Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Mycophenolic acid (MPA), a frequently used immunosuppressant, exhibits large inter‐patient pharmacokinetic variability. This study (a) developed and validated a sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for MPA and metabolites [MPA glucuronide (MPAG) and acyl‐glucuronide (AcMPAG)] in the culture medium of HepaRG cells; and (b) characterized the metabolism interaction between MPA and p‐cresol (a common uremic toxin) in this in vitro model as a potential mechanism of pharmacokinetic variability. Chromatographic separation was achieved with a C₁₈ column (4.6 × 250 mm,5 μm) using a gradient elution with water and methanol (with 0.1% formic acid and 2 mm ammonium acetate). A dual ion source ionization mode with positive multiple reaction monitoring was utilized. Multiple reaction monitoring mass transitions (m/z) were: MPA (320.95 → 207.05), MPAG (514.10 → 303.20) and AcMPAG (514.10 → 207.05). MPA‐d₃ (323.95 → 210.15) and MPAG‐d₃ (517.00 → 306.10) were utilized as internal standards. The calibration curves were linear from 0.00467 to 3.2 μg/mL for MPA/MPAG and from 0.00467 to 0.1 μg/mL for AcMPAG. The assay was validated based on industry standards. p‐Cresol inhibited MPA glucuronidation (IC₅₀ ≈ 55 μm ) and increased MPA concentration (up to >2‐fold) at physiologically relevant substrate‐inhibitor concentrations (n = 3). Our findings suggested that fluctuations in p‐cresol concentrations might be in part responsible for the large pharmacokinetic variability observed for MPA in the clinic.     

Optimisation of the ultrasound-assisted extraction of betalains and polyphenols from Amaranthus hypochondriacus var. Nutrisol

The present study optimised the ultrasound-assisted extraction (UAE) of bioactive compounds from Amaranthus hypochondriacus var. Nutrisol. Influence of temperature (25.86–54.14 °C) and ultrasonic power densities (UPD) (76.01–273.99 mW/mL) on total betalains (BT), betacyanins (BC), betaxanthins (BX), total polyphenols (TP), antioxidant activity (AA), colour parameters (L*, a*, and b*), amaranthine (A), and isoamaranthine (IA) were evaluated using response surface methodology. Moreover, betalain extraction kinetics and mass transfer coefficients (K_La) were determined for each experimental condition. BT, BC, BX, TP, AA, b*, K_La, and A were significantly affected (p < 0.05) by temperature extraction and UPD, whereas L*, a*, and IA were only affected (p < 0.05) by temperature. All response models were significantly validated with regression coefficients (R²) ranging from 87.46 to 99.29%. BT, A, IA, and K_La in UAE were 1.38, 1.65, 1.50, and 29.93 times higher than determined using conventional extraction, respectively. Optimal UAE conditions were obtained at 41.80 °C and 188.84 mW/mL using the desired function methodology. Under these conditions, the experimental values for BC, BX, BT, TP, AA, L*, a*, b*, K_La, A, and IA were closely related to the predicted values, indicating the suitability of the developed quadratic models. This study proposes a simple and efficient UAE method to obtain betalains and polyphenols with high antioxidant activity, which can be used in several applications within the food industry.     

Site-Specific m6A Erasing via Conditionally Stabilized CRISPR-Cas13b Editor

N6-methyladenosine (m⁶A) on RNAs plays an important role in regulating various biological processes and CRIPSR technology has been employed for programmable m⁶A editing. However, the bulky size of CRISPR protein and constitutively expressed CRISPR/RNA editing enzymes can interfere with the native function of target RNAs and cells. Herein, we reported a conditional m⁶A editing platform (FKBP*-dCas13b-ALK) based on a ligand stabilized dCas13 editor. The inducible expression of this m⁶A editing system was achieved by adding or removing the Shield-1 molecule. We further demonstrated that the targeted recruitment of dCas13b-m⁶A eraser fusion protein and site-specific m⁶A erasing were achieved under the control of Shield-1. Moreover, the release and degradation of dCas13b fusion protein occurred faster than the restoration of m⁶A on the target RNAs after Shield-1 removal, which provides an ideal opportunity to study the m⁶A function with minimal steric interference from bulky dCas13b fusion protein.     

Imprinted silica nanoparticles coated with N‐propylsilylmorpholine‐4‐carboxamide for the determination of m‐cresol in synthetic and real samples

m‐Cresol‐imprinted silica nanoparticles coated with N‐propylsilylmorpholine‐4‐carboxamide have been developed that contain specific pockets for the selective uptake of m‐cresol. Silica nanoparticles were synthesized by a sol–gel process followed by functionalization of their surface with N‐propylsilylmorpholine‐4‐carboxamide. The formation of m‐cresol‐imprinted silica nanoparticles was confirmed by UV‐Vis spectrophotometry, infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy and transmission electron microscopy. Electron microscopic studies revealed the formation of monodispersed imprinted silica nanoparticles with spherical shape and an average size of 83 nm. The developed nanoparticles were filled in a syringe and used for the extraction of m‐cresol from aqueous samples followed by quantification using high‐performance liquid chromatography with diode array detection. Various adsorption experiments showed that developed m‐cresol‐imprinted silica nanoparticles exhibited a high adsorption capacity and selectivity and offered a fast kinetics for rebinding m‐cresol. The chromatographic quantification was achieved using mobile phase consisting of acetonitrile/water (70:30 v/v) at an isocratic flow rate of 1.0 mL/min using a reversed‐phase C₁₈ column and detection at λ_max = 275 nm. The limits of detection and quantification were 1.86 and 22.32 ng/mL, respectively, for the developed method. The percent recoveries ranged from 96.66–103.33% in the spiked samples. This combination of this nanotechnique with molecular imprinting was proved as a reliable, sensitive and selective method for determining the target from synthetic and real samples.     

Improved operator comfort and off-road capability through pendulum arm technology

The Nordic forest industry requires just-in-time wood deliveries. Operations must continue regardless of season, weather and terrain. Soil compaction and deep ruts must be avoided while providing high performance and a reasonable working environment for operators.The Xt28 pendulum arm forwarder is a full-size concept forwarder with six hydrostatic propelled wheels on pendulum arms built on a three-piece frame connected with two articulation joints. The Xt28 concept machine was tested according to Skogforsk standard machine tests. Rut depth test focused on soil interaction where rut depth was measured related to number of passes. Machine dynamics were measured using standardized test track with focus on operator comfort.The project proved the potential of pendulum arm technology in off-road transportation. Automatic pendulum arm levelling, equalized ground pressure between wheels and improved operator comfort through reducing adverse vibrations and roll angles, simultaneously reducing dynamic forces transferred to the forest floor. Pendulum arm technology improves travel speed in adverse terrain, providing unparalleled side slope capability and enhanced productivity.     

Non-gaussian diffusion modeling in composite porous media by homogenization: Tail effect

In the paper anomalous diffusion appearing in a porous medium composed of two porous components of considerably different diffusion characteristics is examined. The differences in diffusivities are supposed to result either from two medium types being present or from variations in pore size (double porosity media). The long-tail effect is predicted using the homogenization approach based on the application of multiple scale asymptotic developments. It is shown that, if the ratio of effective diffusion coefficients of two porous media is of the order of magnitude smaller or equal O( ²), where is a homogenization parameter, then the macroscopic behaviour of the composite may be affected by the presence of tail-effect. The results of the theoretical analysis were applied to a problem of diffusion in a bilaminate composite. Analytical calculations were performed to show the presence of the long-tail effect in two particular cases.Notations c _i the concentration of chemical species in water within the medium i - D _i the effective diffusion coefficient for the medium i - D _ij ^eff the macroscopic (or effective) diffusion tensor in the composite - ERV the elementary representative volume - h the thickness of the period - l a chracteristic length of the ERV or the periodic cell - L a characteristic macroscopic length - n the volumetric fraction of the material 2 - 1–n the volumetric fraction of the material 1 - N the unit vector normal to - t the time variable - x the macroscopic (or slow) space variable - y the microscopic (or fast) space variable - c _1c ,C _2c ,D _1c ,D _2c the characteristic quantities - T,T _1L ,T _2L ,T _1l ,T _2l the characteristic times - c ₁ ^* ,c ₂ ^* ,D ₁ ^* ,D ₂ ^* ,t ^* the non-dimensional variables - the homogenization parameter - ₁ the domain occupied by the material 1 - ₂ the domain occupied by the material 2 - the interface between the domains 1 and 2 - the total volume of the periodic cell - /x_i the gradient operator - the gradient operator     

Asymptotic Modeling of Nonlinear Wave Processes in Shock‐Loaded Elastoplastic Materials

Nonlinear wave processes in shockloaded elastoplastic materials are modeled. A comparison of the results obtained with experimental data and numerical solutions of exact systems of dynamic equations shows that the model equations proposed qualitatively describe the stressdistribution evolution in both the elasticflow and plasticflow regions and can be used to solve one and twodimensional problems of pulsed deformation and fracture of elastoplastic media.     

The modified Casson＇s equation and its application to pipe flows of shear-thickening fluid

A few additional data from our previous experiments were plotted to emphasize the shear-thickening behavior of deoxy sickle erythrocyte (SS) suspension. A constitutive equation (named as FX equation) was developed and applied to a cylindrical pipe flow of a shear-thickening fluid. A blunt velocity profile and its volume flow rate were calculated. The flow was non-viscous (potential) in the central part of the pipe (i.e. the central core or the central plug-flow), and became more and more viscous towards the wall of the pipe after a specific radial distance, which was determined by a critical shear rate of (named as Fungs shear rate). Furthermore, combining the FX equation with the original Cassons equation, the author obtained a modified Cassons equation by introducing .The English text was polished by Yunming Chen.     

Characterizations of ( m,n )-Jordan Derivations and ( m,n )-Jordan Derivable Mappings on Some Algebras

Let R be a ring, M be a R-bimodule and m, n be two fixed nonnegative integers with m + n = 0. An additive mapping δ from R into M is called an(m, n)-Jordan derivation if(m +n)δ(A~2) = 2 mAδ(A) + 2nδ(A)A for every A in R. In this paper, we prove that every(m, n)-Jordan derivation with m = n from a C*-algebra into its Banach bimodule is zero. An additive mappingδ from R into M is called a(m, n)-Jordan derivable mapping at W in R if(m + n)δ(AB + BA) =2mδ(A)B + 2 mδ(B)A + 2 nAδ(B) + 2 nBδ(A) for each A and B in R with AB = BA = W. We prove that if M is a unital A-bimodule with a left(right) separating set generated algebraically by all idempotents in A, then every(m, n)-Jordan derivable mapping at zero from A into M is identical with zero. We also show that if A and B are two unital algebras, M is a faithful unital(A, B)-bimodule and U = [A M N B] is a generalized matrix algebra, then every(m, n)-Jordan derivable mapping at zero from U into itself is equal to zero.     

New Mild and Efficient Synthesis of Peptidosulfonamides

This article describes a new route to peptidosulfonamide. Our study shows how sulfinamides were first obtained via nucleophilic cleavage of 3,6‐dihydrothiazine‐1‐oxide system and how the products can be subjected to oxidation with m‐chloroperbenzoic acid to give sulfonamides in good yield.