Broadband vibration mitigation using a two-dimensional acoustic black hole phononic crystala).

Acoustic black holes (ABHs) are known as efficient structural dampers. Periodic lattices are identified as an efficient way to forbidden wave propagation in targeted frequency bandgaps (BGs). The paper demonstrates the possibility to merge the ABH effect with Bragg BGs. The geometrical layout leading to this double effect consists of a plate of periodically modulated thickness by a combination of cosine functions of the spatial coordinates constituting an ABH-like cell, coated with a thin damping layer. The resulting metamaterial allows the realization of solid, stiff, and nonresonant panels over a wide frequency range, including low frequencies, without increasing the mass. First, the band structure is analyzed in the conservative case (without damping layer) using a plane wave expansion model following Kirchhoff's assumptions. The results show the existence of low-frequency BGs that can be controlled by only three geometric parameters, which are defined on the type of lattice chosen (square or hexagonal). Next, a finite size panel is designed for the hexagonal lattice. Experimental characterization of the demonstrator with and without viscoelastic coating shows very attractive broadband vibration mitigation performances due to the fact that the dissipation produced by the ABH effect does not deter filtering effects produced in the BG.

Advancing the use of new approach methodologies for assessing teratogenicity: Building a tiered approach.

Many New Approach Methodologies (NAMs) have been developed for the safety assessment of new ingredients. Research into reproductive toxicity and teratogenicity is a particularly high priority, especially given their mechanistic complexity. Forty-six non-teratogenic and 39 teratogenic chemicals were screened for teratogenic potential using the in silico DART model from the OECD QSAR Toolbox; the devTox quickPredict™ (devTox assay) test and the Zebrafish Embryotoxicity Test (ZET). The sensitivity and specificity were 94.7% and 84.1%, respectively, for the DART tree (83 chemicals), 86.1% and 35.6% for the devTox (81 chemicals) and 77.8% and 76.7% for the ZET (57 chemicals). Fifty-three chemicals were tested in all three assays and when results were combined and based on a "2 out of 3 rule", the sensitivity and specificity were 96.0% and 71.4%, respectively. The specificity of the devTox assay for a sub-set of 43 chemicals was increased from 26.1% to 82.6% by incorporating human plasma concentrations into the assay interpretation. When all 85 chemicals were assessed in a decision tree approach, there was an excellent predictivity and assay robustness of 90%. In conclusion, all three models exhibited a good sensitivity and specificity, especially when outcomes from all three were combined or used in "2 out of 3" or a tiered decision tree approach. The latter is an interesting predictive approach for evaluating the teratogenic potential of new chemicals. Future investigations will extend the number of chemicals tested, as well as explore ways to refine the results and obtain a robust Integrated Testing Strategy to evaluate teratogenic potential.

Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers.

Selective inhibition of BCL-2 is expected to enhance therapeutic vulnerability in luminal estrogen receptor-positive breast cancers. We show here that the BCL-2 dependency of luminal tumor cells is nevertheless mitigated by breast cancer-associated fibroblasts (bCAFs) in a manner that defines MCL-1 as another critical therapeutic target. bCAFs favor MCL-1 expression and apoptotic resistance in luminal cancer cells in a IL-6 dependent manner while their own, robust, survival also relies on MCL-1. Studies based on ex vivo cultures of human luminal breast cancer tissues further argue that the contribution of stroma-derived signals to MCL-1 expression shapes BCL-2 dependency. Thus, MCL-1 inhibitors are beneficial for targeted apoptosis of breast tumor ecosystems, even in a subtype where MCL-1 dependency is not intrinsically driven by oncogenic pathways.

Effect of foliar application of salicylic acid, hydrogen peroxide and a xyloglucan oligosaccharide on capsiate content and gene expression associatedwith capsinoids synthesis in Capsicum annuum L.

Capsinoids are non-pungent analogues of capsaicinoids in pepper (Capsicum spp). The absence of pungency, in addition to their biological activities similar to that of capsaicinoids such as anti-inflammatory, antimicrobial, and antioxidant properties, makes capsinoids an excellent option for increasing use in human and animal nutrition, as well as health and pharmaceutical industries. There are only few sources of pepper producing capsinoids, and one of them (accession 509-45-1), Capsicum annuum L., is a potential source for increasing capsinoids content using strategies as controlled elicitation during plant production in the greenhouse. In this research we evaluated the effect of weekly and one-day-before-harvest foliar applications of hydrogen peroxide, salicylic acid and a xyloglucan oligosaccharide on the concentration of capsiate in fruits of this pepper accession, as well as the gene expression of phenylalanine ammonia-lyase (pal), putative aminotransferase (pamt), capsaicin synthase (at3) and ß-keto acyl synthase (kas). Results showed that the two tested concentrations of H2O2 significantly increased capsiate content and gene expression associated with capsaicinoids (pamt, at3 and kas) and the phenylpropanoids (pal) pathways. Plant yield was not affected using this induction strategy. Our results indicated that the pre-harvest and weekly application of hydrogen peroxide and xyloglucan oligosaccharide improved production of capsiate in C. annuum L.

Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL.

Proapoptotic molecules directly targeting the BCL-2 family network are promising anticancer therapeutics, but an understanding of the cellular stress signals that render them effective is still elusive. We show here that the tumor suppressor p53, at least in part by transcription independent mechanisms, contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL. In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition. This death signal cooperates with BH3-induced activation of BAX and it is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics. The acute sensitivity of mitochondrial priming to p53 revealed here is likely to be critical for the clinical use of BH3 mimetics.

Evaluating hydrogen bonding control in the diastereoselective Diels-Alder reactions of 9-(2-aminoethyl)-anthracene derivatives.

Several 9-(2-aminoethyl)anthracene derivatives were prepared with different nitrogen substitutents including alkyl, acetamide, trifluoroacaeamide and t-butyl carbamate. The selectivity in Diels-Alder cyclodaddition reaction with N-methyl maleimide was evaluated through single crystal X-ray analysis of the products. Models for the change in selectivity with hydrogen bond acceptor are proposed, supported by DFT level calculations.

A strategy for structuring and reporting a read-across prediction of toxicity.

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested.

Bcl-xL controls a switch between cell death modes during mitotic arrest.

Antimitotic agents such as microtubule inhibitors (paclitaxel) are widely used in cancer therapy while new agents blocking mitosis onset are currently in development. All these agents impose a prolonged mitotic arrest in cancer cells that relies on sustained activation of the spindle assembly checkpoint and may lead to subsequent cell death by incompletely understood molecular events. We have investigated the role played by anti-apoptotic Bcl-2 family members in the fate of mitotically arrested mammary tumor cells treated with paclitaxel, or depleted in Cdc20, the activator of the anaphase promoting complex. Under these conditions, a weak and delayed mitotic cell death occurs that is caspase- and Bax/Bak-independent. Moreover, BH3 profiling assays indicate that viable cells during mitotic arrest are primed to die by apoptosis and that Bcl-xL is required to maintain mitochondrial integrity. Consistently, Bcl-xL depletion, or treatment with its inhibitor ABT-737 (but not with the specific Bcl-2 inhibitor ABT-199), during mitotic arrest converts cell response to antimitotics to efficient caspase and Bax-dependent apoptosis. Apoptotic priming under conditions of mitotic arrest relies, at least in part, on the phosphorylation on serine 62 of Bcl-xL, which modulates its interaction with Bax and its sensitivity to ABT-737. The phospho-mimetic S62D-Bcl-xL mutant is indeed less efficient than the corresponding phospho-deficient S62A-Bcl-xL mutant in sequestrating Bax and in protecting cancer cells from mitotic cell death or yeast cells from Bax-induced growth inhibition. Our results provide a rationale for combining Bcl-xL targeting to antimitotic agents to improve clinical efficacy of antimitotic strategy in cancer therapy.

Vibro-acoustics of organ pipes--revisiting the Miller experiment (L).

A century ago, Science published a spectacular experimental study on the physics of organ pipes. Dayton C. Miller observed experimentally that the sound produced by an organ pipe can depend on the vibration of its walls, in addition to its internal geometry and the interaction between the air jet and the labium. The Miller experiment has been repeated and an interpretation is now proposed in terms of vibroacoustic coupling mechanisms between walls and internal fluid, which can lead to "pathological" behavior.

Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL.

Bcl-2 homologues (such as Bcl-x(L)) promote survival in part through sequestration of "activator" BH3-only proteins (such as Puma), preventing them from directly activating Bax. It is thus assumed that inhibition of interactions between activators and Bcl-x(L) is a prerequisite for small molecules to antagonize Bcl-x(L) and induce cell death. The biological properties, described here of a terphenyl-based alpha-helical peptidomimetic inhibitor of Bcl-x(L) attest that displacement of Bax from Bcl-x(L) is also critical. Terphenyl 14 triggers Bax-dependent but Puma-independent cell death, disrupting Bax/Bcl-x(L) interactions without affecting Puma/Bcl-x(L) interactions. In cell-free assays, binding of inactive Bax to Bcl-x(L), followed by its displacement from Bcl-x(L) by terphenyl 14, produces mitochondrially permeabilizing Bax molecules. Moreover, the peptidomimetic kills yeast cells that express Bax and Bcl-x(L), and it uses Bax-binding Bcl-x(L) to induce mammalian cell death. Likewise, ectopic expression of Bax in yeast and mammalian cells enhances sensitivity to another Bcl-x(L) inhibitor, ABT-737, when Bcl-x(L) is present. Thus, the interaction of Bcl-x(L) with Bax paradoxically primes Bax at the same time it keeps Bax activity in check, and displacement of Bax from Bcl-x(L) triggers an apoptotic signal by itself. This mechanism might contribute to the clinical efficiency of Bcl-x(L) inhibitors.

BIS response to tamponade and dobutamine in swine varies with hypnotic/opiate ratio.

OBJECTIVES: This study in swine assessed BIS stability in response to decreases and increases in cardiac output under two propofol/remifentanil dosage combinations, both producing the same depth of surgical anaesthesia. METHODS: Eight anaesthetized-paralyzed ventilated adult swine were studied using a random-order cross-over design. Four received a P low/R high combination (P, 8.4+/-0.9 mg/kg/h; and R, 0.54+/-0.02 microg/kg/min) and then a P high/R low combination (P, 26.7+/-2.1mg/kg/h; and R, 0.34+/-0.01 microg/kg/min). The other four had these two combinations in the reverse order. Under each P/R combination, and after a 60-minutes steady state, a 15-minute stable cardiac tamponade was induced by intrapericardial gelatine infusion. Then, after returning to pre tamponade condition, a 15 minutes period with dobutamine was allowed. RESULTS: Tamponade induced falls in average mean arterial pressure (MAP) (from 79+/-18 to 47+/-9 mm Hg; p<0.05) and cardiac output (Qc) (from 1.90+/-0.46 l/min to 1.20+/-0.38 l/min, p<0.05). Conversely, dobutamine increased both MAP and Qc (p<0.05). During each type of hemodynamic challenges, changes in anaesthesia depth as assessed by BIS differed dramatically between the two drug combinations, despite observing the same percent change in P and R effect-site concentration. With P high/R low and tamponade, BIS fell from 65+/-5 to 29+/-10 (p<0.05); dobutamine produced opposite effects. With P low/R high, in contrast, BIS was not influenced by either of the hemodynamic challenges. CONCLUSION: Conversely to a high propofol/low remifentanil combination, a low propofol/high remifentanil combination allows constant anaesthetic depth in the face of haemodynamic challenges.

Effect of short-term treatment with meloxicam and pimobendan on the renal function in healthy beagle dogs.

The aim of the study was to investigate the renal function in clinically normal dogs receiving meloxicam and pimobendan alone or in combination. Ten adult female beagle dogs were administered the treatment for 7 days in a randomized crossover trial (control/meloxicam/pimobendan/meloxicam and pimobendan). Renal function was assessed by blood urea, creatinine, sodium, potassium and chloride concentrations and by glomerular filtration rate, measured by means of renal scintigraphy [renal uptake of (99m)Tc-diethylenetriaminepentacetic acid (DTPA)] and plasma clearance of (99m)Tc-DTPA. As compared with the control group, renal uptake and plasma clearance of (99m)Tc-DTPA were not significantly modified after a 7-day period of treatment with meloxicam or pimobendan alone, or meloxicam and pimobendan in combination. Furthermore, urea, creatinine, sodium, potassium and chloride levels in the serum of the dogs during the 7-day period treatment were not significantly modified in relation to the treatments. It was therefore concluded that meloxicam and pimobendan alone or in combination did not alter renal function in healthy dogs.

Experimental study of AO and T1 modes of the concert harp.

String instruments are usually composed of a set of strings, a soundboard, and a soundbox with sound holes, which is generally designed to increase the sound level by using the acoustic resonances of the cavity. In the case of the harp, the soundbox and especially the sound holes are primarily designed to allow access to the strings for their mounting. An experimental modal analysis, associated to measurements of the acoustic velocity in the holes, shows the importance of two particular modes labeled A0 and T1 as it was done for the guitar and the violin. Their mode shapes involve coupled motions of the soundboard's bending and of the oscillations of the air pistons located in the sound holes. The A0 mode is found above the frequency of the lowest acoustically significant structural mode T1. Thus, the instrument does not really take advantage of the soundbox resonance to increase its radiated sound in low frequencies. However, contribution of mode A0 is clearly visible in the response of the instrument, confirming the importance of the coupling between the soundboard and the cavity.

Src-mediated phosphorylation regulates subcellular distribution and activity of human inducible nitric oxide synthase.

