TGF beta type II receptor signaling controls Schwann cell death and proliferation in developing nerves

During development, Schwann cell numbers are precisely adjusted to match the number of axons. It is essentially unknown which growth factors or receptors carry out this important control in vivo. Here, we tested whether the type II transforming growth factor (TGF)beta receptor has a role in this process. We generated a conditional knock-out mouse in which the type II TGF beta receptor is specifically ablated only in Schwann cells. Inactivation of the receptor, evident at least from embryonic day 18, resulted in suppressed Schwann cell death in normally developing and injured nerves. Notably, the mutants also showed a strong reduction in Schwann cell proliferation. Consequently, Schwann cell numbers in wild-type and mutant nerves remained similar. Lack of TGF beta signaling did not appear to affect other processes in which TGF beta had been implicated previously, including myelination and response of adult nerves to injury. This is the first in vivo evidence for a growth factor receptor involved in promoting Schwann cell division during development and the first genetic evidence for a receptor that controls normal developmental Schwann cell death

A new data analysis framework for the search of continuous gravitational wave signals

Continuous gravitational wave signals, like those expected by asymmetric spinning neutron stars, are among the most promising targets for LIGO and Virgo detectors. The development of fast and robust data analysis methods is crucial to increase the chances of a detection. We have developed a new and flexible general data analysis framework for the search of this kind of signals, which allows to reduce the computational cost of the analysis by about two orders of magnitude with respect to current procedures. This can correspond, at fixed computing cost, to a sensitivity gain of up to 10%-20%, depending on the search parameter space. Some possible applications are discussed, with a particular focus on a directed search for sources in the Galactic center. Validation through the injection of artificial signals in the data of Advanced LIGO first observational science run is also shown.Comment: 21 pages, 8 figure

An improved algorithm for narrow-band searches of continuous gravitational waves

Continuous gravitational waves signals, emitted by asymmetric spinning neutron stars, are among the main targets of current detectors like Advanced LIGO and Virgo. In the case of sources, like pulsars, which rotational parameters are measured through electromagnetic observations, typical searches assume that the gravitational wave frequency is at a given known fixed ratio with respect to the star rotational frequency. For instance, for a neutron star rotating around one of its principal axis of inertia the gravitational signal frequency would be exactly two times the rotational frequency of the star. It is possible, however, that this assumption is wrong. This is why search algorithms able to take into account a possible small mismatch between the gravitational waves frequency and the frequency inferred from electromagnetic observations have been developed. In this paper we present an improved pipeline to perform such narrow-band searches for continuous gravitational waves from neutron stars, about three orders of magnitude faster than previous implementations. The algorithm that we have developed is based on the {\it 5-vectors} framework and is able to perform a fully coherent search over a frequency band of width $\mathcal{O}$(Hertz) and for hundreds of spin-down values running a few hours on a standard workstation. This new algorithm opens the possibility of long coherence time searches for objects which rotational parameters are highly uncertain.Comment: 19 pages, 8 figures, 6 tables, submitted to CQ

A semi-coherent analysis method to search for continuous gravitational waves emitted by ultra-light boson clouds around spinning black holes

As a consequence of superradiant instability induced in Kerr black holes, ultra-light boson clouds can be a source of persistent gravitational waves, potentially detectable by current and future gravitational-wave detectors. These signals have been predicted to be nearly monochromatic, with a small steady frequency increase (spin-up), but given the several assumptions and simplifications done at theoretical level, it is wise to consider, from the data analysis point of view, a broader class of gravitational signals in which the phase (or the frequency) slightly wander in time. Also other types of sources, e.g. neutron stars in which a torque balance equilibrium exists between matter accretion and emission of persistent gravitational waves, would fit in this category. In this paper we present a robust and computationally cheap analysis pipeline devoted to the search of such kind of signals. We provide a full characterization of the method, through both a theoretical sensitivity estimation and through the analysis of syntethic data in which simulated signals have been injected. The search setup for both all-sky searches and higher sensitivity directed searches is discussed.Comment: 13 pages, 13 figure

Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes

Evaluation of perioperative complications using a newly described staging system for placenta accreta spectrum

Introduction: The antenatal diagnosis of placenta accreta spectrum (PAS) is in large part subjective and based on expert interpretation. The aim of this study was to externally evaluate a recently developed staging system based on specific and defined prenatal ultrasound (US) features in a cohort of women at risk of PAS undergoing specialist prenatal US, in particular relating to surgical morbidity at delivery. Materials and methods: Database study of cases with confirmed placenta previa. In all, the placenta was evaluated in a systematic fashion. PAS was subclassified in PAS0-PAS3 according to the loss of clear zone, placental lacunae, bladder wall interruption, uterovesical hypervascularity and increased vascularity in the parametrial region. Results: 43 cases were included, of whom 33 had major placenta previa. 31 cases were categorized as PAS0; 3, 4 and 5 cases as PAS1, PAS2 and PAS3, respectively. All women underwent caesarean section and hysterectomy was required in 10. The comparison of the perinatal outcomes among the PAS categories yielded greater operative time (50 (35–129) minutes for PAS0 vs 70 (48–120) for PAS1 vs 95 (60–150) for PAS2 vs 100 (87–180) for PAS3, p < 0.001) and estimated blood loss (800 (500–2500) mls for PAS0 vs 3500 (800–7500) for PAS1 vs 2850 (500–7500) for PAS2 vs 6000 (2500–11000) for PAS3, p < 0.001) for the highest PAS categories, which were also associated with a higher rate of hysterectomy (p < 0.001), blood transfusion (p = 0.002) and admission to ITU or HDU (p < 0.001) and longer postoperative admission of 3 (1–9) days for PAS0 vs 3 (2–12) for PAS1 vs 4.5 (3–6) for PAS2 vs 5 (3–22) for PAS3, p = 0.02. Conclusion: Perioperative complications are closely associated with PAS stage. This information is useful for counselling women and may be important in allocating staff and infrastructure resources at the time of delivery

A population approach to characterise amisulpride pharmacokinetics in older people and Alzheimer's disease

Introduction Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. Methods This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65–79 years), with a clinical dataset obtained during off label, low-dose (25–75 mg daily) amisulpride prescribing in older people with Alzheimer’s disease (AD) (n = 25, 69–92 years), as part of an observational study. Results After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. Discussion These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above

All-sky search of NAUTILUS data

A search for periodic gravitational-wave signals from isolated neutron stars in the NAUTILUS detector data is presented. We have analyzed half a year of data over the frequency band $$Hz, the spindown range$$ Hz/s and over the entire sky. We have divided the data into 2 day stretches and we have analyzed each stretch coherently using matched filtering. We have imposed a low threshold for the optimal detection statistic to obtain a set of candidates that are further examined for coincidences among various data stretches. For some candidates we have also investigated the change of the signal-to-noise ratio when we increase the observation time from two to four days. Our analysis has not revealed any gravitational-wave signals. Therefore we have imposed upper limits on the dimensionless gravitational-wave amplitude over the parameter space that we have searched. Depending on frequency, our upper limit ranges from $3.4 \times 10^{-23}$ to $1.3 \times 10^{-22}$. We have attempted a statistical verification of the hypotheses leading to our conclusions. We estimate that our upper limit is accurate to within 18%.Comment: LaTeX, 12 page