Limitations of dual-sgRNA CRISPR strategies for the treatment of CNS genetic disorders

International audienc

Promotility Action of the Probiotic Bifidobacterium lactis HN019 Extract Compared with Prucalopride in Isolated Rat Large Intestine

Copyright © 2017 Dalziel, Anderson, Peters, Lynch, Spencer, Dekker and Roy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Attention is increasingly being focussed on probiotics as potential agents to restore or improve gastrointestinal (GI) transit. Determining mechanism of action would support robust health claims. The probiotic bacterium Bifidobacterium lactis HN019 reduces transit time, but its mechanisms of action and effects on motility patterns are poorly understood. The aim of this study was to investigate changes in GI motility induced by an extract of HN019 on distinct patterns of colonic motility in isolated rat large intestine, compared with a known promotility modulator, prucalopride. The large intestines from male Sprague Dawley rats (3–6 months) were perfused with Kreb's buffer at 37°C in an oxygenated tissue bath. Isometric force transducers recorded changes in circular muscle activity at four independent locations assessing contractile propagation between the proximal colon and the rectum. HN019 extract was perfused through the tissue bath and differences in tension and frequency quantified relative to pre-treatment controls. Prucalopride (1 μM) increased the frequency of propagating contractions (by 75 ± 26%) in the majority of preparations studied (10/12), concurrently decreasing the frequency of non-propagating contractions (by 50 ± 11%). HN019 extract had no effect on contractile activity during exposure (n = 8). However, following wash out, contraction amplitude of propagating contractions increased (by 55 ± 18%) in the distal colon, while the frequency of non-propagating proximal contractions decreased by 57 ± 7%. The prokinetic action of prucalopride increased the frequency of synchronous contractions along the length of colon, likely explaining increased colonic rate of transit in vivo. HN019 extract modified motility patterns in a different manner by promoting propagating contractile amplitude and inhibiting non-propagations, also demonstrating prokinetic activity consistent with the reduction of constipation by B. lactis HN019 in humans

Dynamic responses of B acteroides thetaiotaomicron during growth on glycan mixtures

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98163/1/mmi12228-sup-0001-si.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/98163/2/mmi12228.pd

New M, L, and T Dwarf Companions to Nearby Stars from the Wide-field Infrared Survey Explorer

We present 11 candidate late-type companions to nearby stars identified with data from the Wide-field Infrared Survey Explorer (WISE) and the Two Micron All Sky Survey (2MASS). Eight of the candidates are likely to be companions based on their common proper motions with the primaries. The remaining three objects are rejected as companions, one of which is a free-floating T7 dwarf. Spectral types are available for five of the companions, which consist of M2V, M8.5V, L5, T8, and T8. Based on their photometry, the unclassified companions are probably two mid-M dwarfs and one late-M/early-L dwarf. One of the T8 companions, WISE J142320.84+011638.0, has already been reported by Pinfield and coworkers. The other T8 companion, ULAS J095047.28+011734.3, was discovered by Burningham and coworkers through the United Kingdom Infrared Telescope Infrared Deep Sky Survey, but its companionship has not been previously recognized in the literature. The L5 companion, 2MASS J17430860+8526594, is a new member of a class of L dwarfs that exhibit unusually blue near-IR colors. Among the possible mechanisms that have been previously proposed for the peculiar colors of these L dwarfs, low metallicity does not appear to be a viable explanation for 2MASS J17430860+8526594 since our spectrum of the primary suggests that its metallicity is not significantly subsolar

Transmission dynamics and control of multidrug-resistant Klebsiella pneumoniae in neonates in a developing country.

