Molecular Systems Biology of ErbB1 Signaling: Bridging the Gap through Multiscale Modeling and High-Performance Computing

The complexity in intracellular signaling mechanisms relevant for the conquest of many diseases resides at different levels of organization with scales ranging from the subatomic realm relevant to catalytic functions of enzymes to the mesoscopic realm relevant to the cooperative association of molecular assemblies and membrane processes. Consequently, the challenge of representing and quantifying functional or dysfunctional modules within the networks remains due to the current limitations in our understanding of mesoscopic biology, i.e., how the components assemble into functional molecular ensembles. A multiscale approach is necessary to treat a hierarchy of interactions ranging from molecular (nm, ns) to signaling (μm, ms) length and time scales, which necessitates the development and application of specialized modeling tools. Complementary to multiscale experimentation (encompassing structural biology, mechanistic enzymology, cell biology, and single molecule studies) multiscale modeling offers a powerful and quantitative alternative for the study of functional intracellular signaling modules. Here, we describe the application of a multiscale approach to signaling mediated by the ErbB1 receptor which constitutes a network hub for the cell’s proliferative, migratory, and survival programs. Through our multiscale model, we mechanistically describe how point-mutations in the ErbB1 receptor can profoundly alter signaling characteristics leading to the onset of oncogenic transformations. Specifically, we describe how the point mutations induce cascading fragility mechanisms at the molecular scale as well as at the scale of the signaling network to preferentially activate the survival factor Akt. We provide a quantitative explanation for how the hallmark of preferential Akt activation in cell-lines harboring the constitutively active mutant ErbB1 receptors causes these cell-lines to be addicted to ErbB1-mediated generation of survival signals. Consequently, inhibition of ErbB1 activity leads to a remarkable therapeutic response in the addicted cell lines

Kinematics and neuromuscular recruitment during vertical treadmill exercise

The vertical treadmill (VertiRun) is an unresearched, partial weight-bearing exercise mode for lower limb rehabilitation. The user undertakes a “running-like” action whilst body weight is supported by a bench and the limb is drawn downwards against overhanging resistance cables on a vertically hung nonmotorised treadmill. This study sought to describe the kinematics and neuromuscular recruitment during VertiRun exercise in the supine, 40°, and 70° postures. Twenty-one healthy male participants (age, 25±7 years; stature, 1.79±0.07 m; body mass, 77.7±8.8 kg) volunteered for sagittal plane kinematic analysis of the ankle, knee and hip and electromyography of lower limb musculature in all three postures. Results indicated similar kinematic and neuromuscular profiles in the 40° and 70° postures which differed from the supine. Regardless of posture, a basic movement pattern was observed where the hamstrings and gastrocnemius muscles were active to extend the hip, flex the knee, plantarflex the ankle and draw the leg down the treadmill belt in the contact phase. The rectus femoris and tibialis anterior were active to flex the hip and knee, and dorsiflex the ankle to draw the leg upwards during the swing phase. The vasti muscles were not active during VertiRun exercise. The VertiRun demonstrated similar kinematic and neuro-muscular patterns to overground gait, allows workload progression based on effort and posture changes, and is a low-impact exercise mode that could maintain physical fitness without loading injured tissues. This study suggests that the VertiRun could supplement rehabilitation programmes for lower-limb injuries

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/continuum stochastic dynamics protocols to study the dimermediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines

3D printing the future: scenarios for supply chains reviewed

Purpose: The aim of this paper is to evaluate existing scenarios for 3D Printing in order to identify the “white space” where future opportunities have not been proposed or developed to date. Based around aspects of order penetration points, geographical scope and type of manufacturing, these gaps are identified. Design/methodology/approach: A structured literature review has been carried out on both academic and trade publications. As of the end of May 2016, this identified 128 relevant articles containing 201 future scenarios. Coding these against aspects of existing manufacturing and supply chain theory has led to the development of a framework for identify “white space” in existing thinking. Findings: The coding shows that existing future scenarios are particularly concentrated on job shop applications and pull based supply chain processes, although there are fewer constraints on geographical scope. Five distinct areas of “white space” are proposed, reflecting various opportunities for future 3DP supply chain development. Research limitations: Being a structured literature review, there are potentially articles not identified through the search criteria used. The nature of the findings is also dependent upon the coding criteria selected. However, these are theoretically derived and reflect important aspect of strategic supply chain management. Practical implications: Practitioners may wish to explore the development of business models within the “white space” areas. Originality/value: Currently, existing future 3DP scenarios are scattered over a wide, multi-disciplinary literature base. By providing a consolidated view of these scenarios, it is possible to identify gaps in current thinking. These gaps are multidisciplinary in nature and represent opportunities for both academics and practitioners to exploit

The role of MicroRNAs in cardiac stem cells,”

Stem cells are considered as the next generation drug treatment in patients with cardiovascular disease who are resistant to conventional treatment. Among several stem cells used in the clinical setting, cardiac stem cells (CSCs) which reside in the myocardium and epicardium of the heart have been shown to be an effective option for the source of stem cells. In normal circumstances, CSCs primarily function as a cell store to replace the physiologically depleted cardiovascular cells, while under the diseased condition they have been shown to experimentally regenerate the diseased myocardium. In spite of their major functional role, molecular mechanisms regulating the CSCs proliferation and differentiation are still unknown. MicroRNAs (miRs) are small, noncoding RNA molecules that regulate gene expression at the posttranscriptional level. Recent studies have demonstrated the important role of miRs in regulating stem cell proliferation and differentiation, as well as other physiological and pathological processes related to stem cell function. This review summarises the current understanding of the role of miRs in CSCs. A deeper understanding of the mechanisms by which miRs regulate CSCs may lead to advances in the mode of stem cell therapies for the treatment of cardiovascular diseases

Distributed manufacturing as an opportunity for service growth in logistics firms

Purpose The aim of the paper is to explore the changing role of a logistics service providers (LSPs) to better support their supply chain (SC) partners on their journey of advancing their product-service systems through distributing manufacturing around the world. The purpose of this paper is to investigate a novel route towards service growth followed by the LSP by integrating upstream into the value chain and the resultant consequences in the configuration of the servitisation strategy, SC structure and allocation of roles. Design/methodology/approach A longitudinal exploratory case study design is followed. The case company is one of the world’s largest LSPs. Findings The study highlights how companies can transition towards the development of service solutions when not following a uni-directional, downstream pattern of integration in the value chain. The findings challenge the established model of servitisation as a forward uni-directional process across the continuum from goods to a service-focussed logic. They illustrate how companies can also move in a reversed direction, move possible back-and-forth or extend and restrict their position along the servitisation continuum. Originality/value The study reveals that service transition involves a deliberate developmental process to build capabilities as firms shift the focus of their product-service offering. It provides novel empirical evidence of how the service growth journey can manifest itself in practice. With insights into the benefits and challenges of distributed manufacturing, it also highlights some of the opportunities available to LSPs to expand their product-service offerings and some of the potential threats

Annual changes in the Biodiversity Intactness Index in tropical and subtropical forest biomes, 2001–2012

Few biodiversity indicators are available that reflect the state of broad-sense biodiversity—rather than of particular taxa—at fine spatial and temporal resolution. One such indicator, the Biodiversity Intactness Index (BII), estimates how the average abundance of the native terrestrial species in a region compares with their abundances in the absence of pronounced human impacts. We produced annual maps of modelled BII at 30-arc-second resolution (roughly 1 km at the equator) across tropical and subtropical forested biomes, by combining annual data on land use, human population density and road networks, and statistical models of how these variables affect overall abundance and compositional similarity of plants, fungi, invertebrates and vertebrates. Across tropical and subtropical biomes, BII fell by an average of 1.9 percentage points between 2001 and 2012, with 81 countries seeing an average reduction and 43 an average increase; the extent of primary forest fell by 3.9% over the same period. We did not find strong relationships between changes in BII and countries’ rates of economic growth over the same period; however, limitations in mapping BII in plantation forests may hinder our ability to identify these relationships. This is the first time temporal change in BII has been estimated across such a large region

ARTP statement on cardiopulmonary exercise testing 2021.

Cardiopulmonary exercise testing (CPET) has become an invaluable tool in healthcare, improving the diagnosis of disease and the quality, efficacy, assessment and safety of treatment across a range of pathologies. CPET's superior ability to measure the global exercise response of the respiratory, cardiovascular and skeletal muscle systems simultaneously in a time and cost-efficient manner has led to the application of CPET in a range of settings from diagnosis of disease to preoperative assessment. The Association for Respiratory Technology and Physiology Statement on Cardiopulmonary Exercise Testing 2021 provides the practitioner and scientist with an outstanding resource to support and enhance practice, from equipment to testing to leadership, helping them deliver a quality assured service for the benefit of all patient groups

Capturing complexity: field-testing the use of ‘structure from motion’ derived virtual models to replicate standard measures of reef physical structure

Reef structural complexity provides important refuge habitat for a range of marine organisms, and is a useful indicator of the health and resilience of reefs as a whole. Marine scientists have recently begun to use ‘Structure from Motion’ (SfM) photogrammetry in order to accurately and repeatably capture the 3D structure of physical objects underwater, including reefs. There has however been limited research on the comparability of this new method with existing analogue methods already used widely for measuring and monitoring 3D structure, such as ‘tape and chain rugosity index (RI)’ and graded visual assessments. Our findings show that analogue and SfM RI can be reliably converted over a standard 10-m reef section (SfM RI = 1.348 × chain RI—0.359, r2 = 0.82; and Chain RI = 0.606 × SfM RI + 0.465) for RI values up to 2.0; however, SfM RI values above this number become increasingly divergent from traditional tape and chain measurements. Additionally, we found SfM RI correlates well with visual assessment grades of coral reefs over a 10 × 10 m area (SfM RI = 0.1461 × visual grade + 1.117; r2 = 0.83). The SfM method is shown to be affordable and non-destructive whilst also allowing the data collected to be archival, less biased by the observer, and broader in its scope of applications than standard methods. This work allows researchers to easily transition from analogue to digital structural assessment techniques, facilitating continued long-term monitoring, whilst also improving the quality and additional research value of the data collected