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Background: Inhibition of IL-4/IL-13-driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD)., Objective: Our aim was to assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment., Methods: Skin tape strips (STSs) were collected from lesional/nonlesional skin of 20 patients with AD during a 16-week dupilumab treatment course and from 20 healthy volunteers (HVs) followed for 16 weeks. STS extracts were examined by liquid chromatography-mass spectrometry proteomic analysis and targeted metabolomics., Results: Approximately 2500 individual proteins were identified in the STS extracts. Of those proteins, 490 were present in at least 80% of the AD and HV skin samples and differentially expressed in the AD skin; the levels of 249 proteins were significantly reduced (cluster 1), and the levels of 136 were significantly increased (cluster 2) in the AD skin versus in the HV skin (both P < .0001). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes, and actin filament proteins. A significant increase in cluster 1 and a significant inhibition of cluster 2 proteins expression were achieved in AD skin by 16 weeks of dupilumab treatment (P < .0001 for both vs baseline), approaching the levels in HV skin. These improvements were also revealed in differential metabolite changes in the STS extracts, including amino acids, nucleotide breakdown products, and antioxidants., Conclusion: Longitudinal integrated assessment of the skin proteome and metabolome in patients with AD who were treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. The identified changes were linked to improvements in clinical AD skin assessments, including improvements in transepidermal water loss and disease severity., Competing Interests: Disclosure statement Sponsored by Sanofi and Regeneron Pharmaceuticals. Disclosure of potential conflict of interest: E. Goleva reports receiving research grants from Sanofi. E. Berdyshev reports receiving research grants from LEO Pharma and Sanofi. S. Bafna, I. Agueusop, E. Gloaguen and A. Zhang are employees of Sanofi and may hold stock and/or stock options in the company. R. Bissonnette reports serving as a consultant and/or speaker for and receiving grants and/or research support from AbbVie, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, Bellus Health, Bluefin Biomedicine, BioMimetix, Boehringer Ingelheim, Boston Scientific, Brickell Biotech, Cara Therapeutics, Clexio Biosciences, Dermavant, Eli Lilly, EMD Serono, Evidera, Galderma, GSK, Inmagene Biopharmaceuticals, Incyte, Janssen, Kiniksa Pharmaceuticals, Kyowa Kirin, LEO Pharma, Novan, Novartis, Pfizer, Ralexar Therapeutics, RAPT Therapeutics, Regeneron Pharmaceuticals, Respivant Sciences, Sanofi, Siena Biopharmaceuticals, Target RWE, and Vyne Therapeutics and being an employee and shareholder of Innovaderm Research. J. Zahn reports being an employee and shareholder of Regeneron Pharmaceuticals. D. Y. M. Leung reports being a consultant to Boehringer Ingelheim, Evommune, Genentech, Incyte, LEO and Pharma and receiving a research grant from Sanofi. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2025 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The dissociation of carboxylate and divalent calcium ions is investigated at the molecular level in microsolvation experiments by gradually increasing the number of water molecules around the ions. IR photodissociation (IRPD) laser spectroscopy of H 2 -tagged (Ca 2+ , AcO - )(H 2 O) n =8-21 clusters in the ν(CO 2 - ) spectral range combined with RI-B97-D3-BJ-abc/TZVPPD frequency calculations is used to identify the type of ion pairs involved in this process. These results reveal that the ion dissociation follows a multistep mechanism involving in particular pseudobridged monodentate contact ion pairs (CIPs), which are found to be the first intermediate species formed from bidentate CIPs along the ion dissociation path. Altogether, structural assignments suggest a sequence of simple reactions in the first coordination shell of the carboxylate group, leading us to propose two possible dissociation paths. The appearance threshold of monodentate structures is measured at n = 10, with that of solvent-shared ion pairs (SIPs) being potentially at n = 18. By showing in detail how solvation progressively takes over from the ionic interaction in shaping these supramolecular structures, this study can serve as a reference for solving ion-pairing/dissociation problems.

Microbial processes can influence the complex geochemical behaviour of the toxic metalloid antimony (Sb) in mining environments. The present study is aimed to evaluate the influence of microbial communities on the mobility of Sb from solid phases to water in different compartments and redox conditions of a mining site in southwest (SW) Spain. Samples of surface materials presenting high Sb concentrations, from two weathered mining waste dumps, and an aquatic sediment were incubated in slurries comparing oxic and anoxic conditions. The initial microbial communities of the three materials strongly differed. Incubations induced an increase of microbial biomass and an evolution of the microbial communities' structures and compositions, which diverged in different redox conditions. The presence of active bacteria always influenced the mobility of Sb, except in the neutral pH waste incubated in oxic conditions. The effect of active microbial activities in oxic conditions was dependent on the material: Sb oxic release was biologically amplified with the acidic waste, but attenuated with the sediment. Different bacterial genera involved in Sb, Fe and S oxidation or reduction were present and/or grew during incubation of each material. The results highlighted the wide diversity of microbial communities and metabolisms at the small geographic scale of a mining site and their strong implication in Sb mobility., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We examine peptide model systems designed to probe short-range N-H⋯OS sidechain-backbone hydrogen bonding involving amino acid residues with sidechain sulfoxide or sulfone functional groups and its effects on local conformations. A strong 7-membered ring hydrogen bond of this type accompanies an intra-residue N-H⋯OC interaction and stabilizes an extended backbone conformation in preference to classical folded structures.

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD., Method: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system., Results: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD., Conclusions: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone)., Competing Interests: Dr. Choi has received an honorarium from Depression and Anxiety for service as Deputy Editor. Dr. Raffield has served as a consultant for the TOPMed Administrative Coordinating Center (through Westat). Dr. Andreassen has received speaking honoraria from Janssen, Lundbeck, and Sunovion, and he has served as a consultant for Cortechs.ai and HealthLytix. Dr. Frey has received research support from MediPharm and Janssen. Dr. Grigoriadis has received royalties from the Canadian Pharmacists Association, Norton, and UpToDate. Dr. Jones has received grant funding from Takeda and Akrivia health. Dr. Kennedy has served as a scientific advisory board member for Myriad Neuroscience. Dr. McIntosh has served as a speaker for Illumina and Janssen. Dr. Munk-Olsen has served as a speaker for Lundbeck. Dr. Rubinow has received research funding from the Buszucki Foundation, NIH, and Sage Therapeutics; he serves on scientific advisory boards for the Foundation of Hope, Sage Therapeutics, and Sensorium Therapeutics and on clinical advisory boards for EmbarkNeuro and Felicity Pharma; he has served as a consultant for Aldeyra Therapeutics, Arrivo Bioventures, Brii Biosciences, and GH Research–Ireland; and he has stock options from Sage Therapeutics and Sensorium Therapeutics. Dr. Skalkidou has served as a consultant for Biogen; she receives compensation for lectures and organization of courses in reproductive endocrinology; and she is a shareholder and serves on the board of Svensk Telepsykiatri. Dr. Smoller has served on a scientific advisory board for Sensorium Therapeutics; he has received grant support from Biogen; and he is principal investigator of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe, for which 23andMe provides analysis time as in-kind support but no payments. Dr. Stein has received personal fees from Discovery Vitality, Johnson & Johnson, Kanna, L'Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. Dr. Stowe has served on scientific advisory boards for Sage Therapeutics and Reunion Neuroscience. Dr. Taylor has given a lecture for AbbVie. Dr. Vigod has received royalties from UpToDate. Dr. Zar has received funding from the Bill and Melinda Gates Foundation. Dr. Meltzer-Brody has received sponsored research grant funding from Sage Therapeutics; she has served as a consultant for EmbarkNeuro and the Neuroscience Education Institute; and she serves as a professional corporation owner for Modern Health. Dr. Sullivan has served as an adviser for, and is a shareholder in, Neumora Therapeutics. The other authors report no financial relationships with commercial interests.

The magnesium channel controls Mg 2+ concentration in the cell and plays an indispensable role in biological functions. The crystal structure of the Magnesium Transport E channel suggested that Mg 2+ hydrated by 6 water molecules is transported through a selection filter consisting of COO - groups on two Asp residues. This Mg 2+ motion implies successive pairing with - OOC-R and dissociation mediated by water molecules. For another divalent ion, however, it is known that RCOO - ⋯Ca 2+ cannot be separated even with 12 water molecules. From this discrepancy, we probe the structure of Mg 2+ (CH 3 COO - )(H 2 O) 4-17 clusters by measuring the infrared spectra and monitoring the vibrational frequencies of COO - with the help of quantum chemistry calculations. The hydration by (H 2 O) 6 is not enough to induce ion separation, and partially-separated or separated pairs are formed from 10 water molecules at least. These results suggest that the ion separation between Mg 2+ and carboxylate ions in the selection-filter of the MgtE channel not only results from water molecules in their first hydration shell, but also from additional factors including water molecules and protein groups in the second solvation shell of Mg 2+ .

Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.0 5 -helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain-backbone N-H···N C6γ H-bonds that accompany-and thereby stabilize-C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 3 10 -helix formation in solution and the fully-extended 2.0 5 -helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

S-containing amino acids can lead to two types of local NH···S interactions which bridge backbone NH sites to the side chain to form either intra- or inter-residue H-bonds. The present work reports on the conformational preferences of S-methyl-L-cysteine, Cys(Me), using a variety of investigating tools, ranging from quantum chemistry simulations, gas-phase UV and IR laser spectroscopy, and solution state IR and NMR spectroscopies, on model compounds comprising one or two Cys(Me) residues. We demonstrate that in gas phase and in low polarity solution, the C- and N-capped model compound for one Cys(Me) residue adopts a preferred C5-C6γ conformation which combines an intra-residue N-H···O=C backbone interaction (C5) and an inter-residue N-H···S interaction implicating the side-chain sulfur atom (C6γ). In contrast, the dominant conformation of the C- and N-capped model compound featuring two consecutive Cys(Me) residues is a regular type I β-turn. This structure is incompatible with concomitant C6γ interactions, which are no longer in evidence. Instead, C5γ interactions occur, that are fully consistent with the turn geometry and additionally stabilize the structure. Comparison with the thietane amino acid Attc, which exhibits a rigid cyclic side chain, pinpoints the significance of side chain flexibility for the specific conformational behavior of Cys(Me).

The Ca C[H.sub.3]F reaction CaFC[H.sub.3] reaction is studied experimentally and theoretically. An alternative reaction mechanism involving a transfer to triplet potential energy surfaces is proposed.

The transition state of the reaction, [Ca.sup.*] + C[H.sub.3]F --> Ca[F.sup.*] + C[H.sub.3] was photoinduced in 1:1 Ca...C[H.sub.3]F complexes formed in a supersonic expansion, and were examined by monitoring CaF while scanning the laser that turns on the reaction. Experimental results for the free complex and a comparison with the results of a previous experiment where the Ca...C[H.sub.3]F complexes are deposited at the surface of large argon clusters are presented.

The dynamics of the photoinduced reaction producing electronically excited CaF when 1:1 Ca.CH(sub 3)F complexes are deposited at the surface of large argon clusters are examined using the 'cluster isolated chemical reactions' technique. The observations suggest that a profound alteration of the calcium electronic structure and a control of the reaction by the CF stretch in CH(sub 3)F.

The δ conformation is a local secondary structure in proteins that implicates a π amide N-H⋯N interaction between a backbone N atom and the NH of the following residue. Small-molecule models thereof have been limited so far to rigid proline-type compounds. We show here that in derivatives of a cyclic amino acid with a sulphur atom in the γ-position, specific side-chain/backbone N-H⋯S interactions stabilize the δ conformation sufficiently to allow it to compete with classical C5 and C7 H-bonded conformers.

This work aims to establish Sb mobility, its transfer to biota and its effect on soil health in a semi-arid climate. The results show the presence of stibnite (Sb 2 S 3 ) as the main primary Sb compound, bindhemite (Pb 2 Sb 2 O 6 (O,OH)), and minor proportions of stibiconite (Sb 3+ (Sb 5+ ) 2 O 6 (OH)) as oxidised Sb species. This research also observes very high total Sb contents in mining materials (max: 20,000 mg kg -1 ) and soils (400-3000 mg kg -1 ), with physical dispersion around mining materials restricted to 450 m. The soil-to-plant transfer is very low, (bioaccumulation factor: 0.0002-0.1520). Most Sb remains in a residual fraction (99.9%), a very low fraction is bound to Fe and Mn oxy-hydroxides or organic matter, and a negligible proportion of Sb is leachable. The higher Sb mobility rates has been found under oxidising conditions with a long contact time between solids and water. The main factors that explain the poor Sb mobility and dispersion in the mining area are the low annual rainfall rates that slow down the Sb mobilisation process and the scarce formation of oxidised Sb compounds. All these data suggest poor Sb (III) formation and a low toxicological risk in the area associated with past mining activities. The low mobility of Sb suggests advantages for future sustainable mining of such ore deposits in a semi-arid climate and is also indicative of the limitations of geochemical exploration in the search for new Sb deposits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microhydrated H 2 -tagged ion pairs (Ca 2+ , AcO - )(H 2 O) n =0-8 and (Ba 2+ , AcO - )(H 2 O) n =0-5 are investigated by IR photodissociation laser spectroscopy and DFT-D frequency calculations. The detailed picture of the first steps of ion dissociation reveals two mechanisms, where water molecules promote dissociation either directly or indirectly depending on the nature of the cation.

The side-chain of methionine residues is long enough to establish NH⋯S H-bonds with neighboring carbonyl groups of the backbone, giving rise to so-called intra-residue 6 δ and inter-residue 7 δ H-bonds. The aim of the present article is to document how the substitution of sulfur with a selenium atom affects the H-bonding of the Met system. This was investigated both experimentally and theoretically by conformation-resolved optical spectroscopy, following an isolated molecule approach. The present work emphasizes the similarities of the Met and Sem residues in terms of conformational structures, energetics, NH⋯Se/S H-bond strength and NH stretch spectral shifts, but also reveals subtle behavior differences between them. It provides evidence for the sensitivity of the H-bonding network with the folding type of the Sem/Met side-chains, where a simple flip of the terminal part of the side-chain can induce an extra 50 cm -1 spectral shift of the NH stretch engaged in a 7 δ NH⋯S/Se bond.

Models of asparagine-containing dipeptides specifically designed to favor intrinsic folding into an Asx turn were characterized both theoretically, by using quantum chemistry, and experimentally, by using laser spectroscopy in the gas phase. Both approaches provided evidence for the spontaneous folding of both the Asn-Ala and Asn-Gly dipeptide models into the most stable Asx turn, a conformation stabilized by a C10 H-bond that was very similar to a type II' β-turn. In parallel, analysis of Asx turns implicating asparagine in crystallized protein structures in the Protein Data Bank revealed a sequence-dependent behavior. In Asn-Ala sequences, the Asx turn was found in conjunction with a type I β-turn for which the first of the four defining residues was Asn. The observation that the Asx turn in these structures is mostly of type II' (i. e., its most stable innate structure) suggests that this motif might foster the formation and/or enhance the stability of the backbone β-turn. In contrast, the Asx turns observed in Asn-Gly sequences extensively adopted a type II Asx-turn structure, thus suggesting that their formation should be ascribed to other factors, such as hydration. The fact that the Asx turn in a Asn-Gly sequence is also often found in combination with a hydrated β-bulge supports the premise that a Asn-Gly sequence might efficiently promote the formation of the β-bulge secondary structure., (© 2022 Wiley-VCH GmbH.)