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PubMed2002

Shapes of phospholipid [correction of phosholipid] vesicles with beadlike protrusions.

Giant phospholipid vesicles obtained by the method of electroformation were observed by the phase contrast microscope. Most of these vesicles contain a protrusion which shortens in a slow shape transformation process until it is absorbed into the main vesicle body. We are concerned with the last stages of this shape transformation process, where the protrusions attain a beadlike shape. The number of "beads" decreases one by one in consecutive steps, and it is demonstrated that each such step consists of two distinguishable phases. During the first phase the beadlike shape does not change and the necks connecting the "beads" are narrow. During the second phase the width of the protrusion necks increases. On the basis of the assumption that these shape transformations are driven by the decrease of the equilibrium difference between the outer and the inner membrane monolayers areas, the system behavior is analyzed in terms of the generalized bilayer couple model. The theoretical results confirm the observed time sequence: at a given number of "beads" the protrusion has in the first phase the shape that consists of spheres connected by infinitesimal necks, and during the second phase the protrusion is a single prolate unit with open necks. The discrepancies between the observed and the predicted widths of the necks are interpreted by the repulsive forces between the neighboring "beads" induced by the membrane thermal fluctuations. The analysis presented extends the existing catalog of vesicle shapes to the region of larger differences between the areas of membrane monolayers, and confirms the applicability of the generalized bilayer couple model to the description of the shape behavior of phospholipid vesicles containing beadlike protrusions.

Computer Simulation↗
PubMed2000

Association of the inositol (1,4,5)-trisphosphate receptor ligand binding site with phosphatidylinositol (4,5)-bisphosphate and adenophostin A.

The inositol 1,4,5-trisphosphate receptor (InsP(3)R) is activated by InsP(3) binding to amino-terminal ligand binding domain (InsP(3)R-N). Recently we reported functional coupling of phosphatidylinositol (4, 5)-bisphosphate (PIP(2)) to the InsP(3)R. Specific binding of PIP(2) to InsP(3)R-N domain was postulated as a part of the InsP(3)R-PIP(2) functional coupling model. Here we utilized bacterially expressed and purified InsP(3)R-N domain to characterize its binding specificity for InsP(3), Adenophostin A (AdA) and the water-soluble PIP(2) analog dioctanoyl-(4,5)PIP(2) (ShPIP(2)). Obtained data led us to conclude that specific InsP(3), AdA, and ShPIP(2) binding sites are located within the InsP(3)R-N domain, that the extra receptor binding element responsible for enhanced binding of AdA is an integral part of the InsP(3)R-N domain, that ShPIP(2) is able to displace InsP(3) from the InsP(3)R-N, but InsP(3) or AdA is unable to completely displace ShPIP(2). These results support the InsP(3)R-PIP(2) functional coupling model and provide novel insights into InsP(3)R ligand specificity.

Adenosine↗
PubMed2004

Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation.

An analysis of the human chromosome 22 genomic sequence shows that both Z-DNA forming regions (ZDRs) and promoter sites for nuclear factor-I (NFI) are correlated with the locations of known and predicted genes across the chromosome and accumulate around the transcriptional start sites of the known genes. Thus, the occurrence of Z-DNA across human genomic sequences mirrors that of a known eukaryotic transcription factor. In addition, 43 of the 383 fully annotated chromosomal genes have ZDRs within 2 nucleosomes upstream of strong NFIs. This suggests a distinct class of human genes that may potentially be transcriptionally regulated by a mechanism that couples Z-DNA with NFI activation, similar to the mechanism previously elucidated for the human colony stimulation factor-I promoter [Liu et al. (2001) Cell, 106, 309-318]. The results from this study will facilitate the design of experimental studies to test the generality of this mechanism for other genes in the cell.

Binding Sites↗
PubMed1986

EMG of scapulohumeral muscles in the chimpanzee during reaching and "arboreal" locomotion.

Current views on the function of the deltoid and rotator cuff muscles emphasize their roles in arm-raising as participants in a scapulohumeral force "couple." The acceptance of such a mechanism is based primarily on a 1944 EMG study of human shoulder muscle action. More recently, it has been suggested that shoulder joint stabilization constitutes a second and equally important function of the cuff musculature, especially in nonhuman primates which habitually use their forelimbs in overhead postural and locomotor activities. Few comparative data exist, however, on the actual recruitment patterns of these muscles in different species. In order to assess the general applicability of a scapulohumeral force couple model, and the functional significance of the differential development of the scapulohumeral musculature among primate species, we have undertaken a detailed study of shoulder muscle activity patterns in nonhuman primates employing telemetered electromyography, which permits examination of unfettered natural behaviors and locomotion. The results of our research on the chimpanzee, Pan troglodytes, on voluntary reaching and two forms of "arboreal" locomotion reveal four ways in which previous perceptions of the function of the scapulohumeral muscles must be revised: 1) the posterior deltoid is completely different in function from the middle and anterior regions of this muscle; 2) the integrity of the glenohumeral joint during suspensory postures is not maintained solely by osseoligamentous structures; 3) the function of teres minor is entirely different from that of the other rotator cuff muscles and is more similar to the posterior deltoid and teres major; and 4) each remaining member of the rotator cuff plays a distinct, and often unique, role during natural behaviors. These results clearly refute the view that the muscles of the rotator cuff act as a single functional unit in any way, and an alternative to the force couple model is proposed.

Animals↗
PubMed1996

A cellular automata model of the heart and its coupling with a qualitative model.

Cellular Automata (CA) models offer a good compromise between computational complexity and biological plausibility while qualitative models have expressive power for explicitly describing dynamic processes. In this paper we present a 2D CA model and its coupling with a qualitative model. The CA model includes elements characterizing muscle, nodal tissue, and bypass conduction. Each element exhibits adaptive properties to cycle length and to the prematurity of incoming impulses. A crude electrocardiogram is also simulated via an equivalent source formulation. Arrhythmias such as the Wenckebach phenomenon, atrial flutter, or extrasystole-triggered tachyarrhythmias can be simulated using relatively simple models when they incorporate the fast conduction system with muscle tissue and when the model elements exhibit adaptive properties. We then illustrate how a CA model can be coupled to a qualitative model to produce a system that combines the fine grained description of CA models with the high level interpretative role of qualitative models.

Adaptation, Physiological↗
PubMed1996

Physiologically based pharmacokinetic/pharmacodynamic modeling of the toxicologic interaction between carbon tetrachloride and Kepone.

Carbon tetrachloride (CCl4) lethality in Sprague-Dawley rats is greatly amplified by pretreatment of Kepone (decachlorooctahydro-1,3,2-metheno-2H-cyclobuta[cd] pentalen-2-one). The increase in lethality was attributed to the obstruction of liver regenerative processes. These processes are essential for restoring the liver to its full functional capacity following injury by CCl4. Based on the available mechanistic information on Kepone/CCl4 interaction, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was constructed where the following effects of Kepone on CCl4 toxicity are incorporated: (1) inhibition of mitosis; (2) reduction of repair mechanism of hepatocellular injury; (3) suppression of phagocytosis. The PBPK/PD model provided computer simulation consistent with previously published time-course results of hepatotoxicity (i.e., pyknotic, injured and mitotic cells) of CCl4 with or without Kepone. As a further verification of this model, the computer simulations were also consistent with exhalation kinetic data for rats injected with different intraperitoneal (i.p.) doses of CCl4 in our laboratory. Subsequently, the PBPK/PD model, coupled with Monte Carlo simulation, was used to predict lethalities of rats treated with CCl4 alone and CCl4 in combination with Kepone. The experimental lethality studies performed in our laboratories were as follows: Sprague-Dawley rats were given either control diet or diet containing 10 ppm Kepone for 15 days. On day 16, rats in the Kepone treated group were given i.p. doses of 0, 10, 50, and 100 microliters/kg CCl4 (n = 9) while control rats were exposed to 0, 100, 1000, 3000, and 6000 microliters/kg CCl4 (n = 9). Lethality was observed at the 1000 (1/9), 3000 (4/9), and 6000 (8/9) microliters/kg doses for the control group and at the 50 (4/9) and 100 (8/9) microliters/kg for the treated group. Based on Monte Carlo simulation, which was used to run electronically 1000 lethality experiments for each dosing situation, the LD50 estimates for CCl4 toxicity with and without Kepone pretreatment were 47 and 2890 microliters/kg, respectively. Monte Carlo simulation coupled with the PBPK/PD model produced lethality rates which were not significantly different from the observed mortality, with the exception of CCl4 at very high doses (e.g., 6000 microliters/kg, p = 0.014). Deviation at very high doses of the predicted mortality from the observed may be attributed to extrahepatic systemic toxicities of CCl4, or solvent effects on tissues at high concentrations, which were not presently included in the model. Our modeling and experimental results verified the earlier findings of Mehendale (1990) for the 67-fold amplification of CCl4 lethality in the presence of Kepone. However, much of this amplification of CCl4 lethality with Kepone pretreatment was probably due to pharmacokinetic factors, because when target tissue dose (i.e., model estimated amount of CCl4 metabolites) was used to evaluate lethality, this amplification was reduced to 4-fold.

Animals↗
PubMed2003

A coupled oscillator model of disordered interlimb coordination in patients with Parkinson's disease.

Coordination between the left and right limbs during cyclic movements, which can be characterized by the amplitude of each limb's oscillatory movement and relative phase, is impaired in patients with Parkinson's disease (PD). A pedaling exercise on an ergometer in a recent clinical study revealed several types of coordination disorder in PD patients. These include an irregular and burst-like amplitude modulation with intermittent changes in its relative phase, a typical sign of chaotic behavior in nonlinear dynamical systems. This clinical observation leads us to hypothesize that emergence of the rhythmic motor behaviors might be concerned with nonlinearity of an underlying dynamical system. In order to gain insight into this hypothesis, we consider a simple hard-wired central pattern generator model consisting of two identical oscillators connected by reciprocal inhibition. In the model, each oscillator acts as a neural half-center controlling movement of a single limb, either left or right, and receives a control input modeling a flow of descending signals from higher motor centers. When these two control inputs are tonic-constant and identical, the model has left-right symmetry and basically exhibits ordered coordination with an alternating periodic oscillation. We show that, depending on the intensities of these two control inputs and on the difference between them that introduces asymmetry into the model, the model can reproduce several behaviors observed in the clinical study. Bifurcation analysis of the model clarifies two possible mechanisms for the generation of disordered coordination in the model: one is the spontaneous symmetry-breaking bifurcation in the model with the left-right symmetry. The other is related to the degree of asymmetry reflecting the difference between the two control inputs. Finally, clinical implications by the model's dynamics are briefly discussed.

Ataxia↗
PubMed2004

A role for hTRPC1 and lipid raft domains in store-mediated calcium entry in human platelets.

We have previously suggested that store-mediated Ca2+ entry (SMCE) in human platelets may be activated by a secretion-like coupling model, involving de novo coupling of the type II inositol 1,4,5-trisphosphate receptor (IP(3)RII) to the putative Ca2+ entry channel, hTRPC1. In other cells, hTRPC1 has been reported to be associated with cholesterol-rich lipid raft domains (LRDs) in the plasma membrane. Here we have shown that hTRPC1 is largely associated with detergent-resistant platelet membranes, from which it is partially released when the cells are depleted of cholesterol by treatment with methyl-beta-cyclodextrin (MBCD). MBCD treatment inhibited thapsigargin (TG)-evoked SMCE in a concentration-dependent manner, reducing it to 38.1+/-4.1% at a concentration of 10mM. Similarly, the Ca2+ entry evoked by thrombin (1unit/ml) was reduced to 48.2+/-4.5% of control following MBCD (10mM) treatment. Thrombin- and TG-evoked coupling between IP(3)RII and hTRPC1 was also reduced following cholesterol depletion. These results suggest that hTRPC1 is associated with LRDs in human platelets and that these domains are important for its participation in SMCE.

Blood Platelets↗
PubMed2005

Combined physico-chemical and water transfer modelling to predict bacterial growth during food processes.

The quality and safety of food products depend on the microorganisms, the food characteristics and the process. The prediction of conditions that prevent growth in complex situations due to the characteristics of the process and of the food cannot be obtained by predictive models of bacterial growth only. Thus, a combined modelling approach was developed by integrating three models, which were selected in a first step: (1) a bacterial model that predicts the bacterial growth from the physico-chemical properties of the media; (2) a water transfer model that predicts the effects of the drying process variables on the medium characteristics; and (3) a thermodynamic model that predicts the water activity aw and the pH of the media from its composition. A second step consisted in separately validating each selected model in which all of the physical, chemical or biological parameters appearing in the equations were previously measured. The third step combined the three knowledge models. The global model was validated on the basis of experimental results concerning the growth of Listeria innocua on the surface of a gelatine gel, the surface of which was submitted to a drying process (changes in relative humidity and air velocity). It was shown that bacterial growth models had to be modified: a specific model was set up to predict the maximum growth rate and another for the lag. Additionally, growth models set up in broth could not be applied in gelatine, leading to the development of a specific growth model on a solid surface. The thermodynamic model accurately predicted the pH and aw of bacterial broth in which high concentrations of solutes were added, and those of the solid media, the gelatine. The water transfer model was applied on gelatine data to predict the evolution of its surface aw during the drying process. The three models-bacterial, water transfer and thermodynamic, separately validated-were combined according to an integrated modelling strategy. The water transfer model coupled with the thermodynamic model predicted the aw on the gel surface. The predicted surface aw explained why growth inhibition was observed. Indeed, growth stopped at a predicted surface aw <0.94, corresponding to L. innocua minimum aw during the drying process. The global model satisfactorily predicted L. innocua growth on the surface of the gel. This study proves the validity of the approach and shows that the combination of the water transfer and thermodynamic models compensates for the lack of aw measurement techniques.

