Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD

Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers

Variations in the Galactic star formation rate and density thresholds for star formation

The conversion of gas into stars is a fundamental process in astrophysics and cosmology. Stars are known to form from the gravitational collapse of dense clumps in interstellar molecular clouds, and it has been proposed that the resulting star formation rate is proportional to either the amount of mass above a threshold gas surface density, or the gas volume density. These star-formation prescriptions appear to hold in nearby molecular clouds in our Milky Way Galaxy's disk as well as in distant galaxies where the star formation rates are often much larger. The inner 500 pc of our Galaxy, the Central Molecular Zone (CMZ), contains the largest concentration of dense, high-surface density molecular gas in the Milky Way, providing an environment where the validity of star-formation prescriptions can be tested. Here we show that by several measures, the current star formation rate in the CMZ is an order-of-magnitude lower than the rates predicted by the currently accepted prescriptions. In particular, the region 1 deg < l < 3.5 deg, |b| < 0.5 deg contains ~10^7 Msun of dense molecular gas -- enough to form 1000 Orion-like clusters -- but the present-day star formation rate within this gas is only equivalent to that in Orion. In addition to density, another property of molecular clouds, such as the amplitude of turbulent motions, must be included in the star-formation prescription to predict the star formation rate in a given mass of molecular gas.Comment: 17 pages, 6 figures, submitted MNRA

Associations between small ruminant lentivirus infection and total milk yield and somatic cell count in a dairy sheep flock

BackgroundSmall ruminant lentiviruses (SRLVs) are lentiviruses of sheep and goats, formerly known as maedi–visna (MV) in sheep and caprine encephalitis and arthritis in goats. In sheep, SRLVs commonly cause progressive pneumonia, wasting and indurative mastitis. SRLVs have a long latent period, and chronic production losses are often not recognised until very late. Few studies quantifying the production losses in ewes have been published, and none have been published under UK flock husbandry conditions.MethodsProduction records of milk yield and somatic cell count (SCC) from a dairy flock of 319 milking East Friesian × Lacaune ewes identified as MV infected via routine serological screening for SRLV antibodies were used in multivariable linear regression modelling to estimate the impact of SRLV status on total milk yield and SCC.ResultsMilk yield was reduced in seropositive ewes by 8.1%–9.2% over an entire lactation. SCC counts were not significantly different in SRLV-infected and unifected animals.LimitationsFurther parameters, such as body condition score or clinical mastitis, that were not available may have clarified the underlying cause of milk yield drop.ConclusionsThe study demonstrates substantial production losses in an SRLV-affected flock and highlights the impact of the virus on a farm's economic viability

MALT90 Kinematic Distances to Dense Molecular Clumps

Using molecular-line data from the Millimetre Astronomy Legacy Team 90 GHz Survey (MALT90), we have estimated kinematic distances to 1905 molecular clumps identified in the ATLASGAL 870 μm continuum survey over the longitude range 295° < l < 350°. The clump velocities were determined using a flux-weighted average of the velocities obtained from Gaussian fits to the HCO+, HNC, and N2H+ (1–0) transitions. The near/far kinematic distance ambiguity was addressed by searching for the presence or absence of absorption or self-absorption features in 21 cm atomic hydrogen spectra from the Southern Galactic Plane Survey. Our algorithm provides an estimation of the reliability of the ambiguity resolution. The Galactic distribution of the clumps indicates positions where the clumps are bunched together, and these locations probably trace the locations of spiral arms. Several clumps fall at the predicted location of the far side of the Scutum–Centaurus arm. Moreover, a number of clumps with positive radial velocities are unambiguously located on the far side of the Milky Way at galactocentric radii beyond the solar circle. The measurement of these kinematic distances, in combination with continuum or molecular-line data, now enables the determination of fundamental parameters such as mass, size, and luminosity for each clump

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Chronic paternal morphine exposure increases sensitivity to morphine-derived pain relief in male progeny

