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PubMed2002

Pathways to melanoma development: lessons from the mouse.

Because of subtle differences between mouse and human skin, mice have traditionally not been an ideal model to study melanoma development. Understanding of the molecular mechanisms of melanoma predisposition, however, has been greatly improved by modeling various pathway defects in the mouse. This review analyzes the latest developments in mouse models of melanoma, and summarizes what these may indicate about the development of this neoplasm in humans. Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and Arf/p53 pathways are involved in melanoma development in mice, and possible mechanisms of cross-talk between the two pathways are discussed. We also know from mouse models that Ras/mitogen-activated protein kinase pathway activation is very important in melanoma development, either through direct activation of Ras (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent three major "axes" of melanoma development in mice. Finally, we summarize experiments using genetically modified mice that have given indications of the intensity and timing of ultraviolet radiation exposure that may be most responsible for melanoma development.

Animals↗

PubMedDate not supplied

Bacterial killing by Mytilus hemocyte monolayers as a model for investigating the signaling pathways involved in mussel immune defence.

The signaling pathways involved in mussel immune defence were investigated utilizing a model of killing of Escherichia coli by Mytilus galloprovincialis hemocytes in a co-culture setting. In particular, the role played by different mitogen activated protein kinases (MAPKs) and by the production of eicosanoids were investigated utilising specific cell permeant, pharmacological enzyme inhibitors. Hemocyte pretreatment with the p38 MAPK inhibitor SB203580 significantly reduced bacterial killing, whereas PD98059 (an inhibitor of ERK--extracellularly regulated kinase--MAPK activation) had no significant effect. Wortmannin also inhibited bacterial killing, indicating a crucial role for PI3-kinase activation in the immune response. Killing of E. coli was also reduced by inhibitors of both PLA2 and cyclooxygenase activities, indicating that eicosanoid production is involved in mediating the response to bacterial challenge. The results demonstrate that bacterial killing by mussel hemocytes is particularly sensitive to inhibitors of the key steps involved in the transduction of bacterial signals into the host cell. Moreover, these data indicate that the hemocyte bactericidal activity can be suitably utilized not only for identifying the signaling pathways involved in the response to bacterial infection, but also as a potential investigative-toxicology model to test drugs and contaminants for their effect on the overall mussel immune defence.

Animals↗

PubMed2006

Recurrent neural network architecture with pre-synaptic inhibition for incremental learning.

We propose a recurrent neural network architecture that is capable of incremental learning and test the performance of the network. In incremental learning, the consistency between the existing internal representation and a new sequence is unknown, so it is not appropriate to overwrite the existing internal representation on each new sequence. In the proposed model, the parallel pathways from input to output are preserved as possible, and the pathway which has emitted the wrong output is inhibited by the previously fired pathway. Accordingly, the network begins to try other pathways ad hoc. This modeling approach is based on the concept of the parallel pathways from input to output, instead of the view of the brain as the integration of the state spaces. We discuss the extension of this approach to building a model of the higher functions such as decision making.

Affect↗

PubMed2003

Steady-state flux and lag time in the stratum corneum lipid pathway: results from finite element models.

Finite element model (FEM) solutions of the diffusion through two-dimensional representations of the stratum corneum (SC) lipid pathway are presented. Both simplified, regular "brick and mortar" models and a more complex, irregular model are analyzed. It is assumed that diffusion occurs only within the SC lipids and the lipids are isotropic. The steady-state flux and lag time are solved and compared with the corresponding values for a homogeneous membrane of the same thickness consisting of lipid material. Results confirm that the heterogeneous SC model behaves like a homogeneous membrane, meaning that FEM diffusion simulations are well approximated by an appropriate solution of the diffusion equation for a homogeneous membrane. Additionally, both steady-state flux and lag time (relative to these values in a homogeneous membrane) can be predicted from algebraic equations based on simple dimensionless descriptors of SC geometry. However, values for diffusivity derived from homogeneous membrane approximations to the FEM solutions (effective diffusivity, D*) are not equal to the intrinsic diffusivity of the chemical in lipid. Furthermore, the pathlength derived from homogeneous membrane approximations to FEM solutions (effective pathlength, l*) is not equal to the lipid pathlength and is not dependent on SC tortuosity. Whereas l* is not a function of corneocyte overlap, D* is. These model results suggest that diffusion properties of the SC lipid pathway can be correlated to SC geometry, but intrinsic diffusion coefficients and SC tortuosity cannot be derived from common diffusion cell experiments. Use of the model equations to predict permeability and lag time of lipophilic solutes is described.

Algorithms↗

PubMed2005

Signaling satellite-cell activation in skeletal muscle: markers, models, stretch, and potential alternate pathways.

Activation of skeletal muscle satellite cells, defined as entry to the cell cycle from a quiescent state, is essential for normal growth and for regeneration of tissue damaged by injury or disease. This review focuses on early events of activation by signaling through nitric oxide and hepatocyte growth factor, and by mechanical stimuli. The impact of various model systems used to study activation and the regulation of satellite-cell quiescence are placed in the context of activation events in other tissues, concluding with a speculative model of alternate pathways signaling satellite-cell activation.

Animals↗

PubMed2005

Kinetic modeling of 3'-deoxy-3'-fluorothymidine in somatic tumors: mathematical studies.

UNLABELLED: We present a method to measure the regional rate of cellular proliferation using a positron-emitting analog of thymidine (TdR) for human imaging studies. The method is based on the use of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) to estimate the flux of TdR through the exogenous pathway. The model reflects the retention of FLT-monophosphate (FLTMP), which is generated by the phosphorylation of FLT by thymidine kinase 1 (TK1), the initial step in the exogenous pathway. METHODS: A model of FLT kinetics has been designed based on the assumptions of a steady-state synthesis and incorporation of nucleotides into DNA, an equilibration of the free nucleoside in tissue with the plasma level, and the relative rates of FLT and TdR phosphorylation from prior data using direct analysis with in vitro assays. A 2-compartment model with 4 rate constants adequately describes the kinetics of FLT uptake and retention over 120 min and leads to an estimation of the rate of cellular proliferation using the measured FLT blood clearance and the dynamic FLT uptake curve. RESULTS: Noise characteristics of kinetic parameter estimates for 3 tissues were assessed under a range of conditions representative of human cancer patient imaging. The FLT flux in these tissues can be measured with a SE of <5%, and FLT transport can be estimated with a SE of <15%. Abbreviating the data collection to 60 min or neglecting k(4), giving a 3-parameter model, results in an unsatisfactory loss of accuracy in the flux constant in tumor simulations. CONCLUSION: These analyses depict model behavior and provide expected values for the accuracy of parameter estimates from FLT imaging in human patients. Our companion paper describes the performance of the model for human data in patients with lung cancer. Further studies are necessary to determine the fidelity of K(FLT) (FLT flux) as a proxy for K(TDR) (thymidine flux), the gold standard for imaging cellular proliferation.

Algorithms↗

PubMed2006

[Dissemination pathways for poliovirus cells to animals models].

It is considered there are two main pathways for poliovirus dissemination towards the central nervous system in humans. One is the pathway through the blood brain barrier. The orally ingested virus invades into the blood circulation, and then the virus permeates into the central nervous system through the blood brain barrier. The other is the neural pathway. In this pathway, the intramuscularly-inoculated virus is transported through the axons from the synapse to the cell body in the central nervous system. We have developed the oral infection system using the mouse models. Moreover, we proposed the possibility that PV is transcytosed through the brain capillary epithelia in a specific manner. As for the neural pathway, we have proved that PV is endocytosed into CD155 containing vesicles and the vesicles are retrogradely transported in the axon of rat primary motor neuron. We have also shown that the cytoplasmic dynein takes part in the transport.

Animals↗

PubMed2004

Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers.

BACKGROUND: We have previously described an alternative invasion-independent pathway of cancer metastasis in a murine mammary tumor model. This pathway is initiated by intravasation of tumor nests enveloped by endothelial cells of sinusoidal vasculature within the tumor. In this study, we examined whether evidence for the invasion-independent pathway of metastasis is present in human cancers. METHODS: Archival specimens of 10 common types of human cancers were examined for the presence of sinusoidal vasculature enveloping tumor nests and subsequently generated endothelial-covered tumor emboli in efferent veins. RESULTS: A percentage of tumor emboli in all cancers was found to be enveloped by endothelial cells, but these structures were particularly prevalent in renal cell carcinomas, hepatocellular carcinomas and follicular thyroid carcinomas. A common feature of the vasculature in these tumors was the presence of dilated sinusoid-like structures surrounding tumor nests. A high mean vascular area within tumors, an indication of sinusoidal vascular development, was significantly related to the presence of endothelial-covered tumor emboli. CONCLUSIONS: These results suggest that an invasion-independent metastatic pathway is possible in a wide variety of human cancers. Further investigation of this phenomenon may present new therapeutic strategies for the amelioration of cancer metastasis.

Embolism↗

PubMed2004

Five hierarchical levels of sequence-structure correlation in proteins.

This article reviews recent work towards modelling protein folding pathways using a bioinformatics approach. Statistical models have been developed for sequence-structure correlations in proteins at five levels of structural complexity: (i) short motifs; (ii) extended motifs; (iii) nonlocal pairs of motifs; (iv) 3-dimensional arrangements of multiple motifs; and (v) global structural homology. We review statistical models, including sequence profiles, hidden Markov models (HMMs) and interaction potentials, for the first four levels of structural detail. The I-sites (folding Initiation sites) Library models short local structure motifs. Each succeeding level has a statistical model, as follows: HMMSTR (HMM for STRucture) is an HMM for extended motifs; HMMSTR-CM (Contact Maps) is a model for pairwise interactions between motifs; and SCALI-HMM (HMMs for Structural Core ALIgnments) is a set of HMMs for the spatial arrangements of motifs. The parallels between the statistical models and theoretical models for folding pathways are discussed in this article; however, global sequence models are not discussed because they have been extensively reviewed elsewhere. The data used and algorithms presented in this article are available at http://www.bioinfo.rpi.edu/~bystrc/ (click on "servers" or "downloads") or by request to bystrc@rpi.edu .

Algorithms↗

PubMed1999

Cytokine-induced macrophage differentiation: a tale of 2 genes.

Macrophages are versatile cells found in every tissue in the body. They must perform a number of diverse cellular functions that allow them to kill invading micro-organisms and neoplastic cells as well as produce growth factors involved in wound healing. Macrophages that develop these diverse functions arise from a common precursor. By a process of selective adaptation, the common precursor monocyte/macrophage differentiates into a distinctive macrophage with a different and specific phenotype, characterized by the expression of a specific set of gene products. The local environment plays a critical role in shaping or directing the pattern or pathway of macrophage differentiation. The authors have focused on 2 specific macrophage differentiation pathways in a murine bone marrow-derived macrophage model. One pathway is believed to play a role in wound repair and is characterized by the induction of insulin-like growth factor-1 (IGF-I). The second pathway is involved in macrophage cytocidal activation and is characterized by the induction of the inducible form of nitric oxide synthase (iNOS). The pleotropic cytokine tumour necrosis factor-alpha (TNF-alpha) appears to mediate macrophage differentiation along both of these pathways. Interferon-gamma (IFN-gamma), however, appears to act as a molecular switch. In the presence of IFN-gamma, stimulation of macrophages with TNF-alpha results in macrophage differentiation along a pathway in which iNOS is expressed, whereas, in the absence of IFN-gamma, stimulation of macrophages with TNF-alpha results in differentiation along a pathway in which IGF-I is expressed. The authors focus on some of the molecular events involved in TNF-alpha and IFN-gamma signal transduction and the regulation of iNOS and IGF-I genes in macrophages.

Animals↗

PubMed2004

Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo?

Reactive gliosis is a hallmark of disease-, trauma-, and chemical-induced damage to the central nervous system. The signaling pathways associated with this response to neural injury remain to be elucidated, but recent evidence implicates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we used the known dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to selectively damage striatal dopaminergic nerve terminals and elicit a glial response. We then analyzed changes in gene expression and protein phosphorylation, in vivo, to identify ligands and mediators of the JAK-STAT pathway that accompany glial activation. Administration of MPTP caused rapid tyrosine (Tyr-705) phosphorylation and nuclear translocation of STAT3 in striatal astrocytes, prior to the induction of glial fibrillary acidic protein mRNA and protein. Pharmacological protection of dopaminergic nerve terminals with nomifensine abolished MPTP-mediated phosphorylation and translocation of STAT3 and prevented induction of astrogliosis. Among the Janus kinase family of tyrosine kinases, only JAK2 was associated with the phosphorylation of STAT3 after MPTP and, inhibition of JAK2 by AG490, in vivo, attenuated both the phosphorylation of STAT3 and induction of GFAP. The p44/42 mitogen-activated protein kinase (MAPK; ERK1/2) also was activated by MPTP, but was not associated with activation of STAT3, because serine (Ser-727) was not phosphorylated. The mRNA for ligands of the gp130-JAK/STAT3 signaling pathway, interleukin-6, leukemia inhibitory factor, and oncostatin M were elevated prior to activation of STAT3 and induction of astrogliosis; neuroprotection with nomifensine blocked these effects of MPTP. Taken together, our results suggest that the gp130-mediated activation of JAK2/STAT3 signaling pathway may play a key role in the induction of astrogliosis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2004

FAS-mediated apoptosis and its relation to intrinsic pathway activation in an experimental model of retinal detachment.

PURPOSE: To determine whether the FAS-mediated apoptosis pathway becomes activated in the retina after retinal detachment and to investigate the temporal relationship between the activation of the FAS-pathway and the intrinsic apoptosis pathway involving caspase-9 and cytochrome c. METHODS: Experimental retinal detachments were created in Brown-Norway rats by injecting 10% hyaluronic acid into the subretinal space. Retinal tissue was harvested at 2, 4, 8, 24, 72, and 168 hours after creation of the detachment. Immunoprecipitation was performed to assess for FAS-receptor/FAS-ligand complex formation, and activation of caspase-8 and BID (a member of the Bcl-2 family of proteins) was assessed by Western blot analysis. A caspase-9 activity assay and immunoprecipitation of the caspase-9/cytochrome c complex were performed at these same time points. Specific pathway inhibition was performed with the caspase-9 inhibitor zLEHD.fmk or neutralizing antibodies against either the FAS-receptor or FAS-ligand. Transcription levels of FAS and intrinsic pathway intermediates were assessed as a function of time after retinal detachment by using quantitative real-time polymerase chain reaction. RESULTS: Retinal detachment resulted in the time-dependent formation of the FAS-receptor/FAS-ligand complex that preceded the peak of caspase-9 activity and caspase-9/cytochrome c complex formation. Cleavage of caspase-8 and truncation of BID were also observed. Injection of zLEHD.fmk into the subretinal space of a detached retina resulted in decreased caspase-9 activity, as did injection of anti-FAS-receptor antibody into either the subretinal space or the vitreous. Retinal detachment resulted in the transcriptional upregulation of the FAS-receptor, FAS-ligand, caspase-8 and BID, but not caspase-9 and cytochrome c. CONCLUSIONS: The FAS-mediated apoptosis pathway becomes activated and transcriptionally upregulated after retinal detachment. The peak of FAS activation precedes that of the intrinsic pathway, and inhibition of FAS activation can decrease caspase-9 activity.

Animals↗

PubMed1996

Estimating internal dose due to ingestion of radionuclides from Nevada Test Site fallout.

The U.S. Department of Energy initiated the Radiation Exposure Review Project to provide a critical reexamination of radiation doses to people resulting from testing nuclear devices at the Nevada Test Site. One part of this effort focused on the dose resulting from the ingestion of contaminated food. The PATHWAY radionuclide transport model was developed to provide estimates of food concentrations for 20 radionuclides for each of 86 test events and 15 agricultural scenarios. These results were then used as input to the Human Ingestion model to provide dose estimates for individuals and populations in 9 western states. The model considered the life-style and age of the people, and accounted for the transport of milk between locations. Estimates of uncertainty were provided for all doses using Monte Carlo simulation techniques. Propagation of uncertainty between the PATHWAY model and the Human Ingestion model required the development of special strategies to ensure that the inherent correlations between concentrations of the radionuclides in foods were handled properly. In addition, the size of the input data base (60 megabytes), the number of cases to consider (over 30,000), and the number of Monte Carlo simulations (over 6 million) required the development of efficient and reliable methods of data access and storage while running simulations concurrently on up to 14 UNIX workstations. The problems encountered in this effort are likely to be typical of any dose reconstruction involving geographically heterogeneous environmental conditions. This paper documents the methods used to disaggregate the system to achieve computation efficiency, the methods used to propagate uncertainty through the model system, and the techniques used to manage data in a distributed computing environment. The radionuclide- and age-specific dose factors used in the analysis are also provided.

Environmental Exposure↗

PubMed2005

Animal models of Kennedy disease.

Since the identification of the polyglutamine repeat expansion responsible for Kennedy disease (KD) more than a decade ago, several laboratories have created animal models for KD. The slowly progressive nature of KD, its X-linked dominant mode of inheritance, and its recently elucidated hormone dependence have made the modeling of this lower motor neuron disease uniquely challenging. Several models have been generated in which variations in specificity, age of onset, and rate of progression have been achieved. Animal models that precisely reproduce the motor neuron specificity, delayed onset, and slow progression of disease may not support preclinical therapeutics testing, whereas models with rapidly progressing symptoms may preclude the ability to fully elucidate pathogenic pathways. Drosophila models of KD provide unique opportunities to use the power of genetics to identify pathogenic pathways at work in KD. This paper reviews the new wealth of transgenic mouse and Drosophila models for KD. Whereas differences, primarily in neuropathological findings, exist in these models, these differences may be exploited to begin to elucidate the most relevant pathological features of KD.

Animals↗

PubMed2003

A spatially extended stochastic model of the bacterial chemotaxis signalling pathway.

We have combined two distinct but related stochastic approaches to model the Escherichia coli chemotaxis pathway. Reactions involving cytosolic components of the pathway were assumed to obey the laws of conventional stochastic chemical kinetics, while the clustered membrane receptors were represented in two-dimensional arrays similar to the Ising model. Receptors were assumed to flip between an active and an inactive state with probabilities dependent upon three energy inputs: ligand binding, methylation level due to adaptation, and the activity of neighbouring receptors. Examination of models with different lattice size and geometry showed that the sensitivity to stimuli increases with lattice size and the nearest-neighbour coupling strength up to a critical point, but this amplification was also accompanied by a proportional increase in steady-state noise. Multiple methylation of receptors resulted in diminished signal-to-noise ratio, but showed improved stability to variation in the coupling strength and increased gain. Under the best conditions the simulated output of a coupled lattice of receptors closely matched the time-course and amplitude found experimentally in living bacteria. The model also has some of the properties of a cellular automaton and shows an unexpected emergence of spatial patterns of methylation within the receptor lattice.

Bacterial Proteins↗

PubMedDate not supplied

Threshold fluctuations on temporally modulated backgrounds: a possible physiological explanation based upon a recent computational model.

When a temporally fluctuating background is rapidly modulated (e.g. 30 Hz), the threshold variation of a superimposed flash (the probe) is approximately sinusoidal and in phase with the stimulus. But, with low rates of sinusoidal modulation (e.g. 1 Hz), the threshold variation is distinctly nonsinusoidal in shape. The bases of these aspects of the data, as well as an unmodulated, dc, threshold elevation, are poorly understood. Here 30-Hz and 1-Hz conditions are simulated using a new model of light adaptation (Wilson, 1997). By assuming that the OFF pathway is twice as sensitive as the ON pathway, the model correctly captured the key aspects of both conditions. The results suggest that the 1-Hz data are mediated by a mixture of ON and OFF pathways while the 30-Hz data are largely mediated by the OFF pathway. The probe thresholds on the 30-Hz background appear approximately sinusoidal and approximately in phase with the background stimulus. A number of factors contribute to this deceptively simple observation.

Adaptation, Ocular↗

PubMed1998

Molecular mechanism of action of fluoride on bone cells.

Fluoride is an effective anabolic agent to increase spinal bone density by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of osteoporosis has been controversial, in large part because of a lack of consistent antifracture efficacy. However, information regarding the molecular mechanism of action of fluoride may improve its optimum and correct usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safety profile. Accordingly, this review will address the molecular mechanisms of the osteogenic action of fluoride. In this regard, we and other workers have proposed two competing models, both of which involve the mitogen activated protein kinase (MAPK) mitogenic signal transduction pathway. Our model involves a fluoride inhibition of a unique fluoride-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which results in a sustained increase in the tyrosine phosphorylation level of the key signaling proteins of the MAPK mitogenic transduction pathway, leading to the potentiation of the bone cell proliferation initiated by growth factors. The competing model proposes that fluoride acts in coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leading to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signaling proteins of the MAPK mitogenic signal transduction pathway, ultimately leading to a stimulation of cell proliferation. A benefit of our model, but not the other model, is that it accounts for all the unique properties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirement of PTK-activating growth factors, the sensitivity to changes in medium phosphate concentration, the preference for undifferentiated osteoblasts, and the involvement of the MAPK. Unlike fluoride, the mitogenic action of fluoroaluminate is not specific for skeletal cells. Moreover, the mitogenic action of fluoroaluminate shows several important, different characteristics than that of fluoride. Thus, it is likely that our model of a fluoride-sensitive PTP represents the actual molecular mechanism of the osteogenic action of fluoride.

Animals↗

PubMed2004

Apoptosis: an optimization approach.

The present study examined the levels of procaspases (zymogens of the main apoptosis enzymes, caspases) that are predicted based on application of the optimization principle. Optimization models have previously been successfully developed for many other physiological systems (e.g., circulation, oxygen transport system, fibrinolysis, and blood coagulation) but have not previously been applied to apoptotic biochemical pathways. Our model assumed that apoptotic pathways are designed to minimize protein consumption. Procaspase concentrations were predicted based on this assumption, along with known schemes of apoptosis reactions and kinetic constants for procaspase activation and target cleavage. Good agreement between the model predictions and actual procaspase levels was observed.

Apoptosis↗