Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing

published_or_final_versio

Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb

The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb -- the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells -- are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures

Characterization of the second- and third-harmonic optical susceptibilities of atomically thin tungsten diselenide

Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-28374-1We report the first detailed characterization of the sheet third-harmonic optical susceptibility, χ(3)s, of tungsten diselenide (WSe2). With a home-built multiphoton microscope setup developed to study harmonics generation, we map the second and third-harmonic intensities as a function of position in the sample, pump power and polarization angle, for single- and few-layers flakes of WSe2. We register a value of |χ(3)s| ≈ 0.9 × 10-28 m3 V-2 at a fundamental excitation frequency of ℏω = 0.8 eV, which is comparable in magnitude to the third-harmonic susceptibility of other group-VI transition metal dichalcogenides. The simultaneously recorded sheet second-harmonic susceptibility is found to be |χ(2)s| ≈ 0.7 × 10-19 m2 V-1 in very good agreement on the order of magnitude with recent reports for WSe2, which asserts the robustness of our values for |χ(3)s|.Y.W.H. acknowledges scholarship support from NGS. G.E. acknowledges financial support from National Research Foundation of Singapore (NRF Research Fellowship NRF-NRFF2011-02 and medium-sized centre programme) and Ministry of Education of Singapore (AcRF Tier 2 MOE2015-T2-2-123). V. M. P. acknowledges fnancial support from Ministry of Education of Singapore (FRC AcRF Tier 1 R-144-000-386-114). J.C.V.G. acknowledges fnancial support from CA2DM through National Research Foundation of Singapore (NRF-CRP Grant No. R-144-000-295-281)

Interval estimation and optimal design for the within-subject coefficient of variation for continuous and binary variables

BACKGROUND: In this paper we propose the use of the within-subject coefficient of variation as an index of a measurement's reliability. For continuous variables and based on its maximum likelihood estimation we derive a variance-stabilizing transformation and discuss confidence interval construction within the framework of a one-way random effects model. We investigate sample size requirements for the within-subject coefficient of variation for continuous and binary variables. METHODS: We investigate the validity of the approximate normal confidence interval by Monte Carlo simulations. In designing a reliability study, a crucial issue is the balance between the number of subjects to be recruited and the number of repeated measurements per subject. We discuss efficiency of estimation and cost considerations for the optimal allocation of the sample resources. The approach is illustrated by an example on Magnetic Resonance Imaging (MRI). We also discuss the issue of sample size estimation for dichotomous responses with two examples. RESULTS: For the continuous variable we found that the variance stabilizing transformation improves the asymptotic coverage probabilities on the within-subject coefficient of variation for the continuous variable. The maximum like estimation and sample size estimation based on pre-specified width of confidence interval are novel contribution to the literature for the binary variable. CONCLUSION: Using the sample size formulas, we hope to help clinical epidemiologists and practicing statisticians to efficiently design reliability studies using the within-subject coefficient of variation, whether the variable of interest is continuous or binary

Early Loss of Xist RNA Expression and Inactive X Chromosome Associated Chromatin Modification in Developing Primordial Germ Cells

The inactive X chromosome characteristic of female somatic lineages is reactivated during development of the female germ cell lineage. In mouse, analysis of protein products of X-linked genes and/or transgenes located on the X chromosome has indicated that reactivation occurs after primordial germ cells reach the genital ridges.We present evidence that the epigenetic reprogramming of the inactive X-chromosome is initiated earlier than was previously thought, around the time that primordial germ cells (PGCs) migrate through the hindgut. Specifically, we find that Xist RNA expression, the primary signal for establishment of chromosome silencing, is extinguished in migrating PGCs. This is accompanied by displacement of Polycomb-group repressor proteins Eed and Suz(12), and loss of the inactive X associated histone modification, methylation of histone H3 lysine 27.We conclude that X reactivation in primordial germ cells occurs progressively, initiated by extinction of Xist RNA around the time that germ cells migrate through the hindgut to the genital ridges. The events that we observe are reminiscent of X reactivation of the paternal X chromosome in inner cell mass cells of mouse pre-implantation embryos and suggest a unified model in which execution of the pluripotency program represses Xist RNA thereby triggering progressive reversal of epigenetic silencing of the X chromosome

Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: -0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.This study was funded by a Parkinson's UK grant (J-0802) and supported by Parkinson's UK (CN), Lockhart Parkinson's Disease Research Fund (RAL, TKK, GWD), Michael J. Fox Foundation (AJY), the National Institute for Health Research (NIHR, RG64473) Cambridge Biomedical Research Centre, and Biomedical Research Unit in Dementia, the Wellcome Trust (JBR, 103838); the Medical Research Council of Cognition, and Brain Sciences Unit, Cambridge (JBR, MC-A060-5PQ30); the NIHR Newcastle Biomedical Research Unit based at Newcastle-upon-Tyne Hospitals NHS Foundation Trust and Newcastle University; the NIHR Dementia and Neurodegenerative Diseases Research Network (JTO), and Elijah Mak was in receipt of the Gates Cambridge studentship and Alzheimer's Research UK scholarship

Determinants of seasonal influenza vaccination in pregnant women in Valencia, Spain

Background: In most countries the coverage of seasonal influenza vaccination in pregnant women is low. We investigated the acceptance, reasons for rejection and professional involvement related to vaccine information in pregnant women in Valencia, Spain. Methods: Observational retrospective study in 200 pregnant women, 100 vaccinated and 100 unvaccinated, were interviewed during the 2014/2015 vaccination campaign. Electronic medical records, immunization registry and telephone interviews were used to determine reasons for vaccination and immunization rejection. Results: 40.5% of pregnant women in the health department were vaccinated. The midwife was identified as source of information for 89% of women. The vaccine was rejected due to low perceptions of risk of influenza infection (23%), lack of information (19%), considering the vaccine as superfluous (16%), close proximity of delivery date (13%) and fear of side effects (12%). Conclusion: Pregnant women in Spain declined to be vaccinated due to under-estimation of the risk of contracting or being harmed by influenza, and lack of information. Interventions aiming to optimize vaccination coverage should include information addressing the safety and effectiveness of the current vaccine together with improved professional training and motivation

Monosodium urate crystals promote innate anti-mycobacterial immunity and improve BCG efficacy as a vaccine against tuberculosis

A safer and more effective anti-Tuberculosis vaccine is still an urgent need. We probed the effects of monosodium urate crystals (MSU) on innate immunity to improve the Bacille Calmette-Guerin (BCG) vaccination. Results showed that in vitro MSU cause an enduring macrophage stimulation of the anti-mycobacterial response, measured as intracellular killing, ROS production and phagolysosome maturation. The contribution of MSU to anti-mycobacterial activity was also shown in vivo. Mice vaccinated in the presence of MSU showed a lower number of BCG in lymph nodes draining the vaccine inoculation site, in comparison to mice vaccinated without MSU. Lastly, we showed that MSU improved the efficacy of BCG vaccination in mice infected with Mycobacterium tuberculosis (MTB), measured in terms of lung and spleen MTB burden. These results demonstrate that the use of MSU as adjuvant may represent a novel strategy to enhance the efficacy of BCG vaccination

The perception of disability by community groups: Stories of local understanding, beliefs and challenges in a rural part of Kenya

Cultural narratives on disability have received much attention over the past few decades. In contexts of poverty, limited information and everyday challenges associated with having, or caring for someone with a disability, different understandings have emerged. A project was set up to promote disability awareness in neighborhood communities in a rural part of Kenya, using a process of reflection and education. This paper reports on the first aspect–reflection. The aim was to investigate local understanding of disability as a co-constructed concept. The research questions were: 1. What cultural beliefs shape local understanding of disability? 2. What challenges are perceived to be associated with disability? A phenomenological approach was adopted. Focus group discussions were conducted with twenty-one community groups involving 263 participants and audio-recorded. The data were transcribed and thematic analysis was carried out. Visual maps were created to illustrate any interconnections, before establishing the final conclusions. Local beliefs attributed disability to: human transgression of social conventions, particularly concerning inappropriate family relations, which invoked a curse; supernatural forces affecting the child; the will of God; unexplained events; and biomedical factors. Challenges associated with disability related to the burden of caregiving and perceived barriers to inclusion, with stress as a shared bi-product. Local understanding of disability in this rural part of Kenya demonstrated overlapping explanations and plurality of beliefs. Two possible interpretations are offered. Firstly, oscillation between explanatory lines demonstrated instability, affecting broader acceptance of disability. Secondly, and more positively, in the face of challenges, the desire to make sense of the existing situation, reflected a healthy pluralism

The Prosensory Function of Sox2 in the Chicken Inner Ear Relies on the Direct Regulation of Atoh1

The proneural gene Atoh1 is crucial for the development of inner ear hair cells and it requires the function of the transcription factor Sox2 through yet unknown mechanisms. In the present work, we used the chicken embryo and HEK293T cells to explore the regulation of Atoh1 by Sox2. The results show that hair cells derive from Sox2-positive otic progenitors and that Sox2 directly activates Atoh1 through a transcriptional activator function that requires the integrity of Sox2 DNA binding domain. Atoh1 activation depends on Sox transcription factor binding sites (SoxTFBS) present in the Atoh1 3′ enhancer where Sox2 directly binds, as shown by site directed mutagenesis and chromatin immunoprecipitation (ChIP). In the inner ear, Atoh1 enhancer activity is detected in the neurosensory domain and it depends on Sox2. Dominant negative competition (Sox2HMG-Engrailed) and mutation of the SoxTFBS abolish the reporter activity in vivo. Moreover, ChIP assay in isolated otic vesicles shows that Sox2 is bound to the Atoh1 enhancer in vivo. However, besides activating Atoh1, Sox2 also promotes the expression of Atoh1 negative regulators and the temporal profile of Atoh1 activation by Sox2 is transient suggesting that Sox2 triggers an incoherent feed-forward loop. These results provide a mechanism for the prosensory function of Sox2 in the inner ear. We suggest that sensory competence is established early in otic development through the activation of Atoh1 by Sox2, however, hair cell differentiation is prevented until later stages by the parallel activation of negative regulators of Atoh1 function