BioSimulators: a central registry of simulation engines and services for recommending specific tools.

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.

Compartmental and Spatial Rule-Based Modeling with Virtual Cell.

In rule-based modeling, molecular interactions are systematically specified in the form of reaction rules that serve as generators of reactions. This provides a way to account for all the potential molecular complexes and interactions among multivalent or multistate molecules. Recently, we introduced rule-based modeling into the Virtual Cell (VCell) modeling framework, permitting graphical specification of rules and merger of networks generated automatically (using the BioNetGen modeling engine) with hand-specified reaction networks. VCell provides a number of ordinary differential equation and stochastic numerical solvers for single-compartment simulations of the kinetic systems derived from these networks, and agent-based network-free simulation of the rules. In this work, compartmental and spatial modeling of rule-based models has been implemented within VCell. To enable rule-based deterministic and stochastic spatial simulations and network-free agent-based compartmental simulations, the BioNetGen and NFSim engines were each modified to support compartments. In the new rule-based formalism, every reactant and product pattern and every reaction rule are assigned locations. We also introduce the rule-based concept of molecular anchors. This assures that any species that has a molecule anchored to a predefined compartment will remain in this compartment. Importantly, in addition to formulation of compartmental models, this now permits VCell users to seamlessly connect reaction networks derived from rules to explicit geometries to automatically generate a system of reaction-diffusion equations. These may then be simulated using either the VCell partial differential equations deterministic solvers or the Smoldyn stochastic simulator.

Rule-based modeling with Virtual Cell.

UNLABELLED: Rule-based modeling is invaluable when the number of possible species and reactions in a model become too large to allow convenient manual specification. The popular rule-based software tools BioNetGen and NFSim provide powerful modeling and simulation capabilities at the cost of learning a complex scripting language which is used to specify these models. Here, we introduce a modeling tool that combines new graphical rule-based model specification with existing simulation engines in a seamless way within the familiar Virtual Cell (VCell) modeling environment. A mathematical model can be built integrating explicit reaction networks with reaction rules. In addition to offering a large choice of ODE and stochastic solvers, a model can be simulated using a network free approach through the NFSim simulation engine. AVAILABILITY AND IMPLEMENTATION: Available as VCell (versions 6.0 and later) at the Virtual Cell web site (http://vcell.org/). The application installs and runs on all major platforms and does not require registration for use on the user's computer. Tutorials are available at the Virtual Cell website and Help is provided within the software. Source code is available at Sourceforge. CONTACT: vcell_support@uchc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A reciprocal interdependence between Nck and PI(4,5)P(2) promotes localized N-WASp-mediated actin polymerization in living cells.

Modulation of actin dynamics through the N-WASp/Arp2/3 pathway is important in cell locomotion, membrane trafficking, and pathogen infection. Here, we demonstrate that Nck is essential for actin remodeling stimulated by phosphatidylinositol 4,5 bisphosphate (PI(4,5)P(2)) and, conversely, that PI(4,5)P(2) is necessary for localized actin polymerization induced by Nck in vivo. Nck knockdown or knockout suppressed actin comets induced by phosphatidylinositol 5-kinase (PIP5K), and PIP5K stimulated tyrosine phosphorylation of an Nck SH2 domain binding partner, suggesting that Nck couples phosphotyrosine- and phosphoinositide-dependent signals. We show that PI(4,5)P(2) and PIP5K are both enriched at actin comets induced by Nck aggregates and that formation of actin comets was strongly inhibited by coclustering with an inositol 5-phosphatase domain to decrease local PI(4,5)P(2) levels. The extent of Nck-induced actin polymerization was also modulated by PI(4,5)P(2)-sensitive N-WASp mutants. This study uncovers a strong reciprocal interdependence between Nck and PI(4,5)P(2) in promoting localized N-WASp-mediated actin polymerization in cells.

The modified Dunn procedure for slipped capital femoral epiphysis does not reduce the length of the femoral neck.

