Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification

Specification of Drosophila Corpora Cardiaca Neuroendocrine Cells from Mesoderm Is Regulated by Notch Signaling

Drosophila neuroendocrine cells comprising the corpora cardiaca (CC) are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism

The global naturalized Alien Flora (GloNAF) database

This dataset provides the Global Naturalized Alien Flora (GloNAF) database, ver-sion 1.2. Glo NAF represents a data compendium on th e occurrence and identit y of naturalizedalien vascular plant taxa across geographic regions (e.g. countries, states, provinces, districts,islands) around the globe. The dataset includes 13,939 taxa and covers 1,029 regions (including381 islands). The dataset is based on 210 data sources. For each ta x on-b y-region combination, wepr ovide information on whether the tax on is consider ed to be naturalized in the specific region(i.e. has established self-sustaining popula tions in the wild). Non-native taxa are marked as“alien”, when it is not clear whether they are naturalized. To facilitate alignment with other plantdatabases, we pro v ide f or each taxon the name as given in the original data source and the stan-dardized taxon and family names used by The Plant List Version 1.1 (http://www.theplantlist.org/). We pro vide an ESRI shapefile including polygons f or each region and informa tion on whetherit is an island or a mainland region, the country and the Taxonomic Databases Working Group(TDWG) regions it is part of (TDWG levels 1–4). We also provide several variables that can beused to filter the data according to quality and completeness of alien taxon lists, which varyamong the combinations of regions and da ta sources. A pre vious version of the GloNAF dataset(version 1.1) has already been used in several studies on, for example, historical spatial flows oftaxa between continents and geographical patterns and determinants of naturalization across dif-ferent taxonomic groups. We intend the updated and expanded GloNAF version presented hereto be a global resource useful for studying plant inv asions and changes in biodiversity from regio-nal to global scales. We release these data into the public domain under a Crea ti ve CommonsZer o license waiver (https://creati v ecommons.org/share-y our -work/public-domain/cc0/). Wheny ou use the da ta in your publication, we request that y ou cite this da ta paper. If GloN AF is amajor part of the data analyzed in your study, you should consider inviting the GloNAF coreteam (see Metadata S1: Originators in the Overall project description) as collaborators. If youplan to use the GloNAF dataset, we encourage y ou to contact the GloNAF core team to checkwhether there have been recent updates of the dataset, and whether similar analyses are already ongoing

Introduction to Osteopathic Manipulative Medicine.

During the two month of my ISP, I saw a wide variety of medical conditions that can benefit from osteopathic manipulative treatments. In some cases, OMT was used to successfully alleviate symptoms (in the examples of headaches, muscle strains, or URIs), but occasionally it changed disease progression and significantly improved the outcome (as in the case of a boy with craniosynostosis who was able to avoid neurosurgery). By attending clinic, workshops, the national conference, and through independent study, I was able to fulfill the goals that were established at the beginning of this project

Introduction to Osteopathic Manipulative Medicine.

During the two month of my ISP, I saw a wide variety of medical conditions that can benefit from osteopathic manipulative treatments. In some cases, OMT was used to successfully alleviate symptoms (in the examples of headaches, muscle strains, or URIs), but occasionally it changed disease progression and significantly improved the outcome (as in the case of a boy with craniosynostosis who was able to avoid neurosurgery). By attending clinic, workshops, the national conference, and through independent study, I was able to fulfill the goals that were established at the beginning of this project

Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease

Effects of altitude and ibuprofen on the hypoxic ventilatory response (HVR = ΔV˙i / ΔSa_O2).

<p>Average HVR1 (± SD), which is the initial measure of the acute HVR, is plotted for 48 hrs of treatment with placebo (Pla, gray bars) or ibuprofen (Ibu, black bars) at sea level and high altitude. There was a significant effect of altitude (p = 0.001) and altitude by drug interaction (p = 0.03). Post hoc analysis showed all of the values were significantly different from each other (p < 0.05) except the two sea level values (p = 0.22).</p