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PubMed1998

Amino acid signatures in the detached cat retina.

PURPOSE: Expressions of certain macromolecules are altered by experimental retinal detachment in the cat. Related alterations in micromolecular signatures of neurons, Müller cells, and the retinal pigment epithelium (RPE) were investigated. METHODS: High-performance immunochemical mapping, image registration, and quantitative pattern recognition were combined to analyze the amino acid contents of virtually all retinal cell types after 3 to 84 days of detachment. RESULTS: Retinal micromolecular signatures showed a spectrum of alterations. The glutamate contents of Müller cells increased and remained elevated for weeks after detachment. Multispectral signatures of Müller cells showed massive metabolic instability in early detachment stages that ultimately resolved as a homogeneous profile significantly depleted in glutamine. Retinal pigment epithelial cell signals also changed dramatically, displaying an initial glutamate spike and then a prolonged decline, even as taurine levels followed an opposite pattern of initial loss and slow restoration. Neurotransmitter signatures of surviving neurons showed extensive precursor-level variation, and, in one case, GABAergic horizontal cells displayed anomalous sprouting. CONCLUSIONS: Dramatic changes in Müller cell amino acid signatures triggered by retinal detachment are partially consistent with losses in glutamine synthetase activity. Taurine signal variations suggest that orthotopic RPE cells attempt to regulate abnormal taurine concentrations in the enlarged subretinal space. Surviving neurons possess characteristic neurotransmitter signals, but their metabolite regulation seems abnormal. On balance, microchemical and structural anomalies develop in the detached cat retina that represent serious barriers to recovery of normal visual function.

Amino Acids↗

PubMed2026

Transcriptomic Profiling Reveals NF-κB-Associated Immune Regulatory Signatures Underlying the Regenerative Effects of Hypoxia-Preconditioned Tendon Stem Cell-Derived Extracellular Vesicles.

Remodeling of the immune microenvironment is a critical determinant of tissue regeneration, yet the molecular programs associated with the enhanced therapeutic activity of hypoxia-preconditioned extracellular vesicles remain incompletely defined. In this study, we investigated the regenerative and immunomodulatory effects of hypoxia-preconditioned tendon stem cell-derived extracellular vesicles (Hypo-EVs) and employed transcriptomic profiling to identify molecular signatures associated with their biological activity. The therapeutic effects of Hypo-EVs were evaluated using a rat patellar tendon defect model and lipopolysaccharide-stimulated RAW 264.7 macrophages. Histological analysis, immunostaining, biomechanical testing, and reverse transcription-quantitative polymerase chain reaction were performed to assess tendon healing and macrophage polarization, while RNA sequencing was conducted in macrophages treated with Hypo-EVs or normoxia-derived EVs, followed by Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopaedia of Genes and Genomes pathway analyses. Hypo-EVs significantly alleviated local inflammatory responses, improved collagen organization and biomechanical properties of repaired tendons, and promoted macrophage polarization toward a reparative M2 phenotype both in vivo and in vitro. Consistent with these biological effects, transcriptomic profiling revealed extensive remodeling of inflammation-related gene expression programs, including significant suppression of NF-κB, TNF, IL-17, and cytokine-cytokine receptor interaction pathways. Integrative bioinformatic analyses identified an NF-κB-associated immune-regulatory signature that distinguished Hypo-EV-treated macrophages from those receiving normoxic EVs. Mechanistically, Hypo-EVs attenuated NF-κB activation, as evidenced by reduced phosphorylation of p65 and IκBα, whereas TNF-α-mediated NF-κB activation partially diminished their macrophage-repolarizing effects. Collectively, these findings demonstrate that hypoxic preconditioning enhances the immunomodulatory and regenerative functions of tendon stem cell-derived EVs. Transcriptomic analyses identified an NF-κB-associated immune-regulatory signature linked to the biological activity of Hypo-EVs, providing a molecular framework for understanding EV-mediated immune modulation and supporting the development of transcriptome-guided molecular signatures for regenerative therapies targeting tendon immune homeostasis.

Animals↗

PubMed2026

A novel lactylation-related gene signature deciphers the immunosuppressive microenvironment and stratifies precision therapy in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality, largely due to the heterogeneity of the tumor microenvironment (TME) and the limited efficacy of immunotherapy in microsatellite stable (MSS) tumors. Histone lactylation, a post-translational modification derived from the Warburg effect, serves as a critical bridge linking metabolic reprogramming to gene regulation and immune evasion; however, its specific prognostic value and clinical implications in CRC remain to be fully elucidated. METHODS: In this study, we systematically analyzed transcriptome profiling data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts, supplemented by single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) protein-level validation. By integrating univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox regression, we constructed a novel lactylation-related gene (LRG) risk signature. We extensively evaluated the association between this risk signature and patient prognosis, immune infiltration patterns, somatic mutations, and therapeutic sensitivity. RESULTS: A robust 9-gene prognostic signature (DHRS7, SPR, MBD2, RBM17, CSRP2, S100A4, TMSB4X, TKT, COPS4) was identified and corroborated at the protein level. Patients with high risk scores exhibited significantly worse overall survival (OS) across the training and two independent validation cohorts. Immunogenomic and scRNA-seq analyses revealed that high-risk tumors were characterized by an immunosuppressive and stromal-dense microenvironment-with stromal cells exhibiting the highest lactylation risk scores-enriched with regulatory T cells (Tregs), and frequently harbored PIK3CA mutations. Differential expression analysis indicated that this immune exclusion is structurally maintained by enriched extracellular matrix (ECM) organization and TGF-β signaling. Conversely, low-risk tumors displayed an inflamed phenotype with active antitumor immunity. Pharmacogenomic prediction identified distinct therapeutic stratifications: low-risk patients exhibited significant sensitivity to standard chemotherapeutics (fluorouracil, oxaliplatin) and EGFR/HER2 inhibitors (e.g., lapatinib, erlotinib). In contrast, high-risk patients showed specific vulnerabilities to novel targeted agents, including PI3K pathway inhibitors (TG-100-115, XL765), microenvironment-modulating agents (sildenafil, GANT-61), and epigenetic inhibitors (UNC0638). CONCLUSION: We established a novel lactylation-related risk signature that effectively stratifies CRC patients by prognosis and TME characteristics. By elucidating the crosstalk between metabolic dysregulation, stromal barriers, and immune exclusion, this study provides potential biomarkers and stratified therapeutic strategies-ranging from standard chemotherapy to targeted metabolic and stromal interventions-to optimize precision medicine for CRC patients.

Colorectal cancer↗

PubMed2025

Identification of multicohort-based predictive signature for NMIBC recurrence reveals SDCBP as a novel oncogene in bladder cancer.

BACKGROUND: Despite surgical and intravesical chemotherapy interventions, non-muscle invasive bladder cancer (NMIBC) poses a high risk of recurrence, which significantly impacts patient survival. Traditional clinical characteristics alone are inadequate for accurately assessing the risk of NMIBC recurrence, necessitating the development of novel predictive tools. METHODS: We analyzed microarray data of NMIBC samples obtained from the ArrayExpress and GEO databases. LASSO regression was utilized to develop the predictive signature. We combined gene signature and clinicopathological factors to construct a clinical nomogram for estimating NMIBC recurrence in a local cohort. Finally. the biological functions and potential mechanisms of SDCBP in bladder cancer were investigated experimentally in vitro and in vivo. RESULTS: An 8-gene signature was developed, and its efficiency for predicting NMIBC recurrence was evaluated using Kaplan-Meier and time-dependent ROC curves in both training and validation datasets. Immunohistochemical testing revealed elevated levels of ACTN4 and SDCBP in recurrent NMIBC tissues. We integrated the two proteins with clinical factors to develop a nomogram model, which showed superior accuracy compared to individual parameters. Gene Set Variation Analysis and Gene Set Enrichment Analysis unveiled SDCBP exerted cancer-promoting biological processes, such as angiogenesis, EMT, metastasis and proliferation. Experimental procedures demonstrated that silencing SDCBP attenuated cell growth, glucose metabolism and extracellular acidification rate, accompanied by decreased expression of p-AKT, p-ERK1/2, LDHA and Vimentin. CONCLUSIONS: The established 8-gene signature holds promise as a tool for predicting NMIBC recurrence, while targeting SDCBP may represent a potential strategy for delaying disease relapse.

Urinary Bladder Neoplasms↗

PubMed2025

Development and validation of a novel risk stratification signature derived from migrasome and tumor microenvironment-related genes for molecular subtyping and improving clinical outcomes in head and neck squamous cell carcinoma.

BACKGROUND: The tumor microenvironment (TME) and migrasomes released by tumor cells significantly influence carcinogenesis and immune evasion. However, our understanding of the prognostic and therapeutic implications of migrasome and tumor microenvironment-related genes (mtmRGs) in head and neck squamous cell carcinoma (HNSCC) remains limited. METHODS: We explored the relationship between mtmRGs and HNSCC prognosis by utilizing The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Subsequently, we developed an innovative prognostic signature, and assessed its prognostic significance using the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and Cox regression analyses. To explore the underlying mechanisms, we conducted gene set variation analysis (GSVA), gene set enrichment analysis (GESA), and immune infiltration analysis. A nomogram was developed to estimate the overall survival (OS) rates for HNSCC patients. Lastly, we chose P4HA1, which was part of the signature, for additional experimental validation in vitro and in vivo. RESULTS: The mtmRGs signature effectively classifies HNSCC patients into two distinct risk subgroups, with the high-risk cohort demonstrating significantly poorer OS. The risk score serves as an independent prognostic factor for HNSCC patients; those with lower risk scores are more likely to exhibit favorable responses to immunotherapy, particularly with CTLA4 inhibitors. Furthermore, a lower risk score is significantly correlated with the sensitivity of HNSCC patients to cyclophosphamide, gemcitabine, and axitinib. CONCLUSION: This study presents an innovative gene signature associated with mtmRGs, which may be utilized both for predicting survival and directing personalized chemotherapy and immunotherapy regiments for patients with HNSCC.

Humans↗

PubMed2026

Serum Proteomic Signatures of Rheumatoid Arthritis Risk and Response: Analysis of a Rheumatoid Arthritis Interception Trial.

OBJECTIVE: Our study objective was to identify serum protein signatures associated with progression to rheumatoid arthritis (RA) and response to abatacept in at-risk individuals. METHODS: A total of 440 serum samples from 118 APIPPRA (Arthritis Prevention In the Preclinical Phase of RA with Abatacept) study participants were selected from baseline to RA onset for 46 progressors of RA or to study end for 72 participants who did not develop RA. Samples were analyzed using the SomaScan 7k assay platform. Differential expression analysis was assessed by progression to RA (three pre-RA time intervals to RA, progressors of RA vs nonprogressors, baseline to RA), and by treatment allocation (abatacept vs placebo). Risk and response signatures were identified in the full 7k panel and two prespecified subpanels defined as Inflammatory Mediators and Adaptive Immune Cell panel. RESULTS: We observed significant changes in 80 proteins (68 down-regulated and 12 up-regulated) occurring between RA onset and 6 to 24 months before developing disease. Progression to RA was associated with increased levels of acute-phase reactants SAA1 and SAA2 and reductions in CTLA4, when compared to nonprogressors at the end of treatment. Two up-regulated proteins (CTLA4 and CD86) and seven down-regulated proteins (CXCL13, FCRL4, FCER2, CCL21, LTA|LTB, FDCSP, and IL22RA2) were observed in participants receiving abatacept compared to placebo regardless of RA outcome. CONCLUSION: Protein signatures dominated by acute-phase proteins define progression to RA, whereas changes associated with abatacept therapy highlight potential mechanisms of treatment response. Such signatures provide a better understanding of the immune landscape of the at-risk phase, opening up the possibility of new treatment modalities for RA prevention.

Adult↗

PubMed2006

Theoretical determination of the vibrational Raman optical activity signatures of helical polypropylene chains.

Raman and vibrational Raman optical activity (VROA) spectra of helical conformers of polypropylene chains are simulated using ab initio methods to unravel the relationships between the vibrational signatures and the primary and secondary structures of the chains. For a polypropylene chain containing three units, conformational effects are shown to lead to more acute signatures for VROA than for Raman spectra. In addition to regular polypropylene chains, which can display right and left helicities with the same probability, chirality and therefore helicity are enforced by substituting one chain end with a phenyl group. The simulations predict that the threefold helical structures, which correspond to (TG)(N) conformations of the backbone, have a specific VROA backward signature in the form of an intense couplet around 1100 cm(-1). This couplet is associated with collective wagging and twisting motions, while most of its intensity comes from the anisotropic invariants combining normal coordinate derivatives of the electric dipole-electric dipole polarizability and of the electric dipole-magnetic dipole polarizability. A similar signature has already been found in model helical polyethylene chains, whereas it is very weak in forward VROA.

Journal Article↗

PubMed2006

Identification and meta-analysis of a small gene expression signature for the diagnosis of estrogen receptor status in invasive ductal breast cancer.

In breast cancer, the determination of estrogen receptor (ER) expression is crucial for the decision on therapeutic strategies. Current ER expression analysis is based on immunohistochemical (IHC) staining of ER on formalin fixed tissue sections. However, low levels of ER expression frequently escape detection because of varying sensitivities of routine histopathological laboratories. Moreover, in estimating ER by IHC the receptor protein only is tested instead of the complex underlying ER pathway, which reflects its biological activity. To overcome this limitation, we have used the microarray technology to study 56 samples of invasive ductal carcinoma. We infer a robust and reliable signature of 10 genes, which is associated with ER expression and presumably therapeutically relevant biological processes. In a meta-analysis, the signature was tested on 3 further independent microarray gene expression data sets, covering different laboratories, array platforms, and clinics. The classification based on the signature showed a very low misclassification rate. In summary, the expression of few genes is sufficient to determine ER status. Future decisions on antiestrogen based therapy in breast cancer could be based on this signature rather than on immunostaining alone.

Adult↗

PubMed2026

Sodium Overload-Related Molecular Subtypes and a Four-Gene Prognostic Signature Predict Survival, Immune Landscape, and Therapeutic Response in Acute Myeloid Leukemia.

Sodium overload has recently emerged as a critical metabolic stressor involved in cancer progression; however, its molecular characteristics and clinical relevance in acute myeloid leukemia (AML) remain unexplored. RNA-seq data sets, clinical annotations, and mutational profiles of AML patients were annotations from The Cancer Genome Atlas and integrated with Genotype-Tissue Expression normal samples. Sodium overload-related genes (SORGs) were obtained from GeneCards. Differentially expressed SORGs (DESORGs) screened by applying the limma statistical model, followed by univariate Cox proportional hazards regression, consensus clustering, functional enrichment, immune infiltration analysis, and pathway evaluation. A prognostic signature was developed through least absolute shrinkage and selection operator regression followed by multivariate Cox modeling. The model's performance was further verified in two external GEO data sets (GSE71014 and GSE37642). Nomogram construction, subgroup analysis, tumor mutational burden (TMB) assessment, drug sensitivity prediction, transcription factor (TF) analysis, and competing endogenous RNA (ceRNA) network analyses were also performed. A total of 57 DESORGs were identified, and 2 sodium overload-related molecular subtypes exhibited distinct survival, immune infiltration, and inflammatory pathway activation. A robust four-gene signature (DOCK1, GABRE, HTR7, ACSM1) stratified patients into high- and low-risk categories with significantly different survival across training and validation cohorts. High-risk patients displayed increased immune infiltration, higher TMB, reduced sensitivity to multiple chemotherapeutic drugs, and inferior predicted response to PD-L1 blockade. TF and ceRNA networks revealed multilayered transcriptional and post-transcriptional regulation of the signature genes. This study identifies sodium overload-related molecular heterogeneity in AML and establishes a validated four-gene prognostic signature that integrates genomic, immunologic, and therapeutic features, offering potential utility for personalized risk assessment and treatment optimization.

Humans↗

PubMed2006

Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis.

Sentinel lymph node biopsy for several cancers has shown that metastatic tumour cells are preferentially arrested in the lymph node sinuses. To study the molecular components of this sinusoidal trap, gene profiling of lymph node (sinuses) versus tonsil (no sinuses) was performed. Among other groups of molecules, an intriguing gene signature of scavenger and lectin-like receptors was identified. Nine of the 13 genes were preferentially expressed in sinusoidal cells by immunohistochemistry. Using stabilin-2 and monoclonal antibody 3A5 as exclusive endothelial cell (EC) and macrophage (Mvarphi) markers, respectively, lymph node sinusoidal ECs (stabilin-2+, LYVE-1+, DC-SIGNR+, MARCO+, stabilin-1+, MMR+) and sinusoidal Mvarphi (MMR+, DC-SIGN+, sialoadhesin+, CD163+, stabilin-1+ ) showed distinct, but overlapping expression patterns of the signature molecules by double labelling immunofluorescence. The number of stabilin-1+ sinusoidal Mvarphi, however, varied considerably between samples, indicating turnover/differentiation dynamics in this sinusoidal cell population. In the hepatic sinuses, LYVE-1 and CD36 were strongly up-regulated on both sinusoidal ECs and Mvarphi, while DC-SIGNR and DC-SIGN were strongly down-regulated; in contrast to lymph node sinusoidal ECs, MARCO was confined to Mvarphi (Kupffer cells) in the liver sinuses. As Mvarphi are not present in the wall and lumen of splenic sinuses, splenic sinuses expressed a considerably reduced repertoire of scavenger/lectin receptors lacking sialoadhesin, CD36, CD163, and MARCO; in addition, DC-SIGNR was absent from splenic sinusoidal ECs, while DC-SIGN and thrombomodulin were strongly expressed. Interestingly, most of the signature molecules are known to mediate tumour cell adhesion in addition to their functions as scavenger or pattern recognition receptors. This study establishes a gene and tissue database platform to test the hypothesis that additive expression of the lymph node sinus signature genes in sinusoidal ECs and Mvarphi may contribute to selective tumour cell metastasis in lymph nodes and liver including organ-specific mechanisms, such as intraluminal retention or transmigration, while sparing the spleen.

Biomarkers↗

PubMed1992

A systematic search for protein signature sequences.

Signature sequences are contiguous patterns of amino acids 10-50 residues long that are associated with a particular structure or function in proteins. These may be of three types (by our nomenclature): superfamily signatures, remnant homologies, and motifs. We have performed a systematic search through a database of protein sequences to automatically and preferentially find remnant homologies and motifs. This was accomplished in three steps: 1. We generated a nonredundant sequence database. 2. We used BLAST3 (Altschul and Lipman, Proc. Natl. Acad. Sci. U.S.A. 87:5509-5513, 1990) to generate local pairwise and triplet sequence alignments for every protein in the database vs. every other. 3. We selected "interesting" alignments and grouped them into clusters. We find that most of the clusters contain segments from proteins which share a common structure or function. Many of them correspond to signatures previously noted in the literature. We discuss three previously recognized motifs in detail (FAD/NAD-binding, ATP/GTP-binding, and cytochrome b5-like domains) to demonstrate how the alignments generated by our procedure are consistent with previous work and make structural and functional sense. We also discuss two signatures (for N-acetyltransferases and glycerol-phosphate binding) which to our knowledge have not been previously recognized.

Amino Acid Sequence↗

PubMed2002

Evolution of the delta13C signature related to total carbon contents and carbon decomposition rate constants in a soil profile under grassland.

Evolution of the total carbon (C) content and the (13)C enrichment (delta(13)C signature) of soil organic matter (SOM) with increasing depth in a soil profile under permanent grassland (C(3) vegetation) were investigated. The relationship between the total C content and the delta(13)C signature at different depths in the upper 30 cm of the soil profile could be well fitted by the Rayleigh equation (y = -29.8 - 2.3x, R(2) = 0.95, p < 0.001), describing the enrichment in (13)C as resulting from isotopic fractionation associated with C mineralization (isotope enrichment factor epsilon = -2.3 per thousand). Potential C dynamics of SOM in four depth intervals of the profile (0-10, 10-20, 20-30 and 30-40 cm depth) were investigated through an incubation study. The C decomposition rate constants decreased with increasing sampling depth from 0.0479 yr(-1) (0-10 cm sampling depth) to 0.0256 yr(-1) (30-40 cm sampling depth) and were highly correlated (y = 0.02 + 0.13x, R(2) = 0.93, p < 0.05) with the corresponding deltadelta(13)C values (average change of the delta(13)C signature per depth increment). These results suggest that changes of the delta(13)C signature of SOM in undisturbed soil profiles under continuous C(3) vegetation may serve as an indicator of the variation of SOM quality with increasing depth.

Biodegradation, Environmental↗

PubMed2025

Intratumoral B cell and interferon signatures in newly diagnosed glioblastoma are associated with longer survival in patients treated with SurVaxM.

Glioblastoma (GBM) has proved difficult to treat, and there is dire need for more effective therapies. In a single arm phase IIa trial (NCT02455557), treatment of newly diagnosed GBM patients with the peptide vaccine SurVaxM resulted in promising median progression-free and overall survival. To investigate molecular features that associate with GBM responsiveness to SurVaxM, retrospective whole exome and RNA sequencing was performed on patient tumors (n = 34) collected prior to standard of care treatment plus SurVaxM. Differential gene expression and mutational profiles were characterized between patients with short-term (OS < 18 months) or long-term (OS ≥ 18 months) overall survival. Greater expression of interferon, complement, and humoral immunity signatures were associated with long-term survival. Deconvolution of transcriptomes identified enrichment of intratumoral memory B cell populations in long-term survivors that were validated by CD20 staining in matched samples. A five-gene expression signature and a B cell specific signature predicted survival within the SurVaxM-treated cohort, however, these signatures were not associated with improved outcomes in a similarly treated population obtained from The Cancer Genome Atlas (TCGA) that did not receive immunotherapeutic intervention. Although prospective validation is ongoing, the findings in this discovery cohort specify molecular features of GBM associated with better overall survival and potential responsiveness to immunotherapy with SurVaxM.

Humans↗

PubMed2004

Tissue signature characterisation of diffusion tensor abnormalities in cerebral gliomas.

The inherent invasiveness of malignant cells is a major determinant of the poor prognosis of cerebral gliomas. Diffusion tensor MRI (DTI) can identify white matter abnormalities in gliomas that are not seen on conventional imaging. By breaking down DTI into its isotropic (p) and anisotropic (q) components, we can determine tissue diffusion "signatures". In this study we have characterised these abnormalities in peritumoural white matter tracts. Thirty-five patients with cerebral gliomas and seven normal volunteers were imaged with DTI and T2-weighted sequences at 3 T. Displaced, infiltrated and disrupted white matter tracts were identified using fractional anisotropy (FA) maps and directionally encoded colour maps and characterised using tissue signatures. The diffusion tissue signatures were normal in ROIs where the white matter was displaced. Infiltrated white matter was characterised by an increase in the isotropic component of the tensor (p) and a less marked reduction of the anisotropic component (q). In disrupted white matter tracts, there was a marked reduction in q and increase in p. The direction of water diffusion was grossly abnormal in these cases. Diffusion tissue signatures may be a useful method of assessing occult white matter infiltration.

Adult↗

PubMed2002

Dinucleotide compositional analysis of Sinorhizobium meliloti using the genome signature: distinguishing chromosomes and plasmids.

The symbiotic N(2)-fixing alpha-proteobacterium Sinorhizobium meliloti has three replicons: a circular chromosome (3.7 Mb) and two smaller replicons, pSymA (1.4 Mb) and pSymB (1.7 Mb). Sequence analysis has revealed that an essential gene is carried on pSymB, which brings into question whether pSymB should be considered a chromosome or a plasmid. Based on the criterion that essential genes define a chromosome, several species have been shown to have multiple chromosomes. Many of these species are part of the alpha subdivision of the Proteobacteria family. Here, additional justification is presented for designating the pSymB replicon as a chromosome. It is shown that chromosomes within a species share a more similar dinucleotide composition, or genome signature, than plasmids do with the host chromosome(s). Dinucleotide signatures were determined for each of the S. meliloti replicons, and, consistent with the suggestion that pSymB is a chromosome, it is shown that the pSymB signature more closely resembles that of the S. meliloti chromosome, while the pSymA signature is typical of other alpha-proteobacterial plasmids.

Genome, Bacterial↗

PubMed1992

A signature element distinguishes sibling and independent mutations in a shuttle vector plasmid.

We have developed a new shuttle vector plasmid for studying mutagenesis in mammalian cells that permits proof of independence of identical mutations. Mutations occur more frequently at some sites in a gene than in others, and in a collection of mutant plasmids from a single transfection of mammalian cells the same mutation may appear several times. However, those arising from independent events cannot be distinguished from siblings of an initial event. The new vector system (pSP189) is a population of plasmids, each of which contains an 8-bp 'signature sequence'. This sequence confers a unique identification tag to each plasmid and allows individual members to be identified by a distinctive signature. The plasmid also carries the Escherichia coli bacterial supF gene as a marker for mutagenesis, as well as sequences which support replication in primate (including human) cells and E. coli. We have used the pSP189 system to generate a UV-induced spectrum of mutations in supF following replication in a single plate of human DNA-repair-deficient cells (xeroderma pigmentosum, complementation group A). With the signature sequence, we were able to determine whether identical mutations derived from the transfection were of independent or sibling origin. There were eight identical mutations at the strongest hotspot, all of which had different signature sequences. Only one of these events would have been reported in previous experiments. This plasmid reduces the effort required to generate a spectrum of mutations caused by a DNA-damaging agent and allows a more accurate assessment of mutational hotspot intensity.

Base Sequence↗

PubMed2005

Using the transcriptome to annotate the genome revisited: application of massively parallel signature sequencing (MPSS).

Transcriptome analysis can provide useful data for refining genome sequence annotation. Application of massively parallel signature sequencing (MPSS) revealed reproducible transcription, in multiple MPSS cycles, from 73% of computationally predicted genes in the Theileria parva schizont lifecycle stage. Signatures spanning consecutive exons confirmed 142 predicted introns. MPSS identified 83 putative genes, >100 codons overlooked by annotation software, and 139 potentially incorrect gene models (with either truncated ORFs or overlooked exons) by interfacing signature locations with stop codon maps. Twenty representative models were confirmed as likely to be incorrect using reverse transcription PCR amplification from independent schizont cDNA preparations. More than 50% of the 60 putative single copy genes in T. parva that were absent from the genome of the closely related T. annulata had MPSS signatures. This study illustrates the utility of MPSS for improving annotation of small, gene-rich microbial eukaryotic genomes.

Animals↗

PubMed2004

Characterization of N-terminal processing of group VIA phospholipase A2 and of potential cleavage sites of amyloid precursor protein constructs by automated identification of signature peptides in LC/MS/MS analyses of proteolytic digests.

Dysregulation of proteolytic processing of the amyloid precursor protein (APP) contributes to the pathogenesis of Alzheimer's Disease, and the Group VIA phospholipase A(2) (iPLA(2)beta) is the dominant PLA(2) enzyme in the central nervous system and is subject to regulatory proteolytic processing. We have identified novel N-terminal variants of iPLA(2)beta and previously unrecognized proteolysis sites in APP constructs with a C-terminal 6-myc tag by automated identification of signature peptides in LC/MS/MS analyses of proteolytic digests. We have developed a Signature-Discovery (SD) program to characterize protein isoforms by identifying signature peptides that arise from proteolytic processing in vivo. This program analyzes MS/MS data from LC analyses of proteolytic digests of protein mixtures that can include incompletely resolved components in biological samples. This reduces requirements for purification and thereby minimizes artifactual modifications during sample processing. A new algorithm to generate the theoretical signature peptide set and to calculate similarity scores between predicted and observed mass spectra has been tested and optimized with model proteins. The program has been applied to the identification of variants of proteins of biological interest, including APP cleavage products and iPLA(2)beta, and such applications demonstrate the utility of this approach.

Algorithms↗