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PubMed2001

Coordinate action of the helicase and 3' to 5' exonuclease of Werner syndrome protein.

Werner syndrome is a human disorder characterized by premature aging, genomic instability, and abnormal telomere metabolism. The Werner syndrome protein (WRN) is the only known member of the RecQ DNA helicase family that contains a 3' --> 5'-exonuclease. However, it is not known whether both activities coordinate in a biological pathway. Here, we describe DNA structures, forked duplexes containing telomeric repeats, that are substrates for the simultaneous action of both WRN activities. We used these substrates to study the interactions between the WRN helicase and exonuclease on a single DNA molecule. WRN helicase unwinds at the forked end of the substrate, whereas the WRN exonuclease acts at the blunt end. Progression of the WRN exonuclease is inhibited by the action of WRN helicase converting duplex DNA to single strand DNA on forks of various duplex lengths. The WRN helicase and exonuclease act in concert to remove a DNA strand from a long forked duplex that is not completely unwound by the helicase. We analyzed the simultaneous action of WRN activities on the long forked duplex in the presence of the WRN protein partners, replication protein A (RPA), and the Ku70/80 heterodimer. RPA stimulated the WRN helicase, whereas Ku stimulated the WRN exonuclease. In the presence of both RPA and Ku, the WRN helicase activity dominated the exonuclease activity.

Antigens, Nuclear↗
PubMed2001

Composition of Drosophila melanogaster proteome involved in fucosylated glycan metabolism.

The whole genome approach enables the characterization of all components of any given biological pathway. Moreover, it can help to uncover all the metabolic routes for any molecule. Here we have used the genome of Drosophila melanogaster to search for enzymes involved in the metabolism of fucosylated glycans. Our results suggest that in the fruit fly GDP-fucose, the donor for fucosyltransferase reactions, is formed exclusively via the de novo pathway from GDP-mannose through enzymatic reactions catalyzed by GDP-D-mannose 4,6-dehydratase (GMD) and GDP-4-keto-6-deoxy-D-mannose 3,5-epimerase/4-reductase (GMER, also known as FX in man). The Drosophila genome does not have orthologs for the salvage pathway enzymes, i.e. fucokinase and GDP-fucose pyrophosphorylase synthesizing GDP-fucose from fucose. In addition we identified two novel fucosyltransferases predicted to catalyze alpha1,3- and alpha1,6-specific linkages to the GlcNAc residues on glycans. No genes with the capacity to encode alpha1,2-specific fucosyltransferases were found. We also identified two novel genes coding for O-fucosyltransferases and a gene responsible for a fucosidase enzyme in the Drosophila genome. Finally, using the Drosophila CG4435 gene, we identified two novel human genes putatively coding for fucosyltransferases. This work can serve as a basis for further whole-genome approaches in mapping all possible glycosylation pathways and as a basic analysis leading to subsequent experimental studies to verify the predictions made in this work.

Amino Acid Sequence↗
PubMed2002

Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein.

The breast and ovarian cancer-specific tumor suppressor RING finger protein BRCA1 has been identified as an E3 ubiquitin (Ub) ligase through in vitro studies, which demonstrated that its RING finger domain can autoubiquitylate and monoubiquitylate histone H2A when supplied with Ub, E1, and UBC4 (E2). Here we report that the E3 ligase activity of the N-terminal 110 amino acid residues of BRCA1, which encodes a stable domain containing the RING finger, as well as that of the full-length BRCA1, was significantly enhanced by the BARD1 protein (residues 8-142), whose RING finger domain itself lacked Ub ligase activity in vitro. The results of mutagenesis studies indicate that the enhancement of BRCA1 E3 ligase activity by BARD1 depends on direct interaction between the two proteins. Using K48A and K63A Ub mutants, we found that BARD1 stimulated the formation of both Lys(48)- and Lys(63)-linked poly-Ub chains. However, the enhancement of BRCA1 autoubiquitylation by BARD1 mostly resulted in poly-Ub chains linked through Lys(63), which could potentially activate biological pathways other than BRCA1 degradation. We also found that co-expression of BRCA1 and BARD1 in living cells increased the abundance and stability of both proteins and that this depended on their ability to heterodimerize.

BRCA1 Protein↗
PubMed2000

A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity.

As part of a large scale effort to discover novel secreted proteins, a cDNA encoding a novel cytokine was identified. Alignments of the sequence of the new protein, designated IL-17B, suggest it to be a homolog of the recently described T cell-derived cytokine, IL-17. By Northern analysis, EST distribution and real-time quantitative polymerase chain reaction analysis, mRNA was detected in many cell types. A novel type I transmembrane protein, identified in an EST data base by homology to IL-17R, was found to bind specifically IL-17B, as determined by surface plasmon resonance analysis, flow cytometry, and co-immunoprecipitation experiments. Readily detectable transcription of IL-17BR was restricted to human kidney, pancreas, liver, brain, and intestines and only a few of the many cell lines tested. By using a rodent ortholog of IL-17BR as a probe, IL-17BR message was found to be drastically up-regulated during intestinal inflammation elicited by indomethacin treatment in rats. In addition, intraperitoneal injection of IL-17B purified from Chinese hamster ovary cells caused marked neutrophil migration in normal mice, in a specific and dose-dependent manner. Together these results suggest that IL-17B may be a novel proinflammatory cytokine acting on a restricted set of target cell types. They also demonstrate the strength of genomic approaches in the unraveling of novel biological pathways.

Adjuvants, Immunologic↗
PubMed2000

Lumbar erector spinae oxygenation during prolonged contractions: implications for prolonged work.

Owing to the recent interest in torso stabilization exercises together with many questions regarding the duration of prolonged isometric holds in occupational settings, the authors attempted to assess the level of back muscle oxygenation during prolonged isometric contractions. Specifically, this study recorded relative oxygen saturation of haemoglobin/myoglobin using Near Infrared Spectroscopy (NIRS) in the L3 erector mass during prolonged isometric contractions at intensities from 2 to 30% of maximum voluntary contraction (MVC). It was hypothesized that available oxygen to these muscles is severely compromised even at moderate levels of activation observed in occupational work. Eight volunteers without a history of lower back pain or injury participated in this study. The exercise task involved isometric contraction of the lower erector spinae at five different levels of each subject's maximal voluntary contraction: 2, 5, 10, 20 and 30% MVC, presented in random order. Subjects were placed in a sitting position, with a curved plastic plate secured horizontally to the pelvis to minimize movement at the hip joint. During extensor exertions, they were restrained with a harness that was attached at chest level to a load cell. Each isometric contraction was performed for 30 s followed by 1 min of rest. All levels of contraction demonstrated reduction in oxygen. Given the concern for motion artefact on the NIRS signal, sham trials were conducted where the subjects went through the procedure of attaching the pulling cable but no active pull was performed. These trials showed no change in the NIRS signal. At this time NIRS appears to be the only non-invasive instrumentation available to indicate total available muscle oxygen during low level, prolonged work. Although the specific tissue volume sampled by NIRS cannot be positively identified, it appears that tissue oxygenation in the lumbar extensor musculature is reduced as a function of contraction intensity, even at levels as low as 2% of MVC. These data have implications for prolonged work where postures requiring isometric contractions are sometimes held for hours, and where musculoskeletal illness has been linked to prolonged contraction levels above 2%MVC--these data suggest a possible biological pathway.

Adult↗
PubMed1985

Diet and cancer: value of different types of epidemiological studies.

Diet and nutrition are increasingly recognized as likely to be major determinants of cancer, notably cancers of the gastrointestinal tract, breast, endometrium, ovary, and prostate. Dietary factors may collectively account for a greater proportion of all cancers that occur in contemporary Western society than does any other category of environmental exposure (1). With the development of knowledge of the protective properties of certain components of food, links with diet have been suggested for other cancer sites (2). The epidemiological evidence for the association of diet and cancer is, however, not uniformly convincing; also, the likely biological pathways are not always clear. In this paper, we comment on some current hypotheses in this area and examine the best epidemiological methods to test them.

Diagnosis-Related Groups↗
PubMed2005

Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis.

This study investigated whether integrated analysis of transcriptomics and metabolomics data increased the sensitivity of detection and provided new insight in the mechanisms of hepatotoxicity. Metabolite levels in plasma or urine were analyzed in relation to changes in hepatic gene expression in rats that received bromobenzene to induce acute hepatic centrilobular necrosis. Bromobenzene-induced lesions were only observed after treatment with the highest of 3 dose levels. Multivariate statistical analysis showed that metabolite profiles of blood plasma were largely different from controls when the rats were treated with bromobenzene, also at doses that did not elicit histopathological changes. Changes in levels of genes and metabolites were related to the degree of necrosis, providing putative novel markers of hepatotoxicity. Levels of endogenous metabolites like alanine, lactate, tyrosine and dimethylglycine differed in plasma from treated and control rats. The metabolite profiles of urine were found to be reflective of the exposure levels. This integrated analysis of hepatic transcriptomics and plasma metabolomics was able to more sensitively detect changes related to hepatotoxicity and discover novel markers. The relation between gene expression and metabolite levels was explored and additional insight in the role of various biological pathways in bromobenzene-induced hepatic necrosis was obtained, including the involvement of apoptosis and changes in glycolysis and amino acid metabolism. The complete Table 2 is available as a supplemental file online at http://taylorandfrancis.metapress.com/openurlasp?genre=journal&issn=0192-6233. To access the file, click on the issue link for 33(4), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.

Amino Acids↗
PubMed2002

Microbial beta-glucosidases: cloning, properties, and applications.

Beta-glucosidases constitute a major group among glycosylhydrolase enzymes. Out of the 82 families classified under glycosylhydrolase category, these belong to family 1 and family 3 and catalyze the selective cleavage of glucosidic bonds. This function is pivotal in many crucial biological pathways, such as degradation of structural and storage polysaccharides, cellular signaling, oncogenesis, host-pathogen interactions, as well as in a number of biotechnological applications. In recent years, interest in these enzymes has gained momentum owing to their biosynthetic abilities. The enzymes exhibit utility in syntheses of diverse oligosaccharides, glycoconjugates, alkyl- and aminoglucosides. Attempts are being made to understand the structure-function relationship of these versatile biocatalysts. Earlier reviews described the sources and properties of microbial beta-glucosidases, yeast beta-glucosidases, thermostable fungal beta-glucosidase, and the physiological functions, characteristics, and catalytic action of native beta-glucosidases from various plant, animal, and microbial sources. Recent efforts have been directed towards molecular cloning, sequencing, mutagenesis, and crystallography of the enzymes. The aim of the present article is to describe the sources and properties of recombinant beta-glucosidases, their classification schemes based on similarity at the structural and molecular levels, elucidation of structure-function relationships, directed evolution of existing enzymes toward enhanced thermostability, substrate range, biosynthetic properties, and applications.

Biotechnology↗
PubMed2004

Neuregulin 1 and schizophrenia.

We discuss in this review the role of the neuregulin (NRG1) gene in schizophrenia. NRG1 contributes to the genetics of schizophrenia in both Icelandic and Scottish schizophrenia patients. NRG1 participates in glutamatergic signaling by regulating the N-methyl-D-aspartate (NMDA) receptor through the interaction of the NRG1 protein and its receptors. NRG1 plays a central role in neural development and is most likely involved in regulating synaptic plasticity, or how the brain responds or adapts to the environment. The discovery that defects in NRG1 signaling may be involved in some cases of schizophrenia, not only implicates NRG1, but suggests that its biological pathway, active both at developing and mature synapses, is worth inspecting further in a search for other schizophrenia genes possibly in epistasis with NRG1.

Animals↗
PubMed2005

Gene expression pattern in spontaneously hypertensive rats exposed to urban particulate matter (EHC-93).

Epidemiological studies show associations of short-term exposure to particulate matter with morbidity and mortality. Although many studies investigate the health effects of ambient particulate matter, the associated mechanisms, and the causality, they often focus on classical parameters. The objective of the present study was to gain insight into the roles of a wide range of genes in this process. Particular attention has been paid to immediate oxidative stress in the lung. We isolated total lung RNA from spontaneously hypertensive male rats 2-40 h after exposure to reference EHC-93 (10 mg/kg). Our results show that exposure to particulate matter generates a time-dependent pattern of gene expression. From the 8799 genes or expressed sequence tags tested, we see that 132 genes were up- or downregulated shortly after exposure (i.e., 2-6 h), whereas after 15-21 h and 24-40 h, 46 and 56 genes showed altered expression, respectively. Focusing on the earliest point, 99 of the 132 genes were identified as unique. They include genes involved in an oxidative stress response (hemeoxygenase-1, metallothioneins, and thioredoxin reductase), an inflammatory response macrophage inflammatory protein-2, and tumor necrosis factor alpha), transcription factors belonging to the activating protein-1 family, and genes involved in cardiovascular functions. The present study, although not representing an ambient situation, is used to identify the biological pathways implicated in the initial injury response to PM exposure. Using Affymetrix chips, this study shows time-dependent gene expression, it identifies many genes that can be affected by exposure to particulate matter, and it confirms the involvement of oxidative stress in particulate-matter-related effects.

Air Pollutants↗
PubMed2026

Analytical challenges for mapping non-canonical and non-protein ubiquitin/Ubl modifications by mass spectrometry.

INTRODUCTION: Covalent modification by ubiquitin via Lys isopeptide bonds is fundamental for regulating protein turnover and function. Additionally, ubiquitin esterification occurs on Ser/Thr/Tyr residues in proteins and on non-proteinaceous substrates including ribose, saccharides, lipids, and small molecule drugs. Ubiquitin posttranslational modifications may therefore be much more widespread across cell biological pathways. Recent literature (PubMed) reflects the increased interest in analytical methods for mapping of non-canonical substrates modified by ubiquitin and ubiquitin-like (UBL) proteins. AREAS COVERED: Mass spectrometry (MS)-based methodologies involve advanced proteomic techniques to identify ubiquitin modifications on amino acids other than Lys, such as Ser, Thr, Tyr and Cys as well as protein N-termini. After digestion, standard MS workflows identify canonical ubiquitination by detecting a ubiquitin C-terminal tag attached to the amine side chains of Lys residues of substrate-derived peptides suitable for MS/MS sequencing. For non-canonical modifications on proteins and substrates other than proteins, specialized strategies are required, such as using antibodies to enrich N-terminally modified peptides in combination with using high-resolution MS/MS based on softer fragmentation technologies to detect esterification and possibly other types of substrate modifications. EXPERT OPINION: Enabling such technologies will reveal a previously unrecognized angle of the ubiquitin code's complexity in cells.

Humans↗
PubMed2026

Clinical proteomics in inborn errors of metabolism: from biomarker discovery to implementation.

INTRODUCTION: Inborn errors of metabolism (IEMs) are rare, heterogeneous disorders traditionally diagnosed through genetic testing, enzyme assays, and metabolite measurements. However, these tools often do not fully explain phenotypic variability, organ involvement, disease progression, or treatment response. Clinical proteomics provides a complementary functional layer by capturing changes in protein abundance, proteoforms, post-translational modifications (PTM), and biological pathways, offering insights beyond genotype- and metabolite-based approaches. AREAS COVERED: This review examines the role of high-resolution mass spectrometry and computational proteomics in biomarker discovery and clinical decision-making for IEMs. It focuses on their contribution to diagnosis, variant interpretation, patient stratification, and treatment monitoring. Disease-specific applications are discussed, with the strongest evidence in lysosomal storage disorders, mitochondrial diseases, congenital disorders of glycosylation, and selected neurodegenerative or renal metabolic conditions. The literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar, covering peer-reviewed articles available up to 2026, with emphasis on methodological advances and translational applications in clinical proteomics for IEMs. EXPERT OPINION: Proteomics will not replace established diagnostic tools, but it can help address clinically actionable questions in selected contexts. Translation into clinical practice will require standardized workflows, multicenter validation, clinically anchored endpoints, and integration with other omics approaches.

Humans↗
PubMed2026

Gut microbial diversity at baseline conditions the clinical, microbiome, and metabolic response to paraprobiotic Lactiplantibacillus plantarum LRCC5282 in overweight adults.

The gut microbiota is increasingly recognized as a target for obesity management; however, whether baseline gut microbial diversity conditions responsiveness to microbiota-targeted interventions remains unclear. We aimed to investigate whether baseline gut microbial diversity is associated with responsiveness to a paraprobiotic derived from Lactiplantibacillus plantarum LRCC5282 (LP5282-P) in overweight adults. In a 12-week, randomized, double-blind, placebo-controlled, multicenter trial of 120 overweight adults, LP5282-P produced no significant between-group differences in any clinical outcome across the overall per-protocol population. However, in the low-diversity subgroup, LP5282-P was associated with significant reductions in body weight, body mass index, and circulating leptin levels. These clinical changes were accompanied by compositional shifts in the gut microbiota, including higher relative abundances of Christensenellaceae, Faecalibacterium, and Alistipes. Fecal metabolite profiles showed elevated acetate and butyrate concentrations and altered bile acid composition. Within the low-diversity subgroup, changes in the relative abundances of Akkermansia and Eubacterium were inversely correlated with changes in body weight, body fat mass, and leptin levels. In contrast, the high-diversity subgroup exhibited no consistent response across the outcome domains examined. Overall, baseline gut microbial diversity was associated with differential responsiveness to LP5282-P, supporting its potential use as a stratification variable in future microbiota-targeted intervention trials. Further studies integrating direct measures of microbial activity and host response are warranted to elucidate the biological pathways underlying this diversity-dependent responsiveness. Trial registration: Clinical Research Information Service (CRIS), KCT0008119.

Humans↗
PubMed2003

Amyloid as a natural product.

Amyloid fibrils, such as those found in Alzheimer's and the gelsolin amyloid diseases, result from the misassembly of peptides produced by either normal or aberrant intracellular proteolytic processing. A paper in this issue by Marks and colleagues (Berson et al., 2003) demonstrates that intra-melanosome fibrils are formed through normal biological proteolytic processing of an integral membrane protein. The resulting peptide fragment assembles into fibrils promoting the formation of melanin pigment granules. These results, along with the observation that amyloid fibril formation by bacteria is highly orchestrated, suggest that fibril formation is an evolutionary conserved biological pathway used to generate natural product nanostructures.

Amyloid↗
PubMed1990

Positron emission tomography.

While positron emission tomography (PET) represents the most advanced methodology using radiotracers, it is subject to two main constraints. The first is the physical accuracy with which the regional distribution, time course and concentration of the tracer can be determined. This is principally a function of the instrumentation. The second constraint is the biological accuracy, that a chosen tracer molecule defines the specific biological pathway under study. This paper discusses the application of PET, mainly to the brain, and future possible improvements to this powerful technique.

Brain↗
PubMed2006

Combining gene annotations and gene expression data in model-based clustering: weighted method.

It has been increasingly recognized that incorporating prior knowledge into cluster analysis can result in more reliable and meaningful clusters. In contrast to the standard modelbased clustering with a global mixture model, which does not use any prior information, a stratified mixture model was recently proposed to incorporate gene functions or biological pathways as priors in model-based clustering of gene expression profiles: various gene functional groups form the strata in a stratified mixture model. Albeit useful, the stratified method may be less efficient than the global analysis if the strata are non-informative to clustering. We propose a weighted method that aims to strike a balance between a stratified analysis and a global analysis: it weights between the clustering results of the stratified analysis and that of the global analysis; the weight is determined by data. More generally, the weighted method can take advantage of the hierarchical structure of most existing gene functional annotation systems, such as MIPS and Gene Ontology (GO), and facilitate choosing appropriate gene functional groups as priors. We use simulated data and real data to demonstrate the feasibility and advantages of the proposed method.

Algorithms↗
PubMed2005

Diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction.

BACKGROUND: Endothelial dysfunction is one of the mechanisms linked to an increased risk of cardiovascular disease. OBJECTIVE: We assessed the association between several diet-quality scores and plasma concentrations of markers of inflammation and endothelial dysfunction. DESIGN: Diet-quality scores on the Healthy Eating Index (HEI), Alternate Healthy Eating Index (AHEI), Diet Quality Index Revised (DQI-R), Recommended Food Score (RFS), and the alternate Mediterranean Diet Index (aMED) were calculated by using a food-frequency questionnaire that was administered in 1990 to 690 women in the Nurses' Health Study (ages 43-69 y, no cardiovascular disease or diabetes). Blood collection was completed in the same year. We used regression analysis to assess the associations between these diet-quality scores and plasma concentrations of C-reactive protein, interleukin 6, E-selectin, soluble intercellular cell adhesion molecule 1, and soluble vascular cell adhesion molecule 1. RESULTS: The various diet-quality scores were significantly correlated with each other; correlation coefficients ranged from 0.56 to 0.80 (all P values < 0.0001). After adjustment for age, body mass index, alcohol intake, physical activity, smoking status, and energy intake, the HEI and DQI-R were not significantly associated with any of the biomarkers, whereas the AHEI and aMED scores were associated with significantly lower concentrations of most biomarkers. The RFS was significantly associated with a lower concentration of E-selectin only. C-reactive protein concentrations were 30% (P < 0.05) and 24% (P < 0.05) lower in the top than in the bottom quintile of the AHEI and of the aMED, respectively CONCLUSION: Higher AHEI and aMED scores were associated with lower concentrations of biomarkers of inflammation and endothelial dysfunction and therefore may be useful as guidelines for reducing the risk of diseases involving such biological pathways.

Adult↗
PubMed2003

Sample size needed to detect gene-gene interactions using association designs.

It is likely that many complex diseases result from interactions among several genes, as well as environmental factors. The presence of such interactions poses challenges to investigators in identifying susceptibility genes, understanding biologic pathways, and predicting and controlling disease risks. Recently, Gauderman (Am J Epidemiol 2002;155:478-84) reported results from the first systematic analysis of the statistical power needed to detect gene-gene interactions in association studies. However, Gauderman used different statistical models to model disease risks for different study designs, and he assumed a very low disease prevalence to make different models more comparable. In this article, assuming a logistic model for disease risk for different study designs, the authors investigate the power of population-based and family-based association designs to detect gene-gene interactions for common diseases. The results indicate that population-based designs are more powerful than family-based designs for detecting gene-gene interactions when disease prevalence in the study population is moderate.

Genetic Predisposition to Disease↗