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PubMed2026

Ensemble DNA methylation clock demonstrates Immune-metabolic aging signatures associated with mortality.

Aging is a multifactorial process that is best described in terms of the progressive acquisition of multiple layers of phenotypic changes, such as epigenetic modifications, inflammation, and metabolic dysregulation. DNA methylation clocks have been extensively used to construct epigenetic clocks based on the DNAm profiles that can be used to estimate biological age and predict age-associated outcomes. Nevertheless, the vast majority of clocks constructed so far have been based on linear models, which are unlikely to fully account for the heterogeneity and non-linearity of survival-related DNAm signatures. In this work, we constructed a heterogeneous stacked ensemble survival model based on DNAm data obtained from the Framingham Heart Study. We first identified 190 CpG loci using elastic net Cox regression and subsequently constructed a survival prediction model based on the fusion of five complementary survival models by means of a neural network meta-learner. The prediction power of the survival model was evaluated in an external validation cohort, where we observed strong performance for predicting all-cause mortality that significantly exceeded PhenoAge and was statistically comparable to GrimAge. These performance estimates were derived in cohorts of European ancestry and externally validated in postmenopausal women aged 50-79 years, and should therefore be interpreted as applicable only to demographically similar populations.

Humans↗

PubMed2006

Combinatorial decomposition of an outbreak signature.

We use mathematically rigorous definitions of epidemiological concepts in order to derive a sequential combinatorial model of disease outbreak decomposition. We define the idea of a population specific 'disease signature' and use this in order to decompose and further understand outbreaks as incidents of spatial and temporal spread of disease exposure both in, and across, populations. This allows us to differentiate between different disease spread scenarios with a level of sensitivity that previous models were unable to provide. This perspective leads us to propose a new practical definition for 'outbreak'. In addition, we are able to use this model to understand, estimate, and, in some cases, correct for, the likely instances of reporting error inherent in disease surveillance. We demonstrate our model first with a hypothetical outbreak scenario and then in an analysis of suspected outbreaks of waterborne diseases in Massachusetts (MA) in 1995.

Adult↗

PubMed2024

Identification of a Proteomic Signature for Predicting Immunotherapy Response in Patients With Metastatic Non-Small Cell Lung Cancer.

Immunotherapy has improved survival rates in patients with cancer, but identifying those who will respond to treatment remains a challenge. Advances in proteomic technologies have enabled the identification and quantification of nearly all expressed proteins in a single experiment. Integrating mass spectrometry with high-throughput technologies has facilitated comprehensive analysis of the plasma proteome in cancer, facilitating early diagnosis and personalized treatment. In this context, our study aimed to investigate the predictive and prognostic value of plasma proteome analysis using the SWATH-MS (Sequential Window Acquisition of All Theoretical Mass Spectra) strategy in newly diagnosed patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab therapy. We enrolled 64 newly diagnosed patients with advanced NSCLC treated with pembrolizumab. Blood samples were collected from all patients before and during therapy. A total of 171 blood samples were analyzed using the SWATH-MS strategy. Plasma protein expression in metastatic NSCLC patients prior to receiving pembrolizumab was analyzed. A first cohort (discovery cohort) was employed to identify a proteomic signature predicting immunotherapy response. Thus, 324 differentially expressed proteins between responder and non-responder patients were identified. In addition, we developed a predictive model and found a combination of seven proteins, including ATG9A, DCDC2, HPS5, FIL1L, LZTL1, PGTA, and SPTN2, with stronger predictive value than PD-L1 expression alone. Additionally, survival analyses showed an association between the levels of ATG9A, DCDC2, SPTN2 and HPS5 with progression-free survival (PFS) and/or overall survival (OS). Our findings highlight the potential of proteomic technologies to detect predictive biomarkers in blood samples from NSCLC patients, emphasizing the correlation between immunotherapy response and the idenfied protein set.

Humans↗

PubMed2024

Top-Down Proteomics Identifies Plasma Proteoform Signatures of Liver Cirrhosis Progression.

Cirrhosis, advanced liver disease, affects 2 to 5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and experience life-threatening complications such as gastrointestinal bleeding, confusion (hepatic encephalopathy), and ascites, reducing life expectancy from 12 to less than 2 years. Among patients with compensated cirrhosis, identifying patients at high risk of decompensation is critical to optimize care and reduce morbidity and mortality. Therefore, it is important to preferentially direct them towards specialty care which cannot be provided to all patients with cirrhosis. We used discovery top-down proteomics to identify differentially expressed proteoforms (DEPs) in the plasma of patients with progressive stages of liver cirrhosis with the ultimate goal to identify candidate biomarkers of disease progression. In this pilot study, we identified 209 DEPs across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated), of which 115 derived from proteins enriched in the liver at a transcriptional level and discriminated the three stages of cirrhosis. Enrichment analyses demonstrated DEPs are involved in several metabolic and immunological processes known to be impacted by cirrhosis progression. We have preliminarily defined the plasma proteoform signatures of cirrhosis patients, setting the stage for ongoing discovery and validation of biomarkers for early diagnosis, risk stratification, and disease monitoring.

