Rate Constant Of Phase Research Articles

Dosing Adjustments in Cases of Altered Plasma Protein Binding are Most Needed for Drugs with a Volume of Distribution Below 1.3 L/kg.

The present literature offers conflicting views on the importance of changes in plasma protein binding in clinical therapeutics. Furthermore, there are no methods to calculate a new dosing regimen when such changes occur. Previous models developed by Balaz et al. and Greenblat et al. were used to calculate a plasma protein binding (PPB) score for individual drugs based on the volume of distribution for total concentration and the bound fraction of drug. The models were further used to calculate a new drug dosing interval for cases of altered plasma protein binding. The equations apply best for drugs with fast absorption and fast distribution; they can be used as approximations for drugs with slow distribution by using the volume of distribution at steady state and the rate constant of the elimination phase. The newly developed equations show that changes in plasma protein binding are relevant only for drugs with a positive PPB score; such drugs must have a volume of distribution for total concentration below 1.3 L/kg and high protein binding. It is further shown that the drug dosing interval should be reduced when the remaining fraction of plasma protein binding is below the PPB score. A new method to rank drugs according to the impact of changes in plasma protein binding on their pharmacokinetic profile was developed. The new method was applied to show that drugs with high PPB scores need reductions in their dosing interval when the level of protein binding decreases.

Dephosphorization Kinetics of Hot Metal at Low Slag Basicity and Low Temperature under the Different Fe2O3 Addition Amounts

In this article, the influence of the Fe2O3 addition amount on the dephosphorization kinetics of hot metal at the low slag basicity (CaO/SiO2) of about 1.6 and low temperature of 1623 K is investigated with laboratorial experiments and the kinetic model. Si and P contents in the hot metal during the whole dephosphorization process, and the endpoint FeO content in the slag, show good agreements between the calculated results with the kinetic model and experimental results. The peak value of dephosphorization rate linearly increases from 8.35 × 10−5 to 4.52 × 10−4 mass% s−1 when the weight ratio of Fe2O3 is increased from 5 to 10/100 g hot metal. With the increase in Fe2O3 addition amount, the mass transfer coefficient in the hot metal phase (km) and that in the slag phase (ks) and dephosphorization rate constant (k) all increase. The value of km is found to be 4.34 times that of ks. During the dephosphorization process, the rate‐controlling step converts from the mass transfer in slag phase to the mass transfer in hot metal phase in less than 10 min. With the increase in Fe2O3 addition amount, the value of interfacial oxygen activity of increases from 0.0102 to 0.0201.

Dissolution–precipitation kinetics during C[formula omitted]S hydration: A holographic interferometry study

Tricalcium silicate C3S has been widely employed in model systems to interpret the complex mechanisms of cement hydration. The present study aims at providing an accurate description of the dissolution rate of C3S by implementing a new approach based on holographic interferometry. We propose a protocol that allows the measurement of the pure dissolution rate constant of the C3S phase by experiments performed in supersaturated conditions with respect to C–S–H. In these experiments, a flat polycrystalline surface of C3S was monitored in a quiescent solution. The amount of calcium released within the holographic cell was measured and the aqueous solution composition was constrained to the C–S–H stoichiometry at the interface. An equilibrium approach was applied to assess interfacial pH, saturation indexes, and C–S–H precipitation at the experimental conditions. The rate law of the pure dissolution of C3S was assessed in conditions ranging from far to close-to-equilibrium.

Computing Kinetic Solvent Effects and Liquid Phase Rate Constants Using Quantum Chemistry and COSMO-RS Methods.

