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PubMedDate not supplied

Structural and functional composition of the developing retinogeniculate pathway in the mouse.

The advent of transgenic mice has made the developing retinogeniculate pathway a model system for targeting potential mechanisms that underlie the refinement of sensory connections. However, a detailed characterization of the form and function of this pathway is lacking. Here we use a variety of anatomical and electrophysiological techniques to delineate the structural and functional changes occurring in the lateral geniculate nucleus (LGN) of dorsal thalamus of the C57/BL6 mouse. During the first two postnatal weeks there is an age-related recession in the amount of terminal space occupied by retinal axons arising from the two eyes. During the first postnatal week, crossed and uncrossed axons show substantial overlap throughout most of the LGN. Between the first and second week retinal arbors show significant pruning, so that by the time of natural eye opening (P12-14) segregation is complete and retinal projections are organized into distinct eye-specific domains. During this time of rapid anatomical rearrangement, LGN cells could be readily distinguished using immunocytochemical markers that stain for NMDA receptors, GABA receptors, L-type Ca2+ channels, and the neurofilament protein SMI-32. Moreover, the membrane properties and synaptic responses of developing LGN cells are remarkably stable and resemble those of mature neurons. However, there are some notable developmental changes in synaptic connectivity. At early ages, LGN cells are binocularly responsive and receive input from as many as 11 different retinal ganglion cells. Optic tract stimulation also evokes plateau-like depolarizations that are mediated by the activation of L-type Ca2+ channels. As retinal inputs from the two eyes segregate into nonoverlapping territories, there is a loss of binocular responsiveness, a decrease in retinal convergence, and a reduction in the incidence of plateau potentials. These data serve as a working framework for the assessment of phenotypes of genetically altered strains as well as provide some insight as to the molecular mechanisms underlying the refinement of retinogeniculate connections.

Aging↗

PubMed2016

A probabilistic generative model for quantification of DNA modifications enables analysis of demethylation pathways.

We present a generative model, Lux, to quantify DNA methylation modifications from any combination of bisulfite sequencing approaches, including reduced, oxidative, TET-assisted, chemical-modification assisted, and methylase-assisted bisulfite sequencing data. Lux models all cytosine modifications (C, 5mC, 5hmC, 5fC, and 5caC) simultaneously together with experimental parameters, including bisulfite conversion and oxidation efficiencies, as well as various chemical labeling and protection steps. We show that Lux improves the quantification and comparison of cytosine modification levels and that Lux can process any oxidized methylcytosine sequencing data sets to quantify all cytosine modifications. Analysis of targeted data from Tet2-knockdown embryonic stem cells and T cells during development demonstrates DNA modification quantification at unprecedented detail, quantifies active demethylation pathways and reveals 5hmC localization in putative regulatory regions.

5-Methylcytosine↗

PubMed2006

A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway.

We report a novel mouse model for the generation of sporadic tumors and show the efficiency of this approach by surveying Hedgehog (Hh)-related tumors. Up-regulation of the Hh pathway is achieved by conditionally regulated expression of an activated allele of Smoothened (R26-SmoM2) using either sporadic leakage or global postnatal induction of a ubiquitously expressed inducible Cre transgene (CAGGS-CreER). Following postnatal tamoxifen induction, CAGGS-CreER; R26-SmoM2 mice developed tumors with short latency and high penetrance. All mice exhibited rhabdomyosarcoma and basal cell carcinoma; 40% also developed medulloblastoma. In addition, mice showed a novel pancreatic lesion resembling low-grade mucinous cystic neoplasms in humans. In contrast, widespread activation of SmoM2 in the postnatal prostate epithelium results in no detectable morphologic outcome in 12-month-old mice. Comparison of gene expression profiles among diverse tumors identified several signature genes, including components of platelet-derived growth factor and insulin-like growth factor pathways, which may provide a common mechanistic link to the Hh-related malignancies. This experimental model provides a robust tool for exploring the process of Hh-dependent tumorigenesis and the treatment of such tumors. More generally, this approach provides a genetic platform for identifying tumorigenic potential in putative oncogenes and tumor suppressors and for more effective modeling of sporadic cancers in mice.

Alleles↗

PubMed2004

Rethinking WNT signaling.

Recent research on the WNT signaling pathway warrants a reassessment of the basic mechanism that transmits signal from the membrane-bound receptor to the nucleus. This article incorporates these findings into a revised model for pathway activation. We propose that the control of Axin stability, rather than the control of ZW3 phosphorylation of the Armadillo protein, is the key step in signaling. Axin degradation is controlled by a stabilizing effect of ZW3-dependent phosphorylation, and a destabilizing effect of active Arrow. Removing Axin enables Armadillo to accumulate and re-localize to the nucleus. We argue that nuclear localization of Armadillo is required for transcriptional pathway activity. Finally, we speculate on the effects this revision will have on the major questions facing the WNT field of research.

Animals↗

PubMed1998

Pathways to mental health services among inhabitants of a Mexican village.

The purpose of this article is to provide a description of the pathways to the utilization of mental health services among rural Mexicans in a village with a long-standing tradition of male labor migration to the United States. The authors developed a model of pathways to mental health service utilization on the basis of ethnographic field notes and in-depth interviews with 21 villagers who were "potential immigrants." The model describes five sequential help-seeking strategies that townspeople with mental health problems commonly follow to relieve the psychological and physical symptoms associated with their condition. The applications of the findings include the design of sensitive programs for the migratory population that not only incorporates but maximizes pre-existing culture-specific individual and community resources.

Adult↗

PubMed2004

A quantitative risk assessment model for Salmonella and whole chickens.

Existing data and predictive models were used to define the input settings of a previously developed but modified quantitative risk assessment model (QRAM) for Salmonella and whole chickens. The QRAM was constructed in an Excel spreadsheet and was simulated using @Risk. The retail-to-table pathway was modeled as a series of unit operations and associated pathogen events that included initial contamination at retail, growth during consumer transport, thermal inactivation during cooking, cross-contamination during serving, and dose response after consumption. Published data as well as predictive models for growth and thermal inactivation of Salmonella were used to establish input settings. Noncontaminated chickens were simulated so that the QRAM could predict changes in the incidence of Salmonella contamination. The incidence of Salmonella contamination changed from 30% at retail to 0.16% after cooking to 4% at consumption. Salmonella growth on chickens during consumer transport was the only pathogen event that did not impact the risk of salmonellosis. For the scenario simulated, the QRAM predicted 0.44 cases of salmonellosis per 100,000 consumers, which was consistent with recent epidemiological data that indicate a rate of 0.66-0.88 cases of salmonellosis per 100,000 consumers of chicken. Although the QRAM was in agreement with the epidemiological data, surrogate data and models were used, assumptions were made, and potentially important unit operations and pathogen events were not included because of data gaps and thus, further refinement of the QRAM is needed.

Animals↗

PubMed2002

Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors.

We present a computational model that offers an integrated quantitative, dynamic, and topological representation of intracellular signal networks, based on known components of epidermal growth factor (EGF) receptor signal pathways. The model provides insight into signal-response relationships between the binding of EGF to its receptor at the cell surface and the activation of downstream proteins in the signaling cascade. It shows that EGF-induced responses are remarkably stable over a 100-fold range of ligand concentration and that the critical parameter in determining signal efficacy is the initial velocity of receptor activation. The predictions of the model agree well with experimental analysis of the effect of EGF on two downstream responses, phosphorylation of ERK-1/2 and expression of the target gene, c-fos.

Computational Biology↗

PubMed1993

Growth cone guidance and neuron morphology on micropatterned laminin surfaces.

Neurite growth cones detect and respond to guidance cues in their local environment that determine stereotyped pathways during development and regeneration. Micropatterns of laminin (which was found to adsorb preferentially to photolithographically defined hydrophobic areas of micropatterns) were here used to model adhesive pathways that might influence neurite extension. The responses of growth cones were determined by the degree of guidance of neurite extension and also by examining growth cone morphology. These parameters were found to be strongly dependent on the geometry of the patterned laminin, and on neuron type. Decreasing the spacing of multiple parallel tracks of laminin alternating with non-adhesive tracks, resulted in decreased guidance of chick embryo brain neurons. Single isolated 2 microns tracks strongly guided neurite extension whereas 2 microns tracks forming a 4 microns period multiple parallel pattern did not. Growth cones appear to be capable of bridging the narrow non-adhesive tracks, rendering them insensitive to the smaller period multiple parallel adhesive patterns. These observations suggest that growth cones would be unresponsive to the multiple adhesive cues such as would be presented by oriented extracellular matrix or certain axon fascicle structures, but could be guided by isolated adhesive tracks. Growth cone morphology became progressively simpler on progressively narrower single tracks. On narrow period multiple parallel tracks (which did not guide neurite extension) growth cones spanned a number of adhesive/non-adhesive tracks, and their morphology suggests that lamellipodial advance may be independent of the substratum by using filopodia as a scaffold. In addition to acting as guidance cues, laminin micropatterns also appeared to influence the production of primary neurites and their subsequent branching. On planar substrata, dorsal root ganglion neurons were multipolar, with highly branched neurite outgrowth whereas, on 25 microns tracks, neurite branching was reduced or absent, and neuron morphology was typically bipolar. These observations indicate the precision with which growth cone advance may be controlled by substrata and suggest a role for patterned adhesiveness in neuronal morphological differentiation, but also highlight some of the limitations of growth cone sensitivity to substratum cues.

Animals↗

PubMed2004

Host processing of branched DNA intermediates is involved in targeted transposition of IS911.

A simplified system using bacterial insertion sequence IS911 has been developed to investigate targeted insertion next to DNA sequences resembling IS ends. We show here that these IR-targeted events occur by an unusual mechanism. In the circular IS911 transposition intermediate the two IRs are abutted to form an IR/IR junction. IR-targeted insertion involves transfer of a single end of the junction to the target IR to generate a branched DNA structure. The single-end transfer (SET) intermediate, but not the final insertion product, can be detected in an in vitro reaction. SET intermediates must be processed by the bacterial host to obtain the final insertion products. Sequence analysis of these IR-targeted insertion products and of those obtained in vivo revealed high levels of DNA sequence conversion in which mutations from one IR were transferred to another. These sequence changes cannot be explained by the classic transposition pathway. A model is presented in which the four-way Holliday-like junction created by SET is processed by host-mediated branch migration, resolution, repair and replication. This pathway resembles those described for processing other branched DNA structures such as stalled replication forks.

DNA Transposable Elements↗

PubMed1989

A model for spatiotemporal frequency responses in the X cell pathway of the cat's retina.

A linear model is described for the cat eye's signal-processing pathway, from the visual stimulus at the cornea, to cones, to X-type ganglion cells. The model contains elements representing the eye's optics, phototransduction, gain control, spatiotemporal processing by cell layers, and pure delay. Centre-surround antagonism in the model arises through the presence of a centre element producing a small spatial spread of signals, and an antagonistic element producing a larger spread. Two arrangements were tried, feedforward and feedback, in which the antagonistic element's output was subtracted from the centre element's output, and input, respectively. The model was fitted to empirical spatial and temporal frequency responses collected by Frishman et al. (1987), and accounted qualitatively for these data in the feedback, but not the feedforward, arrangement. The model's centre pathway comprises a cascade of low-pass spatial filters, as does the surround pathway. As a consequence, the spatial frequency responses for these two pathways closely approximate Gaussian functions of spatial frequency, and the spatial frequency response of the complete model at low temporal frequency closely matches that of the difference of Gaussians model.

Adaptation, Ocular↗

PubMed1990

Dynamic Monte Carlo simulations of globular protein folding. Model studies of in vivo assembly of four helix bundles and four member beta-barrels.

As part of an ongoing series of dynamic Monte Carlo simulations of globular protein folding, the nature of the folding pathway, of model four-member beta-barrels and four-helix bundles, under highly idealized conditions in vivo, has been examined. The ribosome is crudely modeled as an inert hard wall on to which the model protein chain is attached. Three cases are considered in detail. The first corresponds to post-translational assembly in which the fully synthesized chain is tethered to the wall and starts out under strongly denaturing conditions. The system is cooled down, and the chain is allowed to fold. Interestingly, the helical motif prefers to assemble parallel to the wall, whereas the beta-barrel, predominantly assembles with its principal axis perpendicular to the wall. In the former case, the dominant intermediate, the helical hairpin, is different from that in free solution, a three-helix bundle. The wall acts to reduce the expanse of configuration space that must be searched and aids in folding. Two situations that might lead to co-translational folding are also simulated. In the first case, to eliminate wall effects, the chain is slowly synthesized in free solution, and in the second case, it is slowly synthesized from the wall. In all cases, the chains are observed to fold post-translationally. While partially folded intermediates are observed during synthesis, they lack the stability to survive until chain synthesis is complete. The implications of these results for the folding in vivo of real protein chains is discussed, and a model of multiple domain protein folding is proposed.

Models, Structural↗

PubMed1998

Drug use pathways among high school students of Mexico.

OBJECTIVE: This study surveyed high school student drug users in urban areas of Mexico to describe use patterns and drug-related behaviors among adolescents and to develop predictor models of pathways to underage drug use. SUBJECT/DESIGN: A National School Survey was conducted among high school students where data are provided by the State. Only urban sites were considered for this study (n = 40,521). Stratified two-stage cluster sampling was used; schools and groups within the schools were the sampling units. CONCLUSIONS: Male adolescents who have worked the previous year, have high exposure within the family and are affiliated with drug using peers are at increased risk of becoming drug users and subject to depression and suicidal ideation as well as drug-related social problems.

Adolescent↗

PubMed2005

Exploring the role of different drug transport routes in permeability screening.

The influence of different drug transport routes in intestinal drug permeability screening assays was studied. Three experimental models were compared: the small-intestine-like 2/4/A1 cell model, which has a leaky paracellular pathway, the Caco-2 cell model, which has a tighter paracellular pathway, and artificial hexadecane membranes (HDMs), which exclusively model the passive transcellular pathway. The models were investigated regarding their ability to divide passively and actively transported compounds into two permeability classes and to rank compounds according to human intestinal absorption. In silico permeability models based on two-dimensional (2D) and three-dimensional (3D) molecular descriptors were also developed and validated using external test sets. The cell-based models classified 80% of the acceptably absorbed compounds (FA >/= 30%) correctly, compared to 60% correct classifications using the HDM model. The best compound ranking was obtained with 2/4/A1 (r(s) = 0.74; r(s) = 0.95 after removing actively transported outliers). The in silico model based on 2/4/A1 permeability gave results of similar quality to those obtained when using experimental permeability, and it was also better than the experimental HDM model at compound ranking (r(s) = 0.85 and 0.47, respectively). We conclude that the paracellular transport pathway present in the cell models plays a significant role in models used for intestinal permeability screening and that 2/4/A1 in vitro and in silico models are promising alternatives for drug discovery permeability screening.

Administration, Oral↗

PubMed1999

Motor effects and mapping of cerebral alterations in animal models of Parkinson's and Huntington's diseases.

Changes in stimulant-induced behavioral effects and subcortical c-Fos expression were compared between rodent models of Parkinson's disease (PD) and Huntington's disease (HD). Rats received either a unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine pathway (PD model) or a unilateral infusion of antisense oligodeoxynucleotides targeting c-fos into the striatum (HD model). Dopamine-lesioned animals received intraperitoneal injections of either d-amphetamine (6-OHDAamp group) or apomorphine (6-OHDAapo group), whereas all animals that received antisense infusions received d-amphetamine (ASF group). All groups exhibited robust circling behavior upon stimulant challenge. Changes in subcortical activation, as assessed by the induction of Fos-like immunoreactivity (Fos-LI), were examined in several brain regions. The 6-OHDAamp and ASF groups exhibited robust, ipsiversive circling behavior, with similar changes in Fos-LI in the striatum, entopeduncular nucleus, superior colliculus, and ventromedial thalamus. The 6-OHDAapo group exhibited contraversive rotation and had reciprocal patterns of Fos-LI in these regions. Despite exhibiting the same direction of rotation, the 6-OHDAamp and ASF groups had markedly different patterns of Fos-LI in the globus pallidus and the pontine reticular formation. These results suggest that the globus pallidus may undergo distinct alterations in PD and HD and that the pontine reticular formation is particularly susceptible to changes in mesencephalic dopamine sources.

Animals↗

PubMed1999

Mouse-to-rabbit xenotransplantation: a new small animal model of hyperacute rejection mediated by the classical complement pathway.

BACKGROUND: Hyperacute rejection of porcine organs transplanted into primate recipients is initiated by the binding of preformed xenoreactive natural antibodies to the vascular endothelium of the graft and activation of the classical complement pathway. Several small animal models are currently employed to study various aspects of xenograft rejection; however, none has been shown to manifest hyperacute rejection mediated by the classical pathway of complement activation. METHODS: We performed heterotopic mouse heart transplants into weanling rabbits, adult rabbits, and C6-deficient rabbits. The recipients received no immunosuppression. Rejected grafts were subjected to histologic analysis and immunofluorescence staining for rabbit IgG, IgM, and C3. Levels of preexisting cytotoxic antibodies as well as classical and alternative complement pathway activities were determined in rabbit serum using mouse red cells as targets. RESULTS: Mean graft survival was 37+/-9.6 min for mouse-to-weanling rabbit transplants (n=10), and 40+/-11.1 min for mouse-to-adult rabbit transplants (n=5). Rejected grafts showed diffuse interstitial hemorrhage, endothelial cell damage, myocyte necrosis, moderate diffuse deposition of rabbit IgG, and dense deposition of rabbit IgM and C3 on the vascular endothelium of the graft, consistent with hyperacute rejection. One mouse-to-C6-deficient rabbit transplant was rejected at 21 hr with severe interstitial hemorrhage, cellular necrosis and a moderate cellular infiltrate consisting primarily of neutrophils and some mononuclear cells. A second transplant in a C6-deficient rabbit was functioning when the recipient died at 6.5 hr as a result of complications of surgery; the graft had normal myocytes and vasculature with minimal spotty interstitial hemorrhage. Both weanling and adult rabbit serum were found to have high titers of cytotoxic IgM anti-mouse antibodies and strong classical complement pathway activity with minimal alternative pathway activity towards mouse red cells. CONCLUSIONS: The mouse-to-rabbit species combination manifests hyperacute xenograft rejection. In vitro studies suggest that this process is mediated by IgM anti-mouse natural antibodies and activation of the classical pathway of complement.

Aging↗

PubMed2001

An algebraic-combinatorial model for the identification and mapping of biochemical pathways.

We develop the mathematical machinery for the construction of an algebraic-combinatorial model using Petri nets to construct an oriented matroid representation of biochemical pathways. For demonstration purposes, we use a model metabolic pathway example from the literature to derive a general biochemical reaction network model. The biomolecular networks define a connectivity matrix that identifies a linear representation of a Petri net. The sub-circuits that span a reaction network are subject to flux conservation laws. The conservation laws correspond to algebraic-combinatorial dual invariants, that are called S- (state) and T- (transition) invariants. Each invariant has an associated minimum support. We show that every minimum support of a Petri net invariant defines a unique signed sub-circuit representation. We prove that the family of signed sub-circuits has an implicit order that defines an oriented matroid. The oriented matroid is then used to identify the feasible sub-circuit pathways that span the biochemical network as the positive cycles in a hyper-digraph.

Linear Models↗

PubMed2008

Maternal control of pattern formation in Xenopus laevis.

We review the essential role of maternal factors in pattern formation for Xenopus laevis, focusing on VegT, Vg1, and Wnt11. Results from loss of function experiments demonstrate a clear requirement for these genes in germ layer specification, dorsal-ventral axis formation, and convergence extension. We also discuss these genes in the broader context of metazoan development, exploring whether and how their functions in the X. laevis model organism may or may not be conserved in other species. Wnt11 signaling in particular provides a classic example where understanding context in development is crucial to understanding function. Genomic sequencing, gene expression, and functional screening data that are becoming available in more species are providing invaluable aid to decoding and modeling signaling pathways. More work is needed to develop a comprehensive catalog of the Wnt signaling, T-box, and TGF-beta genes in metazoans both near and far in evolutionary distance. We finally discuss some specific experimental and modeling efforts that will be needed to understand the behavior of these signaling networks in vivo so that we can interpret these critical pathways in an evolutionary framework.

Animals↗

PubMed2002

Modeling polychlorinated biphenyl congener patterns and dechlorination in dated sediments from the Ashtabula River, Ohio, USA.

Polychlorinated biphenyl (PCB) congeners were analyzed in four deep, dated sediment cores from the Ashtabula River (OH, USA), for the purpose of identifying relevant PCB sources and congener patterns. The time span for three of the cores is from the mid 1960s to 1998, whereas the fourth has a time span of six years. The total PCB concentrations are in the range of 0.4 to 6.8 microg/g dry weight, with the highest concentrations observed in samples from the 1970s. A factor analysis (FA) model with nonnegative constraints was used to investigate the sources and patterns of PCBs. Additionally, a new model, based on a least squares method, was developed to identify possible patterns of anaerobic dechlorination of PCBs in the sediments, and to quantify the relevant dechlorination pathways. Both models were validated successfully either by artificially created data sets (FA model) or by using laboratory data from the literature (dechlorination model). The FA model revealed two significant sources. The first was identified as a slightly altered Aroclor 1248. The second did not resemble any Aroclor closely, but was very similar to the overall average congener profile of all samples. Simulation of anaerobic dechlorination on an Aroclor 1248 profile from the literature, according to dechlorination activities H/H', as defined in the literature, yielded a congener profile very similar to that of the second pattern. This indicates the likelihood of anaerobic dechlorination of PCBs in Ashtabula River sediments.

Anaerobiosis↗