Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes

Biomass offsets little or none of permafrost carbon release from soils, streams, and wildfire : an expert assessment

As the permafrost region warms, its large organic carbon pool will be increasingly vulnerable to decomposition, combustion, and hydrologic export. Models predict that some portion of this release will be offset by increased production of Arctic and boreal biomass; however, the lack of robust estimates of net carbon balance increases the risk of further overshooting international emissions targets. Precise empirical or model-based assessments of the critical factors driving carbon balance are unlikely in the near future, so to address this gap, we present estimates from 98 permafrost-region experts of the response of biomass, wildfire, and hydrologic carbon flux to climate change. Results suggest that contrary to model projections, total permafrost-region biomass could decrease due to water stress and disturbance, factors that are not adequately incorporated in current models. Assessments indicate that end-of-the-century organic carbon release from Arctic rivers and collapsing coastlines could increase by 75% while carbon loss via burning could increase four-fold. Experts identified water balance, shifts in vegetation community, and permafrost degradation as the key sources of uncertainty in predicting future system response. In combination with previous findings, results suggest the permafrost region will become a carbon source to the atmosphere by 2100 regardless of warming scenario but that 65%-85% of permafrost carbon release can still be avoided if human emissions are actively reduced.Peer reviewe

Termination, Transfer, and Propagation Kinetics of Trimethylaminoethyl Acrylate Chloride Radical Polymerization in Aqueous Solution

The SP–PLP–EPR (single pulse–pulsed laser polymerization–electron paramagnetic resonance) method has been used to measure the rate coefficients of termination, intramolecular transfer, and propagation for the radical polymerization of 20 wt % trimethyl­aminoethyl acrylate chloride (TMAEA) in the temperature range 0–90 °C. The high complexity of this acrylate system is due to water being the solvent, to the monomer being a strong electrolyte, and to both secondary chain-end radicals and tertiary midchain radicals being simultaneously present. The termination kinetics, which was analyzed by a chain-length-dependent scheme, largely differs from the situation met with nonionized radicals. The reliability of the rate coefficients obtained from the SP–PLP–EPR experiments has been demonstrated by the almost perfect agreement of TMAEA conversion vs time data from simulation, on the basis of these coefficients, and from the chemically initiated TMAEA polymerization experiment at 70 °C

Propagation and Chain-Length-Dependent Termination Rate Coefficients Deduced from a Single SP–PLP–EPR Experiment

The laser single pulse (SP)–pulsed laser polymerization (PLP)–electron paramagnetic resonance (EPR) technique allows for deducing propagation (<i>k</i>_p) and termination (<i>k</i>_t) rate coefficients, including the chain-length dependence of <i>k</i>_t, from a single pulsed-laser experiment. The method, which is particularly well suited for slowly terminating radicals, e.g., sterically hindered and ionic radicals, is illustrated for di­(<i>n</i>-butyl) itaconate in bulk at temperatures from 30 to 60 °C. The time evolution of the DBI radical concentration is measured with a high time resolution at constant magnetic field. Propagation is associated with a relatively low pre-exponential <i>A</i>(<i>k</i>_p), which is responsible for the small <i>k</i>_p value of 6.8 L mol^–1 s^–1 at 30 °C. The chain-length dependence (CLD) of <i>k</i>_t, deduced from the same SP–PLP–EPR signal as is <i>k</i>_p, turns out to be adequately represented by the composite model. Whereas typical numbers are found for the power-law exponents for short and long radicals and for the crossover chain length, the parameter <i>k</i>_t(1,1), which represents mutual termination of two radicals of chain length unity, is by 2 orders of magnitude below <i>k</i>_t(1,1) of monomers without significant steric hindrance

Termination and Transfer Kinetics of Acrylamide Homopolymerization in Aqueous Solution

The single pulse–pulsed laser polymerization–electron paramagnetic resonance (SP–PLP–EPR) method affords the detailed kinetic analysis of acrylamide polymerization in aqueous solution. Highly time-resolved SP–PLP–EPR experiments for 10 and 20 wt % AAm were first carried out at −5 °C, where only secondary propagating radicals (SPRs) occur. In a second step, the time evolution of midchain radicals (MCRs), produced from SPRs by backbiting, was measured at higher temperatures. The termination kinetics, including chain-length dependent termination of SPRs, the backbiting rate of SPRs, and the propagation rate of MCRs were determined. The rate coefficients from SP–PLP–EPR in conjunction with the known propagation rate coefficient of SPRs, enable the simulation of the kinetics and product properties of AAm radical polymerizations in aqueous solution

Chain-Length-Dependent Termination of Sodium Methacrylate Polymerization in Aqueous Solution Studied by SP-PLP-EPR

Via the single pulse–pulsed laser polymerization–electron paramagnetic resonance (SP-PLP-EPR) technique, the chain-length-dependent termination of 5 and 10 wt % sodium methacrylate (NaMAA) in aqueous solution was measured from 5 to 60 °C. The rate coefficients <i>k</i>_t(<i>i</i>,<i>i</i>) for termination of two ionized radicals of identical size <i>i</i> were analyzed by the composite model. Three out of the four composite-model parameters behave similarly to nonionized monomers, whereas the fourth parameter, the rate coefficient for termination of two radicals of chain length unity, <i>k</i>_t(1,1), exhibits a distinctly different behavior. The temperature dependence of <i>k</i>_t(1,1) is significantly below the one of fluidity (inverse solution viscosity). Moreover, absolute <i>k</i>_t(1,1) increases with NaMAA concentration, i.e., toward higher viscosity. Both observations indicate that the termination kinetics of ionized radicals largely differs from the Smoluchowski-type behavior

Surfactant substitution in ventilated very low birth weight infants: factors related to response types

We investigated factors than may influence the response to surfactant substitution. Thirty-five very low birth weight infants with respiratory distress syndrome were treated with Curosurf at 3-12 h of age. From the changes in oxygenation, the therapeutic response was categorized as rapid and sustained, rapid with relapse, or poor. Phospholipids and surfactant protein A were quantified in gastric aspirate samples obtained immediately after birth. They showed that 16 infants had accelerated lung maturity, despite clinical and radiologic signs of respiratory distress syndrome. Ten of them had suffered from birth asphyxia or connatal infection. Nevertheless, 12 of these 16 infants responded rapidly to surfactant substitution. Poor response was seen in four infants with connatal infection. Of 19 infants with immature lung profile, 18 showed a rapid initial response to surfactant substitution. Dynamic compliance of the respiratory system or arterial blood pressure before substitution, the ultrastructure of the surfactant preparation, or persistence of the ductus arteriosus did not influence the response type, but fraction of inspired oxygen was higher before surfactant substitution in infants with poor response. Prognosis was related to short-term response: Of 17 infants who showed a rapid and sustained response, none died, whereas eight of 18 infants with relapse after rapid initial response or poor response died (p less than 0.05). We conclude that surfactant substitution may be beneficial not only in babies with primary surfactant deficiency but also in other pulmonary disorders that are common in very low birth weight infants. The type of response may be of prognostic value