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BACKGROUND: Of the available medications for treating alcohol-related problems, none are universally effective, and all have side effects that may limit their use. Extracts of kudzu containing a variety of isoflavones have been shown to reduce alcohol drinking in rats and hamsters. METHODS: The present study was designed to test the efficacy of a kudzu extract in a clinical population. Male and female 'heavy' alcohol drinkers were treated with either placebo or a kudzu extract for 7 days and then given an opportunity to drink their preferred brand of beer while in a naturalistic laboratory setting. Participants served as their own controls, and order of treatment exposure was counterbalanced. Drinking behavior was monitored by a digital scale that was located in the top of an end table. RESULTS: Kudzu treatment resulted in significant reduction in the number of beers consumed that was paralleled by an increase in the number of sips and the time to consume each beer and a decrease in the volume of each sip. These changes occurred in the absence of a significant effect on the urge to drink alcohol. There were no reported side effects of kudzu treatment. CONCLUSION: These data suggest that an extract of this leguminous plant may be a useful adjunct in reducing alcohol intake in a naturalistic setting. [ABSTRACT FROM AUTHOR]

Chiral oxygenated aliphatic moieties are recurrent in biological and pharmaceutically relevant molecules and constitute one of the most versatile types of functionalities for further elaboration. Herein we report a protocol for straightforward and general access to chiral γ -lactones via enantioselective oxidation of strong nonactivated primary and secondary C( sp 3 )-H bonds in readily available carboxylic acids. The key enabling aspect is the use of robust sterically encumbered manganese catalysts that provide outstanding enantioselectivities (up to >99.9%) and yields (up to 96%) employing hydrogen peroxide as the oxidant. The resulting γ -lactones are of immediate interest for the preparation of inter alia natural products and recyclable polymeric materials.

Site-selective oxidation of aliphatic C-H bonds is a powerful synthetic tool because it enables rapid build-up of product complexity and diversity from simple precursors. Besides the poor reactivity of alkyl C-H bonds, the main challenge in this reaction consists in differentiating between the multiple similar sites present in most organic molecules. Herein, a manganese oxidation catalyst equipped with two 18-benzo-6-crown ether receptors has been employed in the oxidation of the long chain tetradecane-1,14-diamine. 1 H-NMR studies evidence simultaneous binding of the two protonated amine moieties to the crown ether receptors. This recognition has been used to pursue site-selective oxidation of a methylenic site, using hydrogen peroxide as oxidant in the presence of carboxylic acids as co-ligands. Excellent site-selectivity towards the central methylenic sites (C6 and C7) is observed, overcoming selectivity parameters derived from polar deactivation by simple amine protonation and selectivity observed in the oxidation of related monoprotonated amines.

The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1'-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

The mechanism and the reactive species involved in the oxidation of alkenes, and alcohols with H 2 O 2 , catalysed by an in situ prepared mixture of a Mn II salt, pyridine-2-carboxylic acid and a ketone is elucidated using substrate competition experiments, kinetic isotope effect (KIE) measurements, and atom tracking with 18 O labelling. The data indicate that a single reactive species engages in the oxidation of both alkenes and alcohols. The primary KIE in the oxidation of benzyl alcohols is ca. 3.5 and shows the reactive species to be selective despite a zero order dependence on substrate concentration, and the high turnover frequencies (up to 30 s -1 ) observed. Selective 18 O labelling identifies the origin of the oxygen atoms transferred to the substrate during oxidation, and is consistent with a highly reactive, e. g ., [Mn V (O)(OH)] or [Mn V (O) 2 ], species rather than an alkylperoxy or hydroperoxy species., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. ChemCatChem published by Wiley-VCH GmbH.)

Background: The presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid is associated with a more severe clinical multiple sclerosis (MS) course., Objective: To investigate LS-OCMB as a prognostic biomarker of cognitive long-term outcomes in MS., Methods: Ninety-nine patients underwent neuropsychological assessment. Cognitive performance between LS-OCMB- and LS-OCMB+ patients was compared adjusting by age, education, anxiety-depression, disease duration, and disability., Results: LS-OCMB+ patients of ∼13 years of disease duration performed worse on Symbol Digit Modalities Test (SDMT) (p = 0.005)., Conclusion: LS-OCMB+ perform worse on information processing speed and working memory (SDMT), suggesting that LS-OCMB could be a useful biomarker for long-term cognitive outcomes., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/ or publication of this article: C.C.M: has received support for attending congresses from sanofi, merk, teva and novartis. E.Q: has nothing to disclose. M.B: has nothing to disclose. J.S.P: has nothing to disclose. L.G: has nothing to disclose. A.Q.V: has nothing to disclose. L.C.F: has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Janssen, Roche, Bristol Myers Squibb, TEVA and Almirall. LM.V: Received com compensation for consulting services and speaking fees from Biogen, Novartis, Merck, Sanofi, Genzyme, Roche, and Bristol Myers Squibb, Almirall. E.F.D: has received compensation for consulting services and/or speaking fees from Almirall, Biogen, Merck, Roche and Sanofi-Genzyme. J.G: has received compensation for consulting services and speaking fees from Biogen, Novartis, Merck, Sanofi, Genzyme, Roche and TEVA. Y.A: has received funding for research projects or in the form of conference fees, mentoring, and assistance for conference attendance from: Bayer, Biogen, Roche, Merck, Novartis, Allmirall and Sanofi-Genzime and Bristol Myers Squibb. A.M.B: has nothing to disclose. M.C: has nothing to disclose. L.R.T: has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol Myers Squibb, TEVA and Almirall. J.G.F: has received speaking fees from Novartis, Teva, Sanofi and Merck., (Copyright © 2022. Published by Elsevier B.V.)

Reactions that enable selective functionalization of strong aliphatic C-H bonds open new synthetic paths to rapidly increase molecular complexity and expand chemical space. Particularly valuable are reactions where site-selectivity can be directed toward a specific C-H bond by catalyst control. Herein we describe the catalytic site- and stereoselective γ-lactonization of unactivated primary C-H bonds in carboxylic acid substrates. The system relies on a chiral Mn catalyst that activates aqueous hydrogen peroxide to promote intramolecular lactonization under mild conditions, via carboxylate binding to the metal center. The system exhibits high site-selectivity and enables the oxidation of unactivated primary γ-C-H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at α- and β-carbons. With substrates bearing nonequivalent γ-C-H bonds, the factors governing site-selectivity have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, γ-lactonization at methyl groups in gem -dimethyl structural units of rigid cyclic and bicyclic carboxylic acids can be achieved with unprecedented levels of diastereoselectivity. Such control has been successfully exploited in the late-stage lactonization of natural products such as camphoric, camphanic, ketopinic, and isoketopinic acids. DFT analysis points toward a rebound type mechanism initiated by intramolecular 1,7-HAT from a primary γ-C-H bond of the bound substrate to a highly reactive Mn IV -oxyl intermediate, to deliver a carbon radical that rapidly lactonizes through carboxylate transfer. Intramolecular kinetic deuterium isotope effect and 18 O labeling experiments provide strong support to this mechanistic picture.

The C(sp 3 )-H bond oxygenation of the cyclopropane-containing mechanistic probes 6- tert -butylspiro[2.5]octane and spiro[2.5]octane with hydrogen peroxide catalyzed by manganese complexes bearing aminopyridine tetradentate ligands has been studied. Mixtures of unrearranged and rearranged oxygenation products (alcohols, ketones, and esters) are obtained, suggesting the involvement of cationic intermediates and the contribution of different pathways following the initial hydrogen atom transfer-based C-H bond cleavage step. Despite such a complex mechanistic scenario, a judicious choice of the catalyst structure and reaction conditions (solvent, temperature, and carboxylic acid) could be employed to resolve these oxygenation pathways, leading, with the former substrate, to conditions where a single unrearranged or rearranged product is obtained in good isolated yield. Taken together, the work demonstrates an unprecedented ability to precisely direct the chemoselectivity of the C-H oxidation reaction, discriminating among multiple pathways. In addition, these results conclusively demonstrate that stereospecific C(sp 3 )-H oxidation can take place via a cationic intermediate and that this path can become exclusive in governing product formation, expanding the available toolbox of aliphatic C-H bond oxygenations. The implications of these findings are discussed in the framework of the development of synthetically useful C-H functionalization procedures and the associated mechanistic features.

Precise delivery of a proton plays a key role in O 2 activation at iron oxygenases, enabling the crucial O-O cleavage step that generates the oxidizing high-valent metal-oxo species. Such a proton is delivered by acidic residues that may either directly bind the iron center or lie in its second coordination sphere. Herein, a supramolecular strategy for enzyme-like H 2 O 2 activation at a biologically inspired manganese catalyst, with a nearly stoichiometric amount (1-1.5 equiv) of a carboxylic acid is disclosed. Key for this strategy is the incorporation of an α,ω-amino acid in the second coordination sphere of a chiral catalyst via remote ammonium-crown ether recognition. The properly positioned carboxylic acid function enables effective activation of hydrogen peroxide, leading to catalytic asymmetric epoxidation. Modulation of both amino acid and catalyst structure can tune the efficiency and the enantioselectivity of the reaction, and a study on the oxidative degradation pathway of the system is presented., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: The evidence on the association between ultrafine (UFP) particles and mortality is still inconsistent. Moreover, health effects of specific UFP sources have not been explored. We assessed the impact of UFP sources on daily mortality in Barcelona, Helsinki, London, and Zurich., Methods: UFP sources were previously identified and quantified for the four cities: daily contributions of photonucleation, two traffic sources (fresh traffic and urban, with size mode around 30 nm and 70 nm, respectively), and secondary aerosols were obtained from data from an urban background station. Different periods were investigated in each city: Barcelona 2013-2016, Helsinki 2009-2016, London 2010-2016, and Zurich 2011-2014. The associations between total particle number concentrations (PNC) and UFP sources and daily (natural, cardiovascular [CVD], and respiratory) mortality were investigated using city-specific generalized linear models (GLM) with quasi-Poisson regression., Results: We found inconsistent results across cities, sources, and lags for associations with natural, CVD, and respiratory mortality. Increased risk was observed for total PNC and natural mortality in Helsinki (lag 2; 1.3% [0.07%, 2.5%]), CVD mortality in Barcelona (lag 1; 3.7% [0.17%, 7.4%]) and Zurich (lag 0; 3.8% [0.31%, 7.4%]), and respiratory mortality in London (lag 3; 2.6% [0.84%, 4.45%]) and Zurich (lag 1; 9.4% [1.0%, 17.9%]). A similar pattern of associations between health outcomes and total PNC was followed by the fresh traffic source, for which we also found the same associations and lags as for total PNC. The urban source (mostly aged traffic) was associated with respiratory mortality in Zurich (lag 1; 12.5% [1.7%, 24.2%]) and London (lag 3; 2.4% [0.90%, 4.0%]) while the secondary source was associated with respiratory mortality in Zurich (lag 1: 12.0% [0.63%, 24.5%]) and Helsinki (4.7% [0.11%, 9.5%]). Reduced risk for the photonucleation source was observed for respiratory mortality in Barcelona (lag 2, -8.6% [-14.5%, -2.4%]) and for CVD mortality in Helsinki, as this source is present only in clean atmospheres (lag 1, -1.48 [-2.75, -0.21])., Conclusions: We found inconsistent results across cities, sources and lags for associations with natural, CVD, and respiratory mortality., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b ) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin, very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl β-naphthylamide (PAβN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported.

Oxoiron(IV) complexes bearing tetradentate ligands have been extensively studied as models for the active oxidants in non-heme iron-dependent enzymes. These species are commonly generated by oxidation of their ferrous precursors. The mechanisms of these reactions have seldom been investigated. In this work, the reaction kinetics of complexes [Fe II (CH 3 CN) 2 L](SbF 6 ) 2 ([1](SbF 6 ) 2 and [2](SbF 6 ) 2 ) and [Fe II (CF 3 SO 3 ) 2 L] ([1](OTf) 2 and [2](OTf) 2 (1, L= Me,H Pytacn; 2, L= nP,H Pytacn; R,R' Pytacn=1-[(6-R'-2-pyridyl)methyl]-4,7- di-R-1,4,7-triazacyclononane) with Bu 4 NIO 4 to form the corresponding [Fe IV (O)(CH 3 CN)L] 2+ (3, L= Me,H Pytacn; 4, L= nP,H Pytacn) species was studied in acetonitrile/acetone at low temperatures. The reactions occur in a single kinetic step with activation parameters independent of the nature of the anion and similar to those obtained for the substitution reaction with Cl - as entering ligand, which indicates that formation of [Fe IV (O)(CH 3 CN)L] 2+ is kinetically controlled by substitution in the starting complex to form [Fe II (IO 4 )(CH 3 CN)L] + intermediates that are converted rapidly to oxo complexes 3 and 4. The kinetics of the reaction is strongly dependent on the spin state of the starting complex. A detailed analysis of the magnetic susceptibility and kinetic data for the triflate complexes reveals that the experimental values of the activation parameters for both complexes are the result of partial compensation of the contributions from the thermodynamic parameters for the spin-crossover equilibrium and the activation parameters for substitution. The observation of these opposite and compensating effects by modifying the steric hindrance at the ligand illustrates so far unconsidered factors governing the mechanism of oxygen atom transfer leading to high-valent iron oxo species., (© 2020 Wiley-VCH GmbH.)

The interaction between drugs and transport proteins, such as albumins, is a key factor in drug bioavailability. One of the techniques commonly used for the evaluation of the drug-protein complex formation is fluorescence. This work studies the interaction of human serum albumin (HSA) with four non-steroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, naproxen, and diflunisal-by monitoring the fluorescence quenching when the drug-albumin complex is formed. Two approaches-the double logarithm Stern-Volmer equation and the STAR program-are used to evaluate the binding parameters. The results are analyzed considering the binding properties, determined by using other complementary techniques and the available structural information of albumin complexes with NSAID-related compounds. Finally, this combined analysis has been synergistically used to interpret the binding of flurbiprofen to HSA.

α-Amino acids represent a valuable class of natural products employed as building blocks in biological and chemical synthesis. Because of the limited number of natural amino acids available, and of their widespread application in proteomics, diagnosis, drug delivery and catalysis, there is an increasing demand for the development of procedures for the preparation of modified analogues. Herein, we show that the use of bioinspired manganese catalysts and H 2 O 2 under mild conditions, provides access to modified α-amino acids via γ-C-H bond lactonization. The system can efficiently target 1°, 2° and 3° γ-C-H bonds of α-substituted and achiral α,α-disubstituted α-amino acids with outstanding site-selectivity, good to excellent diastereoselectivity and (where applicable) enantioselectivity. This methodology may be considered alternative to well-established organometallic procedures., (© 2020 Wiley-VCH GmbH.)

Mammalian IκB proteins (IκBs) exert their main function as negative regulators of NF-κB, a central signaling pathway controlling immunity and inflammation. An alternative chromatin role for IκBs has been shown to affect stemness and cell differentiation. However, the involvement of NF-κB in this function has not been excluded. NFKI-1 and IKB-1 are IκB homologs in Caenorhabditis elegans, which lacks NF-κB nuclear effectors. We found that nfki-1 and ikb-1 mutants display developmental defects that phenocopy mutations in Polycomb and UTX-1 histone demethylase, suggesting a role for C. elegans IκBs in chromatin regulation. Further supporting this possibility (1) we detected NFKI-1 in the nucleus of cells; (2) NFKI-1 and IKB-1 bind to histones and Polycomb proteins, (3) and associate with chromatin in vivo, and (4) mutations in nfki-1 and ikb-1 alter chromatin marks. Based on these results, we propose that ancestral IκB inhibitors modulate Polycomb activity at specific gene subsets with an impact on development.

Enantioselective epoxidation of β,β-disubstituted enamides with aqueous hydrogen peroxide and a novel manganese catalyst is described. Epoxidation is stereospecific and proceeds fast under mild conditions. Amides are disclosed as key functional groups to enable high enantioselectivity.

The stereoselective oxidation of hydrocarbons is one of the most challenging reactions for synthetic chemists. However, this transformation is one of the most common reactions in nature. Metalloenzymes that catalyze this transformation are taken as inspiration for the development of new catalysts. There are several examples in the literature where either peptides or metal catalysts are used in the stereoselective oxidation reaction, but the synergistic combination of both systems is still a non-explored field. The use of metallopeptides in biologically inspired oxidation reactions is discussed in this perspective.

The concept of a "proteomic constraint" proposes that DNA repair capacity is positively correlated with the information content of a genome, which can be approximated to the size of the proteome (P). This in turn implies that DNA repair genes are more likely to be present in genomes with larger values of P. This stands in contrast to the common assumption that informational genes have a core function and so are evenly distributed across organisms. We examined the presence/absence of 18 DNA repair genes in bacterial genomes. A positive relationship between gene presence and P was observed for 17 genes in the total dataset, and 16 genes when only nonintracellular bacteria were examined. A marked reduction of DNA repair genes was observed in intracellular bacteria, consistent with their reduced value of P. We also examined archaeal and DNA virus genomes, and show that the presence of DNA repair genes is likewise related to a larger value of P. In addition, the products of the bacterial genes mutY, vsr, and ndk, involved in the correction of GC/AT mutations, are strongly associated with reduced genome GC content. We therefore propose that a reduction in information content leads to a loss of DNA repair genes and indirectly to a reduction in genome GC content in bacteria by exposure to the underlying AT mutation bias. The reduction in P may also indirectly lead to the increase in substitution rates observed in intracellular bacteria via loss of DNA repair genes., (© The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Activation in frontopolar cortex (FPC; BA 10) has been associated both with attending to mental states and with integrating multiple mental relations. However, few previous studies have manipulated both of these cognitive processes, precluding a clear functional distinction among regions within FPC. To address this issue, we developed an fMRI task that combined mentalizing and relational integration processes. Participants saw blocks of single words and performed one of three judgments: how pleasant or unpleasant they found each word (Self condition), how a specific friend would evaluate the pleasantness of the word (Other condition), or the difference between their own pleasantness judgment and that of their friend (Relational condition). We found that medial FPC was modulated by Other relative to Self judgments, consistent with a role in mentalizing. Lateral FPC was significantly activated during Relational compared to Self judgements, suggesting that this region is particularly involved in relational integration. The results point to a strong functional dissociation between medial and lateral FPC. In addition, the data demonstrate a role for lateral FPC in the social domain, provided that the task requires the integration of one's preferences with those of others.

A comparative study of the absorbency properties of different endodontic paper points has been conducted. Twenty standardized absorbent paper points, size 30, from 13 bands (Dentaline, Zipperer, Kerr, Diadent, Roeko novo, Roeko color, Maillefer, P.D., Schein, Spectrapoint, Proclinic, Euronda, and Alpro) of 12 manufacturers were tested. Each dry paper point was weighted using an electronic laboratory balance. A length of 16 mm from the tip was then lowered in distilled water for 5 s, the paper point was weighted again, and the difference between both measurements was taken as the value of the fluid absorbed. Diadent, Kerr, and Dentalite showed significantly higher absorbencies (p < 0.05) than standardized paper points of the remaining brands. The study demonstrates a wide variation in the absorbency properties of this dental accessory.