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OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.
Subject(s)
Autoantibodies , Biomarkers , Protein-Arginine N-Methyltransferases , Scleroderma, Systemic , Scleroderma, Systemic/immunology , Humans , Biomarkers/blood , Autoantibodies/blood , Autoantibodies/immunology , Protein-Arginine N-Methyltransferases/immunology , Animals , Mice , Female , Male , Middle Aged , Case-Control Studies , Adult , Lupus Erythematosus, Systemic/immunology , Immunoprecipitation/methods , Proteomics/methodsABSTRACT
A palladium-catalyzed carbohalogenation of olefins with alkynyl oxime ethers has been described, which provides efficient and practical access to various chlorine-containing isoxazoles. This method exhibits excellent regioselectivity, good functional group compatibility, and mild reaction conditions. The mechanistic studies suggest that the reaction proceeds via a stabilized π-benzyl palladium intermediate, which is essential for the formation of C(sp3)-Cl bonds.
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Heterogeneous palladium catalysts with high efficiency, high Pd atom utilization, simplified separation, and recycle have attracted considerable attention in the field of synthetic chemistry. Herein, we reported a zirconium-based two-dimensional metal-organic framework (2D-MOF)-based Pd(II) photocatalyst (Zr-Ir-Pd) by merging the Ir photosensitizers and Pd(II) species into the skeletons of the 2D-MOF for the Pd(II)-catalyzed oxidation reaction. Morphological and structural characterization identified that Zr-Ir-Pd with a specific nanoflower-like structure consists of ultrathin 2D-MOF nanosheets (3.85 nm). Due to its excellent visible-light response and absorption capability, faster transfer and separation of photogenerated carriers, more accessible Pd active sites, and low mass transfer resistance, Zr-Ir-Pd exhibited boosted photocatalytic activity in catalyzing sterically hindered isocyanide insertion of diarylalkynes for the construction of fused tetracyclic heterocycles, with up to 12 times the Pd catalyst turnover number than the existing catalytic systems. In addition, Zr-Ir-Pd inhibited the competitive agglomeration of Pd(0) species and could be reused at least five times, owing to the stabilization of 2D-MOF on the single-site Pd and Ir sites. Finally, a possible mechanism of the photocatalytic synthesis of fused tetracyclic heterocycles catalyzed by Zr-Ir-Pd was proposed.
ABSTRACT
Molecularly imprinted polymers, a type of special polymer materials, are widely used in biosensing and other fields due to their ability to specifically recognize target molecules, often called "artificial receptors.". Nowadays, researchers are constantly exploring new design and synthesis methods for molecularly imprinted materials to improve the selectivity and sensitivity of molecularly imprinted materials. Among them, the selection of functional monomers has attracted great attention. This review comprehensively analyzes and discusses the selection methods of functional monomers. The most commonly used functional monomers among different types of templates are screened based on the structural properties of the template molecules, including the selection of functional monomers among ion-imprinted polymers, protein-imprinted polymers, and bacterial imprinted polymers. The rich binding sites and functional group types of multifunctional monomers are also highlighted to advance the development of molecular imprinting technology. The article further explores the current challenges and prospects in the selection of functional monomers and emphasizes multiplex experiments and computer simulations as important directions for future research. This review provides comprehensive information and constructive guidelines for researchers in selecting functional monomers in areas such as analytical chemistry and biosensors.
Subject(s)
Molecular Imprinting , Molecularly Imprinted Polymers , Molecularly Imprinted Polymers/chemistry , Biosensing Techniques , Polymers/chemistryABSTRACT
Direct coupling of unactivated olefins with primary alkylamines is considered to be an efficient but unknown method for the construction of complex amines. Herein we report a catalytic intermolecular oxidative amination of unactivated olefins with primary aliphatic amines based on the combination of a palladium catalyst, a bidentate phosphine ligand, and duroquinone. A range of secondary allylic amines were obtained in good yields with excellent regio- and stereoselectivity. Mechanistic control experiments revealed that the reaction proceeds by allylic C(sp3)-H activation and nucleophilic amination. The utility of the protocol is further demonstrated with the late-stage modification and streamlined synthesis of drug molecules.
