The lag-phase during diauxic growth is a trade-off between fast adaptation and high growth rate

Bi-phasic or diauxic growth is often observed when microbes are grown in a chemically defined medium containing two sugars (for example glucose and lactose). Typically, the two growth stages are separated by an often lengthy phase of arrested growth, the so-called lag-phase. Diauxic growth is usually interpreted as an adaptation to maximise population growth in multi-nutrient environments. However, the lag-phase implies a substantial loss of growth during the switch-over. It therefore remains unexplained why the lag-phase is adaptive. Here we show by means of a stochastic simulation model based on the bacterial PTS system that it is not possible to shorten the lag-phase without incurring a permanent growth-penalty. Mechanistically, this is due to the inherent and well established limitations of biological sensors to operate efficiently at a given resource cost. Hence, there is a trade-off between lost growth during the diauxic switch and the long-term growth potential of the cell. Using simulated evolution we predict that the lag-phase will evolve depending on the distribution of conditions experienced during adaptation. In environments where switching is less frequently required, the lag-phase will evolve to be longer whereas, in frequently changing environments, the lag-phase will evolve to be shorter

On the Peripheries of Planetary Urbanization: Globalizing Manaus and its Expanding Impact

In this paper I argue that global urbanism produces peripherality in ways that cannot be adequately problematized without taking into account its actual extent and geographically uneven development. Therefore, planetary urbanization needs to engage scholarly traditions attuned to regional urbanization if the discourse is to move past limitations in the urban globalization canon and its narrow focus on cities. To that end, I examine research on extensive urbanization in the Amazon region. Illustrative case studies show how attempts to globalize Manaus precipitated territorial restructuring and sociospatial change far beyond the city's boundaries. Manaus is now a more unequal city. Selective metropolitan expansion to the Rio Negro's south bank has led to the simultaneous upgrading and peripheralization of Iranduba. Yet, the building of a city-centric regional network of roadways also shaped Roraima State's transformation from isolated borderland to bypassed periphery. Moreover, financial and symbolic appropriations of standing rainforests by metropolitan conservationism marginalize remote communities even in the absence of exploitative deforestation and resource extraction. Final remarks emphasize the need for further research on the hybrid (urban—rural) conditions and functional articulations of distant-yet-impacted peripheries. Such efforts may broaden the political horizons of planetary urbanization by informing extensive contestations of entrepreneurial urbanism

(Dis)entangling Barad: Materialisms and ethics

In the wake of the widespread uptake of and debate surrounding the work of Karen Barad, this article revisits her core conceptual contributions. We offer descriptions, elaborations, problematizations and provocations for those intrigued by or invested in this body of work. We examine Barad’s use of quantum physics, which underpins her conception of the material world. We discuss the political strengths of this position but also note tensions associated with applying quantum physics to phenomena at macro-scales. We identify both frictions and unacknowledged affinities with science and technology studies in Barad’s critique of reflexivity and her concept of diffraction. We flesh out Barad’s overarching position of ‘agential realism’, which contains a revised understanding of scientific apparatuses. Building upon these discussions, we argue that inherent in agential realism is both an ethics of inclusion and an ethics of exclusion. Existing research has, however, frequently emphasized entanglement and inclusion to the detriment of foreclosure and exclusion. Nonetheless, we contend that it is in the potential for an ethics of exclusion that Barad’s work could be of greatest utility within science and technology studies and beyond

Histone deacetylase inhibition results in a common metabolic profile associated with HT29 differentiation