Humans↗

PubMed2006

Signature patterns revealed by microarray analyses of mice infected with influenza virus A and Streptococcus pneumoniae.

We used cDNA microarrays to identify differentially expressed genes in mice in response to infections with influenza virus A/PR/8/34 (H1N1) and Streptococcus pneumoniae. Expression microarray analysis showed up-regulation and down-regulation of many genes involved in the defense, inflammatory response and intracellular signaling pathways including chemokine, apoptosis, MAPK, Notch, Jak-STAT, T-cell receptor and complement and coagulation cascades. We have revealed signature patterns of gene expression in mice infected with two different classes of pathogens: influenza virus A and S. pneumoniae. Quantitative real-time RT-PCR results confirmed microarray results for most of the genes tested. These studies document clear differences in gene expression profiles between mice infected with influenza virus A and S. pneumoniae. Identification of genes that are differentially expressed after respiratory infections can provide insights into the mechanisms by which the host interacts with different pathogens, useful information about stage of diseases and selection of suitable targets for early diagnosis and treatments. The advantage of this novel approach is that the detection of pathogens is based on the differences in host gene expression profiles in response to different pathogens instead of detecting pathogens directly.

Animals↗

PubMed2005

Unexpected results from the application of signature-tagged mutagenesis to identify Yersinia pestis genes required for adherence and invasion.

The signature-tagged mutagenesis (STM) method was applied in a protocol designed to identify genes required for Yersinia pestis invasion into epithelial cells. A library of 3060 mutants of Y. pestis CO99-3015 was made and assayed using an in vitro invasion assay with gentamicin protection. Initial results from the screen identified a set of 23 genes that might be required for invasion; however, screening of individual mutants for decreased invasion, even in a competition assay with the parent strain, failed to reveal obvious invasion defects. Altered colony character or size might have imposed a growth disadvantage for two of the mutants, which could possibly account for apparently decreased invasion. The sensitivity of the mutants to gentamicin was assayed to determine if the presence of the kanamycin-resistance cassette in the STM transposon changed the gentamicin resistance of the individual mutants. It was discovered that the mutants exhibited a variable range of resistance to killing by gentamicin, suggesting that the presence of the kanamycin-resistance cassette or the particular insertion mutation did in many cases affect the bactericidal potency of gentamicin. However, all mutants remained highly sensitive to growth inhibition in a disk assay on plates. These results may warrant precautions for use of kanamycin-resistance markers in studies with fully virulent Y. pestis, since gentamicin has been recommended for treatment of plague. Further, to use STM in the context of invasion assays, a selection other than gentamicin should be applied.

Anti-Bacterial Agents↗

PubMed2006

An Alzheimer's disease-specific beta-amyloid fragment signature in cerebrospinal fluid.

Pathogenic events in Alzheimer's disease (AD) involve an imbalance between the production and clearance of the neurotoxic beta-amyloid peptide (Abeta), especially the 42 amino acid peptide Abeta1-42. While much is known about the production of Abeta1-42, many questions remain about how the peptide is degraded. To investigate the degradation pattern, we developed a method based on immunoprecipitation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry that determines the Abeta degradation fragment pattern in cerebrospinal fluid (CSF). We found in total 18 C-terminally and 2 N-terminally truncated Abeta peptides and preliminary data indicated that there were differences in the detected Abeta relative abundance pattern between AD and healthy controls. Here, we provide direct evidence that an Abeta fragment signature consisting of Abeta1-16, Abeta1-33, Abeta1-39, and Abeta1-42 in CSF distinguishes sporadic AD patients from non-demented controls with an overall accuracy of 86%.

Aged↗

PubMed2006

Molecular evidence of fungal signatures in the marine protist Corallochytrium limacisporum and its implications in the evolution of animals and fungi.

Fungi, animals, and single-celled organisms belonging to the choanozoans together constitute the supergroup Opisthokonta. The latter are considered crucial in understanding the evolutionary origin of animals and fungi. The choanozoan Corallochytrium limacisporum is an enigmatic marine protist of considerable interest in opisthokontan evolution. Several isolates of the organism were obtained from a coral reef lagoon in the Lakshadweep group of islands of the Arabian Sea. The capability of these cultures to grow on media containing inorganic nitrogen sources prompted us to examine the possible presence of fungal signatures, namely the enzyme alpha-aminoadipate reductase (alpha-AAR) involved in the alpha-aminoadipate (AAA) pathway for synthesizing lysine and ergosterol, in one of the isolates. These features, as well as the sterol C-14 reductase gene involved in the sterol pathway of animals and fungi, were detected in the organism. Phylogenetic trees based on the alpha-AAR gene suggested that Corallochytrium limacisporum is a sister clade to fungi, while those based on the C-14 reductase gene did not adequately resolve whether the organism was more closely related to fungi or animals. While many studies indicate that Corallochytrium is a sister clade to animals, we suggest that further studies are required to examine whether this protist is in fact more closely related to fungi rather than to animals.

Animals↗

PubMed2006

BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells.

The BLyS family of receptors includes two cytokines, BLyS and APRIL; and three receptors, BR3, BCMA and TACI. Together, these regulate the size and composition of peripheral B cell pools. The multiplicity of ligand-receptor sets, in conjunction with differential receptor expression, alternative binding partners and disparate downstream signaling characteristics, affords the potential to establish independently regulated homeostatic niches among primary and antigen-experienced B cell subsets. Thus, BLyS signaling via BR3 is the dominant homeostatic regulator of primary B cell pools, whereas APRIL interactions with BCMA likely govern memory B cell populations. Short-lived antibody forming cell populations and their proliferating progenitors express a TACI-predominant signature. Further, within each niche, relative fitness to compete for available cytokine is determined by exogenous inputs via adaptive and innate receptor systems, affording intramural hierarchies that determine clonotype composition.

Animals↗

PubMed2025

Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to human brain evolution.

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, how astrocytes evolve in primates is unsettled. Here, we obtain human, chimpanzee, and macaque induced pluripotent stem-cell-derived astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We identify new loci contributing to the increased human astrocyte. We show that genes and pathways implicated in long-range intercellular signaling are activated in the human iAstrocytes and partake in controlling iAstrocyte complexity. Genes downregulated in human iAstrocytes frequently relate to neurological disorders and were decreased in adult brain samples. Through regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of "stripe" transcription factor binding sites. Altogether, we reveal the transcriptomic signature of primate astrocyte evolution and a mechanism driving the acquisition of the regulatory potential of enhancers.

Astrocytes↗

PubMed2005

Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy.

BACKGROUND: Distinguishing between adrenocortical adenomas and carcinomas is often difficult. Our aim was to investigate the differences in transcriptional profiles between benign and malignant adrenocortical neoplasms using complementary DNA microarray techniques. METHODS: We studied 7 patients with adrenocortical carcinomas and 13 with adenomas. Histopathology was reviewed in all patients; clinical follow-up was at least 1 year. Hybridizations were performed in duplicate against RNA reference. Expression levels were analyzed in the R environment for statistical computing with the use of aroma, limma, statistics, and class packages. RESULTS: Transcriptional profiles were homogeneous among adenomas, while carcinomas were much more heterogeneous. Hierarchical clustering and self-organizing maps could separate clearly carcinomas from adenomas. Among genes that were most significantly upregulated in carcinomas were 2 ubiquitin-related genes (USP4 and UFD1L) and several insulinlike growth factor-related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among genes that were most significantly downregulated in carcinomas were a cytokine gene (CXCL10), several genes related to cell metabolism (RARRES2, ALDH1A1, CYBRD1 and GSTA4), and the cadherin 2 gene (CDH2). CONCLUSIONS: Through the use of cDNA arrays, adrenocortical adenomas and carcinomas appear to be clearly distinguishable on the basis of their specific molecular signature. The biologic importance of the up- and downregulated genes is yet to be determined.

Adrenal Cortex Neoplasms↗

PubMed2026

Comparative toxicoproteomics reveals distinct proteostasis and ribosomal stress signatures of CMIT and PHMG.

Methylchloroisothiazolinone (CMIT) and polyhexamethylene guanidine (PHMG) are antimicrobial biocides associated with pulmonary toxicity, although their comparative cellular stress mechanisms remain unclear. Here, we investigated how CMIT and PHMG differentially alter the proteome of human alveolar epithelial A549 cells under subcytotoxic conditions. Cells were exposed to CMIT or PHMG, and global proteomic profiling was performed using label-free liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified at a 1% false discovery rate with an absolute log2 fold change ≥1. Functional analyses were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis, and selected proteins were validated by western blotting. Comparative toxicoproteomics revealed distinct stress-response signatures induced by the two biocides. CMIT preferentially altered proteins associated with proteostasis, oxidative stress, and protein quality control, whereas PHMG was characterized by coordinated depletion of ribosome-associated and translation-related proteins. A total of 73 and 155 DEPs were identified in CMIT- and PHMG-treated cells, respectively, with 22 proteins shared between treatments. Western blotting confirmed PSMD3, TUBB2A, and GLRX1 as CMIT-responsive proteins and THRAP3, DHX15, and RPL4 as PHMG-responsive markers. These findings provide comparative mechanistic insight into how CMIT and PHMG induce distinct epithelial stress responses and identify candidate protein markers that may support future in vitro assessment of biocide-induced pulmonary toxicity.

CMIT↗

PubMed2026

Multiparametric flow cytometry immune profiling of pulmonary and extra-pulmonary tuberculosis reveals distinct blood-based biomarker signatures.

This study investigated immune cell distributions, cell-specific immune markers, and selected biomarker targets in pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) using multiparametric flow cytometry (MFC). Whole blood was collected from 45 individuals, including healthy controls (HC), EPTB, and PTB patients (n = 15/group). Peripheral blood leukocytes were analysed by MFC to characterize CD4+ and CD8+ T cells, natural killer (NK), invariant NKT (iNKT) and NKT cells, classical (CM), intermediate (IM) and non-classical monocytes (NCM), and activated monocytes (AM). Expression of GBP1, CALCOCO2, IFIT3, SNX10, ARG1, PD-1, and PD-L1 was assessed across these immune subsets. Increased frequencies of NK, NKT, and monocytes were observed in PTB and EPTB compared with HC, while CD4+, CD8+, iNKT, and AM were reduced. Monocyte-to-lymphocyte ratios were incrementally elevated in EPTB and PTB compared with HC. Despite variability of expression within groups, median biomarker fold-change expression changes were found between HC, EPTB and PTB groups; (i) (>2.0FC) for ARG1 in CD4, CD8, CM and AM, for CALCOCO2 in AM, GBP1 in CD8 and NCM, PD-1 in CD4, CD8, NK, IM and AM, PD-L1 in CD4, CD8, iNKT and NKT, NK, IM and AM and SNX10 in CD4, CD8, NCM, IM and AM (ii) (<2.0FC) in TB vs HC for CALCOCO2 in iNKT and NKT, IFIT3 in NCM, PD-1 in NK and NCM, PD-L1 in NCM, IM and AM and SNX10 in AM. Statistical significance was achieved for ARG1 (P = 0.017) in CD4 cells. Our findings highlight distinct immune cell and biomarker signatures in PTB and EPTB.

Humans↗

PubMed2005

Gene expression signatures in neutrophils exposed to glucocorticoids: a new paradigm to help explain "neutrophil dysfunction" in parturient dairy cows.

Neutrophils are the first line of immunity against most pathogens that infect cattle. These normally short-lived white blood cells develop from myeloid-lineage cells in bone marrow. Upon maturation, bone marrow neutrophils are released into the circulation where they marginate on inflamed blood vessel endothelial cells and migrate through them into the area of infection. Once migrated, neutrophils do not reenter the circulation, but rather, perform their bactericidal functions and die by apoptosis in the tissue. The cytokine and hormonal milieu of the blood and extracellular tissue fluid can influence neutrophil development and immunity-related activities, but the molecular basis of these phenotypic changes and physiological benefits or drawbacks of them are poorly understood. In the current paper, we review new gene expression information that resulted from two of our functional genomics studies designed to evaluate effects of glucocorticoid hormones on bovine neutrophils. This work provides one model to describe complex changes that occur in neutrophils as the cells respond to glucocorticoids, which might act to alter the cells' functional priorities and tip the delicate balance between health and disease during stress, including at parturition. A bovine immunobiology microarray and real time RT-PCR were used to study blood neutrophils collected during the natural surge of endogenous glucocorticoid (cortisol) in parturient dairy cows and bone marrow neutrophils collected from glucocorticoid (dexamethasone)-treated dairy steers. The gene expression signatures we observed led us to perform additional phenotyping of the neutrophils and correlation analyses, which together painted a picture suggesting that glucocorticoids have key roles in modulating neutrophil development, life span, and tissue defense functions during parturition and hormone therapy. Based on these observations, we postulate that glucocorticoids orchestrate adaptive changes in the entire neutrophil system that support increased cell numbers and longevity in blood and heightened remodeling activity in tissues, while at the same time decreasing some important antimicrobial defense activities of the cells. Thus, our functional genomics studies have enabled us to elucidate multiple consequences of neutrophil exposure to glucocorticoids, highlighting a probable role for this interaction in the induction of parturition and partly explaining why some parturient dairy cows may experience heightened incidence and severity of inflammatory diseases like mastitis.

Animals↗

PubMed2024

Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk.

Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.

Humans↗

PubMed2004

Comparative sequence analysis of imprinted genes between human and mouse to reveal imprinting signatures.

We performed a comparative genomic sequence analysis between human and mouse for 24 imprinted genes on human chromosomes 1, 6, 7, 11, 13, 14, 15, 18, 19, and 20. The MEME program was used to search for motifs within conserved sequences among the imprinted genes and we then used the MAST program to analyze for the presence or absence of motifs in the imprinted genes and 128 nonimprinted genes. Our analysis identified 15 motifs that were significantly enriched in the imprinted genes. We generated a logistic regression model by combining multiple motifs as input variables and the 24 imprinted genes and the 128 nonimprinted genes as a training set. The accuracy, sensitivity, and specificity of our model were 98, 92, and 99%, respectively. The model was further validated by an open test on 12 additional imprinted genes. The motifs identified in this study are novel imprinting signatures, which should improve our understanding of genomic imprinting and the role of genomic imprinting in human diseases.

Amino Acid Motifs↗

PubMed2004

Abnormal frequency-dependent responses represent the pathophysiologic signature of contractile failure in human myocardium.

BACKGROUND: - The normal increase in isometric developed force (DF) with faster pacing rates, known as the positive force-frequency response/relationship (FFR), is altered in failing myocardium, as shown by its negative response to increased pacing. The objective of this study was to determine if increasing Ca2+ influx with L-type Ca2+ channel (L-CaCh) agonists: BayK 8644 (BayK) and FPL 64176 (FPL) or increased extracellular Ca2+ could increase contractility and normalize the FFR in failing myocardium. METHODS: - Isometric DF was measured in right ventricular trabeculae from failing (n = 28) and non-failing (n = 12) human hearts at various stimulation frequencies (0.5-2.5 Hz) before and after bath application of BayK (250 nM), FPL (100 nM), or high Ca2+ (7.0 mM). Post-rest (PR) experiments were also conducted on several trabeculae. RESULTS: - In trabeculae from failing hearts, the DF decreased with an increase in pacing. Addition of L-CaCh agonists increased DF to similar levels in trabeculae from both failing and non-failing hearts at slow pacing rates, but did not alter the negative FFR in the failing group. During increased rest intervals, the amount of PR potentiation was diminished in trabeculae from failing hearts as compared to the non-failing preparations. CONCLUSION: - This study demonstrates that the abnormal FFR observed in trabeculae from failing hearts is a reliable physiologic signature of the cardiomyopathic state even when DF, at slow stimulation frequencies, is relatively high. These studies further demonstrate that the impaired FFR is not due to an inability to further increase contractility. Rather, our findings suggest that the abnormal FFR and blunted PR potentiation alike are a reflection of an altered functional balance between Ca2+ re-uptake and Ca2+ extrusion.

Calcium↗

PubMed2004

Detection and assignment of CYP21 mutations using peptide mass signature genotyping.

Congenital adrenal hyperplasia (CAH) is a common inborn error of steroidogenesis. The clinical spectrum of CAH ranges from the severe classical form, which can be fatal in the newborn, to simple virilizing forms or a milder non-classical form which is often not diagnosed until puberty. Recessive mutations in the autosomal gene encoding 21-hydroxylase (CYP21) are responsible for approximately 95% of CAH cases. Since CYP21 genotype is generally predictive of the presence and severity of the disorder, accurate CYP21 genotyping is of clear medical significance. Determining the CYP21 genotype of an individual, using standard methods, is difficult due to the presence of a nearly identical pseudogene (CYP21P) in close proximity to the functional gene. To address the need for a comprehensive test for mutations in the CYP21 gene, we developed a multiplexed peptide mass signature genotyping (PMSG) assay and applied the assay to 151 DNA samples. CAH patients had been previously characterized for the 10 most common mutations. The PMSG assay detected all common mutations; in addition it identified six known rare mutations and also discovered four new mutations (two frameshifts in the first half of the gene, P42fs and S171fs, and two point mutations, H365Y and R479L). This assay has the potential to provide high-throughput, cost-effective analysis of the CYP21 gene to detect known mutations and identify novel variants in samples obtained from patients with CAH, individuals suspected to have CAH, and heterozygous carriers.

Adrenal Hyperplasia, Congenital↗