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At least 73 records · Page 4

Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

60 APPLIED LIFE SCIENCES↗

Requirement of ERα and basal activities of EGFR and Src kinase in Cd-induced activation of MAPK/ERK pathway in human breast cancer MCF-7 cells

Cadmium (Cd) is a common environmental toxicant and an established carcinogen. Epidemiological studies implicate Cd with human breast cancer. Low micromolar concentrations of Cd promote proliferation of human breast cancer cells in vitro. The growth promotion of breast cancer cells is associated with the activation of MAPK/ERK pathway. This study explores the mechanism of Cd-induced activation of MAPK/ERK pathway. Specifically, the role of cell surface receptors ERα, EGFR, and Src kinase was evaluated in human breast cancer MCF-7 cells treated with 1–3 μM Cd. The activation of ERK was studied using a serum response element (SRE) luciferase reporter assay. Receptor phosphorylation was detected by Western blot analyses. Cd treatment increased both the SRE reporter activity and ERK1/2 phosphorylation in a concentration-dependent manner. Cd treatment had no effect on reactive oxygen species (ROS) generation. Also, blocking the entry of Cd into the cells with manganese did not diminish Cd-induced activation of MAPK/ERK. These results suggest that the effect of Cd was likely not caused by intracellular ROS generation, but through interaction with the membrane receptors. While Cd did not appear to activate either EGFR or Src kinase, their inhibition completely blocked the Cd-induced activation of ERK as well as cell proliferation. Similarly, silencing ERα with siRNA or use of ERα antagonist blocked the effects of Cd. Based on these results, it is concluded that not only ERα, but also basal activities of EGFR and Src kinase are essential for Cd-induced signal transduction and activation of MAPK/ERK pathway for breast cancer cell proliferation. - Highlights: • Low micromolar concentrations of Cd rapidly activate ERK1/2 in MCF-7 cells. • Signal transduction and resulting cell proliferation require EGFR, ERα, and Src. • These findings implicate Cd in promotion of breast cancer.

60 APPLIED LIFE SCIENCES↗

Structures of the Mycobacterium tuberculosis GlpX protein (class II fructose-1,6-bisphosphatase): implications for the active oligomeric state, catalytic mechanism and citrate inhibition

The crystal structures of native class II fructose-1,6-bisphosphatase (FBPaseII) from Mycobacterium tuberculosis at 2.6 Å resolution and two active-site protein variants are presented. The variants were complexed with the reaction product fructose 6-phosphate (F6P). The Thr84Ala mutant is inactive, while the Thr84Ser mutant has a lower catalytic activity. The structures reveal the presence of a 222 tetramer, similar to those described for fructose-1,6/sedoheptulose-1,7-bisphosphatase from Synechocystis (strain 6803) as well as the equivalent enzyme from Thermosynechococcus elongatus . This homotetramer corresponds to a homologous oligomer that is present but not described in the crystal structure of FBPaseII from Escherichia coli and is probably conserved in all FBPaseIIs. The constellation of amino-acid residues in the active site of FBPaseII from M. tuberculosis ( Mt FBPaseII) is conserved and is analogous to that described previously for the E. coli enzyme. Moreover, the structure of the active site of the partially active (Thr84Ser) variant and the analysis of the kinetics are consistent with the previously proposed catalytic mechanism. The presence of metabolites in the crystallization medium (for example citrate and malonate) and in the corresponding crystal structures of Mt FBPaseII, combined with their observed inhibitory effect, could suggest the existence of an uncharacterized inhibition of this class of enzymes besides the allosteric inhibition by adenosine monophosphate observed for the Synechocystis enzyme. The structural and functional insights derived from the structure of Mt FBPaseII will provide critical information for the design of lead inhibitors, which will be used to validate this target for future chemical intervention.

