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PubMed2006

Parameter estimation in models combining signal transduction and metabolic pathways: the dependent input approach.

Biological complexity and limited quantitative measurements pose severe challenges to standard engineering methodologies for modelling and simulation of genes and gene products integrated in a functional network. In particular, parameter quantification is a bottleneck, and therefore parameter estimation, identifiability, and optimal experiment design are important research topics in systems biology. An approach is presented in which unmodelled dynamics are replaced by fictitious 'dependent inputs'. The dependent input approach is particularly useful in validation experiments, because it allows one to fit model parameters to experimental data generated by a reference cell type ('wild-type') and then test this model on data generated by a variation ('mutant'), so long as the mutations only affect the unmodelled dynamics that produce the dependent inputs. Another novel feature of the approach is in the inclusion of a priori information in a multi-objective identification criterion, making it possible to obtain estimates of parameter values and their variances from a relatively limited experimental data set. The pathways that control the nitrogen uptake fluxes in baker's yeast (Saccharomyces cerevisiae) have been studied. Well-defined perturbation experiments were performed on cells growing in steady-state. Time-series data of extracellular and intracellular metabolites were obtained, as well as mRNA levels. A nonlinear model was proposed and was shown to be structurally identifiable given data of its inputs and outputs. The identified model is a reliable representation of the metabolic system, as it could correctly describe the responses of mutant cells and different perturbations.

Algorithms↗
PubMed2006

Molecular biology of malignant gliomas.

Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies.

Animals↗
PubMed2005

Recasting developmental evolution in terms of genetic pathway and network evolution ... and the implications for comparative biology.

The morphological features of complex organisms are the outcomes of developmental processes. Developmental processes, in turn, reflect the genetic networks that underlie them. Differences in morphology must ultimately, therefore, reflect differences in the underlying genetic networks. A mutation that affects a developmental process does so by affecting either a gene whose product acts as an upstream controlling element, an intermediary connecting link, or as a downstream output of the network that governs the trait's development. Although the immense diversity of gene networks in the animal and plant kingdoms would seem to preclude any general "rules" of network evolution, the material discussed here suggests that the patterns of genetic pathway and network evolution actually fall into a number of discrete modes. The potential utility of this conceptual framework in reconstructing instances of developmental evolution and for comparative neurobiology will be discussed.

Animals↗
PubMed2005

Deconstructing memory in Drosophila.

Unlike most organ systems, which have evolved to maintain homeostasis, the brain has been selected to sense and adapt to environmental stimuli by constantly altering interactions in a gene network that functions within a larger neural network. This unique feature of the central nervous system provides a remarkable plasticity of behavior, but also makes experimental investigations challenging. Each experimental intervention ramifies through both gene and neural networks, resulting in unpredicted and sometimes confusing phenotypic adaptations. Experimental dissection of mechanisms underlying behavioral plasticity ultimately must accomplish an integration across many levels of biological organization, including genetic pathways acting within individual neurons, neural network interactions which feed back to gene function, and phenotypic observations at the behavioral level. This dissection will be more easily accomplished for model systems such as Drosophila, which, compared with mammals, have relatively simple and manipulable nervous systems and genomes. The evolutionary conservation of behavioral phenotype and the underlying gene function ensures that much of what we learn in such model systems will be relevant to human cognition. In this essay, we have not attempted to review the entire Drosophila memory field. Instead, we have tried to discuss particular findings that provide some level of intellectual synthesis across three levels of biological organization: behavior, neural circuitry and biochemical pathways. We have attempted to use this integrative approach to evaluate distinct mechanistic hypotheses, and to propose critical experiments that will advance this field.

Adenylyl Cyclases↗
PubMed2005

Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium.