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The proposal of local differential privacy solves the problem that the data collector must be trusted in centralized differential privacy models. The statistical analysis of numerical data under local differential privacy has been widely studied by many scholars. However, in real-world scenarios, numerical data from the same category but in different ranges frequently require different levels of privacy protection. We propose a hierarchical aggregation framework for numerical data under local differential privacy. In this framework, the privacy data in different ranges are assigned different privacy levels and then disturbed hierarchically and locally. After receiving users' data, the aggregator perturbs the privacy data again to convert the low-level data into high-level data to increase the privacy data at each privacy level so as to improve the accuracy of the statistical analysis. Through theoretical analysis, it was proved that this framework meets the requirements of local differential privacy and that its final mean estimation result is unbiased. The proposed framework is combined with mini-batch stochastic gradient descent to complete the linear regression task. Sufficient experiments both on synthetic datasets and real datasets show that the framework has a higher accuracy than the existing methods in both mean estimation and mini-batch stochastic gradient descent experiments.
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INTRODUCTION: The impacts of education on cognitive decline across different neighborhood environments (NEs) have rarely been studied. METHODS: We investigated and compared the associations between educational attainment and cognitive decline using data of 1286 participants from the Taizhou Imaging Study (TIS) and the Shanghai Aging Study (SAS). RESULTS: Compared with low-educated participants, in TIS with disadvantaged NE, high-educated participants manifested a significantly slower decline in global cognition (.062 Z score per year, P < .001), memory (.054 Z score per year, P < .05), and attention (.065 Z score per year, P < .01), whereas in SAS with advanced NE, highly educated individuals exhibited a slower decline only in attention (.028 Z score per year, P < .05). DISCUSSION: We observed the additive effect of educational attainment and NE on cognitive decline in older adults. Education is especially important for maintaining cognitive health in a disadvantaged environment.
Subject(s)
Cognitive Dysfunction , Humans , Aged , Longitudinal Studies , Prospective Studies , China/epidemiology , Cognitive Dysfunction/epidemiology , Educational Status , Cognition , Neighborhood CharacteristicsABSTRACT
INTRODUCTION: Though consistent evidence suggests that physical activity may delay dementia onset, the duration and amount of activity required remains unclear. METHODS: We harmonized longitudinal data of 11,988 participants from 10 cohorts in eight countries to examine the dose-response relationship between late-life physical activity and incident dementia among older adults. RESULTS: Using no physical activity as a reference, dementia risk decreased with duration of physical activity up to 3.1 to 6.0 hours/week (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.67 to 1.15 for 0.1 to 3.0 hours/week; HR 0.68, 95% CI 0.52 to 0.89 for 3.1 to 6.0 hours/week), but plateaued with higher duration. For the amount of physical activity, a similar pattern of dose-response curve was observed, with an inflection point of 9.1 to 18.0 metabolic equivalent value (MET)-hours/week (HR 0.92, 95% CI 0.70 to 1.22 for 0.1 to 9.0 MET-hours/week; HR 0.70, 95% CI 0.53 to 0.93 for 9.1 to 18.0 MET-hours/week). DISCUSSION: This cross-national analysis suggests that performing 3.1 to 6.0 hours of physical activity and expending 9.1 to 18.0/MET-hours of energy per week may reduce dementia risk.
Subject(s)
Dementia , Humans , Aged , Cohort Studies , Proportional Hazards Models , Dementia/epidemiology , Risk FactorsABSTRACT
Multi-party quantum private comparison (MQPC) assumes responsibility for overseeing the flow of data and communication among diverse entities, wherein it boasts powerful security capabilities that have garnered substantial attention. Most current MQPC protocols rely on difficult-to-prepare quantum states and are inefficient in their use of resources. In this paper, we propose a novel MQPC protocol without entanglement swapping, thereby building upon the assumption of an ideal channel. This protocol is based on Bell states, which simplifies implementation and addresses the challenges associated with using complex quantum states; it also enables the comparison of secret information by having a trusted party prepare and transmit encoded quantum sequences to participants, thereby facilitating efficient equality comparison among all parties. Our MQPC protocol showcased remarkable efficiency in comparison to existing protocols for quantum private comparison. Furthermore, the incorporation of decoy photon and shared key technologies made external and internal attacks ineffective, thereby ensuring the utmost security and integrity of the protocol.
ABSTRACT
In this paper, we propose a secure multi-party summation based on single photons. With the help of a semi-honest third party, n participants can simultaneously obtain the summation result without revealing their secret inputs. Our protocol uses single photon states as the information carriers. In addition, each participant with secret input only performs simple single-particle operators rather than particle preparation and any complex quantum measurements. These features make our protocol more feasible to implement. We demonstrate the correctness and security of the proposed protocol, which is resistant to participant attack and outside attack. In the end, we compare in detail the performance of the quantum summation protocol in this paper with other schemes in terms of different indicators. By comparison, our protocol is efficient and easy to implement.
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BACKGROUND: Previous studies reported the value of blood-based biomarkers in predicting Alzheimer disease (AD) progression among individuals with different disease stages. However, evidence regarding the value of these markers in those with amnestic mild cognitive impairment (aMCI) is insufficient. METHODS: A cohort with 251 aMCI individuals were followed for up to 8 years. Baseline blood biomarkers were measured on a single-molecule array platform. Multipoint clinical diagnosis and domain-specific cognitive functions were assessed to investigate the longitudinal relationship between blood biomarkers and clinical AD progression. RESULTS: Individuals with low Aß42/Aß40 and high p-tau181 at baseline demonstrated the highest AD risk (hazard ratio = 4.83, 95% CI 2.37-9.86), and the most dramatic decline across cognitive domains. Aß42/Aß40 and p-tau181, combined with basic characteristics performed the best in predicting AD conversion (AUC = 0.825, 95% CI 0.771-0.878). CONCLUSIONS: Combining Aß42/Aß40 and p-tau181 may be a feasible indicator for AD progression in clinical practice, and a potential composite marker in clinical trials.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Humans , Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Cognitive Dysfunction/diagnosis , Peptide Fragments , Biomarkers , tau ProteinsABSTRACT
Palladium-catalyzed enantioselective cyclization of enynes has contributed significantly to the construction of chiral cyclic molecules. In contrast, the catalytic asymmetric cyclization involving halopalladation remains an unresolved challenge with the inevitable disturbance of the halide ions. Herein, an intramolecular chlorine transfer strategy is used to accomplish the enantioselective chloropalladation cyclization of 1,6-enynes. This reaction provides a redox-neutral approach to a variety of chiral α-chloromethylene-γ-butyrolactones with excellent E selectivity and enantioselectivity. The precisely controlled coordination of palladium with both the inâ situ generated nucleophilic species and the monodentate phosphoramidite ligand is crucial for enantioselectivity.
Subject(s)
Chlorine , Palladium , Cyclization , Stereoisomerism , Catalysis , HalogensABSTRACT
This report discloses a novel Pd-catalyzed sequential three-component multiple reaction of alkenes, bromoalkynes, and boronic acids using alkenes as hydride and alkenyl donors, leading to highly stereoselective assembly of (Z,E)-1,3-diene derivatives. Mechanistic studies demonstrate that the generation and reutilization of palladium hydride species are critical to the success of this transformation. In addition, the good functional group compatibility, late-stage modification, and investigation of photophysical properties of 1,3-diene products illustrate the synthetic value of this strategy.
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A new synthetic protocol for alicyclic[b]-fused pyridines with complete regioselectivity from α,ß-unsaturated N-acetyl hydrazones and vinyl azides via Pd(II)-catalyzed C-H activation/cyclization/aromatization strategy has been described. A series of five- to eight-membered alicyclic[b]-fused pyridines were prepared in a one-step manner with wide substrate scope and good functional group tolerance.
Subject(s)
Azides , Hydrazones , Catalysis , Cyclization , PyridinesABSTRACT
A crucial step in improving data quality is to discover semantic relationships between data. Functional dependencies are rules that describe semantic relationships between data in relational databases and have been applied to improve data quality recently. However, traditional functional discovery algorithms applied to distributed data may lead to errors and the inability to scale to large-scale data. To solve the above problems, we propose a novel distributed functional dependency discovery algorithm based on Apache Spark, which can effectively discover functional dependencies in large-scale data. The basic idea is to use data redistribution to discover functional dependencies in parallel on multiple nodes. In this algorithm, we take a sampling approach to quickly remove invalid functional dependencies and propose a greedy-based task assignment strategy to balance the load. In addition, the prefix tree is used to store intermediate computation results during the validation process to avoid repeated computation of equivalence classes. Experimental results on real and synthetic datasets show that the proposed algorithm in this paper is more efficient than existing methods while ensuring accuracy.
Subject(s)
Algorithms , Big DataABSTRACT
Herein, we present a direct and efficient synthesis of diverse polysubstituted fused tetracyclic heterocycles with good functional group tolerance from diarylalkynes under different palladium catalytic systems. In this chemistry, an unprecedented intermolecular nucleopalladation of diarylalkynes through the highly selective sequential double insertion of isocyanide was achieved for the first time. The practicality of this method was further demonstrated by the construction of various bioactive molecules and important structural motifs, with potential applications in materials science and biochemistry. In addition, density functional theory calculations (DFT) elucidated an interesting "Pd walk" during the cyclization process.
Subject(s)
Cyanides , Palladium , Catalysis , Cyanides/chemistry , Cyclization , Molecular Structure , Palladium/chemistryABSTRACT
A novel and expedient cascade strategy has been demonstrated for the synthesis of fused benzo-aza-oxa-[5-6-5] tetracycles in high yields and diastereoselectivities (up to 20 : 1 dr). The strategy was fulfilled through palladium-catalyzed oxidative convergent assembly of functionally divergent anilines and 3-butenoic acid with five chemical bonds constructed. Coupled with control experiments and deuterium labelled studies, DFT calculations were performed for the proposed mechanism. The utility of the illustrated strategy is emphasized by gram-scale syntheses, late-stage functionalization, and the transformation to a key core of natural products such as martinellic acid and seneciobipyrrolidine.
Subject(s)
Palladium , Palladium/chemistry , Catalysis , CyclizationABSTRACT
The abundance and type of immune cells in the tumor microenvironment (TME) significantly influence immunotherapy and tumor progression. However, the role of immune cells in the TME of gastric cancer (GC) is poorly understood. We studied the correlations, proportion, and infiltration of immune and stromal cells in GC tumors. Data analyses showed a significant association of infiltration levels of specific immune cells with the pathological characteristics and clinical outcomes of GC. Furthermore, based on the difference in infiltration levels of immune and stromal cells, GC patients were divided into two categories, those with "immunologically hot" (hot) tumors and those with "immunologically cold" (cold) tumors. The assay for transposase-accessible chromatin using sequencing and RNA sequencing analyses revealed that the hot and cold tumors had altered epigenomic and transcriptional profiles. Claudin-3 (CLDN3) was found to have high expression in the cold tumors and negatively correlated with CD8+ T cells in GC. Overexpression of CLDN3 in GC cells inhibited the expression of MHC-I and CXCL9. Finally, the differentially expressed genes between hot and cold tumors were utilized to generate a prognostic model, which predicted the overall survival of GC as well as patients with immunotherapy. Overall, we undertook a comprehensive analysis of the immune cell infiltration pattern in GC and provided an accurate model for predicting the prognosis of GC patients.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Claudin-3/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Signal Transduction/genetics , Stomach Neoplasms/immunology , Stomach Neoplasms/metabolism , Tumor Microenvironment/immunology , Biomarkers, Tumor/genetics , Cell Line, Tumor , Chemokine CXCL9/metabolism , Claudin-3/genetics , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Prognosis , RNA-Seq , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Transcriptome , TransfectionABSTRACT
BACKGROUND: The ultrasensitive detection of blood-based biomarkers such as amyloid ß (Aß), tau, and neurofilament light (NFL) has drawn much attention in Alzheimer disease (AD) diagnosis. However, few studies have been conducted in the Chinese population. This study aimed to evaluate the ability of plasma biomarker diagnostic models for AD in the Chinese population based on a novel digital immunoassay technology. METHODS: 159 patients with AD, 148 patients with amnestic mild cognitive impairment (aMCI), and 121 cognitively normal control participants were recruited from 2 cohorts. The concentrations of plasma Aß42, Aß40, Aß42/Aß40, total tau (t-tau), phosphorylated tau 181 (p-tau 181), and NFL were quantified using an ultrasensitive single molecule array (Simoa) platform. Comprehensive and simplified diagnostic models were established based on the plasma biomarker profile and clinical characteristics. RESULTS: Among all blood biomarkers, p-tau181 had the greatest potential for identifying patients with cognitive impairment. The simplified diagnostic model, which combined plasma p-tau181, Aß42, and clinical features, achieved 93.3% area under the curve (AUC), 78.6% sensitivity, and 94.2% specificity for distinguishing AD from control participants, indicating a diagnostic ability approaching that of the comprehensive diagnostic model including 5 plasma biomarkers and clinical characteristics (95.1% AUC, 85.5% sensitivity, 94.2% specificity). Moreover, the simplified model reached 95.9% AUC and 94.0% AUC for early- and late-onset AD/control participants, respectively. CONCLUSIONS: We established AD diagnostic models using plasma biomarkers for Chinese participants. These findings suggest the simplified diagnostic model provides an accessible and practical way for large-scale screening in the clinic and community, especially in developing countries.
Subject(s)
Alzheimer Disease , Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Biomarkers , China , Humans , Immunoassay , tau ProteinsABSTRACT
BACKGROUND: Gut microbiota (GMB) alteration has been reported to influence the Alzheimer's disease (AD) pathogenesis through immune, endocrine, and metabolic pathways. This study aims to investigate metabolic output of the dysbiosis of GMB in AD pathogenesis. In this study, the fecal microbiota and metabolome from 21 AD participants and 44 cognitively normal control participants were measured. Untargeted GMB taxa was analyzed through 16S ribosomal RNA gene profiling based on next-generation sequencing and fecal metabolites were quantified by using ultrahigh performance liquid chromatography-mass spectrometry (UPLC-MS). RESULTS: Our analysis revealed that AD was characterized by 15 altered gut bacterial genera, of which 46.7% (7/15 general) was significantly associated with a series of metabolite markers. The predicted metabolic profile of altered gut microbial composition included steroid hormone biosynthesis, N-Acyl amino acid metabolism and piperidine metabolism. Moreover, a combination of 2 gut bacterial genera (Faecalibacterium and Pseudomonas) and 4 metabolites (N-Docosahexaenoyl GABA, 19-Oxoandrost-4-ene-3,17-dione, Trigofoenoside F and 22-Angeloylbarringtogenol C) was able to discriminate AD from NC with AUC of 0.955 in these 65 subjects. CONCLUSIONS: These findings demonstrate that gut microbial alterations and related metabolic output changes may be associated with pathogenesis of AD, and suggest that fecal markers might be used as a non-invasive examination to assist screening and diagnosis of AD.