Transient but not genetic loss of miR-451 attenuates the development of pulmonary arterial hypertension

<b>Rationale:</b> MicroRNAs are small non-coding RNAs involved in the regulation of gene expression and have recently been implicated in the development of pulmonary arterial hypertension (PAH). Previous work established that miR-451 is up-regulated in rodent models of PAH.<p></p> <b>Objectives:</b> The role of miR-451 in the pulmonary circulation is unknown. We therefore sought to assess the involvement of miR-451 in the development of pulmonary arterial hypertension.<p></p> <b>Methods:</b> Silencing of miR-451 was performed in vivo using miR-451 knockout mice and an antimiR targeting mature miR-451 in rats. Coupled with exposure to hypoxia, indices of pulmonary arterial hypertension were assessed. The effect of modulating miR-451 on human pulmonary artery smooth muscle cell proliferation and migration was analysed.<p></p> <b>Measurements and Main Results:</b> We observed a reduction in systolic right ventricular pressure in hypoxic rats pre-treated with antimiR-451 compared to hypoxia alone (47.7 ± 1.36mmHg and 56.0 ± 2.03mmHg respectively, p<0.01). In miR-451 knockout mice following exposure to chronic hypoxia, no significant differences were observed compared to wild type hypoxic mice. In vitro analysis demonstrated that over-expression of miR-451 in human pulmonary artery smooth muscle cells promoted migration under serum-free conditions. No effect on cellular proliferation was observed.<p></p> <b>Conclusions:</b> Transient inhibition of miR-451 attenuated the development of pulmonary arterial hypertension in hypoxia exposed rats. Genetic deletion of miR-451 had no beneficial effect on indices of pulmonary arterial hypertension, potentially due to pathway redundancy compensating for the loss of miR-451.<p></p&gt

Connexin 43 plays a role in pulmonary vascular reactivity in mice

Pulmonary arterial hypertension (PAH) is a chronic condition characterized by vascular remodeling and increased vaso-reactivity. PAH is more common in females than in males (~3:1). Connexin (Cx)43 has been shown to be involved in cellular communication within the pulmonary vasculature. Therefore, we investigated the role of Cx43 in pulmonary vascular reactivity using Cx43 heterozygous (Cx43+/−) mice and 37,43Gap27, which is a pharmacological inhibitor of Cx37 and Cx43. Contraction and relaxation responses were studied in intra-lobar pulmonary arteries (IPAs) derived from normoxic mice and hypoxic mice using wire myography. IPAs from male Cx43+/− mice displayed a small but significant increase in the contractile response to endothelin-1 (but not 5-hydroxytryptamine) under both normoxic and hypoxic conditions. There was no difference in the contractile response to endothelin-1 (ET-1) or 5-hydroxytryptamine (5-HT) in IPAs derived from female Cx43+/−mice compared to wildtype mice. Relaxation responses to methacholine (MCh) were attenuated in IPAs from male and female Cx43+/− mice or by pre-incubation of IPAs with 37,43Gap27. Nω-Nitro-L-arginine methyl ester (l-NAME) fully inhibited MCh-induced relaxation. In conclusion, Cx43 is involved in nitric oxide (NO)-induced pulmonary vascular relaxation and plays a gender-specific and agonist-specific role in pulmonary vascular contractility. Therefore, reduced Cx43 signaling may contribute to pulmonary vascular dysfunction

Addressing the Opioid Crisis in Vermont: Lessons Learned from Primary Care Physicians

Background: Opioid Misuse in Vermont: The number of Vermonters seeking treatment for opioid abuse is increasing, particularly in Chittenden County. Emergency department visits and deaths related to opioid misuse continue to increase, both locally and nationally. Opioid Addiction Treatment: The Drug Addiction Treatment Act (2000) was passed to allow physicians to prescribe buprenorphine-naloxone for opioid addiction, termed Office-Based Opioid Therapy (OBOT). OBOT has been shown to be a highly effective treatment for opioid addiction. The Hub and Spoke model was implemented in Vermont to connect specialty treatment centers with outpatient OBOT providers. Project Goal: To identify barriers to providing OBOT that primary care physicians (PCPs) face in Chittenden County, Vermont.https://scholarworks.uvm.edu/comphp_gallery/1221/thumbnail.jp

Fine-scale climate change: modelling spatial variation in biologically meaningful rates of warming