Many industrially and environmentally relevant reactions occur in the liquid phase. An accurate prediction of the rate constants is needed to analyze the intricate kinetic mechanisms of condensed phase systems. Quantum chemistry and continuum solvation models are commonly used to compute liquid phase rate constants; yet, their exact computational errors remain largely unknown, and a consistent computational workflow has not been well established. In this study, the accuracies of various quantum chemical and COSMO-RS levels of theory are assessed for the predictions of liquid phase rate constants and kinetic solvent effects. The prediction is made by first obtaining gas phase rate constants and subsequently applying solvation corrections. The calculation errors are evaluated using the experimental data of 191 rate constants that comprise 15 neutral closed-shell or free radical reactions and 49 solvents. The ωB97XD/def2-TZVP level of theory combined with the COSMO-RS method at the BP-TZVP level is shown to achieve the best performance with a mean absolute error of 0.90 in log10(kliq). Relative rate constants are additionally compared to determine the errors associated with the solvation calculations alone. Very accurate predictions of relative rate constants are achieved at nearly all levels of theory with a mean absolute error of 0.27 in log10(ksolvent1/ksolvent2).

Propyl-cyanide isomer formation on interstellar ices from radical association: a quantum theoretical study

ABSTRACT Both linear and branched isomers of propyl cyanide (PrCN; C3H7CN) are ubiquitous in interstellar space. To date, PrCN is one of the most complex molecules found in the interstellar medium. Furthermore, it is the only one observed species to share the branched atomic backbone of amino acids, some of the building blocks of life. Radical–radical chemical reactions are examined in detail using density functional theory, ab initio methods, and the energy resolved master equation formalism to compute rate constants at a low pressure value prevalent in the ISM. Quantum chemical studies are reported for both isomers considering two possibilities: the gas phase association and the surface reactions of radicals on a 34-water amorphous ice model. The reaction mechanism involves the following radicals association: CH3CHCH3 + CN, CH3 + CH3CHCN and CH3CH2 + CH2CN, CH3 + CH2CH2CN, CN + CH3CH2CH2 for iso-PrCN and n-PrCN formation, respectively. Two DFT methods: M062X and ωB97XD with the 6-311++G(d,p) basis set were tested for reactions in gas phase and on the ice mantle. In the gas phase, MP2/aug-cc-pVTZ level of theory is also used, and the energetics of the five reactions are calculated using explicitly correlated coupled cluster (CCSD(T)-F12) method. All reaction paths are exoergic and barrierless in the gas phase and on the ice-model, suggesting that the formation of iso-PrCN and n-PrCN is efficient on the ice model adopted in this paper. The gas phase rate constants of formation of both isomers can be eventually used as a high limit for the solid state reactions.

Determination of In Vitro and Cellular Turn-on Kinetics for Fluorogenic RNA Aptamers.

Fluorogenic RNA aptamers have been applied in live cells to tag and visualize RNAs, report on gene expression, and activate fluorescent biosensors that detect levels of metabolites and signaling molecules. In order to study dynamic changes in each of these systems, it is desirable to obtain real-time measurements, but the accuracy of the measurements depends on the kinetics of the fluorogenic reaction being faster than the sampling frequency. Here, we describe methods to determine the in vitro and cellular turn-on kinetics for fluorogenic RNA aptamers using a plate reader equipped with a sample injector and a flow cytometer, respectively. We show that the in vitro kinetics for the fluorescence activation of the Spinach2 and Broccoli aptamers can be modeled as two-phase association reactions and have differing fast phase rate constants of 0.56 s-1 and 0.35 s-1, respectively. In addition, we show that the cellular kinetics for the fluorescence activation of Spinach2 in Escherichia coli, which is further limited by dye diffusion into the Gram-negative bacteria, is still sufficiently rapid to enable accurate sampling frequency on the minute timescale. These methods to analyze fluorescence activation kinetics are applicable to other fluorogenic RNA aptamers that have been developed.

Gas Phase and Gas-Solid Interface Ozonolysis of Nitrogen Containing Alkenes: Nitroalkenes, Enamines, and Nitroenamines.

