Computing the Mertens and Meissel-Mertens constants for sums over arithmetic progressions

We give explicit numerical values with 100 decimal digits for the Mertens constant involved in the asymptotic formula for $\sum\limits_{\substack{p\leq x p\equiv a \bmod{q}}}1/p$ and, as a by-product, for the Meissel-Mertens constant defined as $\sum_{p\equiv a \bmod{q}} (\log(1-1/p)+1/p)$, for $q \in \{3$, ..., $100\}$ and $(q, a) = 1$.Comment: 12 pages, 6 table

Time and space in Tristram Shandy and other eighteenth century novels : the issues of progression and continuity.

The thesis argues that the narratives of the eighteenth-century novels selected for this study demonstrate a conscious manipulation of time and space, and that the consequence of this manipulation is to provide the reader with a unique literary journey through the text. The thesis, in its analysis and comparison of these distinctive journeys, chooses to focus on the narrative techniques which facilitate or hamper progression and continuity within the texts. It particularly concentrates on the impact of these narrative techniques on the reading experience. The first chapter studies and compares texts resorting mainly to the present tense with those predominantly written in the past tense. It examines the effects of the tense used in the narration on the reader's engrossment in the fiction. The second chapter concentrates on the repercussions of the author's choice of a beginning and an ending for his story on the nature of the progression of the narrative. The third chapter is devoted to the destabilising reading journey offered by Tristram Shandy. It examines the numerous techniques which react against continuity and progression in time and in space, and the narrator's motivation behind their use. It shows how the narrative choices of Tristram Shandy place the reader face to face with his own act of reading. The fourth and final chapter is concerned with the role and the status of fictional footnotes in some eighteenth-century prose fictions. It demonstrates the fictional nature of the footnotes in Tom Jones. It argues that fictional footnotes affect the reader's progression across the text in time and in space as well as his understanding of the work of fiction, and this in a fundamental way

Myotonic dystrophies : state of the art of new therapeutic developments for the CNS

Myotonic dystrophies are multisystemic diseases characterized not only by muscle and heart dysfunction but also by CNS alteration. They are now recognized as brain diseases affecting newborns and children for myotonic dystrophy type 1 and adults for both myotonic dystrophy type 1 and type 2. In the past two decades, much progress has been made in understanding the mechanisms underlying the DM symptoms allowing development of new molecular therapeutic tools with the ultimate aim of curing the disease. This review describes the state of the art for the characterization of CNS related symptoms, the development of molecular strategies to target the CNS as well as the available tools for screening and testing new possible treatments

The expansion of 300 CTG repeats in myotonic dystrophy transgenic mice does not induce sensory or motor neuropathy

Summary: Although many studies have been carried out to verify the involvement of the peripheral nervous system (PNS) in dystrophia myotonica (DM1) patients, the results remain controversial. The generation of DM1 transgenic mice displaying the human DM1 phenotype provides a useful tool to investigate the type and incidence of structural abnormalities in the PNS. In the present study, the morphological and morphometric analysis of semi-thin sections of sciatic and sural nerves, lumbar dorsal root ganglia (DRG) and lumbar spinal cords revealed that in DM1 transgenic mice carrying 300 CTG repeats, there is no change in the number and diameter of myelinated axons compared to wild type. Only a non-significant reduction in the percentage of thin myelinated axons was detected in electron micrographs of ultra-thin sciatic nerve sections. Analysis of the number of neurons did not reveal a loss in number of either sensory neurons in the lumbar DRG or motor neurons in the lumbar spinal cord in these DM1 mice. Furthermore, in hind limb muscle sections, stained with a neurofilament antibody and α-bungarotoxin, the intramuscular axon arborization appeared normal in DM1 mice and undistinguishable from that in wild-type mice. Moreover, in DM1 mice, there was no irregularity in the structure or an increase in the endplate area. Also statistical analysis did not show an increase in endplate density or in the concentration of acetylcholine receptors. Altogether, these results suggest that 300 CTG repeats are not sufficient to induce axonopathy, demyelination or neuronopathies in this transgenic mouse mode

