Multiscale Stick-Slip Dynamics of Adhesive Tape Peeling

Using a high-speed camera, we follow the propagation of the detachment front during the peeling of an adhesive tape from a flat surface. In a given range of peeling velocity, this front displays a multiscale unstable dynamics, entangling two well-separated spatiotemporal scales, which correspond to microscopic and macroscopic dynamical stick-slip instabilities. While the periodic release of the stretch energy of the whole peeled ribbon drives the classical macro-stick-slip, we show that the micro-stick-slip, due to the regular propagation of transverse dynamic fractures discovered by Thoroddsen et al. [Phys. Rev. E 82, 046107 (2010)], is related to a high-frequency periodic release of the elastic bending energy of the adhesive ribbon concentrated in the vicinity of the peeling front.Comment: to appear in Physical Review Letters (2015

Intermittent stick-slip dynamics during the peeling of an adhesive tape from a roller

We study experimentally the fracture dynamics during the peeling at a constant velocity of a roller adhesive tape mounted on a freely rotating pulley. Thanks to a high speed camera, we measure, in an intermediate range of peeling velocities, high frequency oscillations between phases of slow and rapid propagation of the peeling fracture. This so-called stick-slip regime is well known as the consequence of a decreasing fracture energy of the adhesive in a certain range of peeling velocity coupled to the elasticity of the peeled tape. Simultaneously with stick-slip, we observe low frequency oscillations of the adhesive roller angular velocity which are the consequence of a pendular instability of the roller submitted to the peeling force. The stick-slip dynamics is shown to become intermittent due to these slow pendular oscillations which produce a quasi-static oscillation of the peeling angle while keeping constant the peeling fracture velocity (averaged over each stick-slip cycle). The observed correlation between the mean peeling angle and the stick-slip amplitude questions the validity of the usually admitted independence with the peeling angle of the fracture energy of adhesives.Comment: Forthcoming in Physical Review

SCFβTrCP-mediated degradation of SHARP1 in triple-negative breast cancer

: Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with metastasis, high recurrence rate, and poor survival. The basic helix-loop-helix transcription factor SHARP1 (Split and Hairy-related Protein 1) has been identified as a suppressor of the metastatic behavior of TNBC. SHARP1 blocks the invasive phenotype of TNBC by inhibiting hypoxia-inducible factors and its loss correlates with poor survival of breast cancer patients. Here, we show that SHARP1 is an unstable protein that is targeted for proteasomal degradation by the E3 ubiquitin ligase complex SCFβTrCP. SHARP1 recruits βTrCP via a phosphodegron encompassing Ser240 and Glu245 which are required for SHARP1 ubiquitylation and degradation. Furthermore, mice injected with TNBC cells expressing the non-degradable SHARP1(S240A/E245A) mutant display reduced tumor growth and increased tumor-free survival. Our study suggests that targeting the βTrCP-dependent degradation of SHARP1 represents a therapeutic strategy in TNBC

Multi-scale stick-slip during the peeling of adhesive tape

We study the stick-slip instability when peeling an adhesive tape from a flat substrate at an imposed driving velocity. Using a high-speed camera mounted on a microscope, we image either the detachment front, or the ribbon profile at microscopic scale, while simultaneously recording acoustic emissions. In a given range of driving velocity, the peeling displays a multi-scale unstable dynamics, with two well-separated spatio-temporal scales, which corresponds to microscopic and macroscopic dynamical stick-slip instabilities. We show that the microscopic stick-slip dynamics -- which presents very different characteristics than the well-known macroscopic instability -- is related to a high-frequency periodic release of the elastic bending energy of the adhesive ribbon concentrated at the vicinity of the peeling front. Moreover, we also show that it corresponds to the recently observed periodic propagation of fast transverse fractures across the tape width in the ultrasonic range

Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth

Thymidylate synthase (TS) is a prominent drug target for different cancer types. However, the prolonged use of its classical inhibitors, substrate analogs that bind at the active site, leads to TS overexpression and drug resistance in the clinic. In the effort to identify anti-TS drugs with new modes of action and able to overcome platinum drug resistance in ovarian cancer, octapeptides with a new allosteric inhibition mechanism were identified as cancer cell growth inhibitors that do not cause TS overexpression. To improve the biological properties, 10 cyclic peptides (cPs) were designed from the lead peptides and synthesized. The cPs were screened for the ability to inhibit recombinant human thymidylate synthase (hTS), and peptide 7 was found to act as an allosteric inhibitor more potent than its parent open-chain peptide [Pro3]LR. In cytotoxicity studies on three human ovarian cancer cell lines, IGROV-1, A2780, and A2780/CP, peptide 5 and two other cPs, including 7, showed IC50 values comparable with those of the reference drug 5-fluorouracil, of the open-chain peptide [d-Gln4]LR, and of another seven prolyl derivatives of the lead peptide LR. These promising results indicate cP 7 as a possible lead compound to be chemically modified with the aim of improving both allosteric TS inhibitory activity and anticancer effectiveness

The use of antimicrobials in Italian heavy pig fattening farms

Data on antimicrobial use (AMU) in heavy pig production (>150 kg) are limited. The aim of this study was to investigate the AMU in this production. Data from 2015 were collected for 143 fattening farms. The AMU was estimated through a treatment index per 100 days (TI100) using the defined daily dose animal for Italy (DDDAit). When possible, a comparison with the European Medicines Agency's defined daily doses for animals (DDDvet) was performed. The median TI100 was 10.7 (range, 0.2-49.5). Group treatments represented 94.6% of overall consumption. The AMU calculated using DDDAit and DDDvet were strongly correlated (rho = 0.976; p < 0.001). The AMU was negatively correlated with injectables use (rho = -0.46, p < 0.001) and positively correlated with oral products (rho = 0.21, p = 0.014), premixes (rho = 0.26, p = 0.002), and mortality (rho = 0.18; p = 0.027). Farm size was negatively correlated with AMU (rho = -0.29, p < 0.001). Smaller farms were more frequently above the median TI100 (odds ratio = 2.3, 95% confidence interval = 1.2-4.7), suggesting that they may have lower biosecurity and management standards. The results of this study should provide useful insights for the development of an Italian monitoring system

Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants

Monosodium urate crystals promote innate anti-mycobacterial immunity and improve BCG efficacy as a vaccine against tuberculosis

A safer and more effective anti-Tuberculosis vaccine is still an urgent need. We probed the effects of monosodium urate crystals (MSU) on innate immunity to improve the Bacille Calmette-Guerin (BCG) vaccination. Results showed that in vitro MSU cause an enduring macrophage stimulation of the anti-mycobacterial response, measured as intracellular killing, ROS production and phagolysosome maturation. The contribution of MSU to anti-mycobacterial activity was also shown in vivo. Mice vaccinated in the presence of MSU showed a lower number of BCG in lymph nodes draining the vaccine inoculation site, in comparison to mice vaccinated without MSU. Lastly, we showed that MSU improved the efficacy of BCG vaccination in mice infected with Mycobacterium tuberculosis (MTB), measured in terms of lung and spleen MTB burden. These results demonstrate that the use of MSU as adjuvant may represent a novel strategy to enhance the efficacy of BCG vaccination