Localized Tensional Forces on PECAM-1 Elicit a Global Mechanotransduction Response via the Integrin-RhoA Pathway

SummaryBackgroundMechanical forces regulate cell behavior and function during development, differentiation, and tissue morphogenesis. In the vascular system, forces produced by blood flow are critical determinants not only of morphogenesis and function, but also of pathological states such as atherosclerosis. Endothelial cells (ECs) have numerous mechanotransducers, including platelet endothelial cell adhesion molecule-1 (PECAM-1) at cell-cell junctions and integrins at cell-matrix adhesions. However, the processes by which forces are transduced to biochemical signals and subsequently translated into downstream effects are poorly understood.ResultsHere, we examine mechanochemical signaling in response to direct force application on PECAM-1. We demonstrate that localized tensional forces on PECAM-1 result in, surprisingly, global signaling responses. Specifically, force-dependent activation of phosphatidylinositol 3-kinase (PI3K) downstream of PECAM-1 promotes cell-wide activation of integrins and the small GTPase RhoA. These signaling events facilitate changes in cytoskeletal architecture, including growth of focal adhesions and adaptive cytoskeletal stiffening.ConclusionsTaken together, our work provides the first evidence of a global signaling event in response to a localized mechanical stress. In addition, these data provide a possible mechanism for the differential stiffness of vessels exposed to distinct hemodynamic force patterns in vivo

The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins

How individual cells respond to mechanical forces is of considerable interest to biologists as force affects many aspects of cell behavior1. Application of force on integrins triggers cytoskeletal rearrangements and growth of the associated adhesion complex, resulting in increased cellular stiffness2,3, also known as reinforcement4. While RhoA has been shown to play a role during reinforcement3, the molecular mechanisms that regulate its activity are unknown. By combining biochemical and biophysical approaches, we identified two guanine nucleotide exchange factors (GEFs), LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signaling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signaling cascade that includes FAK and Ras

Cross-imaging system comparison of backscatter coefficient estimates from a tissue-mimicking material

A key step toward implementing quantitative ultrasound techniques in a clinical setting is demonstrating that parameters such as the ultrasonic backscatter coefficient (BSC) can be accurately estimated independent of the clinical imaging system used. In previous studies, agreement in BSC estimates for well characterized phantoms was demonstrated across different laboratory systems. The goal of this study was to compare the BSC estimates of a tissue mimicking sample measured using four clinical scanners, each providing RF echo data in the 1-15 MHz frequency range. The sample was previously described and characterized with single-element transducer systems. Using a reference phantom for analysis, excellent quantitative agreement was observed across the four array-based imaging systems for BSC estimates. Additionally, the estimates from data acquired with the clinical systems agreed with theoretical predictions and with estimates from laboratory measurements using single-element transducers

Localized Tensional Forces on PECAM-1 Elicit a Global Mechanotransduction Response via the Integrin-RhoA Pathway

Mechanical forces regulate cell behavior and function during development, differentiation, and tissue morphogenesis. In the vascular system, forces produced by blood flow are critical determinants not only of morphogenesis and function, but also pathological states such as atherosclerosis. Endothelial cells (ECs) have numerous mechanotransducers, including platelet endothelial cell adhesion molecule-1 (PECAM-1) at cell-cell junctions and integrins at cell-matrix adhesions. However, the processes by which forces are transduced to biochemical signals and subsequently translated into downstream effects are poorly understood

Metformin is a metabolic modulator and radiosensitiser in rectal cancer

Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer

Trajectories of the Earth System in the Anthropocene

This is the final version of the article. Available from National Academy of Sciences via the DOI in this record.We explore the risk that self-reinforcing feedbacks could push the Earth System toward a planetary threshold that, if crossed, could prevent stabilization of the climate at intermediate temperature rises and cause continued warming on a "Hothouse Earth" pathway even as human emissions are reduced. Crossing the threshold would lead to a much higher global average temperature than any interglacial in the past 1.2 million years and to sea levels significantly higher than at any time in the Holocene. We examine the evidence that such a threshold might exist and where it might be. If the threshold is crossed, the resulting trajectory would likely cause serious disruptions to ecosystems, society, and economies. Collective human action is required to steer the Earth System away from a potential threshold and stabilize it in a habitable interglacial-like state. Such action entails stewardship of the entire Earth System-biosphere, climate, and societies-and could include decarbonization of the global economy, enhancement of biosphere carbon sinks, behavioral changes, technological innovations, new governance arrangements, and transformed social values.W.S. and C.P.S. are members of the Anthropocene Working Group. W.S., J.R., K.R., S.E.C., J.F.D., I.F., S.J.L., R.W. and H.J.S. are members of the Planetary Boundaries Research Network PB.net and the Earth League’s EarthDoc Programme supported by the Stordalen Foundation. T.M.L. was supported by a Royal Society Wolfson Research Merit Award and the European Union Framework Programme 7 Project HELIX. C.F. was supported by the Erling– Persson Family Foundation. The participation of D.L. was supported by the Haury Program in Environment and Social Justice and National Science Foundation (USA) Decadal and Regional Climate Prediction using Earth System Models Grant 1243125. S.E.C. was supported in part by Swedish Research Council Formas Grant 2012-742. J.F.D. and R.W. were supported by Leibniz Association Project DOMINOES. S.J.L. receives funding from Formas Grant 2014-589. This paper is a contribution to European Research Council Advanced Grant 2016, Earth Resilience in the Anthropocene Project 743080

Synaptic density in carriers of C9orf72 mutations: a [ 11 C]UCB‐J PET study

Abstract: Synaptic loss is an early and clinically relevant feature of many neurodegenerative diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [11C]UCB‐J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with behavioural variant frontotemporal dementia. The three pre‐symptomatic C9orf72 carriers showed reduced synaptic density in the thalamus compared to controls, and there was an additional extensive synaptic loss in frontotemporal regions of the symptomatic patient. [11C]UCB‐J PET may facilitate early, pre‐symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia

Synaptic density in carriers of C9orf72 mutations: a [ 11 C]UCB‐J PET study

Abstract: Synaptic loss is an early and clinically relevant feature of many neurodegenerative diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [11C]UCB‐J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with behavioural variant frontotemporal dementia. The three pre‐symptomatic C9orf72 carriers showed reduced synaptic density in the thalamus compared to controls, and there was an additional extensive synaptic loss in frontotemporal regions of the symptomatic patient. [11C]UCB‐J PET may facilitate early, pre‐symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia

Identification of epitopes recognised by mucosal CD4+ T-cell populations from cattle experimentally colonised with Escherichia coli O157:H7

Additional file 5. Sequence alignment of Intimin epitopes against Intimin sequences from non-O157 EHEC serotypes. Alignment of Intimin CD4+ T-cell epitope sequences with representative Intimin sequences from EHEC serotypes O145, O127, O26, O103, O121, O45 and O111. Percentage values indicate % similarity to the EHEC O157:H7 reference sequence

A Broadly Applicable Strategy for Entry into Homogeneous Nickel(0) Catalysts from Air-Stable Nickel(II) Complexes

A series of air-stable nickel complexes of the form L[subscript 2]Ni(aryl) X (L = monodentate phosphine, X = Cl, Br) and LNi(aryl)X (L = bis-phosphine) have been synthesized and are presented as a library of precatalysts suitable for a wide variety of nickel-catalyzed transformations. These complexes are easily synthesized from low-cost NiCl[subscript 2]·6H[subscript 2]O or NiBr[subscript 2]·3H[subscript 2]O and the desired ligand followed by addition of 1 equiv of Grignard reagent. A selection of these complexes were characterized by single-crystal X-ray diffraction, and an analysis of their structural features is provided. A case study of their use as precatalysts for the nickel-catalyzed carbonyl-ene reaction is presented, showing superior reactivity in comparison to reactions using Ni(cod)[subscript 2]. Furthermore, as the precatalysts are all stable to air, no glovebox or inert-atmosphere techniques are required to make use of these complexes for nickel-catalyzed reactions.National Institute of General Medical Sciences (U.S.) (GM63755)National Science Foundation (U.S.). Graduate Research Fellowshi