OBJECTIVE: The treatment of slipped capital femoral epiphysis (SCFE) is evolving, with the development of new surgical techniques. |We wanted to study if modified Dunn procedure restores the normal alignment of the proximal femur and the risk of avascular necrosis is increased. METHODS: This is a single centre, retrospective study, comparing the outcomes of in situ pinning and modified Dunn procedure. Between 2001 and 2014, 7 children (7 hips) underwent the modified Dunn procedure and 10 children (10 hips) pinning in situ for stable and unstable SCFE. Mean age of the patients was 12.7 years with a median follow-up of 18 months. RESULTS: The radiological parameters improved in the modified Dunn procedure group, while the length of the femoral neck didn't change significantly (p=0.09). Postoperative clinical outcomes were slightly better in the modified Dunn procedure group (6 hips out of 7 had good and excellent results) compared to the pinning in situ group (8 good and excellent results out of 10 hips) (p=0.04). No avascular necrosis was found and there were no cases of chondrolysis. CONCLUSION: Radiographic parameters of the proximal femur assessed in our study improved in all hips that underwent modified Dunn procedure, without the creation of secondary deformities.

Pathway Commons at virtual cell: use of pathway data for mathematical modeling.

UNLABELLED: Pathway Commons is a resource permitting simultaneous queries of multiple pathway databases. However, there is no standard mechanism for using these data (stored in BioPAX format) to annotate and build quantitative mathematical models. Therefore, we developed a new module within the virtual cell modeling and simulation software. It provides pathway data retrieval and visualization and enables automatic creation of executable network models directly from qualitative connections between pathway nodes. AVAILABILITY AND IMPLEMENTATION: Available at Virtual Cell (http://vcell.org/). Application runs on all major platforms and does not require registration for use on the user's computer. Tutorials and video are available at user guide page.

The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency.

Enterohaemorrhagic Escherichia coli attaches to the intestine through actin pedestals that are formed when the bacterium injects its protein EspF(U) (also known as TccP) into host cells. EspF(U) potently activates the host WASP (Wiskott-Aldrich syndrome protein) family of actin-nucleating factors, which are normally activated by the GTPase CDC42, among other signalling molecules. Apart from its amino-terminal type III secretion signal, EspF(U) consists of five-and-a-half 47-amino-acid repeats. Here we show that a 17-residue motif within this EspF(U) repeat is sufficient for interaction with N-WASP (also known as WASL). Unlike most pathogen proteins that interface with the cytoskeletal machinery, this motif does not mimic natural upstream activators: instead of mimicking an activated state of CDC42, EspF(U) mimics an autoinhibitory element found within N-WASP. Thus, EspF(U) activates N-WASP by competitively disrupting the autoinhibited state. By mimicking an internal regulatory element and not the natural activator, EspF(U) selectively activates only a precise subset of CDC42-activated processes. Although one repeat is able to stimulate actin polymerization, we show that multiple-repeat fragments have notably increased potency. The activities of these EspF(U) fragments correlate with their ability to coordinate activation of at least two N-WASP proteins. Thus, this pathogen has used a simple autoinhibitory fragment as a component to build a highly effective actin polymerization machine.

Porous calcium alginate-gelatin interpenetrated matrix and its biomineralization potential.

Artificial bone composites exhibit distinctive features by comparison to natural tissues, due to a lack of self-organization and intimate interaction apatite-matrix. This explains the need of "bio-inspired materials", in which hydroxyapatite grows in contact with self-assembling natural polymers. The present work investigates the function of a rational design in the hydroxyapatite-forming potential of a common biopolymer. Gelatin modified through intrinsic interactions with calcium alginate led through freeze-drying to porous hydrogels, whose architecture, constitutive features and chemistry were investigated with respect to their role on biomineralization. The apatite-forming ability was enhanced by the porosity of the materials, while the presence of alginate-reinforced Gel elastic chains, definitely favored this phenomenon. Depending on the concentration, polysaccharide chains act as "ionic pumps" enhancing the biomineralization. The mineralization-promoting effect of the peptide-polysaccharide network strictly depends on the hydrogels structural, compositional and morphological features derived from the interaction between the above mentioned two components.

Sonoelastographic Findings in Clubfeet.

