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Alpibectir (also known as BVL-GSK098 and GSK3729098) is a new chemical entity (NCE) with a novel mechanism for the treatment of tuberculosis. The disposition of alpibectir was determined in subjects from a first-time-in-human trial after a single oral dose of 40 mg and after 7 days repeat dosing at 30 mg. Here we present a combined approach of 19 F-NMR (nuclear magnetic resonance), 1 H-NMR, and high-resolution mass spectrometry (HRMS) to confidently determine the human metabolic fate of alpibectir. Utilizing multiple sites of fluorination in the molecule, it was possible to fractionate human urine and plasma to confidently detect and quantify the metabolite responses using 19 F-NMR. Qualitative detection and structural characterization of F-containing NMR fractions were performed using complementary high-resolution ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analyses to further add confidence to the metabolite responses in these fractions. Subsequent 1 H-NMR then provided unequivocal standard-free structural confirmation for key metabolites, which would not be possible with conventional radioactivity detection and LC-MS/MS techniques. Alpibectir was shown to undergo extensive hydrolysis of the central amide moiety, where the resultant N -dealkylated amine and trifluorobutyric acid products were detected initially by unbiased 19 F-NMR detection along with major downstream biotransformations to form a carbamoyl glucuronide conjugate and trifluoroacetic acid, respectively. Parallel UHPLC-MS/MS analyses provided confirmatory or additional structural characterization only where relevant. These concerted data allowed for the qualitative metabolic profile and quantitative determination of drug-related material (DRM) in urine and plasma, along with the percentage of dose excreted in urine, to be reported in a comprehensive, efficient, and data-led manner. SIGNIFICANCE STATEMENT: Combining the selectivity of 19 F-NMR (nuclear magnetic resonance) for unfractionated samples as first-intent, data-led sample fractionation prior to 19 F-NMR and structure-rich 1 H-NMR detection, along with the sensitivity of high-resolution ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), a novel alternative for time-efficient detection and quantification of drug-related material (DRM) in human without use of radiolabeled drug is reported. This allowed more complete data rationalization of human metabolism, permitting early risk assessment and progression of the development of antitubercular agent, alpibectir., (Copyright © 2024 by The Author(s).)

A large number of lepidolites K(LixAl3−x)[Si2xAl4−2xO10](OH)yF2−y and Li-muscovites K(LixAl2-x/3□1-2x/3)[Si3AlO10](OH)yF2−y were synthesised by a gelling method in combination with hydrothermal syntheses at a pressure of 2 kbar and a temperature of 873 K. The nominal composition ranged between 0.0≤x≤2.0 and 0.0≤y≤2.0, i.e. from polylithionite K[Li2.0Al][Si4.0O10](OH)yF2−y over trilithionite K[Li1.5Al1.5][AlSi3.0O10](OH)yF2−y to muscovite K[Al2.0□][AlSi3.0O10](OH)yF2−y. 1H, 19F, 29Si and 27Al magic-angle spinning nuclear magnetic resonance (MAS NMR) and 27Al multiple-quantum magic-angle spinning (MQMAS) NMR spectroscopy has been performed to investigate the order and/or disorder state of Si and Al in the tetrahedral layers and of Li, Al, OH and F in the octahedral layer. The synthetic mica crystals are very small, ranging from 0.1 to 5 µm. With increasing Al content, the crystal sizes decrease. Rietveld structure analyses on 12 samples showed that nearly all samples consist of two mica polytypes (1M and 2M1) of varying proportions. In the case of lepidolites, the 1M / 2M1 ratio depends on the Li/Al ratio of the reaction mixture. The refinement of the occupancy factors of octahedral sites shows that lepidolites (1.5≤x≤2.0) represent a solid solution series with polylithionite and trilithionite as the endmembers. In the case of the Li-muscovites (0.0≤x≤1.5), the 1M / 2M1 ratio depends on the number of impurity phases like eucryptite or sanidine depleting the reaction mixture of Li or Al. There is no solid solution between trilithionite and muscovite; instead, the Li-muscovite crystals consist of domains differing in the relative proportions of muscovite and trilithionite. The overall composition of the synthesised micas which consist of two polytypes can be characterised by 29Si, 1H and 19F MAS NMR spectroscopy. The Si/Al ratio in the tetrahedral layers and thus the content of [4]Al were calculated by analysing the signal intensities of the 29Si MAS NMR experiments. The Li content xest was calculated from the measured tetrahedral Si/Al ratio of the 29Si MAS NMR signals. The calculated Li contents xest of samples between polylithionite and trilithionite agree with the expected values. The F-rich samples show slightly increased values and the OH samples lower values. Lepidolites with only F (x = 1.5 to 2.0, y = 0.0), but not lepidolites with only OH (x = 1.5 to 2.0 and y = 2.0), were observed after synthesis. With decreasing Li content, x≤1.2, Li-muscovites containing mostly hydroxyl (y>1.0) are formed. It was possible to synthesise fluorine containing micas with a Li content as low as 0.3 and y = 0.2 to 1.8. The 19F and 1H MAS NMR experiments reveal that F and OH are not distributed statistically but local structural preferences exist. F is attracted by Li-rich and OH by Al-rich environments. The quadrupolar coupling constant which represents the anisotropy of the Al coordination is low for polylithionite with CQ=1.5 MHz and increases to CQ=3.8 MHz for trilithionite. For tetrahedral Al a smaller increase of CQ from 1.7 to 2.8 MHz is observed. Advancing from trilithionite to muscovite both quadrupolar coupling constants decrease to 2.5 MHz for octahedral and 1.5 MHz for tetrahedral Al. In polylithionite there is the most isotropic environment for octahedral Al; there are only Li2Al sites coordinated by F in the octahedral sheets and O from the tetrahedral sheets which are regular, containing only Si. The distortion and anisotropy for Al in tetrahedral as well as octahedral sheets increases with rising Al content. The most anisotropic environment can be found in trilithionite, especially for octahedral Al.

The Human papillomavirus (HPV) causes tumors in part by hijacking the host cell cycle and forcing uncontrolled cellular division. While there are >200 genotypes of HPV, 15 are classified as high-risk and have been shown to transform infected cells and contribute to tumor formation. The remaining low-risk genotypes are not considered oncogenic and result in benign skin lesions. In high-risk HPV, the oncoprotein E7 contributes to the dysregulation of cell cycle regulatory mechanisms. High-risk E7 is phosphorylated in cells at two conserved serine residues by Casein Kinase 2 (CK2) and this phosphorylation event increases binding affinity for cellular proteins such as the tumor suppressor retinoblastoma (pRb). While low-risk E7 possesses similar serine residues, it is phosphorylated to a lesser degree in cells and has decreased binding capabilities. When E7 binding affinity is decreased, it is less able to facilitate complex interactions between proteins and therefore has less capability to dysregulate the cell cycle. By comparing E7 protein sequences from both low- and high-risk HPV variants and using site-directed mutagenesis combined with NMR spectroscopy and cell-based assays, we demonstrate that the presence of two key nonpolar valine residues within the CK2 recognition sequence, present in low-risk E7, reduces serine phosphorylation efficiency relative to high-risk E7. This results in significant loss of the ability of E7 to degrade the retinoblastoma tumor suppressor protein, thus also reducing the ability of E7 to increase cellular proliferation and reduce senescence. This provides additional insight into the differential E7-mediated outcomes when cells are infected with high-risk verses low-risk HPV. Understanding these oncogenic differences may be important to developing targeted treatment options for HPV-induced cancers.

The objective of this study was to establish an optimized 1D 1 H quantitative nuclear magnetic resonance (qNMR) analytical method for analyzing polar metabolites in meat. Three extraction solutions [0.6 M perchloric acid, 10 mM phosphate buffer, water/methanol (1:1)], three reconstitution buffers [20 mM 3-morpholinopropane-1-sulfonic acid, 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid, phosphate buffer], and two pulse programs (zg30, noesypr1d) were evaluated. Extraction with 0.6 M perchloric acid and 20 mM phosphate resulted in a stable baseline and no additional overlap for quantifying polar metabolites in chicken breast. In qNMR analysis, zg30 pulse program (without water-suppression) showed smaller relative standard deviation (RSD) and faster running time than noesypr1d (water-suppression). High-performance liquid chromatography was compared with qNMR analyses to validate accuracy. The zg30 pulse program showed good accuracy and lower RSD. The optimized qNMR method was able to apply for beef and pork samples. Thus, an optimized 1D 1 H qNMR method for meat metabolomics was established., Competing Interests: Conflict of Interest The authors declare no potential conflict of interest.

The urgent need for efficient energy storage devices (supercapacitors and batteries) has attracted ample interest from scientists and researchers in developing materials with excellent electrochemical properties. Electrode material based on carbon, transition metal oxides, and conducting polymers (CPs) has been used. Among these materials, carbon has gained wide attention in Electrochemical double-layer capacitors (EDLC) due to its variable morphology of pores and structural properties as well as its remarkable electrical and mechanical properties. In this context, the present review article summarizes the history of supercapacitors and the basic function of these devices, the type of carbon electrode materials, and the different strategies to improve the performance of these devices. In addition, we present different approaches to studying the charging mechanism of these devices through different electrochemical techniques existing in the literature, since a deeper understanding of the interfacial charge storage mechanisms is also crucial in the elaboration and performance of the electrode material. We make a comparison of the different techniques and present their advantages and challenges. Taking these advances into account, we consider that the coupling between two methods/techniques provides a better understanding of the charge storage mechanisms in energy storage devices.

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose major characteristics persistent joint inflammation that results in joint destruction and failure of the function. Collagen-induced arthritis (CIA) rat is an autoimmune disease model and in many ways shares features with RA. The CIA is associated with systemic manifestations, including alterations in the metabolism. Nuclear magnetic resonance (NMR) spectroscopy-based metabolomics has been successfully applied to the perchloric acid extract of the joint tissue of CIA rat and control rat for the analysis of aqueous metabolites. GPC (Glycerophosphocholine), carnitine, acetate, and creatinine were important discriminators of CIA rats as compared to control rats. Level of lactate (significance; p = 0.004), alanine (p = 0.025), BCA (Branched-chain amino acids) (p = 0.006) and creatinine (p = 0.023) was significantly higher in CIA rats as compared to control rats. Choline (p = 0.038) and GPC (p = 0.009) were significantly reduced in CIA rats as compared to control rats. Choline to GPC correlation was good and negative (Pearson correlation = -0.63) for CIA rats as well as for control rats (Pearson correlation = -0.79). All these analyses collectively considered as metabolic fingerprinting of the joint tissue of CIA rat as compared to control rat. The metabolic fingerprinting of joint tissue of CIA rats was different as compared to control rats. The metabolic fingerprinting reflects inflammatory disease activity in CIA rats with synovitis, demonstrating that underlying inflammatory process drives significant changes in metabolism that can be measured in the joint tissue. Therefore, the outcome of this study may be helpful for understanding the mechanism of metabolic processes in RA. This may be also helpful for the development of advanced diagnostic methods and therapy for RA.

A large number of lepidolites K(Li x Al 3-x)[Si 2x Al 4-2x O 10 ](OH) y F 2-y and Li-muscovites K(Li x Al 2-x/3□1-2x/3)[Si 3 AlO 10 ](OH) y F 2-y were synthesised by a gelling method in combination with hydrothermal syntheses at a pressure of 2 kbar and a temperature of 873 K. The nominal composition ranged between 0.0≤x≤2.0 and 0.0≤y≤2.0 , i.e. from polylithionite K[Li 2.0 Al][Si 4.0 O 10 ](OH) y F 2-y over trilithionite K[Li 1.5 Al 1.5 ][AlSi 3.0 O 10 ](OH) y F 2-y to muscovite K[Al 2.0□ ][AlSi 3.0 O 10 ](OH) y F 2-y. 1 H, 19 F, 29 Si and 27 Al magic-angle spinning nuclear magnetic resonance (MAS NMR) and 27 Al multiple-quantum magic-angle spinning (MQMAS) NMR spectroscopy has been performed to investigate the order and/or disorder state of Si and Al in the tetrahedral layers and of Li, Al, OH and F in the octahedral layer. The synthetic mica crystals are very small, ranging from 0.1 to 5 µ m. With increasing Al content, the crystal sizes decrease. Rietveld structure analyses on 12 samples showed that nearly all samples consist of two mica polytypes (1M and 2M 1) of varying proportions. In the case of lepidolites, the 1M / 2M 1 ratio depends on the Li/Al ratio of the reaction mixture. The refinement of the occupancy factors of octahedral sites shows that lepidolites (1.5≤x≤2.0) represent a solid solution series with polylithionite and trilithionite as the endmembers. In the case of the Li-muscovites (0.0≤x≤1.5), the 1M / 2M 1 ratio depends on the number of impurity phases like eucryptite or sanidine depleting the reaction mixture of Li or Al. There is no solid solution between trilithionite and muscovite; instead, the Li-muscovite crystals consist of domains differing in the relative proportions of muscovite and trilithionite. The overall composition of the synthesised micas which consist of two polytypes can be characterised by 29 Si, 1 H and 19 F MAS NMR spectroscopy. The Si/Al ratio in the tetrahedral layers and thus the content of [4] Al were calculated by analysing the signal intensities of the 29 Si MAS NMR experiments. The Li content xest was calculated from the measured tetrahedral Si/Al ratio of the 29 Si MAS NMR signals. The calculated Li contents xest of samples between polylithionite and trilithionite agree with the expected values. The F-rich samples show slightly increased values and the OH samples lower values. Lepidolites with only F (x = 1.5 to 2.0, y = 0.0), but not lepidolites with only OH (x = 1.5 to 2.0 and y = 2.0), were observed after synthesis. With decreasing Li content, x≤1.2 , Li-muscovites containing mostly hydroxyl (y>1.0) are formed. It was possible to synthesise fluorine containing micas with a Li content as low as 0.3 and y = 0.2 to 1.8. The 19 F and 1 H MAS NMR experiments reveal that F and OH are not distributed statistically but local structural preferences exist. F is attracted by Li-rich and OH by Al-rich environments. The quadrupolar coupling constant which represents the anisotropy of the Al coordination is low for polylithionite with CQ=1.5 MHz and increases to CQ=3.8 MHz for trilithionite. For tetrahedral Al a smaller increase of CQ from 1.7 to 2.8 MHz is observed. Advancing from trilithionite to muscovite both quadrupolar coupling constants decrease to 2.5 MHz for octahedral and 1.5 MHz for tetrahedral Al. In polylithionite there is the most isotropic environment for octahedral Al; there are only Li 2 Al sites coordinated by F in the octahedral sheets and O from the tetrahedral sheets which are regular, containing only Si. The distortion and anisotropy for Al in tetrahedral as well as octahedral sheets increases with rising Al content. The most anisotropic environment can be found in trilithionite, especially for octahedral Al. [ABSTRACT FROM AUTHOR]

Nuclear magnetic resonance (NMR) is a recently developed, noninvasive technique of increasing importance in pediatric diagnosis. In newborns and very young infants problems may arise with regard to adequate sedation and sufficient patient monitoring during NMR imaging. In 44 of 46 young pediatric patients sedation with oral promazine or rectal diazepam/intravenous ketamine provided good immobilization during NMR scanning. In two patients an additional drug was necessary in order to successfully complete the NMR procedure. Satisfactory monitoring of patients' respiratory motions was obtained by means of a simple optical system. Good cardiovascular monitoring was made possible by lengthening the rubber tubing of a blood pressure cuff. No complications were observed during the NMR-procedures.