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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.
While gene duplication is known to be one of the most common mechanisms of genome evolution, the fates of genes after duplication are still being debated. In particular, it is presently unknown whether most duplicate genes preserve (or subdivide) the functions of the parental gene or acquire new functions. One aspect of gene function, that is the expression profile in gene coexpression network, has been largely unexplored for duplicate genes.
Here we build a human gene coexpression network using human tissue-specific microarray data and investigate the divergence of duplicate genes in it. The topology of this network is scale-free. Interestingly, our analysis indicates that duplicate genes rapidly lose shared coexpressed partners: after approximately 50 million years since duplication, the two duplicate genes in a pair have only slightly higher number of shared partners as compared with two random singletons. We also show that duplicate gene pairs quickly acquire new coexpressed partners: the average number of partners for a duplicate gene pair is significantly greater than that for a singleton (the latter number can be used as a proxy of the number of partners for a parental singleton gene before duplication). The divergence in gene expression between two duplicates in a pair occurs asymmetrically: one gene usually has more partners than the other one. The network is resilient to both random and degree-based in silico removal of either singletons or duplicate genes. In contrast, the network is especially vulnerable to the removal of highly connected genes when duplicate genes and singletons are considered together.
Duplicate genes rapidly diverge in their expression profiles in the network and play similar role in maintaining the network robustness as compared with singletons.
Contact: kdm16/at/psu.edu
Supplementary information: Please see additional files.
Approximately half of human genes are members of duplicate gene families [1] and such genes might be playing an important role in the robustness of organisms against mutations (reviewed in [2-4]). Do most duplicate genes retain the functions of their parental singleton gene? Or do they diverge after duplication? And how rapidly does this divergence occur? Several models predicting preservation of both duplicate gene copies (e.g., gene function conservation, subfunctionalization, neofunctionalization, and subneofunctionalization) have been proposed [5-7] and reviewed in [8,9], however, their relative prevalence in the fates of duplicate genes is presently unknown. Originally, these questions were addressed by analysis of the protein-coding sequences of duplicate genes. Namely, the pattern of nonsynonymous vs. synonymous substitutions between duplicate genes was used to predict divergence in function (e.g., [9-11]). However, protein-coding sequences possess only partial information about gene evolution and function. The availability of genome-wide mRNA expression data allows one to study another important aspect of duplicate gene evolution, that is divergence in gene expression after duplication (e.g., [12-15]).
The divergence of duplicate genes in gene coexpression networks, where connectivity is based on similarity in gene expression patterns (e.g., [16-18]), represents yet another facet of duplicate gene evolution that awaits detailed investigation. Gene coexpression networks as well as many other biological networks (e.g., metabolic and protein-protein interaction networks) were shown to be scale-free [16,17,19,20]: the topology of these networks is dominated by a relatively small number of highly connected nodes, also called hubs [21,22]. Scale-free networks were found to be tolerant against random removal of nodes, but particularly vulnerable to preferential removal of hubs [23]. The studies of the evolutionary origins of scale-free biological networks suggested that gene duplication can lead to both network growth and preferential attachment and to result in a scale-free topology [22,24-26]. Thus, duplicate genes are likely to be the major players in the evolution of biological networks and investigation of their divergence in these networks is of great importance. So far, the divergence of duplicate genes has only been examined in yeast transcriptional regulation and protein-protein interaction networks [9,27-30], however, it has not been explored in networks of more complex organisms, e.g., mammals.
In mammals, where genome-wide transcriptional regulation and protein-protein interaction data are limited [31,32], coexpression networks provide an alternative for investigation of duplicate gene divergence at the systems biology level (protein-protein interaction and transcription regulatory links are a subset of links in gene coexpression networks). Coexpression and functional relationship of genes are expected to be positively correlated. Indeed, clustering of mRNA expression data has been successfully used for grouping genes similar in function [33,34] and a global correlation was found between gene expression and protein-protein interaction data [35,36]. Additionally, thousands of coexpression connections between genes were found to be evolutionarily conserved among distant organisms [18], again suggesting a strong link between similar expression pattern and functional relatedness. However, some individual links between genes might not represent direct functional relationships due to the noisiness of microarray data and network transitivity.
In the present study we build a human gene coexpression network based on human tissue-specific microarray data. We examine the divergence of duplicate genes in this network by addressing the following questions: (1) are duplicate genes or singletons represented more frequently among network hubs; (2) how rapidly do duplicate genes lose shared parental partners; (3) how quickly do they acquire new coexpressed partners; (4) is the divergence in the gene coexpression network symmetric or asymmetric between two duplicate genes in a pair; and (5) do duplicate genes and singletons play different roles in maintaining the robustness of this network.
To build the gene coexpression network, we used the mRNA expression data that provide information about ~45,000 transcripts assayed in 79 human tissues [37]. We mapped probe sets to genes (see Methods) and as a result obtained a data set with one-to-one probe set to gene correspondence. This data set consisted of 14,342 genes, including 261 tissue-specific and 3460 ubiquitously expressed genes.
Two genes (represented by nodes) were connected by an edge if (1) both of them were simultaneously expressed in at least T common tissues, and (2) the Pearson correlation coefficient of their logarithmically transformed (with base 2) expression values was greater than or equal to R [16]. Nine networks were constructed depending on the combination of T and R (T ≥ 5, T ≥ 7, or T ≥ 9; and R ≥ 0.5, R ≥ 0.7, or R ≥ 0.9). Here in addition to the Pearson correlation coefficient we used a threshold of the minimal number of common tissues in which both genes are expressed. Relying on the correlation coefficient alone could lead to non-biological artifacts, e.g., artifactual similarities based on non-expression or expression in a few tissues only. Thus, by adding this additional criterion we obtain a meaningful correlation coefficient as it is calculated from at least five data points and only for tissues in which both genes are expressed (AD>200). To characterize the global topology of these networks, we used several graph measures [38]. First, the average node degree <k> reflected the average number of genes expressed together with a given gene. Second, the average shortest path length <d> specified the average number of edges required to travel from one gene to any other gene. Third, the average clustering coefficient <c> measured the connectivity of the neighborhood of a gene. With increases in T and R, the number of genes in the main cluster and the average number of genes coexpressed with a given gene decreased, while the average shortest path length increased (Additional file 1).
Additionally, we investigated the node degree distribution P(k) describing the frequency of the number of genes with k coexpressed genes. For five (out of nine) networks, this distribution approximated a power law distribution (Figures (Figures11 and Additional file 2), a characteristic of scale-free networks [21]. We used the network with T ≥ 7 and R ≥ 0.7 for further examination, since for these thresholds the degree distribution had a power law tail (Figure (Figure1)1) and we still retained a large number of genes for a statistical analysis (however, our main conclusions hold for all thresholds examined). This network contained 12,897 nodes (all located in the main cluster) with the average degree of 132.4 (Table (Table1).1). The density (the number of observed connections divided by the number of possible connections) of the present network is 0.0103, which is comparable to the value of 0.0057 obtained for a human gene coexpression network consisting of ~9,000 genes and confirmed by at least three microarray data sets [34].
Interestingly, we found a complex relationship between clustering coefficient c and degree k: c increased steadily with increasing k for k < ~300, then it slowly decreased (Figure (Figure2A2A and Additional file 3). The increasing relationship was more pronounced since it represented a larger sample of nodes. This implied that genes with a moderately high number of coexpressed genes usually had highly connected neighbors. This observation was unexpected as other scale-free networks display either negative or no correlation between clustering coefficient and degree [22]. Initially we suspected that the relationship observed here could be explained by a large number of ubiquitously expressed genes that have a high probability of being clustered among themselves and with other genes. However, a largely positive correlation between c and k was observed for either ubiquitously expressed or non-ubiquitously expressed genes (Figures (Figures2B2B and and2C),2C), suggesting that this is a general property of the studied network.
A total of 11,512 duplicate genes were identified among 22,103 Ensembl (NCBI build 34) known and novel proteins (see Methods). The studied network consisted of 6,390 singletons and 6,507 duplicate genes. Interestingly, while genes in the two categories had similar degree distributions (Additional file 4), duplicate genes had a lower average node degree and thus were less connected in the network than singletons, although the difference was small (102.1 vs. 144.9; Table Table1;1; t = -7.74; P < 0.001 as assessed by permutation test). Ranking the nodes by degree indicated that among highly connected genes the proportion of singletons was higher than the proportion of duplicates (Figure (Figure3).3). Thus, the effect of increased copy number might be more severe for genes with numerous coexpressed partners in the network and, as a result, duplications of such genes might have a lower propensity to become fixed in a population as compared with duplications of genes with few connections [27]. Interestingly, the average clustering coefficient was significantly lower for duplicates than for singletons (Table (Table1;1; t = -9.86; P < 0.001 as assessed by permutation test). This suggests a lower likelihood of a duplication fixation for a gene that has a tightly connected neighborhood. In this network, the percentage of duplicate gene pairs with at least one Gene Ontology [39] term overlap was higher among pairs connected by a link vs. unconnected pairs (97% vs. 86%). This is a much higher percentage than that observed for singletons – either linked (22%) or unlinked (15%). Thus, duplicate genes, especially if they are linked, had greater functional similarity.
Among the strongest hubs for duplicates, the proteins participating in nucleotide, nucleic acid, ATP, and protein binding were overrepresented (determined from the Gene Ontology terms). In addition to these categories, mitochondrion, signal transduction, and membrane proteins were overrepresented among singleton hubs. Interestingly, similarly to duplicate hubs, duplicates with the lowest number of links were involved in protein and ATP binding. However, singletons with a small number of links had different functions: e.g., receptor, transcription factor and transcription regulation activity.
We investigated the dynamics of loss and gain of coexpressed partners (genes expressed together with a given gene, henceforth called partners) between two duplicate genes constituting a pair. We denoted the number of partners of one and the other duplicate gene in a pair as n1 and n2, respectively, and the number of partners shared between the two duplicate genes as n12 (Figure (Figure4).4). We assumed that immediately after duplication, each duplicate gene was expressed together with n1 = n2 = n12 other genes (Figure (Figure4B).4B). With time, duplicate genes lose shared partners and acquire new ones. Here we assume that shared partners in a duplicate pair are inherited from a parental gene.
We discovered that duplicate genes lose shared partners rapidly with evolutionary time. We calculated the fraction of shared partners among all partners for each duplicate gene pair, n12/(n1 + n2 - n12), and used the synonymous rate per site, KS, as a proxy of evolutionary time since gene duplication (Figure (Figure5).5). For this analysis we used the 698 independent duplicate gene pairs (i.e. each gene was present only once in this data set, see Methods) for which both genes were present in the network and KS was less than 2. Our initial observation was that the fraction of shared partners for duplicate genes within each pair was usually low: it was <20% for 666 out of 698 duplicate pairs studied (the highest fraction of shared partners for a duplicate gene pair was 68%). A significant negative correlation was observed between n12/(n1 + n2 - n12) and KS (R = -0.66, P < 0.003). The fraction of shared partners for a duplicate pair was on average 6.6% after only ~50 million years (MY) since duplication (this corresponds to KS = 0.13 and requires an assumption that human and Old World monkeys diverged ~25 MY ago and the sequence divergence between them is ~7%, [40]). At KS ≈ 2, this fraction approached 1.9%, and the partners for the two duplicate genes in a pair were as different as those for a pair of unrelated singletons (Figure (Figure55).
Several factors could have affected our results. At low KS, the fraction of shared partners could have been underestimated because the youngest duplicate genes were excluded from the analysis due to the lack of unique microarray probes (see Methods). At high KS, some of the shared partners could have been acquired independently (i.e. convergently) by each gene in a duplicate pair and not inherited from a parental gene. And finally, our assumption of identical expression profiles for two daughter duplicate genes immediately after duplication might not be valid in all cases. Indeed, sometimes the duplication unit is known to partially or completely exclude the promoter of the parental gene and hence the two daughter genes might substantially differ in their expression [41].
We analyzed the same set of 698 independent duplicate genes and explored the change in the total number of partners of each duplicate gene pair (as indicated by n1 + n2 - n12) with evolutionary time. Here we assumed that the average degree of a parental singleton gene before duplication is equal to the average degree of a singleton in the contemporary network. According to this assumption, immediately after gene duplication, the total number of partners of a duplicate gene pair is equal to that of a parental singleton gene, i.e. n1 + n2 - n12 = ns (Figure (Figure4B).4B). Following duplication, as the two genes diverge in their expression profiles, their partners can be classified into three groups (Figure (Figure4):4): (1) partners inherited from a parental singleton gene and still shared between the two genes in a pair (shared ancestral partners); (2) partners inherited from the parental singleton gene but present now only in one of the two duplicates (unique ancestral partners); and (3) new partners acquired independently by one of the duplicates (unique acquired partners). The present study does not allow us to differentiate between unique ancestral and unique acquired partners directly, but we can make indirect inferences about their relative numbers.
In our data set, shared partners constitute a small fraction among the partners of a duplicate gene pair: on average lower than 6.6% (see above). If, on average, following duplication, n1 + n2 - n12 <ns (Figure (Figure4C),4C), this indicates loss of ancestral partners by duplicate gene pairs. If n1 + n2 - n12 ≈ ns (Figure (Figure4D),4D), this can be explained by the presence of a small fraction of shared partners and a large fraction of unique ancestral partners, i.e. all of the original partners of parental genes might still be retained by a duplicate pair (although some of the partners for a duplicate gene pair might be unique acquired partners, in this case such acquisition is compensated by a loss of ancestral partners). If, however, n1 + n2 - n12 > ns (Figure (Figure4E),4E), an excess of an average number of partners for duplicate pairs over that for singletons can be explained by acquisition of new partners.
The average number of partners for duplicate gene pairs in our data set was significantly (~57%) greater than that for singleton genes (227.9 vs. 144.9; t = 10.57; P < 0.001, significance assessed by permutation test), suggesting acquisition of new partners by duplicate gene pairs. This suggests that on average more than one third of partners of a duplicate gene pair were acquired after duplication and not inherited from a parental singleton gene. Such gain of new partners was rapid: even at low KS (KS = 0.13 for the youngest 40 gene pairs), members of a duplicate gene pair were already expressed together with 291.4 genes (on average), while a singleton gene was expressed together with 144.9 genes (on average). Depending on KS, we observed some variation (and some insignificant decline) in the average total number of partners for a duplicate gene pair (Figure (Figure6).6). Importantly, at any time point examined (0.13 <KS <2), n1 + n2 - n12 was greater than ns.
Two duplicate genes in a pair usually diverged asymmetrically in the network and this asymmetry was acquired quickly after duplication. For 1,547 independent duplicate gene pairs with KS < 2 (including pairs with only one copy in the network) we drew a scatter plot with the numbers of partners for two duplicate genes at the X and Y coordinates (Figure (Figure7A).7A). The assignment of a duplicate gene from each pair to either X or Y was random. Note that the plot predominantly reflected unique partners, since the proportion of shared partners was low (see above). Our simulations showed that if the divergence in gene expression were symmetric, we would expect a positive correlation between the numbers of partners for two duplicate genes in a pair (Figure (Figure7B).7B). However, in reality, we found a negative correlation (Figure (Figure7A,7A, Spearman's rank correlation coefficient rs = -0.19, P < 0.001), indicating that usually two duplicate genes had different numbers of partners. Interestingly, 849 out of 1,547 duplicate gene pairs were located on either the horizontal or vertical axis, suggesting that one gene had some partners in the network while the other one had none. Additionally, we observed that the difference in degree between duplicate genes in a pair was not related to KS (Figure (Figure7C).7C). Thus, the asymmetry in expression divergence was established early and was maintained throughout the evolutionary time examined.
To study the role of duplicate genes vs. singletons in the robustness of this coexpression network, we computationally perturbed the network by random removal of nodes (error) and degree-based removal of nodes (attack or the preferential removal of the most highly connected genes; [23]). Error and attack were performed separately on three categories of genes – singletons, duplicate genes, and all genes taken together. Thus, a total of six experiments were performed. In each experiment, we removed nodes in 10%, 20%, 30%, 40%, and 50% increments calculated from the total number of nodes in the network. The relative size S (the fraction of nodes in the giant connected cluster after node removal) and the average path length <d> of the largest connected cluster were measured at each increment (Figure (Figure8).8). The decrease in S and increase in <d> indicate network breakdown.
Random removal of duplicate genes, singletons, or all genes had minimal effect on the network (Figures (Figures8A8A and and8B).8B). The size of the main cluster did not decrease beyond the reduction expected due to node removal and the average path length remained approximately constant, indicating that most unremoved nodes stayed connected. This error tolerance was expected due to the high connectivity and scale-free nature of the network [23] and to the similarity in degree distribution of the three categories of genes (Figure (Figure11 and Additional file 4).
The network also appeared to be resilient to the degree-based node removal of either singletons or duplicate genes. Attack on singletons was expected to lead to a faster crash of the network than attack on duplicate genes because of the higher average degree of singletons (Table (Table1)1) and their higher proportion among hubs (Figure (Figure3).3). At the 40% and 50% increments, the degree-based removal of duplicate genes indeed yielded a slightly smaller average path length (<d>dup = 2.92 vs. <d>sin = 2.96 at 40%; <d>dup = 2.79 vs. <d>sin = 2.86 at 50%; Figure Figure8D),8D), thus providing marginal support for this expectation. However, contrary to the expectation, attack on singletons and attack on duplicate genes led to similarly minimal decreases in the relative sizes of the main cluster (Figure (Figure8C8C).
In contrast with attack on either duplicate genes or singletons, attack on all genes severely damaged the network (Figures (Figures8C8C and and8D).8D). After 50% of all genes were removed by attack, the network broke down into many small clusters and as a result the relative size of the main cluster was only 0.30 as compared with 0.50 after error (Figures (Figures8A8A and and8B).8B). Additionally, this led to ~two-fold increase in the average shortest path length as compared with the effect of error (<d>error = 2.66 vs. <d>attack = 4.91, both after removal of 50% of nodes; Figures Figures8A8A and and8D8D).
Why did the network break down so rapidly after we attacked duplicate genes and singletons combined? We hypothesized that this could be due to the removal of a large number of hubs and edges. Indeed, although the same number of genes was removed in each experiment, more strong hubs were removed by attack on all genes (e.g., 20% of the strongest hubs for the 20% increment; Figure Figure8D)8D) than on either duplicates or singletons separately (e.g., only ~10% of the strongest hubs in each case for the 20% increment; Figure Figure8D).8D). Similarly, more edges were eliminated by attack on all genes (e.g., ~84% of edges for the 20% increment; inset in Figure Figure8D)8D) than on either duplicates or singletons (~62% and ~68%, respectively, for the 20% increment; inset in Figure Figure8D8D).
The analysis of duplicate genes in the human gene coexpression network allowed us to make the following conclusions. First, in agreement with analysis of yeast duplicate genes (e.g., [13,14,29,30]), our observations suggest that human duplicate genes quickly lose similarity in gene expression profiles. As a result, except for immediately after duplication, they cannot be considered redundant parts in the network. This might explain why the network was similarly tolerant to attack and error on either duplicate genes or singletons – rapidly after duplication, duplicate genes diverge in their expression profiles, reaching the level of similarity only slightly higher than that observed for random singletons. Since only 79 tissues were examined in our study, we cannot exclude a possibility that some additional links among duplicate genes could be revealed in other tissues and/or under different physiological conditions.
Second, the acquisition of new coexpressed partners was found to be rapid and to play a prominent role in the evolution of duplicate genes. This process might lead to attainment of new functions and operate as an engine creating diversity at the phenotypic level that is vital for adaptation. The importance of addition of new interactions was also pointed out in the yeast transcriptional regulation network, although there a net loss of interactions was observed [30]. The proportion of unique acquired partners is difficult to determine precisely in the present study, because we cannot directly distinguish between unique ancestral and unique acquired partners. For instance, as mentioned above, acquisition of new partners can be compensated by loss of ancestral partners and in this way will not be reflected in the total number of partners for a duplicate pair. In the future, experiments using expression information for an outgroup should allow one to differentiate between the two classes of unique partners and to provide more precise estimates of their numbers.
Although more evidence is necessary, asymmetry might represent a common scenario in the functional divergence of duplicate genes. Yeast, fruit fly, nematode, and human duplicate genes exhibit asymmetric divergence at the amino acid level [11,42,43]. Additionally, asymmetric divergence of protein-protein interactions was found for yeast duplicate genes [28].
In summary, this study provides an example of the use of duplicate genes to investigate the evolution of a gene coexpression network. By investigating the divergence of duplicate genes in the network, the speed and pattern of divergence within a network can be assessed. An alternative approach is to compare orthologous genes in the networks of different organisms [16]. Unlike the analysis of orthologs where divergence is determined by speciation time, utilization of paralogs provides an opportunity to inspect a range of divergence since duplications usually occur at various times in the evolution of a lineage (unless a duplication is due to a polyploidization event). A paralogous approach has an additional advantage of requiring sequence and expression information from just one genome. Utilization of paralogous and orthologous information is expected to provide complementary information and bring us closer to understanding network evolution.
To map probe sets to genes, the exemplar and consensus sequences for U133A and GNF1H arrays [54] were used as queries to search against the longest transcripts of known and novel genes retrieved from Ensembl (NCBI build 34) using BLAST [44] with E = 10-20. The criteria of acceptable alignments were as described in [45]. Briefly, the alignment was accepted if (1) the identity was higher than 94% and the length was greater than either 99 bp or 90% of the length of the query, or (2) the identity was 100% and the length was greater than 49 bp. There were three cases: (1) a single probe set hit a single gene (9381 genes); (2) multiple probe sets hit a single gene (4961 genes and 13071 probe sets); (3) a single probe set hit multiple genes (18718 genes and 4377 probe sets). All genes and probe sets in case 1 were considered. In case 2, a probe set with the highest expression value (measured by average difference or AD) value was selected, similar to [15]. All genes and probe sets from case 3 were deleted due to potential cross-hybridization. As a result, we obtained a data set of 14,342 genes and probe sets with the one-to-one correspondence. Another data set (9,056 genes) represented a subset of the previous one from which the probe sets with suboptimal design (with _s, _x, _r, _i, _f, _g suffixes) were excluded. However, only the original data set is discussed henceforth since it contained a larger number of genes and the results obtained from the two data sets were similar. Following [37], genes with AD > 200 in a particular tissue were considered to be expressed in this tissue. The AD values were logarithmically transformed (with base equal to 2). Tissue-specific genes were defined as those expressed only in one tissue, and ubiquitously expressed genes were defined as those expressed in at least 78 out of 79 tissues.
A series of Perl and C programs (Additional file 5) were written to conduct the study. Two nodes were connected if they both were expressed in at least T common tissues with the Pearson correlation coefficient (calculated among these T common tissues) greater than R. We used an adjacency matrix A (Additional file 6) to store the topology of the network. The matrix stored binary symbols: "aij = 1" indicated the existence of an edge between nodes i and j and "aij = 0" indicated its absence. The matrix was symmetric with the diagonal equal to zero because of no inference of the direction of edges and no self-loops (simple graph). We focused on the genes located in the main (giant) cluster in which every gene was connected to every other gene by at least one path. Genes that formed small and isolated clusters were regarded as outside of the main network. The clustering coefficient, c, is defined as the ratio between the number of edges among nodes adjacent to i and the maximum possible, ki(ki-1)/2 [46]. The clustering coefficient approaches 1 if the neighbors of a node are connected to each other. The shortest path length was calculated according to the Floyd-Warshall's all pairs shortest paths algorithm [47].
Transitivity is a property of networks that are based on correlation coefficients of gene expression values [16]. If gene A is correlated in expression with gene B and gene B is correlated in expression with gene C, then gene A might be correlated with gene C. However, as mentioned by Jordan et al. [16], the level of such transitive correlation is unknown. In the network investigated in the present study, a link was defined by two parameters – the number of tissues in which the two genes are expressed and the correlation coefficient of expression values. This led to decreased transitivity of the network. Indeed, the average clustering coefficient (c) of the network is only 0.16 (under high transitivity c is expected to approach 1). This can be explained by the following example. Let gene A be expressed in 20 tissues with expression values {eA1, eA2, ..., eA20}, gene B be expressed in the first 10 of these 20 tissues with expression values {eB1, eB2, ..., eB10}, and gene C be expressed in the other 10 of these 20 tissues with expression values {eC11, eC12, ..., eC20}. If the correlation coefficient between {eA1, eA2, ..., eA10} and {eB1, eB2, ..., eB10} is higher than 0.7, then genes A and B form a link. Similarly, if the correlation coefficient between {eA11, eA12, ..., eA20} and {eC11, eC12, ..., eC20} is higher than 0.7, genes A and C form a link. However, in this example genes B and C do not form a link because they are expressed in different tissues. Thus, transitivity is not an inherent feature of all genes in the network.
The 79 tissues studied by Su et al. [37] include six tissues that overlap with several other tissues in the data set. Each of these six tissues represents a more inclusive set of cells (usually an organ, e.g., the whole brain) as compared with its parts also present in the data (e.g., parts of brain). When we generated a separate network without these six tissues, only approximately 88% of connections were the same between this and original networks. Moreover, 84% of connections stayed constant when we removed any six tissues at random (repeated 10 times). This indicates that each tissue possessed unique expression information and we did not exclude any of them from the study.
Duplicate genes among 22,291 protein sequences of known and novel genes in Ensembl (NCBI build 34) were identified according to Gu et al. [48]. Briefly, each protein was used as a query to search against all other proteins using FASTA [49] with E = 10. The alignments were retained if: (1) the alignment length (L) was over 80% of the longer sequence, and (2) the identity (I) was ≥ 0.3 if L was over 150 amino acids or I ≥ 0.06 + 4.8 L-0.32(1+exp(-L/1000)) if otherwise. We deleted proteins if they formed a hit due to the presence of a repetitive element of the same family. A single-linkage clustering algorithm was carried out to assemble duplicate genes into families. As a result, 11,512 duplicate genes were assigned to 2,865 families. The complete protein-coding gene sequences were re-aligned using CLUSTALW [50]. The synonymous and nonsynonymous substitution rates per site (KS and KA, respectively) were calculated using the YN00 module [51] of PAML [52] implemented in PERL. To identify the set of independent duplicate gene pairs we proceeded as follows. First, within each gene family we sorted gene pairs by KS in the ascending order and selected the pair with the lowest KS (pairs with KS < 0.05 were excluded). Next, within each gene family, we selected other independent pairs (with genes that have not yet been selected) sequentially with increasing KS. This resulted in 4,997 independent gene pairs (Additional file 7). Only independent duplicate gene pairs were considered for the analysis of divergence of duplicate genes, however, all duplicate genes were considered for the analysis of robustness and of the differences between duplicate genes and singletons.
The permutation test was used to assess the statistical significance of the difference in the network measures between duplicate genes vs. singletons. First, we removed original labels and randomly relabeled genes keeping the numbers of genes of the two categories consistent with the original data set. Second, we calculated the 2-sample t-statistic [53]. Third, we repeated the process 1000 times and built a null distribution of the t-statistic. Finally, we compared the observed t value (true labeling) with its null distribution to determine the P value.
To simulate symmetric divergence in gene expression, we followed the method developed by Wagner [28]. Briefly, the number of lost partners was randomly generated from binomial distribution B(n1 + n2 - 2n12, P). We tested three possible scenarios: divergence by loss of function (P = 0), divergence by gain of function (P = 1), and equal probability of loss and gain of function (P = 0.5). To test each of the three scenarios we proceeded as follows. The ancestral number of partners for each pair was approximated by the sum of the current number of shared partners (n12) and of a random number (nl) generated from the binomial distribution B(n1 + n2 - 2n12, P). The number of gained partners (ng) after duplication was approximated by n1 + n2 - 2n12 - nl. Within each duplicate gene pair, the lost connections were assessed by nl1 ~ B(nl, 0.5) and nl2 = nl - nl1 for the first and second duplicate copies, respectively. The reconstructed number of coexpression partners from the symmetric divergence model were (n12 + nl) - nl1 + ng1 and (n12 + nl) - (nl - nl1) + (ng - ng1) for the first and second gene copies, respectively.
The degree-based and random node removals were performed separately for duplicate genes, singletons, and duplicates and singletons combined (a total of six experiments). In each experiment, nodes were deleted in five increments (f): 10% (1290 genes), 20% (2580 genes), 30% (3770 genes), 40% (5158 genes) and 50% (6449 genes). The same number of nodes was removed in each experiment. For instance, by attacking 10% of duplicates, we removed 1290 (10% of 12897) duplicate genes with the highest number of connections. Similarly, by attacking 10% of all genes, we removed 1290 of the genes with the highest connections. Two quantities were used to assess the damage to the network: S, the fraction of nodes in the giant connected cluster after node removal (the relative size of the giant cluster), and <d>, the average shortest path length between any two nodes in this cluster. If nodes stay connected except for those that are removed (minimal damage), S = 1-f. For random removal of nodes from a scale-free network, S ≈ 1-f and <d> stays approximately constant until a considerable fraction of nodes is removed [23]. However, degree-based removal leads to a fast decay of S and an increase in <d> until the network breaks down into small isolated clusters. Thus, the average shortest path length tends to first increase (the overall system is still functioning but it takes longer to travel from one node to another) and to decrease later, after a certain number of nodes is removed [23].
WYC and KDM designed the study, WYC conducted the study, RA, IA, and AN contributed expertise necessary to conduct the study, WYC and KM wrote the paper.