Cell differentiation is an orderly process that begins with modifications in gene expression. This process is regulated by the acetylation state of histones. Removal of the acetyl groups of histones by specific enzymes (histone deacetylases, HDAC) usually downregulates expression of genes that can cause cells to differentiate, and pharmacological inhibitors of these enzymes have been shown to induce differentiation in several colon cancer cell lines. Butyrate at high (mM) concentration is both a precursor for acetyl-CoA and a known HDAC inhibitor that induces cell differentiation in colon cells. The dual role of butyrate raises the question whether its effects on HT29 cell differentiation are due to butyrate metabolism or to its HDAC inhibitor activity. To distinguish between these two possibilities, we used a tracer-based metabolomics approach to compare the metabolic changes induced by two different types of HDAC inhibitors (butyrate and the non-metabolic agent trichostatin A) and those induced by other acetyl-CoA precursors that do not inhibit HDAC (caprylic and capric acids). [1,2-13C2]-d-glucose was used as a tracer and its redistribution among metabolic intermediates was measured to estimate the contribution of glycolysis, the pentose phosphate pathway and the Krebs cycle to the metabolic profile of HT29 cells under the different treatments. The results demonstrate that both HDAC inhibitors (trichostatin A and butyrate) induce a common metabolic profile that is associated with histone deacetylase inhibition and differentiation of HT29 cells whereas the metabolic effects of acetyl-CoA precursors are different from those of butyrate. The experimental findings support the concept of crosstalk between metabolic and cell signalling events, and provide an experimental approach for the rational design of new combined therapies that exploit the potential synergism between metabolic adaptation and cell differentiation processes through modification of HDAC activity

Discovery of High-Affinity Protein Binding Ligands – Backwards

BACKGROUND: There is a pressing need for high-affinity protein binding ligands for all proteins in the human and other proteomes. Numerous groups are working to develop protein binding ligands but most approaches develop ligands using the same strategy in which a large library of structured ligands is screened against a protein target to identify a high-affinity ligand for the target. While this methodology generates high-affinity ligands for the target, it is generally an iterative process that can be difficult to adapt for the generation of ligands for large numbers of proteins. METHODOLOGY/PRINCIPAL FINDINGS: We have developed a class of peptide-based protein ligands, called synbodies, which allow this process to be run backwards--i.e. make a synbody and then screen it against a library of proteins to discover the target. By screening a synbody against an array of 8,000 human proteins, we can identify which protein in the library binds the synbody with high affinity. We used this method to develop a high-affinity synbody that specifically binds AKT1 with a K(d)<5 nM. It was found that the peptides that compose the synbody bind AKT1 with low micromolar affinity, implying that the affinity and specificity is a product of the bivalent interaction of the synbody with AKT1. We developed a synbody for another protein, ABL1 using the same method. CONCLUSIONS/SIGNIFICANCE: This method delivered a high-affinity ligand for a target protein in a single discovery step. This is in contrast to other techniques that require subsequent rounds of mutational improvement to yield nanomolar ligands. As this technique is easily scalable, we believe that it could be possible to develop ligands to all the proteins in any proteome using this approach

Notch signaling in glioblastoma: a developmental drug target?

Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM) features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches

Membrane Cholesterol Regulates Lysosome-Plasma Membrane Fusion Events and Modulates Trypanosoma cruzi Invasion of Host Cells

Trypanosoma cruzi, is the etiological agent of a neglected tropical malady known as Chagas' disease, which affects about 8 million people in Latin America. 30–40% of affected individuals develop a symptomatic chronic infection, with cardiomyopathy being the most prevalent condition. T. cruzi utilizes an interesting strategy for entering cells: T. cruzi enhances intracellular calcium levels, which in turn trigger the exocytosis of lysosomal contents. Lysosomes then donate their membrane for the formation of the parasitophorous vacuole. Membrane rafts, cholesterol-enriched microdomains in the host cell plasma membrane, have also been implicated in T. cruzi invasion process. Since both plasma membrane and lysosomes collaborate in parasite invasion, we decided to study the importance of these membrane domains for lysosomal recruitment and fusion during T. cruzi invasion into host cells. Our results show that drug dependent depletion of plasma membrane cholesterol changes raft organization and induces excessive lysosome exocytosis in the earlier stages of treatment, leading to a depletion of lysosomes near the cell cortex, which in turn compromises T. cruzi invasion. Based on these results, we propose that cholesterol depletion leads to unregulated exocytic events of pre-docked lysosomes, reducing lysosome availability at the cell cortex and consequently compromising T. cruzi infection