Brittleness problem imposes a severe restriction on the potential application of tungsten as high-temperature structural material. In this paper, a novel toughening method for tungsten is proposed ...based on reinforcement by tungsten wires. The underlying toughening mechanism is analogous to that of fiber-reinforced ceramic matrix composites. Strain energy is dissipated by debonding and frictional sliding at engineered fiber/matrix interfaces. To achieve maximum composite toughness fracture mechanical properties have to be optimized by interface coating. In this work, we evaluated six kinds of ZrOx-based interface coatings. Interfacial parameters such as shear strength and fracture energy were determined by means of fiber push-out tests. The parameter values of the six coatings were comparable to each other and satisfied the criterion for crack deflection. Microscopic analysis showed that debonding occurred mostly between the W filament and the ZrO coating. Feasibility of interfacial crack deflection was also demonstrated by a three-point bending test.
Severe plastic deformation using high-pressure torsion of ternary Cu-based materials (CuFeCo and CuFeNi) was used to fabricate bulk samples with a nanocrystalline microstructure. The goal was to ...produce materials featuring the granular giant magnetoresistance effect, requiring interfaces between ferro- and nonmagnetic materials. This magnetic effect was found for both ternary systems; adequate subsequent annealing had a positive influence. The as-deformed states, as well as microstructural changes upon thermal treatments, were studied using scanning electron microscopy and X-ray diffraction measurements. Deducing from electron microscopy, a single-phase structure was observed for all as-deformed samples, indicating the formation of a supersaturated solid solution. However, judging from the presence of the granular giant-magnetoresistive effect, small ferromagnetic particles have to be present. The highest drop in room temperature resistivity (2.45% at 1790 kA/m) was found in Cu62Fe19Ni19 after annealing for 1 h at 400 {\deg}C. Combining the results of classical microstructural studies and magnetic measurements, insights into the evolution of ferromagnetic particles are accessible.
Background and purpose: Pharmacological validation of novel functions for the alpha sub(2A)-, alpha sub(2B)-, and alpha sub(2C)-adrenoceptor (AR) subtypes has been hampered by the limited specificity ...and subtype-selectivity of available ligands. The current study describes a novel highly selective alpha sub(2C)-adrenoceptor antagonist, JP-1302 (acridin-9-yl-4-(4-methylpiperazin-1-yl)-phenylamine). Experimental approach: Standard in vitro binding and antagonism assays were employed to demonstrate the alpha sub(2C)-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered alpha sub(2C)-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. Key results: JP-1302 displayed antagonism potencies (K sub(B) values) of 1,500, 2,200 and 16 nM at the human alpha sub(2A)-, alpha sub(2B)-, and alpha sub(2C)-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the alpha sub(2)-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha sub(2)-agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, alpha sub(2)-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha sub(2A)-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit. Conclusions and implications: The results provide further support for the hypothesis that specific antagonism of the alpha sub(2C)-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.
BACKGROUND AND PURPOSE: Pharmacological validation of novel functions for the alpha2A-, alpha2B-, and alpha2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and ...subtype-selectivity of available ligands. The current study describes a novel highly selective alpha2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-4-(4-methylpiperazin-1-yl)-phenylamine). EXPERIMENTAL APPROACH: Standard in vitro binding and antagonism assays were employed to demonstrate the alpha2C-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered alpha2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. KEY RESULTS: JP-1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human alpha2A-, alpha2B-, and alpha2C-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the alpha2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha2-agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, alpha2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit. CONCLUSIONS AND IMPLICATIONS: The results provide further support for the hypothesis that specific antagonism of the alpha2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.
Pharmacological validation of novel functions for the alpha2A-, alpha2B-, and alpha2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ...ligands. The current study describes a novel highly selective alpha2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-4-(4-methylpiperazin-1-yl)-phenylamine).
Standard in vitro binding and antagonism assays were employed to demonstrate the alpha2C-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered alpha2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls.
JP-1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human alpha2A-, alpha2B-, and alpha2C-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the alpha2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha2-agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, alpha2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit.
The results provide further support for the hypothesis that specific antagonism of the alpha2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.
We have evaluated a novel, time-resolved fluorometric GTP binding assay for its suitability for functional screening of neuropeptide FF (NPFF) receptor ligands. Our results suggest that this assay, ...which relies on the use of a europium-labeled GTP analogue, Eu-GTP, provides a powerful alternative to the
35Sguanosine-5′-
O-(3-thio)triphosphate binding assay for assessing the functional properties of NPFF analogs. Further, we demonstrate that the tetrapeptide PMRF-NH
2 exhibited high agonist potency at the NPFF2 receptor, and that the efficacies of this peptide and another shortened NPFF analog were greater than that of NPFF.
The environmentally cued production of cryptic green/yellow or brown/melanized pupae is widespread in butterflies, occurring in the Nymphalidae, Pieridae, and the Papilionidae subfamily Papilioninae. ...The dimorphism is controlled by the hormone pupal melanization reducing factor (PMRF). In the nymphalid
Inachis io dibutryl cAMP mimics PMRF, and inhibits pupal melanization. However, in the papilionid
Papilio polyxenes PMRF stimulates browning, suggesting that the control of pupal color by PMRF has evolved independently in the swallowtail and nymphalid–pierid lineages. We examined this hypothesis by using ligatures to prevent hormone release in five species representing three Papilioninae tribes. One species,
Papilio glaucus, produces only brown pupae. Ligatures resulted in green cuticle posterior to the ligature in all five swallowtail species, including
P. glaucus, suggesting that the mode of action of PMRF is the same in the three tribes. We also found that in
P. polyxenes injections of dibutryl cAMP into prepupal larvae mimic the effect of PMRF, by causing dose-dependent pupal browning. Our results support the hypothesis that the control of pupal color by PMRF has evolved independently in the two lineages. The observation that green pupal color can be induced in
P. glaucus by ligature indicates that environmentally cued pupal color could evolve by facultative inhibition of PMRF release.
Although impairment of vascular smooth muscle contractility occurs during the late stages of polymicrobial sepsis, it is not known whether this also occurs in early stages of sepsis and, if so, ...whether different mechanisms are responsible for such smooth muscle dysfunction. To determine this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Immediately following CLP or sham operation, all animals received 3 ml/100 g body wt normal saline. Septic and sham rats were then sacrificed at 5, 10, or 35 hr after CLP (5-10 hr post-CLP, early sepsis; 35 hr post-CLP, late sepsis), and aortic rings were prepared for contraction studies using organ chamber technique. Dose-response contractions to norepinephrine (NE, 10(-9) to 10(-5) M; receptor-mediated process) and KCl (7.5 to 90 mM; non-receptor mediated) were determined in rings with or without intact endothelium. Endothelial cell removal was confirmed by the absence of relaxation in response to an endothelium-dependent vasodilator, acetylcholine. The results indicate that NE- and KCl-induced vascular contractions were not altered at 5 hr after CLP. At 10 hr post-CLP, however, vascular contractility decreased markedly in the endothelium intact rings. Endothelium removal at 10 hr after CLP restored the contraction induced by NE and KCl to sham levels. In contrast, the smooth muscle contractile dysfunction, observed during late sepsis (35 hr post-CLP), was not restored by the removal of endothelium. Thus, the smooth muscle impairment, observed in early sepsis, is due to mediators released from septic endothelium.
The functional characteristics of two putative neuropeptide FF (NPFF) antagonists, BIBP3226 and PFR(Tic)amide, on the human neuropeptide FF receptor subtype 2 (hNPFF2) were investigated. ...Surprisingly, PFR(Tic)amide was shown to exhibit agonist properties in the
35
S
guanosine-5′-
O-(3-thio)triphosphate (
35
S
GTPγS) binding assay. The efficacy of PFR(Tic)amide was significantly greater than that of (1DMe)Y8Fa, a stable analog of NPFF, and PFR(Tic)amide can therefore be classified as a ‘super-agonist’. BIBP3226 did act as a reversible competitive antagonist on the hNPFF2 receptor. However, high concentrations of BIBP3226 also non-specifically increased
35
S
GTPγS binding. The usefulness of BIBP3226 as an antagonist tool on the NPFF receptor is thus limited.
Background and purpose:
Pharmacological validation of novel functions for the α2A‐, α2B‐, and α2C‐adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype‐selectivity of ...available ligands. The current study describes a novel highly selective α2C‐adrenoceptor antagonist, JP‐1302 (acridin‐9‐yl‐4‐(4‐methylpiperazin‐1‐yl)‐phenylamine).
Experimental approach:
Standard in vitro binding and antagonism assays were employed to demonstrate the α2C‐AR specificity of JP‐1302. In addition, JP‐1302 was tested in the forced swimming test (FST) and the prepulse‐inhibition of startle reflex (PPI) model because mice with genetically altered α2C‐adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild‐type controls.
Key results:
JP‐1302 displayed antagonism potencies (K
B values) of 1,500, 2,200 and 16 nM at the human α2A‐, α2B‐, and α2C‐adrenoceptor subtypes, respectively. JP‐1302 produced antidepressant and antipsychotic‐like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine‐induced PPI deficit. Unlike the α2‐subtype non‐selective antagonist atipamezole, JP‐1302 was not able to antagonize α2‐agonist–induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, α2‐agonist‐induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the α2A‐adrenoceptor subtype. In contrast to JP‐1302, atipamezole did not antagonize the PCP‐induced prepulse‐inhibition deficit.
Conclusions and implications:
The results provide further support for the hypothesis that specific antagonism of the α2C‐adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.
British Journal of Pharmacology (2007) 150, 391–402. doi:10.1038/sj.bjp.0707005
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