text:
BMC Bioinformatics
Automated transition analysis of activated gene regulation during diauxic nutrient shift in Escherichia coli and adipocyte differentiation in mouse cells
Yoichi Takenaka1,2,3,
Kazuma Mikami4,
Shigeto Seno2 &
Hideo Matsuda2
BMC Bioinformatics volume 19, Article number: 89 (2018) Cite this article
Comprehensively understanding the dynamics of biological systems is among the biggest current challenges in biology and medicine. To acquire this understanding, researchers have measured the time-series expression profiles of cell lines of various organisms. Biological technologies have also drastically improved, providing a huge amount of information with support from bioinformatics and systems biology. However, the transitions between the activation and inactivation of gene regulations, at the temporal resolution of single time points, are difficult to extract from time-course gene expression profiles.
Our proposed method reports the activation period of each gene regulation from gene expression profiles and a gene regulatory network. The correctness and effectiveness of the method were validated by analyzing the diauxic shift from glucose to lactose in Escherichia coli. The method completely detected the three periods of the shift; 1) consumption of glucose as nutrient source, 2) the period of seeking another nutrient source and 3) consumption of lactose as nutrient source. We then applied the method to mouse adipocyte differentiation data. Cell differentiation into adipocytes is known to involve two waves of the gene regulation cascade, and sub-waves are predicted. From the gene expression profiles of the cell differentiation process from ES to adipose cells (62 time points), our method acquired four periods; three periods covering the two known waves of the cascade, and a final period of gene regulations when the differentiation to adipocytes was completed.
Our proposed method identifies the transitions of gene regulations from time-series gene expression profiles. Dynamic analyses are essential for deep understanding of biological systems and for identifying the causes of the onset of diseases such as diabetes and osteoporosis. The proposed method can greatly contribute to the progress of biology and medicine.
Acquiring a comprehensive understanding of biological systems dynamics is among the biggest challenges in biology and medicine. The processes of all organisms (including humans) are time-variant. Cells cycle and divide, change their internal states and differentiate into other cell types when stimulated from the outside. Abnormal cell differentiation causes diseases and cancer. Dynamic systems are universal in organisms.
Biological systems dynamics can now be understood through advanced biological technologies. On-chip hybridization and DNA sequencing has enabled the simultaneous measurement of the expression levels of many genes. Many of the accumulated data are registered in public databases such as GEO (Gene Expression Omnibus) [1, 2], Array Express [3] and Sequence Read Archive [4]. Special-purpose databases are also accessible. The references of mammalian tissue gene expressions are stored in RefEx (Reference Expression Dataset) [5], whereas the data from human tissues, cell lines and cancers are distributed through the Human Protein Atlas [6]. Mouse data are archived in the specialized database GXD (Gene expression database) of the Mouse Genome Informatics resource [7]. These databases are freely accessible to all users.
The above databases store the time-course movements of the gene expression levels in multiple organisms. For example, a search for "time-course" (2017/7/12) returned 913 datasets in GEO and 7623 entries in SRA. Based on these data, researchers have revealed the biological mechanisms of processes such as cell cycling [8] and diauxic shifts [9]. The adipogeneses of mice and humans have also been compared using time-course profiles [10]. These studies cover a broad range, from biology, through medicine, to pharmacology.
Numerous systems operate in living cells. Examples are metabolism, genetic and environmental information processing, cellular processes, and organismal systems [11]. Concurrent functioning of these systems in vivo maintains the life activities of the cell. Systems have been extensively researched and summarized as pathways in the KEGG (Kyoto Encyclopedia of Genes and Genomes) database [11]. Control of gene expression levels is another life-sustaining system. Gene regulation defines the relation between a controlling agent and its target gene. The gene regulatory system can be represented as a network of nodes (genes) connected by directed edges (regulation of a downstream gene by an upstream gene). The gene regulatory networks of model organisms are available in databases such as RegulonDB [12, 13], which contains the nearly-complete gene regulation of Escherichia coli, and the yeast network databases YEASTRACT [14–17]. The FANTOM projects have attempted to exhaustively reveal the relations between mouse and human in many tissues [18–22]. Gene regulatory networks are also provided in commercial databases such as TransFac [23, 24] and Quiagen's Ingenuity Pathway Analysis [25]. The regulatory relations between genes, at least in the model organisms, will be revealed exhaustively in the near future. However, although databases provide numerous gene regulations, the relationships are basically static. Each database entry supplies a gene regulatory relation and the experimental environment in which the relation was activated. Very few entries include the chronological order of the activations, despite our increasing knowledge of signaling pathway cascades. When the chronological order is given, the experimental environment includes the cell cycles and diauxic shift of the nutrient source. Adipocyte differentiation is accompanied by a rough sketch of the transition of active expression controls [26] (see Fig. 1). The differentiation involves a single transition point and two waves of activated gene regulations, although more than two waves have been suggested [26]. The dynamics of gene-expression control is a new research topic, with many unknowns at present.
The gene regulatory network of murine cell differentiation into adipocytes occurs in two waves (distinguished by different colors) [26]
Gene regulation activity can be dynamically analyzed from gene expression profiles. Given time-course data, researchers have sought the transformations in the gene regulatory network through models, such as ordinary differential equations and graphical models. Ordinary differential equations can explain the activity level of a gene regulation. The explanatory and objective variables are the expression levels of the upstream genes and the downstream genes, respectively [27–29]. Graphical models describe the control relations in the gene expression as a network of nodes (genes) with directed edges (controls). The dynamics of biological systems can be analyzed by a graphical Gaussian model with a Markov property [30, 31], which measures the independence of any two genes using partial correlations.
Other graphical models are the gene relevance network and the Bayesian network. The former generates a gene regulatory network from the mutual information, and measures the degree of association between gene expression levels [32–34]. This model can also manage time-course gene expression profiles [35].
In the Bayesian network, a directed edge represents the probabilistic relationship between two genes by information-theoretic approaches. The plausibility of the network is measured by the Bayesian information criterion and the minimum description length [36, 37]. Bayesian networks have been extended to time-course data by introducing Markov properties into the joint probability distribution. The time-dependent Bayesian network is called a dynamic Bayesian network [38, 39].
The above-described methods have analyzed not only the gene expression profiles, but also general data. Researchers have obtained meaningful results from all data except time-course gene expression profiles, which are most severely limited by the small number of time points. Figure 2 shows the distribution of time points in the GEO database. There are 913 datasets with time-series expression profiles. The average, mean and standard deviation of the time points are 4.66, 4, and 2.82, respectively. The number of time points is far below the numbers of other common data. To clarify this fact, Table 1 lists the number of data points in benchmark problems for inferring causal relationship networks [37, 40–44]. All of these benchmarks are included in bnlearn of the R package [44]. Comparing Fig. 2 and Table 1, we observe that the number of time points is two orders of magnitude lower in the time-series expression profile than in the benchmarks. This data limitation not only prevents the estimation of correct relationships, but also stifles the dynamic analyses.
Number of time points in datasets returned by a "time course or time-course" query in the Gene Expression Omnibus. The average, mean and standard deviation of the distribution are 4.66, 4 and 2.82, respectively
Table 1 Numbers of samples and variables in benchmark problems for inferring causal relationship networks
Takenaka et al. [45] proposed a method that captures the dynamic changes in gene expression control from time-course expression profiles with a small number of time points. Their method quantifies the intensity at which genes control the expression levels of other genes. The temporal resolution of intensity is one time point (the observation unit of the time-course gene expression profile). Single time-point resolution is finer than the resolutions of other methods [46–49]. Assuming a profile with N time points, the method generates N sub-profiles, each omitting one time point. The effectiveness of the method was confirmed in the diauxic shift of E.coli [9] and the adipocyte cell differentiation in mouse tissue [45, 50, 51]. The results detected the time of the diauxic shift in E. coli, and two waves of active regulations during adipocyte cell differentiation (Fig. 3). The authors concluded that the method effectively reveals the dynamics of gene regulations. But the method does not have any procedure how to determine the number of breakpoints and when the breaks happen. Therefore, finding the breakpoint of active gene expression control by this approach is somewhat subjective, and is undeniably influenced by already known biological findings. In this research, we propose a mechanical method that eliminates this subjectivity.
Six waves and one calm period during adipocyte cell differentiation. The tables show the strengths of the gene regulations calculated by [45]. Eight genes are regulated by other genes, and the strength changes between 0 and 196 h (white and red cells denote low and high strengths of the gene regulation, respectively). The period of each wave is also shown in the table. The left side of the figure presents the active gene regulations in each wave. The waves before and after the calm period correspond to the two waves reported in [26]. This analysis was performed by Takenaka and presented at Recomb 2016 [51]
We propose a method that analyzes the dynamics of gene regulations from time-series gene expression profiles. Here, the dynamics of gene regulations take two meanings. The first interpretation considers the dynamics of each gene regulation; whether the control of gene expression level by other genes is activated or inactivated at each time point in the time-series data. The second considers the dynamics of the gene regulatory network; the periods and pairs of their start and end times. The periods (sometimes called states, waves, or phases) are often biologically meaningful. The most well-known period is the cell cycle, which has two states; interphase and cell division. The interphase is divided into three sub-states called phases (Gap1, Synthesis, and Gap2), each with sub-phases. The cell cycle has four phases in total. Under these dynamics, the number of periods in a cell cycle is not fixed. The same situation occurs in other biological processes. Therefore, determining the number of periods in a biological process is a difficult task, and the dynamics of the gene regulatory network are difficult to analyze, especially in a manual analysis.
To analyze the dynamics of gene regulations in the two interpretations by an automated approach, we formulate the analysis as an optimization problem. The notations of the formulation are listed below.
Exp: time-course gene expression profiles with |T| time points and |G| genes.
T: a set of time points in Exp. If i<j, then t i ∈T is earlier than t j ∈T.
G: a set of genes in Exp.
M: a two-dimensional matrix |G|×|T|, where M ij represents the intensity at which the expression of gene g i ∈G is controlled by others at time t j ∈T. M is calculated from Exp by the method proposed in [45].
In our method, the activity of gene regulation is represented by a binary number, with 1 and 0 denoting active and inactive, respectively. The notations of the gene-regulation dynamics are explained below.
a g : a binary vector of length |T| representing the activity of gene g∈G at time t j ∈T.
Act: a binary matrix of size |G|×|T|, where Act i equals \(a_{g_{i}}\).
Tra: a subset of |T| representing the breaks between periods. For example, if Tra={t3}, the system has two periods; the first ending at t3 and the second starting at t4. If Tra is an empty set, no transition of the gene regulation occurs throughout the period.
Score function
