Mechanical behavior of collagen-fibrin co-gels reflects transition from series to parallel interactions with increasing collagen content

Fibrin and collagen, biopolymers occurring naturally in the body, are biomaterials commonly-used as scaffolds for tissue engineering. How collagen and fibrin interact to confer macroscopic mechanical properties in collagen-fibrin composite systems remains poorly understood. In this study, we formulated collagen-fibrin co-gels at different collagen-to-fibrin ratios to observe changes in the overall mechanical behavior and microstructure. A modeling framework of a two-network system was developed by modifying our micro-scale model, considering two forms of interaction between the networks: (a) two interpenetrating but noninteracting networks ("parallel"), and (b) a single network consisting of randomly alternating collagen and fibrin fibrils ("series"). Mechanical testing of our gels show that collagen-fibrin co-gels exhibit intermediate properties (UTS, strain at failure, tangent modulus) compared to those of pure collagen and fibrin. The comparison with model predictions show that the parallel and series model cases provide upper and lower bounds, respectively, for the experimental data, suggesting that a combination of such interactions exists between the collagen and fibrin in co-gels. A transition from the series model to the parallel model occurs with increasing collagen content, with the series model best describing predominantly fibrin co-gels, and the parallel model best describing predominantly collagen co-gels.     

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters

A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure-activity relationships for two parallel enantiomeric series are described. The (-)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.     

The kinetics of rehydration of detached sunflower leaves from different initial water deficits

Abstract. The tempo of rehydration of sunflower ( Helianthus animus L.) leaves was measured after dehydration in a pressure bomb down to water potentials of −0.5 to −1.6 MPa. When rehydrated from small water deficits (−0.5 to −0.8 MPa) the plot of log rehydration rate versus time is concave. When rehydration starts from large deficits (−1.2 to −1.6 MPa) the semilog plot has a characteristic shoulder, i.e. a rehydration phase of long half-time is followed by a phase of short half-time. The experimental curves were fitted with parallel and series models of rehydration. In the parallel model two compartments are connected by resistances in parallel with the water source and rehydrate independently. In the series model one compartment is connected with the water source via a resistance and the second compartment is connected in series with the first by another resistance so that water entering the second compartment must pass through the first. Amongst nineteen experiments, ten could be fitted very closely by both the parallel and series models and nine could not be fitted by either model.     

Gating of Two Mechanoelectrical Transducer Channels Associated with a Single Tip Link

Although gating of mechanoelectrical transducer (MET) channels has been successfully described by assuming that one channel is associated with a tip link in the hair bundle, recent reports indicate that a single tip link is associated with more than one channel. To address the consistency of the model with the observations, gating of MET channels is described here by assuming that each tip link is associated with two identical MET channels, which are connected either in series or in parallel. We found that series connection does not lead to a single minimum of stiffness with respect to hair bundle displacement unless the minimum is above a certain positive value. Thus, negative stiffness must appear in pairs in the displacement axis. In contrast, parallel connection of the two channels predicts gating compliance similar to that predicted by the one-channel-per-tip-link model of channel gating, within the physiological range of parameters. Parallel connection of MET channels is, therefore, a reasonable assumption to explain most experimental observations. However, the compatibility with series connection cannot be ruled out for experimental data on turtle hair cells.     

Transverse Impedance of Single Frog Skeletal Muscle Fibers

The transverse electrical impedance of single frog skeletal muscle fibers was measured at 31 frequencies that ranged from 1 to 100,000 Hz. Each fiber was bathed entirely in Ringer's solution, but it was positioned so that a central length of 5 mm was in a hollow plastic disk and was electrically isolated from the ends of the fiber. The diameter of the segment of the fiber in the disk was measured and then the segment was pressed from opposite sides by two insulating wedges. Electrical current was passed transversely through the segment between two platinum-platinum black electrodes that were located in the pools of Ringer's solution within the disk. The results were corrected for stray parallel capacitance, series resistance of the Ringer's solution between the fiber and the electrodes, parallel shunt resistance around the fiber, and the phase shift of the measuring apparatus. A nonlinear least-squares routine was used to fit a lumped equivalent circuit to the data from six fibers. The equivalent circuit that was chosen for the fibers contained three parallel branches; each branch was composed of a resistor and a capacitor in series. The model also included a seventh adjustable parameter that was designed to account for the degree of compression of the fibers by the insulating wedges. The branches of the equivalent circuit were assumed to represent the electrical properties of: (a) the myoplasm in series with the membrane capacitance that was exposed directly to the pools of Ringer's solution; (b) the capacitance and series resistance of the transverse tubules that were exposed directly to the pools of Ringer's solution; (c) the membrane capacitance in series with the shunt resistance between the fibers and the insulating wedges. The results gave no indication that current entered the sarcoplasmic reticulum.     

Convergence as an evolutionary process

Convergent evolution may be elucidated as a series of stages which show a decreasing number of common characters and become more and more generalized, the characters defining the stages finally being difficult to interpret as adaptive. The series starts with ecological races (genoecodemes), proceeds with parallel ecological races (ecotypes) to sub-life-forms, life-forms (growth forms), ecophysiological 'types' (e.g. xerophytes, halbphytes), and finishes with morpho-physiological levels. The ecotype concept is discussed, and it is proposed that it be restricted to cover parallel ecological races. Other discussions concern the possible occurrence of neutral or non-adaptive characters, the bunching of character gradients, and the two main classification systems of living entities.     

Le revêtement cutané des raies (Chondrichthyes,Elasmobranchii, Batoidea). II. Morphologie et arrangement des tubercules cutanés

The dermal covering of most batoid fish is constituted by dermal denticles and by different series of tubercles or thorns. The repartition and the morphological variations of these structures can provide complementary information about the taxonomy of skates and rays. The variations in these dermal structures within Pristiforms, Rajiforms and Myliobatiforms have been studied, taking into consideration the number of tubercles, their location and their arrangement in different series. Following Hubbs and Ishiyama [30], two new terms and 15 new series are indicated. The characteristics of the arrangement and of the morphology of these structures can separate the Rajiforms, having spiny tubercles or thorns, from the Myliobatiformes, bearing lanceolate or heart-shaped tubercles. The main taxinomic characters found are: guitar fish characterized by two scapular series, one well-developed rostral series and tubercles with an anterolateral ornamentation (relief). Within this group, Rhinidae and Rhynchobatidae are set apart by the morphology of their tubercles (devoid of any anterolateral ornamentation), by the absence of a middorsal caudal series and by the presence of an outer supraspiracular series. Platyrhina and Platyrhinoidis are distinguishable by the absence of anterolateral relief and by the presence of anterolateral, lateral and parallel series. Rajoids are characterized by thorns, only one scapular series and sometimes a nucho-scapular triangle, malar and alar thorns in adults, and well-developed parallel and lateral series. Myliobatiforms are devoid of rostral, orbito-spiracular, malar, alar, anterolateral, parallel and lateral series but a caudal sting is present in most species. Sawfish are almost entirely devoid of tubercules, except for rostral ‘teeth’. The morphology and arrangement of the rostral teeth can differenciate the two genera within this family.     

Exploring the relationship between binding modes of 9-(aminomethyl)-9,10-dihydroanthracene and cyproheptadine analogues at the 5-HT2A serotonin receptor

Comparison of the serotonin 5-HT2A receptor affinities of a parallel series of structural analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine cyproheptadine suggests that the two agents bind to the receptor in different fashions. Examination of ligand-receptor model complexes supports the experimental data and suggests a potential origin for the differences in binding modes.     

Convective paracellular solute flux. A source of ion-ion interaction in the epithelial transport equations

An electrolyte model of an epithelium (a cell and a tight junction in parallel, both in series with a lateral interspace basement membrane) is analyzed using the formalism of nonequilibrium thermodynamics. It is shown that if the parallel structures are heteroporous (i.e., reflection coefficients for two ion species differ between the components), then a cross-term will appear in the overall transport equations of the epithelium. Formally, this cross-term represents an ion-ion interaction. With respect to the rat proximal tubule, data indicating epithelial ionic reflection coefficients less than unity, together with the assumption of no transcellular solvent drag, imply the presence of convective paracellular solute flux. This means that a model applicable to a heteroporous structure must be used to represent the tubule, and, in particular, the cross-terms for ion-ion interaction must also be evaluated in permeability determinations. A series of calculations is presented that permits the estimation of the Na-Cl interaction for rat proximal tubule from available experimental data. One consequence of tubule heteroporosity is that an electrical potential may be substantially less effective than an equivalent concentration gradient in driving reabsorptive ion fluxes.     

Parallel and serial processes in the human oculomotor system: bimodal integration and express saccades

Saccadic reaction times (SRTs) were analyzed in the context of stochastic models of information processing (e.g., Townsend and Ashby 1983) to reveal the processing architecture(s) underlying integrative interactions between visual and auditory inputs and the mechanisms of express saccades. The results support the following conclusions. Bimodal (visual + auditory) targets are processed in parallel, and facilitate SRT to an extent that exceeds levels attainable by probability summation. This strongly implies neural summation between elements responding to spatially aligned visual and auditory inputs in the human oculomotor system. Second, express saccades are produced within a separable processing stage that is organized in series with that responsible for intersensory integration. A model is developed that implements this combination of parallel and serial processing. The activity in parallel input channels is summed within a sensory stage which is organized in series with a pre-motor and motor stage. The time course of each subprocess is considered a random variable, and different experimental manipulations can selectively influence different stages. Parallels between the model and physiological data are explored.     

Improvement of signal-to-noise ratio in electroantennogram responses using multiple insect antennae

Using an array of insect antennae connected in series or in parallel, electroantennogram (EAG) responses and noise levels were investigated in an attempt to improve signal-to-noise (S/N) ratio and sensitivity. Both the EAG response amplitude and noise level increased when the antennae of male Helicoverpa zea (Lepidoptera: Noctuidae) were connected in series. Due to lower relative increase in noise level than EAG amplitude as the number of antennae increased, the S/N ratio was also significantly improved by the serial connection. As a result the sensitivity of EAG was improved by the serial connection, which showed ca. ten-fold improvement in the threshold detection levels compared with a single antenna when four antennae were connected in series. In contrast to the serial connection, there were no differences in EAG amplitudes and overall noise levels when different numbers of antennae were connected in parallel. When only large-amplitude noise was taken into account, however, the S/N ratio was somewhat improved by the parallel connection. The frequency of overall noise remained at the same level both in the serial and in the parallel connection. However, the frequency of the large-amplitude noise increased in serial connection but decreased in parallel connection. The present study clearly indicates that both the sensitivity and S/N ratio of the EAG biosensor could be significantly improved by using the multiple antennal connections.     

Evaluation methods and design for bioartificial liver based on perfusion model

A bioartificial liver (BAL) is a medical device entrapping living hepatocytes or immortalized cells derived from hepatocytes. Many efforts have already been made to maintain the functions of the hepatocytes in a BAL device over a long term. However, there is still some uncertainty as to their efficacy, and their limitations are unclear. Therefore, it is important to quantitatively evaluate the metabolic functions of a BAL. In previous studies onin vitro BAL devices, two test methods, an initial bolus loading and constant-rate infusion plus initial bolus loading, were theoretically carried out to obtain physiologic data on drugs. However, in the current study, the same two methods were used as a perfusion model and derived the same clearance characterized by an interrelationship between the perfusate flow rate and intrinsic clearance. The interrelationship indicated that the CL increased with an increasing perfusate flow rate and approached its maximum value,i.e. intrinsic clearance. In addition, to set up anin vivo BAL system, the toxic plateau levels in the BAL system were calculated for both series and parallel circuit models. The series model had a lower plateau level than the parellel model. The difference in the toxic plateau levels between the parallel and series models increased with an increasing number of BAL cartridges.     

Generalized theorems for nonlinear state space reconstruction

Takens' theorem (1981) shows how lagged variables of a single time series can be used as proxy variables to reconstruct an attractor for an underlying dynamic process. State space reconstruction (SSR) from single time series has been a powerful approach for the analysis of the complex, non-linear systems that appear ubiquitous in the natural and human world. The main shortcoming of these methods is the phenomenological nature of attractor reconstructions. Moreover, applied studies show that these single time series reconstructions can often be improved ad hoc by including multiple dynamically coupled time series in the reconstructions, to provide a more mechanistic model. Here we provide three analytical proofs that add to the growing literature to generalize Takens' work and that demonstrate how multiple time series can be used in attractor reconstructions. These expanded results (Takens' theorem is a special case) apply to a wide variety of natural systems having parallel time series observations for variables believed to be related to the same dynamic manifold. The potential information leverage provided by multiple embeddings created from different combinations of variables (and their lags) can pave the way for new applied techniques to exploit the time-limited, but parallel observations of natural systems, such as coupled ecological systems, geophysical systems, and financial systems. This paper aims to justify and help open this potential growth area for SSR applications in the natural sciences.     

Tetrahydroquinoline glucocorticoid receptor agonists: discovery of a 3-hydroxyl for improving receptor selectivity

We have previously disclosed a series of glucocorticoid receptor (GR) ligands derived from 6-indole-1,2,3,4-tetrahydroquinolines through structure-activity relationship (SAR) of the pendent C6-indole ring. In parallel with this effort, we now report SAR of the tetrahydroquinoline A-ring that identified the importance of a C3 hydroxyl in improving GR selectivity within a series of non-steroidal GR agonists.     

