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

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

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

Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response

Testing approaches to sharing trial results with participants : The Show RESPECT cluster randomised, factorial, mixed methods trial

Funding: The Show RESPECT study was funded by the Medical Research Council through core grants to MRS at the MRC CTU at UCL for Trial Conduct Methodology (MC_UU12023/24 and MC_UU_00004/08) https://mrc.ukri.org/. The funder had no role in the study design, the collection, analysis and interpretation of data, the writing of the report and the decision to submit the article for publication. All authors had full access to the study data, including statistical reports and tables, and can take responsibility for the integrity of the data and the accuracy of the data analysis. Acknowledgments We are very thankful to the patients who participated in this study and the people who contributed to our Patient and Public Involvement activities. We are very grateful for the work of the Show RESPECT site teams in carrying out this study. A list of team members from sites can be found in S10 Table. We thank Eva Burnett, who is a patient representative on the Study Steering Group for Show RESPECT and ICON8, for her input on the design and conduct of this study and for her comments on this manuscript, and Amanda Hunn for her contributions to the steering group. We also acknowledge the hard work and diligence of Sierra Santana and Ania Spurdens, who were data managers for Show RESPECT. We also wish to thank the ICON8 trial team for their support of this project, particularly Andrew Clamp, Babasola Popoola, Francesca Schiavone, Jonathan Badrock, and Rick Kaplan. We also thank Julia Bailey for her advice and guidance on the qualitative aspect of this study.Peer reviewedPublisher PD