Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading

The mechanoregulated proteins YAP/TAZ are involved in the adipogenic/osteogenic switch of mesenchymal stem cells (MSCs).MSC fate decision can be unbalanced by controlling substrate mechanics, in turn altering the transmission of tension through cell cytoskeleton. MSCs have been proposed for orthopedic and reconstructive surgery applications. Thus, a tight control of their adipogenic potential is required in order to avoid their drifting towards fat tissue. Substrate mechanics has been shown to drive MSC commitment and to regulate YAP/TAZ protein shuttling and turnover. The mechanism by which YAP/TAZ co-transcriptional activity is mechanically regulated during MSC fate acquisition is still debated.Here, we design few bioengineering tools suited to disentangle the contribution of mechanical from biological stimuli to MSC adipogenesis. We demonstrate that the mechanical repression of YAP happens through its phosphorylation, is purely mediated by cell spreading downstream of substrate mechanics as dictated by dimensionality. YAP repression is sufficient to prompt MSC adipogenesis, regardless of a permissive biological environment, TEAD nuclear presence or focal adhesion stabilization.Finally, by harnessing the potential of YAP mechanical regulation, we propose a practical example of the exploitation of adipogenic transdifferentiation in tumors.</p

Construction techniques and performances of a full size prototype Micromegas chamber for the ATLAS muon spectrometer upgrade

A full scale prototype of a Micromegas precision tracking chamber for the upgrade of the ATLAS detector at the LHC Collider has been built between October 2015 and April 2016. This paper describes in detail the procedures used in constructing the single modules of the chamber in various INFN laboratories and the final assembly at the Frascati National Laboratories (LNF). Results of the chamber exposure to the CERN H8 beam line in June 2016 are also presented. The performances achieved in the construction and the results of the test beam are compared with the requirements, which are imposed by the severe environment during the data-taking of the LHC foreseen for the next years

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition

Androgen deprivation therapy (ADT) is a powerful treatment for metastatic hormone-sensitive prostate cancer (mHSPC) patients, but eventually and inevitably, cancer relapses, progressing to the fatal castration-resistant (CR)PC stage. Progression implies the emergence of cells proliferating in the absence of androgen through still elusive mechanisms. We show here for the first time that ADT induces LNCaP mHSPC cells to collectively enter a metastable quasi-apoptotic state (QUAPS) consisting of partial mitochondrial permeabilization, limited BAX and caspase activation, and moderate induction of caspase-dependent dsDNA breaks; despite this, cells maintain full viability. QUAPS is destabilized by poly(ADP)-polymerase inhibition (PARPi), breaking off toward overt intrinsic apoptosis and culture extinction. Instead, QUAPS is rapidly and efficiently reverted upon androgen restoration, with mitochondria rapidly recovering integrity and cells collectively resuming normal proliferation. Notably, replication restarts before DNA repair is completed, and implies an increased micronuclei frequency, indicating that ADT promotes genetic instability. The recovered cells re-acquire insensitivity to PARPi (as untreated LNCaP), pointing to specific, context-dependent vulnerability of mHSPC cells to PARPi during ADT. Summarizing, QUAPS is an unstable, pro-mutagenic state developing as a pro-survival pathway stabilized by PARP, and constitutes a novel viewpoint explaining how ADT-treated mHSPC may progress to CRPC, indicating possible preventive countermeasures

Safe-Shields: Basal and Anti-UV Protection of Human Keratinocytes by Redox-Active Cerium Oxide Nanoparticles Prevents UVB-Induced Mutagenesis

Cerium oxide nanoparticles (nanoceria), biocompatible multifunctional nanozymes exerting unique biomimetic activities, mimic superoxide-dismutase and catalase through a self-regenerating, energy-free redox cycle driven by Ce3+/4+ valence switch. Additional redox-independent UV-filter properties render nanoceria ideal multitask solar screens, shielding from UV exposure, simultaneously protecting tissues from UV-oxidative damage. Here, we report that nanoceria favour basal proliferation of primary normal keratinocytes, and protects them from UVB-induced DNA damage, mutagenesis, and apoptosis, minimizing cell loss and accelerating recovery with flawless cells. Similar cell-protective effects were found on irradiated noncancerous, but immortalized, p53-null HaCaT keratinocytes, with the notable exception that here, nanoceria do not accelerate basal HaCaT proliferation. Notably, nanoceria protect HaCaT from oxidative stress induced by irradiated titanium dioxide nanoparticles, a major active principle of commercial UV-shielding lotions, thus neutralizing their most critical side effects. The intriguing combination of nanoceria multiple beneficial properties opens the way for smart and safer containment measures of UV-induced skin damage and carcinogenesis

Calypso: a full-scale MDT prototype for the ATLAS muon spectrometer

We present a full-scale MDT prototype for the Atlas muon spectrometer. The chamber consists of two multilayers made of three layers of 96 drift tubes each. The main feature of this chamber is the very accurate mechanical construction (20 mu m accuracy on single wire positioning) together with a very good individual tube spatial resolution. In this paper we present results both on the mechanical accuracy of the chamber, and on the performances obtained on the H8 test beam at CERN. In particular, we present an autocalibration method that allows to obtain the space-to-time relation of the tubes with a systematic error less than 20 mu m, the space resolution and the efficiency of the chamber. (C) Published by 1998 Elsevier Science B.V. All rights reserved