Cellular deconvolution of GTEx tissues powers discovery of disease and cell-type associated regulatory variants.

The Genotype-Tissue Expression (GTEx) resource has provided insights into the regulatory impact of genetic variation on gene expression across human tissues; however, thus far has not considered how variation acts at the resolution of the different cell types. Here, using gene expression signatures obtained from mouse cell types, we deconvolute bulk RNA-seq samples from 28 GTEx tissues to quantify cellular composition, which reveals striking heterogeneity across these samples. Conducting eQTL analyses for GTEx liver and skin samples using cell composition estimates as interaction terms, we identify thousands of genetic associations that are cell-type-associated. The skin cell-type associated eQTLs colocalize with skin diseases, indicating that variants which influence gene expression in distinct skin cell types play important roles in traits and disease. Our study provides a framework to estimate the cellular composition of GTEx tissues enabling the functional characterization of human genetic variation that impacts gene expression in cell-type-specific manners

Validating delta-filters for resonant bar detectors of improved bandwidth foreseeing the future coincidence with interferometers

The classical delta filters used in the current resonant bar experiments for detecting GW bursts are viable when the bandwidth of resonant bars is few Hz. In that case, the incoming GW burst is likely to be viewed as an impulsive signal in a very narrow frequency window. After making improvements in the read-out with new transducers and high sensitivity dc-SQUID, the Explorer-Nautilus have improved the bandwidth ($\sim 20$ Hz) at the sensitivity level of $10^{-20}/\sqrt{Hz}$. Thus, it is necessary to reassess this assumption of delta-like signals while building filters in the resonant bars as the filtered output crucially depends on the shape of the waveform. This is presented with an example of GW signals -- stellar quasi-normal modes, by estimating the loss in SNR and the error in the timing, when the GW signal is filtered with the delta filter as compared to the optimal filter.Comment: 7 pages, presented in Amaldi6, accepted for publication in Journal of Physics: Conference Serie

Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression.

While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression

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

Attenuation of choroidal tickness in patients with Alzheimer disease: evidence from an Italian prospective study

INTRODUCTION: To compare the 12-month choroidal thickness (CT) change between Alzheimer disease (AD) patients and normal subjects. METHODS: In this prospective, observational study, 39 patients with a diagnosis of mild to moderate AD and 39 age-matched control subjects were included. All the subjects underwent neuropsychological (Mini Mental State Examination, Alzheimer disease Assessment Scale-Cognitive Subscale, and the Clinical Dementia Rating Scale) and ophthalmological evaluation, including spectral domain optical coherence tomography, at baseline and after 12 months. CT was measured manually using the caliper tool of the optical coherence tomography device. RESULTS: After 12 months, AD patients had a greater reduction of CT than controls (P≤0.05, adjusted for baseline CT, age, sex, axial length, and smoking). DISCUSSION: CT in patients with AD showed a rate of thinning greater than what could be expected during the natural course of aging

High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) offers the possibility of studying the molecular mechanisms underlying human diseases in cell types difficult to extract from living patients, such as neurons and cardiomyocytes. To date, studies have been published that use small panels of iPSC-derived cell lines to study monogenic diseases. However, to study complex diseases, where the genetic variation underlying the disorder is unknown, a sizable number of patient-specific iPSC lines and controls need to be generated. Currently the methods for deriving and characterizing iPSCs are time consuming, expensive, and, in some cases, descriptive but not quantitative. Here we set out to develop a set of simple methods that reduce cost and increase throughput in the characterization of iPSC lines. Specifically, we outline methods for high-throughput quantification of surface markers, gene expression analysis of in vitro differentiation potential, and evaluation of karyotype with markedly reduced cost

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 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