Inducible nitric oxide synthase (iNOS) expression is regulated at both the transcriptional and post-transcriptional level in epithelial cells. The aim of this study was to characterize the effects of tyrosine phosphorylation on iNOS activity. In a human intestinal epithelial cell line stimulated with cytokines, tyrosine phosphorylation of human iNOS protein was observed after 30 min exposure to pervanadate (PV), an inhibitor of protein tyrosine phosphatases. 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a specific inhibitor of Src tyrosine kinases, abolished the PV-induced iNOS tyrosine phosphorylation. Cotransfection of Src with iNOS cDNA in human embryonic kidney (HEK) 293 cells resulted in a threefold (P<0.001) increase of iNOS protein levels and tyrosine phosphorylation of iNOS. In the presence of Src, 76% of wild-type (wt) iNOS was redistributed to detergent-insoluble domains and iNOS activity was decreased by 28% (P<0.05) despite increased iNOS protein levels. Analysis of iNOS tyrosine mutants revealed decreased Src-induced effects in Y151F iNOS mutant. Using a GST-fusion protein containing a domain encompassing Y151, we show that Y151 is a direct substrate for active Src in vitro. These findings indicate a role for iNOS tyrosine phosphorylation in the regulation of iNOS activity and the implication of Src tyrosine kinases in this pathway.

Effect of tepoxalin on renal function in healthy dogs receiving an angiotensin-converting enzyme inhibitor.

The objective of this study was to investigate renal function in clinically normal dogs receiving tepoxalin, a nonsteroidal inflammatory drug, either in association with or without an angiotensin-converting enzyme inhibitor (ACEI). Ten adult female Beagle dogs were used in the three phases of the study. The dogs were administered the drugs once daily for 7 days (experiment 1: placebo/tepoxalin/tepoxalin and benazepril; experiment 2: enalapril/tepoxalin and enalapril) or for 28 days (experiment 3: tepoxalin and benazepril together). Renal function was assessed by measurement of glomerular filtration rate (GFR) by renal scintigraphy [(renal uptake of 99mTc-diethylenetriaminepentacetic acid (DTPA)] and plasma clearance of 99mTc-DTPA. Compared with the placebo group, renal uptake and plasma clearance of 99mTc-DTPA were not significantly modified after a 7-day period of treatment with tepoxalin or enalapril alone, tepoxalin and benazepril or tepoxalin and enalapril together. No significant change was obtained in GFR after a 28-day period of dosing with tepoxalin and benazepril together. Therefore, it was concluded that tepoxalin did not alter renal function in healthy Beagle dogs receiving ACEI.

Postanoxic functional recovery of the developing heart is slightly altered by endogenous or exogenous nitric oxide.

Nitric oxide synthase (NOS) is strongly and transiently expressed in the developing heart but its function is not well documented. This work examined the role, either protective or detrimental, that endogenous and exogenous NO could play in the functioning of the embryonic heart submitted to hypoxia and reoxygenation. Spontaneously beating hearts isolated from 4-day-old chick embryos were either homogenized to determine basal inducible NOS (iNOS) expression and activity or submitted to 30 min anoxia followed by 100 min reoxygenation. The chrono-, dromo- and inotropic responses to anoxia/reoxygenation were determined in the presence of NOS substrate (L-arginine 10 mM), NOS inhibitor L-NIO (1-5 mM), or NO donor (DETA NONOate 10-100 microM). Myocardial iNOS was detectable by immunoblotting and its activity was specifically decreased by 53% in the presence of 5 mM L-NIO. L-Arginine, L-NIO and DETA NONOate at 10 microM had no significant effect on the investigated functional parameters during anoxia/reoxygenation. However, irrespective of anoxia/reoxygenation, DETA NONOate at 100 microM decreased ventricular shortening velocity by about 70%, and reduced atrio-ventricular propagation by 23%. None of the used drugs affected atrial activity and hearts of all experimental groups fully recovered at the end of reoxygenation. These findings indicate that (1) by contrast with adult heart, endogenously released NO plays a minor role in the early response of the embryonic heart to reoxygenation, (2) exogenous NO has to be provided at high concentration to delay postanoxic functional recovery, and (3) sinoatrial pacemaker cells are the less responsive to NO.

[Impairment of atypical beta-adrenergic-mediated relaxation in spontaneously hypertensive rats before and during the development of arterial hypertension]. / Altération de la relaxation beta-adrénergique atypique chez le rat spontanément hypertendu avant et pendant le développement de l'hypertension artérielle.

The aims of this study was to characterize the functional response of atypical beta-adrenoceptors (beta-AR) in rat aorta and to investigate whether this relaxation was altered before and during the development of hypertension. Aortic rings from 4 or 12 weeks old Wistar Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were placed in organ baths and constricted with phenylephrine. Then, cumulative concentration-relaxation curves to the beta-AR agonists were constructed. In intact aortic rings from 12 weeks old WKY rats, CGP 12,177 (CGP) and cyanopindolol (partial beta 3-AR agonists and atypical beta-AR agonists with beta 1/beta 2-AR antagonist properties) produced concentration-dependent relaxation (pD2 = 5.09 +/- 0.03; Emax = 60.4 +/- 2.5%; n = 9; pD2 = 6.17 +/- 0.05; Emax = 95.9 +/- 1%; n = 5 respectively). The endothelium removal did not modify this relaxation. In 12 weeks old WKY rats, the endothelium-independent relaxation to CGP was not modified in the presence of nadolol (beta 1/beta 2-AR antagonist) or L-748 337 (beta 3-AR antagonist) excluding the participation of beta 1, beta 2 et beta 3-AR in this effect. By contrast, this relaxation was significantly inhibited by CGP 20712A or bupranolol, atypical beta-AR antagonists at high concentrations. In 12 weeks old SHR, endothelium-independent relaxation to CGP or cyanopindolol was greatly inhibited. In order to sought out whether impairment of atypical beta-AR-mediated relaxation was due to hypertension, experiments were performed in 4 weeks old SHR. At this age, CGP-induced relaxation was greatly inhibited compared to that obtained in age-matched WKY rats. In 12 weeks old SHR pretreated with pertussis toxin (10 micrograms/kg i.p./3 days), the relaxant effect to CGP was partly restored. We conclude that the atypical beta-AR were functionally expressed in aortic vascular smooth muscle cells of rat aorta. In 4 or 12 weeks old SHR rats, atypical beta-AR-mediated relaxation was impaired, suggesting that this dysfunction occurs before the establishment of hypertension. Gi proteins may be one of the factors that contributes to this impairment.

[Alteration in relaxation of atypical beta-adrenergic but not beta-3 receptors in arterial hypertension in the rat]. / Altération de la relaxation beta-adrénergique atypique non beta 3 dans l'hypertension artérielle chez le rat.

The aim of this study was to investigate the involvement of beta 3-adrenoceptors (beta 3-AR) in hypertension. Aortic rings were isolated from 12 weeks old WKY (Wistar-Kyoto) and SHR (spontaneously hypertensive rat) rats. Rings were placed in organ baths and constricted with phenylephrine. Then, cumulative concentration-relaxation curves to the beta 3-AR agonists were constructed. In both strains, SR58611, a preferential beta 3-agonist, produced similar concentration-dependent relaxation. CGP 12177 (CGP), (a partial beta 3-AR and atypical beta-AR agonist with beta 1-/beta 2-AR antagonistic properties) produced similar relaxation in WKY (pD2 = 5.10 +/- 0.06; Emax = 54 +/- 2%; n = 6) and in SHR (pD2 = 4.98 +/- 0.02; Emax = 58 +/- 4%; n = 6). In WKY, relaxant response to CGP was not modified by nadolol (10 microM) or L-748.337 (3 microM) suggesting an atypical beta-AR activation. By contrast, in SHR, the effect of CGP was strongly decreased by 3 microM L-748.337 (Emax = 27.8 +/- 5.4%; n = 7; p < 0.05 vs CGP alone), suggesting a possible participation of beta 3-AR in CGP-induced relaxation. In order to investigate the role of endothelium in CGP-induced relaxation, experiments were performed in denuded aortic rings. In WKY, CGP-induced relaxation was not modified by endothelium removal, by contrast, this was greatly inhibited in SHR (Emax = 18.3 +/- 1.9%; n = 9; p < 0.05 vs CGP in intact aortic rings). Endothelium-independent relaxation to CGP was resistant to nadolol or L-748.337 treatment which seems to rule out the involvement of beta 1, beta 2 and beta 3-AR. Endothelium-independent relaxation to CGP was significantly reduced by SQ 22536 or MDL 12330A, non-selective adenylyl cyclase inhibitors, indicating a role of cAMP-dependent pathway in CGP response. By contrast, the relaxant effect to CGP was not modified by SQ 22536 in SHR. In conclusion, these results show that [1] functional response to beta 3-AR stimulation was not altered in hypertension [2]. CGP activated an atypical beta-AR distinct from beta 1, beta 2 and beta 3-AR, partly through cAMP-dependent pathway. Impaired atypical beta-AR relaxation to CGP in SHR could contribute to the pathogenesis of the hypertension.