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1.  Bioreactor Design for Tendon/Ligament Engineering 
Tendon and ligament injury is a worldwide health problem, but the treatment options remain limited. Tendon and ligament engineering might provide an alternative tissue source for the surgical replacement of injured tendon. A bioreactor provides a controllable environment enabling the systematic study of specific biological, biochemical, and biomechanical requirements to design and manufacture engineered tendon/ligament tissue. Furthermore, the tendon/ligament bioreactor system can provide a suitable culture environment, which mimics the dynamics of the in vivo environment for tendon/ligament maturation. For clinical settings, bioreactors also have the advantages of less-contamination risk, high reproducibility of cell propagation by minimizing manual operation, and a consistent end product. In this review, we identify the key components, design preferences, and criteria that are required for the development of an ideal bioreactor for engineering tendons and ligaments.
doi:10.1089/ten.teb.2012.0295
PMCID: PMC3589869  PMID: 23072472
2.  Sensory reinforcement as a predictor of cocaine and water self-administration in rats 
Psychopharmacology  2012;226(2):335-346.
Rationale
The ability of locomotor activity in a novel environment (Loco) and visual stimulus reinforcement (VSR) to predict acquisition of responding for cocaine and water reinforcers in the absence of explicit audiovisual signals was evaluated.
Methods
In Experiment 1, rats (n=60) were tested for VSR, followed by Loco, and finally acquisition of responding for cocaine (0.3 mg/kg/inf). In Experiment 2, rats (n=32) were tested for VSR, followed by Loco, and finally acquisition of responding for water (0.01 ml/reinforcer).
Results
There were three main findings. First, Loco and VSR were significantly associated (Exp 1: r = 0.49, p< 0.00; Exp2: r = 0.35, p< 0.05). Second, neither Loco (r = .00, p = 0.998) nor VSR (r = −0.12, p = 0.352) predicted acquisition of cocaine SA. Third, in the sub group of animals that acquired cocaine SA, VSR (r = 0.41, p< 0.01) but not Loco (r = 0.28, p = 0.10) was positively associated with operant responding for cocaine. Both Loco and VSR (Loco: r = 0.37, p< 0.04; VSR: r = 0.51, p< 0.00) were positively associated with operant responding for water reinforcers.
Conclusions
The results indicate that VSR is at least as good a predictor of cocaine reinforced responding as Loco. VSR was predictive of operant responding for both drug and water reinforcers, while Loco was found to be predictive of responding only for water reinforcers. In studies that present visual stimuli in association with drug delivery, Loco may be predicting acquisition of responding for VSR rather than drug.
doi:10.1007/s00213-012-2907-6
PMCID: PMC3581756  PMID: 23142958
cocaine; drug abuse; self-administration; operant conditioning; rat; sensation seeking; novelty
3.  The Effect of the G1 - S transition Checkpoint on an Age Structured Cell Cycle Model 
PLoS ONE  2014;9(1):e83477.
Knowledge of how a population of cancerous cells progress through the cell cycle is vital if the population is to be treated effectively, as treatment outcome is dependent on the phase distributions of the population. Estimates on the phase distribution may be obtained experimentally however the errors present in these estimates may effect treatment efficacy and planning. If mathematical models are to be used to make accurate, quantitative predictions concerning treatments, whose efficacy is phase dependent, knowledge of the phase distribution is crucial. In this paper it is shown that two different transition rates at the - checkpoint provide a good fit to a growth curve obtained experimentally. However, the different transition functions predict a different phase distribution for the population, but both lying within the bounds of experimental error. Since treatment outcome is effected by the phase distribution of the population this difference may be critical in treatment planning. Using an age-structured population balance approach the cell cycle is modelled with particular emphasis on the - checkpoint. By considering the probability of cells transitioning at the - checkpoint, different transition functions are obtained. A suitable finite difference scheme for the numerical simulation of the model is derived and shown to be stable. The model is then fitted using the different probability transition functions to experimental data and the effects of the different probability transition functions on the model's results are discussed.
doi:10.1371/journal.pone.0083477
PMCID: PMC3886982  PMID: 24416166
4.  Brain-Stimulation Induced Blindsight: Unconscious Vision or Response Bias? 
PLoS ONE  2013;8(12):e82828.
A dissociation between visual awareness and visual discrimination is referred to as “blindsight”. Blindsight results from loss of function of the primary visual cortex (V1) which can occur due to cerebrovascular accidents (i.e. stroke-related lesions). There are also numerous reports of similar, though reversible, effects on vision induced by transcranial Magnetic Stimulation (TMS) to early visual cortex. These effects point to V1 as the “gate” of visual awareness and have strong implications for understanding the neurological underpinnings of consciousness. It has been argued that evidence for the dissociation between awareness of, and responses to, visual stimuli can be a measurement artifact of the use of a high response criterion under yes-no measures of visual awareness when compared with the criterion free forced-choice responses. This difference between yes-no and forced-choice measures suggests that evidence for a dissociation may actually be normal near-threshold conscious vision. Here we describe three experiments that tested visual performance in normal subjects when their visual awareness was suppressed by applying TMS to the occipital pole. The nature of subjects’ performance whilst undergoing occipital TMS was then verified by use of a psychophysical measure (d') that is independent of response criteria. This showed that there was no genuine dissociation in visual sensitivity measured by yes-no and forced-choice responses. These results highlight that evidence for visual sensitivity in the absence of awareness must be analysed using a bias-free psychophysical measure, such as d', In order to confirm whether or not visual performance is truly unconscious.
doi:10.1371/journal.pone.0082828
PMCID: PMC3855787  PMID: 24324837
5.  Participatory Development and Analysis of a Fuzzy Cognitive Map of the Establishment of a Bio-Based Economy in the Humber Region 
PLoS ONE  2013;8(11):e78319.
Fuzzy Cognitive Mapping (FCM) is a widely used participatory modelling methodology in which stakeholders collaboratively develop a ‘cognitive map’ (a weighted, directed graph), representing the perceived causal structure of their system. This can be directly transformed by a workshop facilitator into simple mathematical models to be interrogated by participants by the end of the session. Such simple models provide thinking tools which can be used for discussion and exploration of complex issues, as well as sense checking the implications of suggested causal links. They increase stakeholder motivation and understanding of whole systems approaches, but cannot be separated from an intersubjective participatory context. Standard FCM methodologies make simplifying assumptions, which may strongly influence results, presenting particular challenges and opportunities. We report on a participatory process, involving local companies and organisations, focussing on the development of a bio-based economy in the Humber region. The initial cognitive map generated consisted of factors considered key for the development of the regional bio-based economy and their directional, weighted, causal interconnections. A verification and scenario generation procedure, to check the structure of the map and suggest modifications, was carried out with a second session. Participants agreed on updates to the original map and described two alternate potential causal structures. In a novel analysis all map structures were tested using two standard methodologies usually used independently: linear and sigmoidal FCMs, demonstrating some significantly different results alongside some broad similarities. We suggest a development of FCM methodology involving a sensitivity analysis with different mappings and discuss the use of this technique in the context of our case study. Using the results and analysis of our process, we discuss the limitations and benefits of the FCM methodology in this case and in general. We conclude by proposing an extended FCM methodology, including multiple functional mappings within one participant-constructed graph.
doi:10.1371/journal.pone.0078319
PMCID: PMC3820682  PMID: 24244303
6.  Effects of novelty and methamphetamine on conditioned and sensory reinforcement 
Behavioural brain research  2012;234(2):312-322.
Background
Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light.
Methods
The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: Rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: Rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response-contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined.
Results
Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs.
Conclusion
Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction.
doi:10.1016/j.bbr.2012.07.012
PMCID: PMC3422403  PMID: 22814112
Rats; Drug Abuse; Psychomotor Stimulant; Operant Conditioning; Pavlovian Conditioning; Dopamine
7.  Habituation and the reinforcing effectiveness of visual stimuli 
Behavioural processes  2012;91(2):184-191.
The term “sensory reinforcer” has been used to refer to sensory stimuli (e.g. light onset) that are primary reinforcers in order to differentiate them from other more biologically important primary reinforcers (e.g. food and water). Acquisition of snout poke responding for a visual stimulus (5 s light onset) with fixed ratio 1 (FR 1), variable-interval 1 minute (VI 1 min), or variable-interval 6 minute (VI 6 min) schedules of reinforcement was tested in three groups of rats (n = 8/group). The VI 6 min schedule of reinforcement produced a higher response rate than the FR 1 or VI 1 min schedules of visual stimulus reinforcement. One explanation for greater responding on the VI 6 min schedule relative to the FR 1 and VI 1 min schedules is that the reinforcing effectiveness of light onset habituated more rapidly in the FR 1 and VI 1 min groups as compared to the VI 6 min group. The inverse relationship between response rate and the rate of visual stimulus reinforcement is opposite to results from studies with biologically important reinforcers which indicate a positive relationship between response and reinforcement rate. Rapid habituation of reinforcing effectiveness may be a fundamental characteristic of sensory reinforcers that differentiates them from biologically important reinforcers, which are required to maintain homeostatic balance.
doi:10.1016/j.beproc.2012.07.007
PMCID: PMC3438312  PMID: 22868172
Learning; Novelty; Operant Conditioning; Rat; Sensory Reinforcement
8.  Modeling the Human Knee for Assistive Technologies 
In this paper, we use motion capture technology together with an EMG-driven musculoskeletal model of the knee joint to predict muscle behavior during human dynamic movements. We propose a muscle model based on infinitely stiff tendons and show this allows speeding up 250 times the computation of muscle force and the resulting joint moment calculation with no loss of accuracy with respect to the previously developed elastictendon model. We then integrate our previously developed method for the estimation of 3-D musculotendon kinematics in the proposed EMG-driven model. This new code enabled the creation of a standalone EMG-driven model that was implemented and run on an embedded system for applications in assistive technologies such as myoelectrically controlled prostheses and orthoses.
doi:10.1109/TBME.2012.2208746
PMCID: PMC3668098  PMID: 22911539
Assistive technologies; electromyography (EMG); knee joint; musculoskeletal modeling
9.  Between-session progressive ratio performance in rats responding for cocaine and water reinforcers 
Psychopharmacology  2012;222(2):215-223.
Rationale
A between-session progressive ratio (BtwPR) procedure was tested in rats responding for cocaine and water reinforcers.
Objectives
Experiment 1 evaluated the sensitivity of the BtwPR procedure to the magnitude of cocaine and water reinforcers. Experiment 2 compared BtwPR performance to within-session progressive ratio (WinPR) performance.
Methods
In experiment 1, rats were tested on a BtwPR procedure with three doses of cocaine (0.1, 0.3, and 1.0 mg/kg/inf) or volumes of water (0.01, 0.03, and 0.1 mL/reinforcer). BtwPR test sessions began with a seeking phase, during which the animal is required to complete a fixed ratio in order to initiate a 2-h consumption phase, where the reinforcer was available according to a fixed ratio 1 (FR1) schedule. Failure to complete the seeking ratio, which was increased after each test session, determined the breakpoint (BP). In experiment 2, the same BtwPR procedure was used except that the consumption phase was a WinPR schedule of reinforcement for cocaine (1.0 mg/kg/inf) or water (0.1 mL) reinforcers.
Results and conclusions
BtwPR BPs increased as a function of the magnitude of both cocaine and water reinforcers. The BtwPR produced smaller BPs than the WinPR for cocaine reinforcers. In contrast, the BtwPR produced larger BPs than the WinPR for water reinforcers. One possible explanation is that priming and response activating effects of the cocaine reinforcer increased the WinPR BP. BtwPR and WinPR procedures may measure different aspects of drug-seeking.
doi:10.1007/s00213-012-2637-9
PMCID: PMC3571699  PMID: 22277988
Cocaine; Drug abuse; Self-administration; Operant conditioning
10.  Unexpected properties of NADP-dependent secondary alcohol dehydrogenase (ADH-1) in Trichomonas vaginalis and other microaerophilic parasites 
Experimental Parasitology  2013;134(3):374-380.
Graphical abstract
CoA inhibits the oxidation of 2-propanol and the reduction of acetaldehyde, acetone and a yet unidentified “background” substrate by ADH-1.
Highlights
•Trichomonas vaginalis NADPH-dependent alcohol dehydrogenase-1 (ADH-1) reduces acetaldehyde and acetone, and oxidizes 2-propanol.•In addition to its canonical function, a strong reducing background activity was observed.•All reactions catalyzed by ADH-1 are strongly inhibited by CoA.•These observations also apply for the parasites Entamoeba histolytica and Tritrichomonas foetus, but not for Giardia lamblia which lacks ADH-1.
Our previous observation that NADP-dependent secondary alcohol dehydrogenase (ADH-1) is down-regulated in metronidazole-resistant Trichomonas vaginalis isolates prompted us to further characterise the enzyme. In addition to its canonical enzyme activity as a secondary alcohol dehydrogenase, a pronounced, so far unknown, background NADPH-oxidising activity in absence of any added substrate was observed when the recombinant enzyme or T. vaginalis extract were used. This activity was strongly enhanced at low oxygen concentrations. Unexpectedly, all functions of ADH-1 were efficiently inhibited by coenzyme A which is a cofactor of a number of key enzymes in T. vaginalis metabolism, i.e. pyruvate:ferredoxin oxidoreductase (PFOR). These observations could be extended to Entamoeba histolytica and Tritrichomonas foetus, both of which have a homologue of ADH-1, but not to Giardia lamblia which lacks an NADP-dependent secondary alcohol dehydrogenase.
Although we could not identify the substrate of the observed background activity, we propose that ADH-1 functions as a major sink for NADPH in microaerophilic parasites at low oxygen tension.
doi:10.1016/j.exppara.2013.03.034
PMCID: PMC3682184  PMID: 23578856
Trichomonas vaginalis; NADP-dependent alcohol dehydrogenase-1; Background activity; CoA
11.  Structural and functional annotation of the porcine immunome 
BMC Genomics  2013;14:332.
Background
The domestic pig is known as an excellent model for human immunology and the two species share many pathogens. Susceptibility to infectious disease is one of the major constraints on swine performance, yet the structure and function of genes comprising the pig immunome are not well-characterized. The completion of the pig genome provides the opportunity to annotate the pig immunome, and compare and contrast pig and human immune systems.
Results
The Immune Response Annotation Group (IRAG) used computational curation and manual annotation of the swine genome assembly 10.2 (Sscrofa10.2) to refine the currently available automated annotation of 1,369 immunity-related genes through sequence-based comparison to genes in other species. Within these genes, we annotated 3,472 transcripts. Annotation provided evidence for gene expansions in several immune response families, and identified artiodactyl-specific expansions in the cathelicidin and type 1 Interferon families. We found gene duplications for 18 genes, including 13 immune response genes and five non-immune response genes discovered in the annotation process. Manual annotation provided evidence for many new alternative splice variants and 8 gene duplications. Over 1,100 transcripts without porcine sequence evidence were detected using cross-species annotation. We used a functional approach to discover and accurately annotate porcine immune response genes. A co-expression clustering analysis of transcriptomic data from selected experimental infections or immune stimulations of blood, macrophages or lymph nodes identified a large cluster of genes that exhibited a correlated positive response upon infection across multiple pathogens or immune stimuli. Interestingly, this gene cluster (cluster 4) is enriched for known general human immune response genes, yet contains many un-annotated porcine genes. A phylogenetic analysis of the encoded proteins of cluster 4 genes showed that 15% exhibited an accelerated evolution as compared to 4.1% across the entire genome.
Conclusions
This extensive annotation dramatically extends the genome-based knowledge of the molecular genetics and structure of a major portion of the porcine immunome. Our complementary functional approach using co-expression during immune response has provided new putative immune response annotation for over 500 porcine genes. Our phylogenetic analysis of this core immunome cluster confirms rapid evolutionary change in this set of genes, and that, as in other species, such genes are important components of the pig’s adaptation to pathogen challenge over evolutionary time. These comprehensive and integrated analyses increase the value of the porcine genome sequence and provide important tools for global analyses and data-mining of the porcine immune response.
doi:10.1186/1471-2164-14-332
PMCID: PMC3658956  PMID: 23676093
Immune response; Porcine; Genome annotation; Co-expression network; Phylogenetic analysis; Accelerated evolution
12.  Association between locomotor response to novelty and light reinforcement: Sensory reinforcement as a rodent model of sensation seeking 
Behavioural brain research  2012;230(2):380-388.
Background
The human personality trait of sensation seeking (SS) indicates an attraction to novel sensations and experiences, and is associated with greater likelihood of drug abuse. In rodents, locomotor activity in a novel environment (Loco) has been found to predict drug self-administration (SA), and has been hypothesized to be a translational model of human SS. Previously, we reported (Gancarz et al., 2011 [12]) that high responder (HR) animals responded more than low responder (LR) animals to produce a response contingent light onset. The primary goal of this paper was a detailed analysis of the association between Loco and light contingent responding in a large sample of rats (n = 93).
Methods
Male rats were pre-exposed to dark operant test chambers for ten 30 min sessions and baseline levels of responding (snout poking) were determined. The pre-exposure phase was followed by 6 sessions during which active responding produced a visual sensory reinforcer (VSR; 5 s light onset) according to a variable interval 1 min schedule of reinforcement. After completion of the VSR phase, Loco was tested.
Results
The activating effects (total responding) of light were associated with Loco, but the response guiding effects (proportion of active responding) of the light were not. In addition, HR rats habituated more slowly in both the VSR and Loco tests than LR rats.
Conclusions
These data indicate that VSR measures aspects of the rodent’s response to novel sensations and experiences that are not detected by Loco. These data provide some evidence for the use of light reinforcement as an animal model of SS.
PMCID: PMC3580059  PMID: 22586716
Operant conditioning; Drug abuse; Rat; Self-administration; Visual stimuli; Individual differences
13.  Estimation of musculotendon kinematics in large musculoskeletal models using multidimensional B-Splines 
Journal of Biomechanics  2011;45(3):595-601.
We present a robust and computationally inexpensive method to estimate the lengths and three-dimensional moment arms for a large number of musculotendon actuators of the human lower limb. Using a musculoskeletal model of the lower extremity, a set of values was established for the length of each musculotendon actuator for different lower limb generalized coordinates (joint angles). A multidimensional spline function was then used to fit these data. Muscle moment arms were obtained by differentiating the musculotendon length spline function with respect to the generalized coordinate of interest. This new method was then compared to a previously used polynomial regression method. Compared to the polynomial regression method, the multidimensional spline method produced lower errors for estimating musculotendon lengths and moment arms throughout the whole generalized coordinate workspace. The fitting accuracy was also less affected by the number of dependent degrees of freedom and by the amount of experimental data available. The spline method only requires information on musculotendon lengths to estimate both musculotendon lengths and moment arms, thus relaxing data input requirements, whereas the polynomial regression requires different equations to be used for both musculotendon lengths and moment arms. Finally, we used the spline method in conjunction with an electromyography driven musculoskeletal model to estimate muscle forces under different contractile conditions, which showed the method is suitable for the integration into large scale neuromusculoskeletal models.
doi:10.1016/j.jbiomech.2011.10.040
PMCID: PMC3264840  PMID: 22176708
musculoskeletal modeling; musculotendon length; muscle moment arm; muscle force; multidimensional spline interpolation
14.  A musculoskeletal model of human locomotion driven by a low dimensional set of impulsive excitation primitives 
Human locomotion has been described as being generated by an impulsive (burst-like) excitation of groups of musculotendon units, with timing dependent on the biomechanical goal of the task. Despite this view being supported by many experimental observations on specific locomotion tasks, it is still unknown if the same impulsive controller (i.e., a low-dimensional set of time-delayed excitastion primitives) can be used as input drive for large musculoskeletal models across different human locomotion tasks. For this purpose, we extracted, with non-negative matrix factorization, five non-negative factors from a large sample of muscle electromyograms in two healthy subjects during four motor tasks. These included walking, running, sidestepping, and crossover cutting maneuvers. The extracted non-negative factors were then averaged and parameterized to obtain task-generic Gaussian-shaped impulsive excitation curves or primitives. These were used to drive a subject-specific musculoskeletal model of the human lower extremity. Results showed that the same set of five impulsive excitation primitives could be used to predict the dynamics of 34 musculotendon units and the resulting hip, knee and ankle joint moments (i.e., NRMSE = 0.18 ± 0.08, and R2 = 0.73 ± 0.22 across all tasks and subjects) without substantial loss of accuracy with respect to using experimental electromyograms (i.e., NRMSE = 0.16 ± 0.07, and R2 = 0.78 ± 0.18 across all tasks and subjects). Results support the hypothesis that biomechanically different motor tasks might share similar neuromuscular control strategies. This might have implications in neurorehabilitation technologies such as human-machine interfaces for the torque-driven, proportional control of powered prostheses and orthoses. In this, device control commands (i.e., predicted joint torque) could be derived without direct experimental data but relying on simple parameterized Gaussian-shaped curves, thus decreasing the input drive complexity and the number of needed sensors.
doi:10.3389/fncom.2013.00079
PMCID: PMC3693080  PMID: 23805099
EMG-driven modeling; musculoskeletal modeling; lower extremity; multiple degrees of freedom; muscle dynamics; muscle synergy
15.  Habituation of reinforcer effectiveness 
In this paper we propose an integrative model of habituation of reinforcer effectiveness (HRE) that links behavioral- and neural-based explanations of reinforcement. We argue that HRE is a fundamental property of reinforcing stimuli. Most reinforcement models implicitly suggest that the effectiveness of a reinforcer is stable across repeated presentations. In contrast, an HRE approach predicts decreased effectiveness due to repeated presentation. We argue that repeated presentation of reinforcing stimuli decreases their effectiveness and that these decreases are described by the behavioral characteristics of habituation (McSweeney and Murphy, 2009; Rankin etal., 2009). We describe a neural model that postulates a positive association between dopamine neurotransmission and HRE. We present evidence that stimulant drugs, which artificially increase dopamine neurotransmission, disrupt (slow) normally occurring HRE and also provide evidence that stimulant drugs have differential effects on operant responding maintained by reinforcers with rapid vs. slow HRE rates. We hypothesize that abnormal HRE due to genetic and/or environmental factors may underlie some behavioral disorders. For example, recent research indicates that slow-HRE is predictive of obesity. In contrast ADHD may reflect “accelerated-HRE.” Consideration of HRE is important for the development of effective reinforcement-based treatments. Finally, we point out that most of the reinforcing stimuli that regulate daily behavior are non-consumable environmental/social reinforcers which have rapid-HRE. The almost exclusive use of consumable reinforcers with slow-HRE in pre-clinical studies with animals may have caused the importance of HRE to be overlooked. Further study of reinforcing stimuli with rapid-HRE is needed in order to understand how habituation and reinforcement interact and regulate behavior.
doi:10.3389/fnint.2013.00107
PMCID: PMC3885986  PMID: 24409128
ADHD; behavioral regulation; dopamine; drug addiction; obesity; operant conditioning; psychomotor stimulant; sensory reinforcement
16.  EMG-Driven Forward-Dynamic Estimation of Muscle Force and Joint Moment about Multiple Degrees of Freedom in the Human Lower Extremity 
PLoS ONE  2012;7(12):e52618.
This work examined if currently available electromyography (EMG) driven models, that are calibrated to satisfy joint moments about one single degree of freedom (DOF), could provide the same musculotendon unit (MTU) force solution, when driven by the same input data, but calibrated about a different DOF. We then developed a novel and comprehensive EMG-driven model of the human lower extremity that used EMG signals from 16 muscle groups to drive 34 MTUs and satisfy the resulting joint moments simultaneously produced about four DOFs during different motor tasks. This also led to the development of a calibration procedure that allowed identifying a set of subject-specific parameters that ensured physiological behavior for the 34 MTUs. Results showed that currently available single-DOF models did not provide the same unique MTU force solution for the same input data. On the other hand, the MTU force solution predicted by our proposed multi-DOF model satisfied joint moments about multiple DOFs without loss of accuracy compared to single-DOF models corresponding to each of the four DOFs. The predicted MTU force solution was (1) a function of experimentally measured EMGs, (2) the result of physiological MTU excitation, (3) reflected different MTU contraction strategies associated to different motor tasks, (4) coordinated a greater number of MTUs with respect to currently available single-DOF models, and (5) was not specific to an individual DOF dynamics. Therefore, our proposed methodology has the potential of producing a more dynamically consistent and generalizable MTU force solution than was possible using single-DOF EMG-driven models. This will help better address the important scientific questions previously approached using single-DOF EMG-driven modeling. Furthermore, it might have applications in the development of human-machine interfaces for assistive devices.
doi:10.1371/journal.pone.0052618
PMCID: PMC3530468  PMID: 23300725
17.  A Metapopulation Model to Assess the Capacity of Spread of Meticillin-Resistant Staphylococcus aureus ST398 in Humans 
PLoS ONE  2012;7(10):e47504.
