Ability Of Cu Research Articles

Copper signaling in the mammalian nervous system: Synaptic effects

Copper is an essential metal present at high levels in the CNS. Its role as a cofactor in mitochondrial ATP production and in essential cuproenzymes is well defined. Menkes and Wilson's diseases are severe neurodegenerative conditions that demonstrate the importance of Cu transport into the secretory pathway. In the brain, intracellular levels of Cu, which is almost entirely protein bound, exceed extracellular levels by more than 100-fold. Cu stored in the secretory pathway is released in a Ca(2+)-dependent manner and can transiently reach concentrations over 100 μM at synapses. The ability of low micromolar levels of Cu to bind to and modulate the function of γ-aminobutyric acid type A (GABA(A)) receptors, N-methyl-D-aspartate (NMDA) receptors, and voltage-gated Ca(2+) channels contributes to its effects on synaptic transmission. Cu also binds to amyloid precursor protein and prion protein; both proteins are found at synapses and brain Cu homeostasis is disrupted in mice lacking either protein. Especially intriguing is the ability of Cu to affect AMP-activated protein kinase (AMPK), a monitor of cellular energy status. Despite this, few investigators have examined the direct effects of Cu on synaptic transmission and plasticity. Although the variability of results demonstrates complex influences of Cu that are highly method sensitive, these studies nevertheless strongly support important roles for endogenous Cu and new roles for Cu-binding proteins in synaptic function/plasticity and behavior. Further study of the many roles of Cu in nervous system function will reveal targets for intervention in other diseases in which Cu homeostasis is disrupted.

Synergy of Components in CuZnO and CuZnO/Al2O3 on Methanol Synthesis: Analysis at the Site Level by SSITKA

In the present study, the effects of the individual components and an Al2O3 support on CuZnO for methanol (MeOH) synthesis were investigated at the site level for the first time using steady-state isotopic transient kinetic analysis and reaction at 250 °C and 1.8 atm. The presence of ZnO was found to decrease the hydrocarbon (CH4 primarily) formation ability of Cu. By comparing the surface reaction parameters, it could be shown that Cu and ZnO catalysts (supported on Al2O3) exhibit lower MeOH formation rates compared to their combination in either CuZnO or CuZnO/Al2O3 due, especially, to lower intrinsic “site” activities. The synergy between Cu and ZnO was most obvious in the increase in MeOH TOFITK (a measure of site activity for MeOH formation), more than double that for Cu without ZnO. Al2O3 did not seem to impact MeOH synthesis in any way other than to increase dispersion of the CuZnO. However, it did furnish acid sites for the conversion of some MeOH to DME.

Surface-plasmon-based colorimetric detection of Cu(II) ions using label-free gold nanoparticles in aqueous thiosulfate systems

We report colorimetric, label-free and non-aggregation-based gold nanoparticle (AuNP) probes for the highly selective detection of Cu(II) ions in aqueous environments. This detection scheme relies on the ability of Cu(II) ions to catalyze the leaching of gold at room temperature in the presence of thiosulfate species and ammonia. This simple and cost-effective probe provides rapid detection of Cu(II) ions at concentrations as low as 10 ppm. A similar detection method using AuNPs in ammonia-free thiosulfate solution is also viable at moderate reaction temperature (50 °C). The ammonia-free method also leads to marked damping and red-shifting of the surface plasmon resonance signal of the AuNP dispersion. The two methods clearly differ in the nature of the surface plasmon damping phenomenon, and their working mechanisms are plausibly explained based on the experimental investigations.

Analytical methods to determine the comparative DNA binding studies of curcumin–Cu(II) complexes

DNA interaction studies of two mononuclear [1:1(1); 1:2(2)] copper(II) complexes of curcumin have been studied. The interaction of these complexes with CT-DNA has been explored by physical methods to propose modes of DNA binding of the complexes. Absorption spectral titrations of complex 1 with CT-DNA shows a red-shift of 3nm with the DNA binding affinity of Kb, 5.21×104M−1 that are higher than that obtained for 2 (red-shift, 2nm; Kb, 1.73×104M−1) reveal that the binding occurs in grooves as a result of the interaction is via exterior phosphates. The CD spectra of these Cu(II) complexes show a red shift of 3–10nm in the positive band with increase in intensities. This spectral change of induced CD due to the hydrophobic interaction of copper complexes with DNA is the characteristic of B to A conformational change. The EB displacement assay also reveals the same trend as observed in UV–Vis spectral titration. The addition of complexes 1 and 2 to the DNA bound ethidium bromide (EB) solutions causes an obvious reduction in emission intensities indicating that these complexes competitively bind to DNA with EB. The positive shift of both the Epc and E0′ accompanied by reduction of peak currents in differential pulse voltammogram (DPV), upon adding different concentrations of DNA to the metal complexes, are obviously in favor of strong binding to DNA. The super coiled plasmid pUC18 DNA cleavage ability of Cu(II) complexes in the presence of reducing agent reveals the single strand DNA cleavage (ssDNA) is observed. The hydroxyl radical (HO) and the singlet oxygen are believed to be the reactive species responsible for the cleavage.

Mechanical and superconducting properties of 6-filament MgB2 wires reinforced by Cu, Cu–Nb and NbTi

The comparisons of strengthening abilities of Cu, Cu–Nb, and NbTi for 6-filamentary MgB1.92(TiC)0.08/Nb/Cu wires and the electrical properties of the best reinforced wire are investigated. The Cu–Nb reinforcing core is more appropriate for manufacturing MgB2 wires. It is observed that the Cu–Nb reinforced wire sintered at 750°C for 2h has the highest yield strength of 101.8MPa. With the sintering temperature increasing, the yield strength of the Cu–Nb and NbTi reinforced wires increased while the value slightly decreased in the case of Cu reinforced one in this study. According to our calculations, those mechanical properties are suitable for the application requirements of superconducting magnets in low field with the critical engineering current Ic of 197 and 205A (Jce exceeding 1.7×104 and 1.8×104A/cm2) before and after 70MPa axial load on the wire at 20K, 1.5T respectively. And within the working temperature range from 10K to 35K, the Cu–Nb reinforced wires show the lowest resistivity as well. The Cu–Nb reinforced long MgB1.92(TiC)0.08/Nb/Cu wires with unit length over 1km have already been manufactured using the similar process. The Cu, Cu–Nb, and NbTi reinforced 6-filament MgB1.92(TiC)0.08/Nb/Cu wires are fabricated by in situ PIT (Powder-in-Tube) method respectively.

Effect of Gold Content on the Reliability of SnAgCu Solder Joints

Electroplated Ni/Au over Cu is a popular metallization for printed circuit board finish as well as for component leads, especially wire-bondable high-frequency packages, where the gold thickness requirement for wire bonding is high. The general understanding is that less than 3 wt% of Au is acceptable in SnPb solder joints. However, little is known about the effect of Au content on the reliability of SnAgCu solder joints. The purpose of this paper is to determine the acceptable level of Au in SAC305 solder joints. Three different package platforms with different Au thicknesses were assembled on boards with two different Au thicknesses using a standard surface mount assembly line in a realistic production environment. The assembled boards were divided into three groups: as-built, isothermally aged at 125 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">°</sup> C for 30 days, and isothermally aged at 125 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">°</sup> C for 56 days. All boards were then subjected to accelerated mechanical reliability tests including random vibration and drop testing. The results show that solder joints with over 10 wt% Au are unacceptable. If Cu is available to dissolve in the solder joint, then an Au content under 5 wt% will not significantly degrade the reliability of the solder joint. When Ni layers are present on both the board and the component sides of the interface, this limits the ability of Cu to dissolve into the solder joint, and hence an Au content under 3 wt% is acceptable. The failure mechanism for solder joints with high Au content is fractures through the AuSn <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">4</sub> intermetallic compound. Additional findings confirmed that there is a danger of placing parts near high-stress areas and that a high level of voiding reduced reliability.

Improving the quality of barrier/seed interface by optimizing physical vapor deposition of Cu Film in hollow cathode magnetron

The quality of physical vapor deposition (PVD) grown barrier/seed interface in Cu interconnect metallization was significantly improved by enhancing Cu nucleation on the Ta barrier surface. This was accomplished through filtering of nonenergetic species from the deposition flux, increasing the fraction of Cu ions, improving metal ion flux uniformity, and minimizing gas ion bombardment of the growing film. The self-sputtering ability of Cu was combined with a magnetically confined high-density plasma in the Novellus hollow cathode magnetron (HCM®) PVD source. Spatial profiles of plasma density and temperature, as well as ion flux, metal ion fraction, and ion energy, were measured by planar Langmuir probes, quartz crystal microbalances, and gridded energy analyzers, all located at the wafer level. Multiple criteria, such as seed step coverage and roughness, the seed layer’s resistance to agglomeration, and its stability in the plating bath, have been used to evaluate interface quality. As a result, a new and improved Cu PVD process which demonstrates superior stability during subsequent process steps and ensures successful electrofill performance with a more than 50 % reduction in minimal requirement of field thickness as well as sidewall thickness has been developed.

Towards new horizons in brain PET

There is an increasing need in routine clinical neuroimaging for simple and accessible methodologies which can reduce examination times but still provide reliable information about the status of the disease. More widespread use of PET technology would be favoured by avoiding the investment and running expenses associated with an onsite cyclotron. The clinical implementation of PET would benefit from cost reductions. The use of isotope generators could potentially allow centres remote from a cyclotron to have access to a wide range of radiopharmaceuticals. The zinc-62/copper-62 (Zn/Cu) generator is a closeto-optimal radionuclide source for labelling chemically diverse ligands. Zn is produced by the nuclear reaction Cu(p,n)Zn with a proton beam of 27.5 MeV, fitting well with on-demand production by a regional medium-energy cyclotron [1–3]. The generator is compact, is easy to produce and ship and is relatively inexpensive, and the eluate is either automatically chelated by thiosemicarbazone complexes (i.e. ATSM and PTSM) [4] or mixed manually [5]. The 9.3-h half-life of Zn limits the use of the generator to a single day, during which up to 20 doses can be produced. Conversely, the 9.7-min half-life of Cu is short enough to offer the opportunity in a single patient to perform sequential studies as well as studies involving dual tracer combinations in which a Cu investigation can be combined with, for example, an F labelled radiopharmaceutical to provide complementary information [5, 6]. The almost exclusive β emission (97%) of Cu impacts positively on the true coincidences and hence on the sensitivity and count rate, giving good counting statistics even for less-sensitive PET cameras. The short physical halflife of Cu and the biodistribution patterns of its thiosemicarbazone complexes result in effective doses (0.36 mSv/ 100 MBq) of the same order as O-water (0.1 mSv/ 100 MBq), which is in the lower range of the most used radiopharmaceuticals (i.e. F-FDG, 1.9 mSv/100 MBq) [7]. On the other hand, the high positron energy of Cu (E βmax=2.93 MeV) results in a large positron range prior to annihilation and consequently to a significant resolution loss (an intrinsic spatial resolution loss of 4.0 mm compared to 0.7 mm for F). This estimated blur could limit the ability of Cu to precisely detect changes in small areas. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging Isozaki et al. [8] report a wellconducted study with highly accurate assessments of haemodynamic status using a minimally invasive and time-effective methodology. They used for the first time in cerebrovascular disease Cu-ATSM, a radiopharmaceutical originally developed for probing hypoxic tissue [9] and recently proven to be effective in imaging tumours [5] and acute stroke [6]. They were able to demonstrate a highly significant relationship between the early phase (first 3 min after injection) uptake of Cu-ATSM and cerebral blood flow images as evaluated by a bolus injection of O-water. Moreover, the ratio between its late phase (last 10 min after injection) and the early phase was significantly correlated with the oxygen extraction fraction as measured by a bolus inhalation of O2. The conclusion was that dynamic PET acquisition with CuATSM provides information about the haemodynamic status of patients with chronic cerebrovascular disease equivalent to M. Pagani (*) Institute of Cognitive Sciences and Technologies, CNR, Via Palestro 32, 00185 Rome, Italy e-mail: marco.pagani@istc.cnr.it

