The Dynamics of Signaling as a Pharmacological Target

SummaryHighly networked signaling hubs are often associated with disease, but targeting them pharmacologically has largely been unsuccessful in the clinic because of their functional pleiotropy. Motivated by the hypothesis that a dynamic signaling code confers functional specificity, we investigated whether dynamic features may be targeted pharmacologically to achieve therapeutic specificity. With a virtual screen, we identified combinations of signaling hub topologies and dynamic signal profiles that are amenable to selective inhibition. Mathematical analysis revealed principles that may guide stimulus-specific inhibition of signaling hubs, even in the absence of detailed mathematical models. Using the NFκB signaling module as a test bed, we identified perturbations that selectively affect the response to cytokines or pathogen components. Together, our results demonstrate that the dynamics of signaling may serve as a pharmacological target, and we reveal principles that delineate the opportunities and constraints of developing stimulus-specific therapeutic agents aimed at pleiotropic signaling hubs

IκBɛ provides negative feedback to control NF-κB oscillations, signaling dynamics, and inflammatory gene expression

NF-κB signaling is known to be critically regulated by the NF-κB–inducible inhibitor protein IκBα. The resulting negative feedback has been shown to produce a propensity for oscillations in NF-κB activity. We report integrated experimental and computational studies that demonstrate that another IκB isoform, IκBɛ, also provides negative feedback on NF-κB activity, but with distinct functional consequences. Upon stimulation, NF-κB–induced transcription of IκBɛ is delayed, relative to that of IκBα, rendering the two negative feedback loops to be in antiphase. As a result, IκBɛ has a role in dampening IκBα-mediated oscillations during long-lasting NF-κB activity. Furthermore, we demonstrate the requirement of both of these distinct negative feedback regulators for the termination of NF-κB activity and NF-κB–mediated gene expression in response to transient stimulation. Our findings extend the capabilities of a computational model of IκB–NF-κB signaling and reveal a novel regulatory module of two antiphase negative feedback loops that allows for the fine-tuning of the dynamics of a mammalian signaling pathway

Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20

TNF-induced NF-κB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps—one determined by the obligate negative feedback regulator IκBα—that define the duration of the first phase of NF-κB activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of iκbα and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses

Analytical Validation and Capabilities of the Epic CTC Platform: Enrichment-Free Circulating Tumour Cell Detection and Characterization

The Epic Platform was developed for the unbiased detection and molecular characterization of circulating tumour cells (CTCs). Here, we report assay performance data, including accuracy, linearity, specificity and intra/inter-assay precision of CTC enumeration in healthy donor (HD) blood samples spiked with varying concentrations of cancer cell line controls (CLCs). Additionally, we demonstrate clinical feasibility for CTC detection in a small cohort of metastatic castrate-resistant prostate cancer (mCRPC) patients. The Epic Platform demonstrated accuracy, linearity and sensitivity for the enumeration of all CLC concentrations tested. Furthermore, we established the precision between multiple operators and slide staining batches and assay specificity showing zero CTCs detected in 18 healthy donor samples. In a clinical feasibility study, at least one traditional CTC/mL (CK+, CD45-, and intact nuclei) was detected in 89 % of 44 mCRPC samples, whereas 100 % of samples had CTCs enumerated if additional CTC subpopulations (CK-/CD45- and CK+ apoptotic CTCs) were included in the analysis. In addition to presenting Epic Platform’s performance with respect to CTC enumeration, we provide examples of its integrated downstream capabilities, including protein biomarker expression and downstream genomic analyses at single cell resolution

The low-lying quadrupole collective excitations of Ru and Pd isotopes

Quadrupole excitations of even-even Ru and Pd isotopes are described within microscopic approach based on the general collective Bohr model which includes the effect of coupling with the pairing vibrations. The excitation energies and E2 transition probabilities observed in 104-114Ru and 106-110Pd are reproduced in the frame of the calculation containing no free parameters.Comment: 11 pages, 18 figures in EPS forma

Gaussian bosonic synergy: quantum communication via realistic channels of zero quantum capacity

As with classical information, error-correcting codes enable reliable transmission of quantum information through noisy or lossy channels. In contrast to the classical theory, imperfect quantum channels exhibit a strong kind of synergy: there exist pairs of discrete memoryless quantum channels, each of zero quantum capacity, which acquire positive quantum capacity when used together. Here we show that this "superactivation" phenomenon also occurs in the more realistic setting of optical channels with attenuation and Gaussian noise. This paves the way for its experimental realization and application in real-world communications systems.Comment: 5 pages, 4 figures, one appendi

Non-locality and Communication Complexity

Quantum information processing is the emerging field that defines and realizes computing devices that make use of quantum mechanical principles, like the superposition principle, entanglement, and interference. In this review we study the information counterpart of computing. The abstract form of the distributed computing setting is called communication complexity. It studies the amount of information, in terms of bits or in our case qubits, that two spatially separated computing devices need to exchange in order to perform some computational task. Surprisingly, quantum mechanics can be used to obtain dramatic advantages for such tasks. We review the area of quantum communication complexity, and show how it connects the foundational physics questions regarding non-locality with those of communication complexity studied in theoretical computer science. The first examples exhibiting the advantage of the use of qubits in distributed information-processing tasks were based on non-locality tests. However, by now the field has produced strong and interesting quantum protocols and algorithms of its own that demonstrate that entanglement, although it cannot be used to replace communication, can be used to reduce the communication exponentially. In turn, these new advances yield a new outlook on the foundations of physics, and could even yield new proposals for experiments that test the foundations of physics.Comment: Survey paper, 63 pages LaTeX. A reformatted version will appear in Reviews of Modern Physic

First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies

GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors