microbeMASST: a taxonomically informed mass spectrometry search tool for microbial metabolomics data.

microbeMASST, a taxonomically informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbe-derived metabolites and relative producers without a priori knowledge will vastly enhance the understanding of microorganisms' role in ecology and human health.

The 2023 Report on the Proteome from the HUPO Human Proteome Project.

Since 2010, the Human Proteome Project (HPP), the flagship initiative of the Human Proteome Organization (HUPO), has pursued two goals: (1) to credibly identify the protein parts list and (2) to make proteomics an integral part of multiomics studies of human health and disease. The HPP relies on international collaboration, data sharing, standardized reanalysis of MS data sets by PeptideAtlas and MassIVE-KB using HPP Guidelines for quality assurance, integration and curation of MS and non-MS protein data by neXtProt, plus extensive use of antibody profiling carried out by the Human Protein Atlas. According to the neXtProt release 2023-04-18, protein expression has now been credibly detected (PE1) for 18,397 of the 19,778 neXtProt predicted proteins coded in the human genome (93%). Of these PE1 proteins, 17,453 were detected with mass spectrometry (MS) in accordance with HPP Guidelines and 944 by a variety of non-MS methods. The number of neXtProt PE2, PE3, and PE4 missing proteins now stands at 1381. Achieving the unambiguous identification of 93% of predicted proteins encoded from across all chromosomes represents remarkable experimental progress on the Human Proteome parts list. Meanwhile, there are several categories of predicted proteins that have proved resistant to detection regardless of protein-based methods used. Additionally there are some PE1-4 proteins that probably should be reclassified to PE5, specifically 21 LINC entries and ∼30 HERV entries; these are being addressed in the present year. Applying proteomics in a wide array of biological and clinical studies ensures integration with other omics platforms as reported by the Biology and Disease-driven HPP teams and the antibody and pathology resource pillars. Current progress has positioned the HPP to transition to its Grand Challenge Project focused on determining the primary function(s) of every protein itself and in networks and pathways within the context of human health and disease.

Design and Modulation of Selectivity toward Vanadium(V) and Uranium(VI) Ions: Coordination Properties and Affinity of Hydroxylamino-Triazine Siderophores.

Based on the strong binding and high selectivity properties of 2,6-bis[hydroxy(methyl)amino]-4-morpholino-1,3,5-triazine (H2bihyat) for [UVIO2]2+, novel binucleating ligands (BLs) N,N',N″,N‴-((1,4-phenylenebis(oxy))bis(1,3,5-triazine-6,2,4-triyl))tetrakis(N-methylhydroxylamine) (H4qtn), N1,N4-bis(4,6-bis(hydroxy(methyl)amino)-1,3,5-triazin-2-yl)benzene-1,4-diamine (H4pdl), and N1,N2-bis(4,6-bis(hydroxy(methyl)amino)-1,3,5-triazin-2-yl)ethane-1,2-diamine (H4enl) were synthesized. Binuclear complexes formed by coordination of hard metal ions with H4qtn are thermodynamically more stable than their mononuclear analogues with H2bihyat due to the increase in entropy accompanying the formation of more chelate rings. Reaction of either H4qtn or H4pdl or H4enl with [UVIO2]2+ and [VVO2]+ resulted in the isolation of the binuclear complexes [(UVIO2)2(µ-qtn)(H2O)4] (1), [(VVO2)2(µ-qtn)][PPh4]2[PPh4] (2), [(UVIO2)2(µ-pdl)(H2O)2(MeOH)2] (3), [(VVO2)2(µ-pdl)][PPh4]2 (4), [(UVIO2)2(µ-enl)(H2O)4] (5), and [(VVO2)2(µ-enl)][PPh4]2 (6). The binuclear complexes 1-6 were characterized by single-crystal X-ray diffraction analysis in solid state and by NMR and ESI-MS in solution. The comparison of the coordination ability of the BLs with either pyridine-2,6-dicarboxylic acid (H2dipic) or H2bihyat or CO32- toward [UVIO2]2+ and [VVO2]+ was investigated by NMR and UV-vis spectroscopies and DFT theoretical calculations, revealing a superior performance of BLs. The selectivity of the BLs for [UVIO2]2+ over [VVO2]+ is decreased compared to that of H2bihyat but increases considerably at pH > 9 values. Formation of the mixed-metal binuclear species [UVIO2(µ-O)VVO2] influences the selectivity and dynamics of the reaction of H4qtn for [UVIO2]2+ and [VVO2]+ in aqueous solution. The results of this study provide crucial information for the ligand design and the development of stronger and more selective systems.

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data.

MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganisms' role in ecology and human health.

The inert pair effect on heavy noble gases: insights from radon tetroxide.

A quantum chemical survey of radon and xenon tetroxides (NgO4, Ng = Xe, Rn) is reported herein. The intermediate species, which are formed in their explosive decomposition back to their elemental states (Ng and O2), were also studied and their energetics were compared. While Td symmetric RnO4 has a minimum energy structure, its standard enthalpy of formation is 88.6 kJ mol-1 higher than for XeO4. The reason for this higher instability lies in what is known as the inert pair effect. This work establishes that the high-valent chemical trends of the sixth period of groups 13-15 are indeed extended to group 18.

Sulfur Dioxide Oxidation by Zinc and Zinc Oxide Nitrate/Nitrite Complexes in the Gas Phase: An Interplay between Redox-Active Ligands and Metal.

Different oxidative pathways of sulfur dioxide promoted by ZnO(NO3 )2 - , Zn(NO3 )2 - and Zn(NO2 )(NO3 )- are revealed by a joint investigation by mass spectrometry and theoretical calculations. The reactions are triggered by [Zn2+ -O- ⋅]+ or by the low-valence Zn+ through oxygen ion transfer or electron transfer to SO2 , respectively. The NOx - ligands intervene in the oxidation only when sulfur dioxide is converted to SO3 - or SO2 - , leading to the formation of zinc sulfate and zinc sulfite coordinated to nitrate or nitrite anions. Kinetic analyses show that the reactions are fast and efficient, and theory discloses the elementary steps, namely oxygen ion transfer, oxygen atom transfer and electron transfer, occurring through similar energy landscapes for the three reactive anions.

Proteomics Standards Initiative at Twenty Years: Current Activities and Future Work.

The Human Proteome Organization (HUPO) Proteomics Standards Initiative (PSI) has been successfully developing guidelines, data formats, and controlled vocabularies (CVs) for the proteomics community and other fields supported by mass spectrometry since its inception 20 years ago. Here we describe the general operation of the PSI, including its leadership, working groups, yearly workshops, and the document process by which proposals are thoroughly and publicly reviewed in order to be ratified as PSI standards. We briefly describe the current state of the many existing PSI standards, some of which remain the same as when originally developed, some of which have undergone subsequent revisions, and some of which have become obsolete. Then the set of proposals currently being developed are described, with an open call to the community for participation in the forging of the next generation of standards. Finally, we describe some synergies and collaborations with other organizations and look to the future in how the PSI will continue to promote the open sharing of data and thus accelerate the progress of the field of proteomics.

The ProteomeXchange consortium at 10 years: 2023 update.

Mass spectrometry (MS) is by far the most used experimental approach in high-throughput proteomics. The ProteomeXchange (PX) consortium of proteomics resources (http://www.proteomexchange.org) was originally set up to standardize data submission and dissemination of public MS proteomics data. It is now 10 years since the initial data workflow was implemented. In this manuscript, we describe the main developments in PX since the previous update manuscript in Nucleic Acids Research was published in 2020. The six members of the Consortium are PRIDE, PeptideAtlas (including PASSEL), MassIVE, jPOST, iProX and Panorama Public. We report the current data submission statistics, showcasing that the number of datasets submitted to PX resources has continued to increase every year. As of June 2022, more than 34 233 datasets had been submitted to PX resources, and from those, 20 062 (58.6%) just in the last three years. We also report the development of the Universal Spectrum Identifiers and the improvements in capturing the experimental metadata annotations. In parallel, we highlight that data re-use activities of public datasets continue to increase, enabling connections between PX resources and other popular bioinformatics resources, novel research and also new data resources. Finally, we summarise the current state-of-the-art in data management practices for sensitive human (clinical) proteomics data.

The 2022 Report on the Human Proteome from the HUPO Human Proteome Project.

The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 407 (93.2%) of the 19 750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, "A Function for Each Protein".

Hafnium(IV) Chemistry with Imide-Dioxime and Catecholate-Oxime Ligands: Unique {Hf5} and Metalloaromatic {Hf6}-Oxo Clusters Exhibiting Fluorescence.

Hafnium(IV) molecular species have gained increasing attention due to their numerous applications ranging from high-resolution nanolithography, heterogeneous catalysis, and electronics to the design of molecule-based building blocks in metal-organic frameworks (MOFs), with applications in gas separation, sorption, luminescence sensing, and interim storage of radioactive waste. Despite great potential, their chemistry is relatively underdeveloped. Here, we use strong chelators (2Z-6Z)-piperidine-2,6-dione (H3pidiox) and 2,3-dihydroxybenzaldehyde oxime (H3dihybo) to synthesize the first ever reported pentanuclear {Hf5/H3pidiox} and hexanuclear {Hf6/H3dihybo} clusters (HfOCs). The {Hf6} clusters adopt unique core structures [Hf6IV(µ3-O)2(µ-O)3] with a trigonal-prismatic arrangement of the six hafnium atoms and have been characterized via single-crystal X-ray diffraction analysis, UV-vis spectroscopy in the solid state, NMR, fluorescence spectroscopy, and high-resolution mass spectrometry in solution. One-dimensional (1D) and two-dimensional (2D) 1H NMR and mass spectroscopies reveal the exceptional thermodynamic stability of the HfOCs in solution. Interestingly, the conjunction of the oxime group with the catechol resulted in the remarkable reduction of the clusters' band gap, below 2.51 eV. Another prominent feature is the occurrence of pronounced metalloaromaticity of the triangular {Hf3} metallic component revealed by its NICSzz scan curve calculated by means of density functional theory (DFT). The NICSzz(1) value of -44.6 ppm is considerably higher than the -29.7 ppm found at the same level of theory for the benzene ring. Finally, we investigated the luminescence properties of the clusters where 1 emits light in the violet region despite the lack of fluorescence of the free H3pidiox ligand, whereas the {Hf6} 3 shifts the violet-emitting light of the H3dihybo to lower energy. DFT calculations show that this fluorescence behavior stems from ligand-centered molecular orbital transitions and that HfIV coordination has a modulating effect on the photophysics of these HfOCs. This work not only represents a significant milestone in the construction of stable low-band-gap multinuclear HfIV clusters with unique structural features and metal-centered aromaticity but also reveals the potential of Hf(IV) molecule-based materials with applications in sensing, catalysis, and electronic devices.

Enhancing SIM behaviour in a mononuclear tetrahedral [Co(N,N'-2-iminopyrrolyl)2] complex.

A new homoleptic Co(II) complex bearing two highly sterically congested 2-formiminopyrrolyl N,N'-chelating ligands is reported, displaying slow relaxation of the magnetisation at zero static (DC) field. This compound shows a large value for the zero-field splitting (ZFS) parameter D of -42.6(4) cm-1 leading to a spin-reversal energy barrier Ueff of 85 cm-1.

A new krypton complex - experimental and computational investigation of the krypton sulphur pentafluoride cation, [KrSF5]+, in the gas phase.

The gas-phase reactions of noble gas (Ng) cations, namely Kr+ and Xe+, with SF6 were investigated experimentally by Fourier transform ion cyclotron resonance mass spectrometry and computationally using RI-MP2 and BCCD(T) methods. The study revealed a new interaction between Kr+ and neutral SF6 that gave rise to a new cationic, weakly bound complex of Kr, [KrSF5]+, although the major reaction channel was dissociative electron transfer to yield SF5+ and {Kr, F}. Experimental studies examined the formation and stability of the new species and computational studies addressed the energetics of the reaction and indicated that [KrSF5]+ is stable by ca. 1 kcal mol-1. The same computational approach was used to examine the reaction of Xe+ with SF6 and showed it to be thermodynamically unfavourable by ca. 35 kcal mol-1, confirming the non-observation of reaction in the mass spectrometry experiments. An analysis of the bonding in [KrSF5]+ clearly showed that it is a non-covalently bound species, while in its presumed precursor [KrSF6]+ a partially covalent Kr-F bond is present.

Proteomics Standards Initiative's ProForma 2.0: Unifying the Encoding of Proteoforms and Peptidoforms.

It is important for the proteomics community to have a standardized manner to represent all possible variations of a protein or peptide primary sequence, including natural, chemically induced, and artifactual modifications. The Human Proteome Organization Proteomics Standards Initiative in collaboration with several members of the Consortium for Top-Down Proteomics (CTDP) has developed a standard notation called ProForma 2.0, which is a substantial extension of the original ProForma notation developed by the CTDP. ProForma 2.0 aims to unify the representation of proteoforms and peptidoforms. ProForma 2.0 supports use cases needed for bottom-up and middle-/top-down proteomics approaches and allows the encoding of highly modified proteins and peptides using a human- and machine-readable string. ProForma 2.0 can be used to represent protein modifications in a specified or ambiguous location, designated by mass shifts, chemical formulas, or controlled vocabulary terms, including cross-links (natural and chemical) and atomic isotopes. Notational conventions are based on public controlled vocabularies and ontologies. The most up-to-date full specification document and information about software implementations are available at http://psidev.info/proforma.

Experimental and Computational Study of a Tetraazamacrocycle Bis(aryloxide) Uranyl Complex and of the Analogues {E═U═NR}2+ (E = O and NR).

The reaction of [U(κ6-{(t-Bu2ArO)2Me2-cyclam})I][I] (H2{(t-Bu2ArO)2Me2-cyclam} = 1,8-bis(2-hydroxy-3,5-di-tert-butyl)-4,11-dimethyl-1,4,8,11-tetraazacyclotetradecane) with 2 equiv of NaNO2 in acetonitrile results in the isolation of the uranyl complex [UO2{(t-Bu2ArO)2Me2-cyclam}] (3) in 31% yield, which was fully characterized, including by single-crystal X-ray diffraction. Density functional theory (DFT) computations were performed to evaluate and compare the level of covalency within the U═E bonds in 3 and in the analogous trans-bis(imido) [U(κ4-{(t-Bu2ArO)2Me2-cyclam})(NPh)2] (1) and trans-oxido-imido [U(κ4-{(t-Bu2ArO)2Me2-cyclam})(O)(NPh)] (2) complexes. Natural bond orbital (NBO) analysis allowed us to determine the mixing covalency parameter λ, showing that in 2, where both U-Ooxido and U-Nimido bonds are present, the U-Nimido bond registers more covalency with regard to 1, and the opposite is seen for U-Ooxido with respect to 3. However, the covalency driven by orbital overlap in the U-Nimido bond is slightly higher in 1 than in 2. The 15N-labeled complexes [U(κ4-{(t-Bu2ArO)2Me2-cyclam})(15NPh)2] (1-15N) and [U(κ4-{(t-Bu2ArO)2Me2-cyclam})(O)(15NPh)] (2-15N) were prepared and analyzed by solution 15N NMR spectroscopy. The calculated and experimental 15N chemical shifts are in good agreement, displaying the same trend of δN (1-15N) > δN (2-15N) and reveal that the 15N chemical shift may serve as a probe for the covalency of the U═NR bond.

NPOmix: A machine learning classifier to connect mass spectrometry fragmentation data to biosynthetic gene clusters.

Microbial specialized metabolites are an important source of and inspiration for many pharmaceuticals, biotechnological products and play key roles in ecological processes. Untargeted metabolomics using liquid chromatography coupled with tandem mass spectrometry is an efficient technique to access metabolites from fractions and even environmental crude extracts. Nevertheless, metabolomics is limited in predicting structures or bioactivities for cryptic metabolites. Efficiently linking the biosynthetic potential inferred from (meta)genomics to the specialized metabolome would accelerate drug discovery programs by allowing metabolomics to make use of genetic predictions. Here, we present a k-nearest neighbor classifier to systematically connect mass spectrometry fragmentation spectra to their corresponding biosynthetic gene clusters (independent of their chemical class). Our new pattern-based genome mining pipeline links biosynthetic genes to metabolites that they encode for, as detected via mass spectrometry from bacterial cultures or environmental microbiomes. Using paired datasets that include validated genes-mass spectral links from the Paired Omics Data Platform, we demonstrate this approach by automatically linking 18 previously known mass spectra (17 for which the biosynthesis gene clusters can be found at the MIBiG database plus palmyramide A) to their corresponding previously experimentally validated biosynthetic genes (e.g., via nuclear magnetic resonance or genetic engineering). We illustrated a computational example of how to use our Natural Products Mixed Omics (NPOmix) tool for siderophore mining that can be reproduced by the users. We conclude that NPOmix minimizes the need for culturing (it worked well on microbiomes) and facilitates specialized metabolite prioritization based on integrative omics mining.

A proteomics sample metadata representation for multiomics integration and big data analysis.

The amount of public proteomics data is rapidly increasing but there is no standardized format to describe the sample metadata and their relationship with the dataset files in a way that fully supports their understanding or reanalysis. Here we propose to develop the transcriptomics data format MAGE-TAB into a standard representation for proteomics sample metadata. We implement MAGE-TAB-Proteomics in a crowdsourcing project to manually curate over 200 public datasets. We also describe tools and libraries to validate and submit sample metadata-related information to the PRIDE repository. We expect that these developments will improve the reproducibility and facilitate the reanalysis and integration of public proteomics datasets.

Progress Identifying and Analyzing the Human Proteome: 2021 Metrics from the HUPO Human Proteome Project.

The 2021 Metrics of the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 357 (92.8%) of the 19 778 predicted proteins coded in the human genome, a gain of 483 since 2020 from reports throughout the world reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 478 to 1421. This represents remarkable progress on the proteome parts list. The utilization of proteomics in a broad array of biological and clinical studies likewise continues to expand with many important findings and effective integration with other omics platforms. We present highlights from the Immunopeptidomics, Glycoproteomics, Infectious Disease, Cardiovascular, Musculo-Skeletal, Liver, and Cancers B/D-HPP teams and from the Knowledgebase, Mass Spectrometry, Antibody Profiling, and Pathology resource pillars, as well as ethical considerations important to the clinical utilization of proteomics and protein biomarkers.

New Insights on the Interaction of Phenanthroline Based Ligands and Metal Complexes and Polyoxometalates with Duplex DNA and G-Quadruplexes.

This work provides new insights from our team regarding advances in targeting canonical and non-canonical nucleic acid structures. This modality of medical treatment is used as a form of molecular medicine specifically against the growth of cancer cells. Nevertheless, because of increasing concerns about bacterial antibiotic resistance, this medical strategy is also being explored in this field. Up to three strategies for the use of DNA as target have been studied in our research lines during the last few years: (1) the intercalation of phenanthroline derivatives with duplex DNA; (2) the interaction of metal complexes containing phenanthroline with G-quadruplexes; and (3) the activity of Mo polyoxometalates and other Mo-oxo species as artificial phosphoesterases to catalyze the hydrolysis of phosphoester bonds in DNA. We demonstrate some promising computational results concerning the favorable interaction of these small molecules with DNA that could correspond to cytotoxic effects against tumoral cells and microorganisms. Therefore, our results open the door for the pharmaceutical and medical applications of the compounds we propose.