The numerical description of the networks
Degree distributions of networks generated from a combination of thresholds: T (tissue) and R (Pearson correlation coefficient). The degree distribution for the network with T ≥ 7 and R ≥ 0.7 is shown in Figure Figure11
The scatter plots between clustering coefficient c and node degree k for (A) all genes, (B) ubiquitously expressed genes, and (C) nonubiquitously expressed genes.
The degree distribution of the studied network (T ≥ 7 and R ≥ 0.7) for (A) duplicate genes and (B) singletons.
Scripts for the study
Network binary matrix.
The set of independent duplicate gene pairs.
We are thankful to Svitlana Tyekucheva for her help with the R statistical package and to Jianzhi Zhang, Eugene Koonin, Paula Goetting-Minesky, and Svitlana Tyekucheva for critical reading of the manuscript. This study was supported by the start-up funds from Penn State to KM, AN, and RA.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
EMIERT Distinguished Librarian Award
Mark Puente honored as 2015 EMIERT Distinguished Librarian
Leslie Campbell Hime presenting the award to Mark Puente
The award presentation occurred at the EMIERT President's Program, Collective Cultural Competency: Promoting a Dia about Diversity in an Academic Library, Saturday, June 27, 4:30pm, Moscone Convention Center, 3012(W), during ALA's 2015 Annual Conference in San Francisco. http://www.ala.org/news/press-releases/2015/06/mark-puente-recipient-2015-emiert-distinguished-librarian-award
For Immediate Release
Fri, 06/19/2015
CHICAGO – Mark Puente, director of diversity and leadership programs at the Association of Research Libraries (ARL) is the recipient of the 2015 American Library Association Ethnic and Multicultural Information Exchange Round Table (EMIERT) Distinguished Librarian Award. Given annually, the Distinguished Librarian Award recognizes significant accomplishments in library services that are national or international in scope and include improving, spreading and promoting multicultural librarianship.
Puente is recognized for his work to expand diversity efforts within the library profession, specifically toward developing strategies and programs that librarians in all types of libraries can use to enhance their collections and services to underserved users. His work with the National Diversity in Libraries Conference, the Spectrum Scholarship Initiative and individual libraries provides opportunities for librarians to share stories, related research, collection approaches and best practices for increasing workplace diversity and creating an inclusive workplace environment.
"We are impressed with Mark's trajectory from ALA Spectrum Scholar to mentor to national leader in diversity advocacy" said EMIERT Chair Katherine Trouern-Trend. "We are honored to recognize Mark for his dedication, accomplishments and contribution to moving the needle on inclusivity in libraries."
Prior to his work at ARL, Puente worked as coordinator of digital projects and special/gift collections and assistant professor of library administration at the University of Illinois at Urbana-Champaign and as research assistant professor and music librarian at the University at Tennessee, Knoxville. In addition to ALA, Puente is an active member in the Music Library Association and the Association of College & Research Libraries.
As recipient of the 2015 Award, Puente will receive a commemorative plaque and a $500 honorarium to be presented during the EMIERT President's Program, Collective Cultural Competency: Promoting a Dialogue about Diversity in an Academic Library, Saturday, June 27, 4:30pm, Moscone Convention Center, 3012(W), during ALA's 2015 Annual Conference in San Francisco.
For more information, please visit www.ala.org/emiert.
Founded in 1982, the Ethnic and Multicultural Information and Exchange Round Table (EMIERT) serves as a source of information for recommended ethnic and multilingual collections, services and programs.
Ghada Elturk honored as 2013 EMIERT Distinguished Librarian
Ghada Eltruk (right) and Tess Tobin
From the ALA news press release (7/02/2013) as submitted by John L. Amundsen, Program Officer, Outreach and Communications, ALA Office for Literacy and Outreach Services
CHICAGO — Ghada Elturk, outreach librarian at the Boulder (Colo.) Public Library, was honored at ALA Annual Conference as the 2013 recipient of the ALA Ethnic and Multicultural Information Exchange Round Table (EMIERT) Distinguished Librarian Award. Given biennially, the award recognizes a librarian for outstanding achievement and leadership in serving the community by significant collection building and outreach services and developing creative multicultural materials and programs.
As the outreach librarian for Boulder Public Library (BPL) Elturk takes leadership roles in numerous multicultural activities in Boulder. Her many accomplishments at BPL include the design and implementation of its community and cultural outreach program; implementing a wide variety of conversations programs (English, Spanish, Afghan, Arabic); establishing and implementing Cesar Chavez Day in Boulder; establishing diversity literature discussion groups (Arabic, Latino, poetry workshops for youth); and implementing diverse film festivals.
"Ms. Elturk is appreciated by peoples of all cultures in Boulder as they realize what she has done to get them to the library by offering access to all types of materials in their particular cultural, multicultural programs, and other library services," said EMIERT Chair Tess Tobin. "She is a bridge-builder in a diverse society."
Elturk received a monetary award of $500 from EMIERT as part of the award, which she is donating to the American Indian Library Association, Asian/Pacific American Library Association, the Black Caucus of ALA, REFORMA – the National Association to Promote Library & Information Services to Latinos and the Spanish Speaking, as well as EMIERT, all organizations which she has served as a longstanding and active member.
Celebrating its 36th year anniversary, the Ethnic and Multicultural Information and Exchange Round Table (EMIERT) serves as a source of information for recommended ethnic and multilingual collections, services and programs
The EMIERT Multicultural Award
Standards for this award are any significant accomplishments in library services that are national or international in scope and that include improving, spreading, and promoting multicultural librarianship.
- Persons in the library world are eligible to be considered for the award based on outstanding achievement and leadership in serving the community by significant collection building and outreach services, and developing creative multicultural materials and programs. Emphasis here is multicultural/multiethnic as distinguished from multilingual (cf. The Leonard Wertheimer Award).
- There will be an annual award. If no suitable candidate is judged to merit the award in a given year, the award will not be presented. If two candidates are considered very close in their qualifications, the award will be split between the two.
- The Executive Board of EMIERT (Ethnic and Multicultural Information Exchange Round Table) will select a committee of five to administer the award. The chair of the Round Table will be an ex-officio member.
- The deadline for nominations will vary depending upon the ALA Midwinter Meeting's dates. Decision about the award will be made at the ALA Midwinter Meeting. Publicity will be released announcing the results and the date for the award ceremony, to be held at the ALA Annual Conference.
- Screening of candidates will be based on submitted application forms that contain a detailed curriculum vitae with specific information and evidence of the candidate's outstanding achievement and leadership. The documentation for each nominee will be sent to the Awards Committee members who will rate the nominations. A formal ballot will be taken at the ALA Midwinter Meeting and the results tabulated to pick a winner.
- At the ALA Annual Conference, the award ceremony will take place at the scheduled membership meeting of EMIERT.
For more information, contact:

subset: commoncrawl


text:
Questions?: 1-800-406-3474
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text:
Landers is the former "Winston Man", now a spokesperson for
the World Health Organization. He is also professional
actor, model, and acting teacher. He appeared on billboards
and in magazines holding Winston cigarettes and Tiparillo
cigars, urging others to smoke. A smoker himself, he was expected
to portray smoking as stylish, pleasurable and attractive.
Never was he told that cigarettes could be
to anyone's health, including his own. Alan now understands
the hazards of cigarettes and regrets promoting the lethal
and addictive product. He is a two-time lung cancer survivor,
having first been diagnosed in 1987 and undergoing surgery
that year and again in 1993. The surgeries left him permanently
disabled and with chronic shortness of breath. In 1997 he
had double bypass heart surgery.
now devotes himself to the fight against cancer and especially
to urging young people not to smoke. He calls for tobacco
products to be regulated as the addictive drugs they are and
for tobacco companies to compensate their victims. Alan's
testimony is in the Congressional Record. He is going to trial
against the tobacco cartel in Palm Beach, FL in the very near


text:
OxyContin, Roxicodone, Oxycodone
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text:
MSC Family Cruise Reviews
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55% Loved It
Cruise Critic Overview
- MSC Preziosa, MSC's biggest, splashiest ever, debuted in 2013
- MSC Divina sails year-round from Miami
- Features the ship-within-a-ship Yacht Club concept
- Read full overview >>
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We (a family of 3) were on our third MSC cruise and second in the Yacht Club. Nothing earth shattering to write about. ... Read more
This was our second MSC cruise... unfortunately it was not as good as the first. We booked this cruise as a final ... Read more
We are experienced cruisers with 20+ cruises (Celebrity, Princess, Royal Caribbean, Holland American, NCL, Carnival and ... Read more
It seems that not many Brits have heard of MSC Cruises yet - so we're going to do our best to keep it a secret for a ... Read more
Right up front let us say our overall rating is skewed by MSC's abysmal customer service pre cruise. To our queries ... Read more
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This was our first cruise so I did a lot of research before travelling. We decided to book with MSC as the route ... Read more
My worst cruise ever! I've sailed twice with Tompson, twice with MSC Fantasia, with MSC Orchestra and MSC Lirica ... Read more
This was my third cruise and by far the worst. I have previously traveled Royal Caribbean and Carnival and both ... Read more
This was our 2nd cruise and in all fairness I have come to the conclusion that my husband and I are just not cruise ... Read more
Let me start with the good things. This is a beautiful ship. The public spaces are sleek, the Swarovski crystal ... Read more
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Wonderful ship, but all that sparkles is not gold. Beautiful exterior with no substance beneath. Booked cruise in June ... Read more
MSC LIRICA out of Venice: We have always cruised on Norwegian and didn't think MSC would be much different, since the ... Read more
buffet food was horrible, tasteless, fatty, dining room wasn't much better, food only started to improve towards the ... Read more
I can't say enough about how pretty the MSC Divina is. Its a good thing she is relatively new because the maintenence ... Read more
Even though my main goal and reason for this cruise was to see and spend time with my family who lives abroad I gotta ... Read more
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I do have to give myself kudos for my logistical planning as far as arriving at the port and getting back home but our ... Read more
Another beautiful MSC ship, the second MSC ship I've been on, but will definitely book with them for my next cruise. I ... Read more
Our cruise started terribly from the embarkation. we were given the first priority because I have a child in a ... Read more
This was our 3rd cruise but the first with MSC and, in terms of service, it was probably the worst one. To be fair ... Read more
There was 7 of us in our party, including 3 children and every single one of us from 5 years old to 49 years old ... Read more
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The one and only good note was the entertainment. Dinner almost every night was two hours or more. Food not very ... Read more
Went on MSC Divina 4/11/15 to Bermuda. We were suppose to spend 3 full days in Bermuda but they informed us AFTER we ... Read more
We are not first time cruisers but we're not avid cruisers either. Our favorite is Princess. We also enjoyed Celebrity ... Read more
This was my first Mediterranean cruise I have only cruised in Australia and Asia and New Zealand, and I was so ... Read more
We're do we start embarkation at Genoa was a shambles great start .We were all given numbers which u didn't need we ... Read more
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text:
I think it would be stupid for them to try to ban firearms entirely.
#1 - They won't get them all, if they even get most. Just because someone has a CCL doesn't mean they own a firearm. I'd love to see them try to prove it. ;)
#2 - I'm sure a lot of people in some states would be more likely to revolt than give them up. This could be the straw that breaks the camel's back.


text:
copy(v) (1) To copy a piece of data to a temporary location. In word processing, for example, copying refers to duplicating a section of a document and placing it in a buffer (sometimes called a clipboard). The term copy differs from cut, which refers to actually removing a section of a document and placing it in a buffer. After cutting or copying, you can move the contents of the buffer by pasting it somewhere else.
(2) In file management, the term copy refers to making a duplicate of a file.
(n) A duplicate of a piece of data, such as a file or a directory.
From secure messaging to document editing, our top free must-have apps have been rated, reviewed and named the best free Android apps of 2015. Read More »The Five Generations of Computers
Learn about each of the five generations of computers and major technology developments that have led to the current devices that we use today. Read More »Cloud Computing Market Leaders, 2015
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From wacky alarm clocks to lecture hall tools and after class entertainment, these Android apps are a good fit for a student's life and budget. Read More »Network Fundamentals Study Guide
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7/13/2015CLE-Policies, Practices & Procedures for the Friend of the Court & Enforcement Hearings


text:
Over that weekend, teddy stayed up with friends one night, drinking and swapping bawdy tales about the party times with Jack.
Correction: This article misstated that Casey was holding a teddy bear in court.
teddy wore a neck brace, and a woman stood in the crowd with a sign that read "Kennedy for President, 1972."
pet form of masc. proper names Edward, Edmund, and Theodore; meaning "women's undergarment" (with lower-case t-) is recorded from 1924, of unknown origin, perhaps from some fancied resemblance to a teddy bear (q.v.), a theory that dates to 1929. In British slang phrase teddy boy (1954) it is short for Edward, from the preference of such youths for Edwardian styles (1901-10). Teddies (probably from Teddy Roosevelt) was one of the names given to U.S. troops in France in 1917.
the family in America originally bore the name Van Roosevelt, "of the field of roses," descriptive of their estates in Holland. Claes Martenszen Van Rosenvelt, born August 1649, emigrated to New Amsterdam. His son (1653) and all his descendants dropped the "Van." Related: Rooseveltian.
used to form nouns Having the indicated knowledge of, involvement with, or attitude toward technology, esp advanced and computer technology: technobuddy/ technofreak/ technogood/ technopeasant


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Colombia 3-0 Greece Highlights 2014 World Cup
Colombia 3-0 Greece Highlights 2014 World Cup More on: http://brasil2014lhighlights.blogspot.com/...
- published: 14 Jun 2014
- views: 65
BELO HORIZONTE, Brazil — Colombia started its first World Cup campaign in 16 years in dazzling fashion, beating Greece 3-0 to open Group C on Saturday in front of a big, loud pro-Colombian crowd. Left back Armero opened the scoring in the...
Boston Herald 2014-06-14"It was a good debut with players who had never played a World Cup. It's a big satisfaction,"
Colombia 3 Greece 0 ...The Guardian 2014-06-14
Share PhotoReddit✉ Colombia's James Rodriguez (10) celebrates with his teammates after scoring his side's third goal during the group C World Cup soccer match between...U~T San Diego 2014-06-14
This is by far the tightest, most unpredictable group at the World Cup. Colombia is banging down the door of another golden generation and the Ivory Coast's is in its...Penn Live 2014-06-12
The Inquisitr
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A spot in the knockout round is on the line in Group D as Greece and Ivory Coast are scoreless in the first half. Japan and Colombia are also scoreless in the first half. Listen to Ivory Coast vs. Greece LIVE NOW on TSN Radio 1050 Toronto, TSN Radio 690 Montreal and TEAM Radio 1410 Vancouver. UP TO THE MINUTE STANDINGS: Here is how Group C would finish if the current results...TSN Canada 2014-06-24
Share PhotoReddit✉ Colombia's Pablo Armero, right, kicks the ball at Greece's goalkeeper Orestis Karnezis to score his side's first goal during the group C World Cup soccer match between Colombia and Greece at the Mineirao Stadium in Belo Horizonte, Brazil, Saturday, June 14, 2014. (AP Photo/Fernando Vergara) Greece's Kostas Manolas fails to stop the ball as Colombia's Pablo...U~T San Diego 2014-06-14
Colombia started their first World Cup campaign in 16 years in dazzling fashion, beating Greece 3-0 to open Group C on Saturday in front of a big, loud pro-Colombian crowd. Left back Pablo Armero opened the scoring in the fifth minute when his deflected shot rolled past Greece goalkeeper Orestis Karnezis. Striker Teofilo Gutierrez poked in Colombia's second goal from a...Taipei Times 2014-06-15
Colombia and Greece kick off Group C on Saturday evening, with the Colombians looking to show that there is life after Falcao, and that they can still compete as major contenders in Brazil. The injury to their star man was no doubt a major blow, but Colombia can still boast a talented group of players, with the likes of James Rodriguez, Juan Fernando Quintero and Juan Cuadrado...The Independent 2014-06-13
Group C scheduled 2014 World Cup action gets underway with a battle between Colombia and Greece today, which will be broadcast nationally on ABC TV and streaming live and free on Watch-ESPN. Estádio Mineirão in Belo Horizonte, Brazil, will host this intercontinental counter beginning at Noon Eastern Time (11 a.m. CT/10 a.m. MT/9 a.m. PT). As noted by Bleacher Report on June 14,...The Examiner 2014-06-14
Group A TEAM W L T GF GA Pts Brazil 1 0 0 3 1 3 Mexico 1 0 0 1 0 3 Cameroon 0 1 0 0 1 0 Croatia 0 1 0 1 3 0 Tuesday's game Mexico at Brazil at Fortaleza, 3 p.m. Wednesday's game Croatia vs. Cameroon at Manaus, 6 p.m. Group B TEAM W L T GF GA Pts Netherlands 1 0 0 5 1 3 Chile 1 0 0 3 1 3 Australia 0 1 0 1 3 0 Spain 0 1 0 1 5 0 Wednesday's games Netherlands vs. Australia at Porto...The Columbus Dispatch 2014-06-15
BELO HORIZONTE, Brazil — Overcoming solidly defensive teams like Greece has never been the forte of South American teams, which thrive on attractive football. Consequently, Colombia coach Jose Pekerman sees the main challenge for his players in their World Cup opener Saturday as respecting the way Greece plays. Colombia, taking part in its first World Cup since 1998, boasts a...Fresno Bee 2014-06-13


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Discover a selection of top forums brightening understand on the internet. Come to share your passion on forums brightening understand and meet other fans of brightening understand. Then, why don't you create your own forum of brightening understand ?
Coming together in Faith, Love and Unity in God and fellowship. We want to share our spirits with one another and understand what God truly wants to show us.
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Off~Camber 4x4 Northeast Floridas All Vehicle Off Road Forum. All Vehicles Welcome...Lets Get Dirty Togehter. We Are A Local Middleburg/Jacksonville Area Club...Its a 4x4 thing...WE all understand
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Drive Sober campaign launches
Tunica County Sheriff K.C. Hamp has announced that the Drive Sober or Get Pulled Over campaign starts today (Friday, Dec. 13) and runs through January 1, 2014.
During this time, law enforcement officers will be on the lookout for impaired drivers. Various saturations and checkpoints will be set up throughout the county.
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by Luria, Aleksandr R.
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This important book, by the most distinguished Soviet psychologist of our time, is the product of almost forty years of extensive research aimed at understanding the cerebral basis of human psychological activity. The main part of the book describes what we know today about the individual systems that make up the human brain and about the role of the individual zones of the cerebral hemispheres in the task of providing the necessary conditions for higher forms of mental activity to take place. Finally, Luria analyzes the cerebral organization of perception and action, of attention and memory, or speech and intellectual processes, and attempts to fit the facts obtained by neuropsychological studies of individual brain systems into their appropriate place in the grand design of psychological science.
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Salaries for Product Marketing Directors with Product Marketing skills are generous, with average pay above six figures ($133K) per year. Total cash compensation to Product Marketing Directors with Product Marketing skills approaches anywhere from $101K on the lower end to $189K on the higher end; in exceptional cases, this can include more than $30K from bonuses and upwards of $32K from profit sharing. Geography and tenure each impact pay for this group, with the former having the largest influence. Almost all receive medical and dental insurance and a large number get vision insurance. The majority of workers are highly satisfied with their job. This report is based on responses to the PayScale salary survey.
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Median of all compensation (including tips, bonus, and overtime) by years of experience.
Experience does not seem to be a strong driver of pay increase in this role. At career start (within the first five years), average income sits near $130K, and the average for folks who have worked for five to 10 years is only slightly higher at $133K. The average pay reported by folks with 10 to 20 years of experience is around $150K. Survey participants who have spent more than 20 years on the job report a predictably higher median income of $162K, demonstrating that compensation is roughly commensurate with experience in the end.
|Highly satisfied
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based on 57 votes.
31 %
69 %
|Medical: 96%
|Dental: 93%
|Vision: 84%
|None: 3%


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Most of us know Count Leo Tolstoy as the author of War and Peace, a big book that we haven't read. What is less well known about this remarkable individual is that he was a social reformer whose pacifist and anarchist ideas were to have huge influence in the 20th century and to this day. I say all this because Tolstoy has been popping up in my conversations recently: a Viennese journalist, flatteringly if absurdly, compared me to him the other day, and I have just started to read Anna Karenina.
As a student, Tolstoy led an idle and dissipated life. He later joined the army, and then made a failed attempt to improve the everyday life of the peasants on his family estate. He published his first novel at the age of 24. A letter to friends at that time reveals his Epicurean tendencies: "Happiness will consist in being with Nature, seeing her, communing with her," he wrote.
In the 1860s, he started what we would call a free school, where he tested his anti-authoritarian ideas: "Everything that savours of compulsion is harmful and proves either that the method is indifferent or the teaching bad." At Tolstoy's school, children learnt what they wanted and attended when they felt like it, rather like today's Summerhill School. The government inspectors tolerated his project but dismissed it as a fad: "The activity of Count Tolstoy deserves respect and should win co-operation from the educational department, although it cannot agree with all his ideas; ideas which he will in all probability abandon on due consideration." Sadly they were right, and the school closed after two years.
He was married to Sofia Behrs, a doctor's daughter, in 1862. They had 13 children, five of whom died when young. This was a pastoral existence: Tolstoy enjoyed mowing the lawns with a scythe and hoeing the beds at Yasnaya Polyana, his country estate. Here, he wrote War and Peace and Anna Karenina (which contains the most gripping first page of any novel I have read). But he could not leave off his social experiments. His friend Turgenev wished that he would stick to writing books and give up on the changing-the-world stuff: "If only Tolstoy would not philosophise, all might be well," he commented.
His marriage to Sofia reportedly began happily but soon degenerated. And his wife resented his guru-like status. She became consumed with jealousy and resentment: "My life is so mundane," she wrote in her diary. "But he has such a rich internal life."
In around 1880, Tolstoy tried to live like a peasant. He renounced alcohol and meat, and rose early to work in the fields every day. He even gave up his beloved hunting and tobacco. "What makes a man good is having few wants," he said.
He adhered to the doctrine of voluntary poverty, as followed by St Francis of Assisi and the Buddha. However, he would still return to his luxurious house in the evening. And while he publicly renounced sex, Sofia complained that he was only happy when they had made love.
In politics, he was what we might call a Christian anarchist. In his essay "The Kingdom of God is Within You", inspired by the Sermon on the Mount, he accused all governments of violence, and was praised for this view by another Russian reformer, Prince Peter Kropotkin, the anarchist, who himself was a huge influence on Oscar Wilde's politics.
In his 1900 essay, "On Anarchy", Tolstoy wrote: "The Anarchists are right in everything; in the negation of the existing order, and in the assertion that, without Authority, there could not be worse violence than that of Authority under existing conditions. They are mistaken only in thinking that Anarchy can be instituted by a revolution. But it will be instituted only by there being more and more people who do not require the protection of governmental power… There can be only one permanent revolution – a moral one: the regeneration of the inner man."
Tolstoy's doctrine of non-violence had a huge influence on Gandhi, who founded a commune in 1910 called Tolstoy Farm, and agreed with Tolstoy that non-violent protest was the key to Indian emancipation from British rule. Indeed, the two men corresponded during 1910, the last year of Tolstoy's life. That year, aged 82, he ran away from Sofia and died in the stationmaster's house at nearby Astapovo.
His social ideas influenced the foundation of various Tolstoyan communes in the 20th century in Europe and the US. Some thrive to this day: the Whiteway Colony in the Cotswolds hosts 150 colonists and recently celebrated its 100th birthday. There is a group called Tolstoyans (UK) which espouses his values of pacifism and vegetarianism.
I see that AN Wilson has recently reissued his biography of Tolstoy, which I look forward to reading. Maybe it's time for a Tolstoy night at the Idler Academy?
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Ukrainian Christmas Doughnuts
|All purpose flour
|4 1⁄2 Cup (72 tbs)
|Active dry yeast
|1⁄2 Ounce (2 Packages)
|1 Cup (16 tbs)
|1⁄4 Cup (4 tbs)
|1⁄3 Cup (5.33 tbs)
|1 Teaspoon
|1 Teaspoon
|Egg yolks
|Canned prune cake and pastry filling
|12 Ounce (1 Can)
|Cooking oil
|2 Cup (32 tbs) (For Deep-Fat Frying)
|Vanilla glaze
|2 Tablespoon
In large mixer bowl combine 2 cups of the flour and the yeast.
In saucepan heat the milk, shortening, sugar, and salt just till warm (115°F to 120°F), stirring till shortening almost melts.
Add vanilla.
Add to dry ingredients in mixer bowl.
Add eggs and egg yolks.
Beat at low speed of electric mixer for 1/2 minute, scraping sides of bowl constantly.
Beat 3 minutes at high speed.
Stir in as much of the remaining flour as you can mix in using a spoon.
On a lightly floured surface knead in the remaining flour to make a moderately stiff dough.
Continue kneading till smooth and satiny (4 to 5 minutes).
Place in a greased bowl, turning once to grease surface.
Cover and let rise till double (for about 1 1/4 hours).
Punch down.
Let rest 10 minutes.
Roll dough 1/8 inch thick.
Using floured 2 1/2-inch round cookie cutter, cut out 48 circles.
Place 1 teaspoon prune filling on half of the circles; top with remaining circles.
Moisten edges with water and press edges firmly to seal.
Let rise on a floured surface till double.
Fry in deep hot oil (375°F) for 1 to 1 1/2 minutes on each side or till golden.
Drain on paper toweling.
When cool, frost with Vanilla Glaze.


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Auto SolutionsRead MoreSolutions Automotive is an auto repair shop located in McKinney, TX. We work on all makes and models of vehicles and employee some of the best ASE certified technicians in the industry.1513 S Tennessee StMcKinney, TX US


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The immune systems of patients who have recently developed ME/CFS look markedly different from those who have been ill for much longer, according to a major new study from Drs. Ian Lipkin and Mady Hornig at Columbia University. This shift in immune function hadn't been seen before.
Discuss the article on the Forums.
POTS the basics...do I have it?
Discussion in 'Problems Standing: Orthostatic Intolerance; POTS' started by ann09, Oct 19, 2012.
Page 1 of 2
Page 1 of 2


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Chateau Hotel La Vignette Haute overlooks the Siagne Valley and its gorges. This 4-star hotel offers luxury accommodation has a garden, 2 terraces and a swimming pool.
All of the guestrooms at Chateau Hotel La Vignette Haute have spacious luxury bathrooms. Some rooms offer a nice view of the surrounding area.
The restaurant's terrace, overlooking the Roman pool offers panoramic views of the surrounding area. Here you can enjoy gastronomic specialties prepared by the house chef.
You can also learn a bit of local history in the private Musée Le Curiosa which houses a unique collection of art and antique furniture.
Château Hotel La Vignette Haute is just 30 minutes from Nice International Airport, 20 minutes from the beaches of Cannes and 10 minutes from Grasse.


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This stunning Angraecum rutenbergianum orchid from Madagascar is found in the humid, evergreen forests on the trunks and branches of trees and on the shaded wet rocks.
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04-02-2012, 06:45 PM #16Junior Guru
- Join Date
- Aug 2004
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- Italy
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I think LowVM is talking about customers that could use the VPS for spamming purpose from the inside.
In this case there's no much to do except setting Recipient Limits on IIS Smtp or allow smtp via authentication only that will help you to keep track of any possible spammer.█ Dade2 Ltd Premium Hosting Provider Microsoft Partner
█ Managed Servers Secure Hosting Dedicated Account Managers
04-03-2012, 04:33 AM #17Disabled
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I think you should disable the email service because of the free.
06-09-2012, 02:06 PM #18Web Hosting Master
- Join Date
- Mar 2003
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- Jaipur, India
- Posts
- 632
:- If you are looking for spamming solutions, then please check your mail servers configurations and find out the grey listing of the domains, and regularly check their smtp outgoing IPs in the blacklisting check, even if single BL checker block your smtp outgoing IP then immediately remove them, if you are running with smarter mail or any other mail server then please check your spam bots.
I hope this will solve your query. Post me back if you need any further help.ZNetLive
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FEMA Notices on Appealing and Reviewing Claims in the National Flood Insurance Program expected Soon
By the end of April, the Federal Emergency Management Agency (FEMA) is expected to mail notices to all policy holders who filed claims with its National Flood Insurance Program (NFIP) on how to appeal or request a review in light of allegations of fraud and questionable engineering reports that led to underpayments and denials, according to Paul Weberg, Senior Engineer with FEMA Region II in New York.
Brick Township getting its First Farmers' Market
Russia and Immigration Reform Highlight "Ask the Congressman"
Berkeley Township Underwater Search and Rescue Unit Needs Help
Boat Capsizes off Sea Bright
OCLTRG Encouraged after Meeting with FEMA
The Ocean County Long Term Recovery Group is encouraged after a recent meeting with Federal Emergency Management Officials (FEMA) in New York City, according to Sue Marticek, Executive Director of the non-profit agency.
Toms River Police Chief Settles into new Role
UPDATE: Pedestrian Struck on Route 9 in Berkeley Dies
Downtown Toms River Thriving
Have you been to Downtown Toms River lately? The addition of new restaurants and businesses is attracting lots of foot traffic, according to Bill Golkiewicz, Executive Director of the Downtown Toms River Business Improvement District (BID).
Not Guilty Plea in Fatal Drug Overdose of Seaside Mayor's Son
A Lakewood man pleaded not guilty Tuesday in Ocean County Superior Court to charges in connection with the fatal heroin overdose death of the Seaside Heights Mayor's son, according to the Asbury Park Press.