A Test of Highly Optimized Tolerance Reveals Fragile Cell-Cycle Mechanisms Are Molecular Targets in Clinical Cancer Trials

Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g., those involved in cell-cycle regulation, can be resistant to some perturbations while highly sensitive to others. The “robust yet fragile” duality of networks has been termed Highly Optimized Tolerance (HOT) and has been the basis of new lines of inquiry in computational and experimental biology. In this study, we tested the working hypothesis that cell-cycle control architectures obey the HOT paradigm. Three cell-cycle models were analyzed using monte-carlo sensitivity analysis. Overall state sensitivity coefficients, which quantify the robustness or fragility of a given mechanism, were calculated using a monte-carlo strategy with three different numerical techniques along with multiple parameter perturbation strategies to control for possible numerical and sampling artifacts. Approximately 65% of the mechanisms in the G1/S restriction point were responsible for 95% of the sensitivity, conversely, the G2-DNA damage checkpoint showed a much stronger dependence on a few mechanisms; ∼32% or 13 of 40 mechanisms accounted for 95% of the sensitivity. Our analysis predicted that CDC25 and cyclin E mechanisms were strongly implicated in G1/S malfunctions, while fragility in the G2/M checkpoint was predicted to be associated with the regulation of the cyclin B-CDK1 complex. Analysis of a third model containing both G1/S and G2/M checkpoint logic, predicted in addition to mechanisms already mentioned, that translation and programmed proteolysis were also key fragile subsystems. Comparison of the predicted fragile mechanisms with literature and current preclinical and clinical trials suggested a strong correlation between efficacy and fragility. Thus, when taken together, these results support the working hypothesis that cell-cycle control architectures are HOT networks and establish the mathematical estimation and subsequent therapeutic exploitation of fragile mechanisms as a novel strategy for anti-cancer lead generation

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline

The dominant Anopheles vectors of human malaria in the Asia-Pacific region: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here. The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East. Here we discuss the 19 DVS of the Asian-Pacific region. This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally. To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed.</p> <p>Results</p> <p>Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables. Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced. The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model. A detailed summary of the information on the bionomics of each species and species complex is also presented.</p> <p>Conclusions</p> <p>This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria. The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control. This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region. All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain. We hope that this will encourage data sharing to improve future iterations of the distribution maps.</p

Study of multi-muon events produced in p\bar{p} interactions at \sqrt{s}=1.96 TeV

68 pages, 46 figures, 11 tables. Submitted to Phys. Rev. D. Removed typos from the authors' listWe report the results of a study of multi-muon events produced at the Fermilab Tevatron collider and acquired with the CDF II detector using a dedicated dimuon trigger. The production cross section and kinematics of events in which both muon candidates are produced inside the beam pipe of radius 1.5 cm are successfully modeled by known processes which include heavy flavor production. In contrast, we are presently unable to fully account for the number and properties of the remaining events, in which at least one muon candidate is produced outside of the beam pipe, in terms of the same understanding of the CDF II detector, trigger, and event reconstruction.Peer reviewe

One-dimensional ZnO nanostructure arrays: Synthesis and characterization

One-dimensional ZnO nanostructure arrays such as nanowires, nanonails, and nanotrees, have been synthesized by oxygen assisted thermal evaporation of metallic zinc on a quartz substrate over a large area. Morphological evolution of ZnO nanostructures at different time scales and different positions of the substrates have been studied by electron microscopy. A self-catalyzed vapor-liquid-solid (VLS) process is believed to be responsible for the nucleation and subsequently a vapor-solid process is operative for further longitudinal growth. The photoluminescence spectrum showed a weak UV and a broad green emission peak at 3.25 and 2.49 eV, respectively. The latter was attributed to the presence of zinc interstitial defects. Electrical resistivity as a function of temperature showed activated mechanisms to be present. The electrical response of the ZnO nanonail arrays to different gases (CO, NO<SUB>2</SUB>, and H<SUB>2</SUB>S) indicated that there could be possible application as gas sensors for this material

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