text:
- Methodology article
- Open Access
Simultaneous model discrimination and parameter estimation in dynamic models of cellular systems
© Rodriguez-Fernandez et al.; licensee BioMed Central Ltd. 2013
- Received: 8 May 2012
- Accepted: 8 August 2013
- Published: 12 August 2013
Model development is a key task in systems biology, which typically starts from an initial model candidate and, involving an iterative cycle of hypotheses-driven model modifications, leads to new experimentation and subsequent model identification steps. The final product of this cycle is a satisfactory refined model of the biological phenomena under study. During such iterative model development, researchers frequently propose a set of model candidates from which the best alternative must be selected. Here we consider this problem of model selection and formulate it as a simultaneous model selection and parameter identification problem. More precisely, we consider a general mixed-integer nonlinear programming (MINLP) formulation for model selection and identification, with emphasis on dynamic models consisting of sets of either ODEs (ordinary differential equations) or DAEs (differential algebraic equations).
We solved the MINLP formulation for model selection and identification using an algorithm based on Scatter Search (SS). We illustrate the capabilities and efficiency of the proposed strategy with a case study considering the KdpD/KdpE system regulating potassium homeostasis in Escherichia coli. The proposed approach resulted in a final model that presents a better fit to the in silico generated experimental data.
The presented MINLP-based optimization approach for nested-model selection and identification is a powerful methodology for model development in systems biology. This strategy can be used to perform model selection and parameter estimation in one single step, thus greatly reducing the number of experiments and computations of traditional modeling approaches.
- Dynamic modelling
- Parameter estimation
- Model discrimination
- Global optimization
Model development is a key task in systems biology, and involves different steps, such as model calibration, experimental design and model refinement which usually take place in an iterative way (see reviews in [1–5]). The process of building a model of a biological system typically starts by generating an initial model candidate, or by taking one from the pre-existing knowledge, and then involves an iterative cycle of hypotheses-driven model modifications, new experimentation and subsequent model identification steps, finally leading to a satisfactory refined model [6, 7]. Thus, model selection, experimentation and model refinement can be considered the basic elements of systems biology [8].
A number of researches have proposed different iterative schemes for model development involving the steps of parameter estimation, identifiability analysis, and optimal experimental design [9–12]. The related topic of optimal experimental design for parameter estimation [3, 13] and for model discrimination [14–16] is receiving increased attention in recent years. Lillacci and Khammash [17] introduced a new method for parameter estimation based on Kalman filtering that can also be used to discriminate among alternate models of the same biological process.
Verheijen [18] presented an overview of model selection practices, highlighting the main criteria for choosing out of a large set of models: level of rigor, accuracy with respect to data, adequacy of the model, and its flexibility and computational complexity. He also identifies developments in optimization-based approaches [19, 20] as very promising, but recognizing its limitations due to numerical and algorithmic challenges. Although research along this line has continued [21, 22], it still remains as a challenging numerical problem.
Here, we present a method to simultaneously select a model and calibrate it in a single step. This contribution is based on the following four key ideas: (i) frequently, iterative model development cycles can be considered in a more compact way if sets of hypotheses can be grouped together and formulated as a parameterized set of models, from which the best alternative must be selected; (ii) we consider the problem of model selection formulating it as a simultaneous model selection and parameter identification problem; (iii) further, in order to make the selection decision in a systematic way, we formulate it as an optimization problem [23] acting on the parameterized set of models; (iv) the optimization problem, which belongs to the class of mixed-integer nonlinear programming (MINLP) problems, is solved by recently developed algorithms based on metaheuristics.
The paper is organized as follows: First, we describe the framework used for model selection and identification, based on the nested models paradigm. Then we state the corresponding optimization problem using a formulation based on mixed-integer non-linear programming subject to differential and algebraic constraints. In the following sections, we describe the application of this methodology to a case study considering a dynamic model of the KdpD/KdpE system of Escherichia coli. Finally, we provide a discussion of the results and summarize the main conclusions of the study.
To the best of our knowledge, this is the first time that an MINLP framework for simultaneous model selection and identification is presented. The key issues for the successful design of this combined approach are: (i) selection of the integer and binary parameters that accurately describe all the possible nested models; (ii) reliable and accurate parameter estimation; (iii) use of efficient algorithms with reduced computational cost; (iv) assessment of model identifiability.
Nested-models: selection and identification
where p: set of parameters to be estimated NE: number of experiments N V i : number of measured variables in experiment i N M ij : number of measurements of the variable j in experiment i: variance of the measurement k of the variable j in experiment i: measurement k of the variable j in experiment i y ijk : model predicted value k of the variable j in experiment i
Many functions have been suggested to compare two or more models. Despite the fact that several authors have questioned whether AIC is biased towards complex model structures [26], this function has been widely used as a metric to select the most adequate among hierarchical or nested models, since it encompasses model performance and model complexity [27]. It allows establishing a ranking of the models where the most adequate is the one with the smallest value of the criterion [25]. However, most of the available techniques for model selection based on the AIC, require the previous fitting of all the candidate models. Therefore, when the number of possible models is large or the simulation of the models is computationally expensive, these methodologies can become practically impossible [27].
In order to reduce the computational burden, in this work we used the AIC as cost function for finding the optimal set of parameters formed by a subset of binary parameters defining the model structure (e.g. presence or absence of a certain feedback loop) and another subset of integer and real parameters characterizing the model dynamics.
Formulation of the MINLP
subject to:
System dynamics in the form of DAEs, with state variables y(4)(5)
Additional requirements in the form of equality and/or inequality constraints(6)(7)
Upper and lower bounds (superscripts U and L respectively) on decision variables(8)(9)
This set of constraints defines the feasible space S, while the feasible objective space o is the set J (p, q) | (p, q) ∈ S.
Solution of the MINLP problem
The problem of parameter estimation is a crucial step in the development of models of biological systems [17]. Due to the nonlinear and dynamic nature of these systems and the usually sparse and noisy nature of the experimental data available, the resulting parameter estimation problem is frequently ill-conditioned and multi-modal. Therefore, traditional local methods may fail and there is a need to use more sophisticated techniques as global optimization (GO) to successfully fit the model. In our group, different efforts have been devoted to design metaheuristics for efficient and robust parameter estimation in biological models [28, 29].
In the case of the MINLP problem at hand, the need to use GO methods is increased by the additional non-linearities coming from the binary and integer variables and the augmented size of the problem. ACOmi (Ant Colony Optization for mixed-integer problems) [30] and fSSm [31] are robust extensions of metaheuristics (Ant Colony optimization and Scatter Search, respectively) that enable the handling of mixed-integer variable search domains; therefore, they are ideal for solving the MINLP problem introduced in this work.
ACOmi (Ant Colony Optization for mixed integer problems) is an extension of the ant colony optimization metaheuristic that enables to handle mixed integer variable search domains. In this method a new penalization strategy was introduced in order to extend the ACO framework to face constrained optimization problems. A detailed explanation of the hybrid implementation ACOmi, incorporating the extended ACO framework and a robust oracle penalty method, is given by [30].
fSSm is a new evolutionary method for complex-process optimization. It is partially based on the principles of the scatter search methodology, but making use of innovative strategies to be more effective in the context of complex-process optimization using a small number of tuning parameters. In particular, this method uses a new combination method based on path relinking, which considers a broader area around the population members than previous combination methods. It also uses a population-update method which improves the balance between intensification and diversification, as described in [31]. Although fSSm is mainly designed for continuous problems, a rounding operator has been implemented for handling integer and binary variables.
MISQP is a modified sequential quadratic programming method for solving MINLP problems. MISQP assumes that the model functions are smooth in the sense that an increment of an integer variable by one leads to a small change of function values but it does not require that the mixed-integer program is convex or relaxable (i.e. function values are evaluated only at integer points). Thus, this algorithm is expected to be more efficient than any other method that starts from a solution of the relaxed problem [32].
Moreover, in contrast to other local optimization solvers, the evaluation of the exact gradient is not always required for a proper convergence of SQP methods. The evaluation of the performance of the method used in this study, MISQP, on a test set of 186 academic test examples published in [33] showed that analytical partial derivatives subject to the integer variables do not improve robustness or efficiency, and the number of iterations is enlarged [34]. Diehl et al. [35] presented another SQP algorithm which does not require the evaluation of the exact constraint Jacobian matrix.
Model identifiability, sensitivity and correlation analysis
If the FIM is full rank the parameters are considered identifiable [42]. The parameters of a model are not identifiable when an infinite number of parameter sets fitting the experimental data with the same accuracy exist and the confidence intervals are infinite. Moreover, it is also interesting to study the parameter sensitivity and the correlation among parameters.
Sensitivity analysis
A high value of the sensitivity index means that a change in parameter p θ has an important effect on the model outcome making the parameter p θ identifiable with the data available if all the other parameters are fixed. Unless a parameter is unidentifiable due to total correlation with another parameter, the higher the sensitivity the more accurately the parameter can be identified and, on the other hand, a parameter with a small sensitivity will be very difficult to identify since any change on its value will have almost no influence on the model dynamics. Therefore, values of critical parameters should be thoroughly identified while parameters having a little effect can be simplified or even ignored [44].
The main drawback of local sensitivity indices is that they are computed at the nominal values used for the parameters and the behavior of the response function is described only locally in the parameter space. Moreover, preliminary experiments and parameter estimation tests should be carried out in order to obtain a first guess for the parameter values and an iterative scheme involving both steps is required to study the model sensitivity. In addition, these methods are linear; thus, they are not sufficient for dealing with complex models, especially those in which there are nonlinear interactions between parameters.
In contrast, global sensitivity analysis (GSA) methods evaluate the effect of a parameter while all other parameters are varied simultaneously, accounting for interactions between parameters without depending on the stipulation of a nominal point. In this work, a pseudo-global sensitivity analysis as described in [39] was used. For that, 210 sampling points were generated in the parameter space by means of Sobol' low-discrepancy sequences that guarantee an uniform distribution avoiding clustering and empty areas [45]. Then, Bayesian Derivative based Global Sensitivity Measures [39] were computed using SensSB toolbox [46] and their metrics were used to establish an importance ranking for the parameters.
Correlation analysis
For models with several parameters, high parameter sensitivity, although necessary, does not ensure the identifiability of the model. In addition, the sensitivity functions of the parameters have to be linearly independent so a change in one parameter can not be compensated by changes in the other parameters. When the parameters are identifiable, we can study the degree of linear dependence among the sensitivity functions by means of a correlation analysis based on the Fisher Information Matrix (FIM) as described in [28]. This method requires the inversion of the FIM so it can only be applied when the parameters are identifiable and the FIM full rank. However, correlations among parameters close to +1 or -1 mean that the parameters are difficult to identify and the confidence intervals very large (although not infinite as in the case of nonidentifiable parameters). In that case, the model should be reduced by fixing some of the parameters to their nominal values or by properly grouping some sets.
In order to eliminate the dependence on a nominal point, a pseudo-global identifiability analysis as described in [39, 46] was used. A correlation matrix was computed for each set of parameters used for the sensitivity analysis and a weighted average was obtained based on the maximum likelihood of each of the parameter sets. In this way, the influence of parameters not-likely to fit the data is minimized while the dependence on a nominal point is avoided.
Dynamic model of the KdpD/KdpE system of E scherichia coli
Bacteria constantly monitor their environment and adapt immediately to changing conditions to survive. There are several adaptation mechanisms notably special signal transduction systems. A sensor kinase (KdpD) and a response regulator (KdpE) regulate the expression of the KdpFABC operon encoding the high affinity K+ uptake system of Escherichia coli. In [47], a mathematical model for the KdpD/KdpE two-component system was developed and calibrated with the available in vitro and in vivo experimental data. The model can be separated into two submodels connected in a unidirectional way. The parameters corresponding to the signal transduction part were estimated from in vitro data while the parameters of the gene expression functional unit were identified from mRNA and KdpFABC concentrations determined in vivo using various extracellular stimulus, .
where mRNA represents the concentration of messenger RNA, K d p D0 the total concentration of the sensor kinase, K d p D P the concentration of the phosphorylated KdpD, K d p E0 the total concentration of the response regulator, K d p E P the concentration of the phosphorylated KdpE, KdpFABC the concentration of the protein complex and the concentration of the unbound response regulator.
Results and discussion
Computations were carried out using Matlab™ (Version 7.9.0, R2009b; The Mathworks, MA, USA) running on a dual INTEL®;XEON®;2.13 GHz CPU desktop under Windows 7. All the scripts needed to reproduce the results presented in the following are provided in the Additional file 1.
Identifiability analysis of the original model
Simulation studies showed that the concentration of K d p D P was very low and almost in steady state. Therefore, we removed equation (15) from the model and consequently we fixed the concentration of K d p D P to its initial value and parameters k1 and k-1 were eliminated.
A local identifiability analysis of the original model with the best set of parameters was performed. As already suggested by Kremling et al[47], the full set of parameters is not uniquely identifiable with the available in vivo data; thus, some of the parameters were fixed to literature values or to values obtained from in vitro data.
The importance ranking of the parameters estimated from the in vivo data revealed that parameter k-2 has the lowest sensitivity index (it accounts for the 0.002% of the total model sensitivity) while the two most relevant parameters, k tr and D N A0 represent 75% of the total sensitivity. Hence, k-2 was fixed to its nominal value and special attention was payed to the set of most influential parameters. The parameter μ presented high correlations with other parameters so it was fixed to its experimental value μ = 0.5 l/h. Other pairs of parameters showed also high correlation among them but they could still be identified.
These modifications led to a second formulation of the model (Model II) with 7 DAEs and 17 parameters that fits the experimental data equally well.
New hypotheses for the KdpD/KdpE two component system
Regulation of translation (R1)(22)
Regulation of proteolysis (R2)(23)
Stimulus counteraction (R3)
Note that the dynamics of the mutant strain do not depend on parameters b i n3, n4, n5, k hy , and k hy .
These possible new loops were integrated with the Model II considering a superstructure, which has a total of 25 degrees of freedom: 17 reals, 5 integers and 3 binaries, resulting in 1700 nested models. In a traditional setting, each of this model should be identified (calibrated) from experimental data by solving the corresponding minimization problem, that is, a nonlinear-programming problem subject to differential-algebraic constraints (NLP-DAEs), prior model selection. Since the solution of each problem is quite computationally expensive, this is obviously not tractable. As an alternative, we applied the strategy outlined above and performed a simultaneous selection and identification via MINLP optimization.
MINLP solutions
In order to illustrate the capabilities of the methodology presented in this work, we generated in silico data via simulation using a nominal set for parameters and a certain model structure. Starting from a known structure and known parameter values allows us to asses the performance of the MINLP formulation by checking if it is able to recover the original model.
Nominal value for the parameters and MINLP best solution
Nominal value
MINLP solution
k 2
k 3
k tr
k tl
k t l 2
k t l 3
k z
k d 2
K a
k d
k hy
k transf
k degf
k hy
b i n1:
b i n2:
b i n3:
Checking the multi-modality of the MINLP
Identifiability analysis of the resulting model
The FIM computed for the best set of parameters obtained by the global solver is full rank; therefore, we can assert that the parameters are locally identifiable.
The correlation matrix shows several pairs of parameters highly correlated what explains the difficulties encountered by the local method in finding the global solution. Despite the identifiability difficulties of this problem, which make most of the solvers fail when trying to solve it, the residuals for the solution obtained by fSSm are small indicating a precise parameter estimation, e.g., the estimated values are close to the experimental data.
Methodology strengths and limitations
The goal of this study is not to solve the general problem of model inference but a dense subcase of it, i.e., the discrimination among a subset of nested competing models and simultaneous estimation of the model parameters. In other words, we consider the very frequent situation in systems biology where a first model is available based on previous knowledge but new experimental information allow to formulate different hypotheses to refine it. Thus, instead of solving a general inference problem (i.e. find the model structure plus the parameters from a set of data), we consider a subproblem which is smaller (although still very challenging) and dense (so sparsity is not an issue), and which, therefore, does not suffer from many of the ill-posedness and ill-conditioning maladies of the general inference problem [51, 52]. Despite the usefulness and broad applicability of the presented approach for model development in systems biology, there are three major limitations worth mentioning here:
Scaling up to large-scale models: the corresponding MINLPs might become rather large and therefore the computational effort needed for their solution might become prohibitive.
Non-uniqueness of biochemical reaction mechanisms: it is known that biochemical reaction networks with different structure and/or parametrization may produce the same dynamic response describing the time-evolution of species concentrations (see the recent discussion and results in [52]) difficulting the solution of the associated MINLPs. Fortunately, and following our comments above, this work considers a dense subcase of the general inference problem, so these issues are not as important. In fact, our approach can be interpreted as the application of extra constraints that can be used to reduce uniqueness and identifiability issues.
Model identification/selection metric: the use of more advanced metrics for model selection such as the likelihood ratio or the F-test can not be used in this approach since they rely on pair-wise comparisons. However, in the presented methodology the AIC could be replaced by any other metric for model selection as long as it can establish a ranking for the set of competing models encompassing model performance and model complexity.
We consider this cycle in a more compact way grouping sets of hypotheses together and formulating a parameterized set of nested models, from which the best alternative must be selected. We then formulate the decision problem as an MINLP-based optimization for simultaneous model selection and parameter identification.
This procedure has been applied to a case study considering potassium homeostasis in bacteria, arriving to the following conclusions: (i) the presented MINLP-based approach for nested-model selection is a powerful methodology for model selection and identification in systems biology; and (ii) for the case study considered, it has resulted in a model that presents a better fit to the in silico generated experimental data.
Authors MRF and JRB acknowledge financial support from the EU ERASysBio programme and the Spanish MICINN and MINECO (SYSMO grant KOSMOBAC, ref. GEN2006-27747-E/SYS and project MultiScales ref. DPI2011-28112-C04-03, both with partial support from the European Regional Development Fund, ERDF). MR was supported by the Max Planck society and the European Erasmus project. AK was funded in part by the BMBF through the Era-Net initiative SysMO. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).
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Social media is ostensibly all rainbows and butterflies. It's for "making connections" and "friending" people, blah blah blah. But do you ever follow people you really don't like?
Do you ever follow people because you don't like them, and instead you like reading their updates while sighing loudly to yourself and those around you asking how anyone could really be that stupid? Tell us what you think in the comments below.
Picture: auremar/Shutterstock

subset: commoncrawl


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Can You Guess the Celebrity Cleavage?
It's time again to use your encyclopedic knowledge of celebrity chest puppies to guess the owner of this fantastic set of perky pups. Have you identified them yet?
We'll make it easy for you. This celebrity cleave belongs to a model who first got her start on 'America's Next Top Model.' She hailed from Florida and was an 18-year-old student when she began her journey to modeling greatness. She was a part of the 12th Cycle and is still currently a model signed to Ford Models in Los Angeles.
Can you guess who it is?


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SURPRISE, Ariz. - Matt Harrison knew he wasn't going to be as sharp as he was last season, when he won 18 games and made the AL All-Star team. Still, he didn't think his spring training debut would be this bad.
The 27-year-old left-hander gave up four runs on six hits in the first inning as the Texas Rangers lost 7-5 to the Kansas City Royals on Sunday.
"It definitely wasn't the way I wanted my first outing to go," Harrison said. "It's the first outing and your command is not going to be exactly where you want it to be. It definitely was way better in the bullpen than it was in the game. I don't know if it was a matter of trying to force it in there and not letting it be free and easy.
"I just kept missing either in, off too far or down in the dirt," he said.
The Royals batted around in the first, highlighted by Alcides Escobar's RBI triple.
"I didn't want to throw 40 pitches in one inning, but that's the way went today," Harrison said. "Hopefully, I can get better at that."
There was a northwest wind of 22mph, with gusts of 31, blowing out to right field.
"It definitely wasn't ideal conditions to pitch in, but I've pitched in worse," Harrison said. "You can't let that effect the way you go out and do your business. With the wind blowing 100 miles per hour, if the ball gets in the air no telling where it's going to go. I wanted to keep it on the ground like I always do, but it just seemed like they wouldn't hit it at anybody today. It was up the middle or in the hole."
Royals starter Luis Mendoza, the Caribbean Series MVP after throwing 13 1-3 scoreless innings for Mexico, allowed one run and four hits in four innings.
"The wind was so bad, I just tried to let the sinker move by itself," Mendoza said. "I just tried to throw it in the middle and get groundballs. For lefties, especially, I tried to work outside of the plate."
Leury Garcia, who drove in three runs, took advantage of the wind with a two-run homer to right in the sixth as the Rangers tied the score at 5.
Xavier Nady and Brett Hayes stroked RBIs singles in the eighth and ninth innings as the Royals regained the lead. Salvador Perez went 3 for 3 with a double and scored two runs for the Royals.
John Lamb, the Royals top pitching prospect before reconstructive elbow surgery in 2011, allowed one run on four hits in one inning.
"Just getting back out there in front of that baseball atmosphere again was pretty exciting," Lamb said. "It was just a fun day for me. My command can always get better. I'm going to be hard on myself with that. Other than that, I don't like watching runs score when I'm pitching."
Notes: Rangers RHP Kyle McClellan, who had surgery to repair a frayed labrum last July, had a setback in his rehab when his bullpen sessions was shut down before he completed warmups. Pitching for the first time in nine days because of shoulder soreness, McClellan was still feeling soreness in the shoulder. . RHP Joakim Soria, who did not pitch last year after having Tommy John surgery, is scheduled to throw a 45-pitch bullpen Monday for the Rangers. He has had three 30-pitch sessions. . Royals LHP Francisley Bueno sustained a bruised left wrist when struck by a hopper Saturday, but was OK Sunday. He is scheduled to pitch Wednesday against Milwaukee.


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- Cash and all major credit cards accepted.
- All items sold as is, with no warranty or guarantee, and all sales are final.
- We can and will help you to remove your purchases from the home as long as it isn't during a time of heavy traffic.
- Delivery can be arranged for a fee.
- Pick up for large items can be arranged for a later date. The amount of time available for pick up changes: work with us and we will work with you.
- Numbers are given out at the time stated. Should you arrive prior to that time please check to see if a list has been created. You must be present to receive a number.
- We do not give out prices before the start of the sale but we are happy to answer any other questions you may have.
- We welcome out of state buyers.


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|Beach Hunters
Click here to visit site
Short review: This website is most manifestly in the top echelon of voyeur websites. It's obvious the possessors of this internet site are arousing sexual-desire about what they do, and that shines through in virtually every aspect of the internet site; the layout, the wild update schedule, the obvious and consistent improvements in quality throughout the years. One of the cool I've ever seen. Highly recommended!
Content Amount: Over 7,000 scenes and 4,000 photography galleries! Impressive download speeds, too, averaging around 1.4 megs per 2nd.


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Event Information
Date and Time
Location to be confirmed depends on class size
Do you often get frustrated when using Microsoft Excel? In my work I've seen many just like you who wish they could use excel efficiently as they know it would save hours per week. In many cases, such efficiency also makes the difference between submitting timely & impressive works instead of mediocre ones.
But most people struggle with learning Excel because courses online are not relevant to the daily work tasks. Without practice, what is learnt is quickly forgotten. In this course, the materials are tailored to be relevant to working corporate executives & hence the lessons will be memorable for you.
Who should attend?
What if I don't know anything about Excel? While any attendees will be able to understand the content of this course without any prior knowledge, this course will most of all benefit attendees who use Excel often for various purposes such as recording, retrieving, analysis & presentation of data, because such attendees will get to practice during his/her day-to-day work.
What will we learn?
You will learn to use Excel 2010 / 2013 / 2016 to:
• Run data analysis (with filters, pivot tables & conditional formatting etc.)
• Create presentations by creating & formatting charts
• Clean up data for further processing (Removing duplicates, mass correcting errors, etc.)
• Create interactive templates using formulas e.g. =VLOOKUP () / =IF() • Use basic Macro / VBA
How will we learn?
This course consists of circuits interchanging between theoretical & practical to help reinforce learning, followed by Q&A as well as post-course coaching.
• Theoretical: Trainer will walk through a hypothetical problem while explaining the step-by-step solution & highlighting the learning points. Attendees to write down the learning points as outlined in the workbooks to reinforce learning.
• Practical: Attendees will be given a real-life example related to their day-to-day work to practice the solutions learnt.
• Q&A & Post-course coaching: Attendees may raise any real-life / hypothetical problems to the trainer during Q&A or afterwards via email, along with the best solution that the attendees can come up with. Trainer will provide feedback on how to be more efficient (within 1 to 5 business days).
What will we get?
• One day course (teaching, practicing & Q&A)
• Post-course coaching for 4 weeks
A copy of the following will be provided to each attendee:
• Workbook for attendees to practice to reinforce learning
• Cheat sheets for future reference.
Feel free to contact me for any questions. Class date will be decided by majority through doodle.com and confirmed 4 weeks in advance once there are 10 confirmed students. if you are unavailable for the confirmed date you can join the next class. 50% deposit to confirm a seat. remaining 50% is due 2 weeks before the confirmed course date. Bring a friend and both of you get 20% off (offset against balance payment). Full refund if you change your mind within 7 days. Book a seat here: https://goo.gl/gKecfS
Here's a complimentary sneak-peak! :) https://goo.gl/B6r1ED
Date and Time
Location to be confirmed depends on class size


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The Daniels record: successful innovations
by Andrea Neal
Indianapolis Star
November 5, 2012
(Second of two columns on Gov. Mitch Daniels' legacy)
Mitch Daniels used his first term to get Indiana's fiscal house in order. His second term sealed his reputation as the education reform governor.
"Truly historic changes" came to Indiana schools, the American Legislative Exchange Council said in its 2012 Report Card on American Education.
"Indiana moved up into the A's for the first time after the reform-minded governor and legislature greatly improved the state charter law in 2011," said the Center for Education Reform Report.
The Weekly Standard, a national journal of conservative thought, credited Daniels for "taking Indiana from the backwaters of education reform in America to the forefront."
It's a bit early to claim success. It will be several years before Hoosiers know if reforms instituted by Daniels will boost test scores. ISTEP passage rates are creeping up and graduation rates are higher, but there's yet to be noticeable improvement on the National Assessment of Education Progress or the SAT.
Daniels took office in 2005, but his first term was consumed with budget balancing and recession, which delayed his educational initiatives until the middle of term two. Once he and School Superintendent Tony Bennett turned their sights on schools, change was fast and furious:
Collective bargaining with teachers unions was limited to wages and benefits, which means schools can pursue their own reform ideas, such as longer school days.
Teacher pay raises are now based on many factors, including student test scores, as well as the previous criteria of seniority and education. Teachers rated as ineffective can't receive a pay increase.
The State Board of Education uses letter grades — A to F — to judge school quality instead of vague labels like commendable and academic progress. The new system take into account test scores, score improvement, graduation rates and college readiness.
There are more opportunities to open charter schools. Private non-profit universities can sponsor them, and parents with children in poorly performing public schools can demand them.
Indiana greatly expanded its school choice program, with up to 60 percent of middle- and low-income students eligible for scholarships so they can attend private schools of their choice. Indiana also offers a tax deduction for parents of up to $1,000 to help pay for education costs, such as tuition or tutoring.
Robert Enlow, president and CEO of the Foundation for Educational Choice, gives Daniels a rave review for education policy. "Most governors would be pleased just to get one of these things accomplished. Mitch Daniels, along with Dr. Tony Bennett and many courageous state legislators, accomplished them all."
Pat Kiely of the Indiana Manufacturers Association agrees. "The 2011 session was the most dynamic with the passage of teacher performance evaluations, merit pay, charter school expansion and the largest voucher program in the country."
As for higher education, the record is less comprehensive. Experts interviewed for this column say Daniels' focus has been on accountability in spending and in student outcomes. They predict he will make a bigger impact on academia once he takes over as president at Purdue University.
"I believe he will be a major agent of change not only in quality and affordability but improving the communications and value of universities to other segments of the economy," Kiely said.
Daniels will be remembered as a conservative by D. Eric Schansberg, economics professor at Indiana University Southeast, "but more important/interesting, compared to other politicians, he has been quite willing to innovate and take risks."
Schansberg lists as examples not only K-12 ed reform but "right to work" legislation, the Major Moves infrastructure project and overhauls of welfare and the Department of Motor Vehicles.
Kevin Brinegar, president and CEO of the Indiana Chamber of Commerce, said Daniels "showed us that you can tackle tough issues/sacred cows and, if you make your case, Hoosiers will support your leadership and re-elect you."
Indeed, they did. Daniels will hand off to his successor a balanced budget, a healthy business climate, some newly paved highways and a whole set of school reforms likely to soon bear fruit.
Neal is adjunct scholar and columnist with the Indiana Police Review Foundation.Share on Facebook
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Air Cooled Package Chiller With Tank and Pump DAVP0401
Standard Features
- Heavy duty welded, tubular steel frame with high gloss powder coat finish and laminated polyethylene cabinet
- U.L. Listed, and EPA Compliant, eco-friendly R410a refrigeration condensing unit
- Single refrigeration circuit with Copeland scroll compressor with crankcase heater
- Air cooled, high ambient, vertical discharge, condensers for 100°F ambient with fan cycle control
- Weather proof electrical panel with single point power connection and 24 vac control circuit
- Remote control panel for indoor installation provides lighted on/off switches and digital thermostat
- High performance coaxial evaporator with inner copper tubing and protective steel shell. UL and ASME listed coil is insulated against condensation with expanded foam
- Externally equalized thermal expansion valve, liquid line filter drier, and sight glass
- Low water flow compressor interlock safety locks out compressors in low flow condition
- Non-ferrous water lines with FPT connections insulated with 1/2" closed cell insulation
- High density, polyethylene reservoir insulated with 1/2" closed cell insulation
- High head centrifugal process pump rated at 40 psi at 2.5 GPM/ton
- Warranty: one ( 1 ) years limited parts, five ( 5 ) years limited compressor warranty
Options & Accessories
- Receivers for 90% refrigerant storage (heated and insulated for temperatures below
- 30°F ambient)
- Condenser coil coating for corrosion protection in coastal areas
- Fan speed control to maintain steady head pressure in cold ambient
- Voltage and phase monitor in 2 through 7.5 ton
- Cabinet mounted glycerin filled fluid supply pressure gauge
- Cabinet mounted, glycerin filled refrigeration pressure gauges
- Cabinet mounted, analog fluid inlet and outlet gauges
- Inhibited propylene glycol concentrate or 65% / 35% premix in 55 gallon drums or 5 gallon carboys
- Castors for portability
- Factory authorized technician for startup and training
|Electrical Data
|Power Supply: 208-230/1/60
|115 Amps
|21.1 Amps
|Fan Motor:
|1 @ 1.2 Amps
|Pump Motor:
|8.0 Amps
|Total Circuit:
|30.3 Amps
|38.9 Amps
|45 Amps
|Physical Data
|48"L x 35"W x 68"H
|Ship Weight:
|727 lbs.
|Minimum Clearances:
|30" All Sides 60" above Top
|Noise Rating:
|77 dBA @ 10 feet
|Fans CFM:
|3295 cfm @ 125°F
|Tank Capacity:
|50 Gallons ( Atmospheric )
|1.0" FPT CHWS and CHWR


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I wanted to play XTC again recently. But i never liked the huge distances in our XTC universe. They made traveling tedious and everything take considerably longer and result in very low density traffic. I prefer the X3 vanilla distances, they are more cosy, more stuff is happening on the trade lanes (yaharrrrrr).
So i reduced gate distances from average of 100 to 160 km down to 60-80 km. I also moved many suns above/below ecliptic, so you dont have to stare directly into suns when flying to a gate...
Backgrounds are more varied between sectors as well. Not just red and dark for split or blue for borons.
You can download it for standard XTC here
and for AP Experimental here
Read the readme.
I do need to mention however, the sensor ranges in XTC are suited to longer distance. So you might want to reduce it (TGlobals.txt if memory serves right) to match the reduced sector sizes.
If you do not have /maps folder (or addons/maps in case of AP), just extract the zip as is in your X3 installation folder.


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Macross Frontier (Macross 25) general discussion [No Spoilers]
I've read rumours of a new macross series in the works. The rumour I hear is they're looking for VA's. Does that mean that it'll be ready soon? Will it be out this year (25th anniv of MAcross). Is Kawamori involved?
Please don't let this be some sick joke to torment me.
New Macross Project 2007
I found this flyer floating around. Seems to be a voice audition.
can anyone translate it? it would be awesome if it was a new macross series!~~ or heck even a movie!!! :heh:
I heard awhile that they might make a new series. Some info I found here: http://www.animenation.net/news/index.php?id=10919
These guys seem to get the scoop right most of the time. Trust me I'm praying for this
If its what I think it is I think they were for auditions for the next voce of a Minmay type character (I don't know if the plot is like Macross 7 or a direct sequel to SDF Macross, prays for the latter)
But as long as its nothing like Macross II I'll be happy
4-19-07 (8:17PM EDT)---- New Macross To Be Announced This Summer
At this year's Tokyo International Anime Fair 2007 a Satelight representative told ANS the latest Macross anime will be announced this summer. The next Macross idol heroine has been selected through the Victor Vocal And Voice Audition and will be announced at the same time.
Other initial rumours indicate that there will be all new mechas. No more VF1's
will be extremely pissed if its Seed-like in any way, shape of form.
Necro posting
link to preliminary sketches of mecha, characters etc etc
The battloids are a lot different, and I'm having a hard time visualizing them turning into some of the fighter designs on that page. It does seem rather interesting though, so I'm eagerly awaiting something a bit more refined released.
But I think this rules out my hope that the new Macross would follow Hikaru and the rest of his ship. Oh well. :heh:
Let's hope they leave the treehugger stuff for another show this time
Macross Flashback 2012 was the apparent sendoff of Misa, Hikaru and Minmay. I don't think we'll ever see them again. :(
I want more singing whales (oh wait no I don't)
I heard rumors floating around a while ago but forgot all about it. So i guess its confimred now. Does anyone have enough info to give a brief rundown about the plot?
Macross SEED LMAO:heh: dear god NO
No announcement yet. There's a 25th anniversary Macross concert coming up and that's when all details are supposed to be announced.
However from the looks of the battloids I'm pretty sure it will be set after Macross 7. It just looks like the battloids just look too advanced, they look more like advanced versions of VF11's in Mac7, rather than anything in SDF, Mac 0, Mac plus etc etc
EDIT: Just watched SDF MAcross and DYRL again (probably the 50th+ time). Damn the intro theme still gets to me. THe music in general is still so awesome. But then again I am a child of the 80's.