Parental history of opioid exposure is seldom considered when prescribing opioids for pain relief. To explore whether parental opioid exposure may affect sensitivity to morphine in offspring, we developed a “rat pain scale” with high-speed imaging, machine learning, and mathematical modeling in a multigenerational model of pater-nal morphine self-administration. We find that the most commonly used tool to measure mechanical sensitivity in rodents, the von Frey hair, is not painful in rats during baseline conditions. We also find that male progeny of morphine-treated sires had no baseline changes in mechanical pain sensitivity but were more sensitive to the pain-relieving effects of morphine. Using RNA sequencing across pain-relevant brain regions, we identify gene expression changes within the regulator of G protein signaling family of proteins that may underlie this multigen-erational phenotype. Together, this rat pain scale revealed that paternal opioid exposure increases sensitivity to morphine’s pain-relieving effects in male offspring.Temple University. College of Liberal ArtsPsychology and Neuroscienc

Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription

Tumours and immortalized cells avoid telomere attrition by using either the ribonucleoprotein enzyme telomerase or a recombination-based alternative lengthening of telomeres (ALT) mechanism. Available evidence from mice suggests that the epigenetic state of the telomere may influence the mechanism of telomere maintenance, but this has not been directly tested in human cancer. Here we investigated cytosine methylation directly adjacent to the telomere as a marker of the telomere's epigenetic state in a panel of human cell lines. We find that while ALT cells show highly heterogeneous patterns of subtelomeric methylation, subtelomeric regions in telomerase-positive cells invariably show denser methylation than normal cells, being almost completely methylated. When compared to matched normal and ALT cells, telomerase-positive cells also exhibit reduced levels of the telomeric repeat-containing-RNA (TERRA), whose transcription originates in the subtelomere. Our results are consistent with the notion that TERRA may inhibit telomerase: the heavy cytosine methylation we observe in telomerase-positive cells may reflect selection for TERRA silencing in order to facilitate telomerase activity at the telomere. These data suggest that the epigenetic differences between telomerase-positive and ALT cells may underlie the mechanism of telomere maintenance in human tumorigenesis and highlight the broad reaching consequences of epigenetic dysregulation in cancer

Stellar occultations enable milliarcsecond astrometry for Trans-Neptunian objects and Centaurs

Trans-Neptunian objects (TNOs) and Centaurs are remnants of our planetary system formation, and their physical properties have invaluable information for evolutionary theories. Stellar occultation is a ground-based method for studying these small bodies and has presented exciting results. These observations can provide precise profiles of the involved body, allowing an accurate determination of its size and shape. The goal is to show that even single-chord detections of TNOs allow us to measure their milliarcsecond astrometric positions in the reference frame of the Gaia second data release (DR2). Accurated ephemerides can then be generated, allowing predictions of stellar occultations with much higher reliability. We analyzed data from stellar occultations to obtain astrometric positions of the involved bodies. The events published before the Gaia era were updated so that the Gaia DR2 catalog is the reference. Previously determined sizes were used to calculate the position of the object center and its corresponding error with respect to the detected chord and the International Celestial Reference System (ICRS) propagated Gaia DR2 star position. We derive 37 precise astrometric positions for 19 TNOs and 4 Centaurs. Twenty-one of these events are presented here for the first time. Although about 68\% of our results are based on single-chord detection, most have intrinsic precision at the submilliarcsecond level. Lower limits on the diameter and shape constraints for a few bodies are also presented as valuable byproducts. Using the Gaia DR2 catalog, we show that even a single detection of a stellar occultation allows improving the object ephemeris significantly, which in turn enables predicting a future stellar occultation with high accuracy. Observational campaigns can be efficiently organized with this help, and may provide a full physical characterization of the involved object.Comment: 16 pages, 28 figures. The manuscript was accepted and is to be publishe

Diffuse Glioneuronal tumour with Oligodendroglioma‐like features and Nuclear Clusters (DGONC) – a molecularly‐defined glioneuronal CNS tumour class displaying recurrent monosomy 14

Aims: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters