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The stable complex [bis(toluene-3,4-dithiolato)copper(iii)][NEt3H] has been synthesised and characterised as a square-planar Cu(iii) complex by X-ray photoelectron spectroscopy, cyclic voltammetry and DFT calculations. Intriguingly, when fragmented in FTICR-MS, an unusual [(toluene-3,4-dithiolate)Cu(iii)(peroxide)]- complex is formed by reaction with oxygen. Natural 1,2-dithiolenes known to bind molybdenum might stabilise Cu(iii) in vivo.

This paper presents a study of a CH4-CO2 plasma-reforming process carried out in a high power density (5-50 W/cm3), using toroidal transformer-coupled plasma, and operated at low pressure (0.2-0.7 Torr). Using the intermediate between a thermal and nonthermal plasma (electron density, ne ≈ 3 × 1012 cm-3 and a maximum gas temperature of ∼4000-6000 K along the center line), the low-pressure study provides a unique set of conditions to investigate reaction mechanisms, where three-body reactions can be ignored. Reactive species in the plasma were identified by optical emission spectroscopy. End products of the reforming process were measured by mass spectrometry. Quite high conversions of CO2 and CH4 were found (90%), with selectivities for CO and H2 of 80% at 300 sccm feed gas flow rate in a 0.5 Torr plasma, with a mole ratio CO2-CH4 of 1:1. A detailed reaction mechanism is presented, taking into account the combined detection of reactive intermediates in the plasma (H, O, CH, and C2) and stable product downstream.

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure–activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs., The vital roles of metals in nutrients and medicines are not accessible to purely organic compounds.

Discovery of nanometallic Cu0 with Fe0 in the human brain will fundamentally boost our understanding of neurobiology., The chemistry of copper and iron plays a critical role in normal brain function. A variety of enzymes and proteins containing positively charged Cu+, Cu2+, Fe2+, and Fe3+ control key processes, catalyzing oxidative metabolism and neurotransmitter and neuropeptide production. Here, we report the discovery of elemental (zero–oxidation state) metallic Cu0 accompanying ferromagnetic elemental Fe0 in the human brain. These nanoscale biometal deposits were identified within amyloid plaque cores isolated from Alzheimer’s disease subjects, using synchrotron x-ray spectromicroscopy. The surfaces of nanodeposits of metallic copper and iron are highly reactive, with distinctly different chemical and magnetic properties from their predominant oxide counterparts. The discovery of metals in their elemental form in the brain raises new questions regarding their generation and their role in neurochemistry, neurobiology, and the etiology of neurodegenerative disease.

Stem cell therapies are a promising treatment for many patients suffering from diseases with poor prognosis. However, clinical translation is inhibited by a lack of in vivo monitoring techniques to...

Most pet rats have chronic respiratory disease, and end-stage complications are frequently fatal. Drug aerosol delivery in the form of nebulization of antibiotics, expectorants, and bronchodilators is often used as part of their treatment. As rats are obligate nasal breathers, aerosol delivery must be achieved by nasal inhalation, which has the anatomical limitation of a narrower airway lumen. In humans, aerosol delivery of many respiratory drugs is achieved by oral inhalation as it allows administration of very small particles with a concentration loss of only 20% in comparison with 85% by the nasal route. The aim of this pilot study was to determine whether a nebulized fluorescein solution would reach the lungs of rats as no data exists. Ten healthy 13-week-old female Sprague-Dawley rats were nebulized continuously for 15 minutes. The rats were euthanized, and a full postmortem examination was performed. The respiratory tract was sampled, fast-frozen in liquid nitrogen and preserved at −20 °C. Slides were examined with a fluorescence microscope to determine the distribution of fluorescein in the respiratory tract. Fluorescence was observed in the entire respiratory tract of all the nebulized rats, showing that nebulization is an efficient way to deliver medication directly into the alveoli.

In situ, real-time characterization of surfaces exposed to plasmas is of great interest. Common chemical analysis methods such as x-ray photoelectron spectroscopy, Auger electron spectroscopy, and secondary ion mass spectroscopy cannot be used. Here, we discuss the use of glow discharge-optical emission spectroscopy for this purpose. A small coupon piece (aluminum coated with yttria in this study) was mounted on an rf-biased electrode and inserted into an opening in the reactor wall. Silicon or SiO2 substrates on a separately rf-biased electrode were etched in an inductively coupled plasma (ICP) of Cl2/Ar/O2 or C4F8/O2, respectively. Pulsed bias was applied to sputter the surface of the coupon piece in the wall at the edge of the ICP, either after etching in an Ar ICP or during etching in the Cl2/Ar/O2 ICP. Optical emission from the region above the coupon surface was collected and spectrally resolved. The difference in intensity between the coupon bias on and off conditions was used to determine what species were present on the surface. A quantification method for converting emission intensities into atomic composition depth profiles is presented.

Etching of p-Si in 60 mTorr 10%Cl2/90%Ar Faraday-shielded inductively coupled high density plasmas was investigated under both ion-assisted etching (IAE) and photoassisted etching (PAE) conditions. Real-time etching rates and after-etching Si surface chemical compositions were obtained by laser interferometry and vacuum-transfer x-ray photoelectron spectroscopy (XPS), respectively. Precisely controlled ion energy distributions (IEDs) were generated by applying pulsed negative DC bias on the conductive sample stage. Above a 36 eV threshold at a total flow rate of 250 SCCM, the IAE rate increased with the square root of the ion energy. In contrast to the DC bias, etching under RF bias did not exhibit a threshold ion energy because of the wide IED. XPS spectra revealed that the surface layer under PAE conditions had a significantly lower chlorine content, composed of only SiCl. Under IAE conditions, however, silicon dangling bonds (Si•), SiCl2, and SiCl3 were found on the surface, in addition to SiCl, with a relative abundance of SiCl > SiCl2 > SiCl3. The absence of higher chlorides and Si• under PAE conditions suggested that vacuum ultraviolet photons and above threshold-energy ions interact with the surface very differently. By varying the duty cycle of the pulsed DC bias, it was found that the IAE rate scaled with the energetic ion dose, but only for low duty cycles. For higher duty cycles, the apparent IAE yield fell off with an increasing Cl coverage on the surface, as the duty cycle went up, which pointed to a negative synergy (antisynergism) between PAE and IAE as the explanation. This antisynergism was further supported by the observed decrease of the total etching rate with an increasing period of the pulsed DC bias. A plausible mechanism is that increasing the pulsing period causes more near-surface damage, creating more recombination centers that lead to a higher loss rate of electron-hole pairs through recombination, thereby reducing the PAE rate.Etching of p-Si in 60 mTorr 10%Cl2/90%Ar Faraday-shielded inductively coupled high density plasmas was investigated under both ion-assisted etching (IAE) and photoassisted etching (PAE) conditions. Real-time etching rates and after-etching Si surface chemical compositions were obtained by laser interferometry and vacuum-transfer x-ray photoelectron spectroscopy (XPS), respectively. Precisely controlled ion energy distributions (IEDs) were generated by applying pulsed negative DC bias on the conductive sample stage. Above a 36 eV threshold at a total flow rate of 250 SCCM, the IAE rate increased with the square root of the ion energy. In contrast to the DC bias, etching under RF bias did not exhibit a threshold ion energy because of the wide IED. XPS spectra revealed that the surface layer under PAE conditions had a significantly lower chlorine content, composed of only SiCl. Under IAE conditions, however, silicon dangling bonds (Si•), SiCl2, and SiCl3 were found on the surface, in addition to SiCl, with a...

Resistance to the human epidermal growth factor receptor (HER2)-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that cotarget IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1.

Inhibition of cholesteryl ester transfer protein (CETP) has been vigorously pursued as a potential therapy to treat patients who are at an elevated risk for coronary artery disease. Anacetrapib, a novel CETP inhibitor, has been shown clinically to raise HDL cholesterol and reduce LDL cholesterol when provided as monotherapy or when co-administered with a statin. Preclinically, the effects of anacetrapib on the functionality and composition of HDL have been extensively studied. In contrast, the effects of anacetrapib on other parameters related to lipoprotein metabolism and cardiovascular risk have been difficult to explore. The aim of the present investigation was to evaluate the effects of anacetrapib in rhesus macaques and to compare these to effects reported in dyslipidemic humans. Our results from two separate studies show that administration of anacetrapib (150 mg/kg q.d. for 10 days) to rhesus macaques results in alterations in CETP activity (reduced by more than 70%) and HDL cholesterol (increased by more than 110%) which are similar to those reported in dyslipidemic humans. Levels of LDL cholesterol were reduced by more than 60%, an effect slightly greater than what has been observed clinically. Treatment with anacetrapib in this model was also found to lead to statistically significant reductions in plasma PCSK9 and to reduce cholesterol excursion in the combined chylomicron and remnant lipoprotein fraction isolated from plasma by fast protein liquid chromatography. Collectively, these data suggest that rhesus macaques may be a useful translational model to study the mechanistic effects of CETP inhibition.

Chemical reaction probabilities, defined as the number of silicon atoms removed per incident fluorine atom, have been investigated in mixtures of NF3 and SF6 plasmas in an inductively-coupled plasma reactor. Fluorine atom densities were measured by optical emission actinometry, and isotropic etching rates were measured by the degree of undercutting of SiO2-masked silicon by cross-sectional scanning electron microscopy. In addition, atomic force microscopy was used to examine surface morphology of etched Si surfaces. The F atom reaction probabilities derived from isotropic etching rates indicate an ∼30-fold higher reaction probability in SF6 plasmas compared with values in NF3 plasmas. Surfaces etched in SF6 plasmas were much smoother than those etched in NF3 plasmas. The addition of only 10% SF6 to an NF3 plasma produced a much higher reaction probability (∼5-fold) than in a pure NF3 plasma. This surprising enhancement of reaction probabilities for F with Si in SF6 plasmas is further investigated, based on the mechanism of adsorbed sulfur acting as a catalyst to greatly enhance the etching rate of Si. Dilute sulfur solutions in isopropyl alcohol were allowed to evaporate on the masked Si samples, depositing sulfur in relatively high concentrations near mask edges in ∼2 μm diameter periodic “strings of beads.” The sulfur-dosed sample etched several times faster at the center of each bead than a sample not exposed to sulfur that was placed side by side. The catalytic effect of sulfur is ascribed to an enhanced F sticking coefficient and/or decreased desorption rate on a surface covered with sulfur.Chemical reaction probabilities, defined as the number of silicon atoms removed per incident fluorine atom, have been investigated in mixtures of NF3 and SF6 plasmas in an inductively-coupled plasma reactor. Fluorine atom densities were measured by optical emission actinometry, and isotropic etching rates were measured by the degree of undercutting of SiO2-masked silicon by cross-sectional scanning electron microscopy. In addition, atomic force microscopy was used to examine surface morphology of etched Si surfaces. The F atom reaction probabilities derived from isotropic etching rates indicate an ∼30-fold higher reaction probability in SF6 plasmas compared with values in NF3 plasmas. Surfaces etched in SF6 plasmas were much smoother than those etched in NF3 plasmas. The addition of only 10% SF6 to an NF3 plasma produced a much higher reaction probability (∼5-fold) than in a pure NF3 plasma. This surprising enhancement of reaction probabilities for F with Si in SF6 plasmas is further investigated, based o...

Studies of power-modulated chlorine inductively coupled plasmas (ICPs) bounded by yttria-coated chamber walls are presented. Time-resolved optical emissions from Cl and Xe actinometry trace gas were recorded over the 740–920 nm region as power at 13.56 MHz was modulated between high power and no power. The intensity ratio of Cl-to-Xe emission, proportional to Cl number density, nCl, followed the modulation in power, allowing Cl heterogeneous loss coefficients, γCl, to be obtained from a simple time-resolved, 0-dimensional model of the afterglow period that best matched computed relative changes in nCl at the beginning and end of the powered period, with γCl as the only adjustable parameter. This approach only requires a treatment of diffusion and avoids complications introduced by attempting simulations of the full modulation period. Cl recombination coefficients were determined on the mostly yttria surfaces for Cl2 ICPs (a) immediately after NF3 plasma cleaning (γCl = 0.20), (b) during long exposure to the Cl2 plasma with no substrate bias (γCl = 0.11), and (c) during Si etching with substrate bias (γCl = 0.055-0.070). For Cl2/5% O2 ICPs, these values are 0.28, 0.17, and 0.030, respectively. These results compare favorably to qualitative behavior reported previously for continuous Cl2 and Cl2/O2 ICPs in this yttria-coated chamber.Studies of power-modulated chlorine inductively coupled plasmas (ICPs) bounded by yttria-coated chamber walls are presented. Time-resolved optical emissions from Cl and Xe actinometry trace gas were recorded over the 740–920 nm region as power at 13.56 MHz was modulated between high power and no power. The intensity ratio of Cl-to-Xe emission, proportional to Cl number density, nCl, followed the modulation in power, allowing Cl heterogeneous loss coefficients, γCl, to be obtained from a simple time-resolved, 0-dimensional model of the afterglow period that best matched computed relative changes in nCl at the beginning and end of the powered period, with γCl as the only adjustable parameter. This approach only requires a treatment of diffusion and avoids complications introduced by attempting simulations of the full modulation period. Cl recombination coefficients were determined on the mostly yttria surfaces for Cl2 ICPs (a) immediately after NF3 plasma cleaning (γCl = 0.20), (b) during long exposure to t...

Nitric oxide is a vital signaling molecule that controls blood flow and oxygenation and nitrite serves as an important reservoir for nitric oxide in biology. While copper containing enzymes are known to reduce nitrite to nitric oxide, herein we report a new pathway to release nitric oxide via oxygen atom transfer from nitrite at a copper(ii) site.

In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.

Species excitation mechanisms were studied, using optical emission spectroscopy, in a helium 200 kHz radio frequency (RF) plasma jet, emerging into the open air at 1 atm. The jet impinged on a dielectric substrate of either MgF2 or quartz. Optical emissions between 115 and 950 nm were recorded through the substrate either along the jet axis or at a steep angle to isolate emissions originating from the region near the substrate surface. Time-resolved emission was observed close to the substrate surface only during a brief period near the positive peak of the applied RF voltage. No emission close to the substrate was observed during the negative voltage with the exception of a weak emission from N2 (C3Πu → B3Πg) just prior to the peak negative voltage. N2+, H, O, OH, and NO emissions along the discharge axis, from impurities in the He feed, or air diffusing into the He jet just downstream of the end of the tube (nozzle), were dominated by Penning ionization of N2 and dissociative excitation of water and O2 by He metastables (He*). Unlike the fully modulated electron-impact excited emission from N2 and He, emissions produced by collisions with He* were weakly modulated during the RF period and were shifted in phase with respect to the peak positive or peak negative voltage. This was attributed to vacuum ultraviolet emissions, in the radiation-trapped environment of atmospheric pressure, that produced He* outside the discharge tube even during the period when the plasma was confined inside the tube. N2 emission revealed a weak ionization wave propagating during the positive voltage period, well before the peak positive voltage. At peak positive voltage, ionization and excitation in the gap between the nozzle and the substrate maximized. The plasma positively charged the substrate, resulting in the brief N2 emission observed during the negative voltage period, as electrons drifted toward the substrate to neutralize the positive charge.Species excitation mechanisms were studied, using optical emission spectroscopy, in a helium 200 kHz radio frequency (RF) plasma jet, emerging into the open air at 1 atm. The jet impinged on a dielectric substrate of either MgF2 or quartz. Optical emissions between 115 and 950 nm were recorded through the substrate either along the jet axis or at a steep angle to isolate emissions originating from the region near the substrate surface. Time-resolved emission was observed close to the substrate surface only during a brief period near the positive peak of the applied RF voltage. No emission close to the substrate was observed during the negative voltage with the exception of a weak emission from N2 (C3Πu → B3Πg) just prior to the peak negative voltage. N2+, H, O, OH, and NO emissions along the discharge axis, from impurities in the He feed, or air diffusing into the He jet just downstream of the end of the tube (nozzle), were dominated by Penning ionization of N2 and dissociative excitation of water and O2 ...

In low-pressure plasmas commonly used in materials processing, plasma–wall inter-actions play a crucial role in the evolution of the plasma properties both over time and across large-area wafers. We have recently studied the heterogeneous recombination of O and Cl atoms on reactor walls in O2 and Cl2 plasmas through both experiments and modeling. The Langmuir–Hinshelwood (i.e., delayed) recombination was investigated using a “spinning-wall” technique in which a portion of the substrate surface is periodically exposed to an inductively coupled plasma and to a differentially pumped chamber where either Auger electron spectroscopy (AES) or line-of-sight mass spectrometry (MS) is used to detect surface and desorbing species. In this paper, a review of the various effects driving the O and Cl atoms recombination dynamics on anodized aluminum (AA) and stainless steel (SS) surfaces is presented. It is shown that recombination probabilities, γ, can vary following plasma exposure due to surface conditioning. In Cl2 plasmas, γ was also found to depend on the Cl-to-Cl2 number density ratio, a mechanism ascribed to a competition for adsorption sites between Cl and Cl2. We have also determined the recombination rates of Cl atoms in Cl2 high-density plasmas sustained by electromagnetic surface waves by comparing the measured degrees of dissociation of Cl2 to those predicted by an isothermal fluid model. For a reactor with large SS and quartz surfaces exposed to the plasma, γ values and their dependence on the Cl-to-Cl2 number density ratio were consistent with those obtained from the rotating substrate technique. Similar values were obtained for plasmas sustained in a quartz discharge tube. It is expected that for plasmas sustained in or adjacent to a silica tube or plate, the Cl atoms recombination coefficient becomes independent of chamber wall material due to reactor seasoning, producing a silicon-oxychloride layer.

Measurements of electron temperatures (Te) and electron energy distribution functions (EEDFs) in a dual frequency capacitively coupled etcher were performed by using trace rare gas optical emission spectroscopy (TRG-OES). The parallel plate etcher was powered by a high frequency (60 MHz) “source” top electrode and a low frequency (13.56 MHz) “substrate” bottom electrode. Te first increased with pressure up to ∼20 mTorr and then decreased at higher pressures. Increasing the bottom rf power resulted in higher electron temperatures. Electron temperatures in 90% CF4+10% O2 plasmas were similar to those in 80% CF4+20% O2 plasmas. EEDF exhibited bi-Maxwellian characteristics with enhanced high energy tail, especially at pressures >20 mTorr.

In plasma etching processes, the reactor wall conditions can change over time due to a number of intentional and unintentional reasons, leading to a variability in the radical number densities in the plasma, caused by changes in the probabilities for reactions such as recombination at the walls. This leads to loss of reproducibility in the etching process. Here the authors isolated one such effect in which the feed gas was changed in the absence of a substrate. The transient surface composition of an anodized aluminum surface was determined for inductively coupled plasmas as the gas was switched from Cl2 to O2 and vice versa. The study was carried out with the spinning wall method and Auger electron spectroscopy. When the surface was first conditioned in an O2 plasma and then exposed to Cl2 plasmas, a rapid uptake of Cl was found in the first tens of seconds, followed by a slow approach to a steady-state value within ∼5min of plasma exposure. Conversely, when the surface was exposed to a Cl2 plasma for a ...

The authors have investigated the effects of elevated substrate temperature (Ts) on cleaning of boron residues from silicon substrates in 1%H2–Ar plasmas, following etching of HfO2 in BCl3 plasmas. Vacuum-transfer x-ray photoelectron spectroscopy (XPS) provided a measure of total B removal rates, as well as information on individual BClxOy moities. B cleaning rates increased with Ts in an Arrhenius manner, with an apparent activation energy of 1.7kcal∕mol. Conversely, the Si etching rate decreased with increasing substrate temperature with an apparent activation energy of −0.8kcal∕mol. Therefore, when considering selectivity with respect to Si etching, it is advantageous to remove B at higher Ts. For example, at Ts=235°C, ∼90% of B is cleaned from Si in 10s, while

Over the last three decades, semiconductor technology has been aggressively scaled down from micron sized features to 45 nm features. For the upcoming 32 nm technology node, total variation from all sources for a typical gate etch process in low pressure (

We observed the recombination of O atoms on a plasma-conditioned, anodized aluminum surface at room temperature. A cylindrical substrate was continuously exposed to the plasma and to a differential...

The authors have investigated the influence of plasma exposure time (t) on the Langmuir-Hinshelwood (i.e., delayed) recombination of O atoms on electropolished stainless steel surfaces using the spinning-wall method. They found a recombination probability (γO) of 0.13±0.01 after about 60min of plasma exposure. γO decreased to 0.09±0.01 for t⩾12h and was independent of the O flux impinging onto the surface. These recombination probabilities are much lower than those obtained in plasma chambers exclusively made of stainless steel, but similar to values recorded in stainless steel reactors with large silica surfaces exposed to the plasma. Near real-time elemental analysis by in situ Auger electron spectroscopy showed that the stainless steel surface became rapidly coated with a Si-oxide-based layer (Fe:[Si+Al]:O≈2:1:9 for t=60min and 1:2:9 for t=12h), due to the slow erosion of the silica discharge tube and anodized Al chamber walls. Thus, the recombination probability of oxygen atoms on stainless steel in plasma reactors with large amounts of exposed silica is largely determined by the amount of sputtered silica coating the chamber walls.

The authors report for the first time Auger electron spectroscopy (AES) of a surface while it is exposed to a high pressure, reactive environment: a 5mTorr inductively coupled plasma. An anodized aluminum cylindrical substrate (a common plasma reactor coating) was rotated within the reactor wall. Differential pumping allowed the substrate to be exposed to the plasma, and then AES as little as 1ms thereafter. Electron-beam-induced charging, a severe problem for conventional Auger analysis of insulators, is remediated in this experiment because the plasma maintains the surface at a constant floating potential. Chlorine, oxygen, and nitrogen plasmas were investigated. O2 plasmas are effective in removing Cl from Cl2 plasma-conditioned surfaces; N2 plasmas are not. During Cl2 plasma exposure, Cl coverage does not decrease with increasing delay time between plasma exposure and Auger analysis, varied by varying the substrate rotation frequency. This is contrary to desorption of Cl2 (detected by line-of-sight ma...

The chemistry of NH3/Ar/He plasmas was investigated, using a combination of ultraviolet (UV) optical absorption spectroscopy (OAS) and optical emission spectroscopy (OES). Absolute NH3 number densities in 1 Torr plasmas were measured by OAS as a function of inductively coupled plasma power and substrate heater temperature (Th). OES and actinometry were used to determine semi-quantitative H-atom density. A 'self-actinometry' method was introduced to measure the absolute number density of N2 that formed following the dissociation of NH3 and secondary reactions. In this approach, small amounts of N2 are added to the NH3-containing plasma, leading to an increase in the N2(C 3 Πu → B 3 Πg) emission intensity. This provides an accurate calibration factor for converting relative N2 emission intensities into absolute number densities. The number densities of NH3 were found to decrease with increasing power and Th, reaching >90% dissociation at 400 W and 900 K. N2 densities increased with power and Th. The majority of dissociated NH3 was converted to N2 (i.e. the total nitrogen content was conserved in the sum of these two species). The major hydrogen-containing species appeared to be H2; however, a substantial amount of H-atoms (comparable to H2) was present at the highest powers.

A particle-in-cell simulation with Monte Carlo collisions was developed to study ion extraction from a capacitively-coupled argon plasma through a grid. A one-dimensional simulation of the plasma reactor was coupled with a two-dimensional simulation of the sheath region over a grid hole. The 13.56 MHz power applied to the plasma was pulsed 50 µs ON and 50 µs OFF. A dc bias voltage was applied in the afterglow (power OFF fraction of the cycle), to raise the plasma potential and expel ions out of the plasma through the grid. The electron temperature decayed rapidly in the afterglow, minimizing spatial variations of the plasma potential and allowing a nearly mono-energetic ion beam to be extracted. Due to the absence of plasma moulding over the grid holes, the beam was highly directional with an angular spread decreasing with increasing dc bias. The applied dc bias also set the beam energy. Simulation predictions were in good quantitative agreement with measurements. The ion beam could be neutralized by grazing angle collisions on a set of parallel neutralization plates downstream of the extraction grid, to produce a highly directional and nearly mono-energetic neutral beam.

The energy distribution and flux of the fast neutrals and residual ions extracted from a neutral beam source were measured. Positive ions generated in an inductively coupled argon plasma were extracted through a metal grid with high aspect ratio holes. Ions suffered grazing angle collisions with the inside surface of the grid holes, turning into fast neutrals. The neutral energy distribution was always shifted to lower energies compared to the corresponding residual ion energy distribution. The neutralization efficiency increased with power, decreased with boundary voltage and, for thin neutralization grids, was almost independent of plasma gas pressure. The residual ion flux decreased with increasing hole diameter and hole aspect ratio. The fast neutral flux first increased and then dropped as the hole diameter was increased. Results were explained based on plasma molding inside the grid holes.

A particle-in-cell simulation of beam extraction through a hole in contact with plasma was developed. Particular emphasis was placed on plasma moulding over the hole, ion neutralization in high aspect ratio holes and the energy and angular distributions of the residual ions and fast neutrals in the beam downstream of the hole. When the sheath thickness is much smaller than the diameter of the hole, plasma moulding is severe, and the resulting ion and neutral beams are highly divergent. When the sheath thickness is much larger than the hole diameter, plasma moulding is weak, and collimated beams may be extracted. The angular distribution of fast neutrals peaks off axis, less so for smaller diameters and deep holes. Larger diameters and shallow holes (more plasma moulding) yield narrower ion energy distributions. The fast neutral energy distribution is predicted to be similar to that of ions, but it is shifted to lower energies.

BCl3-containing plasmas are used to etch HfO2, a high dielectric constant (“high-k”) material. We have investigated several plasmas for their effectiveness in cleaning boron from the underlying Si surface after BCl3 plasma etching of HfO2, while removing a minimum amount of Si. X-ray photoelectron spectroscopy with vacuum sample transfer was used for surface analysis. B cleaning was optimum in dilute H2 plasmas (in Ar) compared to pure H2 plasmas. Dilute H2 plasmas slowed B cleaning process to a controllable time. In a 1% H2–Ar plasma, 20s was required to clean ∼90% B from the surface after a 60s overetch of HfO2 in BCl3 plasmas. The Si substrate was etched

A series of 21 novel 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides were synthesized and evaluated for the inhibition of IKK-2. In spite of their often modest activity on the enzyme, six selected analogs showed significant inhibition of the production of inflammatory cytokine IL-8 in IL-1β stimulated rheumatoid arthritis-derived synovial fibroblasts, demonstrating their potential usefulness as NF-κB regulators.

Optical emission spectroscopy measurements were performed with added trace probe gases in an atmospheric pressure direct current helium microplasma. Spatially resolved measurements (resolution ~6 µm) were taken across a 200 µm slot-type discharge. Gas temperature profiles were determined from N2 emission rotational spectroscopy. Stark splitting of the hydrogen Balmer-β line was used to investigate the electric field distribution in the cathode sheath region. Electron densities were evaluated from the analysis of the spectral line broadening of Hβ emission. The gas temperature was between 350 and 550 K, peaking nearer the cathode and increasing with power. The electron density in the bulk plasma was in the range (4–7) × 1013 cm−3. The electric field peaked at the cathode (~60 kV cm−1) and decayed to small values over a distance of ~50 µm (sheath edge) from the cathode. These experimental data were generally in good agreement with a self-consistent one-dimensional model of the discharge.

The gene Ag-Aper14 encodes a novel peritrophic matrix (or peritrophic membrane; PM) protein in the mosquito Anopheles gambiae. The Ag-Aper14 protein is merely 89 amino acids long and has a single putative chitin-binding domain. Prior to blood feeding, the Ag-Aper14 protein is stored in secretory vesicles next to the epithelial cell lumenal surface. Immunoelectron microscopy has revealed that Ag-Aper14 co-localizes to the same secretory vesicles as another PM protein, Ag-Aper1, indicating a common mode of regulated secretion. Conversely, Ag-Muc1, an epithelial cell-surface protein, does not co-localize to these secretory vesicles and is detected only on the cell surface. After blood feeding, Ag-Aper14 is secreted and incorporated into the PM that surrounds the ingested blood.

The passivation step used in the “Bosch” process (alternating etching and deposition steps) to perform deep anisotropic silicon etching has been examined in detail. The effect of pressure, inductively coupled plasma power, temperature, flow rate, and bias power on both deposition rate and film composition has been explored over a relatively wide range. Deposition rate was found to vary significantly as a function of temperature, power, and pressure. In contrast, only two film composition regimes were observed: high fluorine-to-carbon ratio (F:C) films (∼1.6) at low pressure∕high power versus low F:C films (∼1.2) at high pressure∕low power. Optical emission spectroscopy of the deposition plasmas also show only two regimes: C2, C3, and F emission dominated (high F:C films) and CF2 emission dominated (low F:C films). A two-step deposition mechanism is assumed: carbon deposition followed by fluorination. Low F concentration and deposition from large fluorine-deficient CxFy species in the CF2-rich plasmas resu...

This article reviews a spectroscopic method for extracting plasma electron temperatures and electron energy distributions: trace rare gases optical emission spectroscopy. Specifically, traces of Ne, Ar, Kr, and Xe are added to the plasma and the intensities of emissions from the Paschen 2p levels are recorded. Intensities are also computed from a model that includes direct excitation from the ground state, as well as two-step excitation through the 3P2, and 3P0 metastable levels. A Maxwellian electron energy distribution function (EEDF), described by an electron temperature (Te), is assumed, and Te is extracted from the best match between the observed and calculated relative emission intensities. By choosing emission from specific sets of levels, the range of electron energies effective in exciting emission can be selected and various portions of the EEDF can be investigated. Accurate measurement of Te depends critically on accurate cross sections for electron impact excitation, and hence a large portion of this article is devoted to a critical review of this subject. Improving on previous treatments, the model for computing emission intensities and electron temperatures includes a complete analysis of the complex excitation and de-excitation of the metastable levels. Previous measurements of Te and EEDFs in chlorine and oxygen inductively coupled plasmas are re-evaluated with the current model. In general, the current version of the model yields similar results; specific differences are discussed.

This paper discusses the growth kinetics of nanometer scale oxide structures grown by atomic force microscope (AFM) assisted lithography. The addition of nitrogen into the sputtering gas during zirconium deposition results in a crystalline ZrN material with oxygen held in solid solution. The diffusion rate of oxygen is high through the crystalline material, allowing it to participate in local anodization and resulting in tall oxide features at low relative humidity. These nanostructures are, in some cases, an order of magnitude higher than previously seen in other material systems. Higher nitrogen content in the plasma results in a crystalline to amorphous transition in the films, and the height enhancement of the AFM-grown features disappears. We propose that mass transport of subsurface oxygen has an influence on surface oxidation kinetics in this material system.

The effect of dosing vehicle excipients such as PEG400, propylene glycol, Tween 80, and hydroxypropyl-beta-cyclodextrin on the accuracy of LC/MS measurements used in pharmacokinetic studies is examined. Using PEG400 as a probe compound, the concentration-time profile of the excipient in plasma from rats dosed both orally and intravenously is determined. These excipient plasma concentrations can result in a 2-5-fold increase in calculated plasma clearance values when the excipient interferes with the quantitation of the dosed compound. This can result in false rejection of a compound in a drug discovery screen. Several plasma purification methods and enhanced chromatographic selectivity are examined as ways to minimize or avoid excipient effects, particularly for very polar compounds. The combination of efficient sample purification and selective chromatography provides an effective way to diminish the significant interference effects of PEG400 and Tween 80. When appropriate, using negative ion mode MS or changing a dosing vehicle excipient, such as substituting propylene glycol for PEG400, provides an alternative approach for eliminating signal interference. The mechanism of excipient-related signal interference is discussed in relation to both competition of gas-phase proton-transfer reactions and high viscosity of dosing excipients.

Previously published applications of optical emission spectroscopy as a quantitative plasma diagnostic technique are reviewed. By adding traces of rare gases to the plasma, electron temperatures (Te) and relative electron and ion densities can be determined from electron impact-induced optical emission. Excitation from both the ground state and metastable states of the rare gases must be considered. At higher rare gas partial pressures, UV radiation trapping and optical cascading must also be taken into account. Absolute species concentrations (e.g. Cl2, Cl, O, and F) can be derived from their optical emissions, combined with Te measurements determined from rare gas optical emission. Examples are given of neutral and ion species density measurements in chlorine, oxygen, and fluorocarbon-containing low-pressure, high charge-density plasmas. Typical results of Te measurements are also presented and compared with Langmuir probe

Recent advances in the interpretation of optical emission spectra from plasmas have made it possible to measure parameters such as electron temperature (Te), relative electron density, and gas temperature (Tg) with this nonintrusive technique. Here we discuss the application of trace rare gas optical emission spectroscopy (TRG-OES), optical actinometry, and N2 rotational spectroscopy to determine Te, relative electron density, fluorine atom concentration, and Tg for fluorocarbon/Ar plasmas in an inductively coupled reactor. Various etch processes, containing mixtures of a carrier gas, C2F6, and C4F8, were evaluated as a function of pressure and flowrate. Ar, Kr, and Ne were used individually or were mixed to comprise the carrier gas. In the case of TRG-OES and optical emission actinometry, a mixture containing equal parts of He, Ne, Ar, Kr, and Xe (∼1% ea.) was added. A method for correcting excitation cross sections is introduced for cases when radiation trapping affects the emission of a rare gas (Ar) t...

Trace rare gases optical emission spectroscopy has been used to measure the electron temperature, Te, in a high-density inductively coupled Cl2–Ar plasma at 18 mTorr as function of the 13.56 MHz radio frequency power and Ar fraction. Only the Kr and Xe emission lines were used to determine Te, because of evidence of radiation trapping when the Ar emission lines were also used for larger Ar fractions. At 600 W (10.6 W cm−2), Te increases from ∼4.0±0.5 eV to ∼6.0±2.0 eV as the Ar fraction increases from 1% to 96%. In the H (inductive, bright) mode, Te, for a “neat” chlorine plasma (including 1% of each He/Ne/Ar/Kr/Xe) increases only slightly from ∼3.8 to 4.0 eV as power increases from 450 to 750 W. This increase is much larger for larger Ar fractions, such as from ∼4.0 to 7.3 eV for 78% Ar. Most of these effects can be understood using the fundamental particle balance equation.

Chemical etching of silicon by fluorine atoms in the absence of ion bombardment is reviewed. Controversies on the identity of etching products and reaction probabilities are discussed. Attempts are made to explain the apparent presence of SiF2 as a primary product in many studies, dating back to 1980, but not in others, including those of Harold Winters from as early as 1979. Reported estimates of reaction probabilities (here defined as the probability of removing a Si atom from the substrate per incident F atom) vary by a factor of 2000. When these values, with some corrections and reasonable adjustments, are plotted as a function of F atom flux, most of them fall on a “universal curve” that reveals a large (∼30-fold) decrease in the reaction probability with increasing F flux, from 0.03 at a F flux 1012 cm−2 s−1 to 0.001 at a flux of 1020 cm−2 s−1. These values were extracted from beam experiments with F atoms generated from cracking of F2, including those by Harold Winters, from isotropic etching in pl...

Atomic layer etching (ALE) of SiO2 was studied by alternating exposure of a 5 nm-thick SiO2 film on Si substrate to (1) a plasma beam emanating from a c-C4F8 inductively coupled plasma (ICP), to grow a fluorocarbon (FC) film composed mainly of CF2, and (2) an energetic (130 eV) Ar+ ion beam extracted from a separate Ar ICP. In situ x-ray photoelectron spectroscopy was used to analyze the chemical composition of the near-surface region, and to quantify the thickness of the FC and SiO2 films. A very thin (3–6 A), near self-limiting thickness CF2-rich FC film was found to deposit on the SiO2 surface with exposure to continuous or pulsed power C4F8 plasma beams, under conditions that generated a large relative flux of CF2. Following this, a FC film of similar composition grew at ~10 times slower rate. Exposure of the thin film to the Ar+ beam led to removal of 1.9 A SiO2. An estimated yield of 1.3 SiO2 molecules-per-Ar+ was found for a single ALE step. The rate of 1.9 A/cycle persisted over multiple ALE cycles, but a carbon-rich residual film did build up. This film can be removed by a brief exposure to an O2-containing plasma beam.

Time-dependent behavior of chlorine inductively coupled plasmas is presented for Si etching, following NF3-Ar plasma cleaning of a chamber coated with Y2O3. Optical emission intensities were recorded throughout the processes for Cl, O, F, Si, SiClx=1-3, SiF, and N2, as well as from added trace rare gases Xe and Ar for determination of number densities for selected species by actinometry. Time-dependent Langmuir probe measurements of ion and electron number densities and electron energy distributions were also carried out. Ex situ x-ray photoelectron spectroscopy measurements of the surface composition of Y2O3 coupon pieces after different etching and clean processes were also performed. Initially fluorinated yttria surfaces are shown to have a relatively high probability for loss (“recombination”) of Cl through formation of both Cl2 and SiClx. As etching proceeds, SiClx abstracts F from the surface and deposits Si and Cl, lowering of the heterogeneous recombination of Cl. The initially high recombination ...

Atomic Layer ETching (ALET) of a solid with monolayer precision is a critical requirement for advancing nanoscience and nanotechnology. Current plasma etching techniques do not have the level of control or damage-free nature that is needed for patterning delicate sub-20 nm structures. In addition, conventional ALET, based on pulsed gases with long reactant adsorption and purging steps, is very slow. In this work, novel pulsed plasma methods with synchronous substrate and/or “boundary electrode” bias were developed for highly selective, rapid ALET. Pulsed plasma and tailored bias voltage waveforms provided controlled ion energy and narrow energy spread, which are critical for highly selective and damage-free etching. The broad goal of the project was to investigate the plasma science and engineering that will lead to rapid ALET with monolayer precision. A combined experimental-simulation study was employed to achieve this goal.

Blood transfusion has been described in ferrets as a treatment for oestrus-associated anaemia and as a life-saving therapy following trauma, iatrogenic (usually surgery-induced) anaemia, autoimmune haemolytic anaemia and pure red cell aplasia. Although blood banking is a common method for storage of feline and canine blood it is not currently done with ferret blood. The aim of this study was to determine the shelf-life of ferret blood using the anticoagulant citrate-phosphate-dextrose-solution with adenine (CPDA). Two male ferrets were used as blood donors. From each ferret, 6 ml o f blood was taken from the cranial vena cava and stored in 10 ml poly ethylene terephthalate (PET) blood tubes containing 1 ml o f CPDA solution. Blood was taken from each ferret once per month for five months. These 10 blood samples were stored in a laboratory refrigerator at 4°C for four weeks. Biochemical (glucose, pH, lactate, potassium, sodium) and haematological (haematocrit, light microscopic blood smear examination) analyses were performed on the stored blood at days 0, 7, 14, 21 and 28. Biochemical analyses revealed a progressive decrease from day seven in the stored blood pH, glucose and sodium, with a concomitant increase in lactate and potassium. These results are attributable to the ongoing metabolism and deterioration of the red blood cells (RBC) while in storage, and are more rapid than described for human or canine stored blood. Haematological analyses revealed a progressive elevation of the haematocrit due to the appearance of hypochromic red blood cells and echinocytes beginning at day 7. Haemolysis was observed in the microhaematocrit capillary tube sample by day 21, and microscopic clots were visible on the blood smear by day 28. The low blood pH and the appearance of many hypochromic RBCs and some echinocytes from day 7 in CPDA-stored ferret blood, suggest stored ferret blood has a short shelf-life when compared with stored human or canine blood. We recommend that ferret blood stored in CPDA should not be used for transfusion after seven days of storage at 4°C.

This work is part of a broader study that creates a set of experimentally measured chlorine plasma parameters (electron and gas temperatures, electron energy distribution function, electron density, densities of ion fractions, and total ion density). This set is obtained over a broad range of operating conditions (1–20 mTorr, 5–1000 W) of an inductively coupled plasma. In this part, we present the electron (ne) and total positive ion (ni+=nCl2++nCl+) densities. ne and ni+ were measured with a Langmuir probe across the diameter or in the middle of the reactor. Line integrated values of ne were independently obtained with microwave interferometry, and converted into the spatially resolved data using the Langmuir probe ne profiles. Finally, a method is presented for measuring relative positive ion densities, based on optical emission at 7504 A from trace amounts of Ar.

Myelopoietins comprise a class of chimeric cytokine receptor agonists consisting of an hIL-3 (human interleukin-3) receptor agonist and an hG-CSF (human granulocyte colony-stimulating factor) receptor agonist linked head-to-tail at their respective carboxy and amino termini. The combination of an early acting cytokine (hIL-3) with a late acting one (hG-CSF) allows efficient hematopoeitic reconstruction following myeloablative insult, and drives differentiation of non-myelocytic lineages (ie thrombocytic lineages) that are inaccessible using hG-CSF alone, in both preclinical models and clinical settings. A myelopoietin species was displayed and mutagenized on filamentous bacteriophage: both component agonists of myelopoietin were presented in biologically functional conformations as each recognized its corresponding receptor. Five amino acid positions in a short region of the hG-CSF receptor agonist module of myelopoietin that had been identified as important for proliferative activity were mutagenized. Display was used because it allows very 'deep' mutagenesis at selected residues:10(5) substitution variants were affinity-screened using the hG-CSF receptor and 130 new, active variants of myelopoietin were identified and characterized. None of the selected variants were significantly more active than the parental myelopoietin species in a hG-CSF-dependent cell proliferation assay, though many were as active. Many of these relatively high-activity variants contained parental amino acids at several positions, suggesting the parental sequence may already be optimal at these positions for the assays used, and potentially accounting for the failure to identify enhanced bioactivity variants. Analysis of substitutions of high-activity variants complements and extends previous alanine scanning, and other genetic and biochemical data for hG-CSF variants.

The surface during the etching of Si in a Cl2 inductively-coupled plasma (ICP) was analyzed by laser desorption (LD), followed by detection of the desorbed species by monitoring the transient changes by plasma-induced emission (PIE). Optical emission from Si, SiCl, SiCl2, and possibly other species was detected in situ using this LD-PIE method as a function of rf power, substrate bias, and pressure. The surface coverage of chlorine was determined by normalizing the LD-PIE signal by either of two ways: by the electron density, as measured by microwave interferometry, or by using the background PIE signal. Little change in surface coverage was observed as the ion density was changed by varying the rf power supplied to the ICP, confirming the observation made using laser-induced fluorescence (LIF) detection (LD-LIF). The LD-PIE signal is related to the density of species desorbed from the surface and subsequently excited by electrons. LD-PIE analysis of the surface is more versatile than LD-LIF—sometimes it can detect the desorbed species while LD-LIF cannot. Still, it requires calibration to account for the electron collision-induced excitation of the laser-desorbed species.

The absolute densities of positive ions (Cl2+ and Cl+) are obtained over a 2–20 mTorr pressure range and 5–1000 W input radio-frequency rf power range in a transformer-coupled Cl2 plasma. The relative number density of Cl2+ is measured by laser-induced fluorescence. These laser-induced fluorescence data are calibrated by Langmuir-probe measurements of total positive-ion density at low powers to yield absolute values for nCl2+ and are corrected for changes in rotational temperature with rf power. In turn, the nCl2+ data are used to determine the effective-mass correction for refined Langmuir-probe measurements of the total positive-ion density. The density of Cl+ is then the difference between the total positive-ion and Cl2+ densities. For all the pressures, Cl2+ is found to be the dominant ion in the capacitively coupled regime (input powers below 100 W), while Cl+ is the dominant ion at higher powers (>300 W) of the inductively coupled regime. Experimental results are compared to those from a simple glob...

We report an analysis of the dynamics of a pulsed power, inductively-coupled chlorine plasma operated with continuous radio frequency (rf) bias applied to the substrate stage. A comparison of pulsed plasmas operated with and without 12.5 MHz rf bias is performed through an investigation of the time dependences of electron (ne) and positive ion (ni+) densities and electron temperatures (Te), measured with a Langmuir probe in a 10 mTorr Cl2 plasma. There is no significant difference in the plasma characteristics with or without bias during the on portion of the power modulation of the source. Once the source power is turned off, Te initially decreases rapidly, and ne and ni+ decay slowly, independent of the presence of the rf bias. About 25 µs into this decay, when Te is about 0.5 eV (and would continue to decay in the absence of the rf bias), the presence of the rf bias (70-100 W) causes Te to increase rapidly and reach values higher than those recorded at the end of the on portion. Meanwhile, ne and ni+ continue to decay, independent of substrate bias. Only much later in the afterglow are charge densities affected by bias. About 50 µs into the off period, ne with added substrate bias is lower than with no bias. If the off period is sufficiently long, the plasma in the presence of the rf bias transforms into a so-called reactive ion etching (RIE) mode that is generated and sustained solely by the capacitively-coupled bias power. This occurs rather abruptly when ni+ decays to the level of positive ion density for RIE operation (i.e. with the stage powered and the source power off). Since ne at this instant has decayed well below the electron density during RIE operation, it rapidly increases when this transition occurs. The behaviour of Te in the off portion of the pulsed plasma indicates that the presence of rf bias prevents the sheath collapse that occurs without bias. Since this will prevent negative ions (Cl-) from reaching the wafer, the reduced plasma-induced damage (with respect to continuous source operation) reported for pulsed plasma operation with high-frequency (e.g. ~13 MHz) bias cannot be caused by the discharging of the wafer by negative ions.