text:
Complexity / 2017 / Article
AbstractIntroductionMaterials and MethodsResults and DiscussionConclusionsAppendixConflicts of InterestAcknowledgmentsReferencesCopyright
Biomolecular Networks for Complex Diseases
Volume 2017 |Article ID 4216797 | https://doi.org/10.1155/2017/4216797
Ling-Yun Dai, Chun-Mei Feng, Jin-Xing Liu, Chun-Hou Zheng, Jiguo Yu, Mi-Xiao Hou, "Robust Nonnegative Matrix Factorization via Joint Graph Laplacian and Discriminative Information for Identifying Differentially Expressed Genes", Complexity, vol. 2017, Article ID 4216797, 11 pages, 2017. https://doi.org/10.1155/2017/4216797
Robust Nonnegative Matrix Factorization via Joint Graph Laplacian and Discriminative Information for Identifying Differentially Expressed Genes
Ling-Yun Dai,1 Chun-Mei Feng ,1 Jin-Xing Liu ,1 Chun-Hou Zheng ,1 Jiguo Yu,1 and Mi-Xiao Hou1
1School of Information Science and Engineering, Qufu Normal University, Rizhao 276826, China
Academic Editor: Fang X. Wu
Received17 Jan 2017
Published06 Apr 2017
Differential expression plays an important role in cancer diagnosis and classification. In recent years, many methods have been used to identify differentially expressed genes. However, the recognition rate and reliability of gene selection still need to be improved. In this paper, a novel constrained method named robust nonnegative matrix factorization via joint graph Laplacian and discriminative information (GLD-RNMF) is proposed for identifying differentially expressed genes, in which manifold learning and the discriminative label information are incorporated into the traditional nonnegative matrix factorization model to train the objective matrix. Specifically, -norm minimization is enforced on both the error function and the regularization term which is robust to outliers and noise in gene data. Furthermore, the multiplicative update rules and the details of convergence proof are shown for the new model. The experimental results on two publicly available cancer datasets demonstrate that GLD-RNMF is an effective method for identifying differentially expressed genes.
Cancer is one of the most serious diseases that endanger the health of human being. Millions of people die of cancer every year. With the development of gene sequencing technology and other gene detection technologies, huge gene data have been generated [1, 2]. Therefore, it is important and challenging for scientists to find pathogenic genes from a large number of gene expression data. Microarray datasets on each chip usually contain many gene expression data, and the number of samples is far less than that of genes, which makes the identification of differentially expressed genes difficult [3]. In addition, irrelevant or noisy variables may reduce the accuracy of the results. In recent years, many effective mathematical methods have been applied to identify differentially expressed genes. For example, principal component analysis (PCA) [4, 5] and penalized matrix decomposition (PMD) [6] have been used to analyze gene expression data. Liu et al. used robust principal component analysis (RPCA) to discover differentially expressed genes [7]. Zheng et al. employed nonnegative matrix factorization (NMF) on the selection of tumor genes [8]. Cai et al. proposed an algorithm named graph regularized nonnegative matrix factorization (GNMF) for data representation [9]. Wang et al. used robust graph regularized nonnegative matrix factorization (RGNMF) for identifying differentially expressed genes [10]. A CIPMD (Class-Information-Based Penalized Matrix Decomposition) algorithm was proposed to identify the differentially expressed genes on RNA-Seq data, which introduced the class information via a total scatter matrix [11]. The Consensus Clustering methodology was proposed for microarray data analysis by Giancarlo and Utro [12].
However, two characteristics of gene expression data pose a serious challenge to the existing methods. Firstly, a large number of researchers hold that gene expression data probably reside in a low dimensional manifold embedded in a high dimensional ambient space. Therefore it is critical to consider the geometrical structure in the original gene expression data. Manifold learning is clearly an effective method to preserve the data geometric structure embedded in the original gene expression data [13, 14]. Cai et al. proposed GNMF [9], in which the geometrical structure of data was constructed by an affinity graph. Another variant of NMF called manifold regularized discriminative nonnegative matrix factorization (MD-NMF) was also introduced [15]. MD-NMF considered both the local geometry of data and the discriminative information of different classes simultaneously. Long et al. proposed a method called graph regularized discriminative nonnegative matrix factorization (GDNMF) [16], in which both the geometrical structure and discriminative label information were considered in the objective function. Secondly, gene expression data often contain a lot of outliers and noise. However, existing methods cannot effectively eliminate outliers and noise. For example, least squares methods are sensitive to outliers and noise. In recent years, many researchers have been devoted to improving the robustness to outliers and noise. Zheng et al. proposed an algorithm named generalized hierarchical fuzzy -means [17], which is robust to noise and outliers. Wang et al. used -norm to reduce the effect of outliers and noise [10].
A novel algorithm, which we call robust nonnegative matrix factorization via joint graph Laplacian and discriminative information (GLD-RNMF), is proposed to overcome the aforementioned problems together. The proposed algorithm preserves the geometric structure of data space by constructing an affinity graph and improves the discriminative ability by the supervised label information. To do so, a new matrix decomposition objective function by integrating the geometric structure and label information is constructed. In addition, we employ -norm instead of -norm on the error function and the regularization term to reduce the influence of outliers and noise. For completeness, we present that the convergence proof of our iterative scheme is also shown in the Appendix. Experimental results indicate that the GLD-RNMF algorithm has better results than other existing algorithms for identifying differentially expressed genes.
The remainder of the paper is arranged as follows. In Section 2, we briefly introduce some relevant mathematical foundation and propose the GLD-RNMF algorithm in detail. In Section 3, the results of differentially expressed gene selection using our GLD-RNMF method and the other four methods (GNMF, NMFSC, RGNMF, and GDNMF) are shown for comparison. Finally, we conclude this paper in Section 4.
2.1. Mathematical Definition of
The mathematical definition of -norm [18] iswhere is the th row of and is matrix. -norm is interpreted as follows. Firstly, we compute -norm of the vector and then compute -norm of vector . The value of the elements of vector represents the importance of each dimension. -norm enables the vector sparse to achieve the purpose of dimension reduction.
2.2. Manifold Learning
The purpose of this work is to get the best approximation of the original data. We also hope that the new representation can respect the intrinsic Riemannian structure. Recently, many researchers hold that high dimensional data often reside on a much lower dimensional manifold. The "manifold assumption" could be that data points nearby in the intrinsic geometry structure are also close under the new basis. Therefore, they usually have similar characteristics and can be categorized into the same class. In this paper, we employ manifold learning to achieve the aforementioned goal.
For a graph with vertices, each vertex corresponds to a data point. For each data point, we can find its nearest neighbors and connect it with the neighbors. There are many ways to define the weight matrix on the graph, for example, 0-1 weighting, heat kernel weighting, and dot-product weighting. Considering that 0-1 weighting is the simplest and easy to compute, we choose 0-1 weighting as the measure in this paper.
0-1 Weight. , if and only if two nodes and are connected by an edge. That is, where consists of nearest neighbors of and the neighbors have the same label with .
Therefore, the smoothness of the dimensional representation can be measured as follows:where represents the trace of a matrix. is a diagonal matrix and is the row sum (or column, because is symmetric, ) of ; that is, . is graph Laplacian matrix and . We measure the distance of two points in the low dimensional space by the Euclidean distance .
2.3. Nonnegative Matrix Factorization (NMF)
We review the standard NMF in this section. Although the algorithm has been widely used in many aspects, there are still many shortcomings.
Given nonnegative samples in , arranged in columns of a matrix , in this paper, each row of represents the transcriptional response of the genes in one sample and each column of represents the expression level of a gene across all samples. Letting matrices , , and , NMF decomposes into the product of and ; that is, .
To ensure an approximate factorization , two update rules are introduced [19]. One of the objective functions is constructed by minimizing the square of the Euclidean distance between and . The optimization problem is described as follows:where denotes the matrix Frobenius norm. The corresponding optimization rules are as follows:
The convergence of the above optimization rules has been proven [19].
2.4. Graph Regularized Discriminative Nonnegative Matrix Factorization (GDNMF)
Supervised label information is added to the objective function of GNMF [16]. The definition and iterative rules of GDNMF are presented below.
Class indicator matrix is defined as follows:where is the class label of and is the total number of classes in .
The objective function of GDNMF is formulated as follows:
The corresponding optimization rules are as follows:where is initialized to a random nonnegative matrix in the algorithm. and are nonnegative regularization parameters, respectively. Essentially, GDNMF incorporates the graph Laplacian and supervised label information into the objective function of NMF, which ensures the algorithm to keep consistent with the intuitive geometric structure of the data and improves the discriminative power of different classes.
2.5. Robust Nonnegative Matrix Factorization via Joint Graph Laplacian and Discriminative Information (GLD-RNMF)
2.5.1. The Objective Function
For the purpose of dimension reduction, NMF represents original data by a product of a nonnegative matrix and coefficient matrix . The approximation error is calculated according to the squared residuals; that is, . Due to the squared term in the objective function, smaller outliers can lead to larger errors. In this paper, we enforce -norm constraint on the objective function to reduce the impact of outliers and noise.
By employing -norm on GDNMF model, we can formulate the objective function of GLD-RNMF as follows:
This objective function can solve high dimensional, negative, noisy and sparse data simultaneously, keep consistent with the intuitive geometric structure of data, and improve the discriminative power of different classes.
2.5.2. The Multiplication Update Rules of GLD-RNMF
Although the objective function is not convex jointly about , it is convex in regard to one of variables in when the others are fixed. The objective function can be expanded as follows:where and both are diagonal matrices and the diagonal elements are as follows:in which is an infinitesimal positive number.
In order to solve the optimization problem in (9), we introduce the Lagrange multipliers , , and for , , and , respectively. Firstly, we formulate the Lagrange function of GLD-RNMF as follows:
Taking the partial derivatives of with respect to , , and and setting them to zero and in view of and , we get
According to the KKT (Karush-Kuhn-Tucker) conditions [20], that is, , , and , we can obtain the following equations:
Then we can get the multivariate updating rules as follows:
The details of our method are described in Algorithm 1. The iterative procedure is performed until the algorithm converges.
Input: Data matrix , indicator matrix , parameters .
Output: Matrices , and .
Initialization: Randomly initialize three nonnegative matrices ,
and , initialize , to be identity
matrix. Set
Update , and separately by
Calculate the diagonal matrices and by (11) and (12), separately.
Until convergence.
GLD-RNMF.
Considering the three update rules above, we ensure the convergence of the algorithm by the following theorem.
Theorem 1. The objective function is nonincreasing under the iterative rules in (16), (17), and (18).
The detailed proof of the theorem is shown in the Appendix.
In order to verify the effectiveness of GLD-RNMF algorithm for identifying differentially expressed genes, we perform experiments on real gene expression datasets to compare our algorithm with the other four feature extraction algorithms: (a) GNMF algorithm (Cai et al. [9]); (b) NMFSC algorithm (Hoyer [21]); (c) RGNMF algorithm (Wang et al. [10]); (d) GDNMF algorithm (Long et al. [16]). We conduct these experiments on two publicly available cancer datasets: pancreatic cancer dataset (PAAD) and cholangiocarcinoma dataset (CHOL).
3.1. Identifying Differentially Expressed Genes by GLD-RNMF
In this section, we use GLD-RNMF to identify differentially expressed genes. The matrix with size is the original gene expression data. Each row of indicates the transcriptional response of genes in a sample. Each column of indicates the expression level of a gene in all samples. Therefore, can be written as follows:where is the basis matrix with size and is the coefficient matrix with size and . Since the matrix contains all of the genes, the differentially expressed genes can be identified from the matrix [10]. By GLD-RNMF, the evaluating vector is obtained in which elements are sorted in descending order:
Generally, the larger the entry in is, the more differential this gene is. Therefore, the differentially expressed genes can be obtained by the first num () largest elements in .
The objective of the experiment is to identify the differentially expressed genes by GLD-RNMF algorithm. The identifying process is described below.(1)Obtain the nonnegative matrix according to the genomic dataset.(2)Construct the label matrix and the diagonal matrixes and .(3)Gain the Laplacian matrix and basis matrix via GLD-RNMF algorithm.(4)Identify differentially expressed genes through the vector .(5)Check differentially expressed genes by gene ontology tool.
3.2. Parameters Selection
We assign parameters in our GLD-RNMF algorithm following the same way proposed by Long et al. [16]. Distinguishingly, there are two parameters, that is, and , in GLD-RNMF method.
Fortunately, if and are set in a reasonable range they have little effect on the performance of the algorithm [15, 16]. In our experiments, we set and in the GLD-RNMF algorithm. Another important parameter in our GLD-RNMF algorithm is which is used to construct a -nearest graph. Empirically, we set and adopt the mode as the heat kernel in LPP [22]. Besides, we set the reduced dimension to 5 for all the methods. All the parameters in the other methods keep in line with those described in their paper [10, 16, 21, 23].
3.3. Gene Ontology Analysis
The gene ontology (GO) tool can interpret the genes that are input and discover the functions that these genes may have in common. As a web-based tool [24], GO Enrichment Analysis can find important GO items from a large number of genes and provide important information for the biological interpretation of high-throughput experiments. Another online tool that we use is ToppFun. It usually is used to interpret the differentially expressed genes.
To be fair, we extract 100 genes from the gene expression data by GNMF, NMFSC, RGNMF, GDNMF, and GLD-RNMF methods. Threshold parameters of ToppFun are set as follows: the maximum value is set to 0.01 and the minimum number of gene products is set to 2.
3.4. Pancreatic Cancer Dataset
Pancreatic cancer is a tumor with high malignancy, which is difficult to diagnose and treat. Early diagnosis of pancreatic cancer is not difficult and the mortality rate is high. The cause of pancreatic cancer is still not clear until now. In the experiment, there are 20502 genes in 180 samples contained in the dataset.
The top 10 GO items extracted and the values of the five methods are listed in Table 1. In this table, "ID" and "Name" represent items and their names associated with the GO in the whole genome and the lowest value of the five methods has been marked in bold font. As we find from Table 1, the values generated by GLD-RNMF are much smaller than those by the other four methods for the PAAD. Therefore, GLD-RNMF method is more superior than the other four methods for the PAAD. The name of "GO:0030198" is extracellular matrix organization. It contains DPT (Dermatopontin), POSTN (Periostin), sec24d (Sec24-related protein d), and other genes which are related to pancreatic cancer [25–27]. For example, POSTN can create a tumor-supportive microenvironment in the pancreas [28]. Genes and gene products associated with extracellular structure organization (GO:0043062) can be found by GO tool, in which, DPT, POSTN, sec24d, uxs1 (UDP-Glucuronate Decarboxylase 1), fkrp (Fukutin Related Protein), and other genes have been illustrated to be associated with pancreatic cancer [29, 30]. For example, Sec24d is ubiquitously expressed but exhibits predominant expression in heart, placenta, liver, and pancreas. The other GO items can also be proven to be related to pancreatic cancer by some relevant literature material. Clearly, GLD-RNMF method is an effective method for identifying differentially expressed genes.
Gene ID Gene name NMFSC GNMF RGNMF GDNMF GLD-RNMF
GO:0030198 Extracellular matrix organization
GO:0043062 Extracellular structure organization
GO:0031012 Extracellular matrix
GO:0005615 Extracellular space
GO:0005578 Proteinaceous extracellular matrix
GO:0044420 Extracellular matrix component
GO:0030574 Collagen catabolic process
GO:0044243 Multicellular organism catabolic process
GO:0032963 Collagen metabolic process
GO:0098644 Complex of collagen trimers
Comparison of values of different methods on PAAD.
Comparing 100 genes extracted by GLD-RNMF with what we obtain from Gene Cards (http://www.genecards.org/) about pancreatic cancer, 82 of the 100 genes are associated with pancreatic cancer. Many genes, which were previously thought to be unrelated to clinical outcomes, are identified. We present the top 10 of 82 genes with higher relevance scores in Table 2, including their gene ID, names, function, and related diseases. Among the identified differentially expressed genes, MMP2, MMP7, IGFBP3, INS, and the other genes have been demonstrated to be related to pancreatic cancer [31–34]. For example, the effect of MMP-2 and its activators MT1-MMP, MT2-MMP, and MT3-MMP in pancreatic tumor cell invasion and the development of the desmoplastic reaction characteristic of pancreatic cancer tissues have been discussed [35]. Akihisa Fukuda et al. demonstrated that serum MMP7 level in human pancreatic ductal adenocarcinoma patients is correlated with metastatic disease and survival. Conditioned medium from Capan-1 pancreatic cancer cells which contains abundant IGFBP-3 has been mentioned [36]. Other genes identified by GLD-RNMF have been illustrated to be related to pancreatic cancer by some relevant literature materials as well.
Gene ID Gene name Gene annotations Relative diseases
4313 MMP2 Serine-type endopeptidase activity and metallopeptidase activity Arthropathy and multicentric osteolysis of Torg
3486 IGFBP3 Fibronectin binding and insulin-like growth factor I binding. Insulin-like growth factor I and acromegaly
3630 INS Identical protein binding and protease binding Diabetes mellitus
4316 MMP7 Peptidase activity and metallopeptidase activity Spastic entropion and focal myositis
3880 KRT19 Structural molecule activity and structural constituent of cytoskeleton Thyroid cancer and lung cancer
7057 THBS1 Calcium ion binding and heparin binding Posterior uveal melanoma and thrombotic thrombocytopenic purpura
3320 HSP90AA1 Poly(A) RNA binding and identical protein binding Lobular neoplasia and candidiasis
1508 CTSB Peptidase activity and cysteine-type peptidase activity Occlusion of gallbladder and ileum cancer
7076 TIMP1 Cytokine activity and protease binding. Oral submucous fibrosis and lung giant cell carcinoma
2335 FN1 Heparin binding and protease binding Glomerulopathy and plasma fibronectin deficiency
Pancreatic cancer genes extracted by GLD-RNMF.
On the other hand, we use Kyoto Encyclopedia of Genes and Genomes (KEGG) online analysis tool to analyze the differentially expressed genes identified by GLD-RNMF. In this experiment, putting the identified 100 genes into KEGG, we can obtain the corresponding disease pathway. Figure 1 is the pathway of pancreatic cancer. The genes that have been found by GLD-RNMF are marked with red. The chromosomal instability pathway records the disease progression from normal duct to pancreatic cancer. Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. Normal duct epithelium progresses to the stage of infiltrating cancer through a series of histologically defined precursors. These differentially expressed genes contain two oncogenes: K-Ras and HER2/neu. p16, p53, BRCA2, and Smad4 are tumor suppressors. Slebos et al. assessed that K-ras oncogene mutations and p53 protein accumulation are associated with known or postulated risk factors for pancreatic cancer [37]. Gu et al. found the expression of Smad4 and p16 is significantly lower in pancreatic cancer tissue compared with normal tissue. The lower expression of the proteins may impact the development of pancreatic cancer [38]. From Figure 1, we can see that the pancreatic cancer pathway map contains six other pathways: PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, VEGF signaling, Jak-STAT signaling pathway, p53 signaling pathway, and TGF- signaling pathway.
Pathway of pancreatic cancer, where pink background represents disease genes, light blue represents drug target genes, and light green represents human genes. Genes found by GLD-RNMF are marked with red.
PI3K-Akt signaling pathway is presented in Figure 2. From Figure 2, we can find four proteinases from the differentially expressed genes identified by GLD-RNMF. Therefore, our algorithm achieves better results.
P13K-AKT signaling pathway, where pink background represents disease genes, light blue represents drug target genes, and light green represents human genes. Genes found by GLD-RNMF are marked with red.
3.5. Cholangiocarcinoma Dataset
Cholangiocarcinoma is diagnosed in 12,000 patients in the US each year, but only 10 percent are discovered early enough to allow for successful surgical treatment. In our experiments, we apply the five methods on CHOL which contains 20502 genes on 45 samples. The 8 GO items closely related to cholangiocarcinoma and the values of the five methods are listed in Table 3. In this table, "ID" and "Name" represent items and their names associated with the GO in the whole genome. The lowest value of the five methods has been marked in bold font. We can see from the table that GLD-RNMF is much better than the other four methods. Genes and gene products associated with blood microparticle (GO:0072562) can be found by the GO tool, in which APOA4 (Apolipoprotein A4), kng1 (Kininogen 1), and other genes have been illustrated to be associated with cholangiocarcinoma [39–41]. The name of "GO:0060205" is cytoplasmic vesicle lumen. It contains ada (Adenosine Deaminase), DBH (Dopamine Beta-Hydroxylase), and other genes which are related to cholangiocarcinoma [42, 43]. The top 8 genes identified by GLD-RNMF are listed in Table 4 including the gene ID, names, gene annotations, and related diseases. Consistent with the previous study, ALB (Albumin), HP (Haptoglobin), SERPINC1 (Serpin Family C Member 1), C3 (Complement C3), and other genes are successfully identified which represent potential biomarkers for cholangiocarcinoma and potential targets for clarifying the molecular mechanisms associated with cholangiocarcinoma. For example, HP was proposed as pronucleating proteins because they were highly expressed in the fast nucleating bile of patients with cholesterol stones [44]. Waghray et al. predicted survival in patients with hilar cholangiocarcinoma by serum albumin [45]. C3 and HP were identified as more abundant in cholangiocarcinoma [46]. The relative documents can illustrate that the other genes identified by GLD-RNMF are associated with cholangiocarcinoma.
GO:0072562 Blood microparticle
GO:0060205 Cytoplasmic membrane-bounded vesicle lumen
GO:0031983 Vesicle lumen
GO:0034774 Secretory granule lumen
GO:0004857 Enzyme inhibitor activity
GO:0004866 Endopeptidase inhibitor activity
GO:0061135 Endopeptidase regulator activity
Comparison of values of different methods on CHOL.
213 ALB Enzyme binding and chaperone binding. Analbuminemia and congenital analbuminemia
3240 HP Serine-type endopeptidase activity and hemoglobin binding Anhaptoglobinemia and plasmodium falciparum malaria
5265 SERPINA1 Identical protein binding and protease binding Emphysema due to Aat deficiency and alpha 1-antitrypsin deficiency
718 C3 Receptor binding and C5L2 anaphylatoxin chemotactic receptor binding Macular degeneration, age-related, 9, and C3 deficiency
2243 FGA Receptor binding and protein binding, bridging Dysfibrinogenemia, congenital, and afibrinogenemia, congenital
7448 VTN Heparin binding and scavenger receptor activity Glanzmann thrombasthenia and camptodactyly-arthropathy-coxa vara-pericarditis syndrome.
7018 TF Ubiquitin protein ligase binding and ferric iron transmembrane transporter activity Atransferrinemia and iron overload In Africa
335 APOA1 Identical protein binding and lipid binding Amyloidosis, familial visceral, and hypoalphalipoproteinemia
Cholangiocarcinoma genes extracted by GLD-RNMF.
By introducing -norm, manifold graph and discriminative label information, we propose an efficient algorithm named robust nonnegative matrix factorization via joint graph Laplacian and discriminative information (GLD-RNMF) in this paper. -norm can reduce the influence of outliers and noise, manifold graph can find the low dimensional manifold in high dimensional data space and the intrinsic law of the observed data, and the label information can increase the discriminative power of different classes. Nonnegative matrix factorization avoids the problems of high dimension and nonnegative data. As a result, GLD-RNMF can handle nonnegative, high dimension, outliers, and noise and improve the discriminative power of different classes. Experimental results on two datasets show that GLD-RNMF is superior to the state-of-the-art methods for identifying differentially expressed gene.
Detailed Proof of Theorem
To prove Theorem, we need to show that the objective function in (9) is nonincreasing under the iterative rules in (16), (17), and (18). For the objective function , we need to fix and when we update . Similarly, we need to fix and when we update , and we need to fix and when we update . For the reason that we have similar update rules for and in GLD-RNMF with those in NMF, the detailed proof can be found [27]. Hence, we just need to prove that is nonincreasing under the iterative rules in (18). We use an auxiliary function similar to what is used in the Expectation-Maximization algorithm [47]. In the demonstration, we present the definition of auxiliary function [16]. Definition is an auxiliary function of if the following conditions are satisfied.
The auxiliary function is vital due to the following lemmas.
Lemma A.1. If is an auxiliary function of , then is nonincreasing under the update rule:
Proof. Obviouslynow, we will present the update step for in (18) is exactly the update in (A.2) with an appropriate auxiliary functionIt is enough to prove that each is nonincreasing under the update rules because our update is essentially wised. Therefore, we present the following lemma.
Lemma A.2. Function,is an auxiliary function of .
Proof. We only need to demonstrate that , because is obvious. Consequently, comparing the Taylor series expansion of ,with (A.2), we can find that is equivalent to Actually, we have
Therefore, (A.7) holds and . Now we can prove the convergence of theorem.
Proof of Theorem. Replacing in (A.2) by (A.5), we can obtain the following update rules:Since is an auxiliary function, is nonincreasing under the update rule.
The authors declare that they have no conflicts of interest.
This work is supported in part by the grants of the National Science Foundation of China, nos. 61572284, 61502272, 61373027, and 61672321.
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Copyright © 2017 Ling-Yun Dai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
Lyouboten ou Ljuboten (en macédonien Љуботен, en albanais Luboteni) est un village situé à Boutel, une des dix municipalités spéciales qui constituent la ville de Skopje, capitale de la Macédoine du Nord. Le village comptait 2343 habitants en 2002. Il se trouve au nord de l'agglomération de Skopje, sur le versant sud de la Skopska Crna Gora. Il est majoritairement albanais. Son église orthodoxe du , dédiée à Saint-Nicolas, conserve des fresques remarquables.

Démographie
Lors du recensement de 2002, le village comptait :
 Albanais : 223
 Macédoniens : 1150
 Serbes : 1
 Autres : 4

Voir aussi

Liens internes
 Boutel
 Skopje

Liens externes
   Site officiel de la municipalité de Boutel

Références

Localité de Skopje

redpajama_set_name: RedPajamaWikipedia


ESPN Classic has suffered another distribution hit: Comcast Corp. has moved the service to digital in the Washington, D.C., market to make room for other networks, including its own Outdoor Life Network, officials said.
As a result of the changes earlier this year, ESPN Classic has lost about 200,000 Comcast subscribers in Arlington, Va., and Montgomery County, Md., according to an ESPN spokeswoman.
The loss of those homes, though not huge, comes alongside a major blow weathered by ESPN Classic at the start of the year. EchoStar Communications Corp. dropped ESPN Classic from its Dish Network lineup, a move that cost the sports-nostalgia network 5.1 million subscribers.
Classic's shift to digital and a number of other changes were the result of Comcast's attempt to standardize the channel lineups of its Washington-area systems, according to an MSO spokeswoman.
In recently upgraded Arlington, Outdoor Life, Speed Channel, Food Network and Cartoon Network were added to analog basic, while ESPN Classic and Toon Disney moved to digital, the spokeswoman said.
Comcast took controlling interest in OLN last year.
In Montgomery County, ESPN Classic and HBO Family were moved to digital, while Discovery Health Channel, OLN and Style were added to expanded basic. Game Show Network was moved from part-time to full-time status on analog.
Comcast had also launched ESPN Classic on a digital tier in Arlington, Va., the MSO spokeswoman said.
With respect to Comcast's shifting ESPN Classic to digital in Arlington, the ESPN spokeswoman said: "They were part of a contractual commitment, and we knew about it for some time. "ESPN Classic now has about 40 million subscribers.


I am sure every one of us welcomed 2016 with great pomp and show. With the new year, comes the tradition of resolutions. And losing weight is something that most of us swear to achieve. For this reason, today we bring you 5 cool fitness gadgets of 2016 that will help you in keeping your new year resolution!
Heart rate monitors come in various shapes and sizes. But you would not have seen anything more flexible and miniature than AmpStrip. This device can be paired with your Smartphone and provides you with real-time heart rate monitoring.
You can use this device to slow down or bump up your workout regime easily. The device will be priced at $150 and will be available later this year.
If you are a fitness freak, you must have surely heard about Garmin fitness tracker. Vivofit 2 is the upgraded version of its predecessor and boasts of additional features.
Apart from tracking your movements, the device will now notify you audibly when you have been sitting idle or not doing any physical activity for a length of time. The device is claimed to last a full year on a single charge. Garmin have also introduced the backlight feature to help you see in the dark. The device is priced at $129 and comes in various colours and style options.
If you are into outdoor activities, then you should try out a fitness tracker for cycling. Moov Now is a fitness tracker that can be strapped on your ankle's. It has a 9-axis motion sensor that records the number of turns the wheels have taken. This helps in determining the accurate distance that you have covered.
It also comes with fitness plans to help encourage and improve your fitness. The device is available at $79.99.
This is a smartwatch that tracks your heart-rate, step and sleep patterns. What makes it unique is the fact that it also tracks your mood throughout the day. Based on your mood, the smartwatch will display 'excited', 'distressed', 'calm' or 'normal' which is tracked alongside your fitness data. You can use this information to compare what might be causing your mood swings and take action to correct it.
If you are a gym going person, this gadget is meant for you. This device nicely pairs up with your iPad and has tons of preloaded workouts and exercise routines. You just need to attach the device to the back of your leg or arm and it will capture your movements and offer suggestion on how to improve it along with providing feedback. There are built-in exercise videos available as well that you can watch and execute.
This was our roundup of the 5 Cool Fitness Gadgets that you must have in 2016. If you have anything else to add to this list, do let us know your thoughts in the comments section below.


In 2012, Aaron Hand was the managing editor for Control Design and for Industrial Networking.
Anyone visiting Disney World's Magic Kingdom in August is likely to appreciate the sweet relief of the cool, slow boat ride of It's a Small World — followed by the frustration of realizing that the sugary, sticky song will never, ever, leave your head. Yes, it can be a surprisingly small world at times, and as I look ahead to next year's coverage of our Global Machine topic, my mind is focused on the ways that machine builders can not only survive themselves, but help their customers compete globally.
And yet, I'm equally struck by the steps manufacturers take to operate on a local level as well, building good relationships with local suppliers and the communities that they live and work in.
In September, Lenze Americas celebrated the official opening of a new production facility in Glendale Heights, Ill. That's just a stone's throw from our office, so Joe Feeley and I checked in on them to take a look at the new digs.
In deciding where to locate their new 100,000 ft² assembly and logistics facility, Lenze got some university folks to run some models. They figured out that the center of Lenze's universe was about 100 miles south of here, so they ultimately settled on this small western suburb of Chicago, where there's no shortage of industrial activity.
While showing us around their production facilities, Lenze officials repeatedly commented on the great relationship they've formed with KMI Systems, a turnkey system manufacturer about an hour up the road in Crystal Lake, Ill. KMI makes the conveyor systems that carry Lenze motors and gearboxes through paint and bake processes.
Lenze necessarily gets some of its supplies, including home-ground gears, from its parent company in Germany, and those supplies take some five weeks to reach the Chicagoland facility. But the facility is also trying to localize sourcing as much as possible, according to Gene Wood, director of operations for Lenze Americas, to help reduce leadtimes and transportation costs, for example. KMI is just one example of those great neighbors you hear about in old movies and State Farm commercials. "There's an abundance of people in the machine business here," Wood notes.
With our publishing offices located in Northwest Chicagoland, we're surrounded by some pretty great neighbors as well. I got to meet several of them at the latest IMTS show — DMG/Mori Seiki in Hoffman Estates, Ill.; Fanuc FA America, also in Hoffman Estates; and Mitsubishi Electric Automation in Vernon Hills, Ill., just to name a few — and we talked about getting together for future play dates.
When I covered semiconductor manufacturing from Chicagoland, I never got that sense of community that my Silicon Valley-based co-editor did. But covering machine automation from Chicagoland — now that's a different story. And it actually surprises me that in this day and age of global coverage, there's something to be said for the closeness you feel to your neighbors.
I've got a similar feeling of camaraderie with my neighbors where I live in Northwest Indiana (i.e. Southeast Chicagoland). I coach their kids in soccer, we carpool to early-morning choir practices, and they tolerate the collapse of their lovely brick mailbox when my 300 lb trampoline sets sail in a wind storm (well, the insurance money probably helped).
So I wasn't too surprised last night when a young neighbor from across the street brought us over a big six-pack of white cheddar shells that her mom had brought home from work. What I was surprised about was to hear that this mother works for the company that makes the machines that shrink-wrap the boxes of noodles. Her company, Arpac, is located in Schiller Park, Ill., just east of our offices here, so we share a very similar commute, skirting the boundaries of the city. I see more carpooling in our future, and I think we'll be having a few more conversations about the world of food packaging machinery.
And what's one of the first things she tells me? How difficult it is to hire engineers and technicians. How many times have we heard that? And what was the No. 1 difficulty Lenze faced when setting up its new shop? Finding the skilled workforce. Wood marveled at the fact that about half the job candidates didn't even show up for their first interviews.
Meanwhile, one thing a company can do is be that good neighbor, building a community where engineers and operators want to work. It's a small world, after all.


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RI-345
An officer of a corporation has informed the corporation's lawyer of his intent to destroy documents that are subject to a judicial discovery order, and asks the lawyer to return copies of those documents in the lawyer's possession. The lawyer should first attempt to dissuade the officer from the threatened misconduct. If the officer does not recant, the lawyer should refer the matter to higher authority in the organization. The lawyer should decline to return copies of the documents in his possession until the matter is resolved so as not to assist in the unlawful destruction or concealment of evidence. The lawyer may continue representing the corporation and is not required to withdraw merely because the officer suggests improper conduct.
MRPC 1.2(c), 1.4(b), 1.6, 1.13, 1.16, 3.4; Restatement of the Law Governing Lawyers, 3d § 96.
A corporation is engaged in litigation. The chief executive officer (CEO) of the corporation has informed the corporation's litigation attorney that he intends to destroy documents relevant to the dispute that are subject to a court discovery order. The corporation is closely held but has a board of directors to which the CEO is accountable; and the CEO is not the sole shareholder. The CEO has directed the lawyer not to produce the documents in response to the order and has threatened to terminate her if she does. The lawyer possesses copies of the documents, and the CEO has requested that she return them to the corporation. The lawyer asks what steps should be taken under the ethical rules to address the CEO's threatened misconduct.
The lawyer's obligations are to the corporation. Although in most instances, the Rules of Professional Conduct defer to other law in determining who is the client, Michigan Rule of Professional Conduct ("MRPC") 1.13(a) provides that the client is the corporation, not the CEO:
A lawyer employed or retained to represent an organization represents the organization as distinct from its directors, officers, employees, members, shareholders, or other constituents.
In representing the corporation, the lawyer is to communicate with the client so as to permit informed decisions regarding the representation under MRPC 1.4(b), and is to take steps to prevent reasonably foreseeable harm to the client, as set forth in MRPC 1.13(b):
If a lawyer for an organization knows that an officer, employee, or other person associated with the organization is engaged in action, intends to act, or refuses to act in a matter related to the representation that is a violation of a legal obligation to the organization, or a violation of law which reasonably might be imputed to the organization, and that is likely to result in substantial injury to the organization, the lawyer shall proceed as is reasonably necessary in the best interest of the organization. In determining how to proceed, the lawyer shall give due consideration to the seriousness of the violation and its consequences, the scope and nature of the lawyer's representation, the responsibility in the organization, and the apparent motivation of the person involved, the policies of the organization concerning such matters, and any other relevant considerations. Any measures taken shall be designed to minimize disruption of the organization and the risk of revealing information relating to the representation to persons outside the organization. Such measures may include among others:
(1) asking reconsideration of the matter;
(2) advising that a separate legal opinion on the matter be sought for presentation to appropriate authority in the organization; and
(3) referring the matter to higher authority in the organization, including, if warranted by the seriousness of the matter, referral to the highest authority that can act in behalf of the organization as determined by applicable law.
The Committee assumes that the CEO's threat to destroy documents that are subject to a discovery order, if carried out, would be "a violation of law which reasonably could be imputed to the organization, and that is likely to result in substantial injury to the organization . . . ." [1] Accordingly, the lawyer is required to proceed as reasonably necessary to protect the best interest of the corporation, taking into account MRPC 1.13(b) and other relevant considerations. The particular steps required of the lawyer will depend on such factors as the governance structure of the organization, the degree of independence of the board, and the CEO's relationship with higher authority.
The lawyer should first attempt to dissuade the CEO from the threatened course of conduct. In asking the CEO to reconsider, the lawyer may discuss such matters as the corporation's duty to comply with court orders and applicable law, any relevant corporate policies such as those involving ethical obligations and document retention, the lawyer's recommendation that a second opinion be obtained regarding the implications of the threatened conduct, and the lawyer's intent to refer the matter to higher authority in the corporation if the CEO does not recant.
If the CEO cannot be dissuaded, the lawyer should consult with higher authority, here presumably the corporation's board of directors.[2] If the CEO is a member of the board, the lawyer should exercise care to assure that any independent directors are duly informed.[3] In referring the matter to higher authority, the lawyer may, as necessary, advise the board that the lawyer's ethical obligations would likely require withdrawal from representing the corporation, and appropriate disclosure to the tribunal, if the CEO carries out the threat and the misconduct is not otherwise rectified[4].
The objectives of MRPC 1.13 are met if the lawyer's referral to higher authority redresses the CEO's threatened misconduct. However, if the lawyer reasonably believes after counseling and remonstrating with the client that the CEO has not retracted his threat, the lawyer should preserve any pertinent documents, or copies thereof, in her possession until the matter of discovery compliance is resolved. Otherwise, the lawyer risks violating MRPC 3.4(a), which provides that a lawyer shall not "unlawfully obstruct another party's access to evidence; unlawfully . . . destroy or conceal a document . . . or assist another person to do any such act." The Comment to the Rule emphasizes that:
[d]ocuments and other items of evidence are often essential to establish a claim or defense . . . [T]he right of an opposing party . . . to obtain evidence through discovery or subpoena is an important procedural right. The exercise of that right can be frustrated if relevant material is . . . concealed or destroyed. Other law makes it an offense to destroy material for purpose of impairing its availability in a pending proceeding or one whose commencement can be foreseen.[5]
The lawyer should decline to return the documents to the CEO or the corporation. Doing so with the knowledge of the CEO's intentions could be considered assisting the client in destroying or concealing a document having potential evidentiary value in violation of MRPC 3.4(a). Returning the documents may serve also to assist the client in conduct the lawyer knows to be illegal or fraudulent, addressed in MRPC 1.2(c).[6]
The lawyer may continue the representation of the corporation notwithstanding the CEO's threat to destroy documents. The Comment to MRPC 1.16 counsels that "[t]he lawyer is not obliged to . . . withdraw simply because a client suggests such a course of conduct [that is illegal or violates the Rules of Professional Conduct or other law]." MRPC 1.16(a)(1) provides that a lawyer shall withdraw if "the representation will result in violation of the Rules of Professional Conduct or other law." Faced with the CEO's threatened misconduct, however, continued representation of the corporation is consistent with the lawyer's previously discussed obligations under MRPC 1.13(b). Such representation will not result in violation of the Rules or other law, but fulfills the lawyer's ethical duties and may forestall a violation of law by the client.
[1] Determining when destruction of evidence is a violation of law and analyzing applicable legal authorities are outside of the Committee's jurisdiction. For purposes of this Opinion, we assume that the CEO's threatened misconduct, if carried out, would be a violation of law regarding preservation of evidence subject to a court order.
[2] This opinion is applicable to any corporation. When the corporation has a single shareholder and single member board, the process described above under MRPC 1.13 is unnecessary.
[3] The lawyer's duty to maintain the confidentiality of client secrets does not, of course, prohibit the lawyer from disclosing communications with the CEO to higher authority within the client corporation. This is true even if the disclosure is against the interests of the CEO or other constituents of the corporation. See generally Restatement of the Law Governing Lawyers, 3d § 96.
[4] A discussion of a lawyer's ethical duties when faced with a client's actual, as opposed to threatened, misconduct is beyond the scope of this opinion.
[5] The reference to "other law" in the comment does not identify the external law defining "unlawful" conduct, and such analysis is beyond the scope of this opinion. See e.g., J. Gorelick, S. Marzon & L. Solum, Destruction of Evidence, Ch 5 (1989 & Supp 1991); 18 USC § 1503, which makes it a crime to "corruptly" obstruct the "due administration of justice," including the intentional destruction of evidence relevant to pending judicial proceedings; United States v. Berkowitz 927 F2d 1376 (CA 7, 1991); 18 USC § 401 (1995), (punishing disobedience of court orders and process). Legal scholars have suggested that the term "unlawful" in Rule 3.4(a) reaches conduct that violates discovery obligations. E.g., 1 G. Hazard & W. Hodes, The Law of Lawyering, § 3.4:201 at 626-627 (2nd ed Supp 1992); J. Gorelick et al., Destruction of Evidence, supra, § 7.7 at pp 258-60; C. Wolfram, Modern Legal Ethics, § 12.3.5 at p 644 (1986).
[6] We note that the threat to destroy the documents is itself not an illegal or fraudulent act (MRPC 1.2(c)) or unlawful destruction (MRPC 3.4(a)). . However, surrendering control of the copies that could substitute for the documents that may be destroyed in the face of such a threat if carried out would expose the lawyer to the substantial risk of such an assertion.
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redpajama_set_name: RedPajamaCommonCrawl


Welcome to the fifth edition of The OE.
The digital age is driving a whole new way of doing business. Those businesses that were "born digital" move at a different speed to "digital immigrants". They behave differently towards customers and the digital business model allows them to be more innovative and responsive.
Capability – how to bring in new talent with possibly very different ways of working and how the leadership team needs to adapt to lead the digital transformation.
We hope this edition will stimulate your thinking, whether you were "born digital", have recently arrived, or are planning your journey.


text:
BALANCING SUPPLEMENTS
DAILY HEALTH JELLIES
GUILT-FREE TREATS
FAQS FOR DOGS
FAQS FOR CATS
FAQS FOR HEALTH JELLIES
WHAT IS GOOD FOOD?
Food quantity app
Ode to Mondoe
Bestie Kitchen
THE CHILL-PUP
Buy 2 or more jellies of any type, and use the code MOREJELLIES at checkout, for 20% off. (Subscription orders get 30% off.) Plus subsidised $5 flat rate shipping across Australia, for orders up to 1kg.
Size: 70gm 140gm
70gm - $32.00 140gm - $50.00
To help puppies mature with less stress.
Leaving the litter, moving into a new home, weaning, growing, training: there's a lot to stress out puppies! This immune-boosting and calming health jelly, with magnesium glycinate and antioxidants for calming & immunity is designed to support your puppy's health as they grow.
Simply add water, mix and set in the fridge. Feed daily.
How much does a pack make?
70 gram packs make a 2 month supply for dogs less than 10kg (small) and a 1 month supply for dogs 10kg to 25kg (medium)
140 gram packs make 1 month supply for a dog 25kg+ (large) and 4 months for a small dog, and 2 months for a medium sized dog
These natural supplements are not like a panadol; they work over time. We recommend that supplements are fed on an ongoing basis - and at least for 3 months
Why should you feed a supplement?
Most commercial pet foods are made to meet the AAFCO and/or FEDIAF nutritional profiles for growth, reproduction or maintenance. However, many vets and animal nutritionists agree that these nutritional profiles do not necessarily enable cats and dogs to thrive and enjoy optimal health.
Your bestie may benefit from extra nutrients to help them thrive. Not only that, but every dog and their environment is different, so some need more help in some areas than others. In particular, acute and chronic health conditions are rife, including skin, gut and cancer and typically get worse as dogs age, so we help combat inflammation over the long term.
Health jellies are a supplementary food for dogs.
HOW TO MAKE THE JELLIES AND OTHER FAQS
DO ANY OF THESE SOUND FAMILIAR?
Do you have a puppy who's recently left the litter, moved in to a new home, been weaning, growing, training…and meeting other dogs and getting vaccinated?
All of these things can stress out your pup. As well as early training and help especially during 'fear periods', your puppy's immune system can do with a bit of boost and their whole being with calming.
RESEARCH-BASED, VET FORMULATED
Our research-based, vet-formulated daily health jellies, support your dog's health, from pup to senior, right from your own kitchen.
Holistic vet, Dr Kathy Cornack, is the vet behind our bestie health jelly formulations, and assessment quiz.
Dr Cornack's work on our bestie health jelly formulations draws on her 35 years in complementary medicine for dogs, cats and other small animals, and a range of peer-reviewed scientific research papers into the effect of functional and nutraceutical supplements for dogs.
Dr Cornack BVSc (hons), MANZCVS (Veterinary Behaviour), M.Agr. Sc (Animal Nutrition), Cert. Vet. acupuncture (IVAS) is still practising as a registered vet working primarily in clinical small animal practice. These days her work is exclusively with clients choosing natural (integrative) medicine as part of their treatment protocols, as well as in referral behavioural practice. Dr Cornack is a founding member and current President of the Integrated Vets Australia group. (IVA is a special interest group of the Australian Veterinary Association, for vets with a special interest in complementary/ holistic/ natural/ integrative veterinary medicine.)
RESEARCH SOURCES
Dr Cornack has developed this formulation based on her clinical experience and a number of research studies.
Young, Lauren & Pipingas, Andrew & White, David & Gauci, Sarah & Scholey, Andrew. (2019). A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and 'At-Risk' Individuals. Nutrients. 11. 2232. 10.3390/nu11092232.
Ando, Izumi & Karasawa, Kaoru & Yokota, Shinichi & Shioya, Takao & Matsuda, Hiroshi & Tanaka, Akane. (2018). Analysis of serum magnesium ions in dogs exposed to external stress: A pilot study. Open Veterinary Journal. 7. 367. 10.4314/ovj.v7i4.13.
Guggenheim AG, Wright KM, Zwickey HL. Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology. Integr Med (Encinitas). 2014;13(1):32–44.
Dunlap, Kriya & Reynolds, Arleigh & Duffy, Lawrence. (2006). Total antioxidant power in sled dogs supplemented with blueberries and the comparison of blood parameters associated with exercise. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology. 143. 429-34. 10.1016/j.cbpa.2005.09.007.
HUMAN-GRADE INGREDIENTS
Nutritional yeast is an inactive form of yeast that's a also a complete protein - containing the 10 amino acids that dogs need. It's also packed with B-vitamins, including B12 (typically only found in meat), has an abundance of trace minerals and the powerful antioxidants glutathione and selenomethionine. It also contains the carbs beta-glucan and alpha-mannan, that boost the immune system. B vitamins have been shown to lift mood and appetite in people. They're also water soluble so need replenishing every day.
MAGNESIUM GLYCINATE
Magnesium glycinate, is magnesium bound to glycine. In people, it's been shown to have a calming effect on the brain due to the presence of glycine and help relieve anxiety and promote better sleep (among other things). The levels of magnesium in dogs go up and down with stress and seasonally.
Milk thistle is a flowering plant in the Aster family, used in traditional medicine as a liver tonic. Milk thistle generally supports the immune system through its powerful antioxidant, free-radical scavenging action, its ability to preserve the supply of another important antioxidant, glutathione, as well as direct effects on immune cells. It's helpful for healing after drug therapy, vaccinations, and infections such as canine parvovirus.
Medicinal mushrooms are reported to have antimicrobial, anti-inflammatory, cardiovascular-protective, antidiabetic, hepatoprotective, and anticancer properties. It is well-established that mushrooms are adept at immune modulation and affect hematopoietic stem cells, lymphocytes, macrophages, T cells, dendritic cells (DCs), and natural killer (NK) cells. Reishi has been used extensively in cancer treatment in humans and mice.
Fruits, such as blueberries, are good antioxidants because they contain phenolics that preferentially react with free radicals. Oxidative damage from free radicals plays an important role in several diseases such as cancer, Alzheimer's disease, and heart disease. It's also been shown that strenuous exercise in people and dogs produces free radicals and that maintaining antioxidant levels by supplementing the diet with blueberries may prevent exercise-induced oxidative damage.
Kale is rightly called a superfood and is rich in betacarotene as well as lutein, and other vitamins and minerals. Dietary lutein has been shown to cause a significantly enhanced cell-mediated and humoral immune response in dogs. It's also been shown to enhance the antibody response of dogs given routine vaccinations.
We use Australian beef-gelatin as the 'jelly' agent in our health jellies.
Gelatin isn't just a 'carrier'; it's also good for dogs, especially ageing ones. For example, it inhibits inflammation and breakdown of the cartilage matrix. Collagen in the cartilage matrix and gelatin have a similar amino acid composition and there are indications that the amino acids in gelatin stimulate the synthesis of collagen cartilage.
This is one of the factors behind research that demonstrates the improvement in canine osteoarthritis due to gelatin supplementation. A trial of 15 dogs, fed gelatin in addition to their normal diet, found an improvement in activity (vitality), stiffness and lameness.[1]
Plant-based jelly carriers don't currently provide the same benefits. Gelatin is also a human-grade ingredient that is generally regarded as safe (GRAS) for all species.
[1] P, Jacobs & Grim, H. & Geene, H. & Beynen, Anton & Vlerk, T.. (2010). Oral Administration of Gelatin Hydrolysate Reduces Clinical Signs of Canine Osteoarthritis in a Double-Blind, Placebo-Controlled Trial. American Journal of Animal and Veterinary Sciences. 5. 10.3844/ajavsp.2010.102.106.
ons.
Gelatin powder, nutritional yeast, blueberry powder, magnesium glycinate, milk thistle, kale powder, reishi extract
HOW TO MAKE THE JELLIES
Surprisingly Good Results
I have just finished feeding a month of The Chill-Pup to my 2 yr old dog. Although he isn't considered a puppy (even though he still acts like one), this product was recommended to us when we took the assessment quiz. I have to admit I was a little skeptical at first about the described effects of this product. Bestie Kitchen also tempered expectations by explaining the product isn't like Panadol and results might not be instant. However, ever since my dog started taking the jellies, I have noticed he has found it a lot easier to settle down at night. While taking these jellies, we also went through some pretty heavy rain where we couldn't go outside for walks. Usually, I would see my dog get fairly restless, but he handled it quite well on these occasions. I could only attribute it to the jellies. Overall, I have noticed a positive effect on my dog while he was taking the jellies and would recommend it anyone who would want to help their pups chill out.
Thanks very much for your thoughtful review - and I'm glad it seems to have made a difference to your young dog.
Obvious change in the puppy
I have been training(socialising) a new puppy who had obvious anxiety issues from day one of coming home. Chil Pup has made a huge difference to his behaviour. It has been a very obvious change and we have been thrilled about it. Very happy. Thankyou!
Super-thrilled to get this feedback, and delighted it's made a difference. Thank you for trying bestie health jellies!
Anne T.
My chilled out Ellie
Ellie loved them straight away, she licked them at first. New texture,but very happy
That's great to hear. It will be interesting to see how she goes over time on them too.
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Sustainable Development Diplomacy Wageningen
Wageningen, The Netherlands
What is SDD?
Defining SDD
SDD Master Track
SDD can be considered a 'successor' of the notion of International Environmental Diplomacy (IED) and originates from three parallel shifts in international environmental politics: (1) from environment to sustainability; (2) from government to governance; and (3) from classical to new diplomacy. Since the UNCED Conference in Rio de Janeiro in 1992, so-called environmental problems can no longer be studied and managed in isolation; they need to be considered in their socio-economic and political contexts. In other words, we need to focus on sustainability instead of the environment. Secondly, non-state actors like NGOs and businesses have become ever more prominent in (international) politics and policy making, which is expressed by the term 'governance'. A similar development, thirdly, can be observed in the world of (international) diplomacy. So-called 'non-traditional diplomatic actors' play crucial roles in sustainability diplomacy today. Without them, historical outcomes like the Paris Agreement on Climate Change can neither be understood nor achieved.
The term 'SDD' comprises new types of diplomacy which emerge on – amongst others – sustainability issues, sometimes referred to as the 'new' diplomacy, 'inclusive' diplomacy, 'informal' diplomacy or 'guerilla' diplomacy. These terms refer to other ways of doing international negotiations than through the traditional, nation state, foreign affairs and international security oriented diplomacy. Some authors claim that this 'new' diplomacy is very different from the traditional one. It is multi-actor (including non-state actors in international negotiations), multi-level (local issues and actors do appear at international negotiation tables, just as global issues and actors do), multi-rule (soft law is currently considered as relevant as hard law) and multi-sector (going beyond security issues and single issues, an example being sustainable development). Indeed, non-state actors are now allowed to play their roles in international diplomacy (think about environmental NGOs and their impact on international treaties), whereas private or public-private instruments to address sustainability issues are emerging (e.g. certification schemes for sustainable products, payment for ecosystem services, REDD+, etc.).
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sdd.wageningen@gmail.com
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Former Lobbyist: The Privatization Movement Is Trying to End Public Education
Getting rid of public education spending would massively reduce the tax burden on wealthy individuals at the state level. (Photo: Ryan Stanton/flickr/cc)
They all have the same purpose: To undo public education—not only the institution but also the public funding of schools.
By Valerie Strauss and Carol Burris
A few years ago I ran a piece by Joanne Barkan about the long history of the movement to privatize public education. It began:When champions of market-based reform in the United States look at public education, they see two separate activities—government funding education and government running schools. The first is okay with them; the second is not. Reformers want to replace their bête noire—what they call the "monopoly of government-run schools"—with freedom of choice in a competitive market dominated by privately run schools that get government subsidies.
Today, that privatization movement is alive and pushing ahead, with Republican legislators in 16 states actively pushing bills to create or expand school vouchers and/or charter schools that are part of that movement.
This post—a continuation of sorts of the Barkan article—is a discussion with a man named Charles Siler, who was once a lobbyist for school privatizers but who came to oppose the very thing he was working toward. Siler worked for two privatization organizations, including the Goldwater Institute in Arizona, where his job was to persuade legislators to pass laws that privatize public services, especially K-12 schooling.
In March, Siler had a conversation with education historian and activist Diane Ravitch as well as with podcaster Jennifer Berkshire, in which he provided insight into the playbook used by "school choice" proponents, the belief system that drives them and their long-term objective. He makes it very clear: Their ultimate goal is to dismantle K-12 public schools.
Carol Burris, a former prizewinning principal and executive director of the nonprofit advocacy group the Network for Public Education, did a Q&A with Siler on the same issues. Here's the interview Burris did with Siler:
BURRIS: Charles, can you tell me about yourself—specifically, for whom did you work as a lobbyist for privatizing public services, and why did you leave that work?
SILER: I am Charles Siler, former Army public affairs and graduate of George Mason University with an economics degree. I lobbied and did public relations for the Goldwater Institute in Phoenix, Arizona, and the Foundation for Government Accountability in Naples, Florida. Both organizations are part of the State Policy Network, a collection of libertarian/conservative policy organizations around the country. While there, I promoted medical freedom legislation, programs to increase limitations on public assistance programs and school privatization programs.
I eventually left as I realized I wasn't a great fit for that work. The outcomes weren't aligning with my values. I grew up truly believing the best way we could help the most people was to get the government out of their lives. But if you take a look at the actual impacts of libertarian policies when they're implemented, it becomes apparent, they aren't helping people, and in fact, they make people worse off. I couldn't continue to do the work I had done. Now I work to educate people about the problematic programs I had helped promote and how we can build something better.
BURRIS: Let's get straight to the point. It is becoming more obvious that all of the voucher and charter expansion legislation we see this year is part of a larger mission being pushed by libertarian Republicans. First, am I right? And second, what is the ultimate goal?
SILER: There's virtually no other initiative in the education space that's a bigger priority for the right today than creating and expanding unaccountable, unrestricted, universal voucher programs. The easiest way to recognize this reality is to look at the incredible number of school voucher bills being pushed across state legislatures just this year.
They aren't doing it because their constituents are demanding these programs. Voters continually reject voucher programs, and in any state where a public response is permitted, the wave of public opposition to these programs dwarfs the AstroTurfed support for them. They also fervently refuse to include any kind of measures to mitigate fraud, waste, abuse and lack of accountability in these voucher programs despite having evidence from established programs. But simply setting up voucher programs isn't their ultimate goal; it's just the current next step towards their ultimate goal.
Their ideal is a world with as minimal public infrastructure and investment as possible. They want the weakest and leanest government possible in order to protect the interests of a few wealthy individuals and families who want to protect their extraction of wealth from the rest of us. They see private wealth accumulation as a virtue signal because a person can only become wealthy by creating something of exceptional value for the public. In their world view, the more money someone has, the more moral life they've lived, and any attempt to take that money through taxation or other means is a moral issue.
That's why they work so diligently to undermine public infrastructure, whether that's public schools, public transportation, military spending, and even the carceral system.
They also work to undermine collective action in the form of unions, voting blocs, protests and more. To them, it's equally immoral for a union to demand higher wages of a business owner as it is for voters to impose a higher minimum wage on business owners. The same people pushing for school privatization are the same ones pushing for voter suppression, and that's why. They fear the power of people.
BURRIS: In many states, we see a multiplicity of voucher programs—all functioning differently and all with different names. Why?
SILER: The hodgepodge of voucher and privatization programs is a result of their unpopularity. Since they are pushing an unpopular agenda across the country, each state presents different opportunities and challenges for school privatizers.
The programs have to have different names to create a sort of moving target. When advocating for voucher programs, I never used the term "voucher" because we knew it was already tainted and politically unpopular. That's why we called them Education Savings Accounts, or Personal Learning Scholarship Accounts, and so on. We knew that the public didn't support our efforts, but there's also a sincere belief that the public doesn't truly understand what is best for them, so we have to trick them into buying what we're selling. So much of our outreach was obfuscation. I spent many phone calls with reporters trying to explain to them why our program wasn't a voucher program and shouldn't be labeled as such.
At the end of the day, the multiplicity you see is a direct result of the unpopularity of vouchers, but make no mistake, they all have the same purpose: To undo public education — not only the institution but also the public funding of schools.
BURRIS: We are now seeing charter expansion legislation paired with voucher legislation. How do charter schools fit into the agenda?
SILER: Charter schools are part of the incremental march towards full privatization. Sometimes charter schools are part of the hook for large donors. A number of wealthy privatization financiers have become part of the movement by funding large grants and other programs for charter schools.
Also, charter schools can be set up in a number of different ways depending on the local political climate, all while starting the shift of public funds into private investments. Charter schools also help garner the support of White voters as charters often find creative ways to discriminate against students of color, increasing segregation. Charters create a number of loopholes in the public education space, from financial and academic accountability to legal protections for marginalized students, which begin to normalize those problems for the general public. In many ways, charter schools are the gateway to total public school dismantling.
BURRIS: What were some of the tricks of the trade, so to speak. Were there certain individuals you searched out to carry the message?
SILER: We would seek out people with sympathetic stories, families or individuals with sincere struggles. The goal was to find people with whom the general public could empathize.
When Florida's voucher program faced a lawsuit by the teachers union there in 2014, I flew to meet with a handful of families who had children with disabilities to create a video series promoting the value of the voucher program. I met with a single mom whose daughter had Down syndrome and needed highly individualized care and therapy. I met with a home-school mom who taught her five kids, but one had severe autism, and she struggled to meet his needs on her own. I met with other families hoping to enroll their kids in special schools that focused on their kids' specific needs. These people were part of the campaign's public face around the legal defense of the voucher program.
Also, if we could ever find minority families willing to speak up about their struggles and desires for school privatization, we'd work to put their faces in as many places as possible. It's one reason privatization advocates focused so heavily on promoting vouchers within the Navajo community recently in a bid to leverage their tribal identity to expand their state's voucher program. In many ways, there's an emphasis on playing identity politics to subvert actual equity efforts, especially when it comes to privatization.
BURRIS: Why is it that many voucher programs start small—with children with disabilities or with military families?
SILER: It goes back to the unpopularity of these voucher and privatization programs, not just with the public but also with many lawmakers. If possible, privatization advocates would completely dismantle public schools tomorrow, but they don't have the political leverage to achieve that right now, so they have to engage in incrementalism. Just this year, we've seen pushes to pass expansive, universal voucher programs in some states, showing that privatizers will abandon elements of incrementalism when they think they have an opportunity.
So, when they can't pull that off, they choose a population they think will be politically unassailable, like children with disabilities or kids in foster care. The idea is that by presenting a small program focused on a small group of vulnerable students, it will be difficult for pro-public education advocates to be directly critical of the programs. It's a "human shield" strategy so they can get any aspect of the program started as it's almost always politically easier to expand something than it is to establish something new. And that's why these voucher programs never stay focused on their original population. They are continually expanding eligibility to more and more students, sometimes at the expense of the initial group of kids the program was established for.
BURRIS: Who are the major funders of the so-called school choice movement, and why are they hostile to public education?
SILER: I can't speak about specific funders or donors who haven't been identified already in a public way, but some are pretty obvious. Former secretary of education Betsy DeVos has made dismantling public schools part of her life's work, and through the DeVos Family Foundation, she funds privatization efforts across the country. Her work as a financier likely has done and will do more damage to public schools than her entire tenure with the Trump administration.
The heirs of the Walmart fortune, the Walton family, also funds privatization across the country—especially charter schools. The Koch Foundation is probably the most publicly villainized supporters of dismantling public schools, and in many ways, there wouldn't be such a vast network of pro-privatization advocates had it not been for the tireless support of Charles and David Koch. There's also the Bradley Foundation, which contributes to numerous conservative groups and is also a financial driver of school privatization.
But it's not just billionaires. It's also local businesses funding privatization efforts, either through donations made by their owners or investments into state and local chambers of commerce. It's individuals, small donors, too. But they really aren't sufficient to make the entire machine, the industry of school privatization, function. It truly takes the massive investment of the exceptionally wealthy to drive the privatization agenda.
Their hostility to public education is best described as being the nexus of three parts. First, they want to minimize any government spending whatsoever, and public education is one of the largest line items in any state budget. Getting rid of public education spending would massively reduce the tax burden on wealthy individuals at the state level.
Public schools are also incredibly popular, and they don't want the general public to view public institutions as effective or popular. It's why they've driven a false narrative about "failing schools" for decades now, and it's also why they continually attack Social Security, Medicare, public pensions, public transportation and more because they know it's impossible to get people to share their vision for limited government when people have so many positive experiences with government programs. And lastly, it's about diminishing collective power. Taking down public schools also means taking down teachers unions, PTOs, local school boards and all the other ways those of us who aren't exceptionally wealthy come together to push for collective investment in our communities.
Public schools and the communities around them represent the kind of togetherness privatization advocates despise.
BURRIS: I know that one of the principles that school choice advocates believe in is "backpack funding," or "the money follows the child." If that were to happen, what would prevent the money in the backpack to become less and less, with parents required to finance the rest? Is that the plan? Is that ever discussed?
SILER: The idea of "backpack funding" is absurd on its face since public investments are in institutions to educate a community rather than any individual. We don't have money for each student, because we have money for schools. And privatizers rarely tell you what all you leave behind when a family decides to take their "backpack," like federal protections against discrimination, protections for disability services, mandatory reporters and much more.
To your question, though, we can already see that privatizers have no interest in increasing the funds in the "backpack." In Arizona, where voters passed a new tax to increase public education funding, which would, in turn, increase the value of vouchers in the state, that tax is being actively undermined by privatization advocates. They are actively working to continue their divestment of our public education system, even at the expense of funds to voucher families, because these programs are not designed to help anyone. They are simply designed to exacerbate the destruction of public funding for education.
If the privatizers could create their ideal education model, which they are building towards every day, individual families would determine how important their children's educations are to them by funding that education on their own. They would create a model similar to what we have for higher education, where individuals can take out loans to cover the cost of their K-12 education. The premise being that if education for an individual is truly a worthwhile investment, then the individual receiving the education should bear those costs. School privatizers want to empty the public "backpack" entirely and leave individual families to figure out funding for their education expenses.
BURRIS: For several years now, I have feared that the school choice movement is not about providing families with choices, but part of a bigger vision that seeks to make the education of America's children a service to be paid for by parents, with a poorly funded public option for those who cannot pay. Now former insider Charles Siler confirmed that fear.
This discussion is relevant not only at the state level but also at the federal level. The fiscal year 2022 federal budget, which is in development, is likely to include funds for the Charter Schools Program (CSP), a program whose purpose is to expand charter schools, which are privately operated but publicly funded. The CSP is about charter school expansion — which plays right into the right-wing/Libertarian agenda that former lobbyist Siler was hired to expand.
There may be well-meaning elected officials in Washington and state capitals who think charters and vouchers are about helping disadvantaged students. And no doubt some families have enjoyed choice. But every bill that passes and every program funded furthers the agenda of the radical libertarian right and Betsy DeVos. They know what their endgame is, and they are rapidly making progress.
Published by Common Dreams, 04.19.2021, under the terms of a Creative Commons Attribution-Share Alike 3.0 license.
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Spices Clovelly Estate exterior
Luxury Bedroom
Spices Clovelly Estate
Spicers Clovelly Estate
Traditional Lodge – typically up to £300 per room per night
French-inspired luxury retreat
Spicers Clovelly Estate is a scenic two-hour drive north of Brisbane, located high in the Blackall Ranges in the hinterlands of the Sunshine Coast. The estate and its surroundings boast spectacular views all the way to the Glass House Mountains in the south. Nearby towns Montville and Maleny retain much of their original identities as arts and crafts hotbeds as they play host to several nationally recognised artist and art galleries. Slightly further afield (a half an hour's drive), will bring you to Mooloolaba and its pristine coastal beaches.
Enter through magnolia groves and pass between grand figs to the main guesthouse and, in doing so, be transported to rural Brittany. Spa Suites come with Carrara marble bathrooms, under floor heating and spa baths while Estate Suites additionally feature bay windows, outdoor terraces and private gardens. For the ultimate stay, book the standalone three bedroom French cottage, which has verandas to the front and back and its own outdoor spa.
Awarded two Chef Hats and ranked in the top 100 restaurants in Australia by The Australian Gourmet Traveller, The Long Apron delivers a modern European-inspired menu. The kitchen makes full use of the extensive onsite herb garden and works closely with local producers to serve the best in seasonal ingredients. For breakfast, expect a selection of favourites with a gourmet twist, for example, scrambled eggs, goats curd served with roasted cherry tomatoes. In the evening, head chef Cameron Matthew's French training comes to the fore but the menu is never far from Australia with dishes such as kangaroo tail and Mooloolaba prawns.
With a swimming pool, 22 acres of landscaped gardens and manicured, rose-terraced lawns, many guests simply wile away their days with a gourmet picnic basket overlooking Lake Baroon. Alternatively, The Long Apron puts on tailored cooking courses so you can learn how exactly the beef was so excellently prepared the night before. The hotel's Spa Anise offers a range of treatments – perfect for a post-walk massage. Venture a little further afield and you'll find the UNESCO listed Fraser Island, the mesmerising Rainbow Beach and seasonal whale watching at Hervey Bay.