PURPOSE: One of the main features of congenital idiopathic clubfoot is the increased stiffness of soft tissues. With the growing popularity and availability of sonoelastography as a method to assess the stiffness of different tissues, we considered applying it to congenital clubfeet in order to to determine whether sonoelastography can be a useful imaging method for the evaluation of clubfeet, to assess whether there are any differences in stiffness of specific tendons between clubfeet and normal contralateral feet and to observe which treatment methods have an impact on the aspect of these structures on the elastograms. PATIENTS AND METHODS: A case-control study was performed involving 10 adolescent patients with unilateral idiopathic congenital clubfeet who were treated either with the Ponseti method or surgically with posteromedial release (PMR) during early infancy. Using compression sonoelastography, we obtained semi-quantitative data expressed as fat to tendon ratios in treated clubfeet and normal contralateral feet. The tendons of the following muscles were examined: tibialis anterior, tibialis posterior, flexor hallucis longus, peroneus longus and Achilles tendon at three levels (calcaneal insertion, lengthened zone and musculotendinous junction). RESULTS: The only statistically significant difference in the strain ratio (p = 0.023) between clubfeet and normal feet was at the level of the calcaneal insertion of the Achilles tendon, which was stiffer in clubfeet. Although other differences were not statistically significant, they may reflect some of the pathological modifications of clubfeet. CONCLUSION: Overall, sonoelastography may be a useful examination tool in the quantitative and qualitative assessment of soft tissue stiffness in clubfeet, but further research is necessary.

Quantum molecular modeling of glycyl-adenylate.

Glycyl-adenylate is the simplest model for understanding the central role played by aminoacyl-adenylates in the protein synthesis, and may be also in the prebiotic evolution. Optimized conformation of glycyl-adenylate (GlyAMP), in vacuum, was determined using ab initio RHF/6-31Gdp computations. GlyAMP in vacuum (form corresponding to neutral pH conditions) possesses a specific conformation of the glycyl-phosphate stem with a double seven membered ring that results from the electrostatic interaction between the anionic phosphate and the cationic ammonium. This structure is explained on the basis of the theoretical infrared vibrational spectrum and discussed with regard to those of glycyl-adenylate (GAP1550 and GAP2550 forms) in the active pockets of glycyl-tRNA synthetase. The electrostatic properties of these different conformations are presented, and the influence of the charged residues (anionic GLU188, GLU239, GLU359, and cationic ARG220) and Mg++, in interaction with GAP1550 are discussed, taking into account the computation of the electronic chemical potential, the electron affinity and the electrophilic index.

Ultrasonography of borderline and asymmetric infant hips - a challenge in the management of developmental dysplasia of the hip.

BACKGROUND AND AIM: Developmental dysplasia of the hip (DDH) is a potentially disabling disease. There are many diagnostic approaches, Graf method ultrasonography being the most popular imaging method. Although considered as a healthy condition, the existence of hips at the 60 degree limit or the asymmetries higher than 4 degrees between left and right side may be a source of unfavorable evolution and consequently of late diagnosed dysplasia cases. METHODS: The retrospective study was conducted in the Radiology Department of the Emergency Clinical County Hospital Cluj-Napoca, by retrospective analysis of the database containing 3013 records of the subjects presented for DDH assessment between January 2008 and December 2014. The study focuses on investigating two possible sources of missed cases by clinical-ultrasound management of DDH: borderline and asymmetric hips. Two conditions were studied in patients considered healthy according to Graf method: borderline hips (those with α angle value of 60° and 61°) and asymmetric hips (left to right difference between the α angle values exceeds 4°). Three study groups were formed: healthy subjects, asymmetric/borderline subjects and patients with immature or mild dysplasia. The incidence of risk factors, clinical suspicion and the success of therapy were evaluated. RESULTS: There were no significant differences between the three groups regarding the role of the risk factors in DDH pathogenesis. Data reveal a high suspicion rate after the clinical examination, in groups II and III, compared to the healthy population. This means that from this point of view, Group II might be considered having at least a dysplastic prognosis. An increased correlation in the therapeutic results was observed between Group II patients and those from mild delayed maturation subgroups from Group III (IIa-, IIa+). CONCLUSIONS: Asymmetric and borderline hips should be approached similarly to immature hips, clinical suspicion and the therapeutic outcome being similar.

Comparative results of the conservative treatment in clubfoot by two different protocols.

The current study aims at presenting the results of the two methods of conservative treatment in clubfoot: the Romanian traditional method and the Ponseti method. The study population included 103 children (148 clubfeet) treated in our department between 1998 and 2005. Between 1998 and 2003, the conservative treatment protocol was based upon the Romanian method. The Ponseti method has been used since 2004. The main criterion for the assessment of the efficiency of the two conservative methods in clubfoot is the number of feet requiring surgical treatment - posteromedial release at 18 months. This criterion is clearly in favor of the Ponseti method: four feet (5%) needed posteromedial release in Ponseti group patients versus 13 feet (18%) in Romanian group patients (P=0.0193). The Ponseti method is safe, efficient in the conservative treatment of clubfoot and decreases the number of surgical interventions needed for the correction of the deformation compared with our traditional method.