Emerging contaminants are of concern due to their rapidly increasing numbers and potential ecological and human health effects. In this study, the synergistic effects of the presence of multifunctional nitro, amino and carbon–carbon double bond (C=C) groups on the gas phase ozonolysis in O2 or at the air/solid interface were investigated using five simple model compounds. The gas phase ozonolysis rate constants at 296 K were (3.5 ± 0.9) × 10–20 cm3 molecule–1 s–1 for 2-methyl-1-nitroprop-1-ene and (6.8 ± 0.8) × 10–19 cm3 molecule–1 s–1 for 4-methyl-4-nitro-1-pentene, with lifetimes of 134 and 7 days in the presence of 100 ppb ozone in the atmosphere, respectively. The rate constants for gas phase E-N,N-dimethyl-1-propenylamine and N,N-dimethylallylamine reactions with ozone were too fast (>10–18 cm3 molecule–1 s–1) to be measured, implying lifetimes of less than 5 days. A multiphase kinetics model (KM-GAP) was used to probe the gas–solid kinetics of 1-dimethylamino-2-nitroethylene, yielding a rate constant for the surface reaction of 1.8 × 10–9 cm2 molecule–1 s–1 and in the bulk 1× 10–16 cm3 molecule–1 s–1. These results show that a nitro group attached to the C=C lowers the gas phase rate constant by 2–3 orders of magnitude compared to the simple alkenes, while amino groups have the opposite effect. The presence of both groups provides counterbalancing effects. Products with deleterious health effects including dimethylformamide and formaldehyde were identified by FTIR. The identified products differentiate whether the initial site of ozone attack is C=C and/or the amino group. This study provides a basis for predicting the environmental fates of emerging contaminants and shows that both the toxicity of both the parent compounds and the products should be taken into account in assessing their environmental impacts.

Formation mechanism and growth kinetics of TiAl3 phase in cold-rolled Ti/Al laminated composites during annealing

Cold-rolled Ti/Al laminated composites were annealed at 525–625 °C for 0–128 h, and the interfacial microstructure evolution was investigated. The results indicate that only the TiAl3 phase was formed at the Ti/Al interface; most of TiAl3 grains were fine equiaxed with average sizes ranging from hundreds of nanometers to several microns and the TiAl3 grain size increased with increasing annealing time and/or temperature, but the effect of annealing temperature on the TiAl3 grain size was far greater than that of annealing time. The growth of the TiAl3 phase consisted of two stages. The initial stage was governed by chemical reaction with a reaction activation energy of 195.75 kJ/mol, and the reaction rate constant of the TiAl3 phase was larger as the Ti/Al interface was bonded with fresh surfaces. At the second stage, the growth was governed by diffusion, the diffusion activation energy was 33.69 kJ/mol, and the diffusion growth rate constant of the TiAl3 phase was mainly determined by the grain boundary diffusion owing to the smaller TiAl3 grain size.

Antioxidant Motifs in Flavonoids: O-H versus C-H Bond Dissociation.

Flavonoids provide potential health benefits due to their antioxidant properties. The antioxidant activity of natural flavonoids is primarily exerted by phenolic hydroxyl groups; however, C–H bonds also contribute to these properties. In this study, the contributions of phenolic groups and C–H bonds to the antioxidant properties of 13 flavonoids were investigated by using the (RO)B3LYP/6-311++G(2df,2p)//B3LYP/6-311G(d,p) model chemistry in the gas phase and water and ethanol solvents. It was found that the C–H bonds have lower bond dissociation energies than O–H bonds in the 4-carbonyl and/or 3-hydroxyl group containing flavonoids and hence define antioxidant activity. The HOO· radical scavenging of the selected flavonoids is also investigated in detail through the potential energy surface, natural bond orbitals, and kinetic calculations. It was found that the favored radical scavenging mechanism of the flavonoids is hydrogen atom transfer, with the gas phase rate constants in the range of 7.23 × 103–2.07 × 109 L·mol–1·s–1. The results suggest that the flavonoids, isomelacacidin, isoteracacidin, melacacidin, and teracacidin, have antioxidant properties as high as typical phenolic compounds such as quercetin, trans-resveratrol, trolox, and ascorbic acid.

Thermochemistry and kinetic analysis for the conversion of furfural to valuable added products.

