A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization

Background Endothelial dysfunction (ED) is functionally characterized by decreased vasorelaxation, increased thrombosis, increased inflammation, and altered angiogenic potential, has been intimately associated with the progression and severity of cardiovascular disease. Patients with compromised cardiac function oftentimes have a state of chronic mild decreased oxygen at the level of the vasculature and organs, which has been shown to exacerbate ED. Hypoxia inducible factor (HIF) is a transcription factor complex shown to be the master regulator of the cellular response to decreased oxygen levels and many HIF target genes have been shown to be associated with ED. Methods Human endothelial and aortic smooth muscle cells were exposed either to A) normoxia (21% O2) for three weeks, or to B) mild decreased oxygen (15% O2) for three weeks to mimic blood oxygen levels in patients with heart failure, or to C) mild decreased oxygen for two weeks followed by one week of normoxia ("memory" treatment). Levels of HIF signaling genes (HIF-1α, HIF-2α, VEGF, BNIP3, GLUT-1, PAI-1 and iNOS) were measured both at the protein and mRNA levels. Results It was found that chronic exposure to mild decreased oxygen resulted in significantly increased HIF signaling. There was also a "memory" of HIF-1α and HIF target gene induction when oxygen levels were normalized for one week, and this "memory" could be interrupted by adding a small molecule HIF inhibitor to the last week of normalized oxygen. Finally, levels of ubiquitylated HIF-1α were reduced in response to chronic mild decreased oxygen and were not full restored after oxygen normalization. Conclusion These data suggest that HIF signaling may be contributing to the pathogenesis of endothelial dysfunction and that normalization of oxygen levels may not be enough to reduce vascular stress

PhylOTU: a high-throughput procedure quantifies microbial community diversity and resolves novel taxa from metagenomic data.

Microbial diversity is typically characterized by clustering ribosomal RNA (SSU-rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, known as metagenomics, avoids amplification bias but generates fragmentary, non-overlapping sequence reads that cannot be clustered by existing OTU-finding methods. To circumvent these limitations, we developed PhylOTU, a computational workflow that identifies OTUs from metagenomic SSU-rRNA sequence data through the use of phylogenetic principles and probabilistic sequence profiles. Using simulated metagenomic data, we quantified the accuracy with which PhylOTU clusters reads into OTUs. Comparisons of PCR and shotgun sequenced SSU-rRNA markers derived from the global open ocean revealed that while PCR libraries identify more OTUs per sequenced residue, metagenomic libraries recover a greater taxonomic diversity of OTUs. In addition, we discover novel species, genera and families in the metagenomic libraries, including OTUs from phyla missed by analysis of PCR sequences. Taken together, these results suggest that PhylOTU enables characterization of part of the biosphere currently hidden from PCR-based surveys of diversity

The Phylogenetic Diversity of Metagenomes

Phylogenetic diversity—patterns of phylogenetic relatedness among organisms in ecological communities—provides important insights into the mechanisms underlying community assembly. Studies that measure phylogenetic diversity in microbial communities have primarily been limited to a single marker gene approach, using the small subunit of the rRNA gene (SSU-rRNA) to quantify phylogenetic relationships among microbial taxa. In this study, we present an approach for inferring phylogenetic relationships among microorganisms based on the random metagenomic sequencing of DNA fragments. To overcome challenges caused by the fragmentary nature of metagenomic data, we leveraged fully sequenced bacterial genomes as a scaffold to enable inference of phylogenetic relationships among metagenomic sequences from multiple phylogenetic marker gene families. The resulting metagenomic phylogeny can be used to quantify the phylogenetic diversity of microbial communities based on metagenomic data sets. We applied this method to understand patterns of microbial phylogenetic diversity and community assembly along an oceanic depth gradient, and compared our findings to previous studies of this gradient using SSU-rRNA gene and metagenomic analyses. Bacterial phylogenetic diversity was highest at intermediate depths beneath the ocean surface, whereas taxonomic diversity (diversity measured by binning sequences into taxonomically similar groups) showed no relationship with depth. Phylogenetic diversity estimates based on the SSU-rRNA gene and the multi-gene metagenomic phylogeny were broadly concordant, suggesting that our approach will be applicable to other metagenomic data sets for which corresponding SSU-rRNA gene sequences are unavailable. Our approach opens up the possibility of using metagenomic data to study microbial diversity in a phylogenetic context

Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer

Radio observations of the planetary nebula around the OH/IR Star OH354.88-0.54 (V1018 Sco)

We present radio observations of the unique, recently formed, planetary nebula (PN) associated with a very long-period OH/IR variable star V1018 Sco that is unequivocally still in its asymptoticgiant branch phase. Two regions within the optical nebula are clearly detected in nonthermal radio continuum emission, with radio spectral indices comparable to those seen in colliding-wind Wolf-Rayet binaries. We suggest that these represent shocked interactions between the hot, fast stellar wind and the cold nebular shell that represents the PN's slow wind moving away from the central star. This same interface produces both synchrotron radio continuum and the optical PN emission. The fast wind is neither spherical in geometry nor aligned withany obvious optical or radio axis. We also report the detection of transient H2O maser emission in this nebula.Comment: 11 pages, LaTeX (mn2e.cls), incl. 9 PostScript (ps or eps) figures and 2 tables. Accepted by MNRA