As previously mentioned, we analyze the dynamics of gene regulations by solving the optimization problem; that is, by finding the most plausible dynamic model of the gene regulations. This model is conditional on the activity of each gene and the model complexity. Regarding the first condition, a positive M ij indicates high likelihood of activating the gene g i at time point t j . The second conditional expression describes the penalty term of the Bayesian information criterion. Here, the complexity of the model is defined as the number of periods in the model, which deals with the trade-off between the goodness of fit to the model and the tractability of the model.
To find a plausible model for M, we must optimize the following score:
$$ \text{Score}(Act) = \sum_{i=1}^{|G|} \sum_{j=1}^{|T|} M_{ij} \cdot {Act}_{ij} - |Tra| \cdot \ln (|G| \cdot |T|), $$
where Tra is calculated from Act. A time point t i ∈T is a member of Tra if ∃jAct ij ≠Acti(j+1).
The algorithm that finds the most plausible dynamic model of gene regulation is described below.
Input a Matrix M calculated from the gene expression profile and a gene regulatory network by the method in [45].
Output a Matrix Act, a set Tra, and a score.
Measure Maximize the score function Score (Act).
k: The integer k represents the number of breaks between the periods in the model.
V: A set of binary vectors of length |T|. Each element of V represents the activity of a gene regulation.
step 1 Initialize k←0 and Tra←{}
step 2 Generate a set of vectors V by the following sub-steps.
add a zero vector to V
add a one vector to V
step 3 score0←0
step 4 for each g i ∈G, select a vector v∈V that maximizes the g i score in the following sub-steps.
select a vector v in V that maximizes M i ·vt, where M i is the i-th row of M.
score0 +=M i ·vt
insert vector v into the i-th row of Act; Act i ←v.
step 5 score best ←score0; Act best ←Act; Tra best ←Tra
step 6 k+=1; If k=|T|, goto Step 9.
step 7 for each Tra={t|t∈T}, where |Tra|=k,
step 7-1 generate a set of vectors V as follows:
for each period i of Tra, generate a set V i with two elements; a zero vector and a unit vector with lengths equal to that of the period.
generate V as the direct product of all V i .
step 7-2 score k ←−2·k· ln(|T|·|G|)
step 7-3 for each g i ∈G, select a vector v∈V that maximizes the score by the following sub-steps.
score k +=M i ·vt
insert vector v into the i-th column of Act; Act i ←v.
step 7-4 if score k >score best , score best ←score k ; Act best ←Act; Tra best ←Tra.
step 8 if score k >scorek−1, goto Step 6.
step 9 output Act best , Tra best and score best .
The above algorithm is a brute-force search with poor computational efficiency. However, as the gene expression profile contains very few time points, the above algorithm satisfies our requirements.
For larger datasets, the calculation time can be shortened by using a hash function from a gene and a period to the sub-score. Meanwhile, the computational complexity can be reduced by dynamic programming.
The effectiveness of the proposed method was tested on two biological datasets. The results of our method were also compared with a manual analysis of the periods in the time series. The first dataset contains the time-course gene expression profiles during the diauxic shift from glucose to lactose metabolism in E. coli. In this test, the method was assessed by its ability to detect the time of the diauxic shift.
The second dataset reports the adipocyte cell differentiation in the house mouse Mus musculus. Two periods (called waves in [26]) of gene regulation have been identified during this differentiation, and more waves are expected. This test evaluated whether the method can detect three or more plausible periods.
Diauxic shift
The first dataset is the time-course gene expression profile GSE7265 in the GEO dataset. The diauxic shift was observed in E. coli MG1655 and isogenetic mutants cultured in a medium containing glucose and lactose [9]. The expression levels of the genes were measured in oligonucleotide microarrays containing 70-base oligonucleotide probes. The wild-type profile contains 17 time points from 780 min. to 1089 min. after inoculation. At each time point, the triplicated expression values were averaged to obtain the representative expression level.
The time points are divided into two phases; the first lasting from 780 min. to 939 min., the second from 969 min.to 1089 min. The diauxic shift from glucose to lactose has been recognized in the first half, but information on the second half is completely lacking. Although the GS2765 gene expression profile contains 17 time points, the original paper [9] trimmed the profile to 10 time points (830-939 min. post-inoculation), and reported the growth ratio in the first half only. Therefore, the full dynamics of the diauxic shift can only be surmised.
The gene regulatory network of the diauxic shift comprises 31 genes and 50 gene regulations [45]. Fourteen enzymes are related to the glycolytic and lactose metabolic pathways. According to RegulonDB [12, 13], the expression levels of the enzymes are controlled by 14 transcription factors (TFs), and 50 TF–enzyme interactions are known. The present study adopts the gene list and the gene regulatory network used in [45].
The proposed method was implemented in R, and the matrix M representing the intensities of the gene regulations was calculated by an R package from GitHub https://github.com/takenakayoichi/tacs. The computed matrix M was input to the proposed method.
The proposed method detected five periods during the diauxic shift of wild type E. coli. The maximum score during each period is tabulated in Table 2. Although the proposed algorithm identified 6 periods, the maximum score was recorded over 8 periods for reference. The score peaks during Period 5 and the between-period breakpoints are 878 min., 908 min., 999 min. and 1049 min. The first, second and third periods belong to the first half of the diauxic shift; the remainder belong to the second half. The periods are also indicated by the vertical lines in Fig. 4.
Expression levels of 31 genes (colored plots) and growth ratio (solid black line) during diauxic shift in E. coli. Vertical lines delineate the periods of the dynamic model detected by the proposed method
Table 2 Maximum scores in each period of diauxic shift in E. coli (central column) and differentiation to murine adipocytes (right column) (maximum scores are in bold)
Takenaka et al. [45] manually detected three periods in the GS2765 gene expression profile, with breakpoints at approximately 888 − 908 min. and 1070 − 1089 min. The breakpoints were expressed as ranges because they were difficult to pinpoint by the manual approach. In their analysis, the first and second periods belonged to the first half of the diauxic shift, and the third period belonged to the second half.
Our method divided the first half of the experiment into three periods. Figure 4 shows the growth ratios in each period. During the first and third periods, the E. coli exist in the logarithmic growth phase and are consuming glucose and lactose, respectively. The second period is consistent with cessation of cell proliferation.
In comparison, the manual curation identified only two periods in the first half. The division point was exactly centered in the growth arrest period. From the difference between our results and the manually curated results, we can identify whether a mechanism that regulates the gene expression level exists independently in the logarithmic and growth-arrest phases.
Which of these methods expresses more realistic biological properties? Manual curation suggests that lactose consumption begins immediately after glucose depletion. On the other hand, the proposed method suggests that once the glucose is depleted, the cells cease growing while seeking a new nutrient source, and resume growth when an alternative nutrient is found. We consider that the proposed method presents a more plausible dynamic model than manual curation. One expects that the E. coli cells cannot immediately access a new nutrition source once the original source is depleted. If this were possible, logarithmic growth would continue without interruption.
The second half of the experiment was continuous in the manual curation, but divided into two periods in the proposed method. Once the E. coli had consumed the glucose and lactose in their nutrient medium, they began seeking the next nutrition source. When no further source was found, the gene expression regulations changed sufficiently for detection by both methods. However, as the expression profile provides the only available information in the second half, the actual number of periods in the second half of the experiment is difficult to judge.
Adipocyte differentiation
The second dataset was a time-course gene expression profile of mouse adipocyte differentiation. The RNAs in this dataset were collected from mouse ST2 bone marrow stroma cell-derived stem cells (RCB0224) obtained from the RIKEN BioResource Center (BRC, Tsukuba, Japan). ST2 cells were induced by changing the medium from RMPI1640 to DMEM supplemented with 10% FBS, 0.5 mM 3-isobutyl-1-methylxanthine (MIX), 0.25 μM DEX, and with insulin-transferrin-selenium-X supplement containing 5 μg/ml of insulin and 1 μM rosiglitazone. After 48 hours, the differentiation medium was replaced with DMEM supplemented with 10% FBS. The RNAs collected at 62 time points during adipocyte differentiation were measured using an Affymetrix GeneChip Mouse Genome 430 2.0 Array. The time points were 0, 5, 15, 30 and 45 min., hourly from 1 to 30 h, and 6-hourly from 36 to 192 h after adipogenesis induction. Each datum was background-subtracted and normalized in the robust multi-array analysis (RMA). The gene expression profiles are available from the Genome Network Platform [50].
Previous research has unveiled the important regulators of adipocyte development and a two-wave cascade in this process [26] (see Fig. 1). The network includes 24 regulations between 14 genes, but undetected sub-waves have been predicted [26].
The expression levels of the 14 genes are shown in Fig. 5. Among them, the line with square indicates pparg, a known marker of adipocyte cells. The expression level of pparg increases from 2 to 6 h and then decreases. The decline is followed by a gradual rise after 14 h.
Expression Levels of 14 genes during murine adipocyte differentiation. Blue and red lines indicate the expression levels of genes belonging to the first and second waves in Fig. 1, respectively. The red line with square markers plots the expression levels of pparg, a marker gene of adipose cells
Figure 6 shows the intensities of the expression levels controlled by other genes, which constitute the intensity matrix M of our algorithm. The intensities were calculated from the gene expression profiles in Fig. 5 and the gene regulatory network in Fig. 1.
Intensity of genes whose expression levels are controlled by other genes. Blue and red lines show the intensities of genes belonging to the first and second waves in Fig. 1, respectively. The red line with square markers plots the intensity of pparg, a marker gene of adipose cells
The proposed method detected four periods of adipocyte differentiation. The maximum score in each period is listed in Table 2. The algorithm terminated after five periods, but 8 periods are included for referencing purposes. The score peaks during period 4, and the between-period breakpoints are 2 h, 26 h and 72 h. Figure 7 shows the dynamics of the gene regulatory network. In the figure, we classify the gene whose expression level during a period is controlled by upstream genes or not by the average of the intensity during the period is larger than zero or not.
The four periods of differentiation into murine adipocytes detected by the proposed method. Dark- and light-shaded boxes enclose genes whose expression level is controlled and not controlled by upstream genes, respectively
The two waves of the known cascade in Fig. 1 appear in the four periods detected by our algorithm. During the first period of adipocyte differentiation, the expression controls of the most upstream genes (Klf4 and Knox20) are activated. During the second period, the expressions of Cebp β and Cebp δ are controlled and the regulations of the second wave (Thr α/β and Srebp-1c) begin activating. The pparg and cebp α genes are regulated during the third period, and the most downstream genes are regulated during the fourth period. The four-period differentiation identified by our method includes the known waves, but appears to be more precise.
The four periods detected by our method differ from the two-wave differentiation in two ways. First, the regulations of Pparg and Cebp α are activated twice. Once at the first period, and re-activated in the second wave composed of third and fourth periods. Pparg is a marker of adipose cells and a known regulator of adipocyte differentiation. The two activations of the pparg gene are confirmed in Fig. 5. The expression level of Pparg peaks at 6 h and 114 h. Most of the gene expression regulations are activated in the fourth period. By the start time of this period (78 h), the cells will have produced lipid droplets [52]. Therefore, we consider that the differentiation into adipocytes was completed during the fourth period, and was stabilized thereafter. It appears that many regulations of the adipocyte-related gene expression levels are activated in the fourth period.
We proposed a method that detects the dynamics of gene regulatory networks at the temporal resolution of single time points in the underlying gene expression profiles. The dynamics are modeled as periods of activated regulations. The plausibility of the model was quantified using the Bayesian information criterion. The problem constitutes a combinatorial optimization problem that find the highest-scoring model. The algorithm inputs the gene expression profiles and a gene regulatory network, and returns the activated regulations, divided into periods.
The effectiveness of the method was validated in two datasets; the diauxic shift from glucose to lactose in E. coli and adipocyte differentiation in the mouse. In both datasets, the proposed method detected more plausible dynamic models than existing models. We believe that the proposed method can precisely reveal the dynamics of biological systems.
Edgar R, Domrachev M, Lash AE. Gene expression omnibus: Ncbi gene expression and hybridization array data repository. Nucleic Acids Res. 2002; 30(1):207–10. https://doi.org/10.1093/nar/30.1.207.
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A. Ncbi geo: archive for functional genomics data sets-update. Nucleic Acids Res. 2013; 41(D1):991–5. https://doi.org/10.1093/nar/gks1193.
Kolesnikov N, Hastings E, Keays M, Melnichuk O, Tang YA, Williams E, Dylag M, Kurbatova N, Brandizi M, Burdett T, Megy K, Pilicheva E, Rustici G, Tikhonov A, Parkinson H, Petryszak R, Sarkans U, Brazma A. Arrayexpress update–simplifying data submissions. Nucleic Acids Res. 2015; 43(Database issue):1113–6.
Kodama Y, Shumway M, Leinonen R. The sequence read archive: Explosive growth of sequencing data. Nucleic Acids Res. 2012; 40(D1):2011–3. https://doi.org/10.1093/nar/gkr854.
Reference Expression Dataset. http://refex.dbcls.jp. Accessed 13 July 2017.
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA-K, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F. Tissue-based map of the human proteome. Science. 2015; 347:6220. https://doi.org/10.1126/science.1260419.
Ringwald M, Eppig JT, Begley DA, Corradi JP, McCright IJ, Hayamizu TF, Hill DP, Kadin JA, Richardson JE. The mouse gene expression database (gxd). Nucleic Acids Res. 2001; 29(1):98–101. https://doi.org/10.1093/nar/29.1.98.
Bähler J. Cell-Cycle Control of Gene Expression in Budding and Fission Yeast. Annu Rev Genet. 2005; 39(1):69–94. https://doi.org/10.1146/annurev.genet.39.110304.095808.
Traxler MF, Chang DE, Conway T. Proc Natl Acad Sci of the United States of America. 2006; 103(7):2374–9.
Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, Lander ES, Rosen ED. Comparative epigenomic analysis of murine and human adipogenesis. Cell. 2010; 143(1):156–69. https://doi.org/10.1016/j.cell.2010.09.006.
Kanehisa M, Goto S. Kegg: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000; 28(1):27–30. https://doi.org/10.1093/nar/28.1.27.
Huerta AM, Salgado H, Thieffry D, Collado-Vides J. Regulondb: A database on transcriptional regulation in escherichia coli. Nucleic Acids Res. 1998; 26(1):55–9. https://doi.org/10.1093/nar/26.1.55.
Salgado H, Peralta-Gil M, Gama-Castro S, Santos-Zavaleta A, Muniz-Rascado L, Garcia-Sotelo JS, Weiss V, Solano-Lira H, Martinez-Flores I, Medina-Rivera A, Salgado-Osorio G, Alquicira-Hernandez S, Alquicira-Hernandez K, Lopez-Fuentes A, Porron-Sotelo L, Huerta AM, Bonavides-Martinez C, Balderas-Martinez YI, Pannier L, Olvera M, Labastida A, Jimenez-Jacinto V, Vega-Alvarado L, del Moral-Chavez V, Hernandez-Alvarez A, Morett E, Collado-Vides J. Regulondb v8.0: omics data sets, evolutionary conservation, regulatory phrases, cross-validated gold standards and more. Nucleic Acids Res. 2013; 41(D1):203–13. https://doi.org/10.1093/nar/gks1201.
Teixeira MC, Monteiro P, Jain P, Tenreiro S, Fernandes AR, Mira NP, Alenquer M, Freitas AT, Oliveira AL, Sá-Correia I. The yeastract database: a tool for the analysis of transcription regulatory associations in saccharomyces cerevisiae. Nucleic Acids Res. 2006; 34(suppl 1):446. https://doi.org/10.1093/nar/gkj013.
Monteiro PT, Mendes ND, Teixeira MC, d'Orey S, Tenreiro S, Mira NP, Pais H, Francisco AP, Carvalho AM, Lourenço AB, Sá-Correia I, Oliveira AL, Freitas AT. Yeastract-discoverer: new tools to improve the analysis of transcriptional regulatory associations in saccharomyces cerevisiae. Nucleic Acids Res. 2008; 36(suppl 1):132. https://doi.org/10.1093/nar/gkm976.
Abdulrehman D, Monteiro PT, Teixeira MC, Mira NP, Lourenço AB, dos Santos SC, Cabrito TR, Francisco AP, Madeira SC, Aires RS, Oliveira AL, Sá-Correia I, Freitas AT. Yeastract: providing a programmatic access to curated transcriptional regulatory associations in saccharomyces cerevisiae through a web services interface. Nucleic Acids Res. 2011; 39(suppl 1):136. https://doi.org/10.1093/nar/gkq964.
Teixeira MC, Monteiro PT, Guerreiro JF, Gonçalves JP, Mira NP, dos Santos SC, Cabrito TR, Palma M, Costa C, Francisco AP, Madeira SC, Oliveira AL, Freitas AT, Sá-Correia I. The yeastract database: an upgraded information system for the analysis of gene and genomic transcription regulation in saccharomyces cerevisiae. Nucleic Acids Res. 2014; 42(D1):161. https://doi.org/10.1093/nar/gkt1015.
Ravasi T, Suzuki H, Cannistraci CV, Katayama S, Bajic VB, Tan K, Akalin A, Schmeier S, Kanamori-Katayama M, Bertin N, et al. An atlas of combinatorial transcriptional regulation in mouse and man. Cell. 2010; 140(5):744–52.
Suzuki H, Forrest AR, van Nimwegen E, Daub CO, Balwierz PJ, Irvine KM, Lassmann T, Ravasi T, Hasegawa Y, de Hoon MJ, et al. The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line. Nat Genet. 2009; 41(5):553–62.
Forrest A, Kawaji H, Rehli M, Baillie J, de HM, Haberle V, Lassmann T, Kulakovskiy I, Lizio M, Itoh M, Andersson R, Mungall C, Meehan T, Schmeier S, Bertin N, Jorgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva Y, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young R, Francescatto M, Alam I, Albanese D, Altschuler G, Arakawa T, Archer J, Arner P, Babina M, Rennie S, Balwierz P, Beckhouse A, Pradhan-Bhatt S, Blake J, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs A, Califano A, Cannistraci C, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers H, Dalla E, Davis C, Detmar M, Diehl A, Dohi T, Drablos F, Edge A, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairb. A promoter-level mammalian expression atlas. Nature. 2014; 507:462. https://doi.org/10.1038/nature13182.
Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014; 507(7493):455–61.
Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drabløs F, Lennartsson A, Rönnerblad M, Hrydziuszko O, Vitezic M, et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science. 2015; 347(6225):1010–4.
Wingender E, Chen X, Hehl R, Karas H, Liebich I, Matys V, Meinhardt T, Prüß M, Reuter I, Schacherer F. Transfac: an integrated system for gene expression regulation. Nucleic Acids Res. 2000; 28(1):316–9.
Wingender E. The transfac project as an example of framework technology that supports the analysis of genomic regulation. Brief Bioinform. 2008; 9(4):326–32.
QUIAGEN's Ingenuity Pathway Analysis. https://www.qiagenbioinformatics.com/. Accessed 14 July 2017.
Siersbæk R, Nielsen R, Mandrup S. Transcriptional networks and chromatin remodeling controlling adipogenesis. Trends Endocrinol Metab. 2012; 23(2):56–64.
Tegner J, Yeung MS, Hasty J, Collins JJ. Reverse engineering gene networks: integrating genetic perturbations with dynamical modeling. Proc Natl Acad Sci. 2003; 100(10):5944–9.
Gardner TS, Di Bernardo D, Lorenz D, Collins JJ. Inferring genetic networks and identifying compound mode of action via expression profiling. Science. 2003; 301(5629):102–5.
Kim S, Kim J, Cho KH. Inferring gene regulatory networks from temporal expression profiles under time-delay and noise. Comput Biol Chem. 2007; 31(4):239–45.
Schäfer J, Strimmer K. An empirical bayes approach to inferring large-scale gene association networks. Bioinformatics. 2005; 21(6):754–64.
Stark E, Drori R, Abeles M. Partial cross-correlation analysis resolves ambiguity in the encoding of multiple movement features. J Neurophys. 2006; 95(3):1966–75.
Butte AJ, Kohane IS. Mutual information relevance networks: functional genomic clustering using pairwise entropy measurements. In: Pac Symp Biocomput. Singapore: World Scientific Pub Co Inc.: 2000. p. 418–29.
Hausser J, Strimmer K. Entropy inference and the james-stein estimator, with application to nonlinear gene association networks. J Mach Learn Res. 2009; 10:1469–84.
Margolin AA, Nemenman I, Basso K, Wiggins C, Stolovitzky G, Favera RD, Califano A. Aracne: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinformatics. 2006; 7(Suppl 1):7.
Zoppoli P, Morganella S, Ceccarelli M. Timedelay-aracne: Reverse engineering of gene networks from time-course data by an information theoretic approach. Bmc Bioinformatics. 2010; 11(1):154.
Jensen FV, Nielsen TD. Bayesian Networks and Decision Graphs, 2nd edn. New York: Springer; 2007.
Neapolitan RE. Learning Bayesian Networks. Upper Saddle River: Prentice-Hall, Inc.; 2003.
Perrin BE, Ralaivola L, Mazurie A, Bottani S, Mallet J, d' Alche–Buc F. Gene networks inference using dynamic bayesian networks. Bioinformatics. 2003; 19(suppl 2):138–48.
Zou M, Conzen SD. A new dynamic bayesian network (dbn) approach for identifying gene regulatory networks from time course microarray data. Bioinformatics. 2005; 21(1):71–9.
Agresti A. Categorical Data Analysis, 3rd edn. Wiley Series in Probability and Statistics. 111 River Street: Wiley-Interscience; 2012.
Lauritzen SL, Spiegelhalter DJ. Local Computation with Probabilities on Graphical Structures and their Application to Expert Systems (with discussion). J R Stat Soc Ser B Stat Methodol. 1988; 50(2):157–224.
Beinlich IA, Suermondt HJ, Chavez RM, Cooper GF. The alarm monitoring system: A case study with two probabilistic inference techniques for belief networks. In: Proceedings of the 2nd European Conference on Artificial Intelligence in Medicine. Berlin: Springer-Verlag: 1989. p. 247–56.
Binder J, Koller D, Russell S, Kanazawa K. Adaptive Probabilistic Networks with Hidden Variables. Mach Learn. 1997; 29(2–3):213–44.
Scutari M. Learning Bayesian Networks with the bnlearn R Package. J Stat Softw. 2010; 35(3):1–22. Accessed 2 Aug 2017.
Takenaka Y, Seno S, Matsuda H. Detecting shifts in gene regulatory networks during time-course experiments at single-time-point temporal resolution. J Bioinforma Comput Biol. 2015; 13(05):1543002. https://doi.org/10.1142/S0219720015430027.
Jia Y, Huan J. Constructing non-stationary dynamic bayesian networks with a flexible lag choosing mechanism. BMC Bioinformatics. 2010; 11(Suppl 6):27.
Nakayama T, Daiyasu H, Seno S, Takenaka Y, Matsuda H. Bioinformatics and Computational Biology: The 2013 WorldComp International Conference Proceedings In: Arabnia HR, Tran Q-N, editors. Herndon: Mercury Learning and Information: 2014. p. 375–9.
Song L, Kolar M, Xing EP. Time-varying dynamic bayesian networks. In: Advances in Neural Information Processing Systems. NY: Curran Associates, Inc.: 2009. p. 1732–40.
Tamada Y, Araki H, Imoto S, Nagasaki M, Doi A, Nakanishi Y, Tomiyasu Y, Yasuda K, Dunmore B, Sanders D, Humphreys S, Print CG, Charnock-Jones SD, Tashiro K, Kuhara S, Miyano S. Unraveling dynamic activities of autocrine pathways that control drug-response transcriptome networks In: Altman RB, Dunker AK, Hunter L, Murray T, Klein TE, editors. Pacific Symposium on Biocomputing. Singapore: World Scientific Pub Co Inc.: 2009. p. 251–63.
Adipocyte Differentiation of Mouse, Genome Network Plaform. ST2 stem cell was induced DMEM with 10% FBS, Affymetrix GeneChip 430 2.0 Array, 62 time points. http://genomenetwork.nig.ac.jp/index_e.html. Accessed 2 Aug 2017.
Takenaka Y, Seno S, Matsuda H. Dynamic Analysis of Gene Regulations 734 using Leaving-One-Out Expression Profile. Proceeding of The 20th Annual International Conference on Research in Computational Molecular Biology, RECOMB2016, P48, 2016.
Qian SW, Li X, Zhang YY, Huang HY, Liu Y, Sun X, Tang QQ. Characterization of adipocyte differentiation from human mesenchymal stem cells in bone marrow,. BMC Dev Biol. 2010; 10:47. https://doi.org/10.1186/1471-213X-10-47.
This work was partially supported by JSPS KAKENHI Grant Numbers 15K00402 and 16H03261.
Funding for the publication of this article was provided by JSPS KAKENHI Grant Number 15K00402.
The E.coli data analyzed in this research was available as GSE7265 Gene Data Set in Gene Expression Omnibus. The mouse data analyzed in this research was downloaded from Genome Network Platform [50]. The code used in this study is available in https://github.com/takenakayoichi/tacs.
About this supplement
This article has been published as part of BMC Bioinformatics Volume 19 Supplement 4, 2018: Selected articles from the 16th Asia Pacific Bioinformatics Conference (APBC 2018): bioinformatics. The full contents of the supplement are available online at https://bmcbioinformatics.biomedcentral.com/articles/supplements/volume-19-supplement-4.
Faculty of Informatics, Kansai University, Ryousenji 2-1-1, Takatsuki, Osaka, Japan
Yoichi Takenaka
Graduate School of Information Science and Technology, Osaka University, Yamadaoka 1-5, Suita, Osaka, Japan
Yoichi Takenaka, Shigeto Seno & Hideo Matsuda
Graduate School of Medicine, Osaka University, Yamadaoka 2, Suita, Osaka, Japan
Recruit Holdings Co. Ltd., Marunouchi 1-9-2, Chiyoda, Tokyo, Japan
Kazuma Mikami
Shigeto Seno
Hideo Matsuda
YT conceived and designed the algorithm and the experiments and wrote the manuscript. YT and KM implemented the algorithm and performed the analyses. SS and HM contributed by providing suggestions. All authors have read and approve the final manuscript.
Correspondence to Yoichi Takenaka.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Takenaka, Y., Mikami, K., Seno, S. et al. Automated transition analysis of activated gene regulation during diauxic nutrient shift in Escherichia coli and adipocyte differentiation in mouse cells. BMC Bioinformatics 19, 89 (2018). https://doi.org/10.1186/s12859-018-2072-y
DOI: https://doi.org/10.1186/s12859-018-2072-y
Gene regulatory network
Network dynamics
Time course
Adipocyte


