The Metallicity of the Redshift 4.16 Quasar BR2248-1242

We estimate the metallicity in the broad emission-line region of the redshift z=4.16 quasar, BR2248-1242, by comparing line ratios involving nitrogen to theoretical predictions. BR2248-1242 has unusually narrow emission lines with large equivalent widths, thus providing a rare opportunity to measure several line-ratio abundance diagnostics. The combined diagnostics indicate a metallicity of ~2 times solar. This result suggests that an episode of vigorous star formation occurred near BR2248-1242 prior to the observed z=4.16 epoch. The time available for this enrichment episode is only ~1.5 Gyr at z=4.16 (for H_{0}=65 km s^-1 Mpc^-1, Omega_{m}=0.3 and Omega_Lambda ~< 1). This evidence for high metallicities and rapid star formation is consistent with the expected early-epoch evolution of dense galactic nuclei.Comment: 8 pages, 3 figures. Prepared in AAStex. Submitted to the Astrophysical Journal Revised version: added 1 referenc

Emission-Line Properties of z > 4 Quasars

We present results of a program of high signal-to-noise spectroscopy for 44 QSOs at redshifts > 4 using the MMT and Keck observatories. The quasar spectra cover 1100 -- 1700 A in the rest frame for sources spanning a luminosity range of approximately 2 orders of magnitude. Comparisons between these data and spectra of lower redshift quasars reveal a high degree of similarity, although differences are present in the profiles and the strengths of some emission features. An examination of the luminosity dependence of the emission lines reveals evidence for a weak or absent Baldwin effect among z > 4 QSOs. We compare measurements for objects in our sample with results from other high redshift surveys characterized by different selection techniques. Distributions of equivalent widths for these different ensembles are consistent with a common parent population, suggesting that our sample is not strongly biased, or in any case, subject to selection effects that are not significantly different from other surveys, including the Sloan Digital Sky Survey. Based on this comparison, we tentatively conclude that the trends identified here are representative of high z QSOs. In particular, the data bolster indications of supersolar metallicities in these luminous, high-z sources, which support scenarios that assume substantial star formation at epochs preceding or concurrent with the QSO phenomena.Comment: 26 pages (incl. 9 figures), AASTeX v5.0, to appear in The Astrophysical Journa

Cosmic Star Formation, Reionization, and Constraints on Global Chemical Evolution

Motivated by the WMAP results indicating an early epoch of reionization, we consider alternative cosmic star formation models which are capable of reionizing the early intergalactic medium. We develop models which include an early burst of massive stars (with several possible mass ranges) combined with standard star formation. We compute the stellar ionizing flux of photons and we track the nucleosynthetic yields for several elements: D, He4, C, N, O, Si, S, Fe, Zn. We compute the subsequent chemical evolution as a function of redshift, both in the intergalactic medium and in the interstellar medium of forming galaxies, starting with the primordial objects which are responsible for the reionization. We apply constraints from the observed abundances in the Lyman alpha forest and in Damped Lyman alpha clouds in conjunction with the ability of the models to produce the required degree of reionization. We also consider possible constraints associated with the observations of the two extremely metal-poor stars HE 0107-5240 and CS22949-037. We confirm that an early top-heavy stellar component is required, as a standard star formation model is unable to reionize the early Universe and reproduce the abundances of the very metal-poor halo stars. A bimodal (or top-heavy) IMF (40 - 100 M_\odot) is our preferred scenario compared to the extreme mass range (\ga 100 M_\odot) often assumed to be responsible for the early stages of reionization. A mode of even more extreme stellar masses in the range (\ge 270 M_\odot) has also been considered. All massive stars in this mode collapse entirely into black holes, and as a consequence, chemical evolution and reionization are de-correlated. [Abstract abbreviated.]Comment: 45 pages, 18 eps figures, as accepted in Ap

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection

Substrate stiffness promotes vascular smooth muscle cell calcification by reducing levels of nuclear actin monomers:Mechanical regulation of VSMC calcification

Background:Vascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) are not fully understood.Methods:Using hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo, we investigated the role of substrate stiffness in the regulation of VSMC calcification.Results:We demonstrate that increased substrate stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of substrate stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft substrate, elevated levels of nuclear actin monomer repress osteogenic differentiation and calcification by repressing YAP-mediated activation of both TEA Domain transcription factor (TEAD) and RUNX Family Transcription factor 2 (RUNX2). Conclusion:This work highlights for the first time the role of nuclear actin in mediating substrate stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes.<br/

Quantifying the Microvascular Origin of BOLD-fMRI from First Principles with Two-Photon Microscopy and an Oxygen-Sensitive Nanoprobe

The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences.National Institutes of Health (U.S.) (Grant P41RR14075)National Institutes of Health (U.S.) (Grant R01NS067050)National Institutes of Health (U.S.) (Grant R01NS057198)National Institutes of Health (U.S.) (Grant R01EB000790)American Heart Association (Grant 11SDG7600037)Advanced Multimodal NeuroImaging Training Program (R90DA023427

A sequence-based survey of the complex structural organization of tumor genomes

Tumors and cancer cell lines were surveyed with end-sequencing profiling, yielding the largest available collection of sequence-ready tumor genome breakpoints and providing evidence that some rearrangements may be recurrent

Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ

Abstract Background Endocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations. Methods Patients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months. Biomarker changes were compared to a cohort of patients who had not received preoperative treatment. Results Median age of the cohort was 53 years (range 38–78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery. Conclusion Preoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention. Trial Registration ClinicalTrials.gov NCT0029074

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

SNP Discovery and Chromosome Anchoring Provide the First Physically-Anchored Hexaploid Oat Map and Reveal Synteny with Model Species

A physically anchored consensus map is foundational to modern genomics research; however, construction of such a map in oat (Avena sativa L., 2n = 6x = 42) has been hindered by the size and complexity of the genome, the scarcity of robust molecular markers, and the lack of aneuploid stocks. Resources developed in this study include a modified SNP discovery method for complex genomes, a diverse set of oat SNP markers, and a novel chromosome-deficient SNP anchoring strategy. These resources were applied to build the first complete, physically-anchored consensus map of hexaploid oat. Approximately 11,000 high-confidence in silico SNPs were discovered based on nine million inter-varietal sequence reads of genomic and cDNA origin. GoldenGate genotyping of 3,072 SNP assays yielded 1,311 robust markers, of which 985 were mapped in 390 recombinant-inbred lines from six bi-parental mapping populations ranging in size from 49 to 97 progeny. The consensus map included 985 SNPs and 68 previously-published markers, resolving 21 linkage groups with a total map distance of 1,838.8 cM. Consensus linkage groups were assigned to 21 chromosomes using SNP deletion analysis of chromosome-deficient monosomic hybrid stocks. Alignments with sequenced genomes of rice and Brachypodium provide evidence for extensive conservation of genomic regions, and renewed encouragement for orthology-based genomic discovery in this important hexaploid species. These results also provide a framework for high-resolution genetic analysis in oat, and a model for marker development and map construction in other species with complex genomes and limited resources