Mining SOM expression portraits: Feature selection and integrating concepts of molecular function

Background: 
Self organizing maps (SOM) enable the straightforward portraying of high-dimensional data of large sample collections in terms of sample-specific images. The analysis of their texture provides so-called spot-clusters of co-expressed genes which require subsequent significance filtering and functional interpretation. We address feature selection in terms of the gene ranking problem and the interpretation of the obtained spot-related lists using concepts of molecular function.

Results: 
Different expression scores based either on simple fold change-measures or on regularized Students t-statistics are applied to spot-related gene lists and compared with special emphasis on the error characteristics of microarray expression data. The spot-clusters are analyzed using different methods of gene set enrichment analysis with the focus on overexpression and/or overrepresentation of predefined sets of genes. Metagene-related overrepresentation of selected gene sets was mapped into the SOM images to assign gene function to different regions. Alternatively we estimated set-related overexpression profiles over all samples studied using a gene set enrichment score. It was also applied to the spot-clusters to generate lists of enriched gene sets. We used the tissue body index data set, a collection of expression data of human tissues, as an illustrative example. We found that tissue related spots typically contain enriched populations of gene sets well corresponding to molecular processes in the respective tissues. In addition, we display special sets of housekeeping and of consistently weak and highly expressed genes using SOM data filtering. 

Conclusions:
The presented methods allow the comprehensive downstream analysis of SOM-transformed expression data in terms of cluster-related gene lists and enriched gene sets for functional interpretation. SOM clustering implies the ability to define either new gene sets using selected SOM spots or to verify and/or to amend existing ones

Expression cartography of human tissues using self organizing maps

Background: The availability of parallel, high-throughput microarray and sequencing experiments poses a challenge how to best arrange and to analyze the obtained heap of multidimensional data in a concerted way. Self organizing maps (SOM), a machine learning method, enables the parallel sample- and gene-centered view on the data combined with strong visualization and second-level analysis capabilities. The paper addresses aspects of the method with practical impact in the context of expression analysis of complex data sets.
Results: The method was applied to generate a SOM characterizing the whole genome expression profiles of 67 healthy human tissues selected from ten tissue categories (adipose, endocrine, homeostasis, digestion, exocrine, epithelium, sexual reproduction, muscle, immune system and nervous tissues). SOM mapping reduces the dimension of expression data from ten thousands of genes to a few thousands of metagenes where each metagene acts as representative of a minicluster of co-regulated single genes. Tissue-specific and common properties shared between groups of tissues emerge as a handful of localized spots in the tissue maps collecting groups of co-regulated and co-expressed metagenes. The functional context of the spots was discovered using overrepresentation analysis with respect to pre-defined gene sets of known functional impact. We found that tissue related spots typically contain enriched populations of gene sets well corresponding to molecular processes in the respective tissues. Analysis techniques normally used at the gene-level such as two-way hierarchical clustering provide a better signal-to-noise ratio and a better representativeness of the method if applied to the metagenes. Metagene-based clustering analyses aggregate the tissues into essentially three clusters containing nervous, immune system and the remaining tissues. 
Conclusions: The global view on the behavior of a few well-defined modules of correlated and differentially expressed genes is more intuitive and more informative than the separate discovery of the expression levels of hundreds or thousands of individual genes. The metagene approach is less sensitive to a priori selection of genes. It can detect a coordinated expression pattern whose components would not pass single-gene significance thresholds and it is able to extract context-dependent patterns of gene expression in complex data sets.
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In Search of Humble Leaders

The significance of moderation and balance across various domains has been sanctioned for millennia and deviations from midpoints of virtues, traits, qualities, and other attributes have been described as dysfunctional suggesting a nonmonotonic, U-shaped curve. Modern scholarship and lay interpretations of the virtue of humility have neglected this perspective and appear to tacitly assume that humility is an unmitigated good that leaders should develop and that more is better. Here we show, however, that what we refer to as authentic humility, is positioned at an intermediate point between negative and positive views of the self and that deviations from this center adversely impact well-being and offer a nonlinear, inverted U-shaped curve. Such an interpretation reconciles views of humility as a weakness or strength and demonstrates its positive impact on self, followers, and organizational well-being. We conclude by suggesting that humility has costs for leaders and therefore not an unmitigated good.&nbsp

Oxidation is an underappreciated post-translational modification in the regulation of immune responses associated with changes in phosphorylation

Although macrophages are known to be affected by their redox status, oxidation is not yet a well-recognized post-translational modification (PTM) in regulating macrophages and immune cells in general. While it has been described that the redox status of single cysteines in specific proteins is relevant for macrophage functions, global oxidation information is scarce. Hence, we globally assessed the impact of oxidation on macrophage activation using untargeted proteomics and PTM-omics. We exposed THP-1 macrophages to lipopolysaccharide (LPS) for 4 h and 24 h and applied a sequential iodoTMT labeling approach to get information on overall oxidation as well as reversible oxidation of cysteines. Thus, we identified 10452 oxidation sites, which were integratively analyzed with 5057 proteins and 7148 phosphorylation sites to investigate their co-occurance with other omics layers. Based on this integrative analysis, we found significant upregulation of several immune-related pathways, e.g. toll-like receptor 4 (TLR4) signaling, for which 19 proteins, 7 phosphorylation sites, and 39 oxidation sites were significantly affected, highlighting the relevance of oxidations in TLR4-induced macrophage activation. Co-regulation of oxidation and phosphorylation was observed, as evidenced by multiply modified proteins related to inflammatory pathways. Additionally, we observed time-dependent effects, with differences in the dynamics of oxidation sites compared to proteins and phosphorylation sites. Overall, this study highlights the importance of oxidation in regulating inflammatory processes and provides a method that can be readily applied to study the cellular redoxome globally

How managers use the Stockdale Paradox to balance “the now and the next”

Recent discussions of leadership paradoxes have suggested that managers who can hold seemingly opposed, yet interrelated perspectives, are more adaptive and effective. One such paradox that has received relatively little attention is the “Stockdale Paradox,” named after Admiral James Stockdale, an American naval officer who was held captive for seven and one-half years during the Vietnam War and survived imprisonment in large part because he held beliefs of optimism about the future, while simultaneously acknowledging the current reality of the desperate situation in which he found himself. This contradictory tension enabled him and his followers to emerge from their situation not just unbroken, but stronger. Such paradoxical thinking has been empirically supported by mental contrasting research demonstrating the effectiveness of visualizing a positive future yet recognizing the reality of the current situation. This apparent dichotomy provides an important lesson for leaders who must remain optimistic, yet face the reality of their present condition, and is symbolic of an overarching, general tension leaders face in addressing “the now and the next.

Never Underestimate the Power of a Backhoe: Integrating Single Points of Failure into Strategic Planning

SWOT (strengths, weaknesses, opportunities, threats) analysis is probably used more often than any other management technique in strategic decision making. There appears to be a greater emphasis, however, on identifying strengths and opportunities while weaknesses and threats are examined less closely. Such bias may be problematic because firms may overlook single points of failure (SPOFs), which are elements that, upon malfunction, render an entire system unavailable or unreliable. These threats and weaknesses are most often presented in information technology and engineering discussions of equipment, machine, and device breakdowns, but may have applicability in a number of other areas important to organizations including people; materials and supplies; methods and processes; and shock events—natural and human-made disasters. To be resilient in today’s 24-7, 365 days a year global business world, it is critical that organizations effectively anticipate, evaluate, prepare for, and mitigate SPOF risks that can have a seriously negative impact on a firm’s performance. The paper concludes with a three-step approach to help managers reduce and effectively respond to SPOFs. Companies that integrate the concept of SPOFs into their strategic planning could develop high-impact management skill, leading to improved corporate profitability

Influence of formic acid treatment on the proteome of the ectoparasite Varroa destructor

The ectoparasite Varroa destructor Anderson and Trueman is the most important parasites of the western honey bee, Apis mellifera L. The most widely currently used treatment uses formic acid (FA), but the understanding of its effects on V. destructor is limited. In order to understand the mechanism of action of FA, its effect on Varroa mites was investigated using proteomic analysis by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). V. destructor was collected from honey bee colonies with natural mite infestation before and 24 h after the initiation of FA treatment and subjected to proteome analysis. A total of 2637 proteins were identified. Quantitative analysis of differentially expressed candidate proteins (fold change ≥ 1.5; p ≤ 0.05) revealed 205 differentially expressed proteins: 91 were induced and 114 repressed in the FA-treated group compared to the untreated control group. Impaired protein synthesis accompanied by increased protein and amino acid degradation suggest an imbalance in proteostasis. Signs of oxidative stress included significant dysregulation of candidate proteins of mitochondrial cellular respiration, increased endocytosis, and induction of heat shock proteins. Furthermore, an increased concentration of several candidate proteins associated with detoxification was observed. These results suggest dysregulated cellular respiration triggered by FA treatment as well as an increase in cellular defense mechanisms, including induced heat shock proteins and detoxification enzymes

Relationship between sources and patterns of VOCs in indoor air

AbstractPeople spend most of their daytime in indoor environments. Their activities influence the composition of the indoor air by emitting volatile organic compounds (VOCs). The increasing number of different VOCs became the focus of attention in recent years as the question arises from the relationship between exposure to air pollutants and diseases. The present study of flats in Leipzig (Germany) is based on measurements of 60 different VOCs and is unique in the field of indoor air quality due to its enormous size of samples (n=2 242) and questionnaire data. The main purpose of our analysis was to identify the sources and patterns that characterize airborne VOCs in occupied flats. We combined two methods, principal components analysis (PCA) and non–negative matrix factorization (NMF), to assign compounds to their origin and to understand the coinstantaneous existence of several VOCs. PCA clustering provided a source apportionment and yielded 10 principal components (PCs) with an explained variance of 72%. However, real indoor air quality is often affected by combined sources. NMF reveals characteristic compositions of VOCs in indoor environments and emphasizes that constantly recurring structures are not single sources, but rather fusions of them, so called patterns. Interpreting these sources, we realized that homes were strongly influenced by ventilation, human activities, furnishings, natural processes (such as solar radiation) or their combinations. The very large set of samples and the combination with questionnaires applied on this comprehensive assessment of VOCs allows generalizing the results to homes in middle–scale cities with minor industrial pollution. As a conclusion, single VOC–dose–response relationships are inopportune for situations when indoor sources occur in combination. Further studies are necessary to assess associated health risks

Non-Genomic AhR-Signaling Modulates the Immune Response in Endotoxin-Activated Macrophages After Activation by the Environmental Stressor BaP

Emerging studies revealed that the Aryl hydrocarbon receptor (AhR), a receptor sensing environmental contaminants, is executing an immunomodulatory function. However, it is an open question to which extent this is achieved by its role as a transcription factor or via non-genomic signaling. We utilized a multi-post-translational modification-omics approach to examine non-genomic AhR-signaling after activation with endogenous (FICZ) or exogenous (BaP) ligand in endotoxin-activated (LPS) monocyte-derived macrophages. While AhR activation affected abundances of few proteins, regulation of ubiquitination and phosphorylation were highly pronounced. Although the number and strength of effects depended on the applied AhR-ligand, both ligands increased ubiquitination of Rac1, which participates in PI3K/AKT-pathway-dependent macrophage activation, resulting in a pro-inflammatory phenotype. In contrast, cotreatment with ligand and LPS revealed a decreased AKT activity mediating an antiinflammatory effect. Thus, our data show an immunomodulatory effect of AhR activation through a Rac1ubiquitination-dependent mechanism that attenuated AKT-signaling, resulting in a mitigated inflammatory response

Effects of Five Substances with Different Modes of Action on Cathepsin H, C and L Activities in Zebrafish Embryos

Cathepsins have been proposed as biomarkers of chemical exposure in the zebrafish embryo model but it is unclear whether they can also be used to detect sublethal stress. The present study evaluates three cathepsin types as candidate biomarkers in zebrafish embryos. In addition to other functions, cathepsins are also involved in yolk lysosomal processes for the internal nutrition of embryos of oviparous animals until external feeding starts. The baseline enzyme activity of cathepsin types H, C and L during the embryonic development of zebrafish in the first 96 h post fertilisation was studied. Secondly, the effect of leupeptin, a known cathepsin inhibitor, and four embryotoxic xenobiotic compounds with different modes of action (phenanthrene—baseline toxicity; rotenone—an inhibitor of electron transport chain in mitochondria; DNOC (Dinitro-ortho-cresol)—an inhibitor of ATP synthesis; and tebuconazole—a sterol biosynthesis inhibitor) on in vivo cathepsin H, C and L total activities have been tested. The positive control leupeptin showed effects on cathepsin L at a 20-fold lower concentration compared to the respective LC50 (0.4 mM) of the zebrafish embryo assay (FET). The observed effects on the enzyme activity of the four other xenobiotics were not or just slightly more sensitive (factor of 1.5 to 3), but the differences did not reach statistical significance. Results of this study indicate that the analysed cathepsins are not susceptible to toxins other than the known peptide-like inhibitors. However, specific cathepsin inhibitors might be identified using the zebrafish embryo