Disproportional surface segregation in ligand-free gold-silver alloy solid solution nanoparticles, and its implication for catalysis and biomedicine.

Catalytic activity and toxicity of mixed-metal nanoparticles have been shown to correlate and are known to be dependent on surface composition. The surface chemistry of the fully inorganic, ligand-free silver-gold alloy nanoparticle molar fraction series, is highly interesting for applications in heterogeneous catalysis, which is determined by active surface sites which are also relevant for understanding their dissolution behavior in biomedically-relevant ion-release scenarios. However, such information has never been systematically obtained for colloidal nanoparticles without organic surface ligands and has to date, not been analyzed in a surface-normalized manner to exclude density effects. For this, we used detailed electrochemical measurements based on cyclic voltammetry to systematically analyze the redox chemistry of particle-surface-normalized gold-silver alloy nanoparticles with varying gold molar fractions. The study addressed a broad range of gold molar fractions (Ag90Au10, Ag80Au20, Ag70Au30, Ag50Au50, Ag40Au60, and Ag20Au80) as well as monometallic Ag and Au nanoparticle controls. Oxygen reduction reaction (ORR) measurements in O2 saturated 0.1 M KOH revealed a linear reduction of the overpotential with increasing gold content on the surface, probably attributed to the higher ORR activity of gold over silver, verified by monometallic Ag and Au controls. These findings were complemented by detailed XPS studies revealing an accumulation of the minor constituent of the alloy on the surface, e.g., silver surface enrichment in gold-rich particles. Furthermore, highly oxidized Ag surface site enrichment was detected after the ORR reaction, most pronounced in gold-rich alloys. Further, detailed CV studies at acidic pH, analyzing the position, onset potential, and peak integrals of silver oxidation and silver reduction peaks revealed particularly low reactivity and high chemical stability of the equimolar Au50Ag50 composition, a phenomenon attributed to the outstanding thermodynamic, entropically driven, stabilization arising at this composition.

Conformal atomic layer deposition of RuOxon highly porous current collectors for micro-supercapacitor applications.

3D porous electrodes have been considered as a new paradigm shift for increasing the energy storage of pseudocapacitive micro-supercapacitors for on-chip electronics. However, the conformal deposition of active materials is still challenging when highly porous structures are involved. In this work, we have investigated the atomic layer deposition (ALD) of ruthenium dioxide RuO2on porous Au and Pt architectures prepared by hydrogen bubble templated electrodeposition, with area enlargement factors ranging from 400 to 10 000 cm2/cm2. Using proper ALD conditions, a uniform RuO2coverage has been successfully obtained on porous Au, with a specific electrode capacitance of 8.1 mF cm-2and a specific power of 160 mW cm-2for a minute amount of active material. This study also shows the importance of the chemical composition and reactivity of the porous substrate for achieving conformal deposition of a ruthenium oxide layer.

Prediction models of diabetes complications: a scoping review.

BACKGROUND: Diabetes often places a large burden on people with diabetes (hereafter 'patients') and the society, that is, in part attributable to its complications. However, evidence from models predicting diabetes complications in patients remains unclear. With the collaboration of patient partners, we aimed to describe existing prediction models of physical and mental health complications of diabetes. METHODS: Building on existing frameworks, we systematically searched for studies in Ovid-Medline and Embase. We included studies describing prognostic prediction models that used data from patients with pre-diabetes or any type of diabetes, published between 2000 and 2020. Independent reviewers screened articles, extracted data and narratively synthesised findings using established reporting standards. RESULTS: Overall, 78 studies reported 260 risk prediction models of cardiovascular complications (n=42 studies), mortality (n=16), kidney complications (n=14), eye complications (n=10), hypoglycaemia (n=8), nerve complications (n=3), cancer (n=2), fracture (n=2) and dementia (n=1). Prevalent complications deemed important by patients such as amputation and mental health were poorly or not at all represented. Studies primarily analysed data from older people with type 2 diabetes (n=54), with little focus on pre-diabetes (n=0), type 1 diabetes (n=8), younger (n=1) and racialised people (n=10). Per complication, predictors vary substantially between models. Studies with details of calibration and discrimination mostly exhibited good model performance. CONCLUSION: This rigorous knowledge synthesis provides evidence of gaps in the landscape of diabetes complication prediction models. Future studies should address unmet needs for analyses of complications n> and among patient groups currently under-represented in the literature and should consistently report relevant statistics. SCOPING REVIEW REGISTRATION: https://osf.io/fjubt/.

Predictive models of diabetes complications: protocol for a scoping review.

BACKGROUND: Diabetes is a highly prevalent chronic disease that places a large burden on individuals and health care systems. Models predicting the risk (also called predictive models) of other conditions often compare people with and without diabetes, which is of little to no relevance for people already living with diabetes (called patients). This review aims to identify and synthesize findings from existing predictive models of physical and mental health diabetes-related conditions. METHODS: We will use the scoping review frameworks developed by the Joanna Briggs Institute and Levac and colleagues. We will perform a comprehensive search for studies from Ovid MEDLINE and Embase databases. Studies involving patients with prediabetes and all types of diabetes will be considered, regardless of age and gender. We will limit the search to studies published between 2000 and 2018. There will be no restriction of studies based on country or publication language. Abstracts, full-text screening, and data extraction will be done independently by two individuals. Data abstraction will be conducted using a standard methodology. We will undertake a narrative synthesis of findings while considering the quality of the selected models according to validated and well-recognized tools and reporting standards. DISCUSSION: Predictive models are increasingly being recommended for risk assessment in treatment decision-making and clinical guidelines. This scoping review will provide an overview of existing predictive models of diabetes complications and how to apply them. By presenting people at higher risk of specific complications, this overview may help to enhance shared decision-making and preventive strategies concerning diabetes complications. Our anticipated limitation is potentially missing models because we will not search grey literature.

High Areal Capacity Porous Sn-Au Alloys with Long Cycle Life for Li-ion Microbatteries.

Long-term stability is one of the most desired functionalities of energy storage microdevices for wearable electronics, wireless sensor networks and the upcoming Internet of Things. Although Li-ion microbatteries have become the dominant energy-storage technology for on-chip electronics, the extension of lifetime of these components remains a fundamental hurdle to overcome. Here, we develop an ultra-stable porous anode based on SnAu alloys able to withstand a high specific capacity exceeding 100 µAh cm-2 at 3 C rate for more than 6000 cycles of charge/discharge. Also, this new anode material exhibits low potential (0.2 V versus lithium) and one of the highest specific capacity ever reported at low C-rates (7.3 mAh cm-2 at 0.1 C). We show that the outstanding cyclability is the result of a combination of many factors, including limited volume expansion, as supported by density functional theory calculations. This finding opens new opportunities in design of long-lasting integrated energy storage for self-powered microsystems.

A Condensed, Scalable Synthesis of Racemic Koningic Acid.

The natural product koningic acid (KA) is a selective covalent inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a critical node in the glycolysis pathway. While KA is available commercially, sources are limited and its cost becomes rapidly prohibitive beyond the milligram scale. Additionally, a practical and flexible synthetic route to KA and analogs remains to be developed. Here we detail a new route that is operationally safer, scalable and offers a five-step reduction in the previously reported longest linear sequence.

3D Interdigitated Microsupercapacitors with Record Areal Cell Capacitance.

Due to their high-power density and long lifetime, microsupercapacitors have been considered as an efficient energy supply/storage solution for the operation of small electronic devices. However, their fabrication remains confined to 2D thin-film microdevices with limited areal energy. In this study, the integration of all-solid-state 3D interdigitated microsupercapacitors on 4 in. silicon wafers with record energy density is demonstrated. The device electrodes are composed of a pseudocapacitive hydrated ruthenium dioxide RuO2 deposited onto highly porous current collectors. The encapsulated devices exhibit cell capacitance of 812 mF cm-2 per footprint area at an energy density of 329 mJ cm-2 , which is the highest value ever reported for planar configuration. These components achieve one of the highest surface energy/power density trade-offs and address the issue of electrical energy storage of modern electronics.

Electrochemical Reduction of CO2 by SnOx Nanosheets Anchored on Multiwalled Carbon Nanotubes with Tunable Functional Groups.

Sn-based electrocatalysts are promising for the electrochemical CO2 reduction reaction (CO2RR), but suffer from poor activity and selectivity. A hierarchical structure composed of ultrathin SnOx nanosheets anchored on the surface of the commercial multiwalled carbon nanotubes (MWCNTs) is synthesized by a simple hydrothermal process. The electrocatalytic performance can be further tuned by functionalization of the MWCNTs with COOH, NH2 , and OH groups. Both SnOx @MWCNTs-COOH and SnOx @MWCNTs-NH2 show excellent catalytic activity for CO2 RR with nearly 100 % selectivity for C1 products (formate and CO). SnOx @MWCNTs-COOH has favorable formate selectivity with a remarkably high faradaic efficiency (FE) of 77 % at -1.25 V versus standard hydrogen electrode (SHE) and a low overpotential of 246 mV. However, SnOx @MWCNTs-NH2 manifests increased selectivity for CO with higher current density. Density functional theory calculations and experimental studies demonstrate that the interaction between Sn species and functional groups play an important role in the tuning of the catalytic activity and selectivity of these functionalized electrocatalysts. SnOx @MWCNTs-COOH and SnOx @MWCNTs-NH2 both effectively inhibit the hydrogen evolution reaction and prove stable without any significant degradation over 20 h of continuous electrolysis at -1.25 V versus SHE.

Variations in the origin of the deep femoral artery: A meta-analysis.

The deep femoral artery (DFA) is the largest branch of the femoral artery (FA) and is responsible for vascularization of the thigh muscles. Knowledge of the anatomical variations in its origin point is important for surgeons and interventional radiologists. The aim of our study was to provide a comprehensive evidence-based assessment of its anatomical properties. An extensive search through the major electronic databases was conducted to find all articles reporting data on the anatomical characteristics of the DFA. No date limits or language restrictions were imposed. A total of 25 articles (n = 2,502 lower limbs) were included in the meta-analysis. Six different patterns of origin of the DFA from the FA were identified, the most common type being a posterior origin (38.8%, 95% CI 22.8-49.5%). The DFA most commonly branched off in the proximal third of the thigh, with a prevalence of 47.6% (95% CI 35.8-59.2%). The pooled mean distance of the DFA from its point of origin to the mid-inguinal point was 41.15 mm (95% CI 32.39-53.73). The point and level of origin of the DFA from the FA varies widely in the general population. Owing to this variability, accurate anatomical knowledge regarding the DFA is crucial for clinicians if iatrogenic injuries are to be avoided during procedures in the femoral region. Clin. Anat. 30:106-113, 2017. © 2016 Wiley Periodicals, Inc.

The origin of the medial circumflex femoral artery: a meta-analysis and proposal of a new classification system.

Background and Objectives. The medial circumflex femoral artery (MCFA) is a common branch of the deep femoral artery (DFA) responsible for supplying the femoral head and the greater trochanteric fossa. The prevalence rates of MCFA origin, its branching patterns and its distance to the mid-inguinal point (MIP) vary significantly throughout the literature. The aim of this study was to determine the true prevalence of these characteristics and to study their associated anatomical and clinical relevance. Methods. A search of the major electronic databases Pubmed, EMBASE, Scopus, ScienceDirect, Web of Science, SciELO, BIOSIS, and CNKI was performed to identify all articles reporting data on the origin of the MCFA, its branching patterns and its distance to the MIP. No data or language restriction was set. Additionally, an extensive search of the references of all relevant articles was performed. All data on origin, branching and distance to MIP was extracted and pooled into a meta-analysis using MetaXL v2.0. Results. A total of 38 (36 cadaveric and 2 imaging) studies (n = 4,351 lower limbs) were included into the meta-analysis. The pooled prevalence of the MCFA originating from the DFA was 64.6% (95% CI [58.0-71.5]), while the pooled prevalence of the MCFA originating from the CFA was 32.2% (95% CI [25.9-39.1]). The CFA-derived MCFA was found to originate as a single branch in 81.1% (95% CI [70.1-91.7]) of cases with a mean pooled distance of 50.14 mm (95% CI [42.50-57.78]) from the MIP. Conclusion. The MCFA's variability must be taken into account by surgeons, especially during orthopedic interventions in the region of the hip to prevent iatrogenic injury to the circulation of the femoral head. Based on our analysis, we present a new proposed classification system for origin of the MCFA.

Laser-synthesized ligand-free Au nanoparticles for contrast agent applications in computed tomography and magnetic resonance imaging.

In recent years, pulsed laser ablation in liquids (PLAL) has emerged as a new green chemistry method to produce different types of nanoparticles (NPs). It does not require the use of reducing or stabilizing agents, therefore enabling the synthesis of NPs with highly-pure surfaces. In this study, pure Au NPs were produced by PLAL in aqueous solutions, sterically stabilized using minimal PEG excess, and functionalized with manganese chelates to produce a dual CT/MRI contrast agent. The small hydrodynamic size (36.5 nm), low polydispersity (0.2) and colloidal stability of Au NPs@PEG-Mn2+ were demonstrated by DLS. The particles were further characterized by TEM, XPS, FTIR and 1H NMR to confirm the purity of the Au surfaces (i.e. free from the common residual chemicals found after NP synthesis) and the presence of the different surface molecules. The potential of these particles as contrast agents for CT/MRI was assessed in vivo (e.g. chicken embryo). Au NPs@PEG-Mn2+ also demonstrated strong blood retention for at least 90 minutes following intravenous injection in mouse models. The promising performance of PEGylated PLAL-synthesized Au NPs containing manganese chelates could open new possibilities for the production of purer dual imaging contrast agents based on Au colloids.

3D RuO2 Microsupercapacitors with Remarkable Areal Energy.

Large areal capacitance electrodes made of ruthenium oxide on highly porous gold current collectors are realized by an attractive approach. The hybrid structure exhibits a capacitance in excess of 3 F cm(-2) and an areal energy density for all-solid-state microsupercapacitors that is comparable to those of microbatteries.

Highly active PtAu alloy nanoparticle catalysts for the reduction of 4-nitrophenol.

To enhance the catalytic activity of gold nanoparticles (AuNPs) for the hydrogenation of nitro-aromatic chemicals, Pt was introduced into AuNPs to form "bare" PtAu alloy NPs using a physical approach, pulsed laser ablation in liquid (PLAL), on single metal-mixture targets. These PLAL-NPs are deemed to favor catalysis due to the absence of any surfactant molecules on their unique "bare and clean" surface. The PLAL-NPs were facilely assembled onto CeO2 nanotubes (NTs) by simply mixing them without conducting any surface functionalization, representing another advantage of these NPs. Their catalytic activity was assessed in 4-nitrophenol (4-NP) hydrogenation. The reaction catalyzed by alloy-NP/CeO2-NT catalysts demonstrates a remarkably higher reaction rate in comparison with that catalyzed by pure Au and Pt NPs, and other similar Au and Pt containing catalysts reported recently. A "volcano-like" catalytic activity dependence of the alloy NPs on their chemical composition suggests a strong synergistic effect between Au and Pt in the 4-NP reduction, far beyond the simple sum of their individual contributions. It leads to the significantly enhanced catalytic activity of Pt30Au70 and Pt50Au50 alloy NPs, outperforming not only each single constituent, but also their physical mixtures and most recently reported AuNP based nanocatalysts. The favorable d-band center shift of Pt after alloying, and co-operative actions between Pt clusters and nearby Au (or mixed PtAu) sites were proposed as possible mechanisms to explain such a strong synergistic effect on catalysis.

Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y14 receptor antagonists.

A weak antagonist of the pyrimidinergic receptor P2Y(14) containing a dihydropyridopyrimidine core was identified through high-throughput screening. Subsequent optimization led to potent, non-UTP competitive antagonists and represent the first reported non-nucleotide antagonists of this receptor. Compound 18q was identified as a 10 nM P2Y(14) antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies.

Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases.

In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.

Potent and highly selective DP1 antagonists with 2,3,4,9-tetrahydro-1H-carbazole as pharmacophore.

We discovered that the introduction of a methyl group to the benzylic position of the N-benzyl group in lead compound 1a has a dramatic effect on improving the binding selectivity of this ligand for the prostanoid receptors DP1 (receptor for prostaglandin D(2)) as compared to TP (receptor for thromboxane A(2)). Based on this discovery, we have synthesized a series of potent and highly selective DP1 antagonists. Among them, compound 1h was identified as a highly selective DP1 antagonist with excellent overall properties. It has a K(i) of 0.43 nM to DP1 in binding assay and an IC(50) of 2.5 nM in the DP1 functional assay. Its selectivity for DP1 over TP (the most potent receptor after DP1) exceeds 750-fold based on both binding and functional assays. These properties make 1h a very potent and highly selective DP1 receptor antagonist suitable for investigating the biological functions of DP1 in normal physiology and models of disease.

Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment.

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.

Therapeutic utility and medicinal chemistry of cathepsin C inhibitors.

The lysosomal cysteine protease cathepsin C (Cat C), also known as dipeptidyl peptidase I, activates a number of granule-associated serine proteases with pro-inflammatory and immune functions by removal of their inhibitory N-terminal dipeptides. Thus, Cat C is a therapeutic target for the treatment of a number of inflammatory and autoimmune diseases. Cathepsin C null mice and humans with Cat C loss of function mutations (Papillon-Lefèvre syndrome) show deficiencies in disease-relevant proteases including neutrophil elastase, cathepsin G, chymases and granzymes and the Cat C mice are protected in a number of disease models. Several methodologies have been recently reported for assessing the effects of Cat C inhibitors on serine protease activities in cellular assays and prolonged treatment of rats with a reversible, selective Cat C inhibitor reduced the activity of three leukocyte serine proteases. Nearly all potent and selective Cat C inhibitors described are based on the preferred dipeptide substrates bearing either irreