The kinase CK1ɛ controls the antiviral immune response by phosphorylating the signaling adaptor TRAF3.

The signaling adaptor TRAF3 is a highly versatile regulator of both innate immunity and adaptive immunity, but how its phosphorylation is regulated is still unknown. Here we report that deficiency in or inhibition of the conserved serine-threonine kinase CK1ɛ suppressed the production of type I interferon in response to viral infection. CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3. Consequently, CK1ɛ-deficient mice were more susceptible to viral infection. Our findings establish CK1ɛ as a regulator of antiviral innate immune responses and indicate a novel mechanism of immunoregulation that involves CK1ɛ-mediated phosphorylation of TRAF3.

Generation of a Deep Mouse Brain Spectral Library for Transmembrane Proteome Profiling in Mental Disease Models.

Transmembrane (TM) proteins constitute over 30% of the mammalian proteome and play essential roles in mediating cell-cell communication, synaptic transmission, and plasticity in the central nervous system. Many of these proteins, especially the G protein-coupled receptors (GPCRs), are validated or candidate drug targets for therapeutic development for mental diseases, yet their expression profiles are underrepresented in most global proteomic studies. Herein, we establish a brain TM protein-enriched spectral library based on 136 data-dependent acquisition runs acquired from various brain regions of both naïve mice and mental disease models. This spectral library comprises 3043 TM proteins including 171 GPCRs, 231 ion channels, and 598 transporters. Leveraging this library, we analyzed the data-independent acquisition data from different brain regions of two mouse models exhibiting depression- or anxiety-like behaviors. By integrating multiple informatics workflows and library sources, our study significantly expanded the mental stress-perturbed TM proteome landscape, from which a new GPCR regulator of depression was verified by in vivo pharmacological testing. In summary, we provide a high-quality mouse brain TM protein spectral library to largely increase the TM proteome coverage in specific brain regions, which would catalyze the discovery of new potential drug targets for the treatment of mental disorders.

Leveraging trans-ethnic genetic risk scores to improve association power for complex traits in underrepresented populations.

Trans-ethnic genome-wide association studies have revealed that many loci identified in European populations can be reproducible in non-European populations, indicating widespread trans-ethnic genetic similarity. However, how to leverage such shared information more efficiently in association analysis is less investigated for traits in underrepresented populations. We here propose a statistical framework, trans-ethnic genetic risk score informed gene-based association mixed model (GAMM), by hierarchically modeling single-nucleotide polymorphism effects in the target population as a function of effects of the same trait in well-studied populations. GAMM powerfully integrates genetic similarity across distinct ancestral groups to enhance power in understudied populations, as confirmed by extensive simulations. We illustrate the usefulness of GAMM via the application to 13 blood cell traits (i.e. basophil count, eosinophil count, hematocrit, hemoglobin concentration, lymphocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, monocyte count, neutrophil count, platelet count, red blood cell count and total white blood cell count) in Africans of the UK Biobank (n = 3204) while utilizing genetic overlap shared in Europeans (n = 746 667) and East Asians (n = 162 255). We discovered multiple new associated genes, which had otherwise been missed by existing methods, and revealed that the trans-ethnic information indirectly contributed much to the phenotypic variance. Overall, GAMM represents a flexible and powerful statistical framework of association analysis for complex traits in underrepresented populations by integrating trans-ethnic genetic similarity across well-studied populations, and helps attenuate health inequities in current genetics research for people of minority populations.

In-Depth Profiling of 4-Hydroxy-2-nonenal Modification via Reversible Thiazolidine Chemistry.

Protein modification by lipid-derived electrophiles (LDEs) is associated with various signaling pathways. Among these LDEs, 4-hydroxy-2-nonenal (HNE) is the most toxic, and protein modified with HNE has been linked to various diseases, including Alzheimer's and Parkinson's. However, due to their low abundance, in-depth profiling of HNE modifications still presents challenges. This study introduces a novel strategy utilizing reversible thiazolidine chemistry to selectively capture HNE-modified proteins and a palladium-mediated cleavage reaction to release them. Thousands of HNE-modified sites in different cell lines were identified. Combined with ABPP, we discovered a set of HNE-sensitive sites that offer a new tool for studying LDE modifications in proteomes.

O-GlycoIsoQuant: A Novel O-Glycome Quantitative Approach through Superbase Release and Isotopic Girard's P Labeling.