Adaptation, Physiological↗
PubMed2004

Community-level analysis of risk of vector-borne disease.

Ecological community structure is particularly important in vector-borne zoonotic diseases with complex life cycles. Qualitative community model analysis may provide a meaningful alternative to standard population-based models of vector-borne disease. We built on recent mathematical developments in qualitative community modeling coupled with conventional biomathematical models of vector-borne disease transmission, to provide a procedure to analyze risk. Using this procedure, we can hypothesize changes in risk of vector-borne disease from disturbances, such as control measures, habitat alteration, or global warming. We demonstrate the application of this procedure to an oak forest community to predict the risk of Lyme disease. Our predictions of Lyme disease risk in an oak forest community confirm reports of positive associations between deer abundance and risk of disease and are consistent with published observations.

Animals↗
PubMed1996

Asymmetric Synthesis of Calyculin C. 2. Synthesis of the C(26)-C(37) Fragment and Model Wittig Couplings.

We report our synthesis of the C(26)-C(37) fragment of serine/threonine protein phosphatase PP1 and PP2A inhibitor calyculin C (1). Outlined in this paper are synthetic approaches to the two components based on disconnection at the C(33)-N(3) amide bond. We report the successful synthesis of the C(33)-C(37) aza-sugar derived from D-lyxose which was coupled onto a C(26)-C(32) aminooxazole originating from L-pyroglutamic acid. Elaboration of the resulting amide to a fully deprotected C(26)-C(37) fragment of calyculin C completed our synthesis. This provided an appropriate phosphonium salt for use in a Wittig olefination for joining both halves of the natural product.

Journal Article↗
PubMed2002

Assessment of climate change effects on Canada's National Park system.

To estimate the magnitude of climate change anticipated for Canada's 38 National Parks (NPs) and Park Reserves, seasonal temperature and precipitation scenarios were constructed for 2050 and 2090 using the Canadian Centre for Climate Modelling and Analysis (CCCma) coupled model (CGCM1). For each park, we assessed impacts on physical systems, species, ecosystems and people. Important, widespread changes relate to marine and freshwater hydrology, glacial balance, waning permafrost, increased natural disturbance, shorter ice season, northern and upward altitudinal species and biome shifts, and changed visitation patterns. Other changes are regional (e.g., combined East coast subsidence and sea level rise increase coastal erosion and deposition, whereas, on the Pacific coast, tectonic uplift negates sea level rise). Further predictions concern individual parks (e.g., Unique fens of Bruce Peninsular NP will migrate lakewards with lowered water levels, but structural regulation of Lake Huron for navigation and power generation would destroy the fens). Knowledge gaps are the most important findings. For example: we could not form conclusions about glacial mass balance, or its effects on rivers and fjords. Likewise, for the East Coast Labrador Current we could neither estimate temperature and salinity effects of extra iceberg formation, nor the further effects on marine food chains, and breeding park seabirds. We recommend 1) Research on specific large knowledge gaps; 2) Climate change information exchange with protected area agencies in other northern countries; and 3) incorporating climate uncertainty into park plans and management. We discuss options for a new park management philosophy in the face of massive change and uncertainty.

Animals↗
PubMed2001

Rapid changes of glacial climate simulated in a coupled climate model.

Abrupt changes in climate, termed Dansgaard-Oeschger and Heinrich events, have punctuated the last glacial period (approximately 100-10 kyr ago) but not the Holocene (the past 10 kyr). Here we use an intermediate-complexity climate model to investigate the stability of glacial climate, and we find that only one mode of Atlantic Ocean circulation is stable: a cold mode with deep water formation in the Atlantic Ocean south of Iceland. However, a 'warm' circulation mode similar to the present-day Atlantic Ocean is only marginally unstable, and temporary transitions to this warm mode can easily be triggered. This leads to abrupt warm events in the model which share many characteristics of the observed Dansgaard-Oeschger events. For a large freshwater input (such as a large release of icebergs), the model's deep water formation is temporarily switched off, causing no strong cooling in Greenland but warming in Antarctica, as is observed for Heinrich events. Our stability analysis provides an explanation why glacial climate is much more variable than Holocene climate.

Journal Article↗