Wolf, Nina M.↗

SU-F-T-57: Delivered Activity Accuracy of Radium 223 Dichloride Injections, When Being Administrated for Castration Resistant Prostate Cancer, Symptomatic Bone Metastases. The Impact of Residual Activity in the Spent Syringe and Dispensing Accuracy of Ra 223

Purpose: To quantify the delivered activity accuracy of Radium 223 dichloride injections, when being administrated for castration – resistant prostate cancer, symptomatic bone metastases. The impact of residual activity in the spent syringe and dispensing accuracy of Ra 223. Methods: The administration is by slow intravenous injection over 1 minute followed by double flushing of the 10 mL syringe and IV with saline. Eighty (80) procedures was used to investigate variations in the activity from the amount prescribed (µCi) = 1.35 × Patient weight Kg. The Activity dispensed into a 10mL syringe using a NIST traceable Capintec CRC-25R Chamber and a cross calibrated capintec CRC-15R to measure activity in the syringe immediately before and after administration Results: The patients weight range from 121Ib to 235lb and doses ranging 74.25 µCi to 144.2 µCi. The deviation of dispensed dose vs Prescribed dose average +2.1% with a range of −1.1% to +5.7%. The Dose measured before administration ranges 79.3 µCi to 154.9 µCi. Deviation from the dispensed dose was show to average +2.9% with a range of −0.8% to +7.3%. The average residual dose post injection was 2.5 µCi or 2.2% of the pre injection activity. Ranging from 0.9 µCi to 6.2 µCi, 0.7% to 5.4% respectively. Subtracting the residual activity from that measured activity before injection and comparing it to prescription dose was shown to have an average variation of +2.7% with a range of −0.8% to 7.4%. Conclusion: The case resulted in the 6.2 µCi maximum residual dose had two syringes. A small, 82.8 µCi activity, case resulted in the 7.4% maximum variation in measures less residual verses prescription dose. The average +2.1 % dispenses activity of Ra 223 over the prescription dosage was seen to counteract the average 2.2% residual dosage found to remain in the syringe.

60 APPLIED LIFE SCIENCES↗

Activation of surface lattice oxygen in single-atom Pt/CeO 2 for low-temperature CO oxidation

To improve fuel efficiency, advanced combustion engines are being designed to minimize the amount of heat wasted in the exhaust. Hence, future generations of catalysts must perform at temperatures that are 100°C lower than current exhaust-treatment catalysts. Achieving low-temperature activity, while surviving the harsh conditions encountered at high engine loads, remains a formidable challenge. In this study, we demonstrate how atomically dispersed ionic platinum (Pt 2+ ) on ceria (CeO 2 ), which is already thermally stable, can be activated via steam treatment (at 750°C) to simultaneously achieve the goals of low-temperature carbon monoxide (CO) oxidation activity while providing outstanding hydrothermal stability. A new type of active site is created on CeO 2 in the vicinity of Pt 2+ , which provides the improved reactivity. These active sites are stable up to 800°C in oxidizing environments.

Nie, Lei (ORCID:0000000343593451)↗

Activation of Water by Thorium Cation: A Guided Ion Beam and Quantum Chemical Study

The reaction of atomic thorium cations with deuterated water as a function of kinetic energy from thermal to 10 eV was studied using guided ion beam tandem mass spectrometry. At thermal energies, both ThO{sup +} + D{sub 2} and DThO{sup +} + D are formed in barrierless exothermic processes and reproduce results in the literature obtained using ion cyclotron resonance mass spectrometry. As the energy is increased, the branching ratio between these two channels changes such that the dominant product changes from ThO{sup +} to DThO{sup +} and back to ThO{sup +}, until ThD{sup +} + OD is energetically available and is the dominant product channel. To help understand these experimental results, a variety of theoretical approaches were tried and used to establish a potential energy surface, which compares well with previous theoretical studies. Utilizing the theoretical results, the kinetic energy dependent branching ratio between the ThO{sup +} + D{sub 2} and DThO{sup +} + D channels was calculated using both RRKM and phase space theory (PST). The results indicate that consideration of angular momentum conservation (as in PST) and spin-orbit corrected energies are needed to reproduce experimental results quantitatively. The PST modeling also provides relative energies for the two competing transition states that lead to the primary products, for which theory provides reasonable agreement. .

