Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs

Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top-down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography-mass spectrometry (LC-MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations. We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence. We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation

Efficacy and Safety/Toxicity Study of Recombinant Vaccinia Virus JX-594 in Two Immunocompetent Animal Models of Glioma

The purpose of this study was to investigate the oncolytic potential of the recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) in vitro and in immunocompetent rodent models. We have found that JX-594 killed all MG cell lines tested in vitro. Intratumoral (i.t.) administration of JX-594 significantly inhibited tumor growth and prolonged survival in rats-bearing RG2 intracranial (i.c.) tumors and mice-bearing GL261 brain tumors. Combination therapy with JX-594 and rapamycin significantly increased viral replication and further prolonged survival in both immunocompetent i.c. MG models with several animals considered “cured” (three out of seven rats >120 days, terminated experiment). JX-594 infected and killed brain tumor-initiating cells (BTICs) from patient samples grown ex vivo, and did so more efficiently than other oncolytic viruses MYXV, Reovirus type-3, and VSVΔM51. Additional safety/toxicity studies in nontumor-bearing rodents treated with a supratherapeutic dose of JX-594 demonstrated GM-CSF-dependent inflammation and necrosis. These results suggest that i.c. administered JX-594 triggers a predictable GM-CSF-mediated inflammation in murine models. Before proceeding to clinical trials, JX-594 should be evaluated in the brains of nonhuman primates and optimized for the viral doses, delivery routes as well as the combination agents (e.g., mTOR inhibitors)

Phase 2 safety and antiviral activity of SAB-185, a novel polyclonal antibody therapy for non-hospitalized adults with COVID-19

SAB-185, a novel fully-human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for non-hospitalized adults with mild-moderate COVID-19.Participants received intravenous SAB-185 3,840 units/kg (low-dose) or placebo, or 10,240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal SARS-CoV-2 RNA <lower limit of quantification (LLoQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.Two-hundred thirteen participants received low-dose SAB-185/placebo (n=107/106) and 215 high-dose SAB-185/placebo (n=110/105). The proportions with SARS-CoV-2 RNA <LLoQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB versus placebo only, relative risk (95% CI) 1.23 (1.01, 1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo, differences in medians of -0.78 log10copies/mL (p=0.08) and -0.71 log10copies/mL (p=0.10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (p=0.24) for low-dose SAB-185/placebo and 8/10 days (p=0.50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo.SAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk non-hospitalized adults with COVID-19

LB2. Safety and Efficacy of Combination SARS-CoV-2 Monoclonal Neutralizing Antibodies (mAb) BRII-196 and BRII-198 in Non-Hospitalized COVID-19 Patients

Abstract Background SARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG. Methods ACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis. Results Between January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs. Conclusion BRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease. Disclosures Kara W. Chew, MD, MS, Amgen (Individual(s) Involved: Self): Grant/Research Support; Merck Sharp & Dohme (Individual(s) Involved: Self): Grant/Research Support David Alain Wohl, MD, Gilead Sciences (Individual(s) Involved: Self): Advisor or Review Panel member, Consultant, Research Grant or Support, Scientific Research Study Investigator; Janssen (Individual(s) Involved: Self): Advisor or Review Panel member; Merck (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support; ViiV (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) David A. Margolis, MD MPH, Brii Biosciences (Employee) Courtney Fletcher, Pharm.D., National Institute of Allergy and Infectious Diseases, NIH (Grant/Research Support) Davey Smith, M.D., Linear Therapies, Matrix Biomed, Bayer (Consultant, Shareholder) Eric Daar, Gilead (Consultant, Grant/Research Support)Merck (Consultant)ViiV (Consultant, Grant/Research Support

Le réseau de radar Stratophérique-Troposphérique au cours de la campagne MAP: aspects observationnels et scientifiques

International audienceEine internationale Kampagne des Mesoscale Alpine Program (MAP) fand vom 7. September bis 15. November 1999 in den Alpen statt. Sie widmete sich der Untersuchung von Wechselwirkungen zwischen großräumigen Prozessen und der mesoskaligen Strömung über komplexem, gebirgigem Untergrund. Zahlreiche Instrumentensysteme in der Luft und am Boden, mesoskalige numerische Modelle, sowie Radiosonden und Satellitenmessungen kamen bei der Kampagne zum Einsatz. Während MAP bestand das französische ST (Strato-troposphärische) Forschungsradarnetz aus fünf VHF (Very High Frequency) und drei UHF (Ultra High Frequency) Profilern. Vier VHFs und zwei UHFs waren in Südfrankreich stationiert und ein VHF sowie ein UHF befanden sich in Italien, im Gebiet des Lago Maggiore. Die VHFs lieferten in 15-minütiger Zeitauflösung Vertikalprofile des Windes und die vertikale SNR (Signal-to-Noise Ratio) von der unteren Troposphäre bis zu oberen Troposphären- und unteren Stratosphärenschichten, je nach Instrument und/oder Atmosphärenbedingungen. Die gleiche Art Daten wurde von den UHFs erzeugt, jedoch aus Höhen von einigen 100 m bis zu etwa 3 km. Alle Instrumente gestatteten es, in ihrem jeweiligen Höhenbereich die zeitliche Entwicklung und die Vertikalstruktur der mesoskaligen dynamischen Prozesse aufzuzeichnen. Es werden hier VHF-Beobachtungen vorgestellt, die während des Durchgangs von Anomalien der PV (Potentielle Vorticity) - sogenannte PV-streamer - über Südfrankreich und der Gegend des Lago Maggiore entstanden. Dies beinhaltet Durchgänge des Strahlstroms und Tropopausen-Variationen. Außerdem werden UHF-Beobachtungen des Winds in der unteren Troposphäre am Ausgang des Rhônetals, als Mistral bekannt, vorgestellt. Vorläufige Analysen zeigen, dass unsere Beobachtungen sowohl untereinander als auch mit Modell-Analysen im synoptischen Scale des ECMWF (European Centre for Medium-Range Weather Forecasts) konsistent sind. Darüber hinaus werden Quervergleiche mit Mesoskalen-Modellen durchgeführt, mit deren Hilfe es möglich ist, einige mesoskalige Aspekte der atmosphärischen Dynamik zu untersuchen.The Mesoscale Alpine Program (MAP) international cooperative campaign took place over and around the Alps between 99/09/07 and 99/11/15 and was devoted to the study of the interactions between large-scale processes and the meso-scale flow over a complex mountainous terrain. Numerous airborne and ground based instrumental systems and meso-scale numerical models were involved in the campaign, as well as radiosoundings and satellite observations. During MAP the French ST (Strato-Tropospheric) radar research-network consisted of five VHF (Very High Frequency) and three UHF (Ultra High Frequency) profilers. Four VHF's and two UHF's were installed in southern France and one VHF and one UHF were in Italy, in the Lago Maggiore target area. The VHF's provided 15-min time-resolution vertical profiles of wind and vertical SNR (Signal-to-Noise Ratio) from the low troposphere up to high tropospheric or low stratospheric levels, depending on the instrument and/or the atmospheric conditions. The same kind of data were obtained by the UHF's, but from a few hundreds of meters up to about 3 km. In their respective altitude ranges, all these instruments allowed the time evolution and the vertical structure of meso-scale dynamic processes to be documented. VHF observations made during upper-level PV-anomaly passages (PV streamers) above southern France and Lago Maggiore area, including jet-stream passages and tropopause variations, are presented here. UHF observations of the low-tropospheric wind at the exit of the Rhône-valley, locally called Mistral, are also presented. Preliminary analyses show that our observations are consistent both between themselves and with synoptic-scale ECMWF (European Centre for Medium-Range Weather Forecasts)-model analyses. In addition, cross-comparisons with meso-scale model simulations are made allowing some meso-scale aspects of the atmospheric dynamics to be investigated

Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs

Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top–down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography–mass spectrometry (LC–MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations. We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence. We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation.rotected area networks help species respond to climate warming. However, the contribution of a site’s environmental and conservation-relevant characteristics to these responsesis not well understood. We investigated how composition of nonbreeding waterbird communities (97 species) in the European Union Natura 2000 (N2K) network (3018 sites)changed in response to increases in temperature over 25 years in 26 European countries.We measured community reshuffling based on abundance time series collected under theInternational Waterbird Census relative to N2K sites’ conservation targets, funding, designation period, and management plan status. Waterbird community composition in sitesexplicitly designated to protect them and with management plans changed more quickly inresponse to climate warming than in other N2K sites. Temporal community changes werenot affected by the designation period despite greater exposure to temperature increaseinside late-designated N2K sites. Sites funded under the LIFE program had lower climate-driven community changes than sites that did not received LIFE funding. Our findingsimply that efficient conservation policy that helps waterbird communities respond to cli-mate warming is associated with sites specifically managed for waterbirds. climate adaptation, colonization, conservation policy, distribution change, EU Birds Directive, LIFE program,wetland. Arctic, Betula, birch, herbivory, metabolomics, plant chemical defence, shrubs, tundr

Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs

Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top–down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography–mass spectrometry (LC–MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations. We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence. We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation.rotected area networks help species respond to climate warming. However, the contribution of a site’s environmental and conservation-relevant characteristics to these responsesis not well understood. We investigated how composition of nonbreeding waterbird communities (97 species) in the European Union Natura 2000 (N2K) network (3018 sites)changed in response to increases in temperature over 25 years in 26 European countries.We measured community reshuffling based on abundance time series collected under theInternational Waterbird Census relative to N2K sites’ conservation targets, funding, designation period, and management plan status. Waterbird community composition in sitesexplicitly designated to protect them and with management plans changed more quickly inresponse to climate warming than in other N2K sites. Temporal community changes werenot affected by the designation period despite greater exposure to temperature increaseinside late-designated N2K sites. Sites funded under the LIFE program had lower climate-driven community changes than sites that did not received LIFE funding. Our findingsimply that efficient conservation policy that helps waterbird communities respond to cli-mate warming is associated with sites specifically managed for waterbirds. climate adaptation, colonization, conservation policy, distribution change, EU Birds Directive, LIFE program,wetland. Arctic, Betula, birch, herbivory, metabolomics, plant chemical defence, shrubs, tundr