OBJECTIVE: Tumor necrosis factor alpha (TNF-alpha), a key proinflammatory cytokine acting on the endothelium, activates endothelial nitric oxide synthase (eNOS). We have examined the signaling pathway leading to this activation and its biological role in endothelium, which are still unknown. METHODS AND RESULTS: In human endothelial cells, we found that eNOS activation by TNF-alpha is time dependent and requires activation of Akt, a known eNOS activator. eNOS activation was preceded by sequential activation of neutral-sphingomyelinase-2 (N-SMase2) and sphingosine-kinase-1 (SK1) and generation of sphingosine-1-phosphate (Sph1P). Inhibition of N-SMase2 inhibited Sph1P formation, whereas inhibition of SK1 did not affect N-SMase2 activation by TNF-alpha. Blockade of N-SMase2, SK1, or the Sph1P receptors S1P1 and S1P3, either by silencing or pharmacological inhibitors, prevented eNOS activation. Thus, eNOS is activated by TNF-alpha via S1P receptors, activated by Sph1P generated through N-SMase2 and SK1 activation. We found that nitric oxide generated through this pathway has a biological role, because it inhibits the expression of E-selectin and the adhesion of dendritic cells to the endothelium stimulated by TNF-alpha. CONCLUSIONS: This study establishes a previously undescribed link among TNF-alpha, Sph1P, and eNOS in a same signaling pathway of biological relevance in the process of endothelial cell activation by TNF-alpha.

Calcium↗
PubMed2000

Molecular breeding of carotenoid biosynthetic pathways.

The burgeoning demand for complex, biologically active molecules for medicine, materials science, consumer products, and agrochemicals is driving efforts to engineer new biosynthetic pathways into microorganisms and plants. We have applied principles of breeding, including mixing genes and modifying catalytic functions by in vitro evolution, to create new metabolic pathways for biosynthesis of natural products in Escherichia coli. We expressed shuffled phytoene desaturases in the context of a carotenoid biosynthetic pathway assembled from different bacterial species and screened the resulting library for novel carotenoids. One desaturase chimera efficiently introduced six rather than four double bonds into phytoene, to favor production of the fully conjugated carotenoid, 3, 4,3',4'-tetradehydrolycopene. This new pathway was extended with a second library of shuffled lycopene cyclases to produce a variety of colored products. One of the new pathways generates the cyclic carotenoid torulene, for the first time, in E. coli. This combined approach of rational pathway assembly and molecular breeding may allow the discovery and production, in simple laboratory organisms, of new compounds that are essentially inaccessible from natural sources or by synthetic chemistry.

Carotenoids↗
PubMed2005

The love-hate relationship between Ras and Notch.

The Ras and Notch signaling pathways are used over and over again during development to control many different biological processes. Frequently, these two signaling pathways intersect to influence common processes, but sometimes they cooperate and sometimes they antagonize each other. The Caenorhabditis elegans vulva and the Drosophila eye are two classic paradigms for understanding how Ras and Notch affect cell fates, and how the two pathways work together to control biological pattern. Recent advances in these systems reveal some of the mechanisms by which Ras and Notch can interact. Similar types of interactions in mammals may be important for determining whether and how alterations in Ras or Notch lead to cancer.

Animals↗
PubMed2026

DNA damage response pathway alterations in urothelial carcinoma: a road to precision oncology or a dead-end street?

Urothelial carcinoma ranks among the most common solid tumors and exhibits aggressive behavior, with limited survival in the metastatic setting despite recent therapeutic advances. Currently, 3 first-line systemic treatment options are supported by level IA evidence, yet no validated predictive biomarkers exist to guide selection among them. Alterations in DNA damage response (DDR) pathways occur in a substantial proportion of urothelial tumors and have emerged as potential predictive biomarkers of treatment sensitivity. This review examines the biological basis of DDR pathways and their implications in carcinogenesis, summarizes the frequency and spectrum of DDR gene alterations in urothelial carcinoma, and critically appraises the available evidence linking these alterations to responses to platinum-based chemotherapy, immune checkpoint inhibitors, and PARP inhibitors in both muscle-invasive and metastatic settings. Although retrospective data suggest associations between DDR alterations and improved outcomes with certain therapies, results across studies are heterogeneous, likely reflecting inconsistent definitions of DDR alterations, the variable functional impact of individual mutations, and differences in patient populations. We discuss these limitations and highlight the need for standardized criteria and prospective validation to determine whether DDR pathway alterations can be reliably integrated into clinical decision-making for patients with urothelial carcinoma.

Humans↗
PubMed1994

The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

The biological response to progesterone is mediated by two distinct forms of the human progesterone receptor (hPR-A and hPR-B). In most cell contexts, hPR-B functions as a transcriptional activator of progesterone-responsive genes, whereas hPR-A functions as a transcriptional inhibitor of all steroid hormone receptors. We have created mutations within the carboxyl terminus of hPR which differentially effect the transcriptional activity of hPR-B in a cell- and promoter-specific manner. Analogous mutations, when introduced into hPR-A, have no effect on its ability to inhibit the transcriptional activity of other steroid hormone receptors. The observed differences in the structural requirements for hPR-B and hPR-A function suggest that transcriptional activation and repression by PR are mediated by two separate pathways within the cell. In support of this hypothesis, we have shown that hPR-A mediated repression of human estrogen receptor (hER) transcriptional activity is not dependent on hER expression level but depends largely on the absolute expression level of hPR-A. Thus, it appears that hPR-A inhibits hER transcriptional activity as a consequence of a noncompetitive interaction of hPR-A with either distinct cellular targets or different contact sites on the same target. We propose that hPR-A expression facilitates a ligand-dependent cross-talk among sex steroid receptor signaling pathways within the cell. It is likely, therefore, that alterations in the expression level of hPR-A or its cellular target can have profound effects on the physiological or pharmacological responses to sex steroid hormone receptor ligands.

Base Sequence↗
PubMed2005

The two-pathway model for the catch-slip transition in biological adhesion.

Some recently studied biological noncovalent bonds have shown increased lifetime when stretched by mechanical force. In each case these counterintuitive "catch-bonds" have transitioned into ordinary "slip-bonds" that become increasingly shorter lived as the tensile force on the bond is further increased. We describe analytically how these results are supported by a physical model whereby the ligand escapes the receptor binding site via two alternative routes, a catch-pathway that is opposed by the applied force and a slip-pathway that is promoted by force. The model predicts under what conditions and at what critical force the catch-to-slip transition would be observed, as well as the degree to which the bond lifetime is enhanced at the critical force. The model is applied to four experimentally studied systems taken from the literature, involving the binding of P- and L-selectins to sialyl Lewis(X) oligosaccharide-containing ligands. Good quantitative fit to the experimental data is obtained, both for experiments with a constant force and for experiments where the force increases linearly with time.

Adhesiveness↗
PubMed2003

Shaken and stirred: muscle structure and metabolism.

Muscles are ideal models with which to examine the relationship between structure and metabolism because they are some of the most highly structured cells, and are capable of the largest and most rapid metabolic transitions as well as the highest metabolic rates known. Studies of metabolism have traditionally been conducted within what can considered as the kinetic paradigm provided by 'solution biochemistry'; i.e. the rates of enzymatic reactions are studied in terms of their regulation by mass-action and allosteric effectors and, most recently, metabolic control analysis of pathways. This approach has served biology well and continues to be useful. Here, we consider the diffusion of small and large molecules in muscles and energy metabolism in the context of intracellular space. We find that in attempting to explain certain phenomena, a purely kinetic paradigm appears insufficient. Instead, phenomena such as the 'shuttling' of high-energy phosphate donors and acceptors and the binding of metabolic enzymes to intracellular structures or to each other are better understood when metabolic rates and their regulation are considered in the context of intracellular compartments, distances, gradients and diffusion. As in all of biology, however, complexity dominates, and to such a degree that one pathway may consist of several reactions that each behave according to different rules. 'Soluble' creatine kinase operates at or near equilibrium, while mitochondrial and myofibrillar creatine kinases directly channel substrate to (or from) the adenine nucleotide translocase and actomyosin-ATPase, their operation being thus displaced from equilibrium. Hexose 6-phosphate metabolism appears to obey the rules of solution biochemistry, e.g. phosphoglucoisomerase behaves as Haldane would have predicted in 1930. In contrast, given low steady-state substrate and product concentrations and high flux rates, a number of glycolytic reactions further downstream must be catalyzed by enzymes localized in close proximity to each other. Metabolites may be channeled within these complexes. When observed, mechanistic differences between species in the same steps or processes should not be surprising, considering how animals vary so much in structures, mechanical properties, mitochondrial contents and metabolic rates. This analysis suggests that declarations of the triumph of one mechanism or paradigm over all others, as well as calls for the abandonment of solution biochemistry, are unwarranted. Rather, metabolic biochemistry would seem better served by reconciling the old and the new.

Cytoplasm↗
PubMed2004

The kynurenine pathway of tryptophan degradation as a drug target.

In mammalian cells, the essential amino acid tryptophan is degraded primarily by the kynurenine pathway, a cascade of enzymatic steps containing several biologically active compounds. Metabolites of this pathway, collectively termed 'kynurenines', have been shown to be involved in many diverse physiological and pathological processes. In particular, fluctuations in the levels of kynurenines have discrete effects on the nervous and immune systems. A considerable number of pharmacological tools have recently become available to probe the kynurenine pathway experimentally. Some of these 'kynurenergic' agents can be envisioned to be of therapeutic value, especially in the treatment of diseases that are associated with impaired kynurenine pathway metabolism.

Animals↗
PubMed1988

An overview of hemostasis.

The normal hemostatic system is complex yet exquisitely well regulated. Interrelationships exist between responses of the vasculature, circulating platelets, coagulation proteins, and fibrinolytic mechanism. These relationships serve to limit blood loss, preserve tissue perfusion, and stimulate local repair processes. Natural inhibitors of coagulation and fibrinolysis modulate these systems to prevent uncontrolled thrombosis or hemorrhage following pathologic stimuli. Vascular endothelial cells play an important role in the maintenance of a thromboresistant luminal interface with circulating cells and proteins. Normal hemostasis also requires the synthetic, metabolic, and repair processes of the vascular endothelium. The initial vascular response to injury produces brief vasoconstriction and exposes subendothelial substances that attract circulating platelets and activate coagulation proteins. Platelets respond by adherence and aggregation at the site of injury, with subsequent release of substances that mitigate blood loss. Platelet adherence to collagen requires von Willebrand's factor, fibrinogen, fibronectin, and specific glycoprotein receptors on platelet surfaces. Platelet-to-platelet interactions (aggregation) recruit additional platelets to the primary hemostatic plug. Aggregation requires fibrinogen, energy, and calcium. Release of ADP, serotonin, and the contents of intracellular granules as well as generation of prostaglandins prepares platelet surfaces for reactions with the coagulation proteins. Activation of the intrinsic or extrinsic coagulation pathway, or of both, causes formation of fibrin from fibrinogen by means of an elaborate and intricate system that also entraps platelets and activated coagulation proteins. The intrinsic system is activated by the contact of factor XII with a negatively charged surface, most likely collagen. Through a series of reactions with prekallikrein, HMWK, and factors XI, IX, and VIII, the common coagulation pathway is propagated. The extrinsic, or tissue factor, system stimulates both the common pathway and factor IX the intrinsic pathway. Discovery of this stimulation of the intrinsic pathway by factor VII in the extrinsic pathway has stimulated reassessment of the biologic importance of the extrinsic system. The common pathway includes factors X and V and causes thrombin to convert fibrinogen to fibrin. Calcium and platelet phospholipids are substances that have important roles in steps in the coagulation scheme. Once fibrin is formed, factor XIII interacts with the substance, providing a stabilizing effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2002

Sit4 is required for proper modulation of the biological functions mediated by Pkc1 and the cell integrity pathway in Saccharomyces cerevisiae.

Maintenance of cellular integrity in Saccharomyces cerevisiae is carried out by the activation of the protein kinase C-mediated mitogen-activated protein kinase (PKC1-MAPK) pathway. Here we report that correct down-regulation of both basal and induced activity of the PKC1-MAPK pathway requires the SIT4 function. Sit4 is a protein phosphatase also required for a proper cell cycle progression. We present evidence demonstrating that the G(1) to S delay in the cell cycle, which occurs as a consequence of the absence of Sit4, is mediated by up-regulation of Pkc1 activity. Sit4 operates downstream of the plasma membrane sensors Mid2, Wsc1, and Wsc2 and upstream of Pkc1. Sit4 affects all known biological functions involving Pkc1, namely Mpk1 activity and cell wall integrity, actin cytoskeleton organization, and ribosomal gene transcription.

Acacia↗
PubMed2006

Comparative genomic and phylogenetic analyses of calcium ATPases and calcium-regulated proteins in the apicomplexa.

The phylum Apicomplexa comprises a large group of early branching eukaryotes that includes a number of human and animal parasites. Calcium controls a number of vital processes in apicomplexans including protein secretion, motility, and differentiation. Despite the importance of calcium as a second messenger, very little is known about the systems that control homeostasis or that regulate calcium signaling in parasites. The recent completion of many apicomplexan genomes provides new opportunity to define calcium response pathways in this group of parasites in comparison to model organisms. Whole-genome comparison between the apicomplexans Plasmodium spp., Cryptosporidium spp., and Toxoplasma gondii revealed the presence of several P-Type Ca2+ transporting ATPases including a single endoplasmic reticulum (ER)-type sarcoplasmic-endoplasmic reticulum Ca2+ ATPase, several Golgi-like Ca2+ ATPases, and a single Ca2+/H+ exchanger. Only T. gondii showed evidence of plasma membrane-type Ca2+ ATPases or voltage-gated calcium channels. Despite pharmacological evidence for IP3 and ryanodine-mediated calcium release, animal-type calcium channels were not readily identified in parasites, indicating they are more similar to plants. Downstream of calcium release, a variety of EF-hand-containing proteins regulate calcium responses. Our analyses detected a single conserved calmodulin (CaM) homologue, 3 distinct centrin (CETN)-caltractin-like proteins, one of which is shared with ciliates, and a variety of deep-branching, CaM-CETN-like proteins. Apicomplexans were also found to contain a wide array of calcium-dependent protein kinases (CDPKs), which are commonly found in plants. Toxoplasma gondii contains more than 20 CDPK or CDPK-related kinases, which likely regulate a variety of responses including secretion, motility, and differentiation. Genomic and phylogenetic comparisons revealed that apicomplexans contain a variety of unusual calcium response pathways that are distinct from those seen in vertebrates. Notably, plant-like pathways for calcium release channels and calcium-dependent kinases are found in apicomplexans. The experimental flexibility of T. gondii should allow direct experimental manipulation of these pathways to validate their biological roles. The central importance of calcium in signaling and development, and the novel characteristics of many of these systems, indicates that parasite calcium pathways may be exploited as new therapeutic targets for intervention.

Amino Acid Sequence↗
PubMed2003

Regulation of adrenomedullin signaling in kidney interstitial fibroblasts.

Adrenomedullin (AM), a potent vasodilatory peptide has beneficial effects in the kidney IN VIVO. The major aim of the present study was to determine the presence of AM receptor and the biological outcomes of AM on kidney interstitial fibroblasts in culture. Utilizing RT-PCR we found that NRK-49F cells express calcitonin receptor like receptor (CRLR) and receptor activity modifying protein 2 (RAMP2) but not RAMP3. Treatment of these cells with AM resulted in a concentration-dependent increase in cAMP activation. The activation of adenylate cyclase system was enhanced by over-expression of CRLR, RAMP2 and RAMP3. Furthermore, AM-stimulated adenylate cyclase activity was inhibited by AM-[22-52] the AM receptor antagonist. AM also caused a PKA-dependent increase in CRE-luciferase activity. To test the biological consequences of AM treatment and the signaling pathways mediating them, we examined the effect of AM on proliferation of NRK-49F cells and the desensitization of AM receptor. AM caused a significant decrease in proliferation that was AM-receptor mediated but was PKA independent. In addition, AM also caused desensitization of cAMP response within a few minutes of treatment. This effect of AM was also not mediated via cAMP pathway as forskolin failed to desensitize AM receptor, and a PKA-inhibitor did not inhibit the desensitization. Taken together these results demonstrate that NRK-49F cells express functional AM receptor that when activated by AM results in a significant reduction of cell proliferation. Although cAMP activation by AM, as in other systems, is also observed in NRK-49F cells, PKA-independent pathways lead to some of the biological responses observed in these cells.

Adenylyl Cyclases↗
PubMed2026

Trio-based whole-exome sequencing identifies convergent epithelial junction-related pathways in syndromic hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed as syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum-PG-, acne and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals sequencing and the absence of parental genomic information limits the possibility to determine inheritance patterns. METHODS: To address these gaps, we performed trio-based whole-exome sequencing (WES) on five individuals diagnosed with sHS and their unaffected parents. RESULTS: The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, TNC) was also retrieved. Also, variants affecting innate immune pathways, including cytokine signalling and antigen presentation, have been observed. CONCLUSION: Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organisation, extracellular matrix interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.

Journal Article↗