Influence of Food Intake on 2-D Shear Wave Elastography Assessment of Liver Stiffness in Healthy Subjects.

Transient elastography and Acoustic Radiation Force Impulse imaging are useful non-invasive methods for liver stiffness estimation, although both are influenced by food intake. The aim of the work described here was to identify liver stiffness variation after a standardized meal using 2-D shear wave elastography. Liver stiffness was estimated in 31 apparently healthy subjects, under fasting conditions and after a standardized meal (20, 40, 60, 80, 100 and 120 min after food intake). In most of the cases, liver stiffness values increased between 20 and 40 min after the meal (p < 0.05) and then significantly decreased between 60 and 80 min (p < 0.05). At 120 min after food intake, liver stiffness values were significantly lower compared with liver stiffness values under fasting conditions (p < 0.05). Gender, but not body mass index, had an important role in liver stiffness variation after food intake (p < 0.01). In conclusion, to avoid the influence of food intake on liver stiffness estimation, 2-D shear wave elastography should be performed only under fasting conditions.

Establishing proper scanning conditions in atomic force microscopy on polyimide and polyurethane samples and their effect on 3D surface texture parameters.

Several atomic force microscopy (AFM) tests have been carried out on both smooth (polyimide) and rough (polyurethane) surfaces so that to obtain the best results; subsequently, the optimization of experiments performed is presented. A special emphasis has been put on the effect of tip geometry, image pre-processing procedure, scanning area, resolution, pixel size, and cantilever oscillation amplitude in tapping mode, as well as on the quality of the topographical images and 3D surface texture parameters. After viewing the scanning tip and finding out its sharpness, degradation, and contamination, a simultaneous calibration in X, Y, and Z directions, lateral calibration of SPM scanners and detection of lateral non-linearity, hysteresis, creep, and cross-coupling effects has been made. We have established the following experimental parameters: proper scanning resolution (512 × 512 pixels), adequate pixel size (between 2.9 and 19.5 nm) and suitable intermittent contact region (moderate tapping) for which the AFM images present good contrast and resolution. Using these parameters, the values of 3D texture parameters remain constant. These kinds of measurements are extremely important to conduct further AFM experiments on polyimide and polyurethane surfaces under optimal conditions, thus avoiding unwanted artifacts on the morphological images or unrealistic values for the 3D surface texture parameters that might occur.

Doppler ultrasound and strain elastography in the assessment of cutaneous melanoma: preliminary results.

AIM: To study the usefulness of color or power Doppler ultrasound (US) in the pre-surgical evaluation of skin melanoma, and to correlate the Doppler characteristics with the appearance on high frequency ultrasound strain elastography (SE) in the preoperative evaluation of cutaneous melanoma. MATERIALS AND METHOD: The study included 42 cutaneous melanoma lesions in 39 adult subjects examined between September 2011 and January 2015. Doppler US features (the presence and aspect of vascularization, and the number of vascular pedicles) and elasticity by strain elastography were evaluated together with the pathological results. RESULTS: The melanoma lesions presented hyper-vascularization, with multiple vascular pedicles and stiff appearance. Significant correlations between the thickness of the tumor, measured histopathologically by the Breslow index, and the degree of vascularization (p=0.0167), and number of vascular pedicles (p=0.0065) were identified. Strong correlations between the SE appearance and vascularization on one hand, and SE and the number of vascular pedicles were also identified (p<0.001). CONCLUSION: Our study demonstrates that Doppler US and SE offer useful information for THE preoperative evaluation of cutaneous melanoma and may contribute to better defining the long term prognosis.

Ultrasonography of desmoplatic fibroma of the mandible; a case report.

Desmoplastic fibroma (DF) is a very rare bone tumor, classified as a benign lesion. It might be locally a very aggressive tumor with a high rate of recurrence after surgical resection. We present a case of a 3-year and 6 month-old patient, with mandibular desmoplastic fibroma. The clinical, imaging, histological findings and surgical treatment are discussed and, also, a brief review of the literature of DF is presented. The purpose of this case report is to emphasize the particularity of the case, ultrasound findings and the main differential diagnostic of this rare bone tumor.

A new sign in the standard hip ultrasound image of the Graf method.

AIM: The aim of the study was to assess the usefulness of obtaining a 900 angle between the plane of the osteochondral plate and the surface of the transducer during standard hip ultrasonography according to Graf method. MATERIAL AND METHODS: In this retrospective study 1078 patients (2156 hips) were included examined between 2008 and 2014 for developmental dysplasia of the hip (DDH) ultrasound screening. The patients were divided in two groups. Group I consisted of 402 patients examined between January 2008 and December 2011 using the standard Graf method. Group II consisted of 676 patients examined from January 2012 to December 2014 using the Graf method with an additional criterion: 900 angle between the plane of the osteochondral plate and the surface of the transducer. RESULTS: We found more dysplastic patients in group I comparing to group II: 55 (13.7%) and 38 (5.6%) respectively. The difference in the incidence of patients diagnosed with DDH was highly significant (p<0.001). The mean alpha angle value in group I was 65.310, respectively 67.520 for group II (p<0.001). CONCLUSION: The new osteochondral plate sign has the potential to reduce the overdiagnosis of DDH and provide a better tailored approach to borderline hips.

Ultrasound and CT imaging features in a patient with salivary duct carcinoma of the parotid gland: a case report with literature review.

The aim of this paper was to present the ultrasound (US) and computed tomography (CT) appearance of a patient with salivary duct carcinoma of the parotid gland. US showed a voluminous mass of the parotid gland, with multiple calcifications. Furthermore, it revealed regional multiple lymph nodes with malignant characters. Sonoelastography of the lesion and lymph nodes detected increased rigidity. Contrast enhanced CT scan of the neck completed the data description regarding the mass expansion and invasion of surrounding tissues. US and CT imaging features played a key role in establishing the malignant character of the mass and lymph nodes.

Comparative study of three sonoelastographic scores for differentiation between benign and malignant cervical lymph nodes.

PURPOSE: The aim of the study was to explore the diagnostic value of three different sonoelastographic scoring systems (labeled S1-S3) for the differentiation between benign and malignant cervical lymph nodes. MATERIALS AND METHOD: The authors propose a six pattern scoring system of the elastographic images with pattern 1 - representing purely soft nodes, pattern 2 - predominantly soft nodes, pattern 3 - predominantly soft nodes with focal had area, pattern 4 - predominantly hard node, pattern 5 - entirely hard node and pattern 6 - node with necrosis. The sonoelastographic images of 50 benign and 70 malignant lymph nodes were assessed. The area under the ROC curve (AUROC) for the differentiation between benign vs. malignant and benign vs. metastatic nodes were analyzed for the three scoring systems. RESULTS: When all the malignant lymph nodes were considered, the S1 score showed an AUROC=0.873 (95%CI [0.805-0.918], where CI=confidence interval; p<0.001), sensibility (Se)=58.57%, and specificity (Sp)=96%. For S2 score the AUROC was 0.890 (95%CI [0.824-0.933], p<0.001), Se=92.86%, and Sp=72%. For S3 score, the AUROC was 0.852 (95%CI [0.778-0.902], p<0.001), Se=64.29%, and Sp=94%). When lymphomatous nodes were excluded, for S1 the AUROC was 0.884 (95%CI [0.809-0.932], p<0.001), Se=64%, and Sp=96%. For S2 the AUROC was 0.894 (95%CI [0.818-0.939], p<0.001), Se=92%, and Sp=72%. For S3, the AUROC was 0.856 (95%CI [0.771-0.911], p<0.001), Se=66%, and Sp=94%. In the S3 scoring system, setting the benign vs. malignant cut off at pattern 3 increases the sensibility (41-65%) with minimal loss of specificity (96-94%). From the gray-scale and Doppler criteria, changes of the nodular margins and the presence of the vessels in the cortical part of the lymph node showed both very high sensibility and specificity, the others criteria taken into account had either very good sensibility with low specificity or high specificity and low sensibility. CONCLUSIONS: Our study suggests that there are no significant differences between the three scoring systems in terms of overall diagnostic value.

Misleading appearance in cervical lymph node US diagnosis - a report on sarcoidosis, Warthin tumor and squamous cell carcinoma metastases.

Ultrasonography, with its various techniques (grey-scale, color Doppler, sonoelastography) offers many signs for the differentiation between benign and malignant neck lymph nodes. In spite of recent progress, the US appearance may be misleading. We present three cases in which the ultrasonographic appearance of the lymph nodes was misleading as compared to the final diagnosis established by histopathology.