Official project name is "Macross 25"
Can anyone translate this? Any juicy stuff in there????
I hear the plot takes place in a school-like environment.
A military academy, perhaps?
Please let this be in 2d. 2d Mecha>>>>>>>>>>>>>>>>>>>>>>3d mecha.
Yeah, Macross Zero was definitely awesome, but I'd rather see 2d then 3d. Must be cause I'm old school when it comes to Macross.
Animating mecha fights is something beautiful. Nowadays it looks like animators are getting lazy and are doing everything with computers.
Not to disappoint you, but animators have not been using many manual animation techniques for years now. Almost all coloring is done on a computer, for example.
Since this is a Satelight production, the mecha are definitely going to be CGI. Which should be fairly awesome, if past work is any indication.
And I am looking forward to finding out who they selected to be this "new Minmei". Let's hope she isn't as annoying as the original one. 8)
Is it just me or does the design on the top left of the image somehow resemble the Solar Aquarion (the head)? Anyway, I'm obviously going to keep an eye on this for all various reasons (because it's a Macross serie, because there's Kawamori, and I do hope that Yoko Kanno will join in again).
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Pushing out to retailers in the United States this week, the CASIO G-SHOCK wristwatch with Bluetooth 4.0 allows iPhone 5 and 4S owners to sync the device in order to trigger a variety of alerts related to calls, email and security. Using a battery that will power the Bluetooth connection up to twelve hours per day for two years, the watch will trigger a beeping sound or vibration to alert the user when a call is incoming. This can be particularly helpful for iPhone owners that keep their phone in a handbag or briefcase instead of a pants pocket. On the display of the watch, the text "Incoming Call" will scroll across the screen, but the name of the person calling the user will not be displayed on the watch.
However, when the watch issues an email alert to the user, it will display the name of the email address that's linked to the alert in addition to a flashing mail icon. In order to set up email alerts, the user is required to download the G-SHOCK+ application for the iPhone and enter their account information. Unfortunately, the watch won't alert the user when a SMS or text message is sent to the iPhone.
Definitely helpful for people that happen to accidentally forget their iPhone occasionally, the G-SHOCK wristwatch will start vibrating when there's too much distance between the watch and the phone. In addition, Casio has included a method of helping someone find their iPhone. With one press of a button on the watch, the iPhone will start emitting a tone. The tone can be turned off again by tapping the same button after the iPhone has been located.
The CASIO G-SHOCK wristwatch also offers an automatic time adjustment feature that syncs the clock on the watch with the data provided by the iPhone. This is ideal for anyone that travels across the country repeatedly and doesn't want to mess with adjusting their watch after entering a new time zone. The watch also enters into a power-saving mode after the watch has been taken off the wrist. In addition, the watch automatically syncs with the phone once it detects movement. The tilt-sensor in the watch is likely very similar to the accelerometer in a typical smartphone.
In addition to the iPhone connectivitys, the watch is water resistant up to 200 meters as well as shock resistant. The device includes a LED backlight, a 1/100-second stopwatch, a countdown timer, five alarms, a hourly time signal, a fully automatic calendar, 12/24 hour formats, a daylight savings setting and a low battery warning that will occur when the first two years is up.
Regarding color selection, the CASIO G-SHOCK wristwatch is available in white, black, brown and blue. Anyone using an iPhone 4S will need to have at least iOS 5.1.1 installed on the phone to use the application. The CASIO G-SHOCK wristwatch with Bluetooth 4.0 is priced at $180 and can be found at Macy's, Finish Line and other retailers.
At the $180 price point, that's slightly more expensive than the $150 Pebble smartwatch. However, the Pebble smartwatch is still unavailable to consumers. According to the Pebble blog, the team behind the Pebble watch has to approve a production verification build of the watch this month before moving into mass production of the device.


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Some towns have made admirable efforts to address this unmet need. Residents of Rockville Centre created a Youth Council — a youth-driven organization that dreams up activities for teens to take part in around town, many of them sponsored by local businesses. There are things like, yes, bowling nights, but also Chinese New Year celebrations, for example. Open mic nights are some of the group's most popular events.
The Long Beach Underage Drinking Coalition has long been trying to reduce the frequency with which teens pursue one of their favorite, and most destructive, activities: gathering surreptitiously to drink. The coalition's tools are education about the myriad dangers of alcohol abuse, and, with the involvement of parents, ongoing efforts to eliminate teens' access to liquor.
One of the coalition's members, Long Beach school board member Roy Lester, has for years trumpeted the need to give teens a place to go at night. A few years ago, Lester started a teen center at one of the Long Beach schools over a summer. It gave them a place to go to be with friends, play basketball, watch movies, take cooking classes and much more. There was adult supervision, but it was unobtrusive.
"Our kids are basically forgotten in this situation," Lester said. "We yell and scream that they shouldn't get in trouble, but we don't give them any opportunities to do something."
If we don't want teens roaming the streets at night, drinking and causing trouble, we need to create alternatives. Our older children deserve to be more than a nuisance to us.


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