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PubMed2004

Extractor for ESI quadrupole TOF tandem MS data enabled for high throughput batch processing.

BACKGROUND: Mass spectrometry based proteomics result in huge amounts of data that has to be processed in real time in order to efficiently feed identification algorithms and to easily integrate in automated environments. We present wiff2dta, a tool created to convert MS/MS data obtained using Applied Biosystem's QStar and QTrap 2000 and 4000 series. RESULTS: Comparing the performance of wiff2dta with the standard tools, we find wiff2dta being the fastest solution for extracting spectrum data from ABIs raw file format. wiff2dta is at least 10% faster than the standard tools. It is also capable of batch processing and can be easily integrated in high throughput environments. The program is freely available via http://www.protein-ms.de, http://sourceforge.net/projects/protms/ and is also available from Applied Biosystems. CONCLUSIONS: wiff2dta offers the possibility to run as stand-alone application or within a batch process as command-line tool integrated in automation and high-throughput environments. It is more efficient than the state-of-the-art tools provided.

Automation↗

PubMed2026

Integrative multi-omics identifies DOC2A as a novel pharmacological target for bipolar disorder.

BACKGROUND: Current bipolar disorder (BD) therapies suffer from limited efficacy and adverse effects, necessitating mechanistically grounded targets. METHODS: We integrated BD genome-wide association study data (158,036 cases; 2,796,499 controls) with brain proteomics (ROSMAP and Banner dorsolateral prefrontal cortex, n = 376 and 152) to perform proteome-wide association studies (PWAS). Bayesian colocalization and summary-data-based Mendelian randomization (SMR) prioritized causal genes. Cell-type-specific transcriptomics validated dysregulation in iPSC-derived neurons, astrocytes, and postmortem hippocampus/prefrontal cortex. Weighted gene co-expression networks (WGCNAs), functional enrichment, and molecular docking assessed functional pathways and druggability. RESULTS: PWAS identified eight BD-associated genes (false discovery rate < 0.05), with DOC2A emerging as the top candidate. Colocalization (H4 > 0.8) and SMR supported a causal association of DOC2A with BD, with no pleiotropy (heterogeneity in dependent instruments P > 0.01); DOC2A expression decreased in BD across neurons (P = 4.26 × 10-2), astrocytes (P = 2.09 × 10-2), hippocampus (P = 9.80 × 10-3, t = -2.738), and prefrontal cortex (P = 1.44 × 10-2, t = -2.580); WGCNA positioned DOC2A as a key regulator (module membership/gene significance P < 0.05) of co-expression networks enriched for BD-associated processes including neurotransmitter secretion and postsynaptic actin cytoskeleton organization (P < 0.05); molecular docking revealed favorable-affinity binding (ΔG < -4 kcal/mol) between DOC2A and BD-related drugs and neuroprotective compounds. CONCLUSIONS: Our convergent multi-omics framework highlights DOC2A dysregulation as a key contributor to synaptic dysfunction in BD and nominates it as a promising therapeutic target. The demonstrated interaction with existing neuroactive compounds provides immediate translational avenues.

Bipolar Disorder↗

PubMed2005

Phosphoproteomics in analyzing signaling pathways.

A surprisingly fewer than expected number of genes in the human genome suggests that sophistication of its biologic system is, in part, due to complex regulation of protein activities. The activities of most cellular proteins are regulated by post-translational modifications. One of the most important post-translational modifications is reversible protein phosphorylation, which decorates more than 30% of the proteome and regulates signal transduction pathways under normal conditions as well as in disorders such as diabetes, neurodegenerative diseases, autoimmune diseases and several forms of cancers. This review examines the recent developments in mass spectrometry-based methods for phosphoproteome analysis and its applications for the study of signal transduction pathways. The basic principles of non-mass spectrometry-based methods, such as chemical genetics and flow cytometry-based approaches, are also discussed as well as their specific advantages to signaling studies. Finally, signaling pathways are discussed in the light of large-scale protein interaction studies. The proteomic methods addressed in this review are emerging as some of the essential components in systems biology, which seeks to describe signaling networks through integration of diverse types of data and, in the future, to allow computational simulations of complex biologic pathways in health and disease.

Chromatography, Affinity↗

PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗

PubMed2004

A method for proteomic identification of membrane-bound proteins containing Asn-linked oligosaccharides.

Glycosylated proteins on the cell surface have been shown to be essential for cell-cell interactions in development and differentiation. Our ultimate goal is to identify Asn-linked oligosaccharides that are directly involved in these critical in vivo functions. Because such oligosaccharides would be expected to reside on the integral plasma membrane proteins, and conventional two-dimensional gel techniques are ineffective at separating such proteins, we have developed a new approach to their identification on a proteomics scale from Caenorhabditis elegans. Membrane proteins are solubilized in guanidine-HCl, precipitated, and digested with trypsin. The glycopeptides are then separated by lectin chromatography. Next, glycopeptidase F digestion removes the oligosaccharides from the peptides and converts to Asp each Asn to which one was attached. The peptides are then analyzed by matrix-assisted laser desorption/ionization quadrupole time-of-flight (MALDI-Q-TOF) mass spectrometry. Thus, the membrane glycoproteins are identified through the sequence tags of these peptides and the conversion of at least one deduced Asn residue to Asp at the Asn-X-Ser/Thr consensus sequence. To validate the utility of this approach, we have identified 13 membrane-bound N-glycosylated proteins from the major peaks observed on MALDI-Q-TOF analysis of our total glycopeptide fraction.

Animals↗

PubMed2025

CSF proteogenomics implicates novel proteins and humoral immunity in Alzheimer's disease risk.

We profiled 2,961 cerebrospinal fluid (CSF) proteins in 1,005 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 1,066 proteins not measured in prior studies, using mass spectrometry (MS). We mapped protein quantitative trait loci (pQTLs) in CSF, compared them with brain and plasma pQTLs, and integrated them with Alzheimer's disease (AD) genome-wide association study (GWAS) data. We identified 1,417 index cis pQTLs for 654 unique genes and 130 index trans pQTLs for 94 unique genes. Cross-tissue and cross-proteomic-platform comparisons show broad consistency between MS-based CSF pQTLs and MS-based brain pQTLs as well as affinity-based CSF and plasma pQTLs. Lastly, through integrating CSF pQTLs with the largest AD GWAS, we identified 24 candidate AD causal proteins in CSF, including 10 novel and 14 previously identified in either brain, CSF, or plasma using similar approaches. These CSF AD candidate causal proteins are involved in immune response - notably humoral immunity (3 of 24) - that expands the role of the immune system in AD beyond innate immunity, as well as lysosomal function and neurovascular growth and remodeling. Together, our findings provide novel insights into AD biology and new targets for biomarker and therapeutic development.

Journal Article↗

PubMed2026

Transcriptomic and Proteomic Insights into Mucosal Immune Responses of Asian Seabass (Lates calcarifer) After Sequential Mucosal Vaccination Against Bacterial Pathogens.

Bacterial diseases caused by Flavobacterium covae (Fc), Vibrio harveyi (Vh), Vibrio vulnificus (Vv) and Photobacterium damselae (Pd) seriously constrain Asian seabass aquaculture. Here we dissect the mucosal immune mechanisms engaged by a five-month sequential vaccination strategy that combines nanoemulsion immersion priming with multivalent oral hydrogel boosting. Juvenile seabass were vaccinated, then challenged with F. covae by freshwater immersion and with a Vibrio-Photobacterium (Vh/Vv/Pd) mix by immersion or intraperitoneal injection. Gills were sampled after immersion challenges and intestine after injection, and profiled by RNA sequencing and label-free quantitative proteomics, with selected genes validated by RT-qPCR. Principal component analysis showed clear separation of vaccinated and control fish in all tissues and challenges, indicating a strong and coherent transcriptional reprogramming. Vaccination markedly increased the number of upregulated genes, with Gene Ontology enrichment revealing dominant signatures of ribosome biogenesis, RNA processing, lysosomal organization and immune response. KEGG analysis highlighted cytokine receptor interaction; NOD and Toll-like receptor signaling; oxidative phosphorylation; and phagosome, lysosome and cell adhesion molecule pathways, consistent with heightened antimicrobial readiness. Volcano plots and focused heatmaps showed strong induction of interferon-stimulated genes, cytokines and chemokine receptors, complement components, macrophage mannose receptor, epithelial barrier mediators and numerous immunoglobulin transcripts, with tissue- and challenge-specific patterns. Proteomics corroborated these trends, demonstrating a higher abundance of immunoglobulin heavy chains, complement proteins, cathepsins, heat shock and redox chaperones, ribosomal proteins and cytoskeletal and adhesion regulators in vaccinated mucosae. Integrated pathway mapping linked endothelial adhesion molecules and leukocyte integrins with T cell costimulation networks and an intestinal immune network for immunoglobulin production, including enhanced pIgR-mediated transcytosis. Overall, the sequential vaccination regimen was associated with coordinated transcriptomic and proteomic signatures related to epithelial responses, innate immunity, and humoral immune functions across gill and intestinal tissues. These molecular patterns were accompanied by improved survival following bacterial challenge; however, the present data do not directly demonstrate the functional activity of the inferred immune mechanisms in Asian seabass.

Animals↗

PubMed2026

Bridging Organ-on-a-Chip and Omics: A Multi-Dimensional Frontier in Biomedical Research.

Organ-on-a-Chip (OOC) technology offers a powerful platform for replicating human tissue-specific microenvironments, thereby narrowing the translational gap between conventional biomedical models and actual human physiology. Concurrently, omics technologies deliver comprehensive molecular-level insights into biological systems. This review highlights the transformative potential of integrating OOC platforms with high-throughput omics methodologies. We systematically examine the classification, structural configurations, and engineering principles underlying OOC systems, alongside the defining attributes of key omics domains-genomics, transcriptomics, proteomics, and metabolomics. The convergence of dynamic OOC models with advanced omics technologies enables high-resolution, multi-dimensional analyses across numerous biomedical applications, including drug metabolism, disease mechanisms, environmental toxicity assessments, and host-microbiome interactions. This interdisciplinary integration is driving a paradigm shift in precision and translational medicine. However, several challenges remain to be addressed, such as the development of whole-organ mimetics, adaptation of sample collection techniques, and real-time artificial intelligence-based integration of biosensor data with multi-omics datasets. Addressing these hurdles will be vital for unlocking the full potential of this technological synergy in biomedical science.

Multiomics↗

PubMed2006

WholePathwayScope: a comprehensive pathway-based analysis tool for high-throughput data.

BACKGROUND: Analysis of High Throughput (HTP) Data such as microarray and proteomics data has provided a powerful methodology to study patterns of gene regulation at genome scale. A major unresolved problem in the post-genomic era is to assemble the large amounts of data generated into a meaningful biological context. We have developed a comprehensive software tool, WholePathwayScope (WPS), for deriving biological insights from analysis of HTP data. RESULT: WPS extracts gene lists with shared biological themes through color cue templates. WPS statistically evaluates global functional category enrichment of gene lists and pathway-level pattern enrichment of data. WPS incorporates well-known biological pathways from KEGG (Kyoto Encyclopedia of Genes and Genomes) and Biocarta, GO (Gene Ontology) terms as well as user-defined pathways or relevant gene clusters or groups, and explores gene-term relationships within the derived gene-term association networks (GTANs). WPS simultaneously compares multiple datasets within biological contexts either as pathways or as association networks. WPS also integrates Genetic Association Database and Partial MedGene Database for disease-association information. We have used this program to analyze and compare microarray and proteomics datasets derived from a variety of biological systems. Application examples demonstrated the capacity of WPS to significantly facilitate the analysis of HTP data for integrative discovery. CONCLUSION: This tool represents a pathway-based platform for discovery integration to maximize analysis power. The tool is freely available at http://www.abcc.ncifcrf.gov/wps/wps_index.php.

Computer Graphics↗

PubMed2003

Beyond the genome--SMi Conference 27-28 January 2003, London, UK.

Over a decade of astonishing developments, genomics and proteomics have promised a fundamentally new approach to drug discovery. Although there has been an undeniable increase in the range of potential targets available, this has not led to an increased output of the drug discovery pipeline into the clinic. With tighter markets and increasing competition, the major pharmaceutical companies are under intense pressure to achieve rapid, concrete delivery of those early promises, but there remain acute problems in the genes-to-drugs pipeline. This meeting showcased a range of novel approaches from proteomics and bioinformatics to address these problems. A common theme in the range of proteomics offerings was the prioritization of potential novel targets on the basis of their accessibility to drugs and their functional link to disease phenotypes. Informatics and in silico offerings also concentrated on fast, accurate, drug-focused workflows built on large integrative databases and novel data-mined algorithms.

Animals↗

PubMed2004

Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus.

Uridine auxotrophy, based on disruption of both URA3 alleles in diploid Candida albicans strain SC5314, has been widely used to select gene deletion mutants created in this fungus by "Ura-blasting" and PCR-mediated disruption. We compared wild-type URA3 expression with levels in mutant strains where URA3 was positioned either within deleted genes or at the highly expressed RPS10 locus. URA3 expression levels differed significantly and correlated with the specific activity of Ura3p, orotidine 5'-monophosphate decarboxylase. Reduced URA3 expression following integration at the GCN4 locus was associated with an attenuation of virulence. Furthermore, a comparison of the SC5314 (URA3) and CAI-4 (ura3) proteomes revealed that inactivation of URA3 caused significant changes in the levels of 14 other proteins. The protein levels of all except one were partially or fully restored by the reintegration of a single copy of URA3 at the RPS10 locus. Transcript levels of genes expressed ectopically at this locus in reconstituted heterozygous mutants also matched the levels found when the genes were expressed at their native loci. Therefore, phenotypic changes in C. albicans can be associated with the selectable marker rather than the target gene. Reintegration of URA3 at an appropriate expression locus such as RPS10 can offset most problems related to the phenotypic changes associated with gene knockout methodologies.

Animals↗

PubMed2004

Comparative proteomic analysis of extracellular proteins of enterohemorrhagic and enteropathogenic Escherichia coli strains and their ihf and ler mutants.

Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC, respectively) strains are closely related human pathogens that are responsible for food-borne epidemics in many countries. Integration host factor (IHF) and the locus of enterocyte effacement-encoded regulator (Ler) are needed for the expression of virulence genes in EHEC and EPEC, including the elicitation of actin rearrangements for attaching and effacing lesions. We applied a proteomic approach, using two-dimensional polyacrylamide gel electrophoresis in combination with matrix-assisted laser desorption ionization-time of flight mass spectrometry and a protein database search, to analyze the extracellular protein profiles of EHEC EDL933, EPEC E2348/69, and their ihf and ler mutants. Fifty-nine major protein spots from the extracellular proteomes were identified, including six proteins of unknown function. Twenty-six of them were conserved between EHEC EDL933 and EPEC E2348/69, while some of them were strain-specific proteins. Four common extracellular proteins (EspA, EspB, EspD, and Tir) were regulated by both IHF and Ler in EHEC EDL933 and EPEC E2348/69. TagA in EHEC EDL933 and EspC and EspF in EPEC E2348/69 were present in the wild-type strains but absent from their respective ler and ihf mutants, while FliC was overexpressed in the ihf mutant of EPEC E2348/69. Two dominant forms of EspB were found in EHEC EDL933 and EPEC E2348/69, but the significance of this is unknown. These results show that proteomics is a powerful platform technology for accelerating the understanding of EPEC and EHEC pathogenesis and identifying markers for laboratory diagnoses of these pathogens.

Escherichia coli↗

PubMed2025

LimROTS: a hybrid method integrating empirical Bayes and reproducibility-optimized statistics for robust differential expression analysis.

MOTIVATION: Differential expression analysis plays a vital role in omics research enabling precise identification of features that associate with different phenotypes. This process is critical for uncovering biological differences between conditions, such as disease versus healthy states. In proteomics, several statistical methods have been used, ranging from simple t-tests to more advanced methods like DEqMS, limma and ROTS. However, a flexible method for reproducibility-optimized statistics tailored for clinical omics data has been lacking. RESULTS: In this study, we developed LimROTS, a hybrid method that integrates a linear regression model and the empirical Bayes approach with reproducibility optimized statistics, to create a novel moderated ranking statistic, for robust and flexible analysis of proteomics data. We validated its performance using twenty-one proteomics gold standard spike-in datasets with different protein mixtures, MS instruments, and techniques for benchmarking. This hybrid approach improves accuracy and reproducibility of complex proteomics data, making LimROTS a powerful tool for high-dimensional omics data analysis. AVAILABILITY AND IMPLEMENTATION: LimROTS has been implemented as an R/Bioconductor package, available at https://doi.org/doi:10.18129/B9.bioc.LimROTS. Additionally, the code used in this study is available in GitHub repository https://github.com/AliYoussef96/LimROTSmanuscript.

Bayes Theorem↗

PubMed2006

[Dynamic change of metabolism related protein in liver tissue of rats' model of hepatic fibrosis and regulatory effect of fuzheng huayu decoction on it].

OBJECTIVE: To investigate the effect of Fuzheng Huayu decoction (FHD) intervention on hepatic fibrosis. METHODS: Wistar rats were randomly divided into 3 groups: rats in the normal group only treated with subcutaneous injection of saline, rats in the model group and the FHD group were made into hepatic fibrosis by subcutaneous injection of 40% carbon tetrachloride (CCl4)-olive solution and then those in the FHD group were treated with FHD by gastric perfusion after modeling. Liver samples of the rats were obtained for routine pathological observation, hydroxyproline determination and proteome quantitative determination. After then, the proteome profile was obtained through 2-dimensional electrophoresis and silver staining, and analyzed. More than 30 proteins with different expression were identified by MALDI-TOF-MS. RESULTS: (1) The integral response of vital movement such as body weight and activity of hepatic fibrosis declined in the CCl4 induced liver fibrosis rats; (2) Liver fibrosis were associated with abnormal metabolism; (3) There were four material metabolism-related protein showed by hepatic proteome mass spectrography, which expressed different between the normal and the fibrotic rats, i. e. the perchloric acid soluble protein, the phosphatidylinositol transferase, the phosphoglycerate kinase and the endoplasmic reticulum-60 protease; (4) The expressions of the above-mentioned four proteins in the FHD group were nearly the same as those of normal level. CONCLUSION: (1) Liver fibrosis is accompanied with abnormal protein synthesis and decomposition, as well as the enhanced activity of glycolysis; (2) The existence of metabolism-related proteins is one of the elements for the liver in regulating metabolism; (3) The regulation on the expressions of metablism-related proteins is one of the pathways for FHD to exert its anti-hepatic fibrosis effect.

Animals↗

PubMed2004

[Application of genomics and proteomics in study of traditional Chinese medicine].

The technique of genomics and proteomics is one of the fastest developments with the farest-reaching consequences in the high and new biotechnology in the world of today. It can be used to screen the target molecules of the action of traditional Chinese medicines, to identify the new effective components from traditional Chinese medicines, and to explore the mechanisms of the effects of traditional Chinese medicines. It meets the shortcomings of the conventional methodology being applied in the current studies of traditional Chinese medicine. Application of the theories and technique of genomics and proteomics in the study of traditional Chinese medicine would be of great significance for opening new research field of traditional Chinese medicine, for facilitating the integration of traditional Chinese medicine and modern biological science and technology, and for promoting the internationalization of traditional Chinese medicine.

Drug Delivery Systems↗

PubMed2004

Utilisation of proteomics datasets generated via multidimensional protein identification technology (MudPIT).

Technological developments in proteomics have had a dramatic impact on biology in recent years. One of these developments--named multidimensional protein identification technology (MudPIT)--couples two-dimensional chromatography of peptides in mass spectrometry-compatible solutions directly to tandem mass spectrometry, allowing for the identification of proteins from highly complex mixtures. Since the initial descriptions of MudPIT, this approach has been implemented in the analysis of whole proteomes, organelles and protein complexes. Key aspects of many of the analyses are the validation of MudPIT datasets with alternate strategies and the integration of MudPIT datasets with other biochemical, cell biology or molecular biology approaches. This paper presents strategies for validating MudPIT datasets and incorporating these datasets into biologically driven experimental design.

Automation↗

PubMed2003

Proteomics: the first decade and beyond.

Proteomics is the systematic study of the many and diverse properties of proteins in a parallel manner with the aim of providing detailed descriptions of the structure, function and control of biological systems in health and disease. Advances in methods and technologies have catalyzed an expansion of the scope of biological studies from the reductionist biochemical analysis of single proteins to proteome-wide measurements. Proteomics and other complementary analysis methods are essential components of the emerging 'systems biology' approach that seeks to comprehensively describe biological systems through integration of diverse types of data and, in the future, to ultimately allow computational simulations of complex biological systems.

Amino Acid Sequence↗

PubMed2006

Proteomic analysis of phosphorylation, oxidation and nitrosylation in signal transduction.

Signal transduction pathways control cell fate, survival and function. They are organized as intricate biochemical networks which enable biochemical protein activities, crosstalk and subcellular localization to be integrated and tuned to produce highly specific biological responses in a robust and reproducible manner. Post translational Modifications (PTMs) play major roles in regulating these processes through a wide variety of mechanisms that include changes in protein activities, interactions, and subcellular localizations. Determining and analyzing PTMs poses enormous challenges. Recent progress in mass spectrometry (MS) based proteomics have enhanced our capability to map and identify many PTMs. Here we review the current state of proteomic PTM analysis relevant for signal transduction research, focusing on two areas: phosphorylation, which is well established as a widespread key regulator of signal transduction; and oxidative modifications, which from being primarily viewed as protein damage now start to emerge as important regulatory mechanisms.

Animals↗