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Latin American applied research
versión impresa ISSN 0327-0793versión On-line ISSN 1851-8796
Lat. Am. appl. res. vol.44 no.4 Bahía Blanca oct. 2014
Levenberg-marquardt method applied to the determination of vapor-liquid equilibrium model parameters
J.A.F. Oliveira†, M.M.L. Duarte†, E.L. Foletto‡,* and O. Chiavone-Filho†
† Chemical Eng. Department, Federal University of Rio Grande do Norte, Natal, 59066-800, Brazil
‡ Chemical Eng. Department, Federal University of Santa Maria, Santa Maria, 97105-900, Brazil. * firstname.lastname@example.com
Abstract In order to correlate and optimize experimental data either from the laboratory or industry, one needs a robust method of data regression. Among the non-linear parameter estimation methods it may be pointed out of Levenberg, which applies the conversion of an arbitrary matrix into a positive definite one. Later, Marquardt applied the same procedure, calculating λ parameter in an iterative form. The Levenberg-Marquardt algorithm is described and two routine for correlating vapor-liquid equilibrium data for pure component and mixtures, based on this efficient method, have been applied. The routines have been written with an interface very accessible for both users and programmers, using Python language. The flexibility of the developed programs for introducing the desired details is quite interesting for both process simulators and modeling properties. Furthermore, for mixtures with electrolytes, it was obtained a coherent and compatible relation for the structural parameters of the salt species, with the aid of the method and the graphical interface designed.
Keywords Nonlinear Regression; Levemberg-Marquardt Method; Vapor-Liquid Equilibria; Mixed Solvents Electrolyte Systems.
The phenomena and properties involved in the chemical processes present, usually, non-linear behavior. Therefore, it is needed a robust method of non-linear regression for providing the required correlation of the experimental data collected, either from the laboratory or from the industry.
Bard (1974) pointed out three methods of parameter estimation, i.e., least squares, maximum likelihood and Bayesian. The method of least squares is the oldest and most widely used estimation procedure. It can be applied directly to a deterministic model, without any knowledge being taken of the probability distribution of the observations. This feature satisfies quite well the propose of correlating most of the desired thermodynamic properties and process variables.
For solving these unconstrained problems, the Levenberg-Marquardt method has proven very reliable results. In this work the Levenberg-Marquardt algoritm is described in a simple form.
This parameter estimation method has been reproduced and applied for the correlation of vapor-liquid equilibrium (VLE) data using activity coefficient and equation of state approaches (Lazzús, 2010; Camacho-Camacho et al., 2007). For the first case, an evaluation of the thermodynamic consistency of the data can be provided, since activity coefficient models fulfill the exact definition of partial molar excess Gibbs energy.
Systematic evaluation of thermodynamic properties of solutions of sodium chloride (NaCl) in water, e.g., boiling point and osmotic coefficient, with an extensive experimental database, was provided by Clarke and Glew (1985). VLE calculation for mixed solvents electrolyte systems have been applied using functional group activity coefficient model, i.e., UNIFAC (Kikic et al., 1991). It was taken into account the electrostatic term with Debye-Huckel term, normalized according to the theory of Mc-Millan-Mayer. However, the estimated parameters present scattering and large order of magnitude. Loehe and Donohue (1997) described a survey of the literature models to determine thermodynamic properties of aqueous systems with strong electrolytes. Thomsen et al. (2004) have presented a systematic modeling work with mixed electrolytes and mixed solvents systems for solid-liquid-vapor equilibrium data, using UNIQUAC also. Haghtalab and Peyvandi (2009) have proposed a new version of UNIQUAC model for electrolyte solutions that requires just two fitted interaction parameters per binary aqueous system. The structural parameters of the ionic species were evaluated considering solvation for the determination of the radii.
This study aimed to describe the Levenberg-Marquardt computational procedure for estimation of vapor-liquid equilibrium model parameters. Validations of the method are present for pure component vapor pressure and binary VLE data. Application to strong electrolytes in mixed solvents systems has also been performed, using UNIQUAC model. It is proposed a new form to determine structural UNIQUAC parameters of the ions that is compatible with the solvent species parameters.
A. Levenberg-Marquardt Method
The method presented by Levenberg (1944) utilizes a conversion of an arbitrary matrix into a positive definite one. This method rests on the observation that if is any positive definite matrix, then is positive definite for λ sufficiently large, no matter what . Marquardt (1963) suggested an iterative algorithm for the selection of λ.
The importance of working with a definite positive matrix is to satisfy the necessary and sufficient conditions of minimization in the data regression, where the least square of the residuals (ei) is to be found.
B. Levenberg-Marquardt Algorithm
In this section the Levenberg-Marquardt algorithm applied for a nonlinear parameter estimation is described in four phases.
(i) Enter ρmin (a minimum value of the step length ρ, e.g. 10-7), ε (a positive small number, e.g. 10-7), (vector of the dependent variables), (matrix of the independent variables) and (vector of the initial guess of the parameters to be estimated). Set J and λ = 0.01 (Marquardt parameter);
(ii) Calculate (vector of the residuals) and (objective function), where and ;
(iii) Calculate (gradient of Φ) and (approximation of the Hessian matrix of the function Φ), where and ;
(iv) Calculate
(v) Calculate , reminding that these values may be directly evaluated by:
(vi) Calculate (vector in the direction of the proposed step), and , where and are evaluated by the Cholesky method, see, e.g., Fox (1964), which is specific for the inversion of a definite positive matrix;
(vii) If accept , replace λ by max(0.1 λ,ε) and go to the step (xxi). Or else, continue from the step (viii);
(viii) Compute , and . With these values is calculated;
(ix) If , then continue from the step (x). Else, go to the step (xvi);
Extrapolation of ρ:
(x) Set J equal to the higher integer number that do not overcome the half of J;
(xi) If set ;
(xii) If continue on the step (xiii). Else, set and go to the step (xx);
(xiii) Compute
(xiv) If continue on the step (xv). Else, set and go to the step (xx);
(xv) Set ρ = ρ* and go to the step (xx);
Interpolation of ρ:
(xvi) Set ;
(xvii) If ρ ≤ ρmin go to the step (xx). Else, continue on the step (xviii);
(xviii) Compute and set J = J + 1;
(xix) If go to the step (xx). Else, set ρ(1) = ρ and , and return to the step (xvi);
(xx) Calculate ;
(xxi) The criterion of termination is tested, using and , as an example suggested by Marquardt (1963), is given according to the following equation:
where .
If the criterion is satisfied for all parameters, iterations are terminated and is accepted as the solution . Otherwise, set λ = 10λ and = , and return to the step (ii).
C. Vapor-Liquid Equilibrium Data Regression
In order to demonstrate the applicability of the implemented Levenberg-Marquardt method, two programs for correlating vapor-liquid equilibrium data have been developed.
Antoine Constants Estimation
The first program allows data correlation of vapor pressure and temperature for pure components, using the Antoine equation. In Eq. (1) we have that Psat is the vapor pressure, T is the saturation temperature, and A, B and C are the adjusted Antoine constants. This form of the Antoine equation is usual in the literature; however the user may, easily, apply a modified version of the correlation both in terms of the logarithm base and units.
To perform the data regression, the following objective function (OF) is to be minimized, which is the defined by the absolute residual in terms of vapor pressure.
The program requires initial guesses of A, B and C parameters to be estimated, name of the substance, number of data points and list of the experimental pairs of vapor pressure and saturation temperature. Indication of the units and the literature source from which the data has been retrieved is also requested. An output is provided where information about the iterations performed during the execution is registered, allowing the detection and identification of an eventual error. After convergence, the values of the estimated constants are displayed together with respective interval confidences, standard deviations and correlation matrix of the parameters. The program also provides the relative and absolute deviations in terms of vapor pressure and the estimation of the normal boiling point, at 760 mmHg, using the obtained correlation. Results for propyl acetate have been compared with Boublik et al. (1984) and validated the implemented program. The Antoine correlation for the propyl acetate has presented relative deviation (ΔP) of 0.04% and estimated the following parameters with corresponding confidence intervals: A = 7.03008±0.03391, B = 1290.200±19.505 and C = 209.466±2.161.
Reduction and consistency test of vapor-liquid equilibrium data for binary systems
The second program developed is to accomplish the correlation of vapor-liquid equilibrium data for mixtures, using activity coefficient models presented in the literature (Prausnitz et al., 1999), i.e. Margules 2-suffixes, Margules 3-suffixes, Van Laar, Wilson and NRTL (Non-Random Two Liquids). Therefore, data regression consists of the corresponding parameter estimation of the activity coefficient model. In the case that the VLE data set is complete, i.e. presents the values of temperature, total pressure, liquid and vapor compositions, the correlation tests also the thermodynamic consistency of the experimental data set. This is due to the fact that the activity coefficient models (γi) respect the exact thermodynamic definition of partial molar excess Gibbs energy.