Sequence-independent Control of Peptide Conformation in Liposomal Vaccines for Targeting Protein Misfolding Diseases

Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be modulated post-liposome assembly by the addition of distinct small molecule β-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing β-sheet aggregated lipopeptide (Palm1-15) induced polyclonal IgG antibodies that specifically recognized β-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases, such as Alzheimer disease.

Removal of Cu(II) from aqueous solution using the rice husk carbons prepared by the physical activation process

Abstract The adsorption of Cu(II) from aqueous solution by carbons prepared from rice husk through pyrolysis and steam activation was studied. The rice husk carbon was characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM), and its pore structure was also examined. After comparing different characteristics of the carbons prepared under different conditions and their adsorption abilities of Cu(II), the optimum temperature for pyrolysis and steam activation was chosen as 700 and 750 °C, respectively, using 3% (V/V) steam as the best activation gas. It was found that the Cu(II) adsorption on the rice husk derived carbons was pH and temperature dependent with an optimum pH value of 5.0, and an equilibrium time of 24 h. The adsorption kinetics and isotherms of Cu(II) by the rice husk derived carbons were also investigated under four different temperatures, and good correlation coefficients were obtained for the pseudo-second-order kinetic models, and the Langmuir isotherm model fitted very well with the experimental data. The mean free energy E (kJ mol −1 ) obtained in the Dubinin-Radushkevitch (D-R) adsorption isortherm equation indicated a chemical ion-exchange mechanism. Several thermodynamic parameters were also caculated to predict the nature of adsorption process.

Copper-Catalyzed Aerobic Oxidative Functionalization of an Arene C−H Bond: Evidence for an Aryl-Copper(III) Intermediate

Recent studies have highlighted the ability of Cu(II) to catalyze the aerobic oxidative functionalization of C-H bonds; however, very little is known about the mechanisms of these reactions. Here, we describe the Cu(II)-catalyzed C-H methoxylation and amidation of a macrocylic arene substrate with O(2) as the stoichiometric oxidant. Kinetic and in situ spectroscopic studies demonstrate the involvement of three different oxidation states of Cu in the catalytic mechanism, including an aryl-Cu(III) intermediate. These observations establish a novel mechanistic pathway that has implications for numerous other Cu-catalyzed aerobic oxidation reactions.

Fabrication and Microstructure of C/Cu Composites

AbstractC/Cu composites were prepared by a melting infiltration technique in vacuum. In order to improve the wettability between Cu and carbon fibers, Ti (8 wt.‐%) and Cr (1 wt.‐%) were added to the Cu alloy. Microstructures of the composites and interface between C and Cu were investigated by XRD, SEM, EDS and HRTEM. The results show that the Ti and Cr improved the wettability between Cu and CC preform and the infiltration ability of Cu into CC preform greatly. The prepared C/Cu composites are characterized as having good interface bonding and high density. In the process of infiltration, Ti and Cr concentrate on the boundary of carbon fiber. Formation of TiC results from the reaction of Ti and C between Cu and carbon fiber.

