Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissue-specific Rbpjk mutant (Prx1Cre;Rbpjk(f/f)), Rbpjk mutant/Sox9 haploinsufficient (Prx1Cre;Rbpjk(f/f);Sox9(f/+)), and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors

Lyman Continuum Escape Fraction of Star-forming Dwarf Galaxies at z ~ 1

To date, no direct detection of Lyman continuum emission has been measured for intermediate-redshift (z ~ 1) star-forming galaxies. We combine Hubble Space Telescope grism spectroscopy with GALEX UV and ground-based optical imaging to extend the search for escaping Lyman continuum to a large (~600) sample of z ~ 1 low-mass log(M)≃ 9.3 M_☉), moderately star-forming (ψ ≾ 10M_☉ yr^(−1)) galaxies selected initially on Hα emission. The characteristic escape fraction of LyC from star-forming galaxies (SFGs) that populate this parameter space remains weakly constrained by previous surveys, but these faint (sub-Lsstarf) SFGs are assumed to play a significant role in the reionization of neutral hydrogen in the intergalactic medium (IGM) at high redshift z > 6. We do not make an unambiguous detection of escaping LyC radiation from this z ~ 1 sample, individual non-detections to constrain the absolute Lyman continuum escape fraction, f_(esc) 200Å), which are thought to be close analogs of high redshift sources of reionization. For reference, we also present an emissivity-weighted escape fraction that is useful for measuring the general contribution SFGs to the ionizing UV background. In the discussion, we consider the implications of these intermediate redshift constraints for the reionization of hydrogen in the IGM at high (z > 6) redshift. If we assume our z ~ 1 SFGs, for which we measure this emissivity-weighted f_(esc), are analogs to the high redshift sources of reionization, we find it is difficult to reconcile reionization by faint (M}_(UV) ≾-13) SFGs with a low escape fraction (f_(esc) < 3%), with constraints from independent high redshift observations. If f_(esc) evolves with redshift, reionization by SFGs may be consistent with observations from Planck

The Hubble Space Telescope Wide Field Camera 3 Early Release Science data: Panchromatic Faint Object Counts for 0.2-2 microns wavelength

We describe the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) Early Release Science (ERS) observations in the Great Observatories Origins Deep Survey (GOODS) South field. The new WFC3 ERS data provide calibrated, drizzled mosaics in the UV filters F225W, F275W, and F336W, as well as in the near-IR filters F098M (Ys), F125W (J), and F160W (H) with 1-2 HST orbits per filter. Together with the existing HST Advanced Camera for Surveys (ACS) GOODS-South mosaics in the BViz filters, these panchromatic 10-band ERS data cover 40-50 square arcmin at 0.2-1.7 {\mu}m in wavelength at 0.07-0.15" FWHM resolution and 0.090" Multidrizzled pixels to depths of AB\simeq 26.0-27.0 mag (5-{\sigma}) for point sources, and AB\simeq 25.5-26.5 mag for compact galaxies. In this paper, we describe: a) the scientific rationale, and the data taking plus reduction procedures of the panchromatic 10-band ERS mosaics; b) the procedure of generating object catalogs across the 10 different ERS filters, and the specific star-galaxy separation techniques used; and c) the reliability and completeness of the object catalogs from the WFC3 ERS mosaics. The excellent 0.07-0.15" FWHM resolution of HST/WFC3 and ACS makes star- galaxy separation straightforward over a factor of 10 in wavelength to AB\simeq 25-26 mag from the UV to the near-IR, respectively.Comment: 51 pages, 71 figures Accepted to ApJS 2011.01.2

Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone

Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug

On the evolution of the size of Lyman alpha halos across cosmic time: no change in the circumgalactic gas distribution when probed by line emission

Lyman $\alpha$ (Ly$\alpha$) is now routinely used as a tool for studying high-redshift galaxies and its resonant nature means it can trace neutral hydrogen around star-forming galaxies. Integral field spectrograph measurements of high-redshift Ly$\alpha$ emitters indicate that significant extended Ly$\alpha$ halo emission is ubiquitous around such objects. We present a sample of redshift 0.23 to 0.31 galaxies observed with the Hubble Space Telescope selected to match the star formation properties of high-$z$ samples while optimizing the observations for detection of low surface brightness Ly$\alpha$ emission. The Ly$\alpha$ escape fractions range between 0.7\% and 37\%, and we detect extended Ly$\alpha$ emission around six out of seven targets. We find Ly$\alpha$ halo to UV scale length ratios around 6:1 which is marginally lower than high-redshift observations, and halo flux fractions between 60\% and 85\% -- consistent with high-redshift observations -- when using comparable methods. However, our targets show additional extended stellar UV emission: we parametrize this with a new double exponential model. We find that this parametrization does not strongly affect the observed Ly$\alpha$ halo fractions. We find that deeper H$\alpha$ data would be required to firmly determine the origin of Ly$\alpha$ halo emission, however, there are indications that H$\alpha$ is more extended than the central FUV profile, potentially indicating conditions favorable for the escape of ionizing radiation. We discuss our results in the context of high-redshift galaxies, cosmological simulations, evolutionary studies of the circumgalactic medium in emission, and the emission of ionizing radiation.Comment: 20 page, 14 figures, 6 tables. Accepted for publication in MNRA

The Lyman Continuum Escape Fraction of Galaxies and AGN in the GOODS Fields

We present our analysis of the LyC emission and escape fraction of 111 spectroscopically verified galaxies with and without AGN from $2.26<z<4.3$. We extended our ERS sample from Smith et al. (2018; arXiv:1602.01555) with 64 galaxies in the GOODS North and South fields using WFC3/UVIS F225W, F275W, and F336W mosaics we independently drizzled using the HDUV, CANDELS, and UVUDF data. Among the 17 AGN from the 111 galaxies, one provided a LyC detection in F275W at $m_{AB}=23.19$ mag (S/N $\simeq$ 133) and $GALEX$ NUV at $m_{AB}=23.77$ mag (S/N $\simeq$ 13). We simultaneously fit $SDSS$ and $Chandra$ spectra of this AGN to an accretion disk and Comptonization model and find $f_{esc}$ values of $f_{esc}^{F275W}\simeq 28^{+20}_{-4}$% and $f_{esc}^{NUV}\simeq 30^{+22}_{-5}$%. For the remaining 110 galaxies, we stack image cutouts that capture their LyC emission using the F225W, F275W, and F336W data of the GOODS and ERS samples, and both combined, as well as subsamples of galaxies with and without AGN, and $all$ galaxies. We find the stack of 17 AGN dominate the LyC production from $\langle z\rangle\simeq 2.3-4.3$ by a factor of $\sim$10 compared to all 94 galaxies without AGN. While the IGM of the early universe may have been reionized mostly by massive stars, there is evidence that a significant portion of the ionizing energy came from AGN.Comment: 36 pages, 17 figures, 5 tables. Accepted for publication in The Astrophysical Journal. v1 abstract latex errors corrected, minor changes to table 5, orcid ID corrected for one autho

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation

A natural history study of X-linked myotubular myopathy

Objective: To define the natural history of X-linked myotubular myopathy (MTM). Methods: We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33). Results: We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non–muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays. Conclusions: MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention