Morphology changes and mechanistic aspects of the electrochemically-induced reversible solid-solid transformation of microcrystalline TCNQ into Co TCNQ 2-based materials (TCNQ= 7, 7, 8, 8-Tetracyanoquinodimethane)

The chemically reversible solid−solid phase transformation of a TCNQ-modified glassy carbon, indium tin oxide, or metal electrode into Co\[TCNQ]2(H2O)2 material in the presence of Co2+(aq) containing electrolytes has been induced and monitored electrochemically. Voltammetric data reveal that the TCNQ/Co\[TCNQ]2(H2O)2 interconversion process is independent of electrode material and identity of cobalt electrolyte anion. However, a marked dependence on electrolyte concentration, scan rate, and method of electrode modification (drop casting or mechanical attachment) is found. Cyclic voltammetric and double potential step chronoamperometric measurements confirm that formation of Co\[TCNQ]2(H2O)2 occurs through a rate-determining nucleation and growth process that initially involves incorporation of Co2+(aq) ions into the reduced TCNQ crystal lattice at the TCNQ|electrode|electrolyte interface. Similarly, the reverse (oxidation) process, which involves transformation of solid Co\[TCNQ]2(H2O)2 back to parent TCNQ crystals, also is controlled by nucleation−growth kinetics. The overall chemically reversible process that represents this transformation is described by the reaction:  2TCNQ0(s) + 2e- + Co2+(aq) + 2H2O \[Co(TCNQ)2(H2O)2](s). Ex situ SEM images illustrated that this reversible TCNQ/Co\[TCNQ]2(H2O)2 conversion process is accompanied by drastic size and morphology changes in the parent solid TCNQ. In addition, different sizes of needle-shaped nanorod/nanowire crystals of Co\[TCNQ]2(H2O)2 are formed depending on the method of surface immobilization.

Electrocrystallization of phase I, CuTCNQ (TCNQ= 7, 7, 8, 8-tetracyanoquinodimethane), on indium tin oxide and boron-doped diamond electrodes

The electrochemical reduction of TCNQ to TCNQ•- in acetonitrile in the presence of [Cu(MeCN)4]+ has been undertaken at boron-doped diamond (BDD) and indium tin oxide (ITO) electrodes. The nucleation and growth process at BDD is similar to that reported previously at metal electrodes. At an ITO electrode, the electrocrystallization of more strongly adhered, larger, branched, needle-shaped phase I CuTCNQ crystals is detected under potential step conditions and also when the potential is cycled over the potential range of 0.7 to −0.1 V versus Ag/AgCl (3 M KCl). Video imaging can be used at optically transparent ITO electrodes to monitor the growth stage of the very large branched crystals formed during the course of electrochemical experiments. Both in situ video imaging and ex situ X-ray diffraction and scanning electron microscopy (SEM) data are consistent with the nucleation of CuTCNQ taking place at a discrete number of preferred sites on the ITO surface. At BDD electrodes, ex situ optical images show that the preferential growth of CuTCNQ occurs at the more highly conducting boron-rich areas of the electrode, within which there are preferred sites for CuTCNQ formation.

Characterisation of two distinctly different processes associated with the electrocrystallization of microcrystals of phase I CuTCNQ (TCNQ= 7, 7, 8, 8-tetracyanoquinodimethane)

Semi-conducting phase I CuTCNQ (TCNQ = 7,7,8,8-tetracyanoquinodimethane), which is of considerable interest as a switching device for memory storage materials, can be electrocrystallized from CH3CN via two distinctly different pathways when TCNQ is reduced to TCNQ˙− in the presence of [Cu(MeCN)4]+. The first pathway, identified in earlier studies, occurs at potentials where TCNQ is reduced to TCNQ˙− and involves a nucleation–growth mechanism at preferred sites on the electrode to produce arrays of well separated large branched needle-shaped phase I CuTCNQ crystals. The second pathway, now identified at more negative potentials, generates much smaller needle-shaped phase I CuTCNQ crystals. These electrocrystallize on parts of the surface not occupied in the initial process and give rise to film-like characteristics. This process is attributed to the reduction of Cu+[(TCNQ˙−)(TCNQ)] or a stabilised film of TCNQ via a solid–solid conversion process, which also involves ingress of Cu+via a nucleation–growth mechanism. The CuTCNQ surface area coverage is extensive since it occurs at all areas of the electrode and not just at defect sites that dominate the crystal formation sites for the first pathway. Infrared spectra, X-ray diffraction, surface plasmon resonance, quartz crystal microbalance, scanning electron microscopy and optical image data all confirm that two distinctly different pathways are available to produce the kinetically-favoured and more highly conducting phase I CuTCNQ solid, rather than the phase II material.

Electrochemically-induced TCNQ/Mn TCNQ 2 (H2O) 2 (TCNQ= 7, 7, 8, 8-Tetracyanoquinodimethane) solid-solid interconversion : two voltammetrically distinct processes that allow selective generation of nanofiber or nanorod network morphologies

Unlike the case with other divalent transition metal M\[TCNQ](2)(H(2)O)(2) (M = Fe, Co, Ni) analogues, the electrochemically induced solid-solid phase interconversion of TCNQ microcrystals (TCNQ = 7,7,8,8-tetracyanoquinodimethane) to Mn\[TCNQ](2)(H(2)O)(2) occurs via two voltammetrically distinct, time dependent processes that generate the coordination polymer in nanofiber or rod-like morphologies. Careful manipulation of the voltammetric scan rate, electrolysis time, Mn(2+)((aq)) concentration, and the method of electrode modification with solid TCNQ allows selective generation of either morphology. Detailed ex situ spectroscopic (IR, Raman), scanning electron microscopy (SEM), and X-ray powder diffraction (XRD) characterization clearly establish that differences in the electrochemically synthesized Mn-TCNQ material are confined to morphology. Generation of the nanofiber form is proposed to take place rapidly via formation and reduction of a Mn-stabilized anionic dimer intermediate, \[(Mn(2+))(TCNQ-TCNQ)(2)(*-)], formed as a result of radical-substrate coupling between TCNQ(*-) and neutral TCNQ, accompanied by ingress of Mn(2+) ions from the aqueous solution at the triple phase TCNQ/electrode/electrolyte boundary. In contrast, formation of the nanorod form is much slower and is postulated to arise from disproportionation of the \[(Mn(2+))(TCNQ-TCNQ)(*-)(2)] intermediate. Thus, identification of the time dependent pathways via the solid-solid state electrochemical approach allows the crystal size of the Mn\[TCNQ](2)(H(2)O)(2) material to be tuned and provides new mechanistic insights into the formation of different morphologies.

Electrochemical formation of porous copper 7, 7, 8, 8-tetracyanoquinodimethane and copper 2, 3, 5, 6-tetrafluoro-7, 7, 8, 8-tetracyanoquinodimethane honeycomb surfaces with superhydrophobic properties

The electrochemical formation of highly porous CuTCNQ (TCNQ = 7,7,8,8-tetracyanoquinodimethane) and CuTCNQF4 (TCNQF4 = 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane) materials was undertaken via the spontaneous redox reaction between a porous copper template, created using a hydrogen bubbling template technique, and an acetonitrile solution containing TCNQ or TCNQF4. It was found that activation of the surface via vigorous hydrogen evolution that occurs during porous copper deposition and TCNQ mass transport being hindered through the porous network of the copper template influenced the growth of CuTCNQ and CuTCNQF4. This approach resulted in the fabrication of a honeycomb layered type structure where the internal walls consist of very fine crystalline needles or spikes. This combination of microscopic and nanoscopic roughness was found to be extremely beneficial for anti-wetting properties where superhydrophobic materials with contact angles as high as 177° were created. Given that CuTCNQ and CuTCNQF4 have shown potential as molecular based electronic materials in the area of switching and field emission, the creation of a surface that is moisture resistant may be of applied interest.

Effect of Imidazolium-based Ionic Liquids on the nanoscale morphology of CuTCNQ (TCNQ= 7, 7, 8, 8-tetracyanoquinodimethane) metal-organic semiconductors

We demonstrate for the first time the ionic-liquid-mediated synthesis of nanostructured CuTCNQ by the simple immersion of copper in a solution of TCNQ where the viscosity of the medium significantly impacts the corrosion–crystallization process and the final morphology of the material.

Effectiveness of 7-valent pneumococcal conjugate vaccine against radiologically diagnosed pneumonia in indigenous infants in Australia

Objective To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) in preventing pneumonia, diagnosed radiologically according to World Health Organization (WHO) criteria, among indigenous infants in the Northern Territory of Australia. Methods We conducted a historical cohort study of consecutive indigenous birth cohorts between 1 April 1998 and 28 February 2005. Children were followed up to 18 months of age. The PCV7 programme commenced on 1 June 2001. All chest X-rays taken within 3 days of any hospitalization were assessed. The primary endpoint was a first episode of WHO-defined pneumonia requiring hospitalization. Cox proportional hazards models were used to compare disease incidence. Findings There were 526 pneumonia events among 10 600 children - an incidence of 3.3 per 1000 child-months; 183 episodes (34.8%) occurred before 5 months of age and 247 (47.0%) by 7 months. Of the children studied, 27% had received 3 doses of vaccine by 7 months of age. Hazard ratios for endpoint pneumonia were 1.01 for 1 versus 0 doses; 1.03 for 2 versus 0 doses; and 0.84 for 3 versus 0 doses. Conclusion There was limited evidence that PCV7 reduced the incidence of radiologically confirmed pneumonia among Northern Territory indigenous infants, although there was a non-significant trend towards an effect after receipt of the third dose. These findings might be explained by lack of timely vaccination and/or occurrence of disease at an early age. Additionally, the relative contribution of vaccine-type pneumococcus to severe pneumonia in a setting where multiple other pathogens are prevalent may differ with respect to other settings where vaccine efficacy has been clearly established.

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer : analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.

Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells

Kallikrein-related peptidases, in particular KLK4, 5, 6 and 7 (4-7), often have elevated expression levels in ovarian cancer. In OV-MZ-6 ovarian cancer cells, combined expression of KLK4-7 reduces cell adhesion and increases cell invasion and resistance to paclitaxel. The present work investigates how KLK4-7 shape the secreted proteome ("secretome") and proteolytic profile ("degradome") of ovarian cancer cells. The secretome comparison consistently identified >900 proteins in three replicate analyses. Expression of KLK4-7 predominantly affected the abundance of proteins involved in cell-cell communication. Among others, this includes increased levels of transforming growth factor β-1 (TGFβ-1). KLK4-7 co-transfected OV-MZ-6 cells share prominent features of elevated TGFβ-1 signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM). Augmented levels of TGFβ-1 and L1CAM upon expression of KLK4-7 were corroborated in vivo by an ovarian cancer xenograft model. The degradomic analysis showed that KLK4-7 expression mostly affected cleavage sites C-terminal to arginine, corresponding to the preference of kallikreins 4, 5 and 6. Putative kallikrein substrates include chemokines, such as growth differentiation factor 15 (GDF 15) and macrophage migration inhibitory factor (MIF). Proteolytic maturation of TGFβ-1 was also elevated. KLK4-7 have a pronounced, yet non-degrading impact on the secreted proteome, with a strong association between these proteases and TGFβ-1 signaling in tumor biology. © 2013 Federation of European Biochemical Societies.

Voltammetric, spectroscopic, and microscopic investigations of electrocrystallized forms of semiconducting AgTCNQ (TCNQ=7,7,8,8-tetracyanoquinodimethane) exhibiting different morphologies and colors

Chemically synthesized AgTCNQ exists in two forms that differ in their morphologies (needles and microcrystals) and colors (red and blue). It is now shown that both forms exhibit essentially indistinguishable X-ray diffraction, spectroscopic, and thermochemical data, implying that they are not separate phases, as implied in some literature. Electrochemical reduction of TCNQ((MeCN)) in the presence of Ag+((MeCN)) generates both red and blue AgTCNQ. On glassy carbon, platinum, or indium tin oxide electrodes and at relatively positive deposition potentials, slow growth of high aspect ratio, red needle AgTCNQ crystals occurs. After longer times and at more negative deposition potentials, blue microcrystalline AgTCNQ thin films are favored. Blue AgTCNQ is postulated to be generated via reduction of a Ag+\[(TCNQ(center dot-))(TCNQ)]((MeCN)) intermediate. At even more negative potentials, Ag-(metal) formation inhibits further growth of AgTCNQ. On a gold electrode, Ag-(metal)) deposition occurs at more positive potentials than on the other electrode materials examined. However, surface plasmon resonance data indicate (hat a small potential region is available between the stripping of Ag-(metal)) and the oxidation of TCNQ(center dot-)(MeCN) back to TCNQ(MeCN) where AgTCNQ may form. AgTCNQ in both the red and blue forms also can be prepared electrochemically on a TCNQ((s)) modified electrode in -0.1 M AgNO3(aq) where deposition of Ag(m,,,I) onto the TCNQ((s)) crystals allows a charge transfer process to occur. However, the morphology formed in this solid-solid phase transformation is more difficult to control.

Cryptanalysis of WG-7 : a lightweight stream cipher

WG-7 is a stream cipher based on WG stream cipher and has been designed by Luo et al. (2010). This cipher is designed for low cost and lightweight applications (RFID tags and mobile phones, for instance). This paper addresses cryptographic weaknesses of WG-7 stream cipher. We show that the key stream generated by WG-7 can be distinguished from a random sequence after knowing 213.5 keystream bits and with a negligible error probability. Also, we investigate the security of WG-7 against algebraic attacks. An algebraic key recovery attack on this cipher is proposed. The attack allows to recover both the internal state and the secret key with the time complexity about 2/27.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. 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Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with β-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.

Mechanism‐based selection of a potent kallikrein‐related peptidase 7 inhibitor from a versatile library based on the sunflower trypsin inhibitor SFTI‐1

Potent and specific enzyme inhibition is a key goal in the development of therapeutic inhibitors targeting proteolytic activity. The backbone-cyclized peptide, Sunflower Trypsin Inhibitor (SFTI-1) affords a scaffold that can be engineered to achieve both these aims. SFTI-1's mechanism of inhibition is unusual in that it shows fast-on/slow-off kinetics driven by cleavage and religation of a scissile bond. This phenomenon was used to select a nanomolar inhibitor of kallikrein-related peptidase 7 (KLK7) from a versatile library of SFTI variants with diversity tailored to exploit distinctive surfaces present in the active site of serine proteases. Inhibitor selection was achieved through the use of size exclusion chromatography to separate protease/inhibitor complexes from unbound inhibitors followed by inhibitor identification according to molecular mass ascertained by mass spectrometry. This approach identified a single dominant inhibitor species with molecular weight of 1562.4 Da, which is consistent with the SFTI variant SFTI-WCTF. Once synthesized individually this inhibitor showed an IC50 of 173.9 ± 7.6 nM against chromogenic substrates and could block protein proteolysis. Molecular modeling analysis suggested that selection of SFTI-WCTF was driven by specific aromatic interactions and stabilized by an enhanced internal hydrogen bonding network. This approach provides a robust and rapid route to inhibitor selection and design.