Nonlinearities make a difference: comparison of two common Hill-type models with real muscle

Compared to complex structural Huxley-type models, Hill-type models phenomenologically describe muscle contraction using only few state variables. The Hill-type models dominate in the ever expanding field of musculoskeletal simulations for simplicity and low computational cost. Reasonable parameters are required to gain insight into mechanics of movement. The two most common Hill-type muscle models used contain three components. The series elastic component is connected in series to the contractile component. A parallel elastic component is either connected in parallel to both the contractile and the series elastic component (model [CC+SEC]), or is connected in parallel only with the contractile component (model [CC]). As soon as at least one of the components exhibits substantial nonlinearities, as, e.g., the contractile component by the ability to turn on and off, the two models are mechanically different. We tested which model ([CC+SEC] or [CC]) represents the cat soleus better. Ramp experiments consisting of an isometric and an isokinetic part were performed with an in situ cat soleus preparation using supramaximal nerve stimulation. Hill-type models containing force–length and force–velocity relationship, excitation–contraction coupling and series and parallel elastic force–elongation relations were fitted to the data. To test which model might represent the muscle better, the obtained parameters were compared with experimentally determined parameters. Determined in situations with negligible passive force, the force–velocity relation and the series elastic component relation are independent of the chosen model. In contrast to model [CC+SEC], these relations predicted by model [CC] were in accordance with experimental relations. In conclusion model [CC] seemed to better represent the cat soleus contraction dynamics and should be preferred in the nonlinear regression of muscle parameters and in musculoskeletal modeling.     

A model of inspiratory muscle mechanics

We have previously shown that the costal and crural parts of the diaphragm have different actions on the rib cage (RC) and that the tension developed in one part is not transmitted perfectly to the other. Thus the diaphragm can be modeled pneumatically or electrically as two generators or pumps in series between the lung and abdomen. As such, the force developed by diaphragmatic contraction is the sum of the forces developed in each part, whereas the volume displaced is the same for each part and equal to the total volume displaced. The costal part of the diaphragm is in series with the intercostal and accessory (IA) muscles between the lung and RC, whereas the crural part is in parallel. The volume displaced by simultaneous contraction of the crural part and IA is the sum of volumes displaced by each part. The action of pleural and abdominal pressure [acting through the area of apposition (Aap) of the diaphragm to RC] can be modelled as a summing junction between IA and RC. With hyperinflation the costal part acts more and more in parallel with both IA and the crural part, whereas Aap diminishes, so that the ability to develop large forces decreases independently of the muscles' force-length relationships. The model also predicts that the factors determining the length of the costal and crural parts are different. Finally, the parallel and serial arrangement of the inspiratory musculature allows for increases in maximum power, maximum force, and maximum velocity by appropriate recruitment of the various muscle groups.     

Structure-based design and optimization of potent renin inhibitors on 5- or 7-azaindole-scaffolds

The selective inhibition of the aspartyl protease renin is of high interest to control hypertension and associated cardiovascular risk factors. Following on preceding contributions, we report herein on the optimization of two series of azaindoles to arrive at potent and non-chiral renin inhibitors. The previously discovered azaindole scaffold was further explored by structure-based drug design in combination with parallel synthesis. This results in the identification of novel 5- or 7-azaindole derivatives with remarkable potency for renin inhibition. The best compounds on both series show IC(50) values between 3 and 8nM.     

Conformational considerations in the design of dual antagonists of platelet-activating factor (PAF) and histamine.

Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)piperidine, Sch 37370, 1, a related series of structures, exemplified by (+/-)-1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)piperazine, Sch 40338, 2, were prepared. Interestingly, the compounds exhibited a parallel structure antiallergy activity relationship, suggesting that the two series may adopt a common conformation at the PAF receptor. Conformational analysis led to a proposal for this bioactive conformation accessible to both series. The synthesis of novel conformationally constrained analogues that might mimic the proposed bioactive conformation of these compounds, and the evaluation of their in vitro antiallergy activity form the subject matter of this report.     

Resonant hopping of a robot controlled by an artificial neural oscillator

The bouncing gaits of terrestrial animals (hopping, running, trotting) can be modeled as a hybrid dynamic system, with spring-mass dynamics during stance and ballistic motion during the aerial phase. We used a simple hopping robot controlled by an artificial neural oscillator to test the ability of the neural oscillator to adaptively drive this hybrid dynamic system. The robot had a single joint, actuated by an artificial pneumatic muscle in series with a tendon spring. We examined how the oscillator-robot system responded to variation in two neural control parameters: descending neural drive and neuromuscular gain. We also tested the ability of the oscillator-robot system to adapt to variations in mechanical properties by changing the series and parallel spring stiffnesses. Across a 100-fold variation in both supraspinal gain and muscle gain, hopping frequency changed by less than 10%. The neural oscillator consistently drove the system at the resonant half-period for the stance phase, and adapted to a new resonant half-period when the muscle series and parallel stiffnesses were altered. Passive cycling of elastic energy in the tendon accounted for 70-79% of the mechanical work done during each hop cycle. Our results demonstrate that hopping dynamics were largely determined by the intrinsic properties of the mechanical system, not the specific choice of neural oscillator parameters. The findings provide the first evidence that an artificial neural oscillator will drive a hybrid dynamic system at partial resonance.