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PubMed2026

Quantitative N-glycoproteomic analysis reveals glycosylation signatures of plasma immunoglobulin G in sepsis.

INTRODUCTION: Sepsis is a life-threatening condition resulting from organ dysfunction due to a dysregulated immune response to infection. Immunoglobulin G (IgG) plays a role in modulating immune responses. However, the precise IgG subclass-specific N-glycosylation profiles in patients with sepsis remain poorly characterized. METHODS: This study aimed to define the site-specific N-glycosylation signatures of plasma IgG subclasses in sepsis patients with different prognoses using quantitative glycoproteomics. By employing our established GlycoQuant strategy, we quantified the intact N-glycopeptides (IGPs) of IgG subclasses in 40 healthy controls and 40 sepsis patients with a clear prognosis. RESULTS: We identified 12 IGPs with altered abundances between patients with sepsis and healthy controls. After Benjamini-Hochberg (BH) correction of the 31 outcome-stratified IGP comparisons, IGP24 and IGP25 remained significant and met the prespecified fold-change criterion. Global BH correction across 124 IGP-clinical parameter correlations retained positive associations of IGP19, IGP22, and IGP23 with procalcitonin (PCT). In exploratory outcome-stratified ROC analyses, candidates were selected using the original unadjusted P-value and fold-change screen; five IGPs were evaluated, with IGP25 and IGP24 yielding the highest individual AUCs. Collectively, our findings underscore the potential of IgG subclass-specific glycosylation profiling as a novel translational approach for clinical applications in sepsis management. SIGNIFICANCE: Sepsis remains a leading cause of global mortality, with patient outcomes heavily dependent on timely diagnosis and accurate prognosis. The dysregulated host immune response, particularly involving immunoglobulins, is central to its pathophysiology. This study provides a significant advance in the field of clinical glycoproteomics by applying a quantitative, site-specific strategy to delineate the plasma IgG subclass N-glycosylation landscape in sepsis. We report, for the first time, a panel of subclass-specific intact IgG N-glycopeptides (IGPs) that are significantly altered in sepsis patients compared to healthy controls. The identified IGPs not only demonstrate diagnostic and prognostic potential but also show a significant correlation with procalcitonin, a key clinical severity index. These findings bridge a critical knowledge gap by moving beyond bulk IgG glycosylation analysis to subclass-resolved profiling, offering novel molecular insights into sepsis immunopathology. The identified glycosylation signatures hold substantial translational promise as a foundation for developing innovative, glycan-based biomarker panels to improve the precision management of this heterogeneous and life-threatening syndrome.

Humans↗
PubMed2005

Signature-tagged mutagenesis: technical advances in a negative selection method for virulence gene identification.

Signature-tagged mutagenesis (STM) is a powerful negative selection method, predominantly used to identify the genes of a pathogen that are required for the successful colonization of an animal host. Since its first description a decade ago, STM has been applied to screen a vast amount of transposon insertion mutants in 31 bacterial species. This has led to the identification of over 1,700 bacterial genes that are involved in virulence. Despite the preservation of the basic design, the STM method has been developed further owing to recent advances including different designs of the signature-tags and profound changes in the mode of detection. These advances promoted substantially the application range and versatility of the STM method.

Bacteria↗
PubMed2025

Methylation Signatures Identify Two Distinct Clusters of Uterine Leiomyosarcoma With Unique Histologic and Clinical Behaviors.

Uterine leiomyosarcoma (uLMS) is a rare and deadly gynecologic malignancy. uLMS is histologically heterogeneous and presents with a wide spectrum of tumor differentiation, with a broad range of genomic DNA instability, which can make the diagnosis and prognosis of uLMS challenging. Methylation has emerged as a useful molecular tool in tumor classification and diagnosis in certain neoplasms. We initiated this study to investigate the role of global methylation in the differential diagnosis of uLMS from its mimics in correlation with pathologic characteristics and clinical outcomes. In this study, we performed array-based global methylation profiling analysis in a total of 71 uLMS and compared the methylation signatures of uLMS with several other uterine mesenchymal tumors and soft tissue leiomyosarcoma. We found that uLMS demonstrated distinct methylation patterns differing from all other tumor types. Notably, methylation profiling defines 2 distinct subgroups of uLMS with differing copy number alterations, resulting in unique histologic and clinical behaviors, further emphasized by differences in methylation pathway analysis. This study is the first to report methylation profiling as a useful diagnostic tool in differentiating uLMS from mimics and defines 2 subtypes of uLMS based on methylation signatures.

Humans↗
PubMed2026

Integrative WGBS and ATAC-seq profiling reveals epigenetic and chromatin accessibility signatures associated with clutch length in goose ovaries.

Clutch length is an important reproductive trait in geese, but its epigenetic basis remains poorly characterized. Daily egg production was recorded for 280 individually housed Zi geese, and clutch-related indices were calculated as described in our previous study. Based on these records, six geese with contrasting clutch-length phenotypes were selected and assigned to the long-clutch (LC) and short-clutch (SC) groups. Ovarian tissues from three geese per group were subjected to whole-genome bisulfite sequencing (WGBS) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to identify candidate epigenetic signatures associated with clutch length. WGBS identified 630,909 differentially methylated regions (DMRs), whereas ATAC-seq identified 902 differentially accessible regions (DARs). Integrated analysis revealed distinct patterns of ovarian DNA methylation and chromatin accessibility between the two groups, suggesting that clutch length variation may be accompanied by epigenomic differences in ovarian tissue. Genes associated with DMRs and/or DARs were enriched in biological processes related to granulosa cell differentiation and endocrine competence, follicular fate regulation, and periovulatory cytoskeletal and signaling remodeling. RERE was prioritized as a candidate locus because it was supported by changes in both DNA methylation and chromatin accessibility, whereas FOXL2, STAR, BAK1, FGF17, PRSS35, ACTR3, and AXIN1 were supported mainly by evidence from a single omics layer. RT-qPCR analysis of selected genes showed expression trends broadly consistent with the corresponding epigenomic differences, providing additional supportive evidence for these candidate associations. Collectively, this study provides an exploratory ovarian epigenomic resource and identifies candidate epigenetic signatures, genes, and biological processes associated with clutch length variation in geese.

DNA methylation↗
PubMed2006

In vitro testing of platelets using the thromboelastogram, platelet function analyzer, and the clot signature analyzer to predict the bleeding time.

BACKGROUND: Platelet aggregation, thromboxane A2 production and platelet annexin V binding are in vitro tests used to assess platelet function. This study was done to evaluate the clot signature analyzer (CSA), platelet function analyzer (PFA), and thromboelastogram (TE) as in vitro tests to predict the template bleeding time (BT). STUDY DESIGN AND METHODS: Twelve normal volunteers were studied before and after removal of 2 units of RBC. Seven females were reinfused their RBC and 5 males were not. Samples were collected prior to and at 24, 48, and 72 h and 7 days after the RBC removal whether or not reinfusion of RBC was performed for measurement of TE, CSA, PFA and template BT. RESULTS: BT increased significantly following the removal of 2 units of RBC and BT decreased significantly after the reinfusion of the 2 units of RBC in the 7 female volunteers. BT decreased during the 7-day period in the 5 male volunteers not reinfused their RBC. No significant correlations were observed between BT and platelet hemostatic time (PHT) and clotting time (CT) in the CSA and between the bleeding time and the closure time (CT) in the platelet function analyzer (PFA). Significant correlations were observed between BT and K time, the MA, and the angle recorded in the thromboelastogram. CONCLUSION: In this study in vitro testing using the clot signature analyzer, platelet function analyzer and the thromboelastogram could not be used to predict the template bleeding time.

Annexin A5↗
PubMed2005

Examination of the molecular signature associated with islet dysfunction.

The aim of this study was to identify the molecular signatures that are predictive of nonfunctional islet preparations. We examined functional outcomes of six islet preparations accepted for research purposes from human donors. Islet were maintained on culture in M-SFM media for 7 to 14 days then transplanted into NOD-SCID mice. At the time of transplant, RNA was extracted from a second aliquot of cultured islets for expression analysis. We also performed gene expression analysis using high-density Affymetrix U133A GeneChips on these preparations. Among 1833 genes selected, hierarchical clustering was performed using the GeneSpring software package (Silicon Genetics, Inc.), where 754 genes (higher in nonfunctional) and 177 genes (lower in nonfunctional) were differentially expressed with tight pattern of expression. Islets with low functionality showed high relative levels of expression of hypoxia-induced genes and increased frequency of expression of proinflammatory and proangiogenic genes, such as vascular endothelial growth factor. Conversely, nonfunctional islets had low levels of insulin-processing message. The general profile of these low-functionality islets shows attempted recovery from hypoxic assault and little effort directed toward insulin production and secretion. Further identification of the molecular signature of nonfunctional islets could allow the development of a potency assay for human transplantation.

Cadaver↗
PubMed2006

Differential expression of genes encoding CD30L and P-selectin in cattle with Johne's disease: progress toward a diagnostic gene expression signature.

Mycobacterium avium subspecies paratuberculosis (Mycobacterium paratuberculosis), the causative agent of paratuberculosis (paraTB) or Johne's disease in ruminants, is a health problem for the global cattle industry with significant economic losses related to decreased milk production and reduced fertility. Commonly paraTB in cattle is diagnosed by antibody detection by serum enzyme-linked immunosorbent assay (ELISA), by detection of the pathogen by cultivation of individual faecal samples, or by in vitro measurement of cell mediated immune responses using the IFN-gamma test. There is an ongoing need for developing new diagnostic approaches as all currently available diagnostic tests for paraTB may fail to detect sub-clinical infection. We used cDNA microarrays to simultaneously measure expression of over 1300 host genes to help identify a subset of gene expression changes that might provide a unique gene expression signature for paraTB infection. In the present study, non-stimulated leukocytes isolated from 10 sub-clinical paraTB infected cows were examined for genes being expressed at significantly different levels than in similar cells from control cows with the same herd background. We included cattle (Holstein) from two locations (Denmark and USA) for the microarray experiment. Our results indicate that expression profiles of at least 52 genes are different in leukocytes from M. paratuberculosis infected cattle compared to control cattle. Gene expression differences were verified by quantitative real-time reverse transcriptase polymerase chain reactions (qRT-PCR) on the same group of cattle (Holstein) used for the microarray experiment. In order to assess the generality of the observed gene expression, a second and different group of cattle (Jersey) was also examined using qRT-PCR. Out of the seven genes selected for qRT-PCR, CD30 ligand (CD30L) and P-selectin were consistently differentially expressed in freshly isolated leukocytes from paraTB infected and control animals of both breeds of cattle. Although further work is clearly needed to develop a more complete gene expression signature specific for paraTB, our results demonstrate that a subset of genes in leukocytes are consistently expressed at different levels, depending upon M. paratuberculosis infection status.

Animals↗
PubMed2006

Signatures from tissue-specific MPSS libraries identify transcripts preferentially expressed in the mouse inner ear.

Specialization in cell function and morphology is influenced by the differential expression of mRNAs, many of which are expressed at low abundance and restricted to certain cell types. Detecting such transcripts in cDNA libraries may require sequencing millions of clones. Massively parallel signature sequencing (MPSS) is well suited to identifying transcripts that are expressed in discrete cell types and in low abundance. We have made MPSS libraries from microdissections of three inner ear tissues. By comparing these MPSS libraries to those of 87 other tissues included in the Mouse Reference Transcriptome online resource, we have identified genes that are highly enriched in, or specific to, the inner ear. We show by RT-PCR and in situ hybridization that signatures unique to the inner ear libraries identify transcripts with highly specific cell-type localizations. These transcripts serve to illustrate the utility of a resource that is available to the research community. Utilization of these resources will increase the number of known transcription units and expand our knowledge of the tissue-specific regulation of the transcriptome.

Animals↗
PubMed2004

Multi-class cancer subtype classification based on gene expression signatures with reliability analysis.

Differential diagnosis among a group of histologically similar cancers poses a challenging problem in clinical medicine. Constructing a classifier based on gene expression signatures comprising multiple discriminatory molecular markers derived from microarray data analysis is an emerging trend for cancer diagnosis. To identify the best genes for classification using a small number of samples relative to the genome size remains the bottleneck of this approach, despite its promise. We have devised a new method of gene selection with reliability analysis, and demonstrated that this method can identify a more compact set of genes than other methods for constructing a classifier with optimum predictive performance for both small round blue cell tumors and leukemia. High consensus between our result and the results produced by methods based on artificial neural networks and statistical techniques confers additional evidence of the validity of our method. This study suggests a way for implementing a reliable molecular cancer classifier based on gene expression signatures.

Artificial Intelligence↗
PubMed2000

Pigment signatures associated with an anoxic coastal zone: Bahia Concepcion, Gulf of California.

Bahia Concepcion is a coastal lagoon that has bottom anoxic conditions and high pigment concentrations during the summer. The phytoplankton responsible for this pigment increase is enigmatic, therefore we sampled the lagoon to analyze the pigment with a C8-HPLC system to look for signatures of phytoplankton groups. Analysis reveals a low pigment concentration in the mixed layer with a higher concentration of zeaxanthin and increasing values of chlorophyll a, peridinin, and fucoxanthin below, which peaked at the depth where oxygen dramatically decreases and H(2)S increases. Below this depth, a high pigmentation was recorded and the most important signatures were six chlorophyll-like pigments that eluted between the fucoxanthin and the chlorophyll a, and one carotenoid that eluted just after the chlorophyll a. Spectral characteristics of these last pigments are very similar to pigments present in the Chlorobiales group. These results suggest that cyanobacteria, diatoms, and dinoflagellates are responsible for the chlorophyll a increases, though in highly pigmented samples, anoxygenic phototrophic bacteria are probably the main contributors to the increase in pigments.

Journal Article↗
PubMed2003

Cytokine signatures in atherosclerotic claudicants.

BACKGROUND: Iron accumulation and inflammation may affect atherosclerosis. This study intended to define a cytokine signature in atherosclerotic claudicants and to determine whether reduction in serum ferritin by phlebotomy influenced this pattern. METHODS: Ninety-one subjects with peripheral vascular disease (PVD; mean age, 67 years) were recruited from the VA Cooperative Iron and Atherosclerosis Study (FeAST) testing the hypothesis that ferritin reduction to 25 ng/ml may ameliorate atherosclerosis. Cytokines TNF-a, IL-2, IL-6, and IL-10 were analyzed by enzyme amplified sensitivity assay (EASIA). Fasting iron and cholesterol panels, complete blood count, C-reactive protein (CRP), uric acid, fibrinogen, glucose, and hemoglobin A1c levels were also quantified. Values were compared with "healthy" controls (n = 21; mean age, 56 years). After randomization of PVD to phlebotomy (intervention group [IG], n = 44) or control (nonintervention group [NG], n = 47), analyses were compared at 6 and 12 months using t test, Wilcoxon rank sum test, chi-square, and robust MM regression. FINDINGS: Age, glucose, and hemoglobin A1c were higher in PVD compared with healthy controls (P < 0.01), whereas serum iron (P < 0.01) and percentage of transferrin saturation (P < 0.05) were lower. Tumor necrosis factor-alpha (TNF-alpha; P < 0.05), IL-6 (P < 0.01), and CRP (P < 0.05) levels were higher in the PVD group, whereas IL-10 was lower (P < 0.01). At 6 months post phlebotomy, ferritin levels were reduced (P < 0.01), although ferritin levels were reduced less in smokers. IL-6 and fibrinogen, CRP and ferritin levels correlated positively. At 6 and 12 months, subjects with TNF-alpha (n= 15) and IL-6 (n = 10) levels in the upper 25th percentile were reduced by phlebotomy. INTERPRETATION: An inflammatory cytokine signature exists in atherosclerosis. Elevated levels of TNF-alpha and IL-6, reportedly associated with recurrent and future myocardial infarction, were reduced by phlebotomy. The utility of the iron/inflammatory hypotheses will ultimately relate to clinical outcomes obtained prospectively by the FeAST trial.

Aged↗
PubMed2003

The distinctive isotopic signature of plant-derived chloromethane: possible application in constraining the atmospheric chloromethane budget.

Chloromethane (CH(3)Cl) is the most abundant halocarbon in the atmosphere. Although largely of natural origin it is responsible for around 17% of chlorine-catalysed ozone destruction. Sources identified to date include biomass burning, oceanic emissions, wood-rotting fungi, higher plants and most recently tropical ferns. Current estimates reveal a shortfall of around 2 million ty(-1) in sources versus sinks for the halocarbon. It is possible that emissions from green plants have been substantially underestimated. A potentially valuable tool for validating emission flux estimates is comparison of the delta13C value of atmospheric CH(3)Cl with those of CH(3)Cl from the various sources. Here we report delta13C values for CH(3)Cl released by two species of tropical ferns and show that the isotopic signature of CH(3)Cl from pteridophytes like that of CH(3)Cl from higher plants is quite different from that of CH(3)Cl produced by biomass burning, fungi and industry. delta13C values for CH(3)Cl produced by Cyathea smithii and Angiopteris evecta were respectively -72.7 per thousand and -69.3 per thousand representing depletions relative to plant biomass of 42.3 per thousand and 43.4 per thousand. The characteristic isotopic signature of CH(3)Cl released by green plants should help constrain their contribution to the atmospheric burden when reliable delta13C values for all other major sources of CH(3)Cl are obtained and a globally averaged delta13C value for atmospheric CH(3)Cl is available.

Air Pollutants↗
PubMed2002

Catchment-specific element signatures in estuarine crocodiles (Crocodylus porosus) from the Alligator Rivers Region, northern Australia.

The concentrations of Na, K, Ca, Mg, Ba, Sr, Fe, Al, Mn, Zn, Pb, Cu, Ni, Cr, Co, Se, U and Ti were determined in the osteoderms and/or flesh of estuarine crocodiles (Crocodylus porosus) captured in three adjacent catchments within the Alligator Rivers Region (ARR) of northern Australia. Results from multivariate analysis of variance showed that when all metals were considered simultaneously, catchment effects were significant (P < or = 0.05). Despite considerable within-catchment variability, linear discriminant analysis (LDA) showed that differences in elemental signatures in the osteoderms and/or flesh of C. porosus amongst the catchments were sufficient to classify individuals accurately to their catchment of occurrence. Using cross-validation, the accuracy of classifying a crocodile to its catchment of occurrence was 76% for osteoderms and 60% for flesh. These data suggest that osteoderms provide better predictive accuracy than flesh for discriminating crocodiles amongst catchments. There was no advantage in combining the osteoderm and flesh results to increase the accuracy of classification (i.e. 67%). Based on the discriminant function coefficients for the osteoderm data, Ca, Co, Mg and U were the most important elements for discriminating amongst the three catchments. For flesh data, Ca, K, Mg, Na, Ni and Pb were the most important metals for discriminating amongst the catchments. Reasons for differences in the elemental signatures of crocodiles between catchments are generally not interpretable, due to limited data on surface water and sediment chemistry of

Alligators and Crocodiles↗
PubMedDate not supplied

Protein expression signatures identified in Mytilus edulis exposed to PCBs, copper and salinity stress.

Applied to environmental toxicology, proteome analysis may be used to isolate chemical-specific protein expression signatures (PES). In this project specific PES were isolated in mussels, Mytilus edulis, from the Baltic Sea subjected in the laboratory to treatment with copper (70 ppb), Aroclor 1248 (1 ppb), and to lowered salinity. Four mussels in each treatment group were acclimated in the laboratory for 24 h before beginning the 7-day exposure. Whole body tissue was homogenized and separated using two-dimensional gel electrophoresis. The protein gels were scanned to TIFF files and compared using MELANIE II 2D gel analysis software (BioRad). Protein expression signatures including proteins induced and repressed by exposure were isolated for each treatment group. The specificity of PES due to environmental changes shows promise in bioindication, toxicity testing and in helping identify possible toxicity mechanisms.

Animals↗
PubMed2001

Adaptation of signature-tagged mutagenesis for Toxoplasma gondii: a negative screening strategy to isolate genes that are essential in restrictive growth conditions.

The obligate intracellular parasite Toxoplasma gondii can infect virtually any nucleated cell in any warm-blooded host. Through the effort of many researchers, we are beginning to learn what makes T. gondii such a successful protozoan parasite. A high throughput genetic screen that allows simultaneous examination of a large panel of mutants would greatly facilitate a global investigation of this parasite. Signature-tagged mutagenesis uses a unique DNA sequence to tag an individual mutant so that it can later be identified within a pool. This system allows the efficient identification of parasites carrying mutations in genes that are essential for growth in restrictive but not permissive conditions. We have generated a bank of approximately 4900 signature-tagged T. gondii tachyzoites represented in 89 pools, each of which contains 60 uniquely tagged mutant parasites. We have demonstrated the usefulness of this negative screening strategy with a tissue culture model for pyrimidine salvage using resistance to the pro-drug FUDR. Mutants that are defective for growth in any defined growth condition versus standard tissue culture conditions can now be identified (eg, sensitive to a specific drug, growth in a specialized cell line, or growth within animals).

Animals↗
PubMed2003

Phylogenetic analysis of the family Thermaceae with an emphasis on signature position and secondary structure of 16S rRNA.

The sequences of the 16S rRNA genes from 38 strains of the family Thermaceae were compared by alignment analysis. The genus-specific and species-specific base substitutions or base deletions (signature positions) were found in three hypervariable regions (in the helices 6, 10 and 17). The differentiation of secondary structures of the high variable regions in the 5' end (38-497) containing several signature positions further supported the concept. Based on the comparisons of the secondary structures in the segments of 16S rRNAs, a key to the species of the family Thermaceae was proposed.

DNA, Bacterial↗
PubMed2002

Gene expression analysis by signature pyrosequencing.

We describe a novel method for transcript profiling based on high-throughput parallel sequencing of signature tags using a non-gel-based microtiter plate format. The method relies on the identification of cDNA clones by pyrosequencing of the region corresponding to the 3'-end of the mRNA preceding the poly(A) tail. Simultaneously, the method can be used for gene discovery, since tags corresponding to unknown genes can be further characterized by extended sequencing. The protocol was validated using a model system for human atherosclerosis. Two 3'-tagged cDNA libraries, representing macrophages and foam cells, which are key components in the development of atherosclerotic plaques, were constructed using a solid phase approach. The libraries were analyzed by pyrosequencing, giving on average 25 bases. As a control, conventional expressed sequence tag (EST) sequencing using slab gel electrophoresis was performed. Homology searches were used to identify the genes corresponding to each tag. Comparisons with EST sequencing showed identical, unique matches in the majority of cases when the pyrosignature was at least 18 bases. A visualization tool was developed to facilitate differential analysis using a virtual chip format. The analysis resulted in identification of genes with possible relevance for development of atherosclerosis. The use of the method for automated massive parallel signature sequencing is discussed.

Base Sequence↗
PubMed2000

Inverse complementary homologues of short cysteine signatures.

Inversions of short genomic sequences may play a central role in the generation of protein complexity. We report here the existence of an heterogeneous group of proteins (the trefoil precursors MUC-1 and MUA-1, six preproendothelins, and five classes of zinc finger knot proteins) having both cysteine signatures (Cs) and their inverse complementary sequences (Cs) in the same polypeptide chain. We have also found cases in which the (Cs) of a given signature is not present in the same protein, but elsewhere. TGEKPYK, a cysteine-free motif of the human transcription factor, Krab, coexists with its inverse complementary sequence in 31 proteins; the inverse complementary alone is present in a great number of proteins. Our findings suggest that short DNA inversions are a widespread feature of the genome.

Amino Acid Sequence↗