Cosmic Ray Acceleration at the Forward Shock in Tycho's Supernova Remnant: Evidence from Chandra X-ray Observations

We present evidence for cosmic ray acceleration at the forward shock in Tycho's supernova remnant (SNR) from three X-ray observables: (1) the proximity of the contact discontinuity to the forward shock, or blast wave, (2) the morphology of the emission from the rim of Tycho, and (3) the spectral nature of the rim emission. We determine the locations of the blast wave (BW), contact discontinuity (CD), and reverse shock (RS) around the rim of Tycho's supernova remnant using a principal component analysis and other methods applied to new Chandra data. The azimuthal-angle-averaged radius of the BW is 251". For the CD and RS we find average radii of 241" and 183", respectively. Taking account of projection effects, we find ratios of 1:0.93:0.70 (BW:CD:RS). We show these values to be inconsistent with adiabatic hydrodynamical models of SNR evolution. The CD:BW ratio can be explained if cosmic ray acceleration of ions is occurring at the forward shock. The RS:BW ratio, as well as the strong Fe Ka emission from the Tycho ejecta, imply that the RS is not accelerating cosmic rays. We also extract radial profiles from ~34% of the rim of Tycho and compare them to models of surface brightness profiles behind the BW for a purely thermal plasma with an adiabatic shock. The observed morphology of the rim is much more strongly peaked than predicted by the model, indicating that such thermal emission is implausible here. Spectral analysis also implies that the rim emission is non-thermal in nature, lending further support to the idea that Tycho's forward shock is accelerating cosmic rays.Comment: 39 pages, 10 figures, accepted by Ap

The Biogeography of Putative Microbial Antibiotic Production

Understanding patterns in the distribution and abundance of functional traits across a landscape is of fundamental importance to ecology. Mapping these distributions is particularly challenging for species-rich groups with sparse trait measurement coverage, such as flowering plants, insects, and microorganisms. Here, we use likelihood-based character reconstruction to infer and analyze the spatial distribution of unmeasured traits. We apply this framework to a microbial dataset comprised of 11,732 ketosynthase alpha gene sequences extracted from 144 soil samples from three continents to document the spatial distribution of putative microbial polyketide antibiotic production. Antibiotic production is a key competitive strategy for soil microbial survival and performance. Additionally, novel antibiotic discovery is highly relevant to human health, making natural antibiotic production by soil microorganisms a major target for bioprospecting. Our comparison of trait-based biogeographical patterns to patterns based on taxonomy and phylogeny is relevant to our basic understanding of microbial biogeography as well as the pressing need for new antibiotics

Quasars and the Big Blue Bump

We investigate the ultraviolet-to-optical spectral energy distributions (SEDs) of 17 active galactic nuclei (AGNs) using quasi-simultaneous spectrophotometry spanning 900-9000 Angstrom (rest frame). We employ data from the Far Ultraviolet Spectroscopic Explorer (FUSE), the Hubble Space Telescope (HST), and the 2.1-meter telescope at Kitt Peak National Observatory (KPNO). Taking advantage of the short-wavelength coverage, we are able to study the so-called "big blue bump," the region where the energy output peaks, in detail. Most objects exhibit a spectral break around 1100 Angstrom. Although this result is formally associated with large uncertainty for some objects, there is strong evidence in the data that the far-ultraviolet spectral region is below the extrapolation of the near-ultraviolet-optical slope, indicating a spectral break around 1100 Angstrom. We compare the behavior of our sample to those of non-LTE thin-disk models covering a range in black-hole mass, Eddington ratio, disk inclination, and other parameters. The distribution of ultraviolet-optical spectral indices redward of the break, and far-ultraviolet indices shortward of the break, are in rough agreement with the models. However, we do not see a correlation between the far-ultraviolet spectral index and the black hole mass, as seen in some accretion disk models. We argue that the observed spectral break is intrinsic to AGNs, although intrinsic reddening as well as Comptonization can strongly affect the far-ultraviolet spectral index. We make our data available online in digital format.Comment: 32 pages (10pt), 12 figures. Accepted for publication in Ap

Developing Innovative Practices Through Third-Space Partnerships: Reflections on Project DARE (Dementia Knowledge, Art, Research and Education)

Partnerships between schools, universities, and community organizations have mutual benefits for all involved. These partnerships value the contributions of all participants and capitalize on the expertise and knowledge that each brings. This reflective paper details a collaborative third-space partnership between a university, a primary school, and a community organization. The partnership facilitated the design, development, and implementation of a unique program called Project DARE (Dementia knowledge, Art, Research, and Education). A research-based evaluation of the Project DARE feasibility study can be found elsewhere (Burns et al., 2020). The aim of this paper is to reflect upon the formation of the partnership and the roles that each party played. It also discusses implications for the future development of third-space partnerships