In-silico Models of Stem Cell and Developmental Systems

Understanding how developmental systems evolve over time is a key question in stem cell and developmental biology research. However, due to hurdles of existing experimental techniques, our understanding of these systems as a whole remains partial and coarse. In recent years, we have been constructing in-silico models that synthesize experimental knowledge using software engineering tools. Our approach integrates known isolated mechanisms with simplified assumptions where the knowledge is limited. This has proven to be a powerful, yet underutilized, tool to analyze the developmental process. The models provide a means to study development in-silico by altering the model’s specifications, and thereby predict unforeseen phenomena to guide future experimental trials. To date, three organs from diverse evolutionary organisms have been modeled: the mouse pancreas, the C. elegans gonad, and partial rodent brain development. Analysis and execution of the models recapitulated the development of the organs, anticipated known experimental results and gave rise to novel testable predictions. Some of these results had already been validated experimentally. In this paper, I review our efforts in realistic in-silico modeling of stem cell research and developmental biology and discuss achievements and challenges. I envision that in the future, in-silico models as presented in this paper would become a common and useful technique for research in developmental biology and related research fields, particularly regenerative medicine, tissue engineering and cancer therapeutics

DESIGN AND OPTIMIZATION OF DOXORUBICIN HCL PRONIOSOMES BY-DESIGN OF EXPERIMENT

Objective: The present research work was designed to formulate and optimize doxorubicin HCl proniosomes by design of experiment (DoE). Methods: A 4-factor, 3-level Box-Behnken design was used to explain multiple linear regression analysis and contour 3D plot responses. The independent variables selected were tween 20, cholesterol, hydration volume and sonication time; dependent variables percentage entrapment efficiency (PEE), mean vesicle size (MVS). Based on the Box-Behnken design 29 trial runs were studied and optimized for PEE and MVS. Further "Model F-Value" was calculated to confirm the omission of insignificant terms from the full-model equation to derive a multiple linear regression analysis to predict the PEE and MVS of niosomes derived from proniosomes. 3D plots were constructed to show the influence of independent variables on dependent variables. Results: PEE of doxorubicin HCl proniosomes was found to be in the range of 40.21-87.5%. The polynomial equation for PEE exhibited a good correlation coefficient (0.5524) and the "Model F-Value" of 7.41 implies the model is significant. P-values less than 0.0500 indicate model terms are significant. The MVS of doxorubicin HCl proniosomes was found to be in the range of 325.2 nm to 420.25 nm. The mathematical model generated for MVS (R2) was found to be significant with model F-value of 54.22. There is only a 0.01% chance that a "Model F-Value" this large could occur due to noise (P<0.0500) and R2 value of 0.9004. Conclusion: The DoE of Box-Behnken design demonstrated the role of the derived equation, 3D plot in predicting the values of dependent variables for the preparation and optimization of doxorubicin HCl proniosomes. The results suggest that doxorubicin HCl proniosomes can act as a promising carrier

PREPARATION, EVALUATION AND STABILITY OF LAMIVUDINE LOADED ALGINATE-TAMARIND MUCILAGE MICROSPHERES

Objective: The objective of the present study was to investigate the possibility of obtaining a controlled, relatively constant effective level of lamivudine microspheres. Methods: Lamivudine loaded sodium alginate (SA) and tamarind mucilage(TM) mucoadhesive microspheres were prepared by ionic gelation technique with three different proportions of SA and TM with different concentrations of CaCl2. The prepared microspheres were evaluated for drug loading, particle size distribution, surface morphology, FTIR, in vitro wash off, in vitro release and stability studies. Results: The microspheres were found to be free flowing having diameter ranging from 769.22 to 978.56 µm, drug encapsulation efficiency (DEE) was found to be 65.28 to 92.33%. Percent drug release after 12 h were ranging from 85±1.51 to 97±1.44. In vitro release profile of all formulations shows slow controlled release up to 12 h. In vitro wash off studies shown fairly good mucoadhesivity with 20% microspheres adhered after 6h. Stability studies showed that no significant change in particle size and maximum DEE in comparison to the formulation stored at room temperature. Results: The lamivudine loaded SA-TM mucoadhesive microspheres can be conveniently prepared which showed better result and it may be used full for controlling the drug release and improve the bioavailability

DRUMSTICK MUCILAGE MICROSPHERES FOR CONTROLLED RELEASE OF LAMIVUDINE: DESIGN, OPTIMIZATION AND IN VITRO EVALUATION

Objective: The objective of this study was to design and evaluate controlled release mucoadhesive microspheres of lamivudine using mucoadhesive polymers and mucilage. Methods: Mucoadhesive microspheres of lamivudine were formulated by ionic gelation method. The response surface methodology was adapted for optimization of formulation using central composite design (CCD) for two factors at three levels each was employed to study the effect of independent variables, Sodium alginate-drumstick mucilage (X1) and calcium chloride (CaCl2) concentration (X2) on dependent variables, namely drug encapsulation efficiency (DEE) and particle size (PS). Optimized drumstick mucilage mucoadhesive microspheres of lamivudine were obtained by using numerical optimization of desirability approach. The observed microspheres were coincided well with the predicted values by the experimental design. Results: The microspheres formed were spherical in shape, and Particle size (PS) ranged between 681.63-941.57μm. Drug encapsulation efficiency (DEE) was ranged between 69.63-94.56 %. The drug release for an optimized formulation was 96.58 %. The mechanism of drug release from microspheres followed Korsemeyer’s-Peppas and exponential ‘n’ value was greater than 0.45, indicating the drug release was non-fickian i.e., swelling followed by erosion mechanism. Conclusion: This work suggests that mucoadhesive microspheres, an effective drug delivery system for lamivudine, can be prepared using drumstick mucilage in improving the bioavailability of the drug

Ultrafine aluminium: Quench collection of agglomerates

Combustion of aluminized solid propellants exhibits phenomena associated with accumulation, agglomeration, ignition, and combustion of ultra-fine aluminium particles. In this study, agglomeration phenomenon of ultra-fine aluminium in solid propellant combustion is investigated using quench collection experimental technique over the pressure ranges from 2MPa to 8MPa. The ultra-fine aluminium powder synthesized by Radio Frequency Induction Plasma technique having harmonic mean size of 438nm is used for agglomeration study. The quenching distance is varied from 5mm to 71mm from the propellant burning surface to estimate the effect on agglomerate size. The morphology and chemical compositions of the collected products were then studied by using scanning electron microscopy coupled with energy dispersive (SEM-EDS) method. Under the explored experimental conditions, the results confirm that ultra-fine aluminium propellant show aggregation/agglomeration with the size ranging from 11 – 21 μm in combustion products. Smaller diameter condensed phase products will likely decrease two-phase flow loss and reduce slag accumulation

A STUDY ON DENITRIFICATION IN A FLUIDIZED BED BIOREACTOR

The work involves experimental investigation on biological denitrification in a fluidized bed reactor under anaerobic conditions using the microorganism Pseudomonas Stutzeri and plastic beads as fluidizing medium. The influence of various parameters like pH, initial nitrate concentration, Carbon/Nitrogen ratio, hydraulic retention time on nitrate-nitrogen removal rate from synthetic effluent prepared at the laboratory were studied in detail. The optimum operating conditions of pH, initial nitrate concentration, Carbon/Nitrogen ratio and flow rate obtained are 7.0–7.5, 15 mg/l, 1.5–2.0 and 4.41 x 10-5 m3/s respectively

Application of artificial neural networks for the prediction of aluminium agglomeration processes

Aluminium is universal and vital constituent in composite propellants and typically used to improve performance. Aluminum agglomeration takes place on the burning surface of aluminized propellants, which leads to reduced combustion efficiency and 2P flow losses. To understand the processes and behaviour of aluminum agglomeration, particles size distribution of composite propellants were studied using a quench particle collection technique, at 2 to 8 MPa and varying quench distances from 5mm to 71mm. To predict the agglomerate diameter of metallized/ultra-fine aluminium of composite propellants, a new artificial neural network (ANN) model was derived. Five Layered Feed Forward Back Propagation Neural Network was developed with sigmoid as a transfer function by varying feed variables in input layer such as Quench distance (QD) and pressure (P). The ANN design was trained victimization stopping criterion as one thousand iterations. Five ANN models dealing with the combustion of AP/Al/HTPB and one ANN model of AP/UFAl/HTPB composite propellants were presented. The validated ANN models will be able to predict unexplored regimes wherein experimental data are not available. From the present work it was ascertained that, for agglomeration produced by quench collection technique, the ANN is one of a substitute method to predict the agglomerate diameter and results can be evaluated rather than experimented, with reduced time and cost. The resulting agglomerates sizes from ANN model, matches with the experimental results. The percentage error is less than 3.0% of the label propellants used in this work

How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex

<p>Abstract</p> <p>Background</p> <p>Neuronal migration, the process by which neurons migrate from their place of origin to their final position in the brain, is a central process for normal brain development and function. Advances in experimental techniques have revealed much about many of the molecular components involved in this process. Notwithstanding these advances, how the molecular machinery works together to govern the migration process has yet to be fully understood. Here we present a computational model of neuronal migration, in which four key molecular entities, Lis1, DCX, Reelin and GABA, form a molecular program that mediates the migration process.</p> <p>Results</p> <p>The model simulated the dynamic migration process, consistent with in-vivo observations of morphological, cellular and population-level phenomena. Specifically, the model reproduced migration phases, cellular dynamics and population distributions that concur with experimental observations in normal neuronal development. We tested the model under reduced activity of Lis1 and DCX and found an aberrant development similar to observations in Lis1 and DCX silencing expression experiments. Analysis of the model gave rise to unforeseen insights that could guide future experimental study. Specifically: (1) the model revealed the possibility that under conditions of Lis1 reduced expression, neurons experience an oscillatory neuron-glial association prior to the multipolar stage; and (2) we hypothesized that observed morphology variations in rats and mice may be explained by a single difference in the way that Lis1 and DCX stimulate bipolar motility. From this we make the following predictions: (1) under reduced Lis1 and enhanced DCX expression, we predict a reduced bipolar migration in rats, and (2) under enhanced DCX expression in mice we predict a normal or a higher bipolar migration.</p> <p>Conclusions</p> <p>We present here a system-wide computational model of neuronal migration that integrates theory and data within a precise, testable framework. Our model accounts for a range of observable behaviors and affords a computational framework to study aspects of neuronal migration as a complex process that is driven by a relatively simple molecular program. Analysis of the model generated new hypotheses and yet unobserved phenomena that may guide future experimental studies. This paper thus reports a first step toward a comprehensive in-silico model of neuronal migration.</p

Testing quantum correlations in a confined atomic cloud by scattering fast atoms

We suggest measuring one-particle density matrix of a trapped ultracold atomic cloud by scattering fast atoms in a pure momentum state off the cloud. The lowest-order probability of the inelastic process, resulting in a pair of outcoming fast atoms for each incoming one, turns out to be given by a Fourier transform of the density matrix. Accordingly, important information about quantum correlations can be deduced directly from the differential scattering cross-section. A possible design of the atomic detector is also discussed.Comment: 5 RevTex pages, no figures, submitted to PR

Association of Coagulation Activation with Clinical Complications in Sickle Cell Disease

Background: The contribution of hypercoagulability to the pathophysiology of sickle cell disease (SCD) remains poorly defined. We sought to evaluate the association of markers of coagulation and platelet activation with specific clinical complications and laboratory variables in patients with SCD. Design and Methods: Plasma markers of coagulation activation (D-dimer and TAT), platelet activation (soluble CD40 ligand), microparticle-associated tissue factor (MPTF) procoagulant activity and other laboratory variables were obtained in a cohort of patients with SCD. Tricuspid regurgitant jet velocity was determined by Doppler echocardiography and the presence/history of clinical complications was ascertained at the time of evaluation, combined with a detailed review of the medical records. Results: No significant differences in the levels of D-dimer, TAT, soluble CD40 ligand, and MPTF procoagulant activity were observed between patients in the SS/SD/Sb 0 thalassemia and SC/Sb + thalassemia groups. Both TAT and D-dimer were significantly correlated with measures of hemolysis (lactate dehydrogenase, indirect bilirubin and hemoglobin) and soluble vascular cell adhesion molecule-1. In patients in the SS/SD/Sb 0 thalassemia group, D-dimer was associated with a history of stroke (p = 0.049), TAT was associated with a history of retinopathy (p = 0.0176), and CD40 ligand was associated with the frequency of pain episodes (p = 0.039). In multivariate analyses, D-dimer was associated with reticulocyte count, lactat