Identifying therapeutic weak spots in cancer using network analysis

Mathematical network analysis has been proven to be a useful and powerful tool for biological networks including networks of protein interactions, gene similarity and metabolic interactions. Here I use network analysis to model human cancer and predict which genes or reactions are essential for cancer to allow it to grow or recovery from stress. A general assumption for biological networks is that the centrality of a node is in some way reflective of its biological importance. So I evaluated a wide range of weighted and unweighted node centralities and measures derived from centralities to predict reaction essentiality in metabolic networks. The metabolic networks are Mass Flow Graphs (MFGs), based on the Recon2 reconstruction of human metabolism and constrains on reaction fluxes from the PRIME algorithm. The edge weights in the networks are computed from Flux Balance Analysis (FBA) results in a selection of human cancer cell lines from NCI-60. I could not detect a direct connection between node essentiality and any centrality, but there is a correlation between the overall change of the centrality distribution in the inhibited condition compared to wild type and the inhibited reaction essentiality. With this I have found a promising network measure that can be used to predict possible drug targets. With MFGs a wide range of cellular conditions can be modelled, but only when we know what the cellular objective for FBA is. When cancer cells are put under stress through treatment, they adapt their metabolism to react to the stress. This dynamic process with fluctuating gene expression is difficult to capture in a metabolic network. A better way to analyse the recovery process is to extract which genes are active during which phase. I evaluated seven time points of gene expression data for multiple myeloma cells that were treated with a proteasome inhibitor (PI), which disrupts the protein recycling process. From the pairwise gene expression similarity I constructed network to cluster the genes into groups that are active at the same time. The networks were clustered with a random walk algorithm called Markov Stability and evaluated with gene enrichment analysis. From the resulting clusters, collaborators were able to extract tRNAs that activate a protein called GCN2 that is essential for recovery. Followup experiments showed that a combination of PI and GCN2 is lethal for multiple myeloma as well as a few other cancer cells.Open Acces

Opportunities at the interface of network science and metabolic modeling

Metabolism plays a central role in cell physiology because it provides the molecular machinery for growth. At the genome-scale, metabolism is made up of thousands of reactions interacting with one another. Untangling this complexity is key to understand how cells respond to genetic, environmental, or therapeutic perturbations. Here we discuss the roles of two complementary strategies for the analysis of genome-scale metabolic models: Flux Balance Analysis (FBA) and network science. While FBA estimates metabolic flux on the basis of an optimization principle, network approaches reveal emergent properties of the global metabolic connectivity. We highlight how the integration of both approaches promises to deliver insights on the structure and function of metabolic systems with wide-ranging implications in discovery science, precision medicine and industrial biotechnology

ALEMÃES VS BRASILEIROS EM NO TEMPO DAS TANGERINAS: A IDENTIDADE EM QUESTÂO

O presente trabalho visa analisar a constituição da identidade e diferença no contexto da representação da imigração alemã em Santa Catarina no romance No tempo das tangerinas (1983), de Urda A. Klueger. O trabalho apresenta, inicialmente, alguns apontamentos teóricos sobre o assunto em questão, com base, principalmente, no pensamento de pesquisadores dos Estudos Culturais: Tomaz Tadeu da Silva, Kathryn Woodward e Stuart Hall. Segue-se a análise do romance, na qual se evidencia como, no contexto de uma comunidade de imigrantes alemães, as diferenças se constituem tanto através da comparação entre indivíduos pertencentes à própria comunidade imigrante, como com respeito aos não alemães com quem estes entram em contato. Diferenças existem, e são necessárias para a constituição identitária dos sujeitos; ressalta-se a capacidade de lidar com essas diferenças e as relações de poder que instauram e motivam a hierarquização entre um indivíduo ou comunidade e seus outros

The Tumor Suppressor HHEX Inhibits Axon Growth when Prematurely Expressed in Developing Central Nervous System Neurons

Neurons in the embryonic and peripheral nervoussystem respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments are focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present only in trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension

A small viral potassium ion channel with an inherent inward rectification

Some algal viruses have coding sequences for proteins with structural and functional characteristics of pore modules of complex K+ channels. Here we exploit the structural diversity among these channel orthologs to discover new basic principles of structure/function correlates in K+ channels. The analysis of three similar K+ channels with ≤ 86 amino acids (AA) shows that one channel (Kmpv1) generates an ohmic conductance in HEK293 cells while the other two (KmpvSP1, KmpvPL1) exhibit typical features of canonical Kir channels. Like Kir channels, the rectification of the viral channels is a function of the K+ driving force. Reconstitution of KmpvSP1 and KmpvPL1 in planar lipid bilayers showed rapid channel fluctuations only at voltages negative of the K+ reversal voltage. This rectification was maintained in KCl buffer with 1 mM EDTA, which excludes blocking cations as the source of rectification. This means that rectification of the viral channels must be an inherent property of the channel. The structural basis for rectification was investigated by a chimera between rectifying and non-rectifying channels as well as point mutations making the rectifier similar to the ohmic conducting channel. The results of these experiments exclude the pore with pore helix and selectivity filter as playing a role in rectification. The insensitivity of the rectifier to point mutations suggests that tertiary or quaternary structural interactions between the transmembrane domains are responsible for this type of gating

The physical oceanography of the transport of floating marine debris

Marine plastic debris floating on the ocean surface is a major environmental problem. However, its distribution in the ocean is poorly mapped, and most of the plastic waste estimated to have entered the ocean from land is unaccounted for. Better understanding of how plastic debris is transported from coastal and marine sources is crucial to quantify and close the global inventory of marine plastics, which in turn represents critical information for mitigation or policy strategies. At the same time, plastic is a unique tracer that provides an opportunity to learn more about the physics and dynamics of our ocean across multiple scales, from the Ekman convergence in basin-scale gyres to individual waves in the surfzone. In this review, we comprehensively discuss what is known about the different processes that govern the transport of floating marine plastic debris in both the open ocean and the coastal zones, based on the published literature and referring to insights from neighbouring fields such as oil spill dispersion, marine safety recovery, plankton connectivity, and others. We discuss how measurements of marine plastics (both in situ and in the laboratory), remote sensing, and numerical simulations can elucidate these processes and their interactions across spatio-temporal scales

Tissue-specific regulatory network extractor (TS-REX): a database and software resource for the tissue and cell type-specific investigation of transcription factor-gene networks

The prediction of transcription factor binding sites in genomic sequences is in principle very useful to identify upstream regulatory factors. However, when applying this concept to genomes of multicellular organisms such as mammals, one has to deal with a large number of false positive predictions since many transcription factor genes are only expressed in specific tissues or cell types. We developed TS-REX, a database/software system that supports the analysis of tissue and cell type-specific transcription factor-gene networks based on expressed sequence tag abundance of transcription factor-encoding genes in UniGene EST libraries. The use of expression levels of transcription factor-encoding genes according to hierarchical anatomical classifications covering different tissues and cell types makes it possible to filter out irrelevant binding site predictions and to identify candidates of potential functional importance for further experimental testing. TS-REX covers ESTs from H. sapiens and M. musculus, and allows the characterization of both presence and specificity of transcription factors in user-specified tissues or cell types. The software allows users to interactively visualize transcription factor-gene networks, as well as to export data for further processing. TS-REX was applied to predict regulators of Polycomb group genes in six human tumor tissues and in human embryonic stem cells

Linking disaster risk reduction, climate change, and the sustainable development goals

PURPOSE: The purpose of this paper is to better link the parallel processes yielding international agreements on climate change, disaster risk reduction, and sustainable development. DESIGN/METHODOLOGY/APPROACH: This paper explores how the Paris Agreement for climate change relates to disaster risk reduction and sustainable development, demonstrating too much separation amongst the topics. A resolution is provided through placing climate change within wider disaster risk reduction and sustainable development contexts. FINDINGS: No reason exists for climate change to be separated from wider disaster risk reduction and sustainable development processes. RESEARCH LIMITATIONS/IMPLICATIONS: Based on the research, a conceptual approach for policy and practice is provided. Due to entrenched territory, the research approach is unlikely to be implemented. ORIGINALITY/VALUE: Using a scientific basis to propose an ending for the silos separating international processes for climate change, disaster risk reduction, and sustainable development