Microwave-Assisted Fabrication of High Energy Density Binary Metal Sulfides for Enhanced Performance in Battery Applications.

Nanomaterials have found use in a number of relevant energy applications. In particular, nanoscale motifs of binary metal sulfides can function as conversion materials, similar to that of analogous metal oxides, nitrides, or phosphides, and are characterized by their high theoretical capacity and correspondingly low cost. This review focuses on structure-composition-property relationships of specific relevance to battery applications, emanating from systematic attempts to either (1) vary and alter the dimension of nanoscale architectures or (2) introduce conductive carbon-based entities, such as carbon nanotubes and graphene-derived species. In this study, we will primarily concern ourselves with probing metal sulfide nanostructures generated by a microwave-mediated synthetic approach, which we have explored extensively in recent years. This particular fabrication protocol represents a relatively facile, flexible, and effective means with which to simultaneously control both chemical composition and physical morphology within these systems to tailor them for energy storage applications.

Probing the Physicochemical Behavior of Variously Doped Li4Ti5O12 Nanoflowers.

This study thoroughly investigated the synthesis of not only 4 triply-doped metal oxides but also 5 singly-doped analogues of Li4Ti5O12 for electrochemical applications. In terms of synthetic novelty, the triply-doped materials were fabricated using a relatively facile hydrothermal method for the first-time, involving the simultaneous substitution of Ca for the Li site, Ln (i.e., Dy, Y, or Gd) for the Ti site, and Cl for the O site. Based on XRD, SEM, and HRTEM-EDS measurements, the resulting materials, incorporating a relatively homogeneous and uniform dispersion of both the single and triple dopants, exhibited a micron-scale flower-like morphology that remained apparently undamaged by the doping process. Crucially, the surface chemistry of all of the samples was probed using XPS in order to analyze any nuanced changes associated with either the various different lanthanide dopants or the identity of the metal precursor types involved. In the latter case, it was observed that the use of a nitrate salt precursor versus that of a chloride salt enabled not only a higher lanthanide incorporation but also the potential for favorable N-doping, all of which promoted a concomitant increase in conductivity due to a perceptible increase in Ti3+ content. In terms of the choice of lanthanide system, it was observed via CV analysis that dopant incorporation generally (albeit with some notable exceptions, especially with Y-based materials) led to the formation of higher amounts of Ti3+ species within both the singly and triply-doped materials, which consequentially led to the potential for increased diffusivity and higher mobility of Li+ species with the possibility for enabling greater capacity within these classes of metal oxides.

Exploring Strategies toward Synthetic Precision Control within Core-Shell Nanowires.

ConspectusAchieving precision and reproducibility in terms of physical structure and chemical composition within arbitrary nanoscale systems remains a "holy grail" challenge for nanochemistry. Because nanomaterials possess fundamentally distinctive size-dependent electronic, optical, and magnetic properties with wide-ranging applicability, the ability to produce homogeneous and monodisperse nanostructures with precise size and shape control, while maintaining a high degree of sample quality, purity, and crystallinity, remains a key synthetic objective. Moreover, it is anticipated that the methodologies developed to address this challenge ought to be reasonably simple, scalable, mild, nontoxic, high-yield, and cost-effective, while minimizing reagent use, reaction steps, byproduct generation, and energy consumption.The focus of this Account revolves around the study of various types of nanoscale one-dimensional core-shell motifs, prepared by our group. These offer a compact structural design, characterized by atom economy, to bring together two chemically distinctive (and potentially sharply contrasting) material systems into contact within the structural context of an extended, anisotropic configuration. Herein, we describe complementary strategies aimed at resolving the aforementioned concerns about precise structure and compositional control through the infusion of careful "quantification" and systematicity into customized, reasonably sustainable nanoscale synthetic protocols, developed by our group. Our multipronged approach involved the application of (a) electrodeposition, (b) electrospinning, (c) a combination of underpotential deposition and galvanic displacement reactions, and (d) microwave-assisted chemistry to diverse core-shell model systems, such as (i) carbon nanotube-SiO2 composites, (ii) SnO2/TiO2 motifs, (iii) ultrathin Pt-monolayer shell-coated alloyed metal core nanowires, and (iv) Cu@TiO2 nanowires, for applications spanning optoelectronics, photocatalysis, electrocatalysis, and thermal CO2 hydrogenation, respectively.In so doing, over the years, we have reported on a number of different characterization tools involving spectroscopy (e.g., extended X-ray absorption fine structure (EXAFS) spectroscopy) and microscopy (e.g., high-resolution transmission electron microscopy (HRTEM) and atomic force microscopy (AFM)) for gaining valuable insights into the qualitative and quantitative nature of not only the inner core and outer shell themselves but also their intervening interface. While probing the functional catalytic behavior of a few of these core-shell structures under realistic operando conditions, using dynamic, in situ characterization techniques, we found that local and subtle changes in chemical composition and physical structure often occur during the reaction process itself. As such, nuanced differences in atomic packing, facet exposure, degree of derivatization, defect content, and/or extent of crystallinity can impact upon observed properties with tangible consequences for performance, mechanism, and durability.

Optimized Microwave-Based Synthesis of Thermally Stable Inverse Catalytic Core-shell Motifs for CO2 Hydrogenation.

The rational synthesis of Cu@TiO2 core@shell nanowire (NW) structures was thoroughly explored using a microwave-assisted method through the tuning of experimental parameters such as but not limited to (i) controlled variation in molar ratios, (ii) the effect of discrete Ti precursors, (iii) the method of addition of the precursors themselves, and (iv) time of irradiation. Uniform coatings were obtained using Cu/Ti molar ratios of 1:2, 1:1, 2:1, and 4:1, respectively. It should be noted that although relative molar precursor concentrations primarily determined the magnitude of the resulting shell size, the dependence was nonlinear. Moreover, additionally important reaction parameters, such as precursor identity, the means of addition of precursors, and the reaction time, were individually explored with the objective of creating a series of optimized reaction conditions. As compared with Cu NWs alone, it is evident that both of the Cu@TiO2 core-shell NW samples, regardless of pretreatment conditions, evinced much better catalytic performance, up to as much as 20 times greater activity as compared with standard Cu NWs. These results imply the significance of the Cu/TiO2 interface in terms of promoting CO2 hydrogenation, because TiO2 alone is known to be inert for this reaction. Furthermore, it is additionally notable that the N2 annealing pretreatment is crucial in terms of preserving the overall Cu@TiO2 core@shell structure. We also systematically analyzed and tracked the structural and chemical evolution of our catalysts before and after the CO2 reduction experiments. Indeed, we discovered that the core@shell wire motif was essentially maintained and conserved after this high-temperature reaction process, thereby accentuating the thermal stability and physical robustness of our as-prepared hierarchical motifs.

Solution-Based, Anion-Doping of Li4 Ti5 O12 Nanoflowers for Lithium-Ion Battery Applications.

Solution-based, anionic doping represents a convenient strategy with which to improve upon the conductivity of candidate anode materials such as Li4 Ti5 O12 (LTO). As such, novel synthetic hydrothermally-inspired protocols have primarily been devised herein, aimed at the large-scale production of unique halogen-doped, micron-scale, three-dimensional, hierarchical LTO flower-like motifs. Although fluorine (F) doping has been explored, the use of chlorine (Cl) dopants is the primary focus here. Several experimental variables, such as dopant amount, lithium hydroxide concentration, and titanium butoxide purity, were probed and perfected. Furthermore, the Cl doping process did not damage the intrinsic LTO morphology. The analysis, based on interpreting a compilation of SEM, XRD, XPS, and TEM-EDS results, was used to determine an optimized dopant concentration of Cl. Electrochemical tests demonstrated an increased capacity via cycling of 12 % for a Cl-doped sample as compared with pristine LTO. Moreover, the Cl-doped LTO sample described in this study exhibited the highest discharge capacity yet reported at an observed rate of 2C for this material at 143mAh g-1 . Overall, these data suggest that the Cl dopant likely enhances not only the ion transport capabilities, but also the overall electrical conductivity of our as-prepared structures. To help explain these favorable findings, theoretical DFT calculations were used to postulate that the electronic conductivity and Li diffusion were likely improved by the presence of increased Ti3+ ion concentration coupled with widening of the Li migration channel.

Nanoscale Perovskites as Catalysts and Supports for Direct Methanol Fuel Cells.

With the ultimate goal of simultaneously finding cost-effective, more earth-abundant, and high-performance alternatives to commercial Pt/Pd-based catalysts for electrocatalysis, this review article highlights advances in the use of perovskite metal oxides as both catalysts and catalyst supports towards the oxygen reduction reaction (ORR) and the methanol oxidation reaction (MOR) within a direct methanol fuel cell (DMFC) configuration. Specifically, perovskite metal oxides are promising as versatile functional replacements for conventional platinum-group metals, in part because of their excellent ionic conductivity, overall resistance to corrosion, good proton-transport properties, and potential for interesting acidic surface chemistry, all of which contribute to their high activity and reasonable stability, especially within an alkaline electrolytic environment.

The Doctor Can See You Now: A Key Stakeholder Study Into The Acceptability Of Ambulance Based Telemedicine.

Using telecommunications technology it would be possible to link a patient and paramedic to a Doctor in the Emergency Department (ED) at the point of first patient contact. A questionnaire-based study on telemedicine in the pre-hospital environment involving patients, paramedics, doctors and nurses in the ED, was performed to assess if they would want and accept telemedicine in pre-hospital emergency care. When asked 98.5% (55) of patients, 89% (11) of doctors, 76% (14) of nurses and 91% (42) of ambulance personnel saw the potential of an audio-visual link from the pre-hospital environment to the ED. The potential benefits were felt to be in diagnosis of time-dependent illnesses, time management, increased hospital preparedness for incoming patients and increased triage efficiency. Stakeholder enthusiasm for pre-hospital telemedicine must be met with the technological requirements to provide such a service. As noted by one patient a pre-hospital audio-visual link to the ED could be "potentially a life saving service".

Medium-Chain Polyprenols Influence Chloroplast Membrane Dynamics in Solanum lycopersicum.

The widespread occurrence of polyprenols throughout the plant kingdom is well documented, yet their functional role is poorly understood. These lipophilic compounds are known to be assembled from isoprenoid precursors by a class of enzymes designated as cis-prenyltransferases (CPTs), which are encoded by small CPT gene families in plants. In this study, we report that RNA interference (RNAi)-mediated knockdown of one member of the tomato CPT family (SlCPT5) reduced polyprenols in leaves by about 70%. Assays with recombinant SlCPT5 produced in Escherichia coli determined that the enzyme synthesizes polyprenols of approximately 50-55 carbons (Pren-10, Pren-11) in length and accommodates a variety of trans-prenyldiphosphate precursors as substrates. Introduction of SlCPT5 into the polyprenol-deficient yeast Δrer2 mutant resulted in the accumulation of Pren-11 in yeast cells, restored proper protein N-glycosylation and rescued the temperature-sensitive growth phenotype that is associated with its polyprenol deficiency. Subcellular fractionation studies together with in vivo localization of SlCPT5 fluorescent protein fusions demonstrated that SlCPT5 resides in the chloroplast stroma and that its enzymatic products accumulate in both thylakoid and envelope membranes. Transmission electron microscopy images of polyprenol-deficient leaves revealed alterations in chloroplast ultrastructure, and anisotropy measurements revealed a more disordered state of their envelope membranes. In polyprenol-deficient leaves, CO2 assimilation was hindered and their thylakoid membranes exhibited lower phase transition temperatures and calorimetric enthalpies, which coincided with a decreased photosynthetic electron transport rate. Taken together, these results uncover a role for polyprenols in governing chloroplast membrane dynamics.

A comparison of measurement methods of hippocampal atrophy rate for predicting Alzheimer's dementia in the Aberdeen Birth Cohort of 1936.

INTRODUCTION: Various methods are available to measure hippocampal atrophy rate. We compared methods to predict Alzheimer's dementia. METHODS: Participants with brain imaging at ages 69 and 73 years were identified from a previous study. Simple manual measures and computationally automated volumetry were performed. Receiver operating characteristics assessed the predictive ability of each method at baseline and on logit regression analysis of two serial scans. RESULTS: Ten of 149 participants developed Alzheimer's dementia and had lower baseline volumes (3647 vs. 4194 mm3P = .002), rates of volume loss (-126 vs. -36 mm3/y; P = .001), and rates of loss in hippocampal fraction (-8.55 vs. -2.35 x 10-5/y; P = .001). Baseline volume with a rate of change gave the highest area under the curve value of 0.96. DISCUSSION: Automated volumetry measuring hippocampal size at age 69 years and subsequent rate of change predicts Alzheimer's dementia development.

Gender, psychopathy factors, and intimate partner violence.

The present study sheds light on relationships between distinct psychopathic traits and perpetration of intimate partner violence (IPV) in women versus men. Men and women with recent drug and/or violence histories (N = 250) were assessed for psychopathic traits using the Psychopathy Checklist: Screening Version and for their and their partner's use of IPV with the Revised Conflict Tactics Scale. The first goal was to examine the moderating role of gender in psychopathy factor relationships to IPV. Although both the interpersonal-affective traits (Factor1) and the impulsive-antisocial traits (Factor 2) of psychopathy were related to higher frequency of IPV perpetration, the relationship between Factor 1 and IPV was stronger in men. Our second goal examined the moderating role of psychopathy traits in the relationship between partner's perpetration of IPV and participant perpetration (mutual violence) in the 2 genders. Relationships between partner- and self-IPV were similar at both low and high levels of Factor 1 in men, although the partner- and self-IPV relationship was significantly stronger among women at low relative to high levels of Factor 1. The relationship between partner- and self-IPV was stronger at high levels of Factor 2 in men, whereas Factor 2 did not moderate mutual violence in women. These results indicate that relationships between psychopathy factors and IPV differ by gender, with psychopathy generally exacerbating IPV perpetration in men and Factor 1 traits playing a unique role in mutual violence in women. These findings add to the literature on female psychopathy and have important implications for future research on gender and IPV. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Identification and validation of inhibitor-responsive kinase substrates using a new paradigm to measure kinase-specific protein phosphorylation index.

Regulation of all cellular processes requires dynamic regulation of protein phosphorylation. We have developed an unbiased system to globally quantify the phosphorylation index for substrates of a specific kinase by independently quantifying phosphorylated and total substrate molecules in a reverse in-gel kinase assay. Non-phosphorylated substrate molecules are first quantified in the presence and absence of a specific stimulus. Total substrate molecules are then measured after complete chemical dephosphorylation, and a ratio of phosphorylated to total substrate is derived. To demonstrate the utility of this approach, we profiled and quantified changes in phosphorylation index for Protein Kinase CK2 substrates that respond to a small-molecule inhibitor. A broad range of inhibitor-induced changes in phosphorylation was observed in cultured cells. Differences among substrates in the kinetics of phosphorylation change were also revealed. Comparison of CK2 inhibitor-induced changes in phosphorylation in cultured cells and in mouse peripheral blood lymphocytes in vivo revealed distinct kinetic and depth-of-response profiles. This technology provides a new approach to facilitate functional analyses of kinase-specific phosphorylation events. This strategy can be used to dissect the role of phosphorylation in cellular events, to facilitate kinase inhibitor target validation studies, and to inform in vivo analyses of kinase inhibitor drug efficacy.

Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia.

Expression of protein kinase CK2 is frequently deregulated in cancer and mounting evidence implicates CK2 in tumorigenesis. Here, we show that CK2 is overexpressed and hyperactivated in chronic lymphocytic leukemia (CLL). Inhibition of CK2 induces apoptosis of CLL cells without significantly affecting normal B and T lymphocytes. Importantly, this effect is not reversed by coculture with OP9 stromal cells, which are otherwise capable of rescuing CLL cells from in vitro spontaneous apoptosis. CLL cell death upon CK2 inhibition is mediated by inactivation of PKC, a PI3K downstream target, and correlates with increased PTEN activity, indicating that CK2 promotes CLL cell survival at least in part via PI3K-dependent signaling. Although CK2 antagonists induce significant apoptosis of CLL cells in all patient samples analyzed, sensitivity to CK2 blockade positively correlates with the percentage of CLL cells in the peripheral blood, ß2 microglobulin serum levels and clinical stage. These data suggest that subsets of patients with aggressive and advanced stage disease may especially benefit from therapeutic strategies targeting CK2 function. Overall, our study indicates that CK2 plays a critical role in CLL cell survival, laying the groundwork for the inclusion of CK2 inhibitors into future therapeutic strategies.

Impact of pharmacometric reviews on new drug approval and labeling decisions--a survey of 31 new drug applications submitted between 2005 and 2006.

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses. The objective of the current report is to assess the role of PM, at the Food and Drug Administration (FDA), in drug approval and labeling decisions. We surveyed the impact of PM analyses on New Drug Applications (NDAs) reviewed over 15 months in 2005-2006. The survey focused on both the approval and labeling decisions through four perspectives: clinical pharmacology primary reviewer, their team leader, the clinical team member, and the PM reviewer. A total of 31 NDAs included a PM review component. Review of NDAs involved independent quantitative evaluation by FDA pharmacometricians. PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs. Case studies are presented to demonstrate the applications of PM analysis.

Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist.

Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).

Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats.

Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRH-stimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonad-intact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [d-Ala(6), des-Gly(10)]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.

Characterization of mono- and diaminopyrimidine derivatives as novel, nonpeptide gonadotropin releasing hormone (GnRH) receptor antagonists.

A novel series of derivatives of mono- and diaminopyrimidines 1 potently displaced binding of a radiolabeled GnRH analogue to human and rat GnRH receptors. Analogues from these series competitively antagonized GnRH-stimulated increases in extracellular acidification in vitro and suppressed GnRH-mediated increases in circulating luteinizing hormone (LH) in castrated rats and testosterone in intact rats. These compounds or their analogues may be useful in treating sex hormone-dependent disease.

Effect of testosterone suppression on the pharmacokinetics of a potent gnRH receptor antagonist.

PURPOSE: The expression of cytochrome P450 enzymes (CYPs) in animals and humans is under complex hormonal regulation. Chronic treatment with drugs that alter sex hormone levels such as GnRH receptor agonists or antagonists may affect the expression of hormone-dependent CYPs, and as a result the pharmacokinetics of drugs metabolized by them. METHODS: Enzyme kinetic parameters were obtained by incubating AG-045572 (0.1-30 microM) with human or rat liver microsomes, or expressed CYP3A4 and CYP3A5. The pharmacokinetics of AG-045572 (10 mg/kg i.v. or 20 mg/kg p.o.) were studied in intact male, female, castrated male and male rats pretreated with AG-045572 for 4 days. RESULTS: AG-045572 is metabolized by CYP3A in both rats and humans. The Km values were similar in male and female human, female rat liver microsomes, and expressed CYP3A4 and CYP3A5 (0.39, 0.27, 0.28, 0.25, and 0.26 microM, respectively). The Km in male rat liver microsomes was 1.5 microM, suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes. The oral bioavailability of AG-045572 in intact male rats was 8%, while in female or castrated male rats it was 24%. Pretreatment of intact male rats with AG-045572 i.m. for 4 days resulted in suppression of testosterone to castrate levels, accompanied by an increase in oral bioavailability of AG-045572 to 27%. In the same experiment, the male-specific pulsatile pattern of growth hormone remained unchanged with slightly elevated baseline levels. CONCLUSIONS: The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A. As a result, suppression of testosterone by pretreatment with AG-045572 "feminized" its own pharmacokinetics.