Palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions.

Asymmetric hydrogenation of esters through homogeneous catalysis is a significantly important transformation in organic synthesis. The systems developed so far mainly focused on chiral iridium and ruthenium catalysts, which required a base to facilitate the activity. Herein, we present a palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions through dynamic kinetic resolution and kinetic resolution. The reaction exhibits high enantioselectivity and excellent functional group tolerance. Remarkably, the hydrogenation proceeds smoothly at the gram scale, and the products can be transformed into several chiral potential building blocks without loss of optical purity. This work provides a new strategy for asymmetric hydrogenation of esters under base-free conditions.

A predictive study of the efficacy of transcutaneous auricular vagus nerve stimulation in the treatment of major depressive disorder: An fMRI-based machine learning analysis.

BACKGROUND: In order to improve taVNS efficacy, the usage of fMRI to explore the predictive neuroimaging markers would be beneficial for screening the appropriate MDD population before treatment. METHODS: A total of 86 MDD patients were recruited in this study, and all subjects were conducted with the clinical scales and resting-state functional magnetic resonance imaging (fMRI) scan before and after 8 weeks' taVNS treatment. A two-stage feature selection strategy combining Machine Learning and Statistical was used to screen out the critical brain functional connections (FC) that were significantly associated with efficacy prediction, then the efficacy prediction model was constructed for taVNS treating MDD. Finally, the model was validated by separated the responding and non-responding patients. RESULTS: This study showed that taVNS produced promising clinical efficacy in the treatment of mild and moderate MDD. Eleven FCs were selected out and were found to be associated with the cortico-striatal-pallidum-thalamic loop, the hippocampus and cerebellum and the HAMD-17 scores. The prediction model was created based on these FCs for the efficacy prediction of taVNS treatment. The R-square of the conducted regression model for predicting HAMD-17 reduction rate is 0.44, and the AUC for classifying the responding and non-responding patients is 0.856. CONCLUSION: The study demonstrates the validity and feasibility of combining neuroimaging and machine learning techniques to predict the efficacy of taVNS on MDD, and provides an effective solution for personalized and precise treatment for MDD.

How Much Storage Precision Can Be Lost: Guidance for Near-Lossless Compression of Untargeted Metabolomics Mass Spectrometry Data.

Several lossy compressors have achieved superior compression rates for mass spectrometry (MS) data at the cost of storage precision. Currently, the impacts of precision losses on MS data processing have not been thoroughly evaluated, which is critical for the future development of lossy compressors. We first evaluated different storage precision (32 bit and 64 bit) in lossless mzML files. We then applied 10 truncation transformations to generate precision-lossy files: five relative errors for intensities and five absolute errors for m/z values. MZmine3 and XCMS were used for feature detection and GNPS for compound annotation. Lastly, we compared Precision, Recall, F1 - score, and file sizes between lossy files and lossless files under different conditions. Overall, we revealed that the discrepancy between 32 and 64 bit precision was under 1%. We proposed an absolute m/z error of 10-4 and a relative intensity error of 2 × 10-2, adhering to a 5% error threshold (F1 - scores above 95%). For a stricter 1% error threshold (F1 - scores above 99%), an absolute m/z error of 2 × 10-5 and a relative intensity error of 2 × 10-3 were advised. This guidance aims to help researchers improve lossy compression algorithms and minimize the negative effects of precision losses on downstream data processing.

Miniature mass spectrometer-based point-of-care assay for quantification of metformin and sitagliptin in human blood and urine.

Metformin (MET) and sitagliptin (STG) are widely used as the first-line and long-term oral hypoglycemic agents for managing type 2 diabetes mellitus (T2DM). However, the current lack of convenient and rapid measurement methods poses a challenge for individualized management. This study developed a point-of-care (POC) assay method utilizing a miniature mass spectrometer, enabling rapid and accurate quantification of MET and STG concentrations in human blood and urine. By combining the miniature mass spectrometer with paper spray ionization, this method simplifies the process into three to four steps, requires minimal amounts of bodily fluids (50 µL of blood and 2 µL of urine), and is able to obtain quantification results within approximately 2 min. Stable isotope-labeled internal standards were employed to enhance the accuracy and stability of measurement. The MS/MS responses exhibited good linear relationship with concentration, with relative standard deviations (RSDs) below 25%. It has the potential to provide immediate treatment feedback and decision support for patients and healthcare professionals in clinical practice.

Ion entropy and accurate entropy-based FDR estimation in metabolomics.

Accurate metabolite annotation and false discovery rate (FDR) control remain challenging in large-scale metabolomics. Recent progress leveraging proteomics experiences and interdisciplinary inspirations has provided valuable insights. While target-decoy strategies have been introduced, generating reliable decoy libraries is difficult due to metabolite complexity. Moreover, continuous bioinformatics innovation is imperative to improve the utilization of expanding spectral resources while reducing false annotations. Here, we introduce the concept of ion entropy for metabolomics and propose two entropy-based decoy generation approaches. Assessment of public databases validates ion entropy as an effective metric to quantify ion information in massive metabolomics datasets. Our entropy-based decoy strategies outperform current representative methods in metabolomics and achieve superior FDR estimation accuracy. Analysis of 46 public datasets provides instructive recommendations for practical application.

MRMPro: a web-based tool to improve the speed of manual calibration for multiple reaction monitoring data analysis by mass spectrometry.

BACKGROUND: As a gold-standard quantitative technique based on mass spectrometry, multiple reaction monitoring (MRM) has been widely used in proteomics and metabolomics. In the analysis of MRM data, as no peak picking algorithm can achieve perfect accuracy, manual inspection is necessary to correct the errors. In large cohort analysis scenarios, the time required for manual inspection is often considerable. Apart from the commercial software that comes with mass spectrometers, the open-source and free software Skyline is the most popular software for quantitative omics. However, this software is not optimized for manual inspection of hundreds of samples, the interactive experience also needs to be improved. RESULTS: Here we introduce MRMPro, a web-based MRM data analysis platform for efficient manual inspection. MRMPro supports data analysis of MRM and schedule MRM data acquired by mass spectrometers of mainstream vendors. With the goal of improving the speed of manual inspection, we implemented a collaborative review system based on cloud architecture, allowing multiple users to review through browsers. To reduce bandwidth usage and improve data retrieval speed, we proposed a MRM data compression algorithm, which reduced data volume by more than 60% and 80% respectively compared to vendor and mzML format. To improve the efficiency of manual inspection, we proposed a retention time drift estimation algorithm based on similarity of chromatograms. The estimated retention time drifts were then used for peak alignment and automatic EIC grouping. Compared with Skyline, MRMPro has higher quantification accuracy and better manual inspection support. CONCLUSIONS: In this study, we proposed MRMPro to improve the usability of manual calibration for MRM data analysis. MRMPro is free for non-commercial use. Researchers can access MRMPro through http://mrmpro.csibio.com/ . All major mass spectrometry formats (wiff, raw, mzML, etc.) can be analyzed on the platform. The final identification results can be exported to a common.xlsx format for subsequent analysis.

Injectiondesign: web service of plate design with optimized stratified block randomization for modern GC/LC-MS-based sample preparation.

BACKGROUND: Plate design is a necessary and time-consuming operation for GC/LC-MS-based sample preparation. The implementation of the inter-batch balancing algorithm and the intra-batch randomization algorithm can have a significant impact on the final results. For researchers without programming skills, a stable and efficient online service for plate design is necessary. RESULTS: Here we describe InjectionDesign, a free online plate design service focused on GC/LC-MS-based multi-omics experiment design. It offers the ability to separate the position design from the sequence design, making the output more compatible with the requirements of a modern mass spectrometer-based laboratory. In addition, it has implemented an optimized block randomization algorithm, which can be better applied to sample stratification with block randomization for an unbalanced distribution. It is easy to use, with built-in support for common instrument models and quick export to a worksheet. CONCLUSIONS: InjectionDesign is an open-source project based on Java. Researchers can get the source code for the project from Github: https://github.com/CSi-Studio/InjectionDesign . A free web service is also provided: http://www.injection.design .

Column storage enables edge computation of biological big data on 5G networks.

With the continuous improvement of biological detection technology, the scale of biological data is also increasing, which overloads the central-computing server. The use of edge computing in 5G networks can provide higher processing performance for large biological data analysis, reduce bandwidth consumption and improve data security. Appropriate data compression and reading strategy becomes the key technology to implement edge computing. We introduce the column storage strategy into mass spectrum data so that part of the analysis scenario can be completed by edge computing. Data produced by mass spectrometry is a typical biological big data based. A blood sample analysed by mass spectrometry can produce a 10 gigabytes digital file. By introducing the column storage strategy and combining the related prior knowledge of mass spectrometry, the structure of the mass spectrum data is reorganized, and the result file is effectively compressed. Data can be processed immediately near the scientific instrument, reducing the bandwidth requirements and the pressure of the central server. Here, we present Aird-Slice, a mass spectrum data format using the column storage strategy. Aird-Slice reduces volume by 48% compared to vendor files and speeds up the critical computational step of ion chromatography extraction by an average of 116 times over the test dataset. Aird-Slice provides the ability to analyze biological data using an edge computing architecture on 5G networks.

G-Aligner: a graph-based feature alignment method for untargeted LC-MS-based metabolomics.

BACKGROUND: Liquid chromatography-mass spectrometry is widely used in untargeted metabolomics for composition profiling. In multi-run analysis scenarios, features of each run are aligned into consensus features by feature alignment algorithms to observe the intensity variations across runs. However, most of the existing feature alignment methods focus more on accurate retention time correction, while underestimating the importance of feature matching. None of the existing methods can comprehensively consider feature correspondences among all runs and achieve optimal matching. RESULTS: To comprehensively analyze feature correspondences among runs, we propose G-Aligner, a graph-based feature alignment method for untargeted LC-MS data. In the feature matching stage, G-Aligner treats features and potential correspondences as nodes and edges in a multipartite graph, considers the multi-run feature matching problem an unbalanced multidimensional assignment problem, and provides three combinatorial optimization algorithms to find optimal matching solutions. In comparison with the feature alignment methods in OpenMS, MZmine2 and XCMS on three public metabolomics benchmark datasets, G-Aligner achieved the best feature alignment performance on all the three datasets with up to 9.8% and 26.6% increase in accurately aligned features and analytes, and helped all comparison software obtain more accurate results on their self-extracted features by integrating G-Aligner to their analysis workflow. G-Aligner is open-source and freely available at https://github.com/CSi-Studio/G-Aligner under a permissive license. Benchmark datasets, manual annotation results, evaluation methods and results are available at https://doi.org/10.5281/zenodo.8313034 CONCLUSIONS: In this study, we proposed G-Aligner to improve feature matching accuracy for untargeted metabolomics LC-MS data. G-Aligner comprehensively considered potential feature correspondences between all runs, converting the feature matching problem as a multidimensional assignment problem (MAP). In evaluations on three public metabolomics benchmark datasets, G-Aligner achieved the highest alignment accuracy on manual annotated and popular software extracted features, proving the effectiveness and robustness of the algorithm.

Palladium-catalyzed stereoselective construction of chiral allenes bearing nonadjacent axial and two central chirality.

It is challenging to enantioselectively construct molecules bearing multiple nonadjacent stereocenters, in contrast to those bearing a single stereocenter or adjacent stereocenters. Herein, we report an enantio- and diastereoselective synthesis of substituted chiral allenes with nonadjacent axial and two central chiral centers through a combination of retro-oxa-Michael addition and palladium-catalyzed asymmetric allenylic alkylation. This methodology exhibits good functional-group compatibility, and the corresponding allenylic alkylated compounds, including flavonoid frameworks, are obtained with good yields and diastereoselectivities and excellent enantioselectivities (all >95% ee). Furthermore, the scalability of the current synthetic protocol was proven by performing a gram-scale reaction.

Diarylborinic Acid-Catalyzed Ring Opening of cis-4-Hydroxymethyl-1,2-Cyclopentene Oxides: Synthesis of 1,2,4-Trisubstituted Cyclopentanes.

A diarylborinic acid-catalyzed ring opening of cis-4-hydroxymethyl-1,2-cyclopentene oxides was developed with N-nucleophiles including anilines, benzotriazole, and alkylamines, as well as S-nucleophiles, affording 1,2,4-trisubstituted cyclopentane compounds containing a quaternary carbon center. The mechanism study indicated that the "half-cage" structure formed by the epoxide substrate and the catalyst prevents the nucleophiles from attacking the inner side of the "half-cage", resulting in the desired ring-opening product.

MetaPro: a web-based metabolomics application for LC-MS data batch inspection and library curation.

INTRODUCTION: Metabolomics analysis based on liquid chromatography-mass spectrometry (LC-MS) has been a prevalent method in the metabolic field. However, accurately quantifying all the metabolites in large metabolomics sample cohorts is challenging. The analysis efficiency is restricted by the abilities of software in many labs, and the lack of spectra for some metabolites also hinders metabolite identification. OBJECTIVES: Develop software that performs semi-targeted metabolomics analysis with an optimized workflow to improve quantification accuracy. The software also supports web-based technologies and increases laboratory analysis efficiency. A spectral curation function is provided to promote the prosperity of homemade MS/MS spectral libraries in the metabolomics community. METHODS: MetaPro is developed based on an industrial-grade web framework and a computation-oriented MS data format to improve analysis efficiency. Algorithms from mainstream metabolomics software are integrated and optimized for more accurate quantification results. A semi-targeted analysis workflow is designed based on the concept of combining artificial judgment and algorithm inference. RESULTS: MetaPro supports semi-targeted analysis workflow and functions for fast QC inspection and self-made spectral library curation with easy-to-use interfaces. With curated authentic or high-quality spectra, it can improve identification accuracy using different peak identification strategies. It demonstrates practical value in analyzing large amounts of metabolomics samples. CONCLUSION: We offer MetaPro as a web-based application characterized by fast batch QC inspection and credible spectral curation towards high-throughput metabolomics data. It aims to resolve the analysis difficulty in semi-targeted metabolomics.

Palladium-catalyzed asymmetric allenylic alkylation: construction of multiple chiral thiochromanone derivatives.

The development of a new strategy for the construction of chiral cyclic sulfide-containing multiple stereogenic centers is highly desirable. Herein, by the combination of base-promoted retro-sulfa-Michael addition and palladium-catalyzed asymmetric allenylic alkylation, the streamlined synthesis of chiral thiochromanones containing two central chiralities (including a quaternary stereogenic center) and an axial chirality (allene unit) was successfully realized with up to 98% yield, 49.0 : 1 dr and >99% ee.

3D-MSNet: a point cloud-based deep learning model for untargeted feature detection and quantification in profile LC-HRMS data.

MOTIVATION: Liquid chromatography coupled with high-resolution mass spectrometry is widely used in composition profiling in untargeted metabolomics research. While retaining complete sample information, mass spectrometry (MS) data naturally have the characteristics of high dimensionality, high complexity, and huge data volume. In mainstream quantification methods, none of the existing methods can perform direct 3D analysis on lossless profile MS signals. All software simplify calculations by dimensionality reduction or lossy grid transformation, ignoring the full 3D signal distribution of MS data and resulting in inaccurate feature detection and quantification. RESULTS: On the basis that the neural network is effective for high-dimensional data analysis and can discover implicit features from large amounts of complex data, in this work, we propose 3D-MSNet, a novel deep learning-based model for untargeted feature extraction. 3D-MSNet performs direct feature detection on 3D MS point clouds as an instance segmentation task. After training on a self-annotated 3D feature dataset, we compared our model with nine popular software (MS-DIAL, MZmine 2, XCMS Online, MarkerView, Compound Discoverer, MaxQuant, Dinosaur, DeepIso, PointIso) on two metabolomics and one proteomics public benchmark datasets. Our 3D-MSNet model outperformed other software with significant improvement in feature detection and quantification accuracy on all evaluation datasets. Furthermore, 3D-MSNet has high feature extraction robustness and can be widely applied to profile MS data acquired with various high-resolution mass spectrometers with various resolutions. AVAILABILITY AND IMPLEMENTATION: 3D-MSNet is an open-source model and is freely available at https://github.com/CSi-Studio/3D-MSNet under a permissive license. Benchmark datasets, training dataset, evaluation methods, and results are available at https://doi.org/10.5281/zenodo.6582912.

Palladium-Catalyzed Asymmetric Hydrogenolysis of Aryl Triflates for Construction of Axially Chiral Biaryls.

Here we report the first palladium-catalyzed asymmetric hydrogenolysis of readily available aryl triflates via desymmetrization and kinetic resolution for facile construction of axially chiral biaryl scaffolds with excellent enantioselectivities and s selectivity factors. The axially chiral monophosphine ligands could be prepared from these chiral biaryl compounds and were further applied to palladium-catalyzed asymmetric allylic alkylation with excellent ee values and high branched and linear ratio, which demonstrated the potential utility of this methodology.

Rhodium-Catalyzed Asymmetric Hydrogenation of All-Carbon Aromatic Rings.

Compared with heteroarenes, homogeneous asymmetric hydrogenation of all-carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine-catalyzed asymmetric hydrogenation of all-carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central-chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group. The key to success is the introduction of chiral diphosphine ligands with steric hindrance and strong electron-donating properties. The axially chiral monophosphine ligands could be obtained by simple conversion of the hydrogenation products bearing the phosphine atom.

Asymmetric Transfer Hydrogenation of 2,3-Disubstituted Flavanones through Dynamic Kinetic Resolution Enabled by Retro-Oxa-Michael Addition: Construction of Three Contiguous Stereogenic Centers.

A ruthenium-catalyzed asymmetric transfer hydrogenation of 2,3-disubstituted flavanones was developed for the construction of three contiguous stereocenters under basic conditions through a combination of dynamic kinetic resolution and retro-oxa-Michael addition, giving chiral flavanols with excellent enantioselectivities and diastereoselectivities. The reaction proceeded via a base-catalyzed retro-oxa-Michael addition to racemize two stereogenic centers simultaneously in concert with a highly enantioselective ketone transfer hydrogenation step. The asymmetric transfer hydrogenation could be achieved at gram scale without loss of the activity and enantioselectivity.

StackZDPD: a novel encoding scheme for mass spectrometry data optimized for speed and compression ratio.

As the pervasive, standardized format for interchange and deposition of raw mass spectrometry (MS) proteomics and metabolomics data, text-based mzML is inefficiently utilized on various analysis platforms due to its sheer volume of samples and limited read/write speed. Most research on compression algorithms rarely provides flexible random file reading scheme. Database-developed solution guarantees the efficiency of random file reading, but nevertheless the efforts in compression and third-party software support are insufficient. Under the premise of ensuring the efficiency of decompression, we propose an encoding scheme "Stack-ZDPD" that is optimized for storage of raw MS data, designed for the format "Aird", a computation-oriented format with fast accessing and decoding time, where the core compression algorithm is "ZDPD". Stack-ZDPD reduces the volume of data stored in mzML format by around 80% or more, depending on the data acquisition pattern, and the compression ratio is approximately 30% compared to ZDPD for data generated using Time of Flight technology. Our approach is available on AirdPro, for file conversion and the Java-API Aird-SDK, for data parsing.