Atmospheric Heating and Wind Acceleration: Results for Cool Evolved Stars based on Proposed Processes

A chromosphere is a universal attribute of stars of spectral type later than ~F5. Evolved (K and M) giants and supergiants (including the zeta Aurigae binaries) show extended and highly turbulent chromospheres, which develop into slow massive winds. The associated continuous mass loss has a significant impact on stellar evolution, and thence on the chemical evolution of galaxies. Yet despite the fundamental importance of those winds in astrophysics, the question of their origin(s) remains unsolved. What sources heat a chromosphere? What is the role of the chromosphere in the formation of stellar winds? This chapter provides a review of the observational requirements and theoretical approaches for modeling chromospheric heating and the acceleration of winds in single cool, evolved stars and in eclipsing binary stars, including physical models that have recently been proposed. It describes the successes that have been achieved so far by invoking acoustic and MHD waves to provide a physical description of plasma heating and wind acceleration, and discusses the challenges that still remain.Comment: 46 pages, 9 figures, 1 table; modified and unedited manuscript; accepted version to appear in: Giants of Eclipse, eds. E. Griffin and T. Ake (Berlin: Springer

Self-consistent Coronal Heating and Solar Wind Acceleration from Anisotropic Magnetohydrodynamic Turbulence

We present a series of models for the plasma properties along open magnetic flux tubes rooted in solar coronal holes, streamers, and active regions. These models represent the first self-consistent solutions that combine: (1) chromospheric heating driven by an empirically guided acoustic wave spectrum, (2) coronal heating from Alfven waves that have been partially reflected, then damped by anisotropic turbulent cascade, and (3) solar wind acceleration from gradients of gas pressure, acoustic wave pressure, and Alfven wave pressure. The only input parameters are the photospheric lower boundary conditions for the waves and the radial dependence of the background magnetic field along the flux tube. For a single choice for the photospheric wave properties, our models produce a realistic range of slow and fast solar wind conditions by varying only the coronal magnetic field. Specifically, a 2D model of coronal holes and streamers at solar minimum reproduces the latitudinal bifurcation of slow and fast streams seen by Ulysses. The radial gradient of the Alfven speed affects where the waves are reflected and damped, and thus whether energy is deposited below or above the Parker critical point. As predicted by earlier studies, a larger coronal ``expansion factor'' gives rise to a slower and denser wind, higher temperature at the coronal base, less intense Alfven waves at 1 AU, and correlative trends for commonly measured ratios of ion charge states and FIP-sensitive abundances that are in general agreement with observations. These models offer supporting evidence for the idea that coronal heating and solar wind acceleration (in open magnetic flux tubes) can occur as a result of wave dissipation and turbulent cascade. (abridged abstract)Comment: 32 pages (emulateapj style), 18 figures, ApJ Supplement, in press (v. 171, August 2007

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.

peer reviewedThe Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Increased placental nutrient transporter expression at midgestation after maternal growth hormone treatment in pigs: a placental mechanism for increased fetal growth

Growth hormone (GH) is important in maternal adaptation to pregnancy, and maternal circulating GH concentrations are reduced in human growth-restricted pregnancies. In the pig, maternal GH treatment throughout early to mid pregnancy increases fetal growth, despite constraining effects of adolescent and primiparous pregnancy, high litter size, and restricted maternal nutrition. Because GH cannot cross the placenta and does not increase placental weight, we hypothesized that its effects on fetal growth might be via improved placental structure or function. We therefore investigated effects of maternal GH treatment in pigs on structural correlates of placental function and placental expression of nutrient transporters important to fetal growth. Multiparous (sows) and primiparous pregnant pigs (gilts) were treated with GH (~15 μg kg(-1) day(-1)) or vehicle from Days 25-50 of gestation (n = 7-8 per group, term ~115 days). Placentas were collected at Day 50 of gestation, and we measured structural correlates of function and expression of SLC2A1 (previously known as GLUT1) and SLC38A2 (previously known as SNAT2) nutrient transporters. Maternal GH treatment did not alter placental size or structure, increased protein expression of SLC2A1 in trophoblast (+35%; P = 0.037) and on its basal membrane (+44%; P = 0.011), and increased SLC38A2 protein expression in the basal (+44%; P = 0.001) but not the apical cytoplasm of trophoblast. Our findings suggest that maternal GH treatment increases fetal growth, in part, by enhancing placental nutrient transporter protein expression and hence fetal nutrient supply as well as trophoblast proliferation and differentiation and may have the potential to ameliorate intrauterine growth restriction

An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9/FLT3 for the Treatment of Acute Myeloid Leukemia

Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately one-third of AML patients and are associated with a particularly poor prognosis. The most common mutation, FLT3-ITD, is a self-activating internal tandem duplication (ITD) in the FLT3 juxtamembrane domain. Many FLT3 inhibitors have shown encouraging results in clinical trials, but the rapid emergence of resistance has severely limited sustainable efficacy. Co-targeting of CDK9 and FLT3 is a promising two-pronged strategy to overcome resistance as the former plays a role in the transcription of cancer cell-survival genes. Most prominently, MCL-1 is known to be associated with AML tumorigenesis and drug resistance and can be down-regulated by CDK9 inhibition. We have developed CDDD11-8 as a potent CDK9 inhibitor co-targeting FLT3-ITD with Ki values of 8 and 13 nM, respectively. The kinome selectivity has been confirmed when the compound was tested in a panel of 369 human kinases. CDDD11-8 displayed antiproliferative activity against leukemia cell lines, and particularly potent effects were observed against MV4-11 and MOLM-13 cells, which are known to harbor the FLT3-ITD mutation and mixed lineage leukemia (MLL) fusion proteins. The mode of action was consistent with inhibition of CDK9 and FLT3-ITD. Most importantly, CDDD11-8 caused a robust tumor growth inhibition by oral administration in animal xenografts. At 125 mg/kg, CDDD11-8 induced tumor regression, and this was translated to an improved survival of animals. The study demonstrates the potential of CDDD11-8 towards the future development of a novel AML treatment

Excitatory glycine responses of CNS myelin mediated by NR1/NR3 "NMDA" receptor subunits

NMDA receptors are typically excited by a combination of glutamate and glycine. Here we describe excitatory responses in CNS myelin that are gated by a glycine agonist alone and mediated by NR1/NR3 ‘NMDA receptor’ subunits. Response properties include activation by d-serine, inhibition by the glycine-site antagonist CNQX, and insensitivity to the glutamate-site antagonist d-APV. d-Serine responses were abrogated in NR3A-deficient mice. Our results suggest the presence of functional NR1/NR3 receptors in CNS myelin

Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep

Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON; n = 6 females and 4 males) and placentally restricted pregnancies (PR; n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4; PR + exendin-4; n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents