text:
- Software
- Open Access
PoPMuSiC 2.1: a web server for the estimation of protein stability changes upon mutation and sequence optimality
- Yves Dehouck1Email author,
- Jean Marc Kwasigroch1,
- Dimitri Gilis1 and
- Marianne Rooman1
© Dehouck et al; licensee BioMed Central Ltd. 2011
- Received: 27 December 2010
- Accepted: 13 May 2011
- Published: 13 May 2011
The rational design of modified proteins with controlled stability is of extreme importance in a whole range of applications, notably in the biotechnological and environmental areas, where proteins are used for their catalytic or other functional activities. Future breakthroughs in medical research may also be expected from an improved understanding of the effect of naturally occurring disease-causing mutations on the molecular level.
PoPMuSiC-2.1 is a web server that predicts the thermodynamic stability changes caused by single site mutations in proteins, using a linear combination of statistical potentials whose coefficients depend on the solvent accessibility of the mutated residue. PoPMuSiC presents good prediction performances (correlation coefficient of 0.8 between predicted and measured stability changes, in cross validation, after exclusion of 10% outliers). It is moreover very fast, allowing the prediction of the stability changes resulting from all possible mutations in a medium size protein in less than a minute. This unique functionality is user-friendly implemented in PoPMuSiC and is particularly easy to exploit. Another new functionality of our server concerns the estimation of the optimality of each amino acid in the sequence, with respect to the stability of the structure. It may be used to detect structural weaknesses, i.e. clusters of non-optimal residues, which represent particularly interesting sites for introducing targeted mutations. This sequence optimality data is also expected to have significant implications in the prediction and the analysis of particular structural or functional protein regions. To illustrate the interest of this new functionality, we apply it to a dataset of known catalytic sites, and show that a much larger than average concentration of structural weaknesses is detected, quantifying how these sites have been optimized for function rather than stability.
The freely available PoPMuSiC-2.1 web server is highly useful for identifying very rapidly a list of possibly relevant mutations with the desired stability properties, on which subsequent experimental studies can be focused. It can also be used to detect sequence regions corresponding to structural weaknesses, which could be functionally important or structurally delicate regions, with obvious applications in rational protein design.
- Catalytic Site
- Protein Stability
- Catalytic Residue
- Solvent Accessibility
- Structural Weakness
The availability of computational tools yielding reasonably accurate estimations of the impact of amino acid substitutions on the stability of proteins is of crucial importance in a wide range of applications. In particular, such tools have the potential to stimulate and support protein engineering and design projects dedicated to the creation of modified proteins that remain active in non-physiological conditions, or that present enhanced functional properties [1, 2]. On the other hand, advances in the ability to predict and rationalize the functional effect of naturally occurring amino acid variants and their relationship to disease will have tremendous implications in medicine. Indeed, they can be expected to lead to significant improvements in the understanding of the mechanisms of various diseases, to the development of enhanced diagnostics, new therapeutic approaches, and more personalized treatment options [3, 4]. Although approaches based on multiple sequence alignments remain predominant in this context, predictions of stability changes upon mutation have been recognized as a relevant input in the identification of deleterious and disease-causing mutations [4–7]. On a more fundamental level, the analysis of the predicted distributions of stabilizing or destabilizing mutations in sets of natural or engineered proteins may be extremely valuable to refine our understanding of the relationships between protein sequence, structure, and function [8–11], or to probe the evolutionary dynamics of protein sequences [11–14].
Over the last decade, several methods have been developed to predict the effects of mutations on the stability of proteins. Many of these methods rely primarily on an energy function describing the interactions between residues, within a simplified structural representation. We may distinguish the approaches based on statistical potentials extracted from datasets of protein structures [15–19], from those based on empirical potentials built from optimised combinations of various physical energy terms [20–23]. Several predictors were set up with the help of machine learning technologies, through the establishment of an empirical relationship between the stability change upon mutation and a large number of sequence and/or structural features of the mutated and mutant amino acids [24–27]. More recently, approaches combining the advantages of statistical energy functions and machine learning tools have also been described [28, 29].
Three recent studies independently assessed and compared the performances of several of those predictors, using datasets of experimentally characterized mutants that had not been used to train any of the predictive models [22, 29, 30]. Overall, the conclusions were mixed: all methods show a correct trend in the predictions, but the accuracies often remain moderate. PoPMuSiC was however shown to be a standout and to perform quite well in comparison with several other methods [29]. It should be considered that most of these methods are extremely fast with respect to more detailed approaches, such as free energy perturbation [31] or thermodynamic integration [32]. In particular, PoPMuSiC allows the estimation of the stability changes resulting from all possible point mutations in an average-sized protein in a matter of seconds.
This advantage was exploited to predict the stability changes induced by all possible point mutations in several globular proteins [10], using the FoldX algorithm [20]. The results were in good agreement with previous experimental studies, in that a large majority of mutations appear to have a destabilizing effect on protein structures. Moreover, the overall distributions of predicted stability changes were shown to be very similar in different globular proteins. However, it has to be stressed that although this trend holds true - on average - for whole proteins, some local regions may present a different behavior. For example, residues belonging to the active site of a protein have been selected during evolution so as to ensure proper functioning, and are thus generally less optimal with respect to stability [33, 34]. Specific protein regions associated with peculiar patterns of stability changes upon mutation corresponding to structural weaknesses were also suggested, using the PoPMuSiC algorithm, to be involved in the occurrence of conformational changes, such as 3D domain swapping [35] or amyloid fibril formation [15]; the latter structural weaknesses were supported by experimental analyses [36].
We present here the PoPMuSiC-2.1 web server, which allows fast and accurate predictions of the stability changes resulting from point mutations in globular proteins. Besides its top-level performances, our server also distinguishes itself from other available tools by an important advantage in terms of computational speed, and by the ability to perform a systematic scan of all possible mutations in a protein. A new functionality of the current PoPMuSiC web server is that it gives the opportunity to obtain easily an estimation of the optimality of each residue in a protein's sequence, with respect to the stability of its structure. To illustrate the general interest of this unique feature, we performed a large-scale investigation of the optimality of residues involved in catalytic sites, and discuss the possibility of using such data to improve methods aiming at predicting functional sites in proteins.
Prediction of protein stability changes upon mutations
where v, w, x are any of the descriptors s, t, a and d, k is the Boltzmann constant and T the absolute temperature. The terms ΔWasdas and ΔWstdst are defined in a similar way [37]. Higher order coupling terms are not taken into account, since they were shown to yield no improvement in the prediction of stability changes upon mutation [29]. In addition to the statistical potentials, two terms in eq.(1), i.e. ΔV±, are related to the volume difference between the mutant and wild-type amino acid: ΔV = Vm-Vw. They are defined as ΔV± = ΔV H(± ΔV), where the H is the Heaviside function. They provide a coarse description of the impact of creating of a cavity (if ΔV<0) or accommodating a larger side-chain within the protein structure (if ΔV>0). Statistical potentials cannot be expected to describe correctly such effects, since they are derived from a dataset of native structures of wild-type proteins, with very few packing defects.
where ci is the inflection point of sigmoid i, ri its slope, fi its scaling factor and bi its vertical shift. The reason for this choice is that it enables the description of a smooth transition between two different environments: the protein core and the protein surface. Indeed, it was shown previously that the relative weights of the different types of interactions vary according to whether they concern residues at the surface or in the core [38].
where ΔΔGM, m is the experimentally measured folding free energy change of mutant m and ΔΔGP, m its predicted value, obtained with eqs. (1)-(3). An iterative parameter reduction procedure was devised to eliminate the parameters that present a large uncertainty, which reduced their number from 64 to 52 [29].
Estimation of protein sequence optimality
PoPMuSiC is fast enough to estimate within seconds the stability changes resulting from all possible mutations in an average-sized protein. It is therefore possible to estimate how robust the structure of a given protein is against mutations in its sequence. It is also possible to identify positions that are particularly poorly optimized with respect to protein stability, i.e. positions for which the predictions suggest that several possible mutations would improve stability. The ability to identify such positions in a protein sequence may be of substantial interest. Indeed, they obviously constitute attractive targets for protein engineering applications. They may also be involved in the mechanisms of protein function [33], the occurrence of structural switches or the development of conformational diseases [15, 35].
where H is the Heaviside function, m is one of the 19 possibilities of mutation of the amino acid w in position i, and ΔΔGP,w i→mis the corresponding predicted stability change. The score Γ is thus the sum of the predicted stability changes of all stabilizing mutations at a given position in the sequence. Since the large majority of mutations have a destabilizing effect on the protein, Γ can be expected to be close to zero for many positions in the sequence. In contrast, very negative values of Γ point out particularly interesting positions, where some mutations are strongly stabilizing and/or many mutations mildly stabilizing.
Web interface
PoPMuSiC is called by a user-friendly PHP/MySQL web interface. Since the predictions of PoPMuSiC are based on the structure of the target protein, all queries require a structure file to be specified. The user may either provide the 4-letter code of the Protein DataBank (PDB) structure, which will then be automatically retrieved from the PDB server [40], upload his own structure file, or select a previously uploaded file. The user may choose to provide a structure file generated by a modeling approach, as long as it complies with the PDB format. Note, however, that the performances of PoPMuSiC were evaluated on the basis of experimentally resolved protein structures and are likely to be lower for modeled structures. Obviously, the accuracy of the predictions will depend on the quality of the model.
Three types of queries may be performed:
The "Single" query allows the prediction of the stability change resulting from one given mutation, specified by the user, in the protein of interest.
The "File" query allows the stability change prediction of a list of single-site mutations in a protein of interest. A (plain text) file containing the list of mutations must be uploaded. The server will output a (plain text) file containing the predicted stability change resulting from each mutation.
The "Systematic" query allows the prediction of the stability changes resulting from all possible single-site mutations in the protein of interest. The server will output a (plain text) file containing the predicted stability change resulting from each mutation. The user may choose how the results will be ordered: either sequentially or on the basis of the value of the predicted ΔΔG P s.
Results and Discussion
Comparison of predicted and measured stability changes
Performances in 5-fold validation
All mutants
Exclusion of 10% outliers
R d / R c a
σ d /σ c (kcal/mol) b
R d / R c a
σ d /σ c (kcal/mol) b
Random predictorc
0.00 (0.02)
2.08 (0.02)
0.22 (0.02)
1.60 (0.02)
Run 1
Run 2
Run 3
Run 4
Run 5
Average 1 d
Average 2 d, e
As expected, the performances are slightly better in direct validation (on the training set) than in cross validation (on the validation set), but the differences are quite small, indicating the absence of overfitting. On average, the correlation coefficient Rc between predicted and measured ΔΔG values is 0.62, and the root mean square error σc is 1.16 kcal/mol. These measures of performance indicate a strong improvement over the random predictor, which uses randomly shuffled ΔΔGM values as predicted ΔΔGP values, and yields on average a root mean square error of 2.08 kcal/mol (Table 1). Setting all ΔΔGP values equal to the average of the ΔΔGM values generates a root mean square error of 1.47 kcal/mol (Table 1), and is thus more efficient than the random predictor, but still far from reaching the performances of PoPMuSiC. The predictive power of PoPMuSiC was also shown to surpass that of five previously published prediction tools, on an independent dataset of 350 mutations. Indeed, these five methods yielded a value of Rc comprised between 0.29 and 0.48, as compared to 0.67 for PoPMuSiC, and a root mean square error σc comprised between 1.43 and 4.12 kcal/mol, as compared to 1.16 kcal/mol for PoPMuSiC [29]. A recently published prediction method, PEAT-SA, was also benchmarked using the same dataset of 350 mutations: a Rc value of 0.5 and a root mean square error of 1.92 kcal/mol were reported [23].
The values of R and σ after removal of the 10% most badly predicted mutations are also reported in Table 1. These values provide relevant complementary information to the performance indicators computed on the whole dataset, since a number of poorly predicted mutations may be related to experimental measurements made in specific, non-physiological, conditions or affected by a significant error, to a poorly resolved structure, to mistakes in the database indexing of the measured ΔΔG value, or to structural modifications that are not taken into account by PoPMuSiC.
The last row of Table 1 corresponds to a second round of parameter identification, performed after removal from the training sets of all mutants for which |ΔΔGP−ΔΔGM| is larger than 1.5 kcal/mol in each of the five initial runs. The validation sets are left unchanged, in order to obtain comparable results. This induces a slight improvement of the performances in cross-validation, indicating that the presence of outliers in the training set had a negative impact on the identification of the model.
A frequent objective of protein engineering studies is the increase of the structural stability of a protein, via the introduction of mutations in its sequence. For such applications, PoPMuSiC can be used to identify a small subset of mutations that are likely to present the desired properties, and can be tested experimentally. An important indicator of the performances would then be the proportion of mutations in this subset that actually stabilize the structure, which is related to the specificity of the predictions with respect to stabilizing mutations. In this regard, PoPMuSiC appears as a very reliable prediction tool. Indeed, in cross-validation, 70% of the mutations predicted as mildly stabilizing (ΔΔGP < -0.5 kcal/mol), and 86% of the mutations predicted as strongly stabilizing (ΔΔGP < -1.0 kcal/mol), are actually stabilizing (ΔΔGM < 0.0 kcal/mol).
The good performances of PoPMuSiC were made possible by using a combination of statistical potentials, whose relative weights were optimized via a simple neural network. The total number of adjusted parameters is 52, which remains very reasonable with respect to the size of the training/validation dataset (2648 non-redundant entries), and with respect to other prediction methods based on machine learning techniques [24–28]. Our model also clearly distinguishes itself from a pure black box, as the overall shapes of the optimized weighting functions were shown to exhibit little dependence on the training set, and possess biophysical significance [29].
Speed of the computations
Comparison of the practical features of different web servers
Maximal number of mutations per querya
Number of mutations processed per minuted
19 × N b
AutoMute [28]
19 × 5
D-mutant [17]
Eris [21]
< 0.1
< 0.1
< 0.1
I-mutant2.0 [24]
Hunter [22]
N b
Case study: sequence optimality scores in catalytic sites
To illustrate the relevance and usefulness of the sequence optimality scores Γ computed by PoPMuSiC-2.1, we investigated the relationship between the involvement of residues in protein function and their nonoptimality with respect to protein stability. More precisely, we computed the Γ-score for each residue in a dataset of proteins whose catalytic sites have been experimentally identified and reported in the literature. Our analysis is based on version 2.2.10 of the Catalytic Site Atlas [41]. We selected only the "original" entries, i.e. proteins for which evidence of the location of the catalytic site comes directly from literature references, and excluded the "homologous" entries found by sequence alignment to one of the original entries. The resulting dataset contains 964 proteins, with 3227 catalytic residues and approximately 3.7 105 other residues.
Γ optimality score for catalytic versus noncatalytic residues
Γ threshold
Catalytic residuesa
Other residuesa
We also investigated the relationship between solvent accessibility and sequence optimality. For that purpose, the residues were distributed in two classes (Core and Surface) according to whether their relative solvent accessibility, computed with NACCESS [42], is smaller or larger than 10%. Table 3 indicates that the overall proportion of nonoptimal catalytic residues is larger in the core than on the surface of proteins (53% versus 48%, for Γ < 0 kcal/mol), and that this difference gets more striking when lower threshold values are considered (e.g. 14% versus 3%, for Γ < -5 kcal/mol). These results denote a stronger trade-off between stability and function in the core of proteins: selecting residue types at specific positions along the sequence to ensure proper functioning is on average more detrimental to protein stability when these residues have a low solvent accessibility. This can be related to the fact that many catalytic residues are charged and/or polar, and thus more likely to have a destabilizing impact when buried in the protein core.
In contrast, in the case of residues that are not involved in catalytic sites, the overall proportion of nonoptimal residues is quite larger on the surface than in the core (46% versus 27% for Γ<0 kcal/mol). It is however interesting to notice that this trend is inverted when threshold values of Γ lower than -2 kcal/mol are considered. These results are in good agreement with previously published studies, which reported that mutations of core residues are more likely to be detrimental to protein stability, while the distribution of stability changes induced by mutations on the surface is quite narrow, with very few highly (de)stabilizing effects [10]. It may also be related to the fact that surface residues have more often nonoptimal conformations because of crystal constraints or interaction with ligands.
Figure 2A is an example of the results obtained with PoPMuSiC on the bifunctional enzyme phosphoribuloseanthranilate isomerase:indoleglycerolphosphate synthase (PRAI:IGPS) from E. Coli (PDB code 1PII) [43]. According to the Catalytic Site Atlas, the residues of the N-terminal domain (residues 1-255) involved in the IGPS catalytic activity are Glu53, Lys55, Lys114, Glu163, Asn184, and Ser215. With a threshold value of -5 kcal/mol on the Γ-score, PoPMuSiC identifies only nine non-optimal residues in this domain, including four of the six catalytic residues. Interestingly, among the five other residues that present a Γ-value lower than -5 kcal/mol, four are located in the same cavity, in close contact with the catalytic residues (Figure 2B). They hold thus probably some importance with respect to the affinity or the specificity of the interaction with the ligand. In the C-terminal domain (residues 256-452) that catalyses the PRAI reaction, PoPMuSiC identifies 11 residues with a Γ-value lower than -5 kcal/mol. The catalytic residues of this domain are not recorded in the Catalytic Site Atlas. However, as can be seen on Figure 2B, many of the residues pointed out by PoPMuSiC are clustered together, in a region previously identified as the PRAI active site [43]. Overall, it appears thus that a large majority of the 20 residues identified as non-optimal by PoPMuSiC in this protein are involved in its enzymatic activity, even though only four of them were recorded in the Catalytic Site Atlas [41].
We present a web server for the prediction of protein stability changes upon mutations and for the estimation of the optimality of each amino acid in a protein's sequence with respect to the stability of its structure. The prediction performances were evaluated by a 5-fold cross validation procedure, and turned out to be quite impressive for a coarse-grained and very fast prediction method: the correlation coefficient R between predicted and measured ΔΔG s is 0.63 and the root mean square error σ = 1.15 kcal/mol. The performances increase up to R = 0.79 and σ = 0.86 kcal/mol after removal of 10% outliers. PoPMuSiC was also shown to outperform several other prediction tools, on an independent dataset of 350 mutations that were not included in the training sets of the compared methods [23, 29].
A significant advantage of PoPMuSiC-2.1 is that it allows the rapid computation of the stability changes resulting from all single-site mutations in a protein. It can thus be used in the context of rational protein design, to help identify, among the multitude of possibilities, a small number of mutations that are likely to present the desired stability properties. For example, the different versions of PoPMuSiC [15, 29] have been successfully applied by several groups (including us) to predict mutations in the prion protein that stabilize the soluble form and occur in a region that has since then been shown to be determinant for the aggregation tendencies [36], to modulate the polymerization propensity of α1-antitrypsin [44], to increase the solubility of a TEV protease by stabilizing the folded state relatively to the aggregated form [45], to stabilize the folded dark state of a photocontrolled DNA-binding protein in view of modulating the degree of photo-switching [46], or to identify mutations that stabilize various enzymes, such as pyruvate formate-lyase [47] or feruloyl esterase [48]. PoPMuSiC has also been used to characterize in silico the effect on stability of specific mutations, in view of rationalizing their impact on a protein of therapeutic interest. The considered mutations were for example naturally occurring variants responsible for the development of hereditary diseases [49–52], mutations related to the acquisition of drug resistance in bacteria [53], or spanning the natural genetic heterogeneity of a viral protein [54].
Another consequence of the speed of the predictions is that PoPMuSiC-2.1 can be used to evaluate the optimality of the sequence of a protein with respect to the stability of its structure. This optimality, which is the result of evolution, is shown to be intimately related to the mechanisms of protein function. We indeed applied our prediction method to a large number of enzymes whose catalytic sites have been previously identified and recorded in the Catalytic Site Atlas [41]. Our results indicate that catalytic residues are on average significantly less optimal than other residues, with respect to protein stability. Although the same general trend is observed both on the surface and in the core of proteins, it is much stronger in the core, which is in agreement with previous studies of protein stability.
Obviously, the distinction between catalytic and noncatalytic residues is not perfectly clearcut. According to our predictions, approximately half of the catalytic residues are nonoptimal with respect to protein stability, which means that the other half are totally optimal and thus that all possible mutations of these residues are predicted as destabilizing. This observation indicates that many residues playing an essential role in protein function are not detrimental to stability, which somewhat relativizes the well-known trade-off between stability and function [33, 34, 55]. On the other hand, a number of noncatalytic residues were also identified as not optimal with respect to stability. It is very likely that many of these residues are somehow involved in protein function without being actually part of the catalytic site. They may for instance be close to this site and important to ensure a proper binding affinity or specificity with a ligand, or to generate a sufficient level of structural flexibility [56, 57]. The example of the PRAI:IGPS protein nicely illustrates this point, given that most of the nonoptimal residues highlighted by PoPMuSiC were clustered in the two active sites of this enzyme (Figure 2). Other nonoptimal residues may be present as a result of a compromise between protein stability and other constraints such as the kinetics of the folding or binding process, the prevention of misfolding [9], or the adjustment of the resistance to proteolysis [58]. Following previously published arguments, we may also note that evolution is a dynamic process, during which protein stability is kept in a near-optimal state by mutations that slightly diminish stability without causing any deleterious effect [14]. Finally, the predictions are of course not perfectly accurate, which may lead to incorrectly label some residues as being not optimal, especially in regions where the structure is poorly defined or subject to crystal constraints.
The inference of protein function is currently often performed through the analysis of sequence conservation data derived from multiple sequence alignments, despite the limitations inherent to this approach [59]. A number of other computational methods have also been developed to identify unknown functional sites in proteins on the basis of structural features [60–62]. These include geometry-based methods such as the detection of pockets or cavities that could accommodate a ligand, energy-based methods such as the identification of sites that interact favorably with various types of probes, and knowledge-based methods that typically involve structural comparisons with datasets or atlases of known functional sites. Some studies were also conducted to investigate the contribution of functional residues to the overall stability of the protein, sometimes with a predictive purpose [9, 63–66]. Recent developments tend to be more focused on the design of prediction schemes integrating various types of information, such as structural attributes and evolutionary sequence conservation, in order to benefit from their complementary [67–69]. To our knowledge, the optimality of the amino acids with respect to protein stability is not explicitly taken into account by any of these integrated methods.
Although further studies are necessary to clarify the relationship between sequence optimality and protein function, our results strongly support the idea that the inclusion of sequence optimality data is likely to improve the performances of methods that aim at identifying unknown catalytic sites or other function-related residues. In addition, such sequence optimality data may be of interest in various types of other applications, such as the assessment of the quality of model protein structures, or the investigation of the evolutionary dynamics of proteins. This data may also provide complementary information to that derived from other prediction tools in view, for instance, of identifying hot spots for molecular recognition [70, 71] or protein aggregation [72].
Availability and Requirements
Project name: PoPMuSiC
Project home page: http://babylone.ulb.ac.be/popmusic
Operating system: Platform independent (web server)
Programming language: C, PHP/HTML
Any restrictions to use by non-academics: none
This work was supported by the Belgian State Science Policy Office through an Interuniversity Attraction Poles Program (DYSCO), the Belgian Fund for Scientific Research (F.R.S.-FNRS) through an FRFC project, and the Brussels Region (TheraVIP project). YD and MR are Postdoctoral Researcher and Research Director, respectively, at the F.R.S.-FNRS.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Marshall Edwards Issued New Method of Use Patent for Lead Oncology Drug Candidate ME-344
Jan 3, 2012
San Diego – Marshall Edwards, Inc. (Nasdaq: MSHL), an oncology company focused on the clinical development of novel therapeutics targeting cancer metabolism, announced today that the U.S. Patent and Trademark Office has issued a new method of use patent, U.S. Patent No. 8,084,628, covering a number of the Company's mitochondrial inhibitor compounds, including lead drug candidate ME-344, for the treatment of cancer or a tumor mass. The patent is expected to provide protection until September 2025.
Treatment of tumor cells with the Company's mitochondrial inhibitor compounds induces a rapid loss of cellular energy and leads to the inhibition of both mammalian target of rapamycin (mTOR1 and mTOR2) pathways. The Company has completed the necessary pre-clinical animal toxicity studies to support submission of an Investigational New Drug (IND) application for ME-344 this quarter, and expects to initiate a Phase I clinical trial of intravenous ME-344 shortly thereafter.
"Given the increased interest in oncology compounds that can impact both the mTOR1 and mTOR2 pathways, we are particularly pleased to receive patent coverage for the use of ME-344 in cancer," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of Marshall Edwards. "This new patent reaffirms our ongoing commitment to expanding and strengthening our intellectual property portfolio while adding to the value of our drug development pipeline. A strong patent estate is essential to the commercial potential of our drug candidates and should be recognized by potential partners."
About Marshall Edwards
Marshall Edwards, Inc. (Nasdaq: MSHL) is a San Diego-based oncology company focused on the clinical development of novel anti-cancer therapeutics. The Company's lead programs focus on two families of small molecules that result in the inhibition of tumor cell metabolism. The first and most advanced is a NADH oxidase inhibitor program that includes lead candidate ME-143. The Company initiated a Phase I clinical trial of intravenous ME-143 in patients with solid refractory tumors in September 2011 and expects final data from the trial by the second quarter of 2012. The second program is a family of mitochondrial inhibitors that includes lead candidate ME-344. The Company has completed the necessary pre-clinical animal toxicity studies to support submission of an Investigational New Drug (IND) application for ME-344 in the first quarter of 2012. For more information, please visit www.marshalledwardsinc.com.
Under U.S. law, a new drug cannot be marketed until it has been investigated in clinical trials and approved by the FDA as being safe and effective for the intended use. Statements included in this press release that are not historical in nature are "forward-looking statements" within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. You should be aware that our actual results could differ materially from those contained in the forward-looking statements, which are based on management's current expectations and are subject to a number of risks and uncertainties, including, but not limited to, our failure to successfully commercialize our product candidates; costs and delays in the development and/or FDA approval, or the failure to obtain such approval, of our product candidates; uncertainties or differences in interpretation in clinical trial results; our inability to maintain or enter into, and the risks resulting from our dependence upon, collaboration or contractual arrangements necessary for the development, manufacture, commercialization, marketing, sales and distribution of any products; competitive factors; our inability to protect our patents or proprietary rights and obtain necessary rights to third party patents and intellectual property to operate our business; our inability to operate our business without infringing the patents and proprietary rights of others; general economic conditions; the failure of any products to gain market acceptance; our inability to obtain any additional required financing; technological changes; government regulation; changes in industry practice; and one-time events. We do not intend to update any of these factors or to publicly announce the results of any revisions to these forward-looking statements.

subset: commoncrawl


text:
Autodesk Alias Studio, Surface or Auto: A Full Description
What is Autodesk Alias Design?
Alias Design (was Alias Studio) a powerful suite of award winning 2D/3D software, used for design and styling in the automotive, marine, aircraft interiors, sporting equipment, electronic enclosures, children's products, and fashion accessory markets. Alias industrial design software supports concept communication, design modeling, technical surfacing, reverse engineering, real-time design visualization, and engineering development collaboration.
Alias Studio is one of the world's leading developers of CAID (Computer Aided Industrial Design) software, especially since it has a tool for every normal industrial design stage. Alias is primary for industrial designer to freeform development, concept design and fast concept modeling.
Using Alias Design in the earliest of shape and form defining to the final modeling complete with rendering, and/or complete engineering. An industrial designer or engineer that knows Alias Design can combine the efforts of the design and engineering sides of a product to cut cost and make projects more efficient to all involved.
What is Autodesk Alias Surface or Alias Auto?
The Auto manufactures use much different standards and modeling techniques to develop Class-A geometry for automotive styling. Although more expensive versions of Alias Surface and Auto offer many more tools available for creating forms and offers greater control over the math and complexity of the surface. Companies like Ford, Harley Davidson, CNH, Tesla, Kohler, Polaris, and John Deere to name a few use higher versions of Alias software.
What is Alias Design from a Design Engine Perspective?
Alias Design is a powerful tool for communicating 3D form. It's easy to learn, therefore designers can ramp up quickly and be a part of the design solution faster. For industrial designers to reach full potential they must communicate in 3D form. Directly sculpting is often different and a more designer friendly approach alternate to the counterpart parametric tools. Therefore coming up with a form in Alias is a different more comfortable direct sculpting process that that of a parametric approach or process.
Why Alias Design and not Creo or Solidworks?
Creo & Solidworks have come to be the final deliverable in many major manufactures. It is an impressive tool in the hands of an industrial designer. However there are techniques in Alias that can not be done in Creo, especially as related to Auto Exteriors and Interiors.
Alias Design has always been the industrial designer's choice of tools for proving shape and form, rendering and simply communicating to engineers and tooling vendors.
Many industrial designers are taught Alias Design in school
Design engine courses will go into more depth and greater detail and move much quicker than in college. Alias Design also has an impressive suite of procedural mapping tools.
Things can be quickly designed in Alias Studio and rendered fairly quickly, then be ready to be shown at a meeting or presentation, which can certainly help any marketing team as well as the engineers that need to see exactly what the usability of a certain product is.
Alias Design is a hard tool to beat with respect to speed with a wide variety of workflow for developing geometry. Engineers often times use Creo or Solidworks to communicate their designs. The parametric workflow can be specific where an Alias workflow is more direct on the model. With respect to Creo imports, Design Engine has the Level 4 Creo Surface Import Data Doctor Workshop to integrate IGES or STEP models into Creo. Many engineers have problems with import geometry inside their native tools but with these classes we make the transition smoother.
The real power of Alias Design though, is the push and pull that Alias Studio allows you and with Alias Surface or Auto Studio we have various tools for managing light reflections better than any other tools. Almost any curve, surface, or line can be "tweaked" to extreme bounds. This allows you to take a product and make it smoother, rougher, taller, shorter, longer, grooved, slanted, and/or many other changes fairly, easily and quickly. This also allows the engineer to look at a product and see exactly what the industrial designer is trying to get across in the modeling. Alias Studio is one of the best and most powerful software packages that can be purchased today.
Manufacturers' Trends?
Many manufacturers do not want their industrial designers using Creo or Solidworks. The engineering directors and high-end Creo and Solidworks users want the parametric controls in their solid modeler and want to implement that control themselves. Although DESIGN-ENGINE|EDUCATION is about empowering our clients & helping them with better methods for managing CAD data, many times we are directed not to empower industrial designers with such solids tools, instead keeping them in Alias, even though the form will be remodeled (capture form) using Creo or Solidworks. In the end we help make more effective teams.
Did you know you can download a 30 day free trial from Autodesk?
We suggest coming for training first so you can maximize you free 30 day trial. It only took us a few minutes to locate the free 30-day trial download on the Autodesk website.


text:
- Home
- Shop by Brand
- Cosilana Organic Wool/ Silk/ Cotton Long Sleeved Shirt for Kids
Cosilana Organic Wool/ Silk/ Cotton Long Sleeved Shirt for Kids
Cosilana Organic Wool/ Silk/ Cotton Long Sleeved Shirt for Kids
Product Description
This long-sleeved top for toddlers and kids is made from Cosilana's soft and durable blend of organic wool, cotton, and silk. This shirt fits snugly and may be worn as an underwear layer during the colder months or on its own as a soft and breathable outfit any time of year. This is a special machine-washable blend. The softness and warmth of silk, the temperature regulating properties and breathability of wool, and the durability of cotton makes this blend ideal for babies and toddlers.
Cosilana developed this special blend of silk/ wool/ cotton with busy families in mind- this blend is machine washable! This lovely blend meets the same strict environmental guidelines that all of Cosilana's line of products adhere to. The yarn blend of 45% cotton, 35% wool and 20% silk has a quality and origin of the material that is consistent with Cosilana's wool, and wool / cotton blends.
Materials: silk / wool / cotton, 45% organic cotton, 35% organic wool, 20% silk.
Care: The silk/wool/cotton blend may be machine washed on a gentle wool cycle up to 30° degrees C (86° F). Lay flat or line dry- do not tumble dry!
Cosilana produces its range of apparel made from natural fibers in the Swabian Alb in southern Germany and guarantees the highest quality of workmanship. The natural fibers used by Cosilana are regularly inspected by a recognized environmental laboratory for residues. Cosilana has been a member of IVN * control system since January 2006. Cosilana is committed to environmentally sound production. The cotton comes from organic farming, and the wool and silk, which is processed at Cosilana is treated as strictly according to ecological guidelines. Cosilana's complete range has been produced since 1994 in Baden-Württemberg in the Swabian Alb.


text:
An easy way to get involved with your union is to join a committee!
We have Review Committees for the three Benefit Funds we administer: Professional Development, Faculty Education, and Health Insurance. These committees meet once per term to review applications and revise best practices for the fair and equitable distribution of funds.
Email firstname.lastname@example.com to join a Benefit Fund Committee
We also have standing committees for outreach and operations, join our:
Collective Bargaining Committee
Email firstname.lastname@example.com to join the committee
Organizing Committee
Email email@example.com
Communications Committee
Email email@example.com to join the committee
Finance Committee
Email firstname.lastname@example.com to join the committee
Grievances Committee


text:
from $0
per person per night
Our beautifully appointed family room is designed to provide quality, comfort and attention to detail.
This room is ideal for small families and has 4 single beds side-by-side.
Great Internal Decor! Enter the caved flight of stairs as you walk to your assigned bedroom.
The beds are straight out of bedrock harmonising easily with our Rockhouse theme. The beautifully appointed rooms are designed to provide quality, comfort and attention to detail.
This property presents a memorable homestay opportunity, only 40 minutes from the Nairobi city centre, yet a world apart from the hustle and bustle of the city. In tune with the hotel's name, Rock House has been modelled by a local architect to reflect the its origins on the slopes of Mt Kenya and the owner's passion for nature's captivating scenes.
For bird-watchers, exotic birds are in love with the property's lush vegetation, flowers and waterfall and the property's management encourages many more by additional feeding. Exotic and indigenous flowers grow freely here, giving it the essence of the Mount Kenya region.
Wireless Internet is available and if you forgot to bring your laptop, a modern internet ready desktop computer is available. Guests enjoy swimming in a beautiful swimming pool with cascading waterfalls. The pool area is well lit to allow both day and night swimming activities.
The well-appointed rooms are designed to provide quality, comfort and attention to detail. The beds are straight out of bedrock harmonising easily with the Rock House theme.
The beautiful interior design and the complementing natural wood furniture are as gratifying as the friendly welcome you'll receive.
At Rock House, guests are hosted by the owner and his wife, and supported by a friendly team who are just like a family. Fresh homemade meals are served in generous portions and the more inquisitive are welcomed to the kitchen to get hints on how to prepare Kenyan delicacies.
from $0
per person per night
|Rock House – Karen
|Space offered
|Private room to yourselves
|1 up to 4
4 × Single bed
|Check in
|Check out
|Meal plans
Accommodation only
| Cancellation
Moderate: 50% refund up until 8 days prior to check-in, except fees.
a) Cancellations made between 0 and 7 full days prior to local check-in time, or no show, guests will be charged 70% of total booking value.
b) Cancellations made between 8 and 29 full days prior to local check-in time, guests will be charged 50% of total booking value.
c) Cancellations made 30 or more full days prior to local check-in time, guests will receive a full refund of their deposit, except fees.
d) In the event of a premature departure or cancellation, the nights not spent 24 hours thereafter are 50% refunded, except fees.


text:
As I start this post, news is breaking that President Obama has formally invoked executive privilege in his administration's running battle with the House Oversight and Government Reform Committee over the latter's investigation of – and demands for documents from – the Justice Department's "Fast and Furious" southwest border gun-tracking (or rather not) operation.
Combined with the President's immigration announcement last week—regarding his plan to cease deportation of (and issue work permits to) young immigrants brought into the country by their parents—this has set off accusations of executive fiat, dictatorship, and the like, augmented today by dark hints of cover-up. For the moment I would note only that neither action is particularly out of line with recent presidential history, and give a quick background on the doctrine of "executive privilege" (from the perspective of presidential power and interbranch relations, rather than from the purified air of legal doctrine.)
First point: there is no such thing, in the Constitution at least. So to say it is "formally invoked," as I did above, is not quite right. However, in the famous Nixon tapes case, U.S. v Nixon, the Court did hold that such a privilege was constitutionally grounded. The president lost the battle, but the presidency might have won the war.


text:
Token Fat Guy...turns it off
I didn't really start the site to make any
money....and I only ever sold a couple shirts...so I'm discontinuing the
This place holder will run for a while so everyone
knows what happened.
I'm thinking about using this spot to run a dog
pound...since I can't keep the dogs out of my site. Dogs and all
the lolcatz....crazy lolcatz.


text: Having issues sending and receiving email from WordPress? Well, you're not alone. This is a common issue among many WordPress users. But don't worry, there's an easy fix. In this article, we're going to explain why WordPress is not sending email and we're also going to show you a fast and easy solution. So, let's […]Continue Reading


text:
|search Mr. R.'s world of math and science free and accessible educational resources for all
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|My Dog Multiplication!
Math Story - 12 x tables and more!
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|multiplication facts- 4 times tables
|multiplication facts song (multiply by 5)
|multiplication facts song (6 times tables)
|7 times tables! (with strategies)
|multiply by 8
|multiplication facts (9 times trick)
|multiplication facts song (multiply by 10)
|11's trick for numbers greater than 9
|12 times tables! (with strategies)
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text: Aunt+Parents+Fighting=leaving! Yep my Aunt and Partents are fighting because my aunt owes my dad $500 for a car she bought and she hasnt payed him back and hes getting mad. So they (as in my mom and dad) were talking about it and my cousin kelsie heard and told her mom. So now her mom is all mad and pissy. Yay I hope they leave.


text:
Liberals win Penrith
The scandal-plagued NSW government has suffered a crushing defeat in a Western Sydney by-election, seeing a swing of 25 per cent against it and its primary vote plummet.
Voters in Penrith took a bat to the government on Saturday, with the party's primary vote halved to about 24 per cent, with two-thirds of the ballots counted.
The Liberal candidate and new MP for Penrith, Stuart Ayres, recorded a primary vote of 51 per cent, an 18 per cent jump on the 2007 election.
Senior Liberals said a 25 per cent swing had been recorded against Labor, who had held the seat by a margin of 9.2 per cent.
Addressing jubilant supporters at Penrith RSL, Mr Ayres said that he was humbled by the size of the win.
"To be elected as the member for Penrith, someone who loves this city so much, to be able to represent it in parliament is a privilege," Mr Ayres told the gathering, with his partner, Federal Liberal MP Marise Payne, at his side.
Opposition Leader Barry O'Farrell said the win proved Labor no longer had a lock on Western Sydney, a traditional Labor stronghold.
"What we've seen this evening is the Liberal Party win its first seat in Western Sydney in 20 years," Mr O'Farrell said.
"It demonstrates once and for all that Labor does not have a lock on Western Sydney."
Saturday's win is only the second time the Liberals have held the seat in its 37 year history.
Labor candidate John Thain received just 24 per cent of the primary vote, half what Labor achieved at the 2007 election.
The corruption scandal that brought down former Penrith MP Karyn Paluzzano, and recent the resignation of ministers David Campbell, Graham West and Ian Macdonald, have clearly hurt Labor.
The unpopular Labor was always going to struggle to win the state election next March, but judging from the Penrith result, victory now appears insurmountable.
NSW Premier Kristina Keneally and party insiders flagged huge swings against the government, particularly in the wake of the allegations against Ms Paluzzano.
The former MP has been accused of misusing public money, then lying about it to the Independent Commission Against Corruption (ICAC).
"In politics integrity is paramount and people understand the implications of an MP who hasn't been truthful to the ICAC, who hasn't been truthful to the parliament, who has been truthful to her own leader," she told reporters at the Penrith South Public School polling booth.
"We do expect that people will respond to that."
A female voter said the resignation of Ms Paluzzano had left her feeling disenchanted with Labor.
"That was a bit of a shame. She let everyone down I think," the woman said.
Swinging voter Peter Mott "hasn't voted Labor for a little while" and, in light of the party's recent troubled times, that wasn't about to change.
"Stuart should get up, but stranger things have happened," Mr Mott said.
Amanda Appleby and husband Anthony stuck with Labor.
"It's just embarrassing for Penrith," she said of the Paluzzano debacle.
"It's put Penrith in a bad light - that's all I care about."
The Greens too benefited from Labor's woes, seeing their primary vote rise seven per cent to 12.5 per cent.
"We're thrilled. It's absolutely wonderful," Greens candidate Suzie Wright told AAP.
"At least now we're hoping we can contribute more to the agenda locally."
Ms Wright said she believed that generally people in the Penrith electorate were fed up with the two major parties.
"They're feeling cynical, they're feeling sold out."


text:
I spent 3 hours shopping for makeup today. How absurd? Half of that time was spent sitting in a high-top stool at a Laura Mercier counter while the best makeup artist in Charlotte applied every single water-proof product she had in her arsenal all over my face. GIRL.CAN.PAINT. I ended up purchasing a lot of the product she recommended. I will buy the rest when I get a j.o.b.; post wedding obviously.Speaking of jobs – quick story:
Sales person at BCBG: What are you shopping for?
Me: Just some vacation clothes….
Sales person at BCBG: Oh, where do you work?
Me: Nowhere.
Sales person at BCBG: (confused look)
Me: I mean, well, I used to work as an intern 40 hours a week, but it's over now — and I am getting married, so I mean, um… I don't technically work right now, but I am on vacation…
Sales person at BCBG: Oh I see, that's great. Congratulations! Just so you know, we are hiring here.
Me: (dumbfounded) Um, I want to use my degree. (!!!!!!!!!)
I mean, really. Back to my beauty adventures.
After leaving the Laura Mercier counter I headed over to the M.A.C counter for foundation, mascara, and a few eyeshadows per my cosmetic savvy friends. I put out a S.O.S on Facebook last night hoping for some solid direction. I just can't have makeup melting off my face while I say, "I do."
Here is what I got:
- Foundation primer
- Three eye colors: a ballet pink pod, 2 waterproof color sticks in cocoa and rosegold
- Waterproof eyeliner
- Waterproof under eye concealer
- Two free samples! A mini flawless skin face polish ("a creamy scrub that cleanses and exfoliates") and a Eyedration (eye cream)
- Pro longwear foundation with SPF 20
- Blot powder
- Zoom waterfast lash mascara
- Two eye shadows for my pallet: tempting (shiny brown) and orb (a base cream color)
- Urban Decay makeup setting spray
- Eyelashes!
- Blending sponge
- Blotting sheets
Beauty and the Heat,


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Recently, Trend Hunter revealed a few of the images from the Versace Spring Summer 2012 campaign featuring Gisele Bundchen. Now, all of the images from the campaign have been released and they are as hot as you probably expected.
Bundchen, with her bronze Brazilian beauty, is nothing short of striking as she poses in white-hot summer ensembles. The blue tinge only works to magnify the collection's stunning pieces, which include fabulously studded frocks, bags and shoes. These new images of the Versace Spring Summer 2012 campaign also reveal some of the collection's must-have jewelry, which comprise sea-inspired baubles like a haute starfish ring and a pair of seahorse hoop earrings.
The campaign was photographed in Borrego Springs, California. According to SassiSam, the hazy blue theme represents "basking" in the hot blue light and heat that characterizes summer in the dessert.
Fresh Fruity Collections (UPDATE)
Lively Rainbow-Hued Shoots
Hipster Polaroid-Inspired Shoots
Male Pink-Tip Tresses
50 Bold Patrick Demarchelier Shoots
All Photos From the Versace Spring Summer 2012 Campaign are Out
- By: Katherine VongJan 10, 2012
References: versace & sassisamblog
References: versace & sassisamblog


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Sunflower scarf
There have been some lovely suggestions already so please have a look at some of the pattern links. The nereid fingerless gloves based on Cookie A's pomatomus socks look lovely or you could knit the pomatomus socks instead:-) There would be enough for a small shawl or scarf like these lace scarf suggestions - Madeira Cascade and the checkerboard lace scarf.
my small magenta Ishbel shawl
Or if you feel up to a more complex lace challenge, you could get a small Ishbel shawl designed by Ysolda out of one skein, but you have to pay for that pattern, or knit up a gail aka nightsong shawl - like the one I'm presently working on over on the sidebar - but you have to be in ravelry to access that one but its free.
I've not finished my nightsong shawl yet but you can have sneek peek:-) I just love this pattern!
I'm getting into the swing of it now so it shouldn't take me that long to finish! Just got to remember not to knit this when I'm tired as I spend more time taking back my mistakes than actually knitting the lace!!
Good luck for today's competition and in answer to a query, you don't have to add a link to your entry, only if you had a specific pattern in mind. But it's very interesting to have a look at all the pattern ideas that are coming in from everyone - lots of knitting ideas to add to our to-do lists:-)
See you tomorrow!


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Snippets from the Life of a Hospice Chaplain
Her interfaith training and background with the Writings of Swedenborg combine to provide Julie with an ability to reach out to and serve people of many denominations in her role as a hospice chaplain. Julie shares this week about some of the wonderful people she has met and the some of the reasons she feels blessed to be doing this work. -Editor.
I feel truly blessed to have spent more than 4 ½ years as a hospice chaplain. I am with people in some of the most difficult moments of their life, both for those on our service and those who love them. It's a profession some people might find morbid. I am with people who are either very ill, very frail, or no longer able to communicate, either because of dementia or other illnesses, and who are not expected to live longer than six months. Yet it's a profession to which I believe I've been led. Most of our people are in facilities, but a few are in their own homes, living with a friend or family member, or occasionally in hospital.
So why do I feel so blessed? Firstly I get to be with the best team of people I have ever worked with: physicians, nurses, aides, volunteers, social workers, my chaplain colleague and the admin team who keeps the business running. We have a simple goal: to support people, and their families, on hospice and give them comfort, dignity and quality of life for their last moments in this world, whether that's literally a few moments or 2 ½ years.
Wondering about the inspiration for this article? Look up the New Church, which is based on the theological writings of Emanuel Swedenborg.


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I brought my 10 year old daughter in for an evaluation. The experience was incredible- state of the art equipment, thorough testing, and passionate doctors. In one appointment, I found out more about what was going on with my daughter than I had in years from different doctors and specialists.
She has been seeing Dr. Eduardo for treatment of POTS/Dysautonomia. I'm very thankful to have found INAPC!
God has got a lot to do with me getting better.He works through these doctors.
Four months ago my hand started shaking. When I went to the doctor to find out what's going on.They told me I had Parkinson's. My cousin Dean suggested I go to these doctor where I've been getting some real help. The therapies they do there have really been helping a lot. These guys are good.I used to get really dizzy and couldn't stand in a line at the store I couldn't play My Guitar which really bothered me.Now I can play my guitar again standing up the dizziness is gone.I still have Tremors in my hand but they are a lot less now.Perhaps a few more weeks and I'll be better. Thanks to the doctors @ INAPC
Every time I leave this clinic, I have tears in my eyes. I have two things I never thought I'd have – hope and relief.
I've suffered from severe migraines and anxiety for most of my life. I've been to various neurologists, been on multiple medications with sporadic results. Most days are a "7" or "8" on a 1-10 scale. '10' days are days that I end up in the ER for an IV and pain meds – at least once every month or two.
To walk into this clinic with only a vague idea of what they actually do and walk out with a better understanding and a "3" on the headache scale is mind-blowing. Because I don't constantly have mind-numbing headaches, my anxiety has lessened a bit too. I've been seeing Dr. Eduardo twice a week for three weeks now and everything has changed.
Dr. Eduardo and Dr. Joe are so knowledgeable, patient, kind, and most importantly, they are passionate about what they do and about helping people. They understand pain – whether it's a migraine or something more severe. I'd recommend them to anyone and everyone.
Edited to Add: I left the quarter on most of the night and I didn't wake up with a headache for the first time in months. Thank you so much.
Joe and Eduardo have been treating me for POTS for only two weeks, and I'm almost completely free of dizziness! My heart rate is much more stable, I haven't blacked out since before I started treatments, and I generally feel more energetic and healthy. I was skeptical at first, because I had gotten my hopes up about medications and other treatments in the past that didn't really help, but these guys are the real deal. The results are astounding! And I've heard many other success stories like mine. It's amazing to feel some relief after so many years of symptoms.Mylee Forgille


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In Many cases, AirPlay icon didn't works or show/ Enabled on control center when your iPhone locked or unlocked. For access, Apple gave Airplay icon in control center so you can easily enable and start entertainment without delay in establishing the connection between your iOS device and AirPlay enabled remote devices. Some of the time you can't see AirPlay icon in control center or AirPlay icon missing in iPhone 7, 7 Plus iPhone 6S / 6S plus due to internal error or connection problem/ AirPlay Settings and Not supporting devices.
In the case of remotely play audio and video file to your other devices at your home or office network without cable, wirelessly through AirPlay.
Best Air Printer for iPhone, iPad & iPod Touch: Remotely print
AirPlay compatible devices: Streaming from iPhone, iPad and iPod touch to Media devices (2nd Generation Apple TV, AirPlay Speaker, AirPlay Receivers)
Fixed: Alternate solution for AirPlay icon missing in iPhone 7/ 7 Plus/ iPhone 6S, 6S Plus
Poor connectivity causes one of the main reasons behind AirPlay icon not showing/ Disabled from the control center. So keep your both sending and receiving devices near to possible.
AirPlay doesn't support the parallel connection between more than one iOS devices to a single AirPlay device. So you can't connect another device for sharing photos, Videos or audio to AirPlay device.
Update device: Check and Update your iOS device
Keep your Apple Device up to date with new iOS version (Setting > General > Software Update). And from Apple TV (Setting > General > Software Update) and more about update TV OS.
Disable or Enable: AirPlay from Apple TV (Setting > AirPlay), Restart your both device for reconfiguration internet setting or remove data packets from the network.
Check router configurations
Reset Network Settings, Go to Settings > General > Reset > All Network Settings.
Remove AlterNet WiFi device
Any other Wi-Fi device is running synchronously, that time your device auto-detect and connects on poor connection with other networks, So you might lose AirPlay connectivity.
RELATED: Airplay missing on Mac or Airplay is shown but Airplay Not Working on Mac, iPhone and start mirroring on SmartTV or Apple TV remotely.
Hope this will help, Most of the possible solution are listed above, Best of luck for AirPlay icon missing in iPhone 7/ 7 Plus, iPhone 6S, 6S Plus, 6, 6 Plus, 5S on iOS 9.


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As more IT organizations get comfortable with cloud computing, many are turning their attention to performance issues in the cloud. Just like on-premise applications, poor performance of cloud-based applications can be detrimental to the business.
A new survey of 700 businesses in North America and Europe from Compuware, a provider of tools for monitoring cloud computing performance, finds that performance issues are already a major concern.
15 Essential BlackBerry Apps Some of the most popular apps in BlackBerry App World to help you through your day.
Nine Key Data Warehousing Trends for the CIO in 2011 and 2012 Optimization, flexible designs and alternative strategies will become more important as the demand for BI and business analytics increases.
The Current State of Identity Management Password overload is adding additional stress and frustration to the workplace.
Related Topics : Cloud Computing, Dell, Services Vendors, SMBs, Web Platform Vendors
IT administrators need to identify zombie assets, verify idle status and shut off anything that is unused. Here's how to get your dormant infrastructure back in shape. ... More >>
Cloud SaaS adoption allows organizations to gain the flexibility and scalability necessary for creating a high-velocity business. ... More >>
IT executives need the right tools to monitor and control their cloud infrastructure to maximize the positive impacts and mitigate security threats. ... More >>


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Masonry Industry Works Together to Build Its Future
By Masonry
Contributing members of the masonry industry participated recently in the 40th annual SkillsUSA National Leadership Conference held in Kansas City, Mo., June 23-25.
The National Masonry Contest, held in conjunction with the SkillsUSA conference, was supported by masonry industry contributions and representation from across the United States. Committee Chairman Bryan Light of the Southern Brick Institute reported greater industry support than ever before for this annual trade competition.
Forty-seven high school and post-secondary contestants from 34 different states, each of them winners of their own state or regional event, competed by completing a written test and then building brick and block composite projects judged, in part, by trade professionals from Bricklayers Local #15.
The winner of the post-secondary competition was Cody Alward, 19, from Mount Pleasant High School in Mount Pleasant, N.C. The high school winner was Terry Miller, 17, from Earnest Pruett Center of Technology in Hollywood, Ala. This was Miller's third national contest. As a sophomore, he finished seventh. Last year he earned a second-place medal. This year, he came back determined to take the grand prize, and take it he did!
Alward, Miller and the other contestants were supported in their efforts by donations of materials from SPEC MIX, Kansas City Brick and Midwest Block & Brick. SPEC MIX staff from around the country were "slingin' mud" throughout the day in support of the aspiring masons.
Sustaining members and sponsors of the contest included Bon Ton Tool Co., Brick Industry Association, Hanley-Wood, Marshalltown Trowel Co., National Concrete Masonry Association, Portland Cement Association and SPEC MIX.
This year, Light gave special recognition to his Education Team, a group of instructors who assist in setting up, conducting and the judging the contest. "Billy Madkins, Charles McDaniel, Edward Mims, Todd Larsen and Jack Wentz literally spend the week here with me," Light says. "I would be hard-pressed without their help."
Other highlights of the three-day conclave included a luncheon in honor of the contestants and their instructors. At the luncheon, Bill Kjorlien of the Southern Brick Institute and former Chair of the Technical Committee pointed out the value of working in a trade, "where you can take your trade anywhere and always have the satisfaction of having a visible representation of your work... every day."
Bob Melton, Executive Director of the Masonry Institute of Tennessee, spoke to the young masons, congratulating them on their accomplishment of reaching the national contest and encouraging them to "do your best."
Over 4,500 outstanding vocational students, all state champions, competed in more than 90 different SkillsUSA trade, technical and leadership competitions. The contestants effectively demonstrated their expertise in the occupational skills required for such trades as masonry, electronics, technical drafting and more.
39th Annual National Masonry Contest Winners
Post-secondary Competition
First Place - Cody Alward, Mount Pleasant High School, Mount Pleasant, NC
Second Place - Paul Shuey, The Williamson Free School of Mechanical Trades, Media, PA
Third Place - J. Cruz Cervantes, PTEC St. Petersburg Campus, St. Petersburg, FL
High School (Secondary) Competition
First Place - Terry Miller, Earnest Pruett Center of Technology, Hollywood, AL
Second Place - Dallas Caudle, Central Cabarrus High School, Concord, NC
Third Place - Alvaro Gutierrez, Lexington Technology Center, Lexington, SC
About the Author
Masonry, the official publication of the Mason Contractors Association of America, covers every aspect of the mason contractor profession - equipment and techniques, building codes and standards, business planning, promoting your business, legal issues and more. Read or subscribe to Masonry magazine at www.masonrymagazine.com.


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Related Tags
- Wulin Square
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- Wulingyang Scenic Area
- Wulingyuan
- Wulingyuan Scenic Area
- Wulingyuan Tours
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Wulin Street
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Wulin Square is located in the northern end of Yanan Road in Hangzhou city, Zhejiang Province, in the People's Republic of China. Wulin Square is situated exactly on the north side of West Lake, in front of Zhejiang Exhibition Hall. This is the new city center where there are lot of commercial cente…


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Gauteng and Dinokeng Full Day Spa Pampering Treatments, Wedding & Function Venue – 45 mins drive north from Pretoria
Enjoy the serenity and tranquillity only the African bush can offer for your dream wedding, birthday celebration or family reunions. Experience Full day pampering treatments to assist your body to heal your soul.
The rustic Bushveld surroundings of Bundhu-Rus strive to provide a relaxing outdoor experience to individuals, wedding guests and corporate clients . Our guests can experience quiet unspoilt nature to relax and refresh their spirit and mind. We are located in the Dinokeng game reserve 50km from Montana, Pretoria


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I was a feature writer for magazines. I couldn't believe I was paid to travel and meet so many amazing people.
I used to be a journalist
For years I met all kinds of folk
Prime Ministers in Downing Street
And one MP who told me jokes
I looked round Julio's bedroom
Of course this was before he wed
And met a couple of Royals
'Oh hailowe thair!' is what they said
Spent a day with Leonard Cohen
That man has a deep, sexy voice
Shame that he had to go back home
To go with would have been my choice
I went inside a killer's cell
He had rows of knives and wood blocks
He was a model prisoner
Even made me a jewellery box
I spent one cold night living rough
Listening to some terrible tales
Kids who were forced to leave their homes
And lives that had gone off the rails
Who was your all time favourite
So many people want to know
They expect some celebrity
It was those who showed strength through woe


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What would you like to do now?
Bedrooms: 3
Bathrooms: 1.75
Sq Feet: 1,258
City: Gilbert
Zip: 85233
Sub Division: Holiday Estates Unit 2
To start a new search please click: Start New Search
Property Description
Welcome home to the heart of Gilbert! Close to parks, elementary school, downtown, shopping, restaurants & the 60 freeway. The huge backyard includes a fun play structure with artificial turf, mature trees, extra long covered patio & built in planters. Wood burning fireplace highlights the family room with vaulted ceiling open to the refreshed kitchen including tile backsplash & wainscoting. Eat-in kitchen with breakfast bar & new light fixture. Updated wood laminate flooring in the living areas. Hall bath has newer granite counter, sink, faucet & water saving toilet. Living room open to family/great room. Recently installed energy saving dual pane windows! Newer garage door & roof. Arizona room/den/office/playroom not included in the square feet. No HOA! Don't miss the virtual tour!