Furfural is a valuable oxygenated compound derived from the thermal decomposition of biomass, and is one of the major problems of bio-oil upgrading. Due to its high reactivity, this compound requires further upgrading to more stable products such as furfuryl alcohol, 2-methylfuran (MF), furan, 2-methyltetrahydrofuran, and tetrahydrofuran. The thermochemical data and kinetic analysis of the reactions involved in the conversion of furfural were investigated by molecular modelingto guide experimental investigations in the process of designing efficient catalysts that allows the control of the reaction pathways in specific directions, towards the production of fuel precursors or chemicals. All calculations for reactants, intermediates, and products were performed using the long range corrected functional WB97XD, with the basis set 6-311+g(d,p), under the density functional theory framework. Thermochemistry results suggest that furfural hydrogenation to form furfuryl alcohol is spontaneous up to a temperature of 523K, but beyond this temperature the reaction becomes a nonspontaneous process. By contrast, the decarbonylation of furfural was thermodynamically favored at temperatures greater than 523K. Therefore, furan is a thermodynamically favored product, while furfuryl alcohol is kinetically preferred. Once furfuryl alcohol is formed, the hydrogenolysis path to produce methylfuran is favored kinetically and thermodynamically, compared to the ring-hydrogenation towards tetrahydrofurfuryl alcohol. Gas phase thermodynamic properties and rate constants of the reactions involved in the conversion of furfural were calculated and compared against existing experimental data. This study provides the basis for further vapor phase catalytic studies required for upgrading of furans/furfurals to value-added chemicals. Graphical abstract Furan is a thermodynamically favored product, while furfuryl alcohol is kinetically preferred.

Performance, mixing and kinetics study in the flotation column reactor using coal

ABSTRACT A flotation column has been designed and characterized with respect to gas velocity, slurry velocity, frother concentration, gas holdup, bubble surface area flux for the study of the mixing property, liquid phase residence time distribution, flotation recovery and rate constant. The study was performed using coal as solid. A strategy of integrating chemical kinetics into the flotation process to test the floatability behaviour of coal and to estimate floatability parameter of coal has been developed. The results indicate that the coal floatability parameter is 3.05 × 10−4. A relationship between gas holdup and bubble surface area flux was developed.

Competition kinetics of OH radical reactions with oxygenated organic compounds in aqueous solution: rate constants and internal optical absorption effects.

Oxygenated organic compounds are omnipresent in the troposphere, due to their strong emissions from either biogenic or anthropogenic sources. Additionally, the degradation and oxidation processes of volatile organic compounds (VOCs) result in the production of oxygenated organic compounds in the troposphere. The degradation and conversion of these compounds are often initiated by radical reactions and occur in the gas phase as well as in the aqueous phase, including cloud droplets, fog, haze, rain or hygroscopic particles containing 'aerosol liquid water (ALW)'. In the present study, the temperature-dependent OH radical reactions with oxygenated organic compounds in the aqueous phase have been investigated by laser flash photolysis. To determine the rate constants, the OH radical - thiocyanate anion competition kinetics method has been used. Once the organic reactant has an absorption at the excitation wavelength of the photolysis laser, the initial OH concentration decreases. This internal absorption effect leads to an overestimated rate constant of the investigated compound. The present study considers this contribution in order to clarify the internal absorption effect of the investigated organic compounds. The following rate constants for OH radical oxidation reactions of the oxygenated organic compounds have been obtained: acetone (2-propanone) k298K = (7.6 ± 1.0) × 107 L mol-1 s-1, 1-hydroxypropan-2-one k298K = (1.1 ± 0.1) × 109 L mol-1 s-1, 1,3-dihydroxypropan-2-one k298K = (1.5 ± 0.1) × 109 L mol-1 s-1, 2,3-dihydroxypropanal k298K = (1.3 ± 0.1) × 109 L mol-1 s-1, butane-1,3-diol k298K = (2.5 ± 0.1) × 109 L mol-1 s-1, butane-2,3-diol k298K = (2.0 ± 0.1) × 109 L mol-1 s-1 and hexane-1,2-diol k298K = (4.6 ± 0.4) × 109 L mol-1 s-1. With the rate constants obtained and their T-dependencies, the source and sink processes of oxygenated organic compounds in the tropospheric aqueous phase are arrived at precisely. These findings might enhance the predictive capabilities of models such as the chemical aqueous-phase radical mechanism (CAPRAM).

An Ultraviolet Resonance Raman Spectroscopic Study of Cisplatin and Transplatin Interactions with Genomic DNA.

Ultraviolet resonance Raman (UVRR) spectroscopy is a label-free method to define biomacromolecular interactions with anticancer compounds. Using UVRR, we describe the binding interactions of two Pt(II) compounds, cisplatin (cis-diamminedichloroplatinum(II)) and its isomer, transplatin, with nucleotides and genomic DNA. Cisplatin binds to DNA and other cellular components and triggers apoptosis, whereas transplatin is clinically ineffective. Here, a 244 nm UVRR study shows that purine UVRR bands are altered in frequency and intensity when mononucleotides are treated with cisplatin. This result is consistent with previous suggestions that purine N7 provides the cisplatin-binding site. The addition of cisplatin to DNA also causes changes in the UVRR spectrum, consistent with binding of platinum to purine N7 and disruption of hydrogen-bonding interactions between base pairs. Equally important is that transplatin treatment of DNA generates similar UVRR spectral changes, when compared to cisplatin-treated samples. Kinetic analysis, performed by monitoring decreases of the 1492 cm-1 band, reveals biphasic kinetics and is consistent with a two-step binding mechanism for both platinum compounds. For cisplatin-DNA, the rate constants (6.8 × 10-5 and 6.5 × 10-6 s-1) are assigned to the formation of monofunctional adducts and to bifunctional, intrastrand cross-linking, respectively. In transplatin-DNA, there is a 3.4-fold decrease in the rate constant of the slow phase, compared with the cisplatin samples. This change is attributed to generation of interstrand, rather than intrastrand, adducts. This longer reaction time may result in increased competition in the cellular environment and account, at least in part, for the lower pharmacological efficacy of transplatin.

Antibacterial evaluation of Salvia miltiorrhizae on Escherichia coli by microcalorimetry coupled with chemometrics

For seeking novel antibacterial agents with high efficacy and low toxicity to deal with drug resistance, the effects of Salvia miltiorrhizae from various sources on Escherichia coli were evaluated by microcalorimetry coupled with chemometrics. Firstly, the heat-flow power-time curves of E. coli growth affected by different S. miltiorrhizae samples were recorded. Then, some crucial quantitative thermo-kinetic parameters including growth rate constant, heat-flow power and heat output, etc. were obtained from theses curves and were further investigated by some powerful chemometric techniques including similarity analysis, multivariate analysis of variance, hierarchical clustering analysis and principle component analysis. By analyzing the principle parameters, growth rate constant of the second exponential phase (k2) and the heat-flow output powers of the second highest peak (P2), together with the derived parameter inhibitory ratio (I, %), it could be quickly concluded that the tested S. miltiorrhizae samples from different sources in China exhibited strong antibacterial effects on E. coli and the samples from Beijing city exhibited the strongest anti-E. coli effects, which might be used as novel and underlying antibacterial candidates for the resistance of E. coli to the existing drugs in practice. This study provides a useful tool and helpful idea to accurately and rapidly evaluate the antibacterial effects of some complex matrices, offering some references for exploring new antibacterial agents.

Force Responses and Sarcomere Dynamics of Cardiac Myofibrils Induced by Rapid Changes in [Pi

The second phase of the biphasic force decay upon release of phosphate from caged phosphate was previously interpreted as a signature of kinetics of the force-generating step in the cross-bridge cycle. To test this hypothesis without using caged compounds, force responses and individual sarcomere dynamics upon rapid increases or decreases in concentration of inorganic phosphate [Pi] were investigated in calcium-activated cardiac myofibrils. Rapid increases in [Pi] induced a biphasic force decay with an initial slow decline (phase 1) and a subsequent 3–5-fold faster major decay (phase 2). Phase 2 started with the distinct elongation of a single sarcomere, the so-called sarcomere “give”. “Give” then propagated from sarcomere to sarcomere along the myofibril. Propagation speed and rate constant of phase 2 (k+Pi(2)) had a similar [Pi]-dependence, indicating that the kinetics of the major force decay (phase 2) upon rapid increase in [Pi] is determined by sarcomere dynamics. In contrast, no “give” was observed during phase 1 after rapid [Pi]-increase (rate constant k+Pi(1)) and during the single-exponential force rise (rate constant k−Pi) after rapid [Pi]-decrease. The values of k+Pi(1) and k−Pi were similar to the rate constant of mechanically induced force redevelopment (kTR) and Ca2+-induced force development (kACT) measured at same [Pi]. These results indicate that the major phase 2 of force decay upon a Pi-jump does not reflect kinetics of the force-generating step but results from sarcomere “give”. The other phases of Pi-induced force kinetics that occur in the absence of “give” yield the same information as mechanically and Ca2+-induced force kinetics (k+Pi(1) ∼ k-Pi ∼ kTR ∼ kACT). Model simulations indicate that Pi-induced force kinetics neither enable the separation of Pi-release from the rate-limiting transition f into force states nor differentiate whether the “force-generating step” occurs before, along, or after the Pi-release.

Schleyer hyperconjugative aromaticity and Diels–Alder reactivity of 5‐substituted cyclopentadienes

Schleyer's discovery of hyperconjugative aromaticity and antiaromaticity in 5-substituted cyclopentadienes further expanded our understanding of the pervasive influence of aromaticity. Acceptors induce antiaromatic character by Schleyer's negative hyperconjugative aromaticity, and donors have the opposite effect. We computationally explored the Diels-Alder reactivity of 5-substituted cyclopentadienes with ethylene and maleic anhydride. The predicted billionfold difference in the computed gas phase rate constants at room temperature for the Diels-Alder reactions of 5-substituted cyclopentadienes with ethylene or maleic anhydride results from differences in the transition state distortion energies, which are directly related to the hyperconjugative aromaticity of these molecules.

Antibacterial evaluation of flavonoid compounds against E. coli by microcalorimetry and chemometrics.

Fighting against multidrug-resistant bacteria requires reliable methods to evaluate the effect of antibacterial agents. As a universal, non-destructive, and highly sensitive tool, microcalorimetry has been used in many biological investigations to provide continuous real-time monitoring of the metabolic activity. This method, based on heat-flow output, was used to evaluate the influence of two flavonoid compounds (liquiritigenin and liquiritin) on Escherichia coli. Some crucial information, such as the thermogenic power-time curve and thermokinetic parameters of E. coli growth affected by the two compounds, was obtained and further studied by chemometric techniques including similarity analysis, multivariate analysis of variance, and principal component analysis. By comparing the values of two main parameters, k 2 (growth rate constant of the second exponential phase) and Q 1 (heat output of the first exponential growth phase) of E. coli based on the box and whisker plot, liquiritigenin and liquiritin could be differentiated according to their antibacterial effects; liquiritin with IC50 (half-inhibitory concentration) of 198.6 μg mL(-1) expressed a stronger antibacterial effect than liquiritigenin with IC50 of 337.8 μg mL(-1). The glucoside group in liquiritin containing four additional free hydroxyls in the diphenylpropane skeleton was crucial for inducing the antibacterial effect. Liquiritin might be a promising candidate against E. coli. This study provides a valuable method for searching for novel antibacterial agents using microcalorimetry with chemometrics.

