Large surveys of galaxy clusters with the Hubble Space Telescope (HST) and Spitzer, including the Cluster Lensing And Supernova survey with Hubble and the Frontier Fields, have demonstrated the power ...of strong gravitational lensing to efficiently deliver large samples of high-redshift galaxies. We extend this strategy through a wider, shallower survey named RELICS, the Reionization Lensing Cluster Survey, described here. Our 188-orbit Hubble Treasury Program observed 41 clusters at 0.182 ≤ z ≤ 0.972 with Advanced Camera for Surveys (ACS) and WFC3/IR imaging spanning 0.4-1.7 m. We selected 21 of the most massive clusters known based on Planck PSZ2 estimates and 20 additional clusters based on observed or inferred lensing strength. RELICS observed 46 WFC3/IR pointings (∼200 arcmin2) each with two orbits divided among four filters (F105W, F125W, F140W, and F160W) and ACS imaging as needed to achieve single-orbit depth in each of three filters (F435W, F606W, and F814W). As previously reported by Salmon et al., we discovered over 300 z ∼ 6-10 candidates, including the brightest z ∼ 6 candidates known, and the most distant spatially resolved lensed arc known at z ∼ 10. Spitzer IRAC imaging (945 hr awarded, plus 100 archival, spanning 3.0-5.0 m) has crucially enabled us to distinguish z ∼ 10 candidates from z ∼ 2 interlopers. For each cluster, two HST observing epochs were staggered by about a month, enabling us to discover 11 supernovae, including 3 lensed supernovae, which we followed up with 20 orbits from our program. Reduced HST images, catalogs, and lens models are available on MAST, and reduced Spitzer images are available on IRSA.
Osteocytes are the terminally differentiated cell type of the osteoblastic lineage and have important functions in skeletal homeostasis. Although the transcriptional regulation of osteoblast ...differentiation has been well characterized, the factors that regulate differentiation of osteocytes from mature osteoblasts are poorly understood. Here we show that miR-23a∼27a∼24-2 (miR-23a cluster) promotes osteocyte differentiation. Osteoblast-specific miR-23a cluster gain-of-function mice have low bone mass associated with decreased osteoblast but increased osteocyte numbers. By contrast, loss-of-function transgenic mice overexpressing microRNA decoys for either miR-23a or miR-27a, but not miR24-2, show decreased osteocyte numbers. Moreover, RNA-sequencing analysis shows altered transforming growth factor-β (TGF-β) signalling. Prdm16, a negative regulator of the TGF-β pathway, is directly repressed by miR-27a with concomitant alteration of sclerostin expression, and pharmacological inhibition of TGF-β rescues the phenotypes observed in the gain-of-function transgenic mice. Taken together, the miR-23a cluster regulates osteocyte differentiation by modulating the TGF-β signalling pathway through targeting of Prdm16.
Abstract
We present constraints on the physical properties (including stellar mass, age, and star formation rate) of 207 6 ≲
z
≲ 8 galaxy candidates from the Reionization Lensing Cluster Survey ...(RELICS) and Spitzer-RELICS surveys. We measure photometry using T-PHOT and perform spectral energy distribution fitting using EA
z
Y and BAGPIPES. Of the 207 candidates for which we could successfully measure (or place limits on) Spitzer fluxes, 23 were demoted to likely
z
< 4. Among the high-
z
candidates, we find intrinsic stellar masses between 1 × 10
6
M
⊙
and 4 × 10
9
M
⊙
, and rest-frame UV absolute magnitudes between −22.6 and −14.5 mag. While our sample is mostly comprised of
L
m
UV
/
L
m
UV
*
<
1
galaxies, it extends to
L
m
UV
/
L
m
UV
*
∼
2
. Our sample spans ∼4 orders of magnitude in stellar mass and star formation rates, and exhibits ages that range from maximally young to maximally old. We highlight 11
z
≥ 6.5 galaxies with detections in Spitzer/IRAC imaging, several of which show evidence for some combination of evolved stellar populations, large contributions of nebular emission lines, and/or dust. Among these is PLCKG287+32-2013, one of the brightest
z
∼ 7 candidates known (AB mag 24.9 at 1.6
μ
m) with a Spitzer 3.6
μ
m flux excess suggesting strong O
iii
+ H-
β
emission (∼1000 Å rest-frame equivalent width). We discuss the possible uses and limits of our sample and present a public catalog of Hubble + Spitzer photometry along with physical property estimates for all objects in the sample. Because of their apparent brightnesses, high redshifts, and variety of stellar populations, these objects are excellent targets for follow-up with the James Webb Space Telescope.
To uncover shared pathogenic mechanisms among the highly heterogeneous autism spectrum disorders (ASDs), we developed a protein interaction network that identified hundreds of new interactions among ...proteins encoded by ASD-associated genes. We discovered unexpectedly high connectivity between SHANK and TSC1, previously implicated in syndromic autism, suggesting that common molecular pathways underlie autistic phenotypes in distinct syndromes. ASD patients were more likely to harbor copy number variations that encompass network genes than were control subjects. We also identified, in patients with idiopathic ASD, three de novo lesions (deletions in 16q23.3 and 15q22 and one duplication in Xq28) that involve three network genes (NECAB2, PKM2, and FLNA). The protein interaction network thus provides a framework for identifying causes of idiopathic autism and for understanding molecular pathways that underpin both syndromic and idiopathic ASDs.
Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the ...G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004-2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site Ø in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune-protected community.
Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. ...This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM. In this report, we identified a novel protein, tripartite motif containing 44 (TRIM44), which is overexpressed in the osteoblastic niche of the BM, enabling MM cells to compete with HSCs for niche support. TRIM44 expression in MM cells promoted cell quiescence but increased bone destruction in xenograft mice, similar to what is observed in MM patients. TRIM44 functions as a deubiquitinase for hypoxia inducible factor-1α (HIF-1α), which stabilizes HIF-1α expression during hypoxia and normoxia. Stabilized HIF-1α stimulates MM cell growth and survival during hypoxia. Our work is the first report to reveal signaling in quiescent MM cells and the functions of TRIM44.
ABSTRACT
In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the ...interferon‐induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.
Purpose The purpose of this study was to evaluate the clinical feasibility of a new method to orient 3-dimensional (3D) computed tomography models to the natural head position (NHP). This method uses ...a small and inexpensive digital orientation device to record NHP in 3 dimensions. This device consists of a digital orientation sensor attached to the patient via a facebow and an individualized bite jig. The study was designed to answer 2 questions: 1 ) whether the weight of the new device can negatively influence the NHP and 2 ) whether the new method is as accurate as the gold standard. Patients and Methods Fifteen patients with craniomaxillofacial deformities were included in the study. Each patient's NHP is recorded 3 times. The first NHP was recorded with a laser scanning method without the presence of the digital orientation device. The second NHP was recorded with the digital orientation device. Simultaneously, the third NHP was also recorded with the laser scanning method. Each recorded NHP measurement was then transferred to the patient's 3D computed tomography facial model, resulting in 3 different orientations for each patient: the orientation generated via the laser scanning method without the presence of the digital orientation sensor and facebow (orientation 1), the orientation generated by use of the laser scanning method with the presence of the digital orientation sensor and facebow (orientation 2), and the orientation generated with the digital orientation device (orientation 3). Comparisons are then made between orientations 1 and 2 and between orientations 2 and 3, respectively. Statistical analyses are performed. Results The results show that in each pair, the difference (Δ) between the 2 measurements is not statistically significantly different from 0°. In addition, in the first pair, the Bland-Altman lower and upper limits of the Δ between the 2 measurements are within 1.5° in pitch and within a subdegree in roll and yaw. In the second pair, the limits of the Δ in all 3 dimensions are within 0.5°. Conclusion Our technique can accurately record NHP in 3 dimensions and precisely transfer it to a 3D model. In addition, the extra weight of the digital orientation sensor and facebow has minimal influence on the self-balanced NHP establishment.
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