The existence of fine‐grain climate heterogeneity has prompted suggestions that species may be able to survive future climate change in pockets of suitable microclimate, termed ‘microrefugia’. However, evidence for microrefugia is hindered by lack of understanding of how rates of warming vary across a landscape. Here, we present a model that is applied to provide fine‐grained, multidecadal estimates of temperature change based on the underlying physical processes that influence microclimate. Weather station and remotely derived environmental data were used to construct physical variables that capture the effects of terrain, sea surface temperatures, altitude and surface albedo on local temperatures, which were then calibrated statistically to derive gridded estimates of temperature. We apply the model to the Lizard Peninsula, United Kingdom, to provide accurate (mean error = 1.21 °C; RMS error = 1.63 °C) hourly estimates of temperature at a resolution of 100 m for the period 1977–2014. We show that rates of warming vary across a landscape primarily due to long‐term trends in weather conditions. Total warming varied from 0.87 to 1.16 °C, with the slowest rates of warming evident on north‐east‐facing slopes. This variation contributed to substantial spatial heterogeneity in trends in bioclimatic variables: for example, the change in the length of the frost‐free season varied from +11 to −54 days and the increase in annual growing degree‐days from 51 to 267 °C days. Spatial variation in warming was caused primarily by a decrease in daytime cloud cover with a resulting increase in received solar radiation, and secondarily by a decrease in the strength of westerly winds, which has amplified the effects on temperature of solar radiation on west‐facing slopes. We emphasize the importance of multidecadal trends in weather conditions in determining spatial variation in rates of warming, suggesting that locations experiencing least warming may not remain consistent under future climate change

Absence of Complex I Is Associated with Diminished Respiratory Chain Function in European Mistletoe

Parasitism is a life history strategy found across all domains of life whereby nutrition is obtained from a host. It is often associated with reductive evolution of the genome, including loss of genes from the organellar genomes [1, 2]. In some unicellular parasites, the mitochondrial genome (mitogenome) has been lost entirely, with far-reaching consequences for the physiology of the organism [3, 4]. Recently, mitogenome sequences of several species of the hemiparasitic plant mistletoe (Viscum sp.) have been reported [5, 6], revealing a striking loss of genes not seen in any other multicellular eukaryotes. In particular, the nad genes encoding subunits of respiratory complex I are all absent and other protein-coding genes are also lost or highly diverged in sequence, raising the question what remains of the respiratory complexes and mitochondrial functions. Here we show that oxidative phosphorylation (OXPHOS) in European mistletoe, Viscum album, is highly diminished. Complex I activity and protein subunits of complex I could not be detected. The levels of complex IV and ATP synthase were at least 5-fold lower than in the non-parasitic model plant Arabidopsis thaliana, whereas alternative dehydrogenases and oxidases were higher in abundance. Carbon flux analysis indicates that cytosolic reactions including glycolysis are greater contributors to ATP synthesis than the mitochondrial tricarboxylic acid (TCA) cycle. Our results describe the extreme adjustments in mitochondrial functions of the first reported multicellular eukaryote without complex I

A Modest Addendum to the English Sediment Core Meta-Database

Compilations of previous studies provide researchers with a source of valuable secondary data for re-analysis, an access route to identify relevant literature and an opportunity to systematically evaluate the research which is conducted and published. Recently Suggitt et al. (2015 Veg Hist Archbot 24, 743–747) presented a valuable compilation of core records for England. Here we present an extended version of this English Sediment Core Meta-database which includes data for 100 additional cores and improves the consistency of presentation. Despite these additions there are clearly large gaps remaining. Maximising the value of such meta-databases requires a community effort and we hope that this contribution will be a first step towards achieving this

Vacuolar iron stores gated by NRAMP3 and NRAMP4 are the primary source of iron in germinating seeds

During seed germination, iron (Fe) stored in vacuoles is exported by the redundant NRAMP3 and NRAMP4 transporter proteins. A double nramp3 nramp4 mutant is unable to mobilize Fe stores and does not develop in the absence of external Fe. We used RNA sequencing to compare gene expression in nramp3 nramp4 and wild type during germination and early seedling development. Even though sufficient Fe was supplied, the Fe-responsive transcription factors bHLH38, 39, 100, and 101 and their downstream targets FRO2 and IRT1 mediating Fe uptake were strongly upregulated in the nramp3 nramp4 mutant. Activation of the Fe deficiency response was confirmed by increased ferric chelate reductase activity in the mutant. At early stages, genes important for chloroplast redox control (FSD1 and SAPX), Fe homeostasis (FER1 and SUFB), and chlorophyll metabolism (HEMA1 and NYC1) were downregulated, indicating limited Fe availability in plastids. In contrast, expression of FRO3, encoding a ferric reductase involved in Fe import into the mitochondria, was maintained, and Fe-dependent enzymes in the mitochondria were unaffected in nramp3 nramp4. Together, these data show that a failure to mobilize Fe stores during germination triggered Fe deficiency responses and strongly affected plastids, but not mitochondria

The effect of surface conductance on lateral gated quantum devices in Si/SiGe heterostructures

Quantum dots in Si/SiGe heterostructures are expected to have relatively long electron spin decoherence times, because of the low density of nuclear spins and the weak coupling between nuclear and electron spins. We provide experimental evidence suggesting that electron motion in a conductive layer parallel to the two-dimensional electron gas, possibly resulting from the donors used to dope the Si quantum well, is responsible for the well-known difficulty in achieving well-controlled dots in this system. Charge motion in the conductive layer can cause depletion on large length scales, making electron confinement in the dot impossible, and can give rise to noise that can overwhelm the single-electron charging signal. Results of capacitance versus gate bias measurements to characterize this conductive layer are presented.National Science Foundation (U.S.) ((PHY-0117795)National Science Foundation (U.S.) (DMR-0701386