The Dilated Cardiomyopathy-Causing Mutation ACTC E361G in Cardiac Muscle Myofibrils Specifically Abolishes Modulation of Ca2+ Regulation by Phosphorylation of Troponin I

Phosphorylation of troponin I by protein kinase A (PKA) reduces Ca2+ sensitivity and increases the rate of Ca2+ release from troponin C and the rate of relaxation in cardiac muscle. In vitro experiments indicate that mutations that cause dilated cardiomyopathy (DCM) uncouple this modulation, but this has not been demonstrated in an intact contractile system. Using a Ca2+-jump protocol, we measured the effect of the DCM-causing mutation ACTC E361G on the equilibrium and kinetic parameters of Ca2+ regulation of contractility in single transgenic mouse heart myofibrils. We used propranolol treatment of mice to reduce the level of troponin I and myosin binding protein C (MyBP-C) phosphorylation in their hearts before isolating the myofibrils. In nontransgenic mouse myofibrils, the Ca2+ sensitivity of force was increased, the fast relaxation phase rate constant, kREL, was reduced, and the length of the slow linear phase, tLIN, was increased when the troponin I phosphorylation level was reduced from 1.02 to 0.3 molPi/TnI (EC50 P/unP = 1.8 ± 0.2, p < 0.001). Native myofibrils from ACTC E361G transgenic mice had a 2.4-fold higher Ca2+ sensitivity than nontransgenic mouse myofibrils. Strikingly, the Ca2+ sensitivity and relaxation parameters of ACTC E361G myofibrils did not depend on the troponin I phosphorylation level (EC50 P/unP = 0.88 ± 0.17, p = 0.39). Nevertheless, modulation of the Ca2+ sensitivity of ACTC E361G myofibrils by sarcomere length or EMD57033 was indistinguishable from that of nontransgenic myofibrils. Overall, EC50 measured in different conditions varied over a 7-fold range. The time course of relaxation, as defined by tLIN and kREL, was correlated with EC50 but varied by just 2.7- and 3.3-fold, respectively. Our results confirm that troponin I phosphorylation specifically alters the Ca2+ sensitivity of isometric tension and the time course of relaxation in cardiac muscle myofibrils. Moreover, the DCM-causing mutation ACTC E361G blunts this phosphorylation-dependent response without affecting other parameters of contraction, including length-dependent activation and the response to EMD57033.

The S229L Colon Tumor-associated Variant of DNA Polymerase β Induces Cellular Transformation as a Result of Decreased Polymerization Efficiency

DNA polymerase β (Pol β) plays a key role in base excision repair (BER) by filling in small gaps that are generated after base adducts are excised from the DNA. Pol β is mutated in a large number of colorectal tumors, and these mutations may drive carcinogenesis. In the present study, we wished to determine whether the S229L somatic Pol β variant identified in a stage 3 colorectal tumor is a driver of carcinogenesis. We show that S229L does not possess any defects in binding to either DNA or nucleotides compared with the WT enzyme, but exhibits a significant loss of polymerization efficiency, largely due to an 8-fold decrease in the polymerization rate. S229L participates in BER, but due to its lower catalytic rate, does so more slowly than WT. Expression of S229L in mammalian cells induces the accumulation of BER intermediate substrates, chromosomal aberrations, and cellular transformation. Our results are consistent with the interpretation that S229L is a driver of carcinogenesis, likely as a consequence of its slow polymerization activity during BER in vivo.

Pharmacokinetics of gallium maltolate in Lawsonia intracellularis‐infected and uninfected rabbits

Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n=6/group) were given a single oral GaM dose (50mg/kg). Serial blood samples were collected from 0 to 216h post-treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma-mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] α=5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116±0.004 (SD) vs. 0.0171±0.0028per hour; P=0.03]; but half-life (59.4±24.0 vs. 39.4±10.8h; P=0.12); Cmax (0.50±0.21 vs. 0.59±0.42μg/mL; P=0.45); tmax (1.75±0.41 vs. 0.9±0.37h; P=0.20); and oral clearance (6.743±1.887 vs. 7.208±2.565L/h; P=0.74) were not. IT's [Ga] and [Fe] were higher (P<0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48h GaM dosing interval is appropriate for multidose studies in EPE rabbits.