Hypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manner

17β-Estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible for this remain unknown. We hypothesized that the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague-Dawley rats and ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs). Hypoxia increased expression of ERβ, but not ERα, in lungs from HPH rats as well as in rat and human PAECs. ERβ mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1α/HIF-2α stabilization increased PAEC ERβ, whereas HIF-1α knockdown decreased ERβ abundance in hypoxic PAECs. In turn, ERβ knockdown in hypoxic PAECs increased HIF-2α expression, suggesting a hypoxia-sensitive feedback mechanism. ERβ knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERβ activation increased PHD2 and decreased both HIF-1α and HIF-2α, suggesting that ERβ regulates the PHD2/HIF-1α/HIF-2α axis during hypoxia. Whereas hypoxic wild-type or ERα knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1α after hypoxia compared with untreated hypoxic mice, ERβ knockout mice exhibited increased HIF-2α and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1α, increases ERβ expression and the E2-ERβ axis targets PHD2, HIF-1α, and HIF-2α to attenuate HPH development

A machine-learning derived model of seafloor sediment accumulation

Abstract Previous studies regarding the depositional pattern and quantity of accumulated seafloor sediment tend to be regional, limited in scope and involving costly and time-consuming geologic field campaigns and laboratory work. Presented herein is a global map of predicted modern (postindustrial, 20th and 21st century) oceanic mass accumulation rates of 5-arc-minute pitch and in log10-space, trained on observed marine mass accumulation rates from 43 peer reviewed sources (n = 1744) and predicted using a k-nearest neighbor geospatial algorithm. The resultant model predicts ~3.3 × 104 Mt. yr−1 of sediment accumulating onto the sea floor (R2 = 0.88). Most sediment accumulates proximal to major river outlets and deltas. Continental regions with the highest sediment accumulation are Asia and Oceania. This model is the first of its kind to predict the rate and quantity of sediment accumulating on to the ocean floor, globally, using decades of regional real-world observations. The generated global map of modern, benthic mass accumulation rates also serves to highlight areas of interest for future study in related fields, such as sediment dynamics and seafloor stability

Deuterium Toward WD1634-573: Results from the Far Ultraviolet Spectroscopic Explorer (FUSE) Mission

We use Far Ultraviolet Spectrocopic Explorer (FUSE) observations to study interstellar absorption along the line of sight to the white dwarf WD1634-573 (d=37.1+/-2.6 pc). Combining our measurement of D I with a measurement of H I from Extreme Ultraviolet Explorer data, we find a D/H ratio toward WD1634-573 of D/H=(1.6+/-0.5)e-5. In contrast, multiplying our measurements of D I/O I=0.035+/-0.006 and D I/N I=0.27+/-0.05 with published mean Galactic ISM gas phase O/H and N/H ratios yields D/H(O)=(1.2+/-0.2)e-5 and D/H(N)=(2.0+/-0.4)e-5, respectively. Note that all uncertainties quoted above are 2 sigma. The inconsistency between D/H(O) and D/H(N) suggests that either the O I/H I and/or the N I/H I ratio toward WD1634-573 must be different from the previously measured average ISM O/H and N/H values. The computation of D/H(N) from D I/N I is more suspect, since the relative N and H ionization states could conceivably vary within the LISM, while the O and H ionization states will be more tightly coupled by charge exchange.Comment: 23 pages, 5 figures; AASTEX v5.0 plus EPSF extensions in mkfig.sty; accepted by ApJ Supplemen

Structural evidence for the partially oxidized dipyrromethene and dipyrromethanone forms of the cofactor of porphobilinogen deaminase: structures of the Bacillus megaterium

The enzyme porphobilinogen deaminase (PBGD; hydroxymethylbilane synthase; EC 2.5.1.61) catalyses an early step of the tetrapyrrole-biosynthesis pathway in which four molecules of the monopyrrole porphobilinogen are condensed to form a linear tetrapyrrole. The enzyme possesses a dipyrromethane cofactor, which is covalently linked by a thioether bridge to an invariant cysteine residue (Cys241 in the Bacillus megaterium enzyme). The cofactor is extended during the reaction by the sequential addition of the four substrate molecules, which are released as a linear tetrapyrrole product. Expression in Escherichia coli of a His-tagged form of B. megaterium PBGD has permitted the X-ray analysis of the enzyme from this species at high resolution, showing that the cofactor becomes progressively oxidized to the dipyrromethene and dipyrromethanone forms. In previously solved PBGD structures, the oxidized cofactor is in the dipyromethenone form, in which both pyrrole rings are approximately coplanar. In contrast, the oxidized cofactor in the B. megaterium enzyme appears to be in the dipyrromethanone form, in which the C atom at the bridging α-position of the outer pyrrole ring is very clearly in a tetrahedral configuration. It is suggested that the pink colour of the freshly purified protein is owing to the presence of the dipyrromethene form of the cofactor which, in the structure reported here, adopts the same conformation as the fully reduced dipyrromethane form

Modelling the chromosphere and transition region of Epsilon Eri (K2 V)

Measurements of ultraviolet line fluxes from Space Telescope Imaging Spectrograph and Far-Ultraviolet Spectroscopic Explorer spectra of the K2-dwarf Epsilon Eri are reported. These are used to develop new emission measure distributions and semi-empirical atmospheric models for the chromosphere and lower transition region of the star. These models are the most detailed constructed to date for a main-sequence star other than the Sun. New ionisation balance calculations, which account for the effect of finite density on dielectronic recombination rates, are presented for carbon, nitrogen, oxygen and silicon. The results of these calculations are significantly different from the standard Arnaud & Rothenflug ion balance, particularly for alkali-like ions. The new atmospheric models are used to place constraints on possible First Ionisation Potential (FIP) related abundance variations in the lower atmosphere and to discuss limitations of single-component models for the interpretation of certain optically thick line fluxes.Comment: 22 pages, 9 figure

A study of velocity fields in the transition region of Epsilon Eri (K2 V)

Analyses of the widths and shifts of optically thin emission lines in the ultraviolet spectrum of the active dwarf Epsilon Eri (K2 V) are presented. The spectra were obtained using the Space Telescope Imaging Spectrograph on the Hubble Space Telescope and the Far Ultraviolet Spectroscopic Explorer. The line widths are used to find the non-thermal energy density and its variation with temperature from the chromosphere to the upper transition region. The energy fluxes that could be carried by Alfven and acoustic waves are investigated, to test their possible roles in coronal heating. Acoustic waves do not appear to be a viable means of coronal heating. There is, in principle, ample flux in Alfven waves, but detailed calculations of wave propagation are required before definite conclusions can be drawn about their viability. The high sensitivity and spectral resolution of the above instruments have allowed two-component Gaussian fits to be made to the profiles of the stronger transition region lines. The broad and narrow components which result share some similarities with those observed in the Sun, but in Epsilon Eri the broad component is redshifted relative to the narrow component and contributes more to the total line flux. The possible origins of the two components and the energy fluxes implied are discussed. On balance our results support the conclusion of Wood, Linsky & Ayres, that the narrow component is related to Alfven waves reaching to the corona, but the origin of the broad component is not clear.Comment: 19 pages, 16 figures. Accepted for publication by MNRA

Movement Interventions for Children with Autism and Developmental Disabilities: An Evidence-Based Practice Project

This review explored the following question: Are the comprehensive treatment models Makoto Therapy, Brain Gym, and Interactive Metronome effective interventions for improving occupational performance including improving executive function, academic performance, and physical coordination in children and adolescents with Autism Spectrum Disorder (ASD)? Because current research on Interactive Metronome, Brain Gym®, and Makoto Therapy fails to address children and adolescents with autism spectrum disorder, presents multiple flaws in research design, and does not measure occupational outcomes such as occupational performance, we recommend that these interventions should not be used as comprehensive treatment models in occupational therapy. We recommend that more occupational-based, methodologically-sound research involving youth with ASD be conducted before implementing these interventions in occupational therapy practice

Expression Levels of a Kinesin-13 Microtubule Depolymerase Modulates the Effectiveness of Anti-Microtubule Agents

Chemotherapeutic drugs often target the microtubule cytoskeleton as a means to disrupt cancer cell mitosis and proliferation. Anti-microtubule drugs inhibit microtubule dynamics, thereby triggering apoptosis when dividing cells activate the mitotic checkpoint. Microtubule dynamics are regulated by microtubule-associated proteins (MAPs); however, we lack a comprehensive understanding about how anti-microtubule agents functionally interact with MAPs. In this report, we test the hypothesis that the cellular levels of microtubule depolymerases, in this case kinesin-13 s, modulate the effectiveness of the microtubule disrupting drug colchicine.We used a combination of RNA interference (RNAi), high-throughput microscopy, and time-lapse video microscopy in Drosophila S2 cells to identify a specific MAP, kinesin-like protein 10A (KLP10A), that contributes to the efficacy of the anti-microtubule drug colchicine. KLP10A is an essential microtubule depolymerase throughout the cell cycle. We find that depletion of KLP10A in S2 cells confers resistance to colchicine-induced microtubule depolymerization to a much greater extent than depletion of several other destabilizing MAPs. Using image-based assays, we determined that control cells retained 58% (+/-2%SEM) of microtubule polymer when after treatment with 2 microM colchicine for 1 hour, while cells depleted of KLP10A by RNAi retained 74% (+/-1%SEM). Likewise, overexpression of KLP10A-GFP results in increased susceptibility to microtubule depolymerization by colchicine.Our results demonstrate that the efficacy of microtubule destabilization by a pharmacological agent is dependent upon the cellular expression of a microtubule depolymerase. These findings suggest that expression levels of Kif2A, the human kinesin-13 family member, may be an attractive biomarker to assess the effectiveness of anti-microtubule chemotherapies. Knowledge of how MAP expression levels affect the action of anti-microtubule drugs may prove useful for evaluating possible modes of cancer treatment

Comparing genetic diversity in three threatened oaks

Genetic diversity is a critical resource for species’ survival during times of environmental change. Conserving and sustainably managing genetic diversity requires understanding the distribution and amount of genetic diversity (in situ and ex situ) across multiple species. This paper focuses on three emblematic and IUCN Red List threatened oaks (Quercus, Fagaceae), a highly speciose tree genus that contains numerous rare species and poses challenges for ex situ conservation. We compare the genetic diversity of three rare oak species-Quercus georgiana, Q. oglethorpensis, and Q. boyntonii-to common oaks; investigate the correlation of range size, population size, and the abiotic environment with genetic diversity within and among populations in situ; and test how well genetic diversity preserved in botanic gardens correlates with geographic range size. Our main findings are: (1) these three rare species generally have lower genetic diversity than more abundant oaks; (2) in some cases, small population size and geographic range correlate with genetic diversity and differentiation; and (3) genetic diversity currently protected in botanic gardens is inadequately predicted by geographic range size and number of samples preserved, suggesting non-random sampling of populations for conservation collections. Our results highlight that most populations of these three rare oaks have managed to avoid severe genetic erosion, but their small size will likely necessitate genetic management going forward

Development of in-situ trap characterisation techniques for EMCCDs

The "trap pumping" technique has seen considerable use over recent years as a means to probe the intrinsic properties of silicon defects that can impact charge transfer performance within CCD-based technologies. While the theory behind the technique is reasonably well understood, it has to date only been applied to relatively simple pixel designs where the motion of charge between pixel phases is fairly easy to predict. For some devices, the intrinsic pixel architecture is more complex and can consist of unequal phase sizes and additional implants that deform the electronic potential. Here, we present the implementation of the trap pumping technique for the CCD201-20, a 2-phase Teledyne e2v EMCCD. Clocking schemes are presented that can provide the location of silicon defects to sub-micron resolution. Experimental techniques that allow determination of trap energy levels and emission cross sections are presented. These are then implemented on an irradiated CCD201-20 to determine the energy level and emission cross section for defects thought to be the double acceptor state of the silicon divacancy (VV--) and carbon-phosphorus (CiPs) pairs. An improvement in charge transfer performance through optimised parallel clock delay is demonstrated and found to correlate with the properties of defects found using the trap pumping technique