The emergence of the livestock-associated clone of meticillin-resistant Staphylococcus aureus (MRSA) ST398 is a serious public health issue throughout Europe. In The Netherlands a stringent ‘search-and-destroy’ policy has been adopted, keeping low the level of MRSA prevalence. However, reports have recently emerged of transmission events between humans showing no links to livestock, contradicting belief that MRSA ST398 is poorly transmissible in humans. The question regarding the transmissibility of MRSA ST398 in humans therefore remains of great interest. Here, we investigated the capacity of MRSA ST398 to spread into an entirely susceptible human population subject to the effect of a single MRSA-positive commercial pig farm. Using a stochastic, discrete-time metapopulation model, we explored the effect of varying both the probability of persistent carriage and that of acquiring MRSA due to contact with pigs on the transmission dynamics of MRSA ST398 in humans. In particular, we assessed the value and key determinants of the basic reproduction ratio (R0) for MRSA ST398. Simulations showed that the presence of recurrent exposures with pigs in risky populations allows MRSA ST398 to persist in the metapopulation and transmission events to occur beyond the farming community, even when the probability of persistent carriage is low. We further showed that persistent carriage should occur in less than 10% of the time for MRSA ST398 to conserve epidemiological characteristics similar to what has been previously reported. These results indicate that implementing control policy that only targets human carriers may not be sufficient to control MRSA ST398 in the community if it remains in pigs. We argue that farm-level control measures should be implemented if an eradication programme is to be considered.
doi:10.1371/journal.pone.0047504
PMCID: PMC3480390  PMID: 23112817
18.  FGF21 Promotes Metabolic Homeostasis via White Adipose and Leptin in Mice 
PLoS ONE  2012;7(7):e40164.
Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.
doi:10.1371/journal.pone.0040164
PMCID: PMC3391219  PMID: 22792234
19.  Modelling and Detecting Tumour Oxygenation Levels 
PLoS ONE  2012;7(6):e38597.
Tumours that are low in oxygen (hypoxic) tend to be more aggressive and respond less well to treatment. Knowing the spatial distribution of oxygen within a tumour could therefore play an important role in treatment planning, enabling treatment to be targeted in such a way that higher doses of radiation are given to the more radioresistant tissue. Mapping the spatial distribution of oxygen in vivo is difficult. Radioactive tracers that are sensitive to different levels of oxygen are under development and in the early stages of clinical use. The concentration of these tracer chemicals can be detected via positron emission tomography resulting in a time dependent concentration profile known as a tissue activity curve (TAC). Pharmaco-kinetic models have then been used to deduce oxygen concentration from TACs. Some such models have included the fact that the spatial distribution of oxygen is often highly inhomogeneous and some have not. We show that the oxygen distribution has little impact on the form of a TAC; it is only the mean oxygen concentration that matters. This has significant consequences both in terms of the computational power needed, and in the amount of information that can be deduced from TACs.
doi:10.1371/journal.pone.0038597
PMCID: PMC3386285  PMID: 22761687
20.  Isolation of Human Mitotic Protein Phosphatase Complexes: Identification of a Complex between Protein Phosphatase 1 and the RNA Helicase Ddx21 
PLoS ONE  2012;7(6):e39510.
Metazoan mitosis requires remodelling of sub-cellular structures to ensure proper division of cellular and genetic material. Faults often lead to genomic instability, cell cycle arrests and disease onset. These key structural changes are under tight spatial-temporal and post-translational control, with crucial roles for reversible protein phosphorylation. The phosphoprotein phosphatases PP1 and PP2A are paramount for the timely execution of mitotic entry and exit but their interaction partners and substrates are still largely unresolved. High throughput, mass-spectrometry based studies have limited sensitivity for the detection of low-abundance and transient complexes, a typical feature of many protein phosphatase complexes. Moreover, the limited timeframe during which mitosis takes place reduces the likelihood of identifying mitotic phosphatase complexes in asynchronous cells. Hence, numerous mitotic protein phosphatase complexes still await identification. Here we present a strategy to enrich and identify serine/threonine protein phosphatase complexes at the mitotic spindle. We thus identified a nucleolar RNA helicase, Ddx21/Gu, as a novel, direct PP1 interactor. Furthermore, our results place PP1 within the toposome, a Topoisomerase II alpha (TOPOIIα) containing complex with a key role in mitotic chromatin regulation and cell cycle progression, possibly via regulated protein phosphorylation. This study provides a strategy for the identification of further mitotic PP1 partners and the unravelling of PP1 functions during mitosis.
doi:10.1371/journal.pone.0039510
PMCID: PMC3386289  PMID: 22761809
21.  What yeast and cardiomyocytes share: ultradian oscillatory redox mechanisms of cellular coherence and survival† 
Integrative Biology  2011;4(1):65-74.
The coherent and robust, yet sensitively adaptable, nature of organisms is an astonishing phenomenon that involves massive parallel processing and concerted network performance at the molecular level. Unravelling the dynamic complexities of the living state underlines the essential operation of ultradian oscillations, rhythms and clocks for the establishment and maintenance of functional order simultaneously on fast and slower timescales. Non-invasive monitoring of respiration, mitochondrial inner membrane potentials, and redox states (especially those of NAD(P)H, flavin, and the monochlorobimane complex of glutathione), even after more than 50 years research, continue to provide both new insights and biomedical applications. Experiments with yeast and in cardiac cells reveal astonishing parallels and similarities in their dynamic biochemical organization.
doi:10.1039/c1ib00124h
PMCID: PMC3348865  PMID: 22143867
22.  Adaptations for economical bipedal running: the effect of limb structure on three-dimensional joint mechanics 
The purpose of this study was to examine the mechanical adaptations linked to economical locomotion in cursorial bipeds. We addressed this question by comparing mass-matched humans and avian bipeds (ostriches), which exhibit marked differences in limb structure and running economy. We hypothesized that the nearly 50 per cent lower energy cost of running in ostriches is a result of: (i) lower limb-swing mechanical power, (ii) greater stance-phase storage and release of elastic energy, and (iii) lower total muscle power output. To test these hypotheses, we used three-dimensional joint mechanical measurements and a simple model to estimate the elastic and muscle contributions to joint work and power. Contradictory to our first hypothesis, we found that ostriches and humans generate the same amounts of mechanical power to swing the limbs at a similar self-selected running speed, indicating that limb swing probably does not contribute to the difference in energy cost of running between these species. In contrast, we estimated that ostriches generate 120 per cent more stance-phase mechanical joint power via release of elastic energy compared with humans. This elastic mechanical power occurs nearly exclusively at the tarsometatarso-phalangeal joint, demonstrating a shift of mechanical power generation to distal joints compared with humans. We also estimated that positive muscle fibre power is 35 per cent lower in ostriches compared with humans, and is accounted for primarily by higher capacity for storage and release of elastic energy. Furthermore, our analysis revealed much larger frontal and internal/external rotation joint loads during ostrich running than in humans. Together, these findings support the hypothesis that a primary limb structure specialization linked to economical running in cursorial species is an elevated storage and release of elastic energy in tendon. In the ostrich, energy-saving specializations may also include passive frontal and internal/external rotation load-bearing mechanisms.
doi:10.1098/rsif.2010.0466
PMCID: PMC3061092  PMID: 21030429
bipedal; joint mechanics; cursorial; ostrich; cost of transport; running
24.  Laparoscopic splenectomy: a personal series of 140 consecutive cases 
Introduction
Laparoscopic splenectomy has emerged as a safe and effective treatment for a variety of haematological conditions. The objective was to review the results from a large personal series from the perspective of outcomes according to operative time, conversion to open operation, complications and mortality. The application of laparoscopic splenectomy to cases of splenomegaly without hand assistance is examined.
Patients and Methods
A retrospective review of 140 patients undergoing laparoscopic splenectomy at a single university hospital by one surgeon during 1994-2006. Case notes were reviewed and data collected on operative time, conversion to open procedure, morbidity and mortality. Particular reference was made towards the results of cases of splenomegaly.
Results
In total 140 laparoscopic splenectomies were performed with a complication rate of 15% and no mortality. The median operative time was 100 min and conversion to open procedure was necessary in 2.1%. Conversion for cases of splenomegaly was only 5.7%. The median hospital stay was 3 days.
Conclusions
Laparoscopic splenectomy is a safe procedure with acceptable morbidity. A laparoscopic approach for splenomegaly is feasible.
doi:10.1308/003588410X12664192076133
PMCID: PMC3180312  PMID: 20487598
Laparoscopic splenectomy; Splenomegaly; Idiopathic thrombocytopenic purpura; Complications
25.  Antimicrobial Use Guidelines for Treatment of Urinary Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases 
Urinary tract disease is a common reason for use (and likely misuse, improper use, and overuse) of antimicrobials in dogs and cats. There is a lack of comprehensive treatment guidelines such as those that are available for human medicine. Accordingly, guidelines for diagnosis and management of urinary tract infections were created by a Working Group of the International Society for Companion Animal Infectious Diseases. While objective data are currently limited, these guidelines provide information to assist in the diagnosis and management of upper and lower urinary tract infections in dogs and cats.
doi:10.4061/2011/263768
PMCID: PMC3134992  PMID: 21776346

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