Cu adhesion on tantalum and ruthenium surface: Density functional theory study

This work reports a first-principles study of copper adhesion on Ta(110) and Ru(0001) surface with the density functional theory. Adsorption energy, electron density difference, and geometrical structures of Cu on pure, oxygen, and nitrogen doped Ta(110), Ru(0001) surfaces, and Ru doped Ta(110) surface were investigated. By analyzing the calculated results and the existing experimental results, it is found that although Ta has stronger chemical interaction with Cu, its larger lattice mismatch with Cu, and easy oxidation and nitridation make Ta a poorer Cu adhesion layer in comparison with Ru. The adhesion ability of Cu on Ta can be improved by doping Ru in Ta. The agglomeration of Cu on Ta or Ru is also studied. The calculation results show that Cu adsorbed on Ta(110) surface is more likely to be desorbed and agglomerated on the top of the second Cu atom layer. The substitutional oxygen OTa in Ta will stimulate the agglomeration of Cu on the Ta surface.

Effectiveness of copper contact surfaces in reducing the microbial burden (MB) in the intensive care unit (ICU) of hospital del Cobre, Calama, Chile

Background: The environment plays a role as reservoir and transmission of microbes in hospital settings. In vitro studies have demonstrated the microbicidal activity of copper (Cu). We studied the ability of Cu to reduce the MB associated with commonly contact surfaces within an ICU of Hospital del Cobre de Calama, located in a semi-desert area in the north of Chile. Methods: Copperized (Cu) surfaces (bed rails, bed lever, tray tables, chair arms, touch screen monitor stylus, and IV poles) were placed into 3 randomly selected ICU rooms. Three paired rooms were compared by measuring the MB during 18 weeks. The mean(m) MB for each Cu object, determined as colony forming units (cfu)/100cm2 was compared to noncopper rooms. Antimicrobial efficacy of Cu was calculated as the difference in mMB between the Cu and non-Cu objects. The environmental cleaning procedures were equivalent for Cu and non-Cu rooms. The Kruskal-Wallist test for two groups was used. Results: The mMB associated with 594 Cu surfaces from 54 rooms containing Cu was compared against the mMB of equivalent surfaces from 54 non-Cu rooms from an ICU with humidity between 7.2 to 19.7%. Cu was effective in reducing mMB on all 6 surfaces tested (bed rails by 86%, bed lever by 84%, tray tables by 93%, chair arms by 88%, monitor pen by 49%, and IV poles by 89%). Total mMB count in rooms with Cu (2,142 cfu/100cm2) was significantly lower than in rooms without Cu (13,215 cfu/100cm2) p < 0.00001 Staphylococci were the most predominant microorganism isolated. Cu was equivalently effective and significant in reducing the staphylococcal burden associated with the objects, p < 0.00001. MRSA and VRE were never isolated, regardless of the presence of Cu. Gram negatives were infrequently isolated from some surfaces, and Cu reduced the Gram negative burden by 74%–88%. Conclusion: The antimicrobial effect of Cu was evident and significant in this arid region of Chile; reduced the total mMB, mMB of staphylococcal and Gram negative in ICU rooms containing Cu. Further studies regarding the clinical impact of reducing the mMB by Cu objects within the environment of hospitals is warranted. Abstracts for SupplementInternational Journal of Infectious DiseasesVol. 14Preview Full-Text PDF Open Archive

Effect of adding elements on glass-forming ability of (Cu47Ti34Zr11Ni8)99M (M=Al, Be, Si, Nb, Fe and Co) bulk amorphous alloys

Bulk amorphous alloys (Cu 47 Ti 34 Zr 11 Ni 8 ) 99 M (M = Al, Be, Si, Nb, Fe and Co) were prepared by arc melting and suction casting. The effect of the addition of alloying elements on the glass-forming ability and thermal stability of Cu 47 Ti 34 Zr 11 Ni 8 was studied. With the addition of Si, the glass-forming ability of the Cu 47 Ti 34 Zr 11 Ni 8 alloy is improved, which is evidenced by the increase of supercooled liquid region Δ T x , the reduced glass transition temperature T rg , γ parameter, K H stability parameter. With the addition of Al, Be, Co, Fe and Nb, the glass-forming ability of the alloys is decreased. Calculation of the formation enthalpies of amorphous alloys by using Miedema’s theory, show that the glass-forming ability of the (Cu 47 Ti 34 Zr 11 Ni 8 ) 99 M decreases with increasing formation enthalpy of the amorphous phase except in the case of Cu 47 Ti 34 Zr 11 Ni 8 . The glass transition activation energy linearly increases with increasing atom size parameter δ .

DNA cleavage promoted by trigonal-bipyramidal zinc(II) and copper(II) complexes formed by asymmetric tripodal tetradendate 2-[bis(2-aminoethyl)amino]ethanol

Asymmetric trigonal-bipyramidal Zn(II) complex 1 formed by 2-[bis(2-aminoethyl)amino]ethanol (L) was found to be able to promote the cleavage of supercoiled plasmid DNA pBR322 to the nicked and linear DNA via a hydrolytic manner but only in neutral Tris–HCl buffer, no cleavage was observed in HEPES or NaH2PO4/Na2HPO4 buffer. However, the copper complex 2 of L, possessing the similar coordination geometry, can only promote DNA cleavage via an oxidative mechanism in the presence of ascorbic acid. ESI-MS study implies that complex 1 exist mainly as [Zn(L)]2+/[Zn(L–H)]+ in neutral Tris–HCl buffer. Moreover, there is no discriminable species for complex 1 in HEPES or NaH2PO4/Na2HPO4 buffer. A phosphate activation mechanism via phosphate coordinating to Zn(II) center of [Zn(L)]2+/[Zn(L–H)]+ to form the stable trigonal-bipyramidal structure is proposed for the hydrolytic cleavage promote by complex 1. For complex 2, the abundance of [Cu(L)Cl]+ is higher than that of [Cu(L)]2+/[Cu(L–H)]+ in Tris–HCl buffer. The lower phosphate binding/activating ability of Cu(II) in complex 2 may be the origin for its incapability to promote the hydrolytic DNA cleavage. However, the readily accessible redox potential of Cu(II) makes complex 2 promote the oxidative DNA cleavage. Although the DNA cleavage promoted by complex 1 has no specificity, trigonal-bipyramidal Zn(II) complexes formed by asymmetric tripodal polyamine with ethoxyl pendent should be a novel potential model for practical artificial nuclease.

Positron lifetime evolution during room temperature ageing in Al‐Zn‐Mg‐(Cu)

AbstractThe effect on the formation of vacancy‐solute clusters by the addition of small percentages of Cu to Al‐Zn‐Mg has been studied by positron annihilation lifetime spectroscopy. The results document the ability of Cu to increase the number of vacancies retained after quenching, by forming an additional population of vacancy‐solute clusters in competition with pure Zn clusters. It has also been shown that Cu accelerates the decomposition of the alloy at 150°, thereby leaving a reduced supersaturation of the matrix after an early interruption. An unexpected result is that the curve positron lifetime vs, ageing time at RT displays the symptoms of a change in the nature of the coherent aggregates that occurs in about 10 hours of RT exposure. (© 2009 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

Modular kinetic analysis reveals differences in Cd2+ and Cu2+ ion‐induced impairment of oxidative phosphorylation in liver

Impaired mitochondrial function contributes to copper- and cadmium-induced cellular dysfunction. In this study, we used modular kinetic analysis and metabolic control analysis to assess how Cd(2+) and Cu(2+) ions affect the kinetics and control of oxidative phosphorylation in isolated rat liver mitochondria. For the analysis, the system was modularized in two ways: (a) respiratory chain, phosphorylation and proton leak; and (b) coenzyme Q reduction and oxidation, with the membrane potential (Delta psi) and fraction of reduced coenzyme Q as the connecting intermediate, respectively. Modular kinetic analysis results indicate that both Cd(2+) and Cu(2+) ions inhibited the respiratory chain downstream of coenzyme Q. Moreover, Cu(2+), but not Cd(2+) ions stimulated proton leak kinetics at high Delta psi values. Further analysis showed that this difference can be explained by Cu(2+) ion-induced production of reactive oxygen species and membrane lipid peroxidation. In agreement with modular kinetic analysis data, metabolic control analysis showed that Cd(2+) and Cu(2+) ions increased control of the respiratory and phosphorylation flux by the respiratory chain module (mainly because of an increase in the control exerted by cytochrome bc(1) and cytochrome c oxidase), decreased control by the phosphorylation module and increased negative control of the phosphorylation flux by the proton leak module. In summary, we showed that there is a subtle difference in the mode of action of Cd(2+) and Cu(2+) ions on the mitochondrial function, which is related to the ability of Cu(2+) ions to induce reactive oxygen species production and lipid peroxidation.

Glass forming ability in Cu–Zr binary alloy: Effect of nucleation mode

In the present work, thermodynamic and kinetic calculations were combined to study the glass forming ability of Cu–Zr binary system. Applying thermodynamic association model, the primarily crystallized phase and its corresponding driving force can be determined firstly. Then, the whole Time–Temperature–Transformation (TTT) diagrams basing on homogeneous and heterogeneous nucleation modes have been constructed quantitatively. As for the former case, the critical cooling rate is underestimated by about three orders of magnitude in comparison with the experimental observation. As for the latter case adopting suitable values of catalytic factor f(θ) and potential nuclei N 1, the predictions agree well with the experimental results, and moreover, the nose temperature of TTT diagram is upper-shifted. This has been discussed using a competition of the atomic mobility and the reduced nucleation barrier, as well as its further effect on the nucleation and growth process.

The isatin-Schiff base copper(II) complex Cu(isaepy) 2 acts as delocalized lipophilic cation, yields widespread mitochondrial oxidative damage and induces AMP-activated protein kinase-dependent apoptosis

We previously demonstrated that Bis[(2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N']copper(II) [Cu(isaepy)(2)] was an efficient inducer of the apoptotic mitochondrial pathway. Here, we deeply dissect the mechanisms underlying the ability of Cu(isaepy)(2) to cause mitochondriotoxicity. In particular, we demonstrate that Cu(isaepy)(2) increases NADH-dependent oxygen consumption of isolated mitochondria and that this phenomenon is associated with oxy-radical production and insensitive to adenosine diphosphate. These data indicate that Cu(isaepy)(2) behaves as an uncoupler and this property is also confirmed in cell systems. Particularly, SH-SY5Y cells show: (i) an early loss of mitochondrial transmembrane potential; (ii) a decrease in the expression levels of respiratory complex components and (iii) a significant adenosine triphosphate (ATP) decrement. The causative energetic impairment mediated by Cu(isaepy)(2) in apoptosis is confirmed by experiments carried out with rho(0) cells, or by glucose supplementation, where cell death is significantly inhibited. Moreover, gastric and cervix carcinoma AGS and HeLa cells, which rely most of their ATP production on oxidative phosphorylation, show a marked sensitivity toward Cu(isaepy)(2). Adenosine monophosphate-activated protein kinase (AMPK), which is activated by events increasing the adenosine monophosphate:ATP ratio, is deeply involved in the apoptotic process because the overexpression of its dominant/negative form completely abolishes cell death. Upon glucose supplementation, AMPK is not activated, confirming its role as fuel-sensing enzyme that positively responds to Cu(isaepy)(2)-mediated energetic impairment by committing cells to apoptosis. Overall, data obtained indicate that Cu(isaepy)(2) behaves as delocalized lipophilic cation and induces mitochondrial-sited reactive oxygen species production. This event results in mitochondrial dysfunction and ATP decrease, which in turn triggers AMPK-dependent apoptosis.