Branching principles of animal and plant networks identified by combining extensive data, machine learning, and modeling

Branching in vascular networks and in overall organismic form is one of the most common and ancient features of multicellular plants, fungi, and animals. By combining machine-learning techniques with new theory that relates vascular form to metabolic function, we enable novel classification of diverse branching networks--mouse lung, human head and torso, angiosperm and gymnosperm plants. We find that ratios of limb radii--which dictate essential biologic functions related to resource transport and supply--are best at distinguishing branching networks. We also show how variation in vascular and branching geometry persists despite observing a convergent relationship across organisms for how metabolic rate depends on body mass.Comment: 55 pages, 8 figures, 8 table

An adrenal beta-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo.

Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT(1)Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G(q/11)-proteins, to which the AT(1)R normally couples. Here, we describe a novel signaling pathway underlying this AT(1)R-dependent aldosterone production mediated by beta-arrestin-1 (betaarr1), a universal heptahelical receptor adapter/scaffolding protein. This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein, a steroid transport protein regulating aldosterone biosynthesis in AZG cells. Also, this betaarr1-mediated pathway appears capable of promoting aldosterone turnover independently of G protein activation, because treatment of AZG cells with SII, an AngII analog that induces betaarr, but not G protein coupling to the AT(1)R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal betaarr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a betaarr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical betaarr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal betaarr1 activity on AT(1)Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism

βARKct gene-therapy improves β2-adrenergic receptor-dependent neoangiogenesis following hindlimb ischemia

Following hindlimb ischemia (HI) increased catecholamine levels within the ischemic muscle can cause dysregulation of β2-adrenergic receptor (β2AR) signaling leading to reduced revascularization. Indeed, in vivo β2AR overexpression, via gene therapy, enhances angiogenesis in a rat model of HI. G protein-coupled receptor kinase 2 (GRK2) is a key regulator of βAR signaling, and βARKct, a peptide inhibitor of GRK2, has been shown to prevent βAR down-regulation and to protect cardiac myocytes and stem cells from ischemic injury, through restoration of β2AR protective signaling (i.e. Akt/eNOS). Herein, we tested potential therapeutic effects of adenoviral-mediated βARKct gene transfer in an experimental model of HI and its effects on βAR signaling and on endothelial cell (EC) function in vitro. Accordingly, in this study, we surgically induced HI in rats by femoral artery resection (FAR). Fifteen days of ischemia resulted in significant βAR down-regulation that was paralleled by an about 2-fold increase in GRK2 levels in the ischemic muscle. Importantly, in vivo gene transfer of the βARKct in the hindlimb of rats at the time of FAR resulted in a marked improvement of hindlimb perfusion, with increased capillary and βAR density in the ischemic muscle, compared to control groups. The effect of βARKct expression was also assessed, in vitro in cultured ECs. Interestingly, in ECs expressing the βARKct, fenoterol, a β2AR-agonist, induced enhanced β2AR pro-angiogenic signaling and increased EC function. In conclusion, our results suggest that βARKct gene-therapy and subsequent GRK2 inhibition promotes angiogenesis in a model of HI by preventing ischemia-induced β2AR downregulation

Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms

β-Arrestin (βarr)-1 and β-arrestin-2 (βarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac β-adrenergic receptor (βAR) function via βAR desensitization and downregulation. In addition, they mediate G-protein-independent βAR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac βAR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal βarr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of βarr1 in post-myocardial infarction (MI) HF by testing the effects of βarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied βarr1 knockout (βarr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) βarr1KO mice display enhanced βAR-dependent contractility and post-MI βarr1KO mice enhanced overall cardiac function (and βAR-dependent contractility) compared with wild type. Post-MI βarr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac βAR signaling and function, as evidenced by increased βAR density and procontractile signaling, via reduced cardiac βAR desensitization because of cardiac βarr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal βarr1 absence. Thus, βarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF

Angiotensin Receptor Blocker Drugs and Inhibition of Adrenal Beta-Arrestin-1-Dependent Aldosterone Production: Implications for Heart Failure Therapy

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II (AngII). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure (HF), is induced by AngII type 1 receptors (AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1 (βarr1) or -2 (βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 protein-independent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers (ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes (G protein-, and βarr1-dependent) at the AngII-activated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by AngII and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-“biased” blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan (and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone

SAFETY ISSUES WHEN MONITORING CO2 STORAGE IN THE PRINOS AREA, GREECE

 Η γεωλογική αποθήκευση του CO2 σε γεωλογικές δομές κάτω από την επιφάνεια της γης μπορεί να μετριάσει την υπερθέρμανση του πλανήτη. Μια ασφαλής αποθήκευση του CO2 μπορεί να εξασφαλιστεί μέσω της ανάπτυξης ολοκληρωμένων προγραμμάτων παρακολούθησης που αποτρέπουν οποιαδήποτε πιθανή διαρροή CO2. Η εργασία αυτή παρουσιάζει διάφορες στρατηγικές παρακολούθησης της υπόγειας μετακίνησης του CO2 στον ταμιευτήρα του Πρίνου, στη Βόρεια Ελλάδα, τα αποτελέσματα προσομοίωσης μιας διαρροής CO2 μέσω μιας γεώτρησης, και μια εκτίμηση των περιβαλλοντικών κινδύνων που σχετίζονται με πιθανή υποθαλάσσια διαρροή CO2 ή πετρελαίου. Μετά από μόλις 13.7 χρόνια, από την αρχή της έγχυσης, η διαρροή του CO2 φθάνει στον πυθμένα με τη μορφή αερίου. Για την περιβαλλοντική αξιολόγηση έχουμε  ένα μοντέλο, με τη χρήση του λογισμικού ArcGIS, που βασίζεται στη χρήση των δεδομένων σχετικά με τις ταχύτητες των ανέμων και των ρευμάτων που συναντώνται στην περιοχή. Επίσης, έγιναν εκτιμήσεις σχετικά με τον ρυθμό ροής του CO2. Τα αποτελέσματα της προσομοίωσης δείχνουν ότι αρκεί ένα διάστημα 10 ημερών από την έναρξη της διαρροής πετρελαίου μέχρι να αρχίσουν να επηρεάζονται οι προστατευόμενες περιοχές "Natura". Τα αποτελέσματα της προσομοίωσης δείχνουν το CO2 που έχει διαρρεύσει να ρέει αρχικά κατά μήκος της επικρατούσας κατεύθυνσης ροής, η οποία είναι προς τα ΒΑ. Εντούτοις, 5 ημέρες μετά την έναρξη της διαρροής του CO2, αυτό ρέει επίσης και προς τα ΑΒΑ. Οι συνέπειες μιας ενδεχόμενης διαρροής CO2 θεωρούνται χωρικά περιορισμένες και το οικοσύστημα είναι ικανό από μόνο του να επανέλθει στην πρωταρχική του κατάσταση.Geological storage of CO2 in geological structures in the subsurface can mitigate global warming. A safe storage of CO2 can be ensured through the development of comprehensive monitoring programs that prevent any possible leakage of CO2. This paper presents various monitoring strategies of CO2 subsurface movement in the Prinos reservoir, northern Greece, the results of a simulation of a CO2 leak through a well, and an environmental risk assessment study related to the leakage of CO2 or oil from the seafloor. After only 13.7 years, from the beginning of injection, the CO2 leak reaches the seabed in the form of gas. For the assessment we set up a model, using ArcGIS software, based on the use of data regarding the speeds of the winds and currents encountered in the region. Assumptions were also made related to the flow rate of CO2. Modeling results show that it only takes a period of 10 days from the start of oil leakage until the “Natura” protected areas start to be affected. CO2 leakage modelling results show CO2 to be initially flowing along a preferential flow direction, which is towards NE. However, 5 days after the start of leakage of CO2, it is also flowing towards ENE. The consequences of a potential CO2 leak are considered spatially limited and the ecosystem is capable of recovering by itself

Impaired desensitization of a human polymorphic α2B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells

<p>Abstract</p> <p>Background</p> <p>α₂-adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine and inhibit their secretion from adrenal chromaffin cells. Like many other G-protein coupled receptors (GPCRs), they undergo agonist-dependent phopshorylation and desensitization by GPCR Kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A deletion polymorphism in the human α_2B-AR gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization in heterologous cell lines. Given the importance of α₂-ARs in regulation of catecholamine secretion from chromaffin cells, we sought to investigate, in the present study, the desensitization properties and the sympatho-inhibitory activity of this variant in a chromaffin cell line. For this purpose, we expressed this variant and its wild type counterpart in the well-established chromaffin cell line PC12, and performed receptor phosphorylation and desensitization studies, as well as in vitro catecholamine secretion assays.</p> <p>Results</p> <p>Both the agonist-induced phosphorylation and agonist-dependent desensitization of the human Glu301-303 deletion polymorphic α_2B-AR are significantly impaired in PC12 cells, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in vitro.</p> <p>Conclusion</p> <p>This α_2B-AR gene polymorphism (Glu301-303 deletion) might confer better protection against conditions characterized and aggravated by sympathetic/catecholaminergic overstimulation in vivo.</p