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PubMed2026

Proteomic Immune Signatures of Severe HIV-Associated Tuberculosis in Sub-Saharan Africa: A Prospective, Multicenter Analysis From Uganda.

OBJECTIVES: Severe tuberculosis (TB) is a major cause of critical illness and death in people living with HIV (PLWH) worldwide. Despite this, the immunopathology of severe HIV-associated TB (HIV/TB) is poorly understood. We aimed to identify an immunopathologic signature of severe HIV/TB in sub-Saharan Africa. DESIGN AND SETTING: We analyzed proteomic data from two prospective observational cohorts of adults hospitalized with severe undifferentiated infection in Uganda: an urban discovery cohort (Entebbe, n = 241) and a rural validation cohort (Tororo, n = 253). PATIENTS: Adults (age ≥ 18 yr) hospitalized with severe febrile illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, severe HIV/TB was common, affecting 18% of participants in the discovery cohort and 21% in the validation cohort. Overall mortality was significant (30-d mortality of 22% in the discovery cohort and 60-d mortality of 26% in the validation cohort). Participants were stratified into three HIV/TB phenotypes: HIV-negative without TB, PLWH without TB, and PLWH with microbiologically diagnosed TB. We applied ordinal random forest models in the discovery cohort as a supervised feature-selection approach to identify proteins associated with progressive HIV/TB phenotype. In both cohorts, PLWH with microbiologically diagnosed TB were at highest risk of critical illness and death (30-d mortality of 42% in the discovery cohort and 60-d mortality of 52% in the validation cohort). An eight-protein signature reliably distinguished this phenotype, reflecting mediators of macrophage/dendritic cell activation (lysosome-associated membrane glycoprotein 3), natural killer cell and T-cell stimulation and cytotoxicity (cluster of differentiation 70, class I-restricted T-cell-associated molecule), B-cell activation (immunoglobulin lambda constant 2), protease-mediated tissue injury (protease, serine 2 [trypsin-2]), dysregulated coagulation (serpin peptidase inhibitor, clade A [alpha-1 antitrypsin], member 5), extracellular matrix remodeling (epidermal growth factor-containing fibulin-like extracellular matrix protein 1), and growth hormone/insulin-like growth factor axis dysregulation (insulin-like growth factor binding protein 3). CONCLUSIONS: We identified an immunologic signature of severe HIV/TB defined by mediators of macrophage/dendritic cell and cytotoxic lymphocyte activation, extracellular matrix remodeling, and dysregulated coagulation. These findings offer new insight into HIV/TB pathobiology and highlight potential targets for host-directed therapies in this high-risk population.

Humans↗
PubMed2026

The association of cardiovascular health with new-onset pulmonary hypertension and the mediating role of proteomic signatures.

BACKGROUND: The cardiovascular health (CVH) metrics have been reported to play an important role in the development of noncommunicable chronic diseases, yet its link to pulmonary hypertension (PH) risk and the underlying biological mechanisms remain unclear. This study aimed to investigate the association of CVH with PH risk and elucidate the mediating role of plasma proteomic signatures. METHODS: A total of 279 220 participants without PH at enrollment of the UK Biobank were included. Cox regression was used to quantify the association between CVH and incident PH. Proteome-wide association analysis, mediation analysis, and functional enrichment analysis were conducted to identify protein mediators. Key hub proteins were further validated at the transcriptional level through quantitative polymerase chain reaction (qPCR) in an animal model of PH, as well as at the protein level, and by macrophage-specific knockdown of interleukin (IL)-6 and CCL4 to evaluate its impact on rat pulmonary artery smooth muscle cell (PASMC) migration and proliferation. RESULTS: Over a median 13.2-year follow-up, 1325 PH cases occurred. Compared to the lowest CVH, participants with moderate and high CVH had 59% [hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.33-0.49] and 82% (HR: 0.18; 95% CI: 0.14-0.23) lower risk, respectively. Proteomic analyses revealed that this association was significantly mediated by a distinct plasma protein signature. Pathway enrichment analysis indicates that proteins are significantly enriched in inflammatory/immune pathways, and key hub proteins were identified as participating in the central mechanism pathway. In the lung tissue of PH rat models, the mRNA and protein expression levels of IL-6 and C-C motif chemokine ligand 4 (CCL4) were significantly elevated. Furthermore, functional assays demonstrated that knockdown of IL-6 or CCL4 in macrophages significantly attenuated the migration and proliferation of rat PASMCs in vitro. CONCLUSION: High CVH level, defined by Life's Essential 8 (LE8), is significantly linked to a reduced risk of developing PH. This protective effect is primarily mediated by a proteomic signature, revealing the role of signaling pathways such as cytokine-cytokine receptor interaction in the prevention of PH.

Hypertension, Pulmonary↗
PubMed2005

Reverse taxonomy: an approach towards determining the diversity of meiobenthic organisms based on ribosomal RNA signature sequences.

Organisms living in or on the sediment layer of water bodies constitute the benthos fauna, which is known to harbour a large number of species of diverse taxonomic groups. The benthos plays a significant role in the nutrient cycle and it is, therefore, of high ecological relevance. Here, we have explored a DNA-taxonomic approach to access the meiobenthic organismic diversity, by focusing on obtaining signature sequences from a part of the large ribosomal subunit rRNA (28S), the D3-D5 region. To obtain a broad representation of taxa, benthos samples were taken from 12 lakes in Germany, representing different ecological conditions. In a first approach, we have extracted whole DNA from these samples, amplified the respective fragment by PCR, cloned the fragments and sequenced individual clones. However, we found a relatively large number of recombinant clones that must be considered PCR artefacts. In a second approach we have, therefore, directly sequenced PCR fragments that were obtained from DNA extracts of randomly picked individual organisms. In total, we have obtained 264 new unique sequences, which can be readily placed into taxon groups, based on phylogenetic comparison with currently available database sequences. The group with the highest taxon abundance were nematodes and protozoa, followed by chironomids. However, we find also that we have by far not exhausted the diversity of organisms in the samples. Still, our data provide a framework within which a meiobenthos DNA signature sequence database can be constructed, that will allow to develop the necessary techniques for studying taxon diversity in the context of ecological analysis. Since many taxa in our analysis are initially only identified via their signature sequences, but not yet their morphology, we propose to call this approach 'reverse taxonomy'.

Animals↗
PubMed2005

Offline geometric parameters for automatic signature verification using fixed-point arithmetic.

This paper presents a set of geometric signature features for offline automatic signature verification based on the description of the signature envelope and the interior stroke distribution in polar and Cartesian coordinates. The features have been calculated using 16 bits fixed-point arithmetic and tested with different classifiers, such as hidden Markov models, support vector machines, and Euclidean distance classifier. The experiments have shown promising results in the task of discriminating random and simple forgeries.

Algorithms↗
PubMed2005

Estimating the pen trajectories of static signatures using hidden Markov models.

Static signatures originate as handwritten images on documents and by definition do not contain any dynamic information. This lack of information makes static signature verification systems significantly less reliable than their dynamic counterparts. This study involves extracting dynamic information from static images, specifically the pen trajectory while the signature was created. We assume that a dynamic version of the static image is available (typically obtained during an earlier registration process). We then derive a hidden Markov model from the static image and match it to the dynamic version of the image. This match results in the estimated pen trajectory of the static image.

Algorithms↗
PubMed2006

A shared gene-expression signature in innate-like lymphocytes.

Innate and adaptive immunities are the two major arms of the immune system, which rely on distinct cell types. These cells can be distinguished not only by the source of diversity for non-self recognition, of germline or somatic origin, but also by their localization and the pattern and rates of response after encounter of antigenic triggers. In addition, subsets of lymphocytes exist whose receptors require rearrangement but result in semi-invariant structures with a high degree of self-specificity. We hypothesized that these innate-like lymphocytes might share a common gene transcription signature that relates them to classic members of the innate immune system. This relationship was first observed in agonist-induced CD8alphaalpha T cells in fetal/neonatal thymus. We then asked whether this notion could be extended to other innate-like lymphocytes, by comparison of gene expression profiles of innate-like lymphocytes and closely paired adaptive system counterparts (NKT versus CD4T, CD8alphaalphaT versus CD8alphabetaT, and B1 versus B2). A statistically significant 'innate signature' indeed was distilled. Particularly intriguing was the high representation of interferon-inducible guanosine triphophatases crucial for resistance against intracellular pathogens and of small G proteins involved in intracellular vacuole maturation and trafficking. Overall, this combined expression pattern can be designated as an innate signature among lymphocytes.

Animals↗
PubMed2004

Identification of signature genes for rapid and specific characterization of Yersinia pestis.

Polymerase chain reaction (PCR) amplification of DNA-based unique markers, the signature sequences, is ideal for rapid detection and identification of pathogens. We described the discovery of twenty-eight signature genes of Yersinia pestis by DNA microarray-based comparative genome hybridization in conjunction with PCR validation. Three pairs of Y. pestis-specific primers designed from signature genes were demonstrated to have the expected specificity to this target bacterium, without cross-reaction with the closely related Y. pseudotuberculosis or a large collection of genomic DNAs from other organisms.

Bacterial Proteins↗
PubMed2006

Relationships between optically assessed polyphenols and chlorophyll contents, and leaf mass per area ratio in woody plants: a signature of the carbon-nitrogen balance within leaves?

Chlorophyll (Chl) and epidermal polyphenol (EPhen) contents were estimated in vivo using two optical leaf-clips, SPAD-502 and Dualex, respectively. The area-based measurements were transformed into mass-based data by taking into account the leaf dry mass per area (LMA). Measurements were performed on forest trees and on saplings grown under controlled conditions. While LMA increased with irradiance along a vertical transect in a beech canopy or in saplings grown under different and increasing irradiance levels, mass-based EPhen (EPhen(m)) increased, whereas mass-based Chl (Chl(m)) decreased. This was a signature of a gradual switch of investment from protein into polyphenol production. A similar signature was obtained in saplings grown on nitrogen-deficient soil with respect to fertilized controls. However, nitrogen effects remained moderate compared to irradiance-induced effects. EPhen(m) and Chl(m) both declined with plant ageing-induced increases in LMA, under all tested growth conditions. This was a signature of an accumulation of dry matter that diluted Chl and EPhen. The described competition between Chl and EPhen in leaves fits well with the predictions of the Protein Competition Model (PCM), that is, that the total leaf mass-based polyphenols content (Phen(t)) is controlled by the competition between protein and polyphenol biosynthetic pathways and its metabolic regulation.

Carbon↗
PubMed2006

Vibration and sound signatures of human footsteps in buildings.

The acoustic signature of a footstep is one of several signatures that can be exploited for human recognition. Early research showed the maximum value for the force of multiple footsteps to be in the frequency band of 1-4 Hz. This paper reports on the broadband frequency-dependent vibrations and sound pressure responses of human footsteps in buildings. Past studies have shown that the low-frequency band (below 500 Hz) is well known in the literature, and generated by the force normal to the ground/floor. The seismic particle velocity response to footsteps was shown to be site specific and the characteristic frequency band was 20-90 Hz. In this paper, the high-frequency band (above 500 Hz) is investigated. The high-frequency band of the vibration and sound of a human footstep is shown to be generated by the tangential force to the floor and the floor reaction, or friction force. The vibration signals, as a function of floor coverings and walking style, were studied in a broadband frequency range. Different walking styles result in different vibration signatures in the low-frequency range. However, for the walking styles tested, the magnitudes in the high-frequency range are comparable and independent of walking style.

Female↗
PubMed2006

Preliminary evidence for signature vocalizations among free-ranging narwhals (Monodon monoceros).

Animal signature vocalizations that are distinctive at the individual or group level can facilitate recognition between conspecifics and re-establish contact with an animal that has become separated from its associates. In this study, the vocal behavior of two free-ranging adult male narwhals (Monodon monoceros) in Admiralty Inlet, Baffin Island was recorded using digital archival tags. These recording instruments were deployed when the animals were caught and held onshore to attach satellite tags, a protocol that separated them from their groups. The signature content of two vocal categories was considered: (1) combined tonal/pulsed signals, which contained synchronous pulsatile and tonal content; (2) whistles, or frequency modulated tonal signals with harmonic energy. Nonparametric comparisons of the temporal and spectral features of each vocal class revealed significant differences between the two individuals. A separate, cross-correlation measure conducted on the whistles that accounted for overall contour shape and absolute frequency content confirmed greater interindividual compared to intraindividual differences. These data are consistent with the hypothesis that narwhals produce signature vocalizations that may facilitate their reunion with group members once they become separated, but additional data are required to demonstrate this claim more rigorously.

Acoustics↗
PubMed1995

Signatures of the martian atmosphere in glass of the Zagami meteorite.

Isotopic signatures of nitrogen, argon, and xenon have been determined in separated millimeter-sized pockets of shock-melted glass in a recently identified lithology of the meteorite Zagami, a shergottite. The ratio of nitrogen-15 to nitrogen-14, which is at least 282 per mil larger than the terrestrial value, the ratio of xenon-129 to xenon-132 = 2.40, and the argon isotopic abundances match the signatures previously observed in the glassy lithology of the Antarctic shergottite EETA 79001. These results show that the signatures in EETA 79001 are not unique but characterize the trapped gas component in shock-melted glass of shergottites. The isotopic and elemental ratios of nitrogen, argon, and xenon closely resemble the Viking spacecraft data for the martian atmosphere and provide compelling evidence for a martian origin of the two shergottites and, by extension, of the meteorites in the shergottites-nakhlites-chassignites (SNC) group.

Argon↗
PubMed1992

Development of polymerase chain reaction primer sets for diagnosis of Lyme disease and for species-specific identification of Lyme disease isolates by 16S rRNA signature nucleotide analysis.

We have determined and compared partial 16S rRNA sequences from 23 Lyme disease spirochete isolates and aligned these with 8 sequences previously presented. The 16S rRNA signature nucleotide compositions were defined for each isolate and compared with the genomic species signature nucleotide sets previously established. To identify positions truly indicative of species classification which could serve as targets for polymerase chain reaction species-specific identification primers, 16S rRNA-based phylogenetic analyses were conducted. On the basis of the identified signature nucleotides, we designed polymerase chain reaction primer sets which (i) amplify all spirochete species associated with Lyme disease and (ii) differentiate between these species. The primer sets were tested on 38 Borrelia isolates associated with Lyme disease and were found to be sensitive and specific. All Lyme disease isolates tested were amplification positive. These primers allow for the rapid species identification of Lyme disease isolates.

Base Sequence↗
PubMed2004

Expression profiling of murine acute promyelocytic leukemia cells reveals multiple model-dependent progression signatures.

Leukemia results from the expansion of self-renewing hematopoietic cells that are thought to contain mutations that contribute to disease initiation and progression. Studies of the gene expression profiles of human acute myeloid leukemia samples has allowed their classification based on the presence of translocations and French-American-British subtypes, but it is not yet clear whether their molecular signatures reflect the initiating mutations or mutations acquired during progression. To begin to address this question, we examined the expression profiles of normal murine promyelocyte-enriched samples, nontransformed murine promyelocytes expressing human promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion gene, and primary acute promyelocytic leukemia cells. The expression profile of nontransformed cells expressing PML-RARalpha was remarkably similar to that of wild-type promyelocytes. In contrast, the expression profiles of fully transformed cells from three acute promyelocytic leukemia model systems were all different, suggesting that the expression signature of acute promyelocytic leukemia cells reflects the genetic changes that contributed to progression. To further evaluate these progression events, we compared two high-penetrance acute promyelocytic leukemia models that both commonly acquire an interstitial deletion of chromosome 2 during progression. The two models exhibited distinct gene expression profiles, suggesting that the dominant molecular signatures of murine acute promyelocytic leukemia can be influenced by several independent progression events.

Animals↗
PubMed2004

A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells.

BACKGROUND: In previous studies the presence of a distinct gene expression pattern has been shown in peripheral blood cells from patients with autoimmune disease. OBJECTIVE: To determine whether other specific signatures might be used to identify subsets of these autoimmune diseases and whether gene expression patterns in early disease might identify pathogenetic factors. METHODS: Peripheral blood mononuclear cells were acquired from patients with rheumatoid arthritis (RA) and analysed by microarrays containing over 4300 named human genes. Patients with RA for <2 years were compared with subjects with longstanding RA (average duration 10 years) and with patients with other immune or autoimmune diagnoses. RESULTS: Cluster analyses permitted separation of the patients with early RA (ERA) from those with longstanding disease. Comparison with other patient groups suggested that the ERA signature showed some overlap with that seen in the normal immune response to viral antigen as well as with a subset of patients with systemic lupus erythematosus. CONCLUSIONS: The ERA signature may reflect, in part, a response to an unknown infectious agent. Furthermore, shared features with some lupus patients suggest that common aetiological factors and pathogenetic pathways may be involved in these two autoimmune disorders.

Acute Disease↗
PubMed1990

Signature patterns of DNA restriction fragments of Helicobacter pylori before and after treatment.

The genomic DNA of Helicobacter pylori was studied by electrophoretic analysis of restriction endonuclease fragments. Twenty seven isolates from eight patients in the United Kingdom, obtained before and after treatment with nitrofurantoin, and two reference strains from Australia and Peru were investigated. Digestion of DNA with HaeIII, which gave the clearest band pattern of the 20 enzymes tested, showed that each set of isolates from a single patient had a unique band pattern. The DNA signature band patterns of strains from different patients were less than or equal to 62% similar (average 43%); similarities of patterns from the same patient were generally greater than or equal to 86%. Some minor but reproducible polymorphisms (less than or equal to five bands) in the signature region were detected in most consecutive isolates. Plasmid DNA was detected in isolates from five patients, but major pattern differences were attributed to genomic variation. It is concluded that the HaeIII DNA digest signature fingerprints provide a reproducible and sensitive method of discriminating between isolates of H pylori.

Campylobacter↗
PubMed2003

Remarkable sequence signatures in archaeal genomes.

Complete archaeal genomes were probed for the presence of long (> or = 25 bp) oligonucleotide repeats (words). We detected the presence of many words distributed in tandem with narrow ranges of periodicity (i.e., spacer length between repeats). Similar words were not identified in genomes of non-archaeal species, namely Escherichia coli, Bacillus subtilis, Haemophilus influenzae, Mycoplasma genitalium and Mycoplasma pneumoniae. BLAST similarity searches against the GenBank nucleotide sequence database revealed that these words were archaeal species-specific, indicating that they are of a signature character. Sequence analysis and genome viewing tools showed these repeats to be restricted to non-coding regions. Thus, archaea appear to possess a non-coding genomic signature that is absent in bacterial species. The identification of a species-specific genomic signature would be of great value to archaeal genome mapping, evolutionary studies and analyses of genome complexity.

Base Sequence↗
PubMed2006

A gene expression signature that can predict green tea exposure and chemopreventive efficacy of lung cancer in mice.

Green tea has been shown to be a potent chemopreventive agent against lung tumorigenesis in animal models. Previously, we found that treatment of A/J mice with either green tea (0.6% in water) or a defined green tea catechin extract (polyphenon E; 2.0 g/kg in diet) inhibited lung tumor tumorigenesis. Here, we described expression profiling of lung tissues derived from these studies to determine the gene expression signature that can predict the exposure and efficacy of green tea in mice. We first profiled global gene expressions in normal lungs versus lung tumors to determine genes which might be associated with the tumorigenic process (TUM genes). Gene expression in control tumors and green tea-treated tumors (either green tea or polyphenon E) were compared to determine those TUM genes whose expression levels in green tea-treated tumors returned to levels seen in normal lungs. We established a 17-gene expression profile specific for exposure to effective doses of either green tea or polyphenon E. This gene expression signature was altered both in normal lungs and lung adenomas when mice were exposed to green tea or polyphenon E. These experiments identified patterns of gene expressions that both offer clues for green tea's potential mechanisms of action and provide a molecular signature specific for green tea exposure.

Algorithms↗
PubMed2006

Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung.

Non-small-cell lung cancers (NSCLC) compose 80% of all lung carcinomas with squamous cell carcinomas (SCC) and adenocarcinoma representing the majority of these tumors. Although patients with early-stage NSCLC typically have a better outcome, 35% to 50% will relapse within 5 years after surgical treatment. We have profiled primary squamous cell lung carcinomas from 129 patients using Affymetrix U133A gene chips. Unsupervised analysis revealed two clusters of SCC that had no correlation with tumor stage but had significantly different overall patient survival (P = 0.036). The high-risk cluster was most significantly associated with down-regulation of epidermal development genes. Cox proportional hazard models identified an optimal set of 50 prognostic mRNA transcripts using a 5-fold cross-validation procedure. Quantitative reverse transcription-PCR and immunohistochemistry using tissue microarrays were used to validate individual gene candidates. This signature was tested in an independent set of 36 SCC samples and achieved 84% specificity and 41% sensitivity with an overall predictive accuracy of 68%. Kaplan-Meier analysis showed clear stratification of high-risk and low-risk patients [log-rank P = 0.04; hazard ratio (HR), 2.66; 95% confidence interval (95% CI), 1.01-7.05]. Finally, we combined the SCC classifier with our previously identified adenocarcinoma prognostic signature and showed that the combined classifier had a predictive accuracy of 71% in 72 NSCLC samples also showing significant differences in overall survival (log-rank P = 0.0002; HR, 3.54; 95% CI, 1.74-7.19). This prognostic signature could be used to identify patients with early-stage high-risk NSCLC who might benefit from adjuvant therapy following surgery.

Adenocarcinoma↗