Thus, the Euler theorem may be applied, i.e. the additive property, together with the fundamental equation for GE, resulting in the so-called Gibbs-Duhem relation, see Prausnitz et al. (1999). This is the base of the thermodynamic consistency test of an experimental phase equilibrium data set. We may find in the literature, in general, two tests for thermodynamic consistency of VLE data, i.e. area test and deviation test. In our case, we have applied the deviation test which is in fact a data correlation followed by the analysis of the deviations (see Fredenslund et al., 1977). We may describe, easily, the VLE data correlation of a binary system by writing the total pressure equation (Barker, 1953), and neglecting the nonidealities of the vapor phase, which is a reasonable simplification for low pressures and nonassociating components.
It may be pointed out that the activity coefficients depend on the temperature, liquid mole fraction and their parameters, which are adjusted from phase equilibrium data reduction. To give an illustration, Eq. (5) shows the simple Margules 2-suffixes gamma model, for both components.
Therefore, the data reduction for the mixture is similar to the Antoine correlation, and may also be represented by Eq. (2), which defines the objective function in terms of the pressure. For the mixture the differences are that the saturation pressure is replaced by the total pressure and the parameters come from the activity coefficient model instead of the Antoine equation. After the data regression, the vapor composition may be evaluated, according to Eq. (6).
The vapor-liquid equilibrium data set for the n-heptane(1) + ethyl butyrate(2) system at 100 °C presented by Kojima and Tochigi (1979) has been used to test the nonlinear regression method implemented. The developed program allows parameter estimation of the five activity coefficient models listed at Table 1. It may be observed that all models have fitted satisfactorily the experimental data. Furthermore, the deviations presented indicate that the experimental data is consistent. Concerning the operation of the program for correlating vapor-liquid equilibrium data of mixtures, it may be pointed out that all information relative to the system is given by the input file. The model is chosen during the execution of the program, together with the initial guess of the gamma coefficients and the Marquardt parameter. An output file is also created. Similar to the Antoine program, this output file contains information related to the iterations realized, during the execution of the Levenberg-Marquardt method.
Table 1. Correlation and consistency test of the vapor-liquid equilibrium data for the n-heptane(1) + ethyl butyrate(2) at 100 °C (Kojima and Tochigi, 1979).
* C is the random parameter and has been set to 0.3, as default value.
** The values of the absolute average deviation are lower than 0.01 (Δy1 < 0.01), indicating that the data are considered to be consistent, according to Fredenslund et al. (1977).
After convergence, the values of the estimated parameters together with confidence intervals are presented together with the correlation matrix and standard deviations. Furthermore, the dependent variables are properly compared, and for the case of isothermic data, the percent average pressure deviation and the absolute average mole fraction of the vapor phase deviation are displayed, from which a thermodynamic consistence evaluation of the equilibrium data is prompt provided.
Vapor-liquid equilibrium correlation for mixtures with electrolytes
The Levenberg-Marquardt method was also applied for two aqueous ternary mixtures with methanol and NaCl and ethanol and NaCl with the second program. The corresponding binary systems have also been correlated. The UNIQUAC activity coefficient model (Abrams and Prausnitz, 1975) was applied in its original form and considering NaCl as one molecular species, i.e., neglecting the dissociation.
Table 2 reports structural parameters used for the studied species. It should be pointed out that structural parameters of the salt species, i.e., surface area and volume parameters were determined from the values of the water and a molar mass ratio. Two goals have been achieved using this approach. One was to provide data fitting capability with a reasonable order of magnitude of the structural parameters. Secondly, compatibility with the interaction parameters estimated for non-electrolyte binary mixtures are encountered. This is also an important feature for predictability of the model and group contribution applications like UNIFAC (Kikic et al., 1991). Values of r and q for ionic species have been fitted by Macedo et al. (1990). Another approach encountered in the literature is the increment of the parameters from the ionic radii by considering solvation. However, the use of these two methods demands estimation of new solvent-solvent parameters and thereby compatibility requirement is not fulfilled. By the other hand, using the values of r and q calculated from the values of water and a ratio of the molar masses, as presented in Table 2, it was obtained the desired compatibility and simultaneously good correlation capability, eliminating the problem of low structural values due to the size of the ion for UNIQUAC equation.
Table 2: Structural parameters for UNIQUAC model.
Table 3 presents the estimated UNIQUAC interaction parameters for the species studied. It should be pointed out that the non-electrolyte binary systems have been correlated initial and separately and then with these predetermined values the salt-solvent constants were estimated from the corresponding experimental data. All calculations have presented absolute average deviation in terms of vapor mole fraction lower than 0.01 and relative average deviation in terms of pressure less than 2%. These deviations indicate the consistency of the experimental data and also the quality of the parameters that gather many experimental points and different sources.
Table 3: Estimated UNIQUAC interaction parameters (aij) in kelvin for the studied systems with methanol (MeOH), ethanol (EtOH), water (H2O) and sodium chloride (NaCl)
aParameters estimated from methanol+ethanol VLE data (Niesen et. al., 1986; Kurihara et al., 1993).
bParameters estimated from methanol+water VLE data (Soujanya et. al., 2010; Yao et. al., 1999; Kurihara et al., 1993).
cParameters estimated from ethanol+water VLE data (Pemberton and Mash, 1978; Niesen et. al., 1986; Kurihara et al., 1993, 1995; Arce et. al., 1996; Navarro-Espinosa et al., 2010; Lai et al. 2014).
dParameters estimated from water+NaCl, methanol+water+NaCl and ethanol+water+NaCl VLE data (Clarke and Glew, 1985; Gmehling, 1997; Yang and Lee, 1998; Jõdecke et al., 2005), fixing MeOH+EtOH, MeOH+H2O and EtOH+H2O parameters determined previouslya,b,c.
Figures 1 and 2 illustrate the quality of the correlation obtained for the aqueous ternary systems with methanol and NaCl at 314.6 K and with ethanol and NaCl at 700 mmHg, respectively.
Fig. 1. Vapor-liquid equilibrium diagrams for methanol(1)+water(2)+NaCl(3) at 314.6 K; solid symbols experimental (Jõdecke et. al., 2005) and open symbols: UNIQUAC this work: and , x'1 =0.0328; and , x'1=0.0789; and , x'1=0.216; and , x'1=0.466.
Fig. 2. VLE y-x diagram for the system ethanol(1)+water (2)+NaCl(3) at 700 mmHg; 32 experimental points with salt mole fraction in the range of 0.001-0.1; experimental data (Gmehling, 1997); calculated values with UNIQUAC (this work).
The coherence of the developed programs has been verified via comparison with the parameters estimated for the same data set, confirming the reliability of the Levenberg-Marquardt routines implemented.
The results of the correlation program for mixtures are also efficient and analysis of the deviations allows the evaluation of the thermodynamic consistence of the experimental data. This qualification of the data may be useful for their application, i.e. for the development of models, and design and operation of processes.
The developed tool of calculation may be applied in problems of simulation and optimization of processes, using inclusive the visual recourses, which facilitates the interaction with the users. Furthermore, new correlation programs may also be developed to describe other thermodynamic and physical-chemistry properties, since Levenberg-Marquardt has been properly implemented.
These new salt species structural parameters demonstrated also to be flexible for the data correlation and coherent to respect to order of magnitude. The electrostatic contribution has not been considered for VLE calculations. The original form of the UNIQUAC model demonstrated to be feasible with the molecular approach for strong electrolyte species in mixed solvents systems.
|UNIQUAC interaction parameters
|Antoine constants or activity coefficient parameters
|approximation of the Hessian matrix of the function Φ
|calculated value
|vector of the residuals
|residue of point
|experimental value
|molar excess Gibbs energy and partial molar excess Gibbs energy of species i
|number of experimental data points or atomic mass or molecular mass
|molality of species i
|n, ni
|total number of moles and number of moles of species i
|Non Randon Two-Liquid
|objective function
|total pressure
|any positive definite matrix
|vapor pressure of species i
|gradient of Φ or UNIQUAC surface area parameter
|r, q
|volume and surface area parameter
|universal ideal gas constant
|Vapor-Liquid Equilibrium
|matrix of the independent variables
|xi, yi
|mole fraction of the component i in the liquid and vapor phase
|salt free mole fraction of the component i in the liquid phase
|vector of the dependent variables
|mole fraction of the component i in the vapor phase
Greek letters
|percent average deviation, defined as
|absolute average deviation, defined as
|a positive small number
|activity coefficient of the component i
|vector of the parameters
|vector of the parameters, initial guess
|vector of the parameters at iteration i
|value of the step length
|Marquadt parameter
|vector in the direction of the proposed step
|objective function
|objective function at the iteration 1
|objective function at
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Received: May 21, 2013
Accepted: March 24, 2014
Recommended by Subject Editor: Mariano Martín


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Kurtz, who is the J. Alton Hosch Professor of Law, specializes in criminal law and family law. Active in legislative issues throughout his career, he was reporter for the Georgia Supreme Court's Indigent Defense Reform Commission, the driving force behind landmark legislation enacted in 2003. He served on Georgia's 11-member Public Defender Standards Council, which is responsible for delivering indigent criminal defense services within Georgia's criminal justice system, from 2003-09. He was also instrumental on the Public Interest Loan Repayment Task Force, which wrote legislation creating a state fund for this cause passed by the Georgia Legislature in 2002. Kurtz has also represented Georgia on the National Conference of Commissioners on Uniform State Laws and was a member of the NCCUSL's drafting committee of the Uniform Interstate Family Support Act. He is a member of the American Law Institute and served as adviser on the ALI Project on Principles of Family Dissolution in 1998-99.
Kurtz clerked for Chief Judge Harry Phillips of Sixth Circuit Court of Appeals and then taught at the law schools of Boston University and Boston College before joining UGA. In addition to his J.D. from Vanderbilt, Kurtz holds an LL.M. from Harvard.
Brown, who specializes in civil procedure and legal ethics, holds UGA's A. Gus Cleveland Distinguished Chair of Legal Ethics and Professionalism. Since joining UGA Law in 2002, he has received the Student Bar Association's Professionalism Award six times as well as the Ellington Award for Excellence in teaching. He has served as a Senior Teaching Fellow at UGA and is a member of the UGA Teaching Academy. As the inaugural Administrative Fellow in UGA's Office of the Senior Vice President for Academic Affairs and Provost in 2007-08, he was exposed to the inner workings of academic administration.
He is also very active in the broader legal community, serving on the Drafting Committee for the Multistate Professional Responsibility Exam and on the State Bar of Georgia Formal Advisory Opinion Board. Additionally, he was recently selected by the U.S. District Court for the Northern District of Georgia as the principal substantive consultant for the court's Local Rules Revision Project.
Before joining UGA's law faculty, Brown was an assistant professor of law at the University of Illinois and a visiting assistant professor at Vanderbilt. After earning his J.D., he clerked for Judge William C. O'Kelley of the Northern District of Georgia and then practiced law for eight years as an associate and a partner at Alston & Bird in Atlanta. "I am humbled to follow in Paul's footsteps," Brown said. "He has been a wonderful colleague and friend to me over the years, as well as the very embodiment of all that is good about our law school. I hope that I can live up to his example and carry on his tremendous legacy."
"I am delighted to be succeeded by my longtime friend and colleague, Lonnie Brown," Kurtz said. "He has been a tremendous teacher and scholar and I know he will be a wonderful associate dean. The fact that he and I share the tie to Vanderbilt is simply icing on the cake to me."
Kurtz is the general chair of the 45th reunion of Vanderbilt University's Class of 1968 this fall. His work as fundraising chair for the 40th reunion of the law school's Class of 1972 reunion in 2012 resulted an overwhelming response from his class. "Paul has long served Vanderbilt as an enthusiastic volunteer, and his classmates say Paul is the glue that has held his class together," Scotty Mann, associate dean for alumni relations and development, said.


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Search engine optimization is a process to optimize the pages of a site to help it rank higher. So these are the packages which we are providing at the initial level and once we start sailing in the same boat then it can be extended or minimised as per the project.
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The table below represents our fix packages, however if your needs are apart from these packages then we can provide some custom quotes all the time. Feel free to contact us to set up a custom package for your business.
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200 hrs/month
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I'm thinking of that child left behind. The one who cannot follow a lesson because she cannot read what the teacher has written on the blackboard, even though she has faithfully and correctly copied it all down in her notebook. The child who cannot ask a question in class, because she cannot read her notebook, hence can't put a finger on what exactly it is that she does not understand. This is the child who does not know how to read.
In classes as high as 8, in children as old as 14, we're encountering a frightening lapse of reading skills. If we make them sit in a line, it almost always seems to be the children towards the back (they seem to gravitate there), always the quietest (you'll almost miss seeing them, and will certainly miss hearing them), yet always with that curious, desperate shine in their eyes, wishing and hoping that they could cut through the fog of their illiteracy.
One of the early partnerships we had explored for our community radio station was with Pratham, especially Pratham Books. I'd met them off and on at assorted meetings and book fairs, and their work, and their books had been sitting at the back of my mind as something exceptional. On a whim, I wrote on their website. Within a day, I had an answer. Actually, I had several. All of them positive, energetic, and gung-ho.
Now, all these weeks later, we're looking at a concrete plan to air a regular slot, at least twice a day, that takes Pratham's reading pedagogy to a wider audience through the radio. To those children left behind. To those children left at home.
As we hammer out the programming, train the volunteers, and learn from the process about what works and what doesn't, I'm hoping that the content we create in this process can be used by community radios and Pratham across India. To start with, in the Hindi speaking states, since that is the language in which we are working, and later, as regional language adaptations in other states.
First published on November 14, 2008
#community-radio, #education, #radio
You may also be interested in these related posts:
Community radio: teaching English
School Kids make a trip to the Yamuna River
Educating the rural children


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Have you ever found yourself thinking about what to wear, spending a generous amount of time looking around your closet and then ending up wearing an all-black outfit because that's the easiest option? Yeah, me too. Too many times to count, to be honest.
I love black. Half of my wardrobe consists of black items: black coats, black bottoms, black tops, black bags… pretty much everything I own is black. I've been trying to change this a little bit though, buying more light coloured items. However, I always end up going back to my black outfits because those are the easiest to style and they are pretty much fool-proof.
Today I've gathered a few different ways you can wear all black and look extremely stylish.


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Mini Review ARTICLE
Cell tropism and pathogenesis of measles virus in monkeys
- Division of Biomedical Science, Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
Measles virus (MV) is an enveloped negative strand RNA virus belonging to the family of Paramyxoviridae, genus Morbillivirus, and causes one of the most contagious diseases in humans. Experimentally infected non-human primates are used as animal models for studies of the pathogenesis of human measles. We established a reverse genetics system based on a highly pathogenic wild-type MV. Infection of monkeys with recombinant MV strains generated by reverse genetics enabled analysis of the molecular basis of MV pathogenesis. The essential in vivo function of accessory genes was indicated by infecting monkeys with recombinant MV strains deficient in the expression of accessory genes. Furthermore, recombinant wild-type MV strains expressing enhanced green fluorescent protein enabled visual tracking of MV-infected cells in vitro and in vivo. To date, three different molecules have been identified as receptors for MV. Signaling lymphocyte activation molecule (SLAM, also called CD150), expressed on immune cells, is a major receptor for MV. CD46, ubiquitously expressed in all nucleated cells in humans and monkeys, is a receptor for vaccine and laboratory-adapted strains of MV. The newly identified nectin-4 (also called poliovirus-receptor-like-4) is an epithelial cell receptor for MV. However, recent findings have indicated that CD46 acts as an MV receptor in vitro but not in vivo. The impact of the receptor usage of MV in vivo on the disease outcome is now under investigation.
Measles is a febrile disease that typically occurs in small children; the incubation period is 10–14 days, after which clinical symptoms such as fever, coughing, and a characteristic rash appears. Since measles is accompanied by immunosuppression, it has a high frequency of complication with secondary bacterial infections, such as otitis media or pneumonia. Although developed countries are eradicating measles by promoting effective vaccination, measles remains an important issue, especially in developing countries (Griffin, 2007).
Measles virus (MV), belonging to the genus Morbillivirus of the family Paramyxoviridae, is an enveloped virus with a non-segmented negative strand RNA genome. The MV genome has six genes that encode the nucleocapsid (N), phospho (P), matrix (M), fusion (F), hemagglutinin (H), and large (L) proteins (Figure 1A). MV contains two envelope glycoproteins: the H protein, which is responsible for receptor binding and is important for determining cell tropism of MV; and the F protein, which mediates membrane fusion (Navaratnarajah et al., 2009). The P gene encodes the P protein and the non-structural V and C proteins. The V and C proteins are important for antagonizing the host interferon (IFN) response (Gerlier and Valentin, 2009).
Figure 1. (A) Schematic diagram of measles virus genome. The P gene encodes the P protein and the non-structural V and C proteins. The V protein is translated from an edited RNA with a non-templated G residue. The V protein-specific region is indicated in red. The C protein is translated from an alternative open reading frame (purple) initiated by the second AUG. (B) Isolation of wild-type MV using B95a cells. Pathogenic wild-type MV strains can be isolated by inoculating throat swabs from measles patients in B95a cells. MV strains isolated in Vero cells lose their pathogenicity.
To date, three different molecules have been identified as receptors for MV. Signaling lymphocyte activation molecule (SLAM, also called CD150), expressed in certain immune system cells including activated B and T lymphocytes, mature dendritic cells, and macrophages, is a receptor for wild-type MV and vaccine and laboratory-adapted strains of MV (Tatsuo et al., 2000). CD46 (also called membrane cofactor protein), expressed in all human and monkey nucleated cells, is a receptor for vaccine and laboratory-adapted strains of MV (Dorig et al., 1993; Naniche et al., 1993). Recently, nectin-4 [also called poliovirus-receptor-like-4 (PVRL4)] has been identified as the epithelial receptor for wild-type MV (Muhlebach et al., 2011; Noyce et al., 2011).
Several animal models have been used for studying the pathogenesis of MV (Griffin, 2007). Cotton rats, rats, hamsters, mice, and ferrets can be infected with MV and are commonly used as small animal models for MV pathogenesis. After identification of CD46 and SLAM as MV receptors, numerous transgenic and knock-in mice expressing human CD46 and/or SLAM were established and intensively used to study different aspects of MV infection (Sellin and Horvat, 2009). However, non-human primates are the only animals that exhibit acute disease similar to that seen in humans. In this review, we discuss recent findings regarding tropism and pathogenesis of MV; these findings were obtained by infecting monkeys with recombinant wild-type MV.
Historical Background of Monkey Models
When infected with measles, monkeys exhibit similar symptoms as seen in humans. This was reported as early as 1911, after inoculating monkeys with blood from measles patients (Anderson and Goldberger, 1911). In 1921, it was reported that measles could be transmitted from humans to monkeys by placing a filtered throat swab from a measles patient into the tracheae of monkeys (Blake and Trask, 1921a). These authors also performed histological analysis of infected monkeys (Blake and Trask, 1921b). However, at this time, "MV" had not yet been discovered. MV was first isolated in 1954 from a specimen obtained from a measles patient (Enders and Peebles, 1954). Enders and Peebles (1954) inoculated human and monkey cell cultures with a throat swab taken from a young boy named David Edmonston and isolated MV from these cultures. After this, it was discovered that MV isolated from normal human renal cells caused clinical signs similar to those of human measles in monkeys (Peebles et al., 1957). Since then, numerous studies have been carried out by infecting monkeys with MV, measles vaccines, or specimens from measles patients (Griffin, 2007). In such experiments, two species of monkeys, cynomolgus monkey (Macaca fascicularis) and rhesus monkey (Macaca mulatta), serve as good animal models. New World monkeys are more susceptible to MV than Old World monkeys, and infection of marmoset (Saguinus mystax) with MV results in a fulminant disease (Levy and Mirkovic, 1971; Albrecht et al., 1980).
In the past, it was well known that infection of monkeys with materials from measles patients induced clinical signs similar to those of human measles (Nii et al., 1964; Yamanouchi et al., 1970; Sakaguchi et al., 1986). However, curiously enough, infection of monkeys with MV isolated and propagated in cultured cells did not always induce these clinical signs (Enders et al., 1960; Yamanouchi et al., 1970; van Binnendijk et al., 1994). This riddle was solved by the introduction of B95a cells (a marmoset B-lymphoid cell line) for isolation and propagation of MV (Kobune et al., 1990). Kobune et al. (1990, 1996) found that MV strains could be efficiently isolated in B95a cells using materials from measles patients. More importantly, MV strains isolated from B95a cells retained their original pathogenicity in monkeys. These studies indicated that vaccine and laboratory-adapted strains of MV previously isolated from non-lymphoid cells such as Vero cells were not true MV (Figure 1B). A decade later, it was found that the MV receptor SLAM is highly expressed on B95a cells (Tatsuo et al., 2000), which accounts for the efficient isolation of pathogenic MV from patient samples. Similar to MV strains isolated from B95a cells, MV strains isolated and propagated in monkey mononuclear cells, human cord blood cells, human B lymphoblastoid cell lines, and Vero cells expressing SLAM replicated well in monkeys and induced clinical signs of measles (van Binnendijk et al., 1994; McChesney et al., 1997; Zhu et al., 1997; Auwaerter et al., 1999; El Mubarak et al., 2007; Bankamp et al., 2008). These results suggest that expression of SLAM on cells used for isolation is important for isolation of pathogenic MV.
Reverse Genetics of MV
Reverse genetics refers to the methods used for recovering infectious viruses from the cDNA that encodes the viral genome. By using this method, mutations or extra transcription units can be introduced into viral genomes by the modification of cDNA plasmids. Reverse genetics of MV was first established based on the Edmonston vaccine strain (Radecke et al., 1995). However, as previously mentioned, viruses derived from the Edmonston vaccine strain do not induce clinical symptoms of measles in monkeys. Therefore, reverse genetics of pathogenic wild-type MV was needed for the study of MV pathogenesis in monkeys. To this end, we first determined the complete nucleotide sequence of the genome of the pathogenic wild-type IC-B strain (NC_001498/AB016162; Takeuchi et al., 2000), which was isolated in Tokyo in 1984 by using B95a cells (Kobune et al., 1990). Then, we constructed a complete cDNA plasmid of the IC-B strain named p(+)MV323, and successfully recovered infectious MV (IC323 strain) from the p(+)MV323 plasmid (Takeda et al., 2000). Importantly, the IC323 strain induced clinical signs such as rash, Koplik's spots, and lymphopenia similar to human measles in infected monkeys, indicating that the IC323 strain retains the original pathogenicity of the IC-B strain. Now, infectious MV strains can be easily recovered from cDNA plasmids by using an improved protocol (Takeda et al., 2005).
Reverse genetics of other wild-type MV strains has been reported for the HL strain isolated in Japan (Terao-Muro et al., 2008) and the KS strain isolated in Sudan (Lemon et al., 2011). For vaccine strains of MV, reverse genetics for the Schwarz/Moraten vaccine strain (Combredet et al., 2003; del Valle et al., 2007) and the AIK-C vaccine strain (Nakayama et al., 2001) have also been reported. Reverse genetics for vaccine strains are being used as a platform to generate new multivalent vaccines expressing antigens of other pathogens (Billeter et al., 2009) and oncolytic viruses for cancer therapy (Russell and Peng, 2009).
Function of MV Accessory Proteins in vivo
The P gene of MV encodes two non-structural proteins, namely the C and V proteins. However, the function of the C and V proteins in vivo was not well understood. The C protein is a small (186 amino acid), highly positively charged protein. To study the function of the C protein in the context of the natural course of MV pathogenesis, we generated an IC323 strain deficient in the expression of the C protein, wtMV(C−), by using the reverse genetics of wild-type MV (Takeuchi et al., 2005). Notably, the growth of wtMV(C−) in cynomolgus monkeys was dramatically reduced when compared to the IC323 strain. A similar growth defect of the IC323 strain deficient in the expression of the C protein, Cko, in vivo was observed in rhesus monkeys (Devaux et al., 2008). Interestingly, Cko induced more inflammatory cytokines such as tumor necrosis factor alpha (TNF)-α and interleukin (IL)-6 and interferon (IFN)-α and -β in infected monkeys.
The V protein is translated from an edited mRNA of the P gene (Griffin, 2007). Thus, the amino-terminal domain of the V protein has the same amino acid sequence as the P protein, and the carboxyl-terminal domain of the V protein has a highly conserved amino acid sequence forming a zinc-binding domain, which is important for function as an interferon antagonist (Gerlier and Valentin, 2009). An IC323 strain deficient in the expression of the V protein, Vko, was generated by introducing nucleotide mutations in the RNA-editing signal in the P gene (Devaux et al., 2008). The growth of Vko in infected rhesus monkeys was lower than that of the parental IC323 strain. Vko induced more inflammatory cytokines (TNF-α and IL-6) and IFN-α and -β. An IC323 strain unable to antagonize STAT1 function, STAT1-blind virus, was generated by introducing three amino acid substitutions in the shared domain of the P and V proteins (Devaux et al., 2011). The STAT1-blind virus induced short-lived viremia and no clinical signs in infected rhesus monkeys. This virus induced more inflammatory cytokines (TNF-α and IL-6) and a Th1/Th2 balance cytokine (IL-12) in infected monkeys. Taken together, these findings indicate that the C and V proteins are not non-essential gene products as previously thought, but are stringently required for antagonizing host innate immune and inflammatory responses in vivo.
In contrast, in vitro studies indicated that the V protein blocks IFN-α/β signal transductions in infected cells, inhibits TLR7-mediated IFN-α production in human plasmacytoid dendritic cells, and inhibits IFN induction in infected cells by interacting with MDA5 (Gerlier and Valentin, 2009). Furthermore, the C protein appears to inhibit IFN induction in infected cells by regulating viral RNA synthesis (Nakatsu et al., 2008). Thus, it is necessary to elucidate whether the in vivo phenotypes of C- and V-deficient viruses are similar to the in vitro phenotypes.
MV Tropism in vivo
Recent advances in the study of virus tropism have included the introduction of enhanced green fluorescent protein (EGFP)-expressing viruses. In vivo tropism of Morbillivirus can be visualized with high sensitivity in living animals as well as tissue samples by using EGFP-expressing recombinant canine distemper viruses (von Messling et al., 2004). Similarly, MV target tissues or organs can be visualized with high sensitivity by infecting cynomolgus monkeys with an EGFP-expressing IC323 strain (Figure 2). de Swart et al. (2007) infected rhesus and cynomolgus monkeys with an IC323 strain expressing EGFP (Hashimoto et al., 2002) and examined the tropism of wild-type MV in vivo. They indicated that the major target cells of wild-type MV were B and T lymphocytes and CD11c-positive, major histocompatibility complex (MHC) class-II-positive dendritic cells. This result is consistent with the fact that SLAM is a receptor for wild-type MV. Infection of ciliated epithelial cells in the trachea and lungs was also detected, suggesting the presence of another receptor for MV in epithelial cells.
Figure 2. Schematic diagram of reverse genetics of wild-type MV expressing EGFP and infection of monkeys. A plasmid carrying the full-genome cDNA of the IC-B strain and the EGFP gene under the control of the T7 promoter is introduced into CHO cells expressing human SLAM (CHO/hSLAM), along with three supporting plasmids expressing N, P, and L proteins, respectively, under the control of the T7 promoter. After infection with vaccinia virus expressing the T7 RNA polymerase, wild-type MV expressing EGFP can be recovered by mixing with B95a cells. EGFP fluorescence in tissues and organs of infected monkeys can be detected using a fluorescence microscope.
Regarding the early target cells of wild-type MV, classical textbooks describe that the primary targets of MV are the epithelial cells of the respiratory tract. However, SLAM is not expressed in these epithelial cells. To examine the early target cells of wild-type and vaccine strains of MV in the lung, de Vries et al. (2010) infected cynomolgus monkeys with EGFP-expressing IC323 or vaccine strains of MV via the intratracheal or aerosol route. They found that CD11c-positive cells, which include alveolar macrophages and dendritic cells, were the major targets of both viruses. Interestingly, although viral replication and cellular tropism in the lungs were similar for the two viruses, only wild-type MV caused significant viremia, suggesting a growth defect of the vaccine strain in lymphocyte cells. Similarly, to examine the early target cells of wild-type MV, Lemon et al. (2011) infected cynomolgus monkeys with an EGFP-expressing wild-type MV based on the KS strain by aerosol infection and found that the early target cells of wild-type MV in monkeys are macrophages and dendritic cells. These studies indicated that alveolar macrophages and dendritic cells but not the epithelial cells of the respiratory tract are the early target cells of wild-type MV.
Nectin-4 is a newly identified epithelial cell receptor (EpR) for MV. To examine the effect of nectin-4-using activity of MV on disease outcomes in monkeys, an IC323 strain recognizing SLAM but not nectin-4 was generated by introducing amino acid mutations in the H protein (Leonard et al., 2008). At that time, nectin-4 had not been identified as a MV receptor, and this strain was called EpR-blind virus. When rhesus monkeys were infected with EpR-blind virus via the conjunctiva and nares, this virus induced viremia and clinical signs in infected monkeys but did not propagate in the lungs. This result indicates the importance of nectin-4 for the propagation of MV in the lungs, which is required for the subsequent exit of MV from the host. Inversely, to examine the impact of the recognition of SLAM by MV, an IC323 strain recognizing nectin-4 but not SLAM, SLAM-blind, was generated (Leonard et al., 2010). When rhesus monkeys were infected with the SLAM-blind virus, it elicited no clinical symptoms. This result indicates that SLAM recognition is necessary for MV virulence and pathogenesis.
Vaccine and laboratory-adapted strains of MV can utilize both CD46 and SLAM as cellular receptors. However, surprisingly, the impact of the CD46-using activity of vaccine and laboratory-adapted strains of MV on their tissue and organ tropism and attenuation is not well understood. As CD46 is ubiquitously expressed on all nucleated human and monkey cells, vaccine, and laboratory-adapted strains of MV may infect all tissues and organs of humans and monkeys. If so, this tropism shift may have great consequences on vaccine attenuation. In this context, de Vries et al. (2010) indicated that only CD11c-positive cells were infected with the EGFP-expressing vaccine strain via the aerosol route, suggesting that vaccine strains do not use CD46 in vivo. However, when the replication of vaccine and laboratory-adapted strains of MV in monkeys is limited, it will be difficult to identify infected cells in tissues. Furthermore, the infection of vaccine and laboratory-adapted strains of MV may be restricted because of mutations in the P/C/V genes, which are important for antagonizing the host IFN response (Gerlier and Valentin, 2009). Therefore, the tropism shift that solely occurs via the H protein should be evaluated using the wild-type MV expressing EGFP, which bears the H protein of a vaccine strain, such as the IC/EdH strain we developed previously (Takeuchi et al., 2002).
We recently infected cynomolgus monkeys with EGFP-expressing wild-type or IC/EdH strains and found that SLAM-expressing lymphocytes were the main targets of both strains, indicating that CD46 does not act as a receptor for vaccine and laboratory-adapted strains of MV in vivo (Figure 3; Takeuchi et al., 2012). One possible explanation for the limited expansion of the EGFP-expressing IC/EdH strain in vivo is the activation status of lymphocytes. It is known that stimulated lymphocytes are efficiently infected with MV and that stimulated lymphocytes express SLAM (Tatsuo et al., 2000). Thus, lymphocytes expressing SLAM may appear to be infected with both strains. The EGFP-expressing IC/EdH strain that entered into quiescent lymphocytes via the CD46 may not grow well in those cells. Alternatively, the expression level of CD46 in vivo may be too low to allow MV dissemination by cell–cell fusion, as it was reported that high CD46 density is required for MV-induced cell–cell fusion (Anderson et al., 2004). For whatever the reason, the growth of the EGFP-expressing IC/EdH strain was less efficient than that of the EGFP-expressing wild-type strain (Takeuchi et al., 2012), suggesting that the CD46-recognition ability of vaccine and laboratory-adapted MV strains plays a role in the MV attenuation. Further studies are required to elucidate the relationship between CD46-recognition ability and MV attenuation.
Figure 3. Receptor usage of the wild-type and vaccine and laboratory-adapted strains of MV. Nectin-4 is a recently identified epithelial cell receptor for MV.
As described in this review, our IC323 strain, recovered from a plasmid carrying the full-genome cDNA of the IC-B strain, is now used as a standard wild-type MV strain in MV research. Furthermore, EGFP-expressing IC323 strains are ideal tools for the study of tissue and organ tropism of wild-type MV in vivo. Although the use of monkeys has several limitations, monkey models still provide the only reliable animal model for the study of the pathogenesis of MV in humans. The combination of wild-type and vaccine MV strains generated by reverse genetics and monkey models will provide new insights into the relationship between viral gene functions or individual mutation(s) and the pathogenesis of MV.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This paper was supported by a grant-in-aid (No. 23659227) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Enders, J. F., and Peebles, T. C. (1954). Propagation in tissue cultures of cytopathic agents from patients with measles. Proc. Soc. Exp. Biol. Med. 86, 277–286.
Gerlier, D., and Valentin, H. (2009). Measles virus interaction with host cells and impact on innate immunity. Curr. Top. Microbiol. Immunol. 329, 163–191.
Griffin, D. E. (2007). "Measles virus," in Fields Virology, 5th Edn, eds D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman, and S. E. Straus (Philadelphia, PA: Lippincott Williams & Wilkins), 1551–1585.
Hashimoto, K., Ono, N., Tatsuo, H., Minagawa, H., Takeda, M., Takeuchi, K., and Yanagi, Y. (2002). SLAM (CD150)-independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein. J. Virol. 76, 6743–6749.
Kobune, F., Sakata, H., and Sugiura, A. (1990). Marmoset lymphoblastoid cells as a sensitive host for isolation of measles virus. J. Virol. 64, 700–705.
Kobune, F., Takahashi, H., Terao, K., Ohkawa, T., Ami, Y., Suzaki, Y., Nagata, N., Sakata, H., Yamanouchi, K., and Kai, C. (1996). Nonhuman primate models of measles. Lab. Anim. Sci. 46, 315–320.
Lemon, K., de Vries, R. D., Mesman, A. W., McQuaid, S., van Amerongen, G., Yuksel, S., Ludlow, M., Rennick, L. J., Kuiken, T., Rima, B. K., Geijtenbeek, T. B. H., Osterhaus, A. D. M. E., Duprex, W. P., and de Swart, R. L. (2011). Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathog. 7, e1001263. doi: 10.1371/journal.ppat.1001263
Leonard, V. H. J., Hodge, G., Valle, J. R., McChesney, M. B., and Cattaneo, R. (2010). Measles virus selectively blind to signaling lymphocytes activation molecule (SLAM; CD150) is attenuated and induces strong adaptive immune responses in rhesus monkeys. J. Virol. 84, 3413–3420.
