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PubMed2026

Proteomic pathways mediating low socioeconomic status and cardiovascular events in older adults in CHS and ARIC.

BACKGROUND AND AIMS: Many studies have linked socioeconomic status (SES) and cardiovascular outcomes, yet the biologic mechanisms mediating these associations are only partially understood. The objective of this study was to identify molecular mediators of the association of low SES with coronary heart disease (CHD) and stroke. METHODS: This research was conducted in 2942 Black and White adults in the Cardiovascular Health Study (mean age 76.2 years) and 10,689 Black and White adults in the Atherosclerosis Risk in Communities Study (mean age 60.0 years). We used factor analysis to create a composite measure of low educational attainment, low-income, and blue-collar occupation. Approximately 5000 proteins were measured with an aptamer-based method, and CHD and stroke events were adjudicated. Results were stratified by race, which was conceptualized as a social factor. RESULTS: Low SES was associated with 44 and 262 proteins, in Black and White adults, respectively. No protein met the Bonferroni adjusted threshold for statistically significantly mediation among Black participants. Among White participants, 23 proteins mediated the association between SES adversity and CHD and 5 mediated the association between SES adversity and stroke. The strongest mediating associations for CHD included PTPRS, SCG3, and MMP12. The strongest mediating associations for stroke included NCAN, FAM20B, and APLP1. SPARCL1 and CDCP1 remained the strongest mediators of the association between SES adversity and CHD, after adjusting for potential confounders and traditional cardiovascular risk factors. CONCLUSION: We identified several biomarkers that characterize the biologic risk of SES adversity on CHD and stroke.

Aged↗
PubMed1999

Influence of a periodic field on the distant electron transfer in biological systems.

Generalization of the Marcus transfer rate is derived for the case of a dissipative long-range donor-acceptor electron transfer (ET) mediated by specific bridging electron pathways in biological systems and driven by ac-electric field. High-frequency electric field is shown to block and even to invert the transfer if a specific relation between amplitude and frequency of the ac-field is fulfilled.

Electricity↗
PubMed2005

Hyaluronan is apically secreted and expressed by proliferating or regenerating renal tubular cells.

BACKGROUND: Hyaluronan has diverse biologic functions in the body, varying from structural tasks to cell stress-induced CD44-mediated activation of intracellular signaling pathways. Hyaluronan biology is relatively unexplored in the kidney. Previously, we identified hyaluronan as binding molecule for crystals in the renal tubules. Crystal retention is a crucial early event in the etiology of kidney stones. The present study was performed to determine the polarized distribution of hyaluronan and CD44 by renal tubular cells. METHODS: Madin-Darby canine kidney (MDCK) strain I and primary cultures of human renal tubular cells were grown on permeable supports in a two-compartment culture system. Studies were performed during growth and after scrape-injury. Metabolic labeling studies and an enzyme-linked hyaluronan -binding assay were used to measure the molecular mass and the amount of secreted hyaluronan in apical and basal medium. Confocal microscopy was applied to detect membrane hyaluronan and CD44. Hyaluronan synthase (HAS) mRNA expression was studied with reverse transcriptase-polymerase chain reaction (RT-PCR). The in vitro expression profile of hyaluronan was compared with that in biopsies of transplanted human kidneys with acute tubular necrosis. RESULTS: Proliferating cells produced more hyaluronan (M(r) > 10(6) Da) than growth-inhibited cells in intact monolayers and up to 85% was targeted to the apical compartment, which was accompanied by increased HAS2 mRNA expression and slightly decreased HAS3 mRNA, while HAS1 mRNA remained undetectable. Hyaluronan and CD44 were exclusively expressed at the apical surface of proliferating/regenerating cells. After (re)establishment of tight junctions, hyaluronan was no longer detectable while CD44 was targeted to basolateral membrane domains. In vivo in inflamed human kidneys hyaluronan was abundantly expressed in the cortical tubulointerstitial space as well as at the luminal surface of regenerating renal tubular cells. CONCLUSION: These results demonstrate that the production of hyaluronan by renal tubular cells is activated during proliferation and in response to mechanical injury and that hyaluronan and CD44 expression is highly polarized. The targeted delivery of hyaluronan to the apical compartment suggests that hyaluronan produced by renal tubular cells supports proliferation/regeneration in the renal tubules, but that it does not contribute to hyaluronan accumulation in the renal interstitium. These data further support the concept that mitogen/stress-induced hyaluronan deposition in the renal tubules increases the risk for crystal retention and stone formation.

