Alzheimer’s disease early diagnostic and staging biomarkers revealed by large-scale cerebrospinal fluid and serum proteomic profiling

Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.

Dear-DIA^(XMBD): Deep Autoencoder Enables Deconvolution of Data-Independent Acquisition Proteomics

Data-independent acquisition(DIA)technology for protein identification from mass spectrometry and related algorithms is developing rapidly.The spectrum-centric analysis of DIA data without the use of spectra library from data-dependent acquisition data represents a promising direction.In this paper,we proposed an untargeted analysis method,Dear-DIA^(XMBD),for direct analysis of DIA data.Dear-DIA^(XMBD) first integrates the deep variational autoencoder and triplet loss to learn the representations of the extracted fragment ion chromatograms,then uses the k-means clustering algorithm to aggregate fragments with similar representations into the same classes,and finally establishes the inverted index tables to determine the precursors of fragment clusters between precursors and peptides and between fragments and peptides.We show that Dear-DIA^(XMBD) performs superiorly with the highly complicated DIA data of different species obtained by different instrument platforms.

Longitudinal proteomic investigation of cOVID-19 vaccination

Although the development of covID-19 vaccines has been a remarkable success,the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict.In this study,blood samples were collected from 163 participants who next received two doses of an inactivated COvVID-19 vaccine(CoronaVac)at a 28-day interval.Using TMT-based proteomics,we identified 1,715 serum and 7,342 peripheral blood mononuclear cells(PBMCs)proteins.We proposed two sets of potential biomarkers(seven from serum,five from PBMCs)at baseline using machine learning,and predicted the individual seropositivity 57 days after vaccination(AUC=0.87).Based on the four PBMC's potential biomarkers,we predicted the antibody persistence until 180 days after vaccination(AUC=0.79).Our data highlighted characteristic hematological host responses,including altered lymphocyte migration regulation,neutrophil degranulation,and humoral immune response.This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after coVID-19 vaccination,shedding light on immunization mechanisms and individual booster shot planning.

Gut microbiota,inflammation,and molecular signatures of host response to infection

Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection.Here,we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers,which have recently been identified as molecular signatures predicting the progression of the COVID-19.We demonstrate that in our cohort of 990 healthy individuals without infection,this proteomic risk score is positively associated with proinflammatory cytokines mainly among older,but not younger,individuals.We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals.Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation.Overall,our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals.These results may provide novel insights into the cross-talk between gut microbiota and host immune system.

METTL9 mediated N1-histidine methylation of zinc transporters is required for tumor growth

Dear Editor,Histidine methylation has been known for many years(Searle and Westall,1951),but only a few proteins carrying such modifications have been studied(Webb et al.,2010;Al-Hadid et al.,2014;Kwiatkowski et al.,2018;Guo et al.,2019;Wilkinson et al.,2019;Kwiatkowski and Drozak,2020).

Proteomics profiling of colorectal cancer progression identifies PLOD2 as a potential therapeutic target

Dear editors,Colorectal cancer(CRC)is the second leading cause of cancer deaths in developed countries[1].The malignant transformation from small clumps to cancer takes about 10 years[2].This study aimed to characterize proteomic dynamics associated with CRC development and progres-sion,and identify novel therapeutic targets for intercepting the underlying oncogenic processes.We have optimized pressure cycling technology(PCT)coupled with data-independent acquisition mass spectrometry(DIA-MS)for robust and reproducible proteomic analysis of biopsy-level formalin-fixed paraffin-embedded(FFPE)tissues[3].

约4900年前东亚和东南亚枢纽地区狩猎采集向农业的转变

The southward expansion of East Asian farmers profoundly influenced the social evolution of Southeast Asia by introducing cereal agriculture.However,the timing and routes of cereal expansion in key regions are unclear due to limited empirical evidence.Here we report macrofossil,microfossil,multiple isotopic(C/N/Sr/O)and paleoproteomic data directly from radiocarbon-dated human samples,which were unearthed from a site in Xingyi in central Yunnan and which date between 7000 and 3300 a BP.Dietary isotopes reveal the earliest arrival of millet ca.4900 a BP,and greater reliance on plant and animal agriculture was indicated between 3800 and 3300 a BP.The dietary differences between hunter-gatherer and agricultural groups are also evident in the metabolic and immune system proteins analysed from their skeletal remains.The results of paleoproteomic analysis indicate that humans had divergent biological adaptations,with and without farming.The combined application of isotopes,archaeobotanical data and proteomics provides a new approach to documenting dietary and health changes across major subsistence transitions.

Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils

Inhibitory immune receptors set thresholds for immune cell activation,and their deficiency predisposes a person to autoimmune responses.However,the agonists of inhibitory immune receptors remain largely unknown,representing untapped sources of treatments for autoimmune diseases.Here,we show that V-set and transmembrane domain-containing 1(VSTM1)is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1(Gal1)is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production.However,in patients with systemic lupus erythematosus(SLE),circulating Gal1 is oxidized and cannot be recognized by VSTM1,leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability.Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes.Interestingly,serum levels of glutathione,an antioxidant able to convert oxidized Gal1 to its reduced form,were negatively correlated with SLE disease activity.Taken together,our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.

Diffuse midline glioma treated with epigenetic agent-based immunotherapy

Dear Editor,Diffuse midline glioma,H3K27-altered(DMG),is a pediatric-type high-grade diffuse glioma that preferentially localizes to the brainstem or pons,thalamus,and spinal cord.Surgical resection is challenging and biopsy is often performed in most cases.To date,no conventional,targeted or immune therapy has been convincingly shown to improve patients’overall survival(OS).

ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker

The evolution of coronaviruses,such as SARS-CoV-2,makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after.Here we report a human angiotensin-converting enzyme 2(ACE2)-targeting monoclonal antibody,3E8,blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2,SARS-CoV-2 mutant variants(SARS-CoV-2-D614G,B.1.1.7,B.1.351,B.1.617.1,and P.1).

DPHL:A DIA Pan-human Protein Mass Spectrometry Library for Robust Biomarker Discovery

To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel reaction monitoring(PRM),and massively parallel dataindependent acquisition(DIA),have been developed.For optimal performance,they require the fragment ion spectra of targeted peptides as prior knowledge.In this report,we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples.To build the spectral resource,we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker.We then applied the workflow to generate DPHL,a comprehensive DIA pan-human library,from 1096 data-dependent acquisition(DDA)MS raw files for 16 types of cancer samples.This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer(PCa)patients.Thereafter,PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated.As a second application,the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma(DLBCL)patients and 18 healthy control subjects.Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM.These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery.DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.

sRAGE alleviates SARS-CoV-2-induced pneumonia in hamster

Dear Editor Since last year,the most demanding task of the global pharmaceutical community has been focused on the development of strategies to treat coronavirus disease 2019(COVID-19).To date,several vaccines have been developed and already demonstrated their efficacy in reducing the incidence of COVID-19.1 However,the development of drugs treating COVID-19 is lagging far behind,and all the current treatment regimens have their limitations.

Broadly neutralizing antibodies against Omicron-included SARS-CoV-2 variants induced by vaccination

The SARS-CoV-2 Omicron variant shows substantial resistance to neutralization by infection-and vaccination-induced antibodies,highlighting the demands for research on the continuing discovery of broadly neutralizing antibodies(bnAbs).Here,we developed a panel of bnAbs against Omicron and other variants of concern(VOCs)elicited by vaccination of adenovirus-vectored COVID-19 vaccine(Ad5-nCoV).