text:
Q: Testing Firebase Database with an in-memory fake/db Is there any in-memory implementation for Firebase database for testing Android client logic and integration? I have seen node.js fakes but could not find anything in java. I am not looking for a plain mock which is only good for basic unit-testing.

A: You must do refactoring your application, and implement an architectural approach. For example, such as MVP, MVVM, Clean, etc. The main thing is the layers. In this case, you can test these layers independently of each other using mock objects.
On the Internet you will find a lot of documentation on this topic,
eg Essential Guide For Designing Your Android App Architecture,
Why to choose MVVM over MVP — Android Architecture and many others.

redpajama_set_name: RedPajamaStackExchange


Four Dexter wrestlers finished among the top four at the Division 2 Individual Regionals (7-2) at Eaton Rapids on Saturday and advanced to the state finals at the Palace of Auburn Hills on March 2-4.
The top four wrestlers in each weight class advance to the State Finals. All four of the Dreadnaughts who qualified for the Regionals made it through to the Palace.
At 160 pounds, Adam Burton defeated Zach Miller of Coldwater 8-7 before falling 7-6 to Chelsea's Guy Reynolds, who ended up finishing second overall. A senior, Burton bounced back with an 11-6 win over Charlotte's Anthony Williams. In the three-four finals, Burton lost to Niles' Davin Simpson.
Burton, who finished fourth, will take his 33-12 record to the State Finals.
Dexter's Will Feldkamp entered and exited Saturday's Regionals with an undefeated record at 189 pounds after running the table to finish first overall. The senior opened with a pin of Sturgis' Gage Bail in 51 seconds and then defeated Brad Wilton of Mason 6-5. He won the championship match 8-0 over Haslett's Nevin Brittain.
Feldkamp improved to an impressive 51-0 on the season.
Dexter's Ryan Clements brought his 42-7 record into regionals and had a solid day for the Dreadnaughts as the senior took second overall to advance to the State Finals.
He defeated Trever Brooks of Harper Creek in the opener and then defeated Cade Stephenson of Niles 10-3 to advance to the championship match. Austin Franco of Niles pinned Clements in 55 seconds to take first overall.
At 152 pounds, Dexter's Kyle Burton (43-14) advanced to the Palace after coming back from a tough 10-7 opening-match loss to Cody Carlisle of Stevensville Lakeshore. The Dexter senior defeated Carter Hall of St. Johns (4-1) and then beat Robert Glover of Niles 3-2 to reach the consolation finals where he lost 11-3 to Tanner Beach of Jackson Northwest.
The Dexter wrestling team also held two bottle/can drives to help raise money for a suite at The Palace for the wrestlers to have a place to relax before and in between matches and for their families during the state finals. With the two drives they were able to raise half of the money for the suite.


text:
HQIP / News / Specialist rehabilitation audit reports good early progress
Specialist rehabilitation audit reports good early progress
The National Clinical Audit of Specialist Rehabilitation for Patients with Complex Needs Following Major Injury has reported an enthusiastic reception since launching earlier this summer.
The three-year programme, commissioned by HQIP as part of the National Clinical Audit and Patient Outcomes Programme (NCAPOP), went live in July 2015 and is conducted in partnership with the British Society of Rehabilitation Medicine (BSRM) and led by a tripartite partnership between:
The UK Rehabilitation Outcomes Collaborative (UKROC), London North West Healthcare NHS Trust
The Trauma Audit and Research Network (TARN), Manchester University
The Cicely Saunders Institute, King's College London
The audit will provide a national comparative assessment of the organisation, quality, outcomes and efficiency of specialist rehabilitation services provided for adults with complex needs following major injury (physical injury caused by events such as road traffic accidents, falls etc). It will seek to drive improved and equitable access to specialist rehabilitation services for these patients.
The work has begun with an organisational audit to identify specialist rehabilitation services and map pathways of care.
"We are very pleased with the responses we have had so far and would welcome patients and carers who would to get in touch to find out more." said project lead Roxanna Vanderstay from King's College.
Find out more about the programme and how to get in touch
Including the organisational audit, the programme has three main elements:
To find out more visit the Kings College, London website

redpajama_set_name: RedPajamaCommonCrawl


text:
The Awards Keep Coming for One of the Top Family Friendly Restaurants Downtown Joe's
Napa, CA-based restaurant Downtown Joe's Brewery & Restaurant has recently announced that their bartender "Big" John Herkins has won the Bohemian Magazine Best Bartender in Napa award. They have also announced that server India Robinson has been given the Best Server in Napa award, highlighting her commitment to delivering the highest caliber of service to Napa clientele. As one of the top Napa family friendly restaurants, Downtown Joe's Brewery & Restaurant now offers a full selection of meals, specials and quality craft beer to local Napa patrons.
Businesses that continue to win awards in the Napa restaurant industry have proven their excellence over time. The competition in this area, known for its wineries, vineyards and top restaurants, is tough. Only by working with top-quality staff and offering superior meal and drink options local restaurants can thrive. Providing service excellence is a key part of the mission and the reason why Downtown Joe's Brewery & Restaurant and their team has won these two recent awards.
The Best Bartender Award has been given to Big John for his continued excellence over many years serving local Napa patrons with craft beer options and drink specials. His calm demeanor and his understanding of the bartending craft is second-to-none and now he has the award to prove it. He has a larger than life personality that makes all patrons feel welcomed.
The restaurant was also proud to receive the Best Server Award for 2017. This award was given to India Robinson for her ability to easily engage with everyone and to build a rapport with all guests. India's advice to the next aspiring Best Server" is "To enjoy your work and don't let the bad times affect you."
Downtown Joe's Brewery & Restaurant is the hub for sports viewing, summer events, and dance parties this year. To discover more on the venue and its award-winning services, please contact their team at 707-258-2337 or visit their business website directly at www.downtownjoes.com.


It rained on Monday and Tuesday this week, which reminded me that sneakers with mesh panels at the toe are not the best thing to walk in when it rains.
Can anyone recommend good urban walking shoes (mostly pavement, some grass and packed dirt paths) that are waterproof, have wide toe boxes, have good arch support (or removable insoles that I can replace), are comfortable enough for all-day wear, and are cute? I have a pair of Keen boots that I like a lot, but they are well-worn and probably should be replaced.
Actually, if you have recommendations for insoles, too, that would rock. I usually just get whatever brand the shoe store sells. Sometimes they work out and sometimes they don't.
ps. I loved all the great advice on the "what shoes do you pack" thread!
Janine -- I'm particular to shoes by Brooks, and they sell a couple of running shoe models that are waterproof. They use GoreTex, and they use the "GTX" suffix on their shoe models. I don't know that these would work for you, but they may be the kind of feature to look out for.
As for insoles, it depends on what your're looking for. If you're looking for good arch supports and cushioning, you might try Superfeet insoles. If you want to spend a lot of money, the SOLE brand (designed by runner Dean Karnazes) is pretty nifty. You actually put your SOLE insoles in the oven for a couple of minutes to soften them up, and then you stand on them to get a custom orthotic-type fit. You can buy both brands at an REI store.
I prefer the fit/feel/construction of Sanita every since Dansko lost their patent. I have quite a few pair of Dansko pre-patent loss and 2 pair post patent. I love them, wear them year round, and in the professional style haven't had any issues with my feet getting wet. I'm curious to see what you end up with Janine.
ps the orthotic insoles are "Powerstep Pinnacle." They were recommended by an independent running shoe store and have really helped me a lot.
I think this is the brand that my local running store carries. I got a pair a few years ago, and the man who fitted me started with larger insoles and cut them down to fit. He actually had to cut 3 pairs because my left and right arches didn't line up with the arches in the same size of left and right insoles. That's customer service, huh?
I'm glad you mentioned Danskos. I have been eyeing the Professional clogs. I think they would make a great everyday shoe for me. The only reason that I don't have a pair is that I'm too chicken to pay for them, LOL. Maybe now is the time to face my fears?
Ooooh! Blundstones look very interesting, and your location really does give you instant respect on the waterproof footwear issue. Thank you for the link!
Hey Lani. I've got Brooks sneakers right now and they work pretty well. Thanks for the names of other insoles and the GoreTex recommendation - now I've got some things to look for!
Oh yes, Sanitas rock too. I have the professional clogs in black leather. They are incredible shoes that I wear to work and they certainly can handle rain. But, I'm still partial to the Blunnies, particularly when it is rainingrainingrainingraining and there might be mud, or big puddles, or big, wet, sloppy dogs stepping all over your toes.
+1 on the Blundstones...I live in CT and pretty much live in my Blunnies during Fall/Winter/Spring (I have two pair). I also love the Salomon Goretex trail running shoes...very comfortable and waterproof.
Janine, if you buy the Dansko professional clogs at REI and don't like them, you can return them even after you've worn them (as long as you're a member). REI is great about that, and a large reason why I get shoes there whenever I can.
Is there any difference between Danskos and Sanitas? They look an awful lot alike.
I'm very attached to my New Balance 978s. Comfortable, comes in various widthsm, and waterproof!
There used to be no difference other than choices in finish/material, but now there is in structure. Dansko lost the patent to the footbed, last and sole for their stapled clogs. Sanita has the patent. Now the clogs for Dansko are made in China, Sanitas are still made in Denmark. Dansko's are now wider at the heel cup and toe box. Some have complained that the new Dansko last squeaks over time, though I haven't had this problem. If you are used to the original fit, then the new fit may not work as well. here's (http://shoeinsider.blogspot.com/2009/08/dansko-vs-sanita-whats-difference.html) an article on the deets.
i am a mailman and i have tried many brands. for the prize and comfort, i have chosen KEEN shoes for my work now. waterproof, light and very boxy up front in the shoes for the toes. keen does not use goretex. they use their own technology and it works and therefore keen waterproof shoes aren't as expensive as goretexed shoes. you should try a pair on. KEEN.
Thanks for the link, @dorayme! Nice, concise, and informative!
Yeah! I just found a pair of waterproof KEENs in black and purple. I have a pair of KEEN boots that I like well, but they aren't waterproof (found that out the hard way and had soggy feet all day!). The fit is very good, though, so I thought I'd give this brand another try.
I thought REI membership is lifetime. . . I could be mistaken though.
You are mistaken about being mistaken! REI memberships are indeed for life. Were they always for life, or were they annual memberships long ago?
So, I got a pair of Keens and I love them. They are more hiking-bootish, though, and I wouldn't mind a pair of sneaker-like waterproof shoes. So I looked back for Lani's recommendation and you know what?
There's a pair of Brooks Adrenaline sneakers on my feet right now.
Glad you found what works!
Hey Audrey, are these hiking shoes? If so, they look very nice! I've had New Balance shoes before and they fit my feet very well.
They are hiking boots. Very comfortable.
In 2009 I went to buy Blundstones in Tasmania, where they're from, and no one wanted to sell them to me. Reason: they transferred their manufacturing and Blunnies are now made in Korea. Instead, they steered me to Rossi boots in a similar style. I bought a pair of these (http://www.rossiboots.com.au/catalogue/detail/150-rft/) (or something like them; they have lots of boots in that style and I can't tell the difference between models) and I've been wearing them ever since. best boots ever; they're waterproof, easy to pull on (good for airport security) and comfortable for walking miles and miles. And apparently they are also sold in the US (http://www.rossibootsusa.com/welcome).
How cool! I didn't know NB made hiking boots.
That's an interesting story about the Rossi boots. I'm glad they worked out for you!
I ordered a pair of the Gore-Tex Adrenalines from my local running shop this weekend. They didn't have my size in stock, boo. Two of the salespeople raved about Gore-Tex running shoes and how they are great for accidental puddle-stomping. That's perfect for me! I watch the weather carefully so I know how to dress my kids, but sometimes that information doesn't transfer over to how I dress myself.
New Stability MT20V2 are fantastic. It's what I use for hurdle competitions. They havevibram feet which removes the query of versatility. Offer fantastic hold up dirty mountains also. Merrel-trail safety gloves are also another excellent choice. I've observed a lot of people also using Solomon.
PS I wear mine with Smartwool socks.


text:
Citrus shows spike in interest on Produce Market Guide
Nov 13, 2019 by Amelia Freidline #Produce Retail, #Oranges, #Citrus, #Lemons, #Clementines, #FRUIT, #Apples, #Pomegranates
( Graphic by Amelia Freidline )
Though the holiday season is ramping up and autumnal favorites are still in the mix, searches on Produce Market Guide the week of Nov. 4 showed a marked interest in one of winter's domestic specialties: citrus.
The Produce Market Guide platform connects produce buyers and sellers. Below, find the top 20 searched commodities on Produce Market Guide during the week of Nov. 4.
Oranges maintained their No. 1 status from the previous week, while avocados climbed from No. 8 to No. 2, and apples slid down to the No. 3 spot. Lettuce moved up a place to No. 4, and pomegranates shot up to No. 5 from No. 11 the previous week.
Mandarins and tangerines showed a dramatic gain in interest, going from No. 19 the previous week to No. 7 the week of Nov. 4. Potatoes slipped one spot, to No. 8, while sweet potatoes held steady at No. 9 and cabbage climbed from No. 17 to No. 10.
Lemons maintained their spot at No. 13, while turnips returned to the list at No. 14. The citrus giant pummelo made its first appearance in the top 20 at No. 16, while pears and tomatoes rounded out the top 20.
Move over, pumpkins: Oranges are in on Produce Market Guide
What's hot on Produce Market Guide? Pink pumpkins, cabbage and citrus
Pomegranates on the rise on Produce Market Guide
Produce Retail


Christopher Hitchens – In defense of WWII  | Utopia – you are standing in it!
This entry was posted in defence economics, economics of crime, International law, law and economics, laws of war, war and peace and tagged World War II on April 25, 2018 by Jim Rose.
I am in the other camp.


-50c ~ +70c. 1. wet, 2. comfort, 3. dry, 4. no display. +/- 1 deg.c (-50 - 70 deg.c). Lcd thermometer. Temperature sensor: Meter diode. 100mhz. 14 * 10.5 * 5.2cm / 5.51 * 4.13 * 2.05in. Temperature transmitter. Thermometer battery. Ut81c. Magnification range: Rms m42. Mouth. 0.35x-90x.
Gross weight: Furbis boom. Accuracy class: Gauge dragon. Max. test voltage: 19.50 x 9.20 x 5.50 cm. Wholesale regulator thermostat. Usb port: Prism system: Mdt33d.
Ndir sensor co2. Wholesale 50ml glass syringe. Voltage&water temperature car. Bak4 roof. Rex-c100fk02-m. Wh7016e-220v. 5nf/50nf/500nf/5uf/50uf/100uf. 12v power using. Aa battery. Under water thermometer.


text:
Quality Digest employees work for free. Our offices are donated. We don't pay for electricity.
That's fake news. Real news COSTS. Please turn off your ad blocker for our web site.
Our PROMISE: Our ads will never cover up content.
3D Metrology-CMSC
Videos / Webinars
Back Issues (newer)
Back Issues (older)
Can We Improve Continuous Improvement?
ISO 9001 Documentation Is Like a Box of Chocolates
Profile Projectors Keep Pace With the Digital Age
Advancing Quality Through Visual Thinking
2009 Six Sigma Services and Software Buyers Guide
A Fresh Wind Blows in Alternative Energy
Don't Fail Your Customers With the 5 Whys
First Word
H. James Harrington
Denise Robitaille
Scott Paton
Donald J. Wheeler
Tom Pyzdek
Bretta Kelly | 01/29/2009
Don't worry about the packaging; it's the content you sink your teeth into.
Standards such as ISO 9001 mandate documentation requirements as part of a company's compliance with the standard. Although the requirements are intentionally broad-based and open, many organizations tend to over-document their systems. ISO 9001:2008 requires a manual and six documented procedures. AS9100 requires seven, and ISO 14001 requires one. Yet companies continue to write additional procedures, often for the wrong reasons. Let's end the confusion about implementing a management system vs. documenting one.
A common belief is that the standards' requirements are satisfied if detailed procedures exist to define a system. Additionally, many managers and executives think that a documented procedure for every element in the company results in better control and accountability. Although no requirements are enumerated in these standards for procedure format, more emphasis is placed on this than on the information contained within the procedures.
For example, ISO 9001 requires a documented procedure for controlling a nonconforming product. The standard doesn't describe what the documented procedure should look like, how it should be titled, or even how it should be controlled. ISO 9001 doesn't state that a scope, purpose, reference documents section, or any other type of format is required. The documented procedure can be a flowchart, a one-page instruction sheet, or a 15-page detailed document. It's always the company's choice.
Additionally, the documented system doesn't have to be complicated or overly specific. A company can start with a set of templates to define an ISO quality management system, so long as it's committed to revising these documents to reflect what the company actually does as it evolves.
Stuck on formatting
It's not just companies that tend to over-document. Misinformed consultants and auditors expect to see procedures written in the formal manner described above. This prevailing mindset began 20 years ago, when quality systems started to migrate from older U.S. military requirements to ISO 9001 requirements.
Let's be clear: The objective for documenting a management system is content, not packaging. Unfortunately, some companies think that they can buy a ready-made, documented system and become ISO 9001-compliant, but generic templates simply can't portray every organization's unique system. Companies must assess and document their management systems to reflect their operating processes. It's absurd to think that all companies operate in the same way and can therefore use the same documented management system.
Getting through a third-party audit is difficult when a company doesn't customize or understand its templated system. When the auditor is asking questions, the company representative often struggles to respond because he or she doesn't know where in the system the answer resides. This is never a problem when a company defines its own system.
Some companies are quite proud of their systems. They will give the auditor a 30-page quality manual along with 20 procedures averaging 10 to 15 pages each. The documents are beautifully written, with perfect formatting and spacing. The procedures are revision-controlled and impressive, but once the auditor begins comparing actual processes to the procedures, there's usually a disconnection between the two. Many times these procedures call for specific forms, timelines for completion, and other unnecessary details. Companies often set higher standards than they can maintain. Procedures are often obsolete minutes after they're written and approved.
Registrars estimate that the majority of nonconformances found in external audits are not due to a company's ability to meet a standard's requirement, but rather to the company's inability to meet a requirement in one of its own internal documents. Again, documents must be written to define a process and not simply make it look more impressive. When processes change, procedures must change simultaneously. If a procedure isn't required, it shouldn't exist. There's nothing wrong with training documents, videos, and flow diagrams to illustrate how to conduct a process. Written procedures are often overkill.
What's really happening?
The following true story illustrates these points. A small company implemented a system for compliance to AS9100 using a set of templates that were claimed to meet the aerospace standard's requirements. Its quality manager left the company before the stage-one audit was scheduled, but he told the owner that he went through the templates to make sure it matched the company processes.
The stage-one audit revealed that the company was in no way ready for the audit. None of the employees knew what the documents said or where to find required information. Furthermore, the system wasn't entirely implemented. Company managers threw the templates in the trash and documented a new system from scratch, focusing on what they actually did. The new system was elementary--just the required procedures, a few flowcharts, and a seven-page quality manual. One month later, the company was registered to AS9100 with no findings of nonconformance--a 100-percent score.
This company didn't change anything about how it managed its business. In one month, it went from a failed audit to a perfect score. The only difference was the manner in which the organization documented its processes.
The myth of process templates
The same holds true for companies that use a software program to maintain their management systems.
A set of documents alone doesn't make a company compliant to ISO 9001, and neither does a software package by itself. There's a significant difference between saying, "We use a quality management software system and therefore meet all the requirements of the standard," and "We use software to execute processes more efficiently, track data more effectively, and simplify the overall compliance process."
Another example of an over-documented or inaccurate system is having multiple documents covering the same processes or programs. There's no difference between the continual improvement found in lean programs and in aerospace or ISO standards, for instance. There's only confusion over the terminology, as seen in figure 1, below.
Much of the confusion lies in misunderstanding these different programs. AS9100 and ISO 9001 include internal audits, corrective and preventive action, and many other similar elements. Companies often operate a stand-alone lean program not even referenced in their ISO 9001 or AS9100 documentation. This leads to a mismatch between documented procedures and current processes. It also duplicates efforts that cost additional money for compliance and system maintenance. The same situation exists in other industries, such as having a separate food safety program in the food industry. Similarly stray programs that remain undocumented in management systems often include customs, emergency response, safety and security programs, hazardous material programs, and even separate employee policy manuals.
If a company has spent thousands of dollars and training hours for a lean program, then its ISO 9001 or AS9100 program should reference the training in all areas of continual improvement. Some of the required procedures for ISO 9001 or AS9100 that should include references to lean programs can be seen in figure 2, above.
There's no reason for a company to have separate processes for internal audits, corrective action, or preventive action just to comply to ISO 9001.
Often, a company's ISO 9001 continual improvement processes (e.g., objectives, data analysis, internal audit, management review, and corrective action/preventive action) are prescriptive. Typically, internal audits are scheduled by element or section of the standard and audited once a year. An audit log is maintained, and progress is recorded about the assigned corrective actions. The corrective action reports (CARs) are written up and kept in a CAR log, and preventive action reports (PARs) are documented and logged as well. Other results may be documented on similar forms. During an audit, when asked about preventive actions, the company will report that one preventive action was accomplished in the past year and recorded on the PAR form (which must be used per company procedure). Then the auditor walks down the hallway and sees that eight kaizen events have been accomplished during the past four months, and that more than 20 preventive actions are assigned and accomplished with these events. The company has no idea that these preventive actions "count" as preventive actions in its ISO 9001 system.
A documented process doesn't have to be called an "internal audit" or a "management review." It can be called anything, so long as the company collects and analyzes data, sets and measures objectives, assesses and audits processes and performance, and assigns and carries through with actions.
The following rules should be considered when documenting your management system:
• A written procedure isn't necessary for every process and program. You must write some procedures because they're required, such as an internal audit procedure, but the standard doesn't require you to write a procedure for every type of internal audit or program your company has. One procedure can describe the different processes and programs.
• Don't write a procedure for the sake of writing one. Learn and understand when a procedure is required.
• Don't write a procedure around how you want to do a process or think a process should be done. The procedure should reflect what you actually do.
• Create the documentation in a format that makes the most sense for the process or people using the document. (Don't be afraid of pictures and videos, and don't be afraid to call them "training materials.")
• Don't forget that the majority of audit nonconformances are cited because the procedure didn't reflect the actual process, not because the process didn't comply to the standard.
• If an instruction manual is used for training, it's acceptable to say so. Be specific in saying that it's not a document describing an operational process. In reality, most documented processes exist to train personnel. When personnel are trained and competent in a process, the document loses its importance until new employees are hired.
• Appearance and formatting aren't important. It's content that matters.
For more information about the ISO 9001 standard, see the Quality Digest knowledge guide, "What Is ISO 9001:2015?"
( 1 ) View Comments
Bretta Kelly
Bretta Kelly is the owner/operator of Business Management Systems Consulting LLC (BMSC). Kelly began consulting in 1999, implementing, managing, training, and auditing ISO 1994, ISO 9001:2000, and AS 9100 programs for semiconductor, aerospace, chemical, cosmetic, and distribution companies. Currently Kelly conducts third-party audits for several registrars; she conducts internal audits and facilitates management reviews as well. Kelly also provides seminars for internal process auditing and how to conduct management reviews and set measurable objectives. Kelly holds bachelor's and master's degrees in industrial engineering, and certifications for Exemplar-QMS Lead Auditor, Probitas-AS 9100 Auditor, HACCP, and SQF 1000 and 2000 auditing and expert training.
02/12/2014 - 03:39 am — R Prasanna
ISO DOCUMENTATION..........
Respected ms.Bretta
This ISO documentation part you have covered in-depth.and it was easy to understand for beginers.very nice
Prasanna


text:
Private Clients & Advisers
Reyker
Mark Ford, Adam Stephens and Henry Shinners of Smith & Williamson LLP were appointed Joint Special Administrators ("the JSAs") of Reyker Securities Plc (in special administration) ("Reyker") on 8 October 2019.
For updates on the progress of the Special Administration, together with links to key documents, please refer to the JSAs' dedicated website www.smithandwilliamson.com/reyker-securities-plc.
You can also access more information at www.fscs.org.uk and https://www.fscs.org.uk/failed-firms/reyker-securities/
Fraudulent communications
Given several instances of fraudulent communications seeking advance payments from Clients have been reported, we continue to encourage you to remain vigilant and to exercise caution when dealing with correspondence regarding the Special Administration.
Fraudsters are typically using fake website domain names or email addresses to impersonate Reyker and Smith & Williamson, such as 'clientservices@reyker-securities.co.uk' [please note the differing email suffix] or 'smithandwilliamsoninfo@gmail.com' and may be masking their caller IDs to appear connected to Reyker, Smith & Williamson or other intermediary providers.
We continue to communicate such approaches to the relevant authorities, including the FCA, and ask Clients to remain vigilant to such fraudulent communications.
If you are in any doubt regarding the legitimacy of any communication regarding the special administration, please refer to the information provided on the dedicated webpage or contact client services directly on 0800 048 9512 or, alternatively, by email at clientservices@reyker.com. Further information can also be found at https://www.fca.org.uk/consumers/protect-yourself-scams.
If you have lost money as a result of a scam, you should contact Action Fraud on 0300 123 2040 or visit www.actionfraud.police.uk.
Should you have any queries, the JSAs have a dedicated telephone, website and email address for affected parties. These are:
Email: clientservices@reyker.com
Website: www.smithandwilliamson.com/reyker-securities-plc
Mark Ford, Adam Stephens & Henry Shinners
Joint Special Administrators
The affairs, business and property of Reyker are being managed by the Joint Special Administrators who act as agents of the Company, without personal liability. Mark Ford, Adam Stephens and Henry Shinners are authorised to act as insolvency practitioners by the Institute of Chartered Accountants in England and Wales. Reyker remains authorised and regulated by the Financial Conduct Authority. FCA reference number 115308. Registered in England No. 01747595
AIM IHT
Reyker's AIM IHT Portfolio provides a cost-effective way of mitigating inheritance tax. The portfolio invests in companies listed on the AIM segment of the London Stock Exchange.
Reyker provides access to a wide range of securities from the major stock exchanges across the globe as well as an extensive connectivity to a range of worldwide fund platforms and managers.
Discretionary Fund Management
Our discretionary service is designed for investors who are targeting a real return from their investment, through capital growth or income, and risk is actively managed.
Integrity at our core
Our award-winning, vertically integrated services are carried out in-house, with access to first-hand expertise from our own people.
Reyker Securities Plc (in special administration) ("the Company")
In the High Court of Justice, Business and Property Courts of England and Wales, Insolvency and Companies List, Court Case Number: CR-2019-006671
The affairs, business and property of the Company are being managed by the joint special administrators, Mark Christopher Ford, Adam Henry Stephens, and Henry Anthony Shinners who act as agents of the Company and without personal liability. Details of the licensing bodies for Smith & Williamson insolvency practitioners can be accessed here.
The Fair Processing Notice in relation to the General Data Protection Regulation can be accessed here. Should you wish to be supplied with a hard copy, free of charge, please contact this office.
Reyker Securities Plc was authorised and regulated by the Financial Conduct Authority. FCA registration number: 115308. LSE No. 780
Registered in England, Company number: 01747595. Registered office: 25 Moorgate, London, ECR2R 6AY. Formerly 17 Moorgate, London EC2R 6AR.
EC2R 6AR
E: invest@reyker.com
Reyker Securities plc FCA No. 115308
LSE No. 780. Reg No. 1747595
LEI 213800TWIOR1UEZ6WP12
Reyker Trust & Depositary Services Ltd
FCA No. 613470 Reg No. 8835247
LEI: 213800U1XOHG8RC1YS80
This website is published by Reyker Securities plc which is authorised and regulated by the Financial Conduct Authority No. 115308 and is a member of the London Stock Exchange No. 730. Registered in England and Wales No. 1747595. Reyker is a member of the Financial Services Compensation scheme (FSCS) in respect of eligible investments.
The material and information contained in this website is for general informational purposes only and protected by Copyright. Reyker has taken reasonable steps to ensure that the information herein is accurate, current and in compliance with relevant legislation and regulation and it makes no representation or warranty regarding the accuracy and completeness of this website.
This website is intended for use by residents of the United Kingdom only and is not aimed at residents of any other jurisdiction. Any information published should not be construed as a recommendation to buy or sell any investment, nor any form of investment or taxation advice. If you are a retail investor, some products and services on this website may not be available or suitable for you without financial advice. Capital may be at risk and the value of investments may go down as well as up.
By using our website, you agree to our Website terms and conditions. Please familiarise yourself with our Privacy Policy which governs the way we collect and process your personal data. Reyker's website uses cookies, by using our website, you consent to our use of cookies in accordance with the terms of our Cookies Policy. You can both control and delete our cookies at any time.
By clicking I accept, you acknowledge this notice and accept this disclaimer. If you do not accept these, then please do not continue to use this website.
Please be aware, there is a clone of Reyker targeting people in the UK, claiming to be an authorised firm. Please take care. This clone firm has no affiliation whatsoever with the Reyker group.
I acceptNo


Status: CR A2B1B2bceC1C2b Endemism: Near endemic Threats: Collection, alien plant infestation, road network Distribution: Lebombo (South of Stegi) Grew in a pan, but a road has been developed near the locality. High density area. Used for its medicinal properties. Reported to occur in South Africa.
Reported to occur in South Africa.


Grand Annual Steeplechase-winning jockey Nathan Dunn could think of no better place to train his first winner.
Dunn now prepares a small team on the Mornington Peninsula and was at Warrnambool on Wednesday to saddle Bedroucho in the Idetect Maiden Plate.
Circling the field under Aaron Lynch, Bedroucho, who was backed from $91 to $31 with bookmakers while returning a dividend on more than $74 on the TAB, went on to score a three-quarter length win over Euroman.
Dunn rode Kwila's Quest to victory in the 2004 Grand Annual while in 2010 he was crowned the Warrnambool carnival's leading jumps jockey riding champion jumper Bashboy to two wins in hurdle races and finishing third on Volkswagin in the Grand Annual.
He said to train his first winner, which came at his 12th runner, at the May carnival was special but could not compare to winning the Grand Annual.
"To win a Grand Annual is an amazing feeling so I can't compare the feeling of riding a winner and now training a winner at the carnival," Dunn said.
Dunn said it had been tough going since he retired from riding with pre-training now his main business.
"Switching from being a jumps jockey, to horse breaker, to pre-trainer and now trainer and slowly building up your business has been tough, but worth it," he said.


text:
Christian Krell (* 20. Dezember 1977 in Siegen) ist ein deutscher Politikwissenschaftler und Erwachsenenbildner. Er ist Professor für Politikwissenschaft und Soziologie an der HSPV NRW (Köln) und Honorarprofessor der Rheinischen Friedrich-Wilhelms-Universität Bonn.

Werdegang
Krell studierte von 1997 bis 2003 Soziologie, Politik-, Geschichts- und Wirtschaftswissenschaft an der Universität Siegen und der University of York. Von 1998 bis 2005 war er Stipendiat der Friedrich-Ebert-Stiftung in der Grund- und Graduiertenförderung. Krell promovierte 2006 mit einer Untersuchung der Europapolitik der britischen, deutschen und französischen Sozialdemokratie im Vergleich.

Von 2007 bis 2016 leitete Krell die Akademie für Soziale Demokratie der Friedrich-Ebert-Stiftung und war in dieser Funktion Autor und Herausgeber zahlreicher Lehrbücher. 2014 wurde er in die Grundwertekommission der SPD berufen. Zwischen 2016 und 2018 hatte Christian Krell die Leitung des Nordischen Büros der Friedrich-Ebert-Stiftung mit Sitz in Stockholm und Zuständigkeit für Schweden, Dänemark, Finnland, Island und Norwegen inne. Ein Tätigkeitsschwerpunkt war dabei die vergleichende Wohlfahrtsstaatsforschung.

Im November 2018 wurde Krell an der Hochschule des Bundes für öffentliche Verwaltung zum Professor für Staatsrecht und Politik berufen. Im April 2019 wurde ihm auf Vorschlag der Philosophischen Fakultät an der Rheinischen Friedrich-Wilhelms-Universität Bonn die Bezeichnung Honorarprofessor verliehen. Zuvor war er als Lehrbeauftragter an der Universität Siegen tätig. Zum Oktober 2021 nahm Krell einen Ruf an die HSPV NRW (Köln) an und lehrt dort Politikwissenschaft und Soziologie.

Krell tritt gelegentlich in Medien, wie etwa BBC World, dem Deutschlandfunk und anderen Rundfunkanstalten und Zeitungen zu aktuellen politischen Themen als Experte auf. Darüber hinaus ist Krell als Moderator tätig. In dieser Funktion hat er die Webtalk-Reihe "Rausgeblickt" moderiert. Gesprächspartner von Krell waren dabei unter anderem der französische Ökonom Thomas Piketty, die deutschen Soziologen Andreas Reckwitz und Heinz Bude, die Philosophin und Sozialwissenschaftlerin Lisa Herzog und der Ökonomie-Nobelpreisträger Joseph E. Stiglitz.

Wissenschaftliche Arbeit
Forschungsschwerpunkte sind die Parteienforschung, die Demokratieforschung, die vergleichende Politikwissenschaft, europabezogene Themen sowie Theorie und Praxis Sozialer Demokratie. In diesem Zusammenhang hat Krell zu verschiedenen Akteuren der Ideengeschichte publiziert. Darüber hinaus betrachtet er aktuelle Fragestellungen aus normativer Perspektive, etwa in Beiträgen zur Digitalisierung, zum Grundeinkommen, zum Solidaritätsbegriff oder zu Staatlichkeit im Wandel. Krell ist Vertrauensdozent der Friedrich-Ebert-Stiftung sowie Mitglied der Deutschen Vereinigung für Politikwissenschaft.

Veröffentlichungen (Auswahl)
 Reclaiming Action – Progressive Strategies in times of growing right-wing populism in Denmark, Norway, Sweden and Germany. Herausgegeben mit Henri Möllers und Niklas Ferch (2018). Stockholm, Friedrich-Ebert-Stiftung Nordic Countries. ISBN 978-3-96250-166-2. Online kostenlos verfügbar.
 Gesellschaftliche Spaltung und Soziale Demokratie. Mit Sönke Hollenberg. In: Hartmann, Thomas/Dahm, Jochen / Decker, Frank (Hrsg.): Die Zukunft der Demokratie. Erkämpft. Verteidigt. Gefährdet? (2019) Bonn, S. 58–72.
 Thinkers of Social Democracy. Herausgeber. (2016) Bonn. ISBN 978-3-8012-0482-2.
 Vordenkerinnen und Vordenker der Sozialen Demokratie. Herausgeber. (2015) Bonn. ISBN 978-3-8012-0459-4.
 Werte und Politik. Herausgegeben mit Tobias Mörschel (2015) Wiesbaden. ISBN 978-3-658-06606-2.
 Freiheit, Gerechtigkeit und Solidarität in Zeiten der Digitalisierung. In: Neue Gesellschaft/Frankfurter Hefte (1/2/2015), S. 68–71.
 Die Geschichte der Sozialen Demokratie Mit Michael Reschke und Jochen Dahm. (2013, 3. Auflage) Bonn. ISBN 978-3-86498-233-0.
 Demokratie in Deutschland – Zustand, Herausforderungen, Perspektiven. Herausgegeben mit Tobias Mörschel. (2012) Wiesbaden. ISBN 978-3-531-18582-8.
 Zur wertepolitischen Verortung deutscher Parteien. In: Neue Gesellschaft/Frankfurter Hefte (10/2012), S. 36–40.
 Mehr Gleichheit, mehr Bildung, mehr Europa – Die Demokratiedebatte in Deutschland. In: spw – Zeitschrift für sozialistische Politik und Wirtschaft. (06/2011), S. 13–21.
 Lessons learned? – Was man aus den sozialdemokratischen Reformdiskursen lernen kann. In: Neue Gesellschaft/Frankfurter Hefte (05/2011), S. 77–79.
 Кризис германской социал-демократии: пять причин и способов его преодоления. Социал-демократия в современном мире. Материалы научно-практической конференции "Кризис европейской социал-демократии: причины, формы проявления, пути преодоления". Москва,2010. С. 75-89. (russische Übersetzung von: Die Krise der deutschen Sozialdemokratie – Fünf Ursachen und fünf Handlungsansätze Sozialdemokratie in der modernen Welt. Ergebnisse der Konferenz "Die Krise der europäischen Sozialdemokratie: Ursachen, Erscheinungsformen, Handlungsansätze". Moskau [2010], S. 75–89.)
 Sozialdemokratie und Europa – Die Europapolitik der britischen, deutschen und französischen Sozialdemokratie (2009) Wiesbaden. ISBN 978-53649-8-4.
 Ein Kompass in bewegten Zeiten – Kompetenzvermittlung in der Akademie für Soziale Demokratie. In: Praxis Politische Bildung (04/2008), S. 270–277.
 Laggard or Leader – Der britische Sozialstaat im Spiegel der sozialen Demokratie. In: Meyer, Thomas (2006) (Hrsg.): Praxis der Sozialen Demokratie. Wiesbaden. ISBN 978-3-531-15179-3, S. 130–241.

Weblinks
 Christian Krell auf den Seiten der HSPV NRW
 Christian Krell auf den Seiten der Universität Bonn
 Das Büro der Friedrich-Ebert-Stiftung in Stockholm

Einzelnachweise

Politikwissenschaftler
Person (Köln)
Person (Friedrich-Ebert-Stiftung)
Stipendiat der Friedrich-Ebert-Stiftung
Deutscher
Geboren 1977
Mann

redpajama_set_name: RedPajamaWikipedia


That's a lot of ground to cover. This is my second marriage. I have lived in Texas since 1975. My mom lives with me and my sister Kristen moved here also her senior year in high school, so my whole family is here.
I'll have to think about that and update later. I guess the first thing that comes to mind is all the fun we had traveling to and from the State Championship Game and winning made it even better. Friends, band, choir, the pool, canteen....I could go on and on.
Karen Murphy Jones has a birthday today.
Karen Murphy Jones posted a message.
Happy birthday beverly. Hope you are doing okay. Live in texa . Love the state, but hate the heat!!! Have a great day.
Karen Murphy Jones has left an In Memory comment for Ronald G. Trevino.
Happy birthday, hope u have a wonderful day!
Hey stephanie, happy birthday to you. Hope u have a wonderful day!!!
Happy Birthday - hope your day is wonderful!!!
Karen Murphy Jones posted a message. New comment added.
Sorry I missed your B-day. Hope it was wonderful and that you are well and happy.
Hey Gary, sorry I missed your B-day but better late than never! Hope you had a great day and are doing okay.
Karen Murphy Jones added a comment on Profile.
Happy Birthday Beverly....seems like they come around more and more often. Hope to see you in 2017 for our 50th. Have a wonderful day!
Happy Birthday - hope your day is wonderful!!
Sorry I missed your B-day. Hope it was wonderful!!! Also hope you and yours are good too. Life in Texas is great. Kids and grandkids make it wonderful. Take care.
Happy Birthday Ginger! Hope all is well with you.
Happy Birthday Dennis, hope you have a wonderful day!
Happy Birthday and my best wishes for many more! Hope you have a wonderful day.


text:
Will the Japanese be the first to elevate to space?
By Paul Adams | Published Sep 25, 2008 1:08 AM
A: Not enough to lose sleep over. The space elevator - a permanent structure to economically transport material into space - would extend along a ribbon from an oceanic platform on the equator to an 800-ton counterweight 62,000 miles above the Earth´s surface. Every time the elevator´s âa'¬carâa'¬ ascended with a 15-ton payload, the extended mass would increase the length of an average day by a femtosecond. (It´s the same idea as when a spinning ice-skater puts his arms out to slow down.) Brad Edwards, an expert on the space-elevator concept and president of X-Tech, a developer of high-strength materials, says it´s hardly something to be concerned about. Contemporary events such as melting glaciers (which move millions of tons of water from the poles to the equator) slow down the Earth´s rotation orders of magnitude more than one trip on a space elevator would. Moreover, the elevator would not affect the Earth´s movement around the sun in the slightest. The only real way to significantly hinder the Earth´s rotation would be to deploy approximately 1 percent of its mass. âa'¬You´re talking about launching something that´s roughly the same mass as the moon,âa'¬ Edwards explains. âa'¬That´s just not going to happen.âa'¬. Melissa A. Calderone
Space Elevator
Most of a rocket's fuel is spent blasting through Earth's thick atmosphere and out of the planetâa'¬s strong gravitational field. But here's an alternate strategy for getting payloads up to space: Construct a 62,000-mile-long cable jutting straight out from the equator, hold it in place with centripetal force, then lift satellites and spacecraft out of the atmosphere with a giant freight elevator. One major hang-up: Cable strong enough to support the system does not yet exist, though it could be made from carbon nanotubes. Shown above is "The Climber" which sill carry the payload.
One of the most promising technologies for the aspiring outer-space commuter is the space elevator. The concept, like quite a few others, was pressed into the public imagination by Arthur C. Clarke, who in his 1979 novel The Fountains of Paradise described a incredibly thin, incredibly strong carbon filament with one end anchored on Earth and the other extending up to a satellite in geostationary orbit. Now, a group of Japanese scientists are convinced that they can build a space elevator more quickly and cheaply than has been believed possible.
Such a cable could convey cargo into space very cheaply and easily. Carriages would travel up and down the cable under modest power, not the vast expenditures of energy that are currently needed to send anything into orbit.
Technology has crept closer to making it a reality: we have geostationary satellites, and carbon nanotubes promise to be strong and light enough to form the filament, if they can be produced in sufficient quantity. A space elevator would be tens of thousands of miles long.
A few initiatives already exist to make a space elevator a reality. Elevator:2010 sponsors annual contests; LiftPort promises to have an elevator built by October 27, 2031, and is selling tickets on it, at $25/ounce.
The Japan Space Elevator Association, a new player in the field anticipates that Japan's industrial and research power — "using the technology employed in our bullet trains," according to Association director Yoshio Aoki — will be able to surmount the outstanding obstacles. The carbon fiber, which needs to have 180 times the tensile strength of steel, is currently under development by Japanese textile companies. The total price tag estimated for erecting the elevator is being estimated at just a trillion yen, or about 10 billion dollars.
[Via the Times of London]


text:
Sam Adams Launching Boston Lager In Cans
Starting early this summer, Samuel Adams Boston Lager will be available in cans for the first time, the brewer has announced.
Jim Koch, founder and brewer of Samuel Adams, said that the debate over bottles versus cans has been a "sticking point" for brewers in the craft beer industry for years -- but Sam Adams believes that it's designed a can that "provides a slight but noticeably better drinking experience than the standard beer can."
To create the new "Sam Can," Koch and other Sam Adams brewers worked with Ball Corp. for two years, conducting ergonomic and sensory research and testing. The position of the can's opening and its wider lid "naturally opens up the mouth, allowing for more air flow" and positioning the drinker's nose closer to the hop aromas of the beer, thereby enhancing the overall sensory experience, according to the brewer.
The can -- representing a $1 million investment in equipment and research -- was developed to provide the brand's fans with "the best possible Boston Lager drinking experience" in circumstances where bottles are inconvenient or not allowed, the company explained.
The canned lager will be sold in 12-packs nationwide, for a suggested retail of $14.99 to $17.99.
beverages, packaging
Ivonne Kinser - Avocados From Mexico, Head of Digital marketing
Montage Enlists E! News Host For Effort Focusing On Kids


For a lot of reasons 2017 was a pretty tough year. Picture proof included below.
2018 however has been fantastic (although West Ham still struggle). I was promoted at work (maybe not such a great thing for my writing) and my family has been going from strength to strength.
Writing wise, after much thought, I released my debut novel. I'm extremely happy to report that sending The Game Bird out into the wild has been insanely rewarding.
It's scored some incredibly generous reviews.
It was long-listed for BookNest best fantasy debut novel.
It was selected as a SPFBO Qwillery semifinalist.
But most of all PEOPLE BOUGHT the thing. In a world full of fantastic books – many of which are free – people put down their hard earned cash (and time) to read the thing.
If you're someone who has or will or might read The Game Bird, all I can say is thank you. It's an amazing buzz and you really made 2018 for me.
Well, The Game Bird has now been out and about for a month and a half.
It's been a pretty amazing time. The book has been selling better than I expected, and has even been getting some nice reviews on Amazon and goodreads – which is very pleasing! (Not that I was stressed of course. Haha, not at all. Definitely not).
The Game Bird is a swashbuckling, stand-alone tale of high adventure and romance, set in a beautifully realised world. Walsh's writing is rich in history and lore, which he uses to masterfully colour his world – never once letting the details overwhelm the story and to present us with vivid characters that leap off the page and into your heart.
To say I was incredibly pleased would be quite the understatement.
Mark has also subsequently interviewed me on the subjects of life and writing and things. If you're interested, you can find the interview here.
This was the first piece of my writing that did well, so it has a special place in my heart.
I entered it into the Conflux 9 (2013 Natcon) short story competition and was lucky enough to win first prize (and a very generous $500!). The writing prompt for the competition was 'angels, junk and steam'.
The work was subsequently republished in the Novascapes anthology.


text:
Covid-resistant people point way to universal coronavirus vaccine
Health 10 November 2021
By Michael Le Page
Illustration of a T cell targeting SARS-CoV-2 particles
JUAN GAERTNER/SCIENCE PHOTO LIBRARY
Many groups worldwide are trying to develop vaccines that protect against a wide range of coronaviruses and prevent another pandemic. These efforts have now been boosted by the discovery that some healthcare workers had pre-existing immunity to the SARS-CoV-2 virus during the first wave of the pandemic.
During the first half of 2020, around 700 healthcare workers in the UK were tested weekly as part of a crowdfunded study called COVIDsortium. Most of these people, who wore protective equipment, never tested positive for covid-19 in PCR tests or developed covid-19 antibodies – proteins that bind to the outside of viruses, preventing cells from being infected.
However, when Leo Swadling and Mala Maini at University College London and their colleagues looked more closely, they found some of those who tested negative had a protein in their blood that is linked to covid-19 infection, as well as T cell responses to the SARS-CoV-2 virus. T cells are part of the immune system. It appears these people had what Swadling calls an "abortive infection", where a strong, early T cell response enabled them to get rid of the virus very quickly.
Cells infected by viruses sound the alarm by displaying viral proteins on their surface, and T cells are the immune cells that learn to recognise these proteins and destroy infected cells. Crucially, while antibodies can only target proteins on the outside of a virus, T cells can learn to recognise any viral proteins.
When the team looked at early blood samples from the people who had an abortive infection, they found that even before being exposed to SARS-CoV-2, they had some T cells that could recognise the proteins that this virus uses to replicate itself inside infected cells.
The most likely explanation is that these people were often exposed to the existing human coronaviruses that cause around 10 per cent of colds, says Maini. "We don't know the historic infections of these individuals, so we don't know for sure where the T cells are coming from," she says.
Preventing another pandemic
The proteins involved in viral replication are very similar in SARS-CoV-2 and other human and animal coronaviruses, meaning that if vaccines can be developed that elicit a strong T cell response against these proteins, they should protect against a very broad range of coronaviruses – a so-called universal or pan-coronavirus vaccine. One way to do this would be to add mRNAs coding for these proteins to mRNA vaccines that target the virus's external spike protein.
Adding extra components to the next generation of coronavirus vaccines might protect both against any new variants that might evolve and against animal coronaviruses that could jump into people and spark a new pandemic, says Swadling. "There is a strong rationale for adding these proteins alongside the spike protein," he says.
Many groups are already trying to develop coronavirus vaccines that provide broader protection, says Olga Pleguezuelos at UK-based company SEEK. Her team has already created such a vaccine based on the most conserved parts of coronavirus proteins. "It's a matter of time before another of these members [of the coronavirus family] creates an epidemic or pandemic," she says. "If we end up with something that is as infectious as covid and as lethal as MERS, then we are in serious trouble."
However, it isn't clear how effective a vaccine that only produces a T cell response would be, Maini says. Most vaccines work by stimulating an antibody response, though many do also produce a T cell response.
Many groups are developing universal flu vaccines based on eliciting a T cell response, but so far these haven't proved highly effective. Other teams are instead focusing on getting antibodies to target parts of the outer viral proteins of the flu virus that don't mutate. However, this won't work with coronaviruses, says Peter Palese at the Icahn School of Medicine at Mount Sinai in New York. "They just don't have a conserved region."
Journal reference: Nature, DOI: 10.1038/s41586-021-04186-8
ChatGPT can find and fix bugs in computer code
Magazine issue 3361 , published 20 November 2021
Having impostor syndrome may actually make you better at your job
Psilocybin therapy steps closer to credibility with largest trial yet
Scientists are getting to grips with the real effect that social distancing during the covid-19 lockdowns had on babies' and young people's immunity