Multidrug-resistant Klebsiella pneumoniae is an increasing cause of infant mortality in developing countries. We aimed to develop a quantitative understanding of the drivers of this epidemic by estimating the effects of antibiotics on nosocomial transmission risk, comparing competing hypotheses about mechanisms of spread, and quantifying the impact of potential interventions. Using a sequence of dynamic models, we analysed data from a one-year prospective carriage study in a Cambodian neonatal intensive care unit with hyperendemic third-generation cephalosporin-resistant K. pneumoniae. All widely-used antibiotics except imipenem were associated with an increased daily acquisition risk, with an odds ratio for the most common combination (ampicillin + gentamicin) of 1.96 (95% CrI 1.18, 3.36). Models incorporating genomic data found that colonisation pressure was associated with a higher transmission risk, indicated sequence type heterogeneity in transmissibility, and showed that within-ward transmission was insufficient to maintain endemicity. Simulations indicated that increasing the nurse-patient ratio could be an effective intervention

The Carnegie Supernova Project: Analysis of the First Sample of Low-Redshift Type-Ia Supernovae

We present the analysis of the first set of low-redshift Type Ia supernovae (SNe Ia) by the Carnegie Supernova Project. Well-sampled, high-precision optical (ugriBV) and near-infrared (NIR; YJHKs) light curves obtained in a well-understood photometric system are used to provide light-curve parameters, and ugriBVYJH template light curves. The intrinsic colors at maximum light are calibrated to compute optical--NIR color excesses for the full sample, thus allowing the properties of the reddening law in the host galaxies to be studied. A low value of Rv~1.7, is derived when using the entire sample of SNe. However, when the two highly reddened SNe in the sample are excluded, a value Galactic standard of Rv~3.2 is obtained. The colors of these two events are well matched by a reddening model due to circumstellar dust. The peak luminosities are calibrated using a two-parameter linear fit to the decline rates and the colors, or alternatively, the color excesses. In both cases, dispersions in absolute magnitude of 0.12--0.16 mag are obtained, depending on the filter-color combination. In contrast to the results obtained from color excesses, these fits give Rv~1--2, even when the two highly reddened SNe are excluded. This discrepancy suggests that, beyond the "normal" interstellar reddening produced in the host galaxies, there is an intrinsic dispersion in the colors of SNe Ia which is correlated with luminosity but independent of the decline rate. Finally, a Hubble diagram is produced by combining the results of the fits for each filter. The resulting scatter of 0.12 mag appears to be limited by peculiar velocities as evidenced by the strong correlation between the distance-modulus residuals among the different filters. The implication is that the actual precision of SN Ia distances is 3--4%.Comment: 76 pages, 20 figures, accepted for publication in A

Cocapture of cognate and bystander antigens can activate autoreactive B cells

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with autoimmune central nervous system diseases like acute disseminated encephalomyelitis (ADEM). For ADEM, it is speculated that a preceding infection is the trigger of the autoimmune response, but the mechanism connecting the infection to the production of MOG antibodies remains a mystery. We reasoned that the ability of B cells to capture cognate antigen from cell membranes, along with small quantities of coexpressed “bystander” antigens, might enable B-cell escape from tolerance. We tested this hypothesis using influenza hemagglutinin as a model viral antigen and transgenic, MOG-specific B cells. Using flow cytometry and live and fixed cell microscopy, we show that MOG-specific B cells take up large amounts of MOG from cell membranes. Uptake of the antigen from the membrane leads to a strong activation of the capturing B cell. When influenza hemagglutinin is also present in the membrane of the target cell, it can be cocaptured with MOG by MOG-specific B cells via the B-cell receptor. Hemagglutinin and MOG are both presented to T cells, which in turn are activated and proliferate. As a consequence, MOG-specific B cells get help from hemagglutinin-specific T cells to produce anti-MOG antibodies. In vivo, the transfer of MOG-specific B cells into recipient mice after the cocapture of MOG and hemagglutinin leads to the production of class-switched anti-MOG antibodies, dependent on the presence of hemagglutinin-specific T cells. This mechanism offers a link between infection and autoimmunity. Keywords: tolerance; autoantibodies; antigen capture; antigen presentation; influenz

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent