Impedance Responses Reveal β2-Adrenergic Receptor Signaling Pluridimensionality and Allow Classification of Ligands with Distinct Signaling Profiles

The discovery that drugs targeting a single G protein-coupled receptor (GPCR) can differentially modulate distinct subsets of the receptor signaling repertoire has created a challenge for drug discovery at these important therapeutic targets. Here, we demonstrate that a single label-free assay based on cellular impedance provides a real-time integration of multiple signaling events engaged upon GPCR activation. Stimulation of the β2-adrenergic receptor (β2AR) in living cells with the prototypical agonist isoproterenol generated a complex, multi-featured impedance response over time. Selective pharmacological inhibition of specific arms of the β2AR signaling network revealed the differential contribution of Gs-, Gi- and Gβγ-dependent signaling events, including activation of the canonical cAMP and ERK1/2 pathways, to specific components of the impedance response. Further dissection revealed the essential role of intracellular Ca2+ in the impedance response and led to the discovery of a novel β2AR-promoted Ca2+ mobilization event. Recognizing that impedance responses provide an integrative assessment of ligand activity, we screened a collection of β-adrenergic ligands to determine if differences in the signaling repertoire engaged by compounds would lead to distinct impedance signatures. An unsupervised clustering analysis of the impedance responses revealed the existence of 5 distinct compound classes, revealing a richer signaling texture than previously recognized for this receptor. Taken together, these data indicate that the pluridimensionality of GPCR signaling can be captured using integrative approaches to provide a comprehensive readout of drug activity

Relaxin: Review of Biology and Potential Role in Treating Heart Failure

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure

The mammals of Angola

Scientific investigations on the mammals of Angola started over 150 years ago, but information remains scarce and scattered, with only one recent published account. Here we provide a synthesis of the mammals of Angola based on a thorough survey of primary and grey literature, as well as recent unpublished records. We present a short history of mammal research, and provide brief information on each species known to occur in the country. Particular attention is given to endemic and near endemic species. We also provide a zoogeographic outline and information on the conservation of Angolan mammals. We found confirmed records for 291 native species, most of which from the orders Rodentia (85), Chiroptera (73), Carnivora (39), and Cetartiodactyla (33). There is a large number of endemic and near endemic species, most of which are rodents or bats. The large diversity of species is favoured by the wide range of habitats with contrasting environmental conditions, while endemism tends to be associated with unique physiographic settings such as the Angolan Escarpment. The mammal fauna of Angola includes 2 Critically Endangered, 2 Endangered, 11 Vulnerable, and 14 Near-Threatened species at the global scale. There are also 12 data deficient species, most of which are endemics or near endemics to the countryinfo:eu-repo/semantics/publishedVersio

A new flavanolignan and a new alkane from the Stem bark of <i>Newtonia griffoniana</i>

<p>Two new compounds a flavanolignan (<b>1</b>), and an alkane (<b>2</b>) along with four known compounds including two fatty acid esters (<b>3–4</b>) and two isocoumarins (<b>5–6</b>) were isolated from the methanolic extract of the stem bark of <i>Newtonia griffoniana</i>. Their structures were elucidated using spectroscopic methods including extensive 1-D and 2-D NMR experiments.</p

Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia

A young, adult, African male patient presented with progressive proximal muscle weakness, external ophthalmoplegia and ptosis, as well as cardiac conduction abnormalities resembling Kearns-Sayre syndrome (KSS). Magnetic resonance imaging (MRI) of the brain revealed normal basal ganglia but bilateral well-circumscribed lesions in the cerebellar peduncles. Enzyme deficiencies in oxidative phosphorylation (OXPHOS) complexes I, IV and V was measured in muscle tissue. Blue native polyacrylamide gel electrophoresis (BN-PAGE) confirmed decreased protein content and activity of these complexes and revealed the presence of two catalytically active complex V sub-complexes. Upon investigation by molecular genetics, the mitochondrial DNA (mtDNA) copy number was found to be elevated and a novel deletion of 3431 bp was found in 80% of muscle mtDNA between positions 7115 and 10546, flanked by a 5 bp direct repeat sequence. In addition, it could also be concluded that the absence of mtDNA-encoded ATPase6 and ATPase8 genes in this patient clearly resulted in aberrant synthesis of ATP synthase

Readiness to change is a predictor of reduced substance use involvement: Findings from a randomized controlled trial of patients attending South African emergency departments

Background: This study examines whether readiness to change is a predictor of substance use outcomes and explores factors associated with RTC substance use among patients at South African emergency departments. Methods: We use data from participants enrolled into a randomized controlled trial of a brief substance use intervention conducted in three emergency departments in Cape Town, South Africa. Results: In adjusted analyses, the SOCRATES "Recognition" (B = 11.6; 95 % CI = 6.2-17.0) and "Taking Steps" score (B = -9.5; 95 % CI = -15.5- -3.5) as well as alcohol problems (B = 4.4; 95 % CI = 0.9-7.9) predicted change in substance use involvement at 3 month follow-up. Severity of depression (B = 0.2; 95 % CI = 0.1-0.3), methamphetamine use (B = 3.4; 95 % CI = 0.5- 6.3) and substance-related injury (B = 1.9; 95 % CI = 0.6-3.2) were associated with greater recognition of the need for change. Depression (B = 0.1; 95 % CI = 0.04 -0.1) and methamphetamine use (B = 2.3; 95 % CI = 0.1 -4.2) were also associated with more ambivalence about whether to change. Participants who presented with an injury that was preceded by substance use were less likely to be taking steps to reduce their substance use compared to individuals who did not (B = -1.7; 95 % CI = -5.0- -0.6). Conclusion: Findings suggest that brief interventions for this population should include a strong focus on building readiness to change substance use through motivational enhancement strategies. Findings also suggest that providing additional support to individuals with depression may enhance intervention outcomes. Trial registration: This trial registered with the Pan African Clinical Trial Registry ( PACTR201308000591418 ) on 14/07/2013