Leonard, V. H. J., Sinn, P. L., Hodge, G., Miest, T., Devaux, P., Oezguen, N., Braun, W., McCray, P. B. Jr., McChesney, M. B., and Cattaneo, R. (2008). Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. J. Clin. Invest. 118, 2448–2458.
Levy, B. M., and Mirkovic, R. R. (1971). An epizootic of measles in a marmoset colony. Lab. Anim. Sci. 21, 33–39.
McChesney, M. B., Miller, C. J., Rota, P. A., Zhu, Y., Antipa, L., Lerche, N. W., Ahmed, R., and Bellini, W. J. (1997). Experimental measles. I. Pathogenesis in the normal and the immunized host. Virology 233, 74–84.
Muhlebach, M. D., Mateo, M., Sinn, P. L., Prufer, S., Uhlig, K. M., Leonard, V. H., Navaratnarajah, C. K., Frenzke, M., Wong, X. X., Sawatsky, B., Ramachandran, S., McCray, P. B. Jr., Cichutek, K., von Messling, V., Lopez, M., and Cattaneo, R. (2011). Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 480, 530–533.
Nakatsu, Y., Takeda, M., Ohno, S., Shirogane, Y., Iwasaki, M., and Yanagi, Y. (2008). Measles virus circumvents the host interferon response by different actions of the C and V proteins. J. Virol. 82, 8296–8306.
Nakayama, T., Komase, K., Uzuka, R., Hoshi, A., and Okafuji, T. (2001). Leucine at position 278 of the AIK-C measles virus vaccine strain fusion protein is responsible for reduced syncytium formation. J. Gen. Virol. 82, 2143–2150.
Naniche, D., Varior-Krishnan, G., Cervoni, F., Wild, T. F., Rossi, B., Rabourdin-Combe, C., and Gerlier, D. (1993). Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032.
Navaratnarajah, C. K., Leonard, V. H. J., and Cattaneo, R. (2009). Measles virus glycoprotein complex assembly, receptor attachment, and cell entry. Curr. Top. Microbiol. Immunol. 329, 59–76.
Nii, S., Kamahora, J., Mori, Y., Takahashi, M., Nishimura, S., and Okuno, Y. (1964). Experimental pathology of measles in monkeys. Biken J. 6, 271–297.
Noyce, R. S., Bondre, D. G., Ha, M. N., Lin, L. T., Sisson, G., Tsao, M. S., and Richardson, C. D. (2011). Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus. PLoS Pathog. 7, e1002240. doi: 10.1371/journal.ppat.1002240
Peebles, T. C., McCarthy, K., Enders, J. F., and Holloway, A. (1957). Behavior of monkeys after inoculation of virus derived from patients with measles and propagated in tissue culture together with observations on spontaneous infections of these animals by an agent exhibiting similar antigenic properties. J. Immunol. 78, 63–74.
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Russell, S. J., and Peng, K. W. (2009). Measles virus for cancer therapy. Curr. Top. Microbiol. Immunol. 330, 213–241.
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Sellin, C. I., and Horvat, B. (2009). Current animal models: transgenic animal models for study of measles pathogenesis. Curr. Top. Microbiol. Immunol. 330, 111–127.
Takeda, M., Ohno, S., Seki, F., Hashimoto, K., Miyajima, N., Takeuchi, K., and Yanagi, Y. (2005). Efficient rescue of measles virus from cloned cDNA using SLAM-expressing Chinese hamster ovary cells. Virus Res. 108, 161–165.
Takeda, M., Takeuchi, K., Miyajima, N., Kobune, F., Ami, Y., Nagata, N., Suzaki, Y., Nagai, Y., and Tashiro, M. (2000). Recovery of pathogenic measles virus from cloned cDNA. J. Virol. 74, 6643–6647.
Takeuchi, K., Miyajima, N., Kobune, F., and Tashiro, M. (2000). Comparative nucleotide sequence analyses of the entire genomes of B95a cell-isolated and Vero cell-isolated measles viruses from the same patient. Virus Genes 20, 253–257.
Takeuchi, K., Nagata, N., Kato, S., Ami, Y., Suzaki, Y., Suzuki, T., Sato, Y., Tsunetsugu-Yokota, Y., Mori, K., Nguyen, V. N., Kimura, H., and Nagata, K. (2012). Wild-type measles virus with the hemagglutinin protein of the Edmonston vaccine strain retains wild-type tropism in macaques. J. Virol. PMID: 22238320. [Epub ahead of print].
Takeuchi, K., Takeda, M., Miyajima, N., Ami, Y., Nagata, N., Suzaki, Y., Shahnewaz, J., Kadota, S., and Nagata, K. (2005). Stringent requirement for the C protein of wild-type measles virus for growth in vitro and in macaques. J. Virol. 79, 7838–7844.
Takeuchi, K., Takeda, M., Miyajima, N., Kobune, F., Tanabayashi, K., and Tashiro, M. (2002). Recombinant wild-type and Edmonston strain measles viruses bearing heterologous H proteins: role of H protein in cell fusion and host cell specificity. J. Virol. 76, 4891–4900.
Tatsuo, H., Ono, N., Tanaka, K., and Yanagi, Y. (2000). SLAM (CDw150) is a cellular receptor for measles virus. Nature 406, 893–897.
Terao-Muro, Y., Yoneda, M., Seki, T., Watanabe, A., Tsukiyama-Kohara, K., Fujita, K., and Kai, C. (2008). Heparin-like glycosaminoglycans prevent the infection of measles virus in SLAM-negative cell lines. Antiviral Res. 80, 370–376.
van Binnendijk, R. S., van der Heijden, R. W., van Amerongen, G., UytdeHaag, F. G., and Osterhaus, A. D. (1994). Viral replication and development of specific immunity in macaques after infection with different measles virus strains. J. Infect. Dis. 170, 443–448.
von Messling, V., Milosevic, D., and Cattaneo, R. (2004). Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system. Proc. Natl. Acad. Sci. U.S.A. 101, 14216–14221.
Yamanouchi, K., Egashira, Y., Uchida, N., Kodama, H., Kobune, F., Hayami, M., Fukuda, A., and Shishido, A. (1970). Giant cell formation in lymphoid tissue of monkeys inoculated with various strains of measles virus. Jpn. J. Med. Sci. Biol. 23, 131–145.
Zhu, Y., Heath, J., Collins, J., Greene, T., Antipa, L., Rota, P., Bellini, W., and McChesney, M. (1997). Experimental measles. II. Infection and immunity in the rhesus macaque. Virology 233, 85–92.
Keywords: measles virus, monkey, pathogenesis, tropism, reverse genetics, receptor, EGFP
Citation: Kato S-i, Nagata K and Takeuchi K (2012) Cell tropism and pathogenesis of measles virus in monkeys. Front. Microbio. 3:14. doi: 10.3389/fmicb.2012.00014
Received: 30 November 2011; Accepted: 09 January 2012;
Published online: 30 January 2012.
Edited by:Yasuko Yokota, National Institute of Infectious Diseases, Japan
Reviewed by:Yasuko Yokota, National Institute of Infectious Diseases, Japan
Michael D. Muehlebach, Paul-Ehrlich-Institut, Germany
Katsuhiro Komase, National Institute of Infectious Diseases, Japan
Copyright: © 2012 Kato, Nagata and Takeuchi. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
*Correspondence: Kaoru Takeuchi, Division of Biomedical Science, Department of Infection Biology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. e-mail: email@example.com


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Date Posted: Tuesday, January 12, 2016
StateScoop published an article today examining how state lawmakers introduced twice as many bills involving cybersecurity issues in 2015 compared to a year ago, according to a review of legislative analytics company FiscalNote's database. Virginia passed a pair of bills in March to more aggressively shield cybersecurity information.
For additional information contact VITA Communications at firstname.lastname@example.com


text: GrowthWorks WV Management Becomes Manager of Income FundClosing Date: Dec 2, 2002 lexpert Tweet On December 2, 2002, Toronto-headquartered Working Ventures announced that agreements were entered into with Vancouver-based GrowthWorks Ltd. under which its subsidiary GrowthWorks WV Management Ltd. will become the new manager of Working Ventures Canadian Fund and Working Ventures Opportunity Fund, formerly Working Ventures II Technology Fund. The Working Ventures funds are sponsored by the Canadian Federation of Labour and together are one of Canada's largest national venture capital fund groups. With over $700 million in combined assets under management as a result of the new arrangements, GrowthWorks is the third-largest labour sponsored venture capital fund manager in Canada. Under the agreements, GrowthWorks WV Management acquired all the shares of GrowthWorks (WVIS) Ltd., formerly Working Ventures Investment Services Inc., the current manager of the Working Ventures funds. During a transition period, which is not expected to exceed 12 months, GrowthWorks WV Management will manage the Working Ventures funds through the current manager pursuant to the existing management agreements. After the transition period, GrowthWorks WV Management will manage the Working Ventures funds under a new management agreement. Working Ventures was represented in-house by Susan Silma, general counsel, and by McMillan Binch LLP with a team that included Margaret McNee, Beverley Flynn, Walter Lehman, Shendra Matijacish, Andrew McFarlane and Kimberly Poster (corporate and securities) and David Wentzell (tax). Alex Irwin, Tamara Howarth and Jill McFarlane (corporate finance and securities) of Irwin, White & Jennings in Vancouver represented GrowthWorks. Lawyer(s):Kimberly J. Poster,Tamara L. Howarth,Alexander H. Irwin,Andrew E.C. McFarlane,Shendra Matijasich,Beverley G. Flynn,Margaret C. McNee,Walter C. Lehman,David G. WentzellFirm(s):McMillan LLP,Irwin, White & Jennings


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BEGIN:VCALENDAR VERSION:2.0 PRODID:-//www.stjoseph-baden.org//NONSGML kigkonsult.se iCalcreator 2.26.9/ / CALSCALE:GREGORIAN METHOD:PUBLISH X-WR-CALNAME:Sisters of St. Joseph X-WR-CALDESC:Serving God and the Dear Neighbor without Distinction X-FROM-URL:https://www.stjoseph-baden.org X-WR-TIMEZONE:America/New_York BEGIN:VTIMEZONE TZID:America/New_York X-LIC-LOCATION:America/New_York BEGIN:STANDARD DTSTART:20201101T020000 TZOFFSETFROM:-0400 TZOFFSETTO:-0500 RDATE:20211107T020000 TZNAME:EST END:STANDARD BEGIN:DAYLIGHT DTSTART:20200308T020000 TZOFFSETFROM:-0500 TZOFFSETTO:-0400 RDATE:20210314T020000,20220313T020000 TZNAME:EDT END:DAYLIGHT END:VTIMEZONE BEGIN:VEVENT UID:firstname.lastname@example.com DTSTAMP:20200922T225500Z CATEGORIES: CONTACT:Sister Valerie Zottola\; firstname.lastname@example.com DESCRIPTION:Our December Adoration\, Praise and Retreat Day has been cancel ed. If future Adoration dates are scheduled\, they will be announced on ou r website and Facebook page. Thank you!\nJoin us for an afternoon of praye r\, beginning with music in our chapel to draw us deeper into God's presen ce. This is followed by a brief reflection\, Adoration of the Blessed Sacr ament\, a variety of options of prayer\, and a social to conclude the afte rnoon. This is one of three Adoration gatherings co-sponsored by our Vocat ions Office and St. Joseph Spirituality Center.\nAdoration Dates: Saturday s from 12:30-3:00 PM\nSeptember 22\, December 8 and March 23\nCost: There is no cost for these events\, but registration is requested.\nTickets: htt ps://docs.google.com/forms/d/e/1FAIpQLSdZtxSpDOgmh1YTdFAsXZInAMvRV1CtqtOni obJvTxTZxi_9Q/viewform. DTSTART;TZID=America/New_York:20181208T123000 DTEND;TZID=America/New_York:20181208T150000 GEO:+40.647937;-80.232484 LOCATION:Sisters of St. Joseph Chapel/Grounds @ 1020 W State St\, Baden\, P A 15005\, USA RDATE;TZID=America/New_York:20181208T123000 RDATE;TZID=America/New_York:20190323T123000 SEQUENCE:7480 SUMMARY:Adoration *CANCELED* URL:https://www.stjoseph-baden.org/event/adoration-praise-and-retreat-day/ X-COST-TYPE:external X-ALT-DESC;FMTTYPE=text/html:\\n\\n\\n
Our December Adoration\, Praise and Retreat Day has been canceled. If future Adoration dates are scheduled\, they will be announced on our website and Fa cebook page. Thank you!\n
Join us for an afterno on of prayer\, beginning with music in our chapel to draw us deeper into G od's presence. This is followed by a brief reflection\, Adoration of the B lessed Sacrament\, a variety of options of prayer\, and a social to conclu de the afternoon. This is one of three Adoration gatherings co-sponsored b y our Vocations Office and St. Joseph Spirituality Center.\n
\nSeptember 22\, December 8 and March 23
Cost: There is no c ost for these events\, but registratio n is requested.\n
Tickets: https://docs.google.com/forms/d/e/1FAIpQL SdZtxSpDOgmh1YTdFAsXZInAMvRV1CtqtOniobJvTxTZxi_9Q/viewform.X-TICKETS-URL:https://docs.google.com/forms/d/e/1FAIpQLSdZtxSpDOgmh1YTdFAsX ZInAMvRV1CtqtOniobJvTxTZxi_9Q/viewform END:VEVENT END:VCALENDAR


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Why sleep on a single memory foam bed when you can enjoy the comfort of 700 tiny mattresses. Each independent cushion hugs your body to offer the ideal balance between spine support and comfort.
The sleep innovation bed outshines any other hybrid mattress you have come across. Unlike a regular foam bed that uses a few layers of foam material over a coil system, the SleepOvation has a three-inch piece of foam suspended above each independent coil.
The good thing about the small units of foam is that they do a great job of conforming to your body. They do this for every sleeping position. This ensures that your spine is always properly aligned. Continue reading to learn more about this unique product.
Your Takeaways:
- 1 Who is Suitable for SleepOvation?
- 2 Who is Not Suitable for SleepOvation?
- 3 Construction and Materials of SleepOvation Mattress
- 4 Firmness and Sleeping Experience
- 5 Delivery and Off-Gassing
- 6 Sleep Trial, Return, Warranty
- 7 Price
- 8 Final Review
Who is Suitable for SleepOvation?
The SleepOvation is suitable for pinpoint pressure relief for the joint and backache. The 700 tiny units conform to the shape of your body to provide optimum pressure relief, ensuring that you do not turn and toss during sleep.
This is the bed for you if you want a cool sleeping surface. The cushion layer is equipped with an active airflow system that allows you to sleep cool. You will wake up fully rejuvenated.
Apart from great conformity, this mattress has a superb pressure response. This allows you to change sleeping positions without feeling stuck in the bed. It also has superior motion isolation that allows you to sleep with your partner, kid, or pet without any disturbance.
Who is Not Suitable for SleepOvation?
The SleepOvation mattress may not be suitable for people who prefer an extra firm or extra soft bed. This may also not be a suitable choice for you if you are after a pure innerspring, latex or memory foam.
Construction and Materials of SleepOvation Mattress
The first thing you will notice is that underneath the removable, zippered, knit cover is a miniature cushion pad that provides a little bit more consistency, but also it is loose enough to allow for each of the pieces to work independently.
You can take off the miniature cushion pad just like you would a normal mattress pad. This will allow you to see the 700 foam pieces we mentioned earlier.
Each individual cushion measures 2.25 by 2.25 by 3 inches and made of hybrid high-density foam cylinder optimized for the brand's CPS technology. The independent foam cylinders are encased in cushion pockets.
Each pocket coil spring is made up of eight-inch of first-rate high carbon steel that is wrapped in a fabric pocket. Then each foam cylinder is attached to its own independent pocket coil spring to complete the assembly.
Firmness and Sleeping Experience
We give this bed a firmness feel of 5 out of 10, 10 being the firmest. This is a medium firmness setting that is suitable for most sleeping positions. Unlike conventional hybrid beds, the SleepOvation tiny mattress technology makes it ideal for side, back, and stomach sleeping.
When you sleep on your back, the bed conforms right into the spine, and it takes the pressure off, even on the neck without a pillow. This ensures that there are no gaps between the mattress and your body.
The independent suspension foam of each cylinder supports every bone of your spine separately. The foam cylinders cradle and shape the curves of your body, while delivering adequate firmness for your back's bony and muscular structures.
This is definitely a great choice for side sleeping. The medium firmness allows your body to sink in the mattress. This allows superior conformity between you and the mattress. As a result, the shoulders, hips, and soles. This eliminates any pressure points while sleeping on the side.
This may also be a good choice for most stomach sleepers. When you sleep on your stomach, the SleepOvation allows your entire body to sink in without creating pressure. This feature prevents your hips from sinking in, allowing you to maintain proper spinal alignment.
The tiny mattress technology uses the pressure applied by the body to smoothly stretch the back as well as spinal column. This amazing traction slowly increases the space between the vertebrae, which alleviates back pain and improves blood circulation.
The individual foam pieces use the body's weight to disperse pressure from the lumbar area through the legs and down to the feet. The patented support coils below the tiny foams provide the required body support.
The SleepOvation is proven to dissipate pressure points as well as muscular contractions. The integrated miniature cushion pad is pressure sensitive as opposed to heat sensitive and contours to the body for long lasting support and comfort.
The breathable, outlast, knit cover is a good temperature regulating material, which along with the numerous air channels helps you to sleep cool and more comfortable for longer.
Responsiveness and Motion Transfer
The integrated miniature cushion pad improves the elasticity that has already been developed by the individual foam cylinders. This is what allows the bed to conform to your body curves without the firmness setting of one area affecting another.
When you push into the mattress, the independent foams respond quickly and separately. This tells you how responsive the underlying individual springs are. The fast response allows the bed to adjust easily to the weight and size of separate sleepers.
Apart from the amazing spinal support and comfort, the distinctive structure of SleepOvation mattress allows for superior motion isolation for a hybrid. The individually assembled pieces of foam create columns and rows.
The columns and arrows isolate movements to where they occur. During our drop test, the weight bounces back quickly with very little motion transfer. You would hardly feel the movement if you were sleeping on the other side of the bed.
Sleeping Cool
If you have been looking for a bed that delivers unmatched cooling, then SleepOvation mattress is the ideal choice. The unique tiny mattress technology is superb from a cooling perspective.
The 700 individual foam pieces create air channels, which develop an excess of airflow, providing a cooler sleeping surface. The air channels are particularly made to maintain cooler temperatures for a revitalizing night's sleep.
The cover is thin and soft, and looks very appealing and attractive. It is made of stretch and elastin knit polyester fabric that is flexible, strong, resists shrinking and wrinkles, breathable, and dries quickly.
The cover is made to complement the seven hundred tiny foam pieces. This feature gives the bed the ability to adjust to personal weight and size. The cover comes with zippered closure, allowing you to remove it for cleaning or access to the tiny mattresses layer.
Edge Support
The one thing that can go wrong about the SleepOvation construction is the ability to provide a solid perimeter, especially for people who like to sit on the edges. This bed is very effective at distributing body weight evenly during sleeping.
However, the tiny mattress technology is not adequately reinforced for edge support. This is usually most visible if you need to use your bed for sitting. When sitting on the edge, you get to sink inwards but on the sliding of position.
Delivery and Off-Gassing
Once you place an order of your brand new SleepOvation bed, it will ship in about two weeks' time. The bed will be delivered compress in a box.
The regular box may be difficult to move for a single person. So, you should consider the back saver box that is fitted with wheels for easier transportation.
This mattress is GREENGUARD Gold certified and designed in the United States with Certi-PUR foams. This simply means that the bed does not sit too long in a warehouse or shipped internationally.
Therefore, the top quality materials do hardly produce noxious off-gassing. However, you will notice some form of smell that is emitted by the plastic material that comes with the shipment.
If you are too sensitive to plastic odor, you should give the bed twenty-four hours or more for the smell to disappear. You should also make sure the bedroom is properly ventilated.
Sleep Trial, Return, Warranty
The brand gives you 100 risk-free nights to test the performance of the bed. You are required to give the mattress at least 30 nights to adjust to your body before you can decide whether or not it is a good choice for your needs.
If after 30 nights you are still unsatisfied with the performance of the SleepOvation, then you should return it within the 100 night trial period. The company will pick the bed for free from your house and refund your money.
The SleepOvation mattress comes with a 10 year limited warranty. This cover allows you specific rights, which may vary from one state to another. The cover is only viable for the original buyer, change of ownership cancels the warranty.
|Price ($)
|Twin XL
|Cal King
Final Review
With SleepOvation tiny mattress technology, you are basically sleeping on seven hundred tiny mattresses. This bed is the breakthrough of a steadfast team of experts with years of experience, creating the most unique bed in the industry.
Not only is the bed made in the United States, it also provides seven hundred pressure relief points. Not to mention that it is endorsed by chiropractors. As far as a bed in box mattresses are concerned, SleepOvation is one of a kind.


text: Greater Cincinnati Looks to Us for Geothermal Heating & Cooling! We're Bill Spade Electric, Heating & Cooling. And we're known throughout Greater Cincinnati, Ohio, for our geothermal heating and cooling expertise. People turn to us for ... superior geothermal system installation and service qualified, highly trained personnel who understand every detail of geothermal heating and cooling - and know how to effectively communicate the process to you geothermal systems from one of the industry's most trusted names - WaterFurnace advice on how to get the most from their geothermal heating and cooling installation Obviously, a significant reason people look to us to begin with is for the savings they can get on their energy bills with a geothermal system. Want a snap shot? Give our Geothermal Savings Calculator a go. Then take the next step and contact Bill Spade Electric, Heating & Cooling. We'll walk you through more of what makes geothermal systems the optimum choice for year-round heating and cooling comfort in Greater Cincinnati.


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Ensuring the Safest Environment Possible for Homeowners
March 15, 2018
SEELEY LAKE – Purchasing a home in the Seeley-Swan area just got a little easier. John Homen, co-owner of Homen Hearth of Seeley Lake, recently passed his state and national home inspector certification. Homen's desire is to provide the safest environment for the homeowners and provide the best possible services so the potential home buyer has a good understanding of what they are purchasing.
Homen and his wife Rachel started their chimney cleaning service Homen Hearth in June 2013. Homen has an Associate in Applied Sciences (AAS) degree in facility maintenance and heating systems and a...
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November 24th, 2018 by WCBC Radio
Allegany County Emergency Management reports a multi vehicle crash on the Clarysville Bridge on Interstate 68 West. Five vehicles were involved and three people have been transported from the scene. I 68 West is currently closed as the scene is being cleared. Police and emergency units remain on the scene.


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On the Survival of Overconfident Traders in A Competitive Securities Market
David Hirshleifer and Guo Ying Luo
Journal of Financial Markets, January 2001
Recent research has proposed several ways in which overconfident traders can persist in competition with rational traders. This paper offers an additional reason: overconfident traders do better than purely rational traders at exploiting mispricing caused by liquidity or noise traders. We examine both the static profitability of overconfident versus rational trading strategies, and the dynamic evolution of a population of overconfident, rational and noise traders. Replication of overconfident and rational types is assumed to be increasing in the recent profitability of their strategies. The main result is that the long-run steady-state equilibrium always involves overconfident traders as a substantial positive fraction of the population.


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The Game Over crew take over Lío
When winter started, a question on a lot of island dwellers minds was whether Pacha would open for the off-season. It wasn't long until we got the answer from the company – this year unfortunately not. However, coupled with this we got a delightful piece of news that the brand's glittering Marina Botafoch dining and partying destination Lío was staying open for business.
Amongst the parties to take up residence in the lavish halls are Lift. The collective that pops up during the colder months is powered by the Game Over crew, who are well known for their summer One Night Stand party pop-ups and retro residency, WILDCHILD.
This year they have signed up for a series of shows to see off the rest of the year. Three dates remain; Saturday 23rd November, Thursday 5th December and Saturday 21st December. As one of the most exciting party enterprises active at the moment, the club night is worth marking the date in the calendar.
When you step into a Lift club night you are not quite sure what to expect. From Ibiza residents to well off winter travellers, the usually universal mix of clientele make for an intriguing dance floor congregation. But as the night progresses from post-dinner drinks to past-midnight delights, you can see a common theme amongst the guests – they all love to party all night long.
On this particular evening, Dave Lubin, Javi Bora and Dave Mantra were in session behind the DJ booth. Having witnessed the skills of all three DJ previously, we knew that the audience was in for a good show. An hour after hour they kept creeping the tempo and the energy up just a little to keep the intimate club space bustling.
In the early hours, Dave Lubin kicked things off with a more downtempo blend matching the casual atmosphere. Constantly analysing the floor, he grabbed any opportunity given to entice more and more guests to stay for 'one more drink' or 'just the next tune'. This is how a perfect warm-up DJ operates and gets you hooked on the party vibe.
As the intimate room started to fill, it was entertaining to listen to the music style fluctuate from rarities and underground sounds to more mainstream affair. Some tracks like Purple Disco Machine's remix of Joys were massive club hits of the summer, so naturally went down like a charm with the grooving crowd.
Game Over cohort, Dave Mantra stepped things up a gear as he took the helm next. A firm favourite when he played DC-10 earlier this year, he channelled that same raving spirit for the Lift attendees. As he mixed in Bappi by Jamie Jones & The Martinez Brothers as his final tune, the last set was met by rapturous applause – job well done Dave.
The best was yet to come. Javi Bora was intent in keeping the patrons of Lío in for the long run, so he upped the ante with banger after banger. Although it was Patrick Topping's Turbo Time that really got us moving. A product of the newly formed Trick label, the screaming vocals and thudding electro bassline is a bone fide stomper.
As the early hours of the morning approached, Dave Lubin took over the controls once again, opting for again for a slower approach, even heading into hip-hop territory, something he is well known at parties like Keep On Dancing. We left the remaining crowd to it, having danced our shoes off. We were certain of one thing however – we'll definitely be going to Lift again this Winter.