CRISPR/Cas9-induced (CTG⋅CAG)n repeat instability in the myotonic dystrophy type 1 locus: implications for therapeutic genome editing

Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG)n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5′ or 3′ unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1

A high-resolution image time series of the Gorner Glacier – Swiss Alps – derived from repeated unmanned aerial vehicle surveys

Modern drone technology provides an efficient means to monitor the response of alpine glaciers to climate warming. Here we present a new topographic dataset based on images collected during 10 UAV surveys of the Gorner Glacier glacial system (Switzerland) carried out approximately every 2 weeks throughout the summer of 2017. The final products, available at https://doi.org/10.5281/zenodo.2630456 (Benoit et al., 2018), consist of a series of 10&thinsp;cm resolution orthoimages, digital elevation models of the glacier surface, and maps of ice surface displacement. Used on its own, this dataset allows mapping of the glacier and monitoring surface velocities over the summer at a very high spatial resolution. Coupled with a classification or feature detection algorithm, it enables the extraction of structures such as surface drainage networks, debris, or snow cover. The approach we present can be used in the future to gain insights into ice flow dynamics.</p

Aberrant splicing and expression of the non muscle myosin heavy-chain gene MYH14 in DM1 muscle tissues

Myotonic dystrophy type 1 (DM1) is a complex multisystemic disorder caused by an expansion of a CTG repeat located at the 3' untranslated region (UTR) of DMPK on chromosome 19q13.3. Aberrant messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms of DM1 including insulin resistance, muscle wasting and myotonia. In this paper we analyzed the expression of the MYH14 mRNA and protein in the muscle of DM1 patients (n=12) with different expansion lengths and normal subjects (n=7). The MYH14 gene is located on chromosome 19q13.3 and encodes for one of the heavy chains of the so called class II "nonmuscle" myosins (NMHCII). MYH14 has two alternative spliced isoforms: the inserted isoform (NMHCII-C1) which includes 8 amino acids located in the globular head of the protein, not encoded by the non inserted isoform (NMHCII-C0). Results showed a splicing unbalance of the MYH14 gene in DM1 muscle, with a prevalent expression of the NMHCII-C0 isoform more marked in DM1 patients harboring large CTG expansions. Minigene assay indicated that levels of the MBNL1 protein positively regulates the inclusion of the MYH14 exon 6. Quantitative analysis of the MYH14 expression revealed a significant reduction in the DM1 muscle samples, both at mRNA and protein level. No differences were found between DM1 and controls in the skeletal muscle localization of MYH14, obtained through immunofluorescence analysis. In line with the thesis of an "RNA gain of function" hypothesis described for the CTG mutation, we conclude that the alterations of the MYH14 gene may contribute to the DM1 molecular pathogenesis

Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.

Obesity and extracellular matrix (ECM) density are considered independent risk and prognostic factors for breast cancer. Whether they are functionally linked is uncertain. We investigated the hypothesis that obesity enhances local myofibroblast content in mammary adipose tissue and that these stromal changes increase malignant potential by enhancing interstitial ECM stiffness. Indeed, mammary fat of both diet- and genetically induced mouse models of obesity were enriched for myofibroblasts and stiffness-promoting ECM components. These differences were related to varied adipose stromal cell (ASC) characteristics because ASCs isolated from obese mice contained more myofibroblasts and deposited denser and stiffer ECMs relative to ASCs from lean control mice. Accordingly, decellularized matrices from obese ASCs stimulated mechanosignaling and thereby the malignant potential of breast cancer cells. Finally, the clinical relevance and translational potential of our findings were supported by analysis of patient specimens and the observation that caloric restriction in a mouse model reduces myofibroblast content in mammary fat. Collectively, these findings suggest that obesity-induced interstitial fibrosis promotes breast tumorigenesis by altering mammary ECM mechanics with important potential implications for anticancer therapies