121 research outputs found
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
Dose-response association between cigarette smoking and gastric cancer risk: a systematic review and meta-analysis
This study aims at providing an accurate and up-to-date quantification of the dose-response association between cigarette smoking and gastric cancer (GC) risk, overall and by subsite. We conducted a systematic review and meta-analysis of case-control and cohort studies on the association between cigarette smoking and GC risk published up to January 2023. We estimated pooled relative risks (RR) of GC and its subsites according to smoking status, intensity, duration, and time since quitting. Among 271 eligible articles, 205 original studies were included in this meta-analysis. Compared with never smokers, the pooled RR for GC was 1.53 (95% confidence interval; CI 1.44-1.62; n = 92) for current and 1.30 (95% CI 1.23-1.37; n = 82) for former smokers. The RR for current compared with never smokers was 2.08 (95% CI 1.66-2.61; n = 21) for gastric cardia and 1.48 (95% CI 1.33-1.66; n = 8) for distal stomach cancer. GC risk nonlinearly increased with smoking intensity up to 20 cigarettes/day (RR:1.69; 95% CI 1.55-1.84) and levelled thereafter. GC risk significantly increased linearly with increasing smoking duration (RR: 1.31; 95% CI 1.25-1.37 for 20 years) and significantly decreased linearly with increasing time since quitting (RR: 0.65; 95% CI 0.44-0.95 for 30 years since cessation). The present meta-analysis confirms that cigarette smoking is an independent risk factor for GC, particularly for gastric cardia. GC risk increases with a low number of cigarettes up to 20 cigarettes/day and increases in a dose-dependent manner with smoking duration
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
Towards an integrated interactive database for the search of stratification biomarkers in Alkaptonuria
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
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
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