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Near Activation and Differential Activation in Enzymatic Reactions

A framework that introduces the concept of near-activation complexation and differential free energy of activation is presented to extend the capabilities of the classical transition-state theory in enzymatic reactions. In our approach, reaching a near-equilibrium energy level is assumed to be necessary for complexation near the activation point, whereas an additional differential energy level is required for the near-equilibrium complex to activate and release reaction products. Integration of these energy levels within the transition-state theory explains the thermodynamic nature of the Michaelis–Menten (affinity) constant and its relationship with the rate constant under the quasi-steady-state assumption. The concepts of near-activation complexation and differential free energy of activation were tested on 57 independent experiments of NH$+\atop{4}$ and NO$-\atop{3}$ uptake by various microalgae and bacteria at temperatures ranging between 1 and 45°C. Results showed that near-activation complexation was always favored, whereas the differential energy of activation led to an apparent energy barrier consistent with earlier observations. Temperature affected all energy levels within this framework but did not alter substantially their thermodynamic features. Finally, the approach (1) mutually links the thermodynamics and kinetics of Michaelis–Menten and rate constants with a mathematical expression; (2) describes the likelihood of formation of sub-, super-, and activated complexes; and (3) shows direction and thermodynamic likelihood of each reaction branch within the transition state.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Ni5Ga3 Catalysts for CO2 Reduction to Methanol: Exploring the Role of Ga Surface Oxidation/reductions on Catalytic Activity

Ad-Ni5Ga3/SiO2 catalyst, which is highly active and stable for thermal CO2 hydrogenation to methanol, was investigated to understand its surface dynamics during reaction conditions. The catalyst was prepared, tested and characterized using a multitude of techniques, including ex-situ XRD, TEM, H2-TPR, CO chemisorption and in-situ ETEM and APXPS. The formation of Ga2O3 upon air exposure was observed and the consequences on catalytic activity were investigated. Results revealed that upon air exposure Ga migrates from the subsurface region to the surface of the nanoparticles forming a Ga-oxide shell surrounding a metallic core. The oxide shell can be reduced completely at high temperatures and the temperature of the reduction activation treatment plays a crucial role on the catalytic activity. This air exposure-reduction procedure results in a redistribution of the Ga species in the surface/subsurface region, promoted by a higher Ga affinity for oxygen. XRD analysis of the post-reaction samples provide evidence for the partial transformation of a Ni5Ga3 intermetallic phase into a Ni-rich Ni3Ga phase. APXPS data indicate that the Ni-rich phase forms in the subsurface region. A Ga-rich phase exists on the surface, where the Ni/Ga ratio reaches 2/3 upon activation in hydrogen. At low reduction temperatures an amorphous Ga2O3 shell remains, indicating a promotion effect on methanol synthesis activity.

Ni-Ga, intermetallic, methanol synthesis, in-situ ↗

Transient activation of AMP-activated protein kinase at G1/S phase transition is required for control of S phase in NIH3T3 cells

Highlights: • AMPK is transiently activated at G1/S phase of NIH3T3 cell cycle. • Temporal activation of AMPK is required for control of S phase. • AMPK activation at G1/S phase depends on intracellular calcium and CaMKKbeta. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor by monitoring the cellular AMP:ATP ratio and plays a central role in cellular and whole-body energy homeostasis. Recent studies have suggested that AMPK also contribute to cell cycle regulation, but its role in this field remains almost elusive. In the present study, we report that AMPKα1 was transiently activated during G{sub 1}/S transition phase in NIH3T3 cells in the absence of any metabolic stress. Inhibition of AMPK activity at G{sub 1}/S transition phase completely blocked cells from entering S phase; in contrast, persistent activation of AMPK at G{sub 1}/S transition phase allowed cells to normally enter S phase, but these cells failed to proceed to G{sub 2}/M phase, stacking at S phase. We further demonstrated that activation of AMPK at G{sub 1}/S transition phase depends on Ca{sup 2+} transients and CaMKKβ activity, but not on energy status. Collectively, these data indicate that temporal regulation of AMPK is required for proper control of S phase in NIH3T3 cells.

60 APPLIED LIFE SCIENCES↗

Thermal Activation of Zirconium(IV) Acetylacetonate Catalysts to Enhance Polyurethane Synthesis and Reprocessing

Carbamate formation and exchange catalysts enable efficient polyurethane (PU) manufacturing, as well as emerging recycling and reprocessing methods for PU thermosets. Zirconium β-diketonate complexes, such as Zr acetylacetonate [Zr(acac) 4 ], are effective alternatives to toxic organotin catalysts that have been used for PU reprocessing. Here, we report that Zr(acac) 4 undergoes a thermally activated process in the PU network during reprocessing that transforms it into a more active carbamate exchange catalyst. This process is associated with the irreversible loss of acetylacetonate ligands and is not observed for the more sterically hindered Zr 2,2,6,6-tetramethyl-3,5-heptanedione [Zr(tmhd) 4 ] complex. Crossover experiments between PU thermoplastics indicated enhanced carbamate exchange after the thermal activation of Zr(acac) 4 in the presence of one of the PUs, whereas a sample of Zr(acac) 4 activated in the absence of the PU had no catalytic activity. Thermal gravimetric analysis suggested that this process is associated with the loss of one protonated acac ligand. Stress relaxation analysis of PU thermosets indicated a distinct change in the characteristic relaxation time associated with the thermal activation of Zr(acac) 4 at temperatures above 140 °C; no such change was observed for samples reprocessed using Zr(tmhd) 4 . Density functional theory and molecular experiments suggest that irreversible ligand exchange of acac with alkoxide or carbamate reduces the activation energy for urethane formation and reversion. Furthermore, the Zr(acac) 4 catalyst activated in the presence of a PU’s polyol precursor provided more porous and less dense PU foams compared to those made using the unactivated Zr(acac) 4 catalyst. Furthermore, these findings are important for developing improved PU synthesis and recycling processes. Thermally activating a catalyst during reprocessing may provide more nuanced control of the in-use and reprocessing characteristics of PU thermosets.

Alcohols↗

Machine-Learning Methods Enable Exhaustive Searches for Active Bimetallic Facets and Reveal Active Site Motifs for CO 2 Reduction

Bimetallic catalysts are promising for the most difficult thermal and electrochemical reactions, but modeling the many diverse active sites on polycrystalline samples is an open challenge. Here, we present a general framework for addressing this complexity in a systematic and predictive fashion. Active sites for every stable low-index facet of a bimetallic crystal are enumerated and cataloged, yielding hundreds of possible active sites. The activity of these sites is explored in parallel using a neural-network-based surrogate model to share information between the many density functional theory (DFT) relaxations, resulting in activity estimates with an order of magnitude fewer explicit DFT calculations. Sites with interesting activity were found and provide targets for follow-up calculations. This process was applied to the electrochemical reduction of CO 2 on nickel gallium bimetallics and indicated that most facets had similar activity to Ni surfaces, but a few exposed Ni sites with a very favorable on-top CO configuration. This motif emerged naturally from the predictive modeling and represents a class of intermetallic CO 2 reduction catalysts. These sites rationalize recent experimental reports of nickel gallium activity and why previous materials screens missed this exciting material. Most importantly these methods suggest that bimetallic catalysts will be discovered by studying facet reactivity and diversity of active sites more systematically.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Electrodermal activity as a proxy for sweat rate monitoring during physical and mental activities

Electrodermal activity has long been used for mental activity monitoring by measuring skin conductance at specific locations, such as fingertips, with high sweat gland density. However, electrodermal activity has not been considered useful for physical activity monitoring, where large sweat volumes are generated, resulting in the accumulation of sweat at the skin–electrode interface and, thus, preventing further dynamic response to sweating events. Here we show that electrodermal activity can be used as a proxy for sweat loss measurement under both low and high physical activity levels. We use wearable sweat sensors that consist of water-permeable electrodes and microfluidic-based sweat analysers, and show that skin conductance is proportional to the instantaneous sweat loss. We demonstrate that sweat loss during exercise can be estimated by integrating skin conductance over time, which can be applied to assess the body hydration status of exercisers. From multisite measurements of skin conductance, we show that the wrist, forearm and upper arm are reflective of physical activity levels, whereas the finger is indicative of mental activity. Simultaneous measurement of two different sites selectively decouples mental and physical activities.

Biomedical engineering↗

An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance.

60 APPLIED LIFE SCIENCES↗

PATTERNS OF ACTIVITY IN A GLOBAL MODEL OF A SOLAR ACTIVE REGION

In this work we investigate the global activity patterns predicted from a model active region heated by distributions of nanoflares that have a range of frequencies. What differs is the average frequency of the distributions. The activity patterns are manifested in time lag maps of narrow-band instrument channel pairs. We combine hydrodynamic and forward modeling codes with a magnetic field extrapolation to create a model active region and apply the time lag method to synthetic observations. Our aim is not to reproduce a particular set of observations in detail, but to recover some typical properties and patterns observed in active regions. Our key findings are the following. (1) Cooling dominates the time lag signature and the time lags between the channel pairs are generally consistent with observed values. (2) Shorter coronal loops in the core cool more quickly than longer loops at the periphery. (3) All channel pairs show zero time lag when the line of sight passes through coronal loop footpoints. (4) There is strong evidence that plasma must be re-energized on a timescale comparable to the cooling timescale to reproduce the observed coronal activity, but it is likely that a relatively broad spectrum of heating frequencies are operating across active regions. (5) Due to their highly dynamic nature, we find nanoflare trains produce zero time lags along entire flux tubes in our model active region that are seen between the same channel pairs in observed active regions.

79 ASTRONOMY AND ASTROPHYSICS↗

Recurrent Activity from Active Asteroid (248370) 2005 QN 173 : A Main-belt Comet

We present archival observations of main-belt asteroid (248370) 2005 QN 173 (also designated 433P) that demonstrate this recently discovered active asteroid (a body with a dynamically asteroidal orbit displaying a tail or coma) has had at least one additional apparition of activity near perihelion during a prior orbit. We discovered evidence of this second activity epoch in an image captured 2016 July 22 with the DECam on the 4 m Blanco telescope at the Cerro Tololo Inter-American Observatory in Chile. As of this writing, (248370) 2005 QN 173 is just the eighth active asteroid demonstrated to undergo recurrent activity near perihelion. Our analyses demonstrate (248370) 2005 QN 173 is likely a member of the active asteroid subset known as main-belt comets, a group of objects that orbit in the main asteroid belt that exhibit activity that is specifically driven by sublimation. We implement an activity detection technique, wedge photometry, that has the potential to detect tails in images of solar system objects and quantify their agreement with computed antisolar and antimotion vectors normally associated with observed tail directions. We present a catalog and an image gallery of archival observations. The object will soon become unobservable as it passes behind the Sun as seen from Earth, and when it again becomes visible (late 2022) it will be farther than 3 au from the Sun. Our findings suggest (248370) 2005 QN 173 is most active interior to 2.7 au (0.3 au from perihelion), so we encourage the community to observe and study this special object before 2021 December.

79 ASTRONOMY AND ASTROPHYSICS↗