Quantitative glycosylation analysis serves as an effective tool for detecting changes in glycosylation patterns in cancer and various diseases. However, compared with N-glycans, O-glycans present challenges in both qualitative and quantitative mass spectrometry analysis due to their low abundance, ease of peeling, lack of a universal enzyme, and difficult accessibility. To address this challenge, we developed O-GlycoIsoQuant, a novel O-glycome quantitative approach utilizing superbase release and isotopic Girard's P labeling. This method facilitates rapid and efficient nonreducing ß-elimination to dissociate O-glycans from proteins using the organic superbase, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), combined with light and heavy isotopic Girard's reagent P (GP) labeling for relative quantification of O-glycans by mass spectrometry. Employing this method, labeled O-glycans exhibit a double peak with a mass difference of 5 Da, suitable for stable relative quantification. The O-GlycoIsoQuant method is characterized by its high labeling efficiency, excellent reproducibility (CV < 20%), and good linearity (R2 > 0.99), across a dynamic range spanning a 100-fold range. This method was applied to various complex sample types, including human serum, porcine spermatozoa, human saliva, and urinary extracellular vesicles, detecting 33, 39, 49, and 37 O-glycans, respectively, thereby demonstrating its broad applicability.

Identifying pleiotropic genes for complex phenotypes with summary statistics from a perspective of composite null hypothesis testing.

Pleiotropy has important implication on genetic connection among complex phenotypes and facilitates our understanding of disease etiology. Genome-wide association studies provide an unprecedented opportunity to detect pleiotropic associations; however, efficient pleiotropy test methods are still lacking. We here consider pleiotropy identification from a methodological perspective of high-dimensional composite null hypothesis and propose a powerful gene-based method called MAIUP. MAIUP is constructed based on the traditional intersection-union test with two sets of independent P-values as input and follows a novel idea that was originally proposed under the high-dimensional mediation analysis framework. The key improvement of MAIUP is that it takes the composite null nature of pleiotropy test into account by fitting a three-component mixture null distribution, which can ultimately generate well-calibrated P-values for effective control of family-wise error rate and false discover rate. Another attractive advantage of MAIUP is its ability to effectively address the issue of overlapping subjects commonly encountered in association studies. Simulation studies demonstrate that compared with other methods, only MAIUP can maintain correct type I error control and has higher power across a wide range of scenarios. We apply MAIUP to detect shared associated genes among 14 psychiatric disorders with summary statistics and discover many new pleiotropic genes that are otherwise not identified if failing to account for the issue of composite null hypothesis testing. Functional and enrichment analyses offer additional evidence supporting the validity of these identified pleiotropic genes associated with psychiatric disorders. Overall, MAIUP represents an efficient method for pleiotropy identification.

Post-diagnostic lifestyle and mortality of cancer survivors: Results from a prospective cohort study.

OBJECTIVE: Lifestyle factors after cancer diagnosis could influence cancer survival. This study aimed to investigate the joint effects of smoking, physical activity, alcohol consumption, diet and sleep duration on all-cause, cancer and non-cancer mortality of cancer survivors in UK biobank. METHODS: The follow-up period concluded in December 2021, with post-diagnostic lifestyle factors assessed at baseline. A lifestyle score ranging from 0 to 5 was assigned based on adherence to the selected lifestyle factors. The study employed Cox regression models for hazard ratios (HRs) and Kaplan-Meier for survival rates, with stratified and sensitivity analyses to assess the robustness of our findings under various assumptions. RESULTS: During a median follow-up of 12.7 years, 5652 deaths were documented from 34,184 cancer survivors. Compared to scoring 0-1, the HRs (95% CIs) for all-cause mortality with lifestyle scores of 2, 3, 4, and 5 were 0.70 (95% CI: 0.64, 0.76), 0.57 (0.52, 0.62), 0.50 (0.45, 0.54) and 0.43 (0.38, 0.48), respectively. Specific cancer types, particularly digestive, breast, female reproductive, non-solid, and skin cancers, showed notable benefits from adherence to healthy lifestyle, with the HRs of 0.55 (0.39, 0.79), 0.54 (0.42, 0.70), 0.32 (0.19, 0.53), 0.58 (0.39, 0.86), and 0.36 (0.28, 0.46) for lifestyle score of 5, respectively. Stratified analyses indicated the association was particularly significant among those with normal/lower BMI and higher Townsend Deprivation Index (Pinteraction = 0.001 and < 0.001, respectively). CONCLUSIONS: Healthier lifestyles were significantly linked with reduced mortality among cancer survivors. These findings highlight the need for adherence to healthy lifestyle habits to improve survival.

Simultaneous and site-specific profiling of heterogeneity and turnover in protein S-acylation by intact S-acylated peptide analysis with a cleavable bioorthogonal tag.

Protein S-acylation is an important lipid modification characteristic for heterogeneity in the acyl chain and dynamicity in the acylation/deacylation cycle. Most S-acylproteomic research has been limited by indirect identification of modified proteins/peptides without attached fatty acids, resulting in the failure to precisely characterize S-acylated sites with attached fatty acids. The study of S-acylation turnover is still limited at the protein level. Herein, aiming to site-specifically profile both the heterogeneity and the turnover of S-acylation, we first developed a site-specific strategy for intact S-acylated peptide analysis by introducing an acid cleavable bioorthogonal tag into a metabolic labelling method (ssMLCC). The cleavable bioorthogonal tag allowed for the selective enrichment and efficient MS analysis of intact S-acylated peptides so that S-acylated sites and their attached fatty acids could be directly analysed, enabling the precise mapping of S-acylated sites, as well as circumventing false positives from previous studies. Moreover, 606 S-palmitoylated (C16:0) sites of 441 proteins in HeLa cells were identified. All types of S-acylated peptides were further characterized by an open search, providing site-specific profiling of acyl chain heterogeneity, including S-myristoylation, S-palmitoylation, S-palmitoleylation, and S-oleylation. Furthermore, site-specific monitoring of S-palmitoylation turnover was achieved by coupling with pulse-chase methods, facilitating the detailed observation of the dynamic event at each site in multi-palmitoylated proteins, and 85 rapidly cycling palmitoylated sites in 79 proteins were identified. This study provided a strategy for the precise and comprehensive analysis of protein S-acylation based on intact S-acylated peptide analysis, contributing to the further understanding of its complexity and biological functions.

A high-performance, sensitive, low-cost LIG/PDMS strain sensor for impact damage monitoring and localization in composite structures.

Health monitoring of composite structures in aircraft is critical, as these structures are commonly utilized in weight-sensitive areas and innovative designs that directly impact flight safety and reliability. Traditional monitoring methods have limitations in monitoring area, strain limit, and signal processing. In this paper, a multifunctional sensor has been developed using acid-treated laser-induced graphene (A-LIG) with a multi-layer three-dimensional conductive network. Compared to untreated laser-induced graphene, the sensitivity of A-LIG sensor is increased by 100%. Furthermore, PDMS is used to fill the pores, which improves the fatigue performance of the A-LIG sensor. To obtain clear monitoring results, a data conversion algorithm is provided to convert the electrical signal obtained by the sensor into a strain field contour cloud map. The impact test of the A-LIG/PDMS sensor on the carbon fiber panel of the aircraft wing box segment verifies the effectiveness of its strain sensing. This work introduces a novel approach to fabricating flexible sensors with improved sensitivity, extended strain range, and cost-effectiveness. The sensor exhibits high sensitivity (gauge factor,GF≈ 387), is low hysteresis (∼53 ms), and has a wide working range (up to 47%), and a highly stable and reproducible response over multiple test cycles (>18 000) with good switching response. It presents a promising and innovative direction for utilizing flexible sensors in the field of aircraft structural health monitoring.

Glyco-signatures in patients with advanced lung cancer during anti-PD-1/PD-L1 immunotherapy.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) have significantly prolonged the survival of advanced/metastatic patients with lung cancer. However, only a small proportion of patients can benefit from ICIs, and clinical management of the treatment process remains challenging. Glycosylation has added a new dimension to advance our understanding of tumor immunity and immunotherapy. To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins, a series of serum samples from 12 patients with metastatic lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC), collected before and during ICIs treatment, are firstly analyzed with mass-spectrometry-based label-free quantification method. Second, a stratification analysis is performed among anti-PD-1/PD-L1 responders and non-responders, with serum levels of glycopeptides correlated with treatment response. In addition, in an independent validation cohort, a large-scale site-specific profiling strategy based on chemical labeling is employed to confirm the unusual characteristics of IgG N-glycosylation associated with anti-PD-1/PD-L1 treatment. Unbiased label-free quantitative glycoproteomics reveals serum levels' alterations related to anti-PD-1/PD-L1 treatment in 27 out of 337 quantified glycopeptides. The intact glycopeptide EEQFN 177STYR (H3N4) corresponding to IgG4 is significantly increased during anti-PD-1/PD-L1 treatment (FC=2.65, P=0.0083) and has the highest increase in anti-PD-1/PD-L1 responders (FC=5.84, P=0.0190). Quantitative glycoproteomics based on protein purification and chemical labeling confirms this observation. Furthermore, obvious associations between the two intact glycopeptides (EEQFN 177STYR (H3N4) of IgG4, EEQYN 227STFR (H3N4F1) of IgG3) and response to treatment are observed, which may play a guiding role in cancer immunotherapy. Our findings could benefit future clinical disease management.

Separation methods for system-wide profiling of protein terminome.

Protein N- and C-termini have specific biochemical properties and functions. They play vital roles in various biological processes, such as protein stability and localization. In addition, post-translational modifications and proteolytic processing generate different proteoforms at protein termini. In recent years, terminomics has attracted significant attention, and numerous strategies have been developed to achieve high-throughput and global terminomics analysis. This review summarizes the recent protein N-termini and C-termini enrichment methods and their application in different samples. We also look ahead further application of terminomics in profiling protease substrates and discovery of disease biomarkers and therapeutic targets.

Comprehensive review of MS-based studies on N-glycoproteome and N-glycome of extracellular vesicles.

Extracellular vesicles (EVs) are lipid bilayer-enclosed particles that can be released by all type of cells. Whereas, as one of the most common post-translational modifications, glycosylation plays a vital role in various biological functions of EVs, such as EV biogenesis, sorting, and cellular recognition. Nevertheless, compared with studies on RNAs or proteins, those investigating the glycoconjugates of EVs are limited. An in-depth investigation of N-glycosylation of EVs can improve the understanding of the biological functions of EVs and help to exploit EVs from different perspectives. The general focus of studies on glycosylation of EVs primarily includes isolation and characterization of EVs, preparation of glycoproteome/glycome samples and MS analysis. However, the low content of EVs and non-standard separation methods for downstream analysis are the main limitations of these studies. In this review, we highlight the importance of glycopeptide/glycan enrichment and derivatization owing to the low abundance of glycoproteins and the low ionization efficiency of glycans. Diverse fragmentation patterns and professional analytical software are indispensable for analysing glycosylation via MS. Altogether, this review summarises recent studies on glycosylation of EVs, revealing the role of EVs in disease progression and their remarkable potential as biomarkers.

Peptide- and Protein-Level Combined Strategy for Analyzing Newly Synthesized Proteins by Integrating Tandem Orthogonal Proteolysis with Cleavable Bioorthogonal Tagging.

A newly synthesized proteome reflects perturbations sensitively and maintains homeostasis in cells. To investigate the low abundant newly synthesized proteins (NSPs) from a complex background proteome, an enrichment process with high selectivity and reliability is essential. Here, we have developed a strategy to realize comprehensive analysis of NSPs by integrating tandem orthogonal proteolysis (TOP) with cleavable bioorthogonal tagging (CBOT) called TOP-CBOT. A solid-phase-conjugated probe with a clickable moiety and a protease-cleavable site was designed, which allowed NSPs to be covalently captured along with tandem release by trypsin and orthogonal tobacco etch virus (TEV) protease. Our method has integrated the advantages of protein-level and peptide-level enrichment. Trypsin digests larger number of peptides from the recovered proteins for NSPs identification and quantification, while the specific tag-contained peptides from TEV data set enabled further NSPs confirmation. Integrating information from two complementary data sets, the reliability in NSPs identification and quantitation were remarkably enhanced. A total of 3699 proteins were recovered in the trypsin data set. Additionally, 1931 proteins were confirmed as NSPs with 5019 identified peptides in the TEV data set, over 90% of which were overlapped with the tryptic data set. Our strategy was further applied to profile NSP degradation kinetics during rapamycin-induced macroautophagy. The newly synthesized proteome displayed varied alteration of degradation rates among stimulation and more than half of NSPs showed decreased half-lives during autophagy.

Multi-comparative Thermal Proteome Profiling Uncovers New O-GlcNAc Proteins in a System-wide Method.

Among diverse protein post-translational modifications, O-GlcNAcylation, a simple but essential monosaccharide modification, plays crucial roles in cellular processes and is closely related to various diseases. Despite its ubiquity in cells, properties of low stoichiometry and reversibility are hard nuts to crack in system-wide research of O-GlcNAc. Herein, we developed a novel method employing multi-comparative thermal proteome profiling for O-GlcNAc transferase (OGT) substrate discovery. Melting curves of proteins under different treatments were profiled and compared with high reproducibility and consistency. Consequently, proteins with significantly shifted stabilities caused by OGT and uridine-5'-diphosphate N-acetylglucosamine were screened out from which new O-GlcNAcylated proteins were uncovered.

Global Analysis of Endogenously Intact S-Acylated Peptides Reveals Localization Differentiation of Heterogeneous Lipid Chains in Mammalian Cells.

S-acylation is a widespread lipidation form in eukaryotes in which various fatty acids can be covalently attached to specific cysteine residues. However, due to the low reactivity of the lipid moieties and lack of specific antibodies, purification of intact S-acylated peptides remains challenging. Here, we developed a pretreatment method for direct separation and global analysis of endogenously intact S-acylated peptides by nanographite fluoride-based solid-phase extraction (nGF-SPE), together with the investigation and optimization of the enrichment procedure as well as the LC-MS/MS analysis process. Consequently, we performed the first global profiling of endogenously intact S-acylated peptides, with 701 S-palmitoylated peptides from HeLa cell lysates in a restricted search. Furthermore, coupling the nGF-SPE method with open search mode, altogether 1119 intact S-acylated peptides were identified with the attached palmitate, palmitoleate, myristate, and octanoate chain, respectively, providing a global insight into the endogenously heterogeneous modification state. Notably, we found and validated that S-palmitoleoylation (C16:1) provided less affinity toward lipid rafts compared with S-palmitoylation (C16:0). This study developed the first straightforward way to characterize endogenously intact S-acylated peptides on a proteome-wide scale, providing the modified residues together with their attached lipid moieties simultaneously, which paves the way for further understanding of protein S-acylation.

Potential impact of time trend of whole grain intake on burden of major cancers in China.

Numerous studies have revealed associations between high intake of whole grains and reduced risk of various cancers. Yet, in recent decades, the traditional Chinese diets have been challenged by reduction in whole grains and increase in refined grains. To assess the impact of this dietary transition on cancer prevention, we analyzed the time trend of whole grain intake using nationally representative sampling data of over 15 thousand individuals from the China Health and Nutrition Survey. We applied the comparative risk assessment method to estimate the population attributable fraction of cancers due to insufficient whole grain intake from 1997 to 2011 and projected the trend of whole grain intake and the associated burden of cancers to 2035. We found a significant decrease of approximately 59% of whole grain intake in the Chinese population from 1997 to 2011. Compared with 1997, insufficient intake of whole grains was responsible for 9940 more cases of breast cancer, 12,903 more cases of colorectal cancer and 434 more cases of pancreatic cancer in 2011. Our projections suggest that if every Chinese would consume 125 g whole grain per day as recommended by the latest Chinese Dietary Guidelines, 0.63% bladder cancer, 8.98% breast cancer, 15.85% colorectal cancer, 3.86% esophageal cancer, 2.52% liver cancer and 2.22% pancreatic cancer (totaling 186,659 incident cases) could theoretically be averted by 2035. Even if everyone maintained the 2011 whole grain intake level, an estimated 8.38% of cancer events could still be prevented by 2035.

Elucidation of N-/O-glycosylation and site-specific mapping of sialic acid linkage isomers of SARS-CoV-2 human receptor angiotensin-converting enzyme 2.

Human angiotensin-converting enzyme 2 (hACE2) is the primary receptor for cellular entry of SARS-CoV-2 into human host cells. hACE2 is heavily glycosylated and glycans on the receptor may play a role in viral binding. Thus, comprehensive characterization of hACE2 glycosylation could aid our understanding of interactions between the receptor and SARS-CoV-2 spike (S) protein, as well as provide a basis for the development of therapeutic drugs targeting this crucial interaction. Herein, 138 N-glycan compositions were identified, most of which are complex-type N-glycans, from seven N-glycosites of hACE2. Among them, 67% contain at least one sialic acid residue. At the level of glycopeptides, the overall quantification of sialylated glycan isomers observed on the sites N322 and N546 have a higher degree of NeuAc (α2-3)Gal (over 80.3%) than that of other N-glycosites (35.6-71.0%). In terms of O-glycans, 69 glycan compositions from 12 O-glycosites were identified, and especially, the C-terminus of hACE2 is heavily O-glycosylated. The terminal sialic acid linkage type of H1N1S1 and H1N1S2 are covered highly with α2,3-sialic acid. These findings could aid the investigation of the interaction between SARS-CoV-2 and human host cells.

Discovery of age-related early-stage glycated proteins based on deep quantitative serum glycated proteome analysis.

Aging is a pressing global health issue that is linked to various diseases, such as diabetes and Alzheimer's disease. It is well known that glycation plays a pathological role in the aging process and age-related diseases. Thus, it is of great significance to discover protein glycation at an early stage for monitoring and intervention in the aging process. However, the endogenous age-related early-stage glycated proteome remains insufficiently profiled. To address this research gap, our study focuses on assessing glycated proteomics profiles in the serum of mice. We employ a robust and quantitative strategy previously developed by our team, to analyze endogenous glycated proteome in serum samples of 4 age groups of mice (10 weeks, 16 weeks, 48 weeks and 80 weeks). In total, 2959 endogenous glycated peptides corresponding to 296 serum proteins are identified from 48 runs of serum samples from 16 mice across the four age groups. By comparing these glycated peptides between adjacent age groups, we discover 49 glycated peptides from 35 proteins that show significant upregulation between the 48-week and 80-week age groups. Furthermore, we identify 10 glycated proteins (or protein groups) that are significantly upregulated only between the 48-week and 80-week age groups, including lecithin-cholesterol acyltransferase (LCAT) and apolipoprotein A-II (Apo A-II). These novel findings provide unique signatures for understanding the aging process and age-related diseases. By shedding light on the early-stage glycated proteome, our study contributes valuable insights that may have implications for future interventions and therapeutic approaches.

Relationship between birth weight and chronic kidney disease: evidence from systematics review and two-sample Mendelian randomization analysis.

Observational studies showed an inverse association between birth weight and chronic kidney disease (CKD) in adulthood existed. However, whether such an association is causal remains fully elusive. Moreover, none of prior studies distinguished the direct fetal effect from the indirect maternal effect. Herein, we aimed to investigate the causal relationship between birth weight and CKD and to understand the relative fetal and maternal contributions. Meta-analysis (n = ~22 million) showed that low birth weight led to ~83% (95% confidence interval [CI] 37-146%) higher risk of CKD in late life. With summary statistics from large scale GWASs (n = ~300 000 for birth weight and ~481 000 for CKD), linkage disequilibrium score regression demonstrated birth weight had a negative maternal, but not fetal, genetic correlation with CKD and several other kidney-function related phenotypes. Furthermore, with multiple instruments of birth weight, Mendelian randomization showed there existed a negative fetal casual association (OR = 1.10, 95% CI 1.01-1.16) between birth weight and CKD; a negative but non-significant maternal casual association (OR = 1.09, 95% CI 0.98-1.21) was also identified. Those associations were robust against various sensitivity analyses. However, no maternal/fetal casual effects of birth weight were significant for other kidney-function related phenotypes. Overall, our study confirmed the inverse association between birth weight and CKD observed in prior studies, and further revealed the shared maternal genetic foundation between low birth weight and CKD, and the direct fetal and indirect maternal causal effects of birth weight may commonly drive this negative relationship.

Specific and Reversible Enrichment of Early-Stage Glycated Proteome Based on Thiazolidine Chemistry and Palladium-Mediated Cleavage.

Comprehensive analysis of protein glycation is important for better understanding of its formation mechanism and biological significance. The current preconcentration methods of glycated proteome mainly depend on the reversible combination of boronic acid and cis-dihydroxy group by pH adjustment, but it has inherent limitations (e.g., poor specificity and time-consuming). Herein, for the first time, a novel enrichment method for glycated peptides is proposed based on the reversible chemical reaction between aldehyde and 1,2-aminothiol groups, in which oxidized glycated peptides are captured onto the magnetic nanoparticles via thiazolidine chemistry and then released by palladium-mediated cleavage. The method is rapid, with excellent selectivity (even at a 1:1000 molar ratio of glycated peptides/nonglycated peptides) and high sensitivity (1 fmol/µL). As a good evidence, 1549 glycated peptides were identified from glycated human serum with 94.6% specificity, providing a powerful technique for high-throughput analysis of glycated peptides.