Animals↗
PubMed1992

Tissue- and treatment-specific usage of multiple preproenkephalin transcriptional start sites.

The significance of the 5' heterogeneity of the transmitter gene ppEnk was evaluated by comparing start site usage (E1-E4) between 12 tissues from untreated rats, using primer extension analysis. In the basal state, we found that E3- and E4-initiated transcripts accounted for 80% of the total striatal RNA present compared with a preferential usage of the E2 start site in all other tissues. To determine whether this selective expression could be modified by biologically relevant pathways, rats were made hypoglycemic. After insulin shock, only E3 + E4-initiated transcripts increased (16-fold at 1 day) in the adrenal medulla but were unaffected in the striatum. As the effects of insulin shock on the adrenal medulla are mediated by cholinergic pathways and the striatum also receives cholinergic inputs, we also compared the effects of cholinergic drug treatments on start site usage in these two tissues. Rats were treated with cholinergic agonists (nicotine + oxotremorine) which induced adrenomedullary E2 and E3 + E4 transcripts (5- and 80-fold, respectively). This effect peaked at 2 days. In contrast, in the same animals, striatal ppEnk RNA (E3 + E4) increased only 10-15-fold after drug treatment. Hence it appears that biologically relevant whole animal stimuli (insulin shock or cholinergic agents) activate biochemical pathways, which affect start site usage in a tissue-specific fashion. Selective RNA start site usage suggests a biological significance, which may be important in the widespread tissue expression of this gene.

Adrenal Medulla↗
PubMed2005

New directions in incidence-dose modeling.

Many cellular responses are quantal; that is, they either take place or they do not. Examples of "either-or" responses include cell replication, differentiation and apoptosis. Surprisingly, induction of suites of genes and coordinated phenotypic changes in cells are also often quantal, where embedded molecular circuitry creates on-off switches. Mechanistic incidence-dose (ID) models need to account for the quantal characteristics of cellular switches that contribute, in turn, to dose thresholds and to the incidence of biological responses in individuals. Interdisciplinary systems biology approaches create mechanistic ID models based on: (i) detailed knowledge of the cellular circuitry controlling signal transduction; (ii) evolving biological modeling tools describing cellular circuits and their perturbations by chemicals and (iii) high throughput, high coverage "omic" screens for examining cell signaling pathways and biological responses. These interdisciplinary approaches should produce novel, quantitative ID models for biological responses and greatly improve the biological basis of safety and risk assessments.

Incidence↗
PubMed2000

DNA base excision repair in human malaria parasites is predominantly by a long-patch pathway.

Mammalian cells repair apurinic/apyrimidinic (AP) sites in DNA by two distinct pathways: a polymerase beta (pol beta)-dependent, short- (one nucleotide) patch base excision repair (BER) pathway, which is the major route, and a PCNA-dependent, long- (several nucleotide) patch BER pathway. The ability of a cell-free lysate prepared from asexual Plasmodium falciparum malaria parasites to remove uracil and repair AP sites in a variety of DNA substrates was investigated. We found that the lysate contained uracil DNA glycosylase, AP endonuclease, DNA polymerase, flap endonuclease, and DNA ligase activities. This cell-free lysate effectively repaired a regular or synthetic AP site on a covalently closed circular (ccc) duplex plasmid molecule or a long (382 bp), linear duplex DNA fragment, or a regular or reduced AP site in short (28 bp), duplex oligonucleotides. Repair of the AP sites in the various DNA substrates involved a long-patch BER pathway. This biology is different from mammalian cells, yeast, Xenopus, and Escherichia coli, which predominantly repair AP sites by a one-nucleotide patch BER pathway. The apparent absence of a short-patch BER pathway in P. falciparum may provide opportunities to develop antimalarial chemotherapeutic strategies for selectively damaging the parasites in vivo and will allow the characterization of the long-patch BER pathway without having to knock-out or inactivate a short-patch BER pathway, which is necessary in mammalian cells.

Animals↗
PubMed2004

Genetic inheritance of gene expression in human cell lines.

Combining genetic inheritance information, for both molecular profiles and complex traits, is a promising strategy not only for detecting quantitative trait loci (QTLs) for complex traits but for understanding which genes, pathways, and biological processes are also under the influence of a given QTL. As a primary step in determining the feasibility of such an approach in humans, we present the largest survey to date, to our knowledge, of the heritability of gene-expression traits in segregating human populations. In particular, we measured expression for 23,499 genes in lymphoblastoid cell lines for members of 15 Centre d'Etude du Polymorphisme Humain (CEPH) families. Of the total set of genes, 2,340 were found to be expressed, of which 31% had significant heritability when a false-discovery rate of 0.05 was used. QTLs were detected for 33 genes on the basis of at least one P value <.000005. Of these, 13 genes possessed a QTL within 5 Mb of their physical location. Hierarchical clustering was performed on the basis of both Pearson correlation of gene expression and genetic correlation. Both reflected biologically relevant activity taking place in the lymphoblastoid cell lines, with greater coherency represented in Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathways than in Gene Ontology database pathways. However, more pathway coherence was observed in KEGG pathways when clustering was based on genetic correlation than when clustering was based on Pearson correlation. As more expression data in segregating populations are generated, viewing clusters or networks based on genetic correlation measures and shared QTLs will offer potentially novel insights into the relationship among genes that may underlie complex traits.

Cell Line↗
PubMed2003

Gibberellin signalling pathway.

Recent molecular biological and genetical studies have identified several positive and negative regulators of gibberellin (GA) signalling pathways in higher plants. The DELLA protein functions as a negative regulator of GA signalling; its degradation through the ubiquitin/proteasome pathway is a key event in the regulation of GA-stimulated processes.

Gene Expression Regulation, Developmental↗
PubMed2000

Characterization of class II apurinic/apyrimidinic endonuclease activities in the human malaria parasite, Plasmodium falciparum.

We have reported that the human malaria parasite, Plasmodium falciparum, repairs apurinic/apyrimidinic (AP) sites on DNA by a long-patch base excision repair (BER) pathway. This biology is different from that in mammalian cells, which predominantly repair AP sites by a DNA-polymerase-beta-dependent, one-nucleotide patch BER pathway. As a starting point for the identification and biochemical characterization of the enzymes involved in the parasite DNA BER pathway, we chose characterization of the AP endonuclease activity in a P. falciparum cell-free lysate. Evidence is provided for the presence of class II, Mg(2+)-dependent and independent AP endonucleases in the parasite lysate. The investigation of the processing of AP sites in Plasmodium will provide new information about long-patch BER pathways; if they are different from those in the human host they might provide a new target for anti-malarial chemotherapy.

Animals↗
PubMed1993

The mevalonate pathway: importance in mesangial cell biology and glomerular disease.

Products of intracellular mevalonate metabolism are critical for the growth and proliferation of eukaryotic cells. These products include cholesterol and several nonsterol isoprenoids. The isoprenoid farnesyl is a particularly important intermediate in the mevalonate pathway. Farnesyl can be used to synthesize cholesterol and can also bind covalently to several low molecular mass GTP-binding proteins such as p21 ras. Farnesylated p21 ras may be critical for mitogenic signalling stimulated by growth factors such as platelet-derived growth factor. Inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, such as lovastatin and compactin, block the production of mevalonate and its metabolites. These agents have been shown to inhibit proliferation of many cell types. Recently we demonstrated that lovastatin inhibited proliferation of cultured glomerular mesangial cells. Lovastatin inhibition was overcome by the simultaneous addition of either mevalonate or farnesol, but not by exogenous low density lipoprotein cholesterol. These results suggested that farnesyl is critical for mesangial cell proliferation. In several experimental models of renal disease, chronic lovastatin administration reduced the extent of glomerular injury. The beneficial effects of lovastatin have been attributed to lowering of circulating lipid and lipoprotein levels. In view of recent data, however, it is possible that lovastatin may act to reduce glomerular injury, at least in part, through a direct action on mesangial cell proliferation.

Animals↗
PubMed2001

Functional neuroanatomy of biological motion perception in humans.

We used whole brain functional MRI to investigate the neural network specifically engaged in the recognition of "biological motion" defined by point-lights attached to the major joints and head of a human walker. To examine the specificity of brain regions responsive to biological motion, brain activations obtained during a "walker vs. non-walker" discrimination task were compared with those elicited by two other tasks: (i) non-rigid motion (NRM), involving the discrimination of overall motion direction in the same "point-lights" display, and (ii) face-gender discrimination, involving the discrimination of gender in briefly presented photographs of men and women. Brain activity specific to "biological motion" recognition arose in the lateral cerebellum and in a region in the lateral occipital cortex presumably corresponding to the area KO previously shown to be particularly sensitive to kinetic contours. Additional areas significantly activated during the biological motion recognition task involved both, dorsal and ventral extrastriate cortical regions. In the ventral regions both face-gender discrimination and biological motion recognition elicited activation in the lingual and fusiform gyri and in the Brodmann areas 22 and 38 in superior temporal sulcus (STS). Along the dorsal pathway, both biological motion recognition and non-rigid direction discrimination gave rise to strong responses in several known motion sensitive areas. These included Brodmann areas 19/37, the inferior (Brodmann Area 39), and superior parietal lobule (Brodmann Area 7). Thus, we conjecture that, whereas face (and form) stimuli activate primarily the ventral system and motion stimuli primarily the dorsal system, recognition of biological motion stimuli may activate both systems as well as their confluence in STS. This hypothesis is consistent with our findings in stroke patients, with unilateral brain lesions involving at least one of these areas, who, although correctly reporting the direction of the point-light walker, fail on the biological motion task.

Adult↗
PubMed1996

The human immunodeficiency virus type 1 Vpu protein tethered to the CD4 extracellular domain is localized to the plasma membrane and is biologically active in the secretory pathway of mammalian cells: implications for the mechanisms of Vpu function.

The HIV-1 Vpu protein induces the proteolysis of CD4 in the endoplasmic reticulum (ER) and enhances the release of virus particles from the plasma membrane. The two biological activities of HIV-1 Vpu appear to be reconstituted in distinct membrane compartments of the mammalian cell. We carried out experiments to understand the role of Vpu sequences in membrane trafficking of the Vpu protein and to gain insights into Vpu-mediated proteolytic reactions. To this end, we generated CD4/Vpu hybrid proteins and analyzed their biochemical and biological properties in HeLa cells. We show here that all hybrid proteins are delivered to the plasma membrane undergoing endo-H-resistant modifications in the Golgi complex. Importantly, a hybrid protein bearing the CD4 extracellular domain and full-length Vpu induced the degradation of HIV envelope glycoproteins bearing the transmembrane and cytoplasmic domains of CD4 (Vpu-responsive elements, VRE). Glycoproteins lacking the VRE are stable under these conditions. In addition, a hybrid protein having the extracellular-transmembrane domains of CD4 and the Vpu cytoplasmic domain was only partially active in inducing the degradation of Vpu-sensitive proteins. These results suggest that the Vpu transmembrane domain is capable of regulating Vpu activity in the cell. Mutational studies have further demonstrated that casein kinase-2 phosphorylation is critically important in the degradation reaction, but does not regulate membrane trafficking of the CD4/Vpu hybrid proteins. We also show that the CD4 extracellular domain appended to the Vpu protein is protected from degradation while existing in a complex with Vpu-sensitive ectodomains. Taken together, these studies have revealed that the Vpu protein does not possess sequences that have the ability to sequester CD4 in the intracellular compartments of mammalian cells and that the Vpu protein tethered to the CD4 extracellular domain was biologically active in inducing the degradation of VRE-bearing glycoproteins in the ER.

Animals↗
PubMedDate not supplied

Modelling spatiotemporal olfactory data in two steps: from binary to Hodgkin-Huxley neurones.

Network models of synchronously updated McCulloch-Pitts neurones exhibit complex spatiotemporal patterns that are similar to activities of biological neurones in phase with a periodic local field potential, such as those observed experimentally by Wehr and Laurent (1996, Nature 384, 162-166) in the locust olfactory pathway. Modelling biological neural nets with networks of simple formal units makes the dynamics of the model analytically tractable. It is thus possible to determine the constraints that must be satisfied by its connection matrix in order to make its neurones exhibit a given sequence of activity (see, for instance, Quenet et al., 2001, Neurocomputing 38-40, 831-836). In the present paper, we address the following question: how can one construct a formal network of Hodgkin-Huxley (HH) type neurones that reproduces experimentally observed neuronal codes? A two-step strategy is suggested in the present paper: first, a simple network of binary units is designed, whose activity reproduces the binary experimental codes; second, this model is used as a guide to design a network of more realistic formal HH neurones. We show that such a strategy is indeed fruitful: it allowed us to design a model that reproduces the Wehr-Laurent olfactory codes, and to investigate the robustness of these codes to synaptic noise.

Models, Neurological↗
PubMed2006

Managing the expanded use of biologics across therapeutic areas: an example from b-cell targeted therapies.

Greater understanding of disease pathology at the molecular and cellular level has enhanced the roles of various proteins in disease pathogenesis. Because so many diseases have common physiologic pathways, many biologic therapies have been found to work in multiple therapeutic areas, particularly cancer, inflammation, infections, and metabolic and blood disorders. Thus, the search for agents to inhibit or block these critical therapeutic agents has been accelerated. This supplement reviews the factors contributing to the enormous growth of biotechnology drugs--both those currently marketed and those in late-stage development--from a clinical and managed care perspective. Specifically, the growth of expanded indications for drugs approved by the US Food and Drug Administration (FDA) will be examined, along with the challenges of managing biotechnology therapies being used beyond their original indications. A review of currently marketed biologics under investigation for new indications will be presented, along with a discussion of the implications of expanding indications and the resultant impact on managed care organizations in terms of cost, benefit design, access management strategy, safety and efficacy, and other pertinent issues. Managed care executives will face the challenge of making critical formulary decisions within the context of ever-increasing biologic options, including greater utilization of biotechnology drugs, more biologics for common conditions, and expanded indications for FDA-approved drugs.

B-Lymphocytes↗
PubMed2026

Genetic associations in sepsis and ARDS.

Critical illness syndromes, such as sepsis and acute respiratory distress syndrome (ARDS), are characterized by substantial clinical heterogeneity and remain major causes of morbidity and mortality worldwide. Increasing evidence suggests that genetic variation contributes to susceptibility, disease severity, and clinical outcomes in critically ill patients. However, the molecular mechanisms linking genetic predisposition to the pathophysiology of sepsis and ARDS remain incompletely understood. In this review, we evaluated genetic associations reported in sepsis and ARDS, including 13 genome-wide studies identifying 19 unique single-nucleotide polymorphisms (SNPs) across 17 distinct genomic loci, as well as 21 meta-analyses of candidate-gene studies identifying 21 SNPs across 16 genes. The identified variants were primarily associated with pathways involved in pathogen recognition, immune and inflammatory signaling, leukocyte recruitment, and endothelial dysfunction. Collectively, these findings support a polygenic basis for susceptibility to critical illness and highlight several biologically relevant pathways that may contribute to sepsis and ARDS pathogenesis. Improved understanding of the functional consequences of these variants may facilitate the identification of potential therapeutic targets and support the development of precision-guided approaches to critical care.

ARDS↗
PubMed2026

13C Stable Isotope Tracing-Based MFA Reveals the Contribution of Glucose to Glycolytic and TCA Fluxes and Its Application in Depression Research.

Metabolomics is widely applied to dissect metabolic pathways and their correlations with biological phenotypes. Unlike genomics and proteomics, metabolites exhibit substantial heterogeneity in chemical structure, physicochemical properties, and biological origin. Accordingly, pathway enrichment and annotation relying merely on alterations in metabolite abundance are prone to incomplete coverage, ionization bias, and ambiguous annotation, which inevitably impair the accuracy of pathway interpretation. Metabolic flux analysis (MFA) coupled with stable isotope-resolved metabolomics (SIRM) offers a powerful quantitative framework for tracing in vivo carbon flow and estimating reaction fluxes across key metabolic nodes. Glucose metabolism lies at the core of systemic energy homeostasis; however, most current investigations are confined to cell lines or in vitro systems, and a simple, easy-to-implement computational pipeline for in vivo glucose flux analysis in animal models is still lacking. Herein, we established an in vivo 13C-labeling-based MFA workflow to trace and resolve the systemic metabolic fate of glucose in rats. The pipeline covers tracer administration, sample preparation, LC-MS detection, isotopologue data acquisition and correction, construction of a glucose-metabolism-related metabolite database, MFA model establishment, and metabolic flux quantification. By infusing rats with [U-13C6]-glucose and [U-13C3]-sodium L-lactate, we precisely characterized the in vivo metabolic fates of circulating glucose and lactate and quantified their respective contributions to glycolytic flux and tricarboxylic acid (TCA) cycle flux. We further applied this workflow to profile energy metabolic reprogramming in depression. The results revealed a systemic shift toward aerobic glycolysis in rats exposed to chronic unpredictable mild stress (CUMS). Overall, the expanded application of this MFA strategy can provide mechanistic and quantitative insights into the regulation of metabolic pathways.

Animals↗
PubMed2005

Differential responses of visceral and subcutaneous fat depots to nutrients.

Increased visceral adiposity is a pivotal component of the metabolic syndrome. Differential gene expression patterns of fat-derived peptides (FDPs) in visceral fat and subcutaneous fat have been characterized in the fasting state. Here we examined whether delivery of nutrients differentially affects the expression of FDPs in visceral fat versus subcutaneous fat (in the fed state). We increased the rate of glucose flux into adipose tissue of normal rats (n = 16) by hyperglycemia or hyperinsulinemia using the clamp technique. Glucose uptake was associated with increased expression of FDPs, including resistin ( approximately 5-fold), adiponectin ( approximately 2-fold), leptin ( approximately 15-fold), plasminogen activating inhibitor-1 ( approximately 10-fold), and angiotensinogen ( approximately 4-fold) in visceral fat, but markedly less in subcutaneous fat. Cytokine expression derived mainly from vascular/stromal/macrophage components of adipose tissue was less dramatically increased. Infusion of glucosamine amplified the results obtained by increasing glucose uptake into adipose tissue, suggesting that flux through the hexosamine biosynthetic pathway may serve as a mechanism for "nutrient sensing." Nutrient-dependent expression of FDPs in visceral fat was also associated with increased plasma levels of several FDPs. Because a biologic sensing pathway can dynamically couple daily food intake to abnormal plasma levels of important FDPs, we challenge the practice of obtaining plasma levels after fasting to assess risk factors for metabolic syndrome.

Adipose Tissue↗
PubMedDate not supplied

Biosynthesis and biological properties of compounds containing highly reactive, reduced sulfane sulfur.

The covalent modifications of sulfhydryl groups (-SH) may occur through oxidation to mixed disulfides (S-thiolation), S-nitrosylation, as well as persulfide and trisulfide formation. The latter possibilities of -SH group modification connected with compounds containing sulfur called sulfane sulfur are described in this paper. Sulfane sulfur compounds contain a labile, highly reactive sulfur atom at a reduced oxidation state with a valence of 0 or -1, covalently bound to another sulfur atom. These compounds include persulfides, polysulfides, polythionates, thiosulfate, elemental sulfur and disulfides, which enable tautomerization to thiosulfoxides. Sulfane sulfur compounds are formed in the anaerobic cysteine sulfur metabolism with the participation of such enzymes as cystathionase (CST), 3-mercaptopyruvate sulfurtransferase (MpST) and rhodanese (thiosulfate: cyanide sulfurtransferase). Compounds containing sulfane sulfur participate in cell regulation processes through activation or inactivation of some enzymes. Other important roles of sulfane sulfur compounds are their antioxidative properties, significance in the processes of carcinogenesis, participation in the tRNA sulfuration as well as an influence on the activity of immune cells. To recognize completely the biological role of compounds with sulfane sulfur it is necessary to have sensitive methods of quantitative determination, so a review of these methods is presented in this paper. Moreover, biosynthetic pathways and biological properties of these compounds have been discussed.

Animals↗