time with new linguistic features

Deep unsupervised domain adaptation applied to the Cherenkov Telescope Array Large-Sized Telescope

The Cherenkov Telescope Array is the next generation of observatory using imaging air Cherenkov technique for very-high-energy gamma-ray astronomy. Its first prototype telescope is operational on-site at La Palma and its data acquisitions allowed to detect known sources, study new ones, and to confirm the performance expectations. The application of deep learning for the reconstruction of the incident particle physical properties (energy, direction of arrival and type) have shown promising results when conducted on simulations. Nevertheless, its application to real observational data is challenging because deep-learning-based models can suffer from domain shifts. In the present article, we address this issue by implementing domain adaptation methods into state-of-art deep learning models for Imaging Atmospheric Cherenkov Telescopes event reconstruction to reduce the domain discrepancies, and we shed light on the gain in performance that they bring along

Plant capitalism and company science: the Indian career of Nathaniel Wallich

The career of the Danish-born botanist Nathaniel Wallich, superintendent of the Calcutta Botanic Garden from 1815 to 1846, illustrates the complex nature of botanical science under the East India Company and shows how the plant life of South Asia was used as a capital resource both in the service of the Company's economic interests and for Wallich's own professional advancement and international reputation. Rather than seeing him as a pioneer of modern forest conservation or an innovative botanist, Wallich's attachment to the ideology of ‘improvement’ and the Company's material needs better explain his longevity as superintendent of the Calcutta garden. Although aspects of Wallich's career and botanical works show the importance of circulation between Europe and India, more significant was the hierarchy of knowledge in which indigenous plant lore and illustrative skill were subordinated to Western science and in which colonial science frequently lagged behind that of the metropolis

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event

Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report

CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)-a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55-199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing. © 2016 Wiley Periodicals, Inc

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype-first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior

Early neurological impairment and severe anemia in a newborn with Pearson syndrome

Background: Pearson marrow-pancreas syndrome (PS) is usually a fatal mitochondrial disease, mostly diagnosed during infancy or postmortem. PS is caused by the deletions or duplications of mitochondrial DNA (mtDNA). The tissue distribution and relative proportions of expressed abnormal mtDNA determine the phenotype and the clinical course. Materials and methods: We describe the case of a term baby boy who was diagnosed with PS early in the neonatal period due to severe aregenerative anemia and persistent lactic acidosis. Results: His neurological examination was abnormal since birth. Brain magnetic resonance imaging (MRI) at term was abnormal, indicating that mitochondrial encephalopathy in PS can be already manifested in the neonatal period. To our knowledge, neonatal encephalopathy in PS has not been previously described. Conclusion: PS is a rare condition diagnosed in the newborn. It should be suspected in the presence of severe anemia and persistent lactic acidosis, and may manifest with early encephalopath

Mitochondrial tRNALeu(UUR) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study

Mitochondrial tRNALeu(UUR) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNALeu(UUR) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected familie

Low complexity implementation of variable band filters using filters banks

The paper introduces an innovative method for variable passband filters synthesis using filters banks. This technique allows a fast filter passband modification with a low complexity implementation. This method, called Rcos, has been designed by deeply analysing the DFT (Discrete Fourier Transform) method, and the OLS (Overlap Save) method. By introducing an appropriate weighting during the selection of the elementary frequency bands which belong to the desired filter, it is possible to reduce the aliasing effect due to the time varying behavior of the filter, and to obtain a simple and efficient method which has a lower complexity than that of OLS. The paper’s contribution is the analysis, the development and the comparison between the different methods.Nous présentons dans cet article une méthode originale de synthèse de filtres à bande passante variable à l'aide des bancs de filtres qui permettent une faible complexité d'implémentation et un changement rapide de la bande passante. Cette méthode, que nous appellerons Rcos, s'appuie sur une analyse approfondie de la méthode TFD (Transformée de Fourier Discrète) et de la méthode OLS (Overlap Save). En introduisant une pondération lors de la sélection des bandes de fréquence élémentaires composant le filtre souhaité, il est possible de réduire l'effet de repliement dû au comportement variant dans le temps du filtre, et d'obtenir ainsi une méthode simple et rapide de synthèse de filtre à bandes passantes variables qui possède de plus une complexité inférieure à l'OLS. La contribution de cet article consiste donc en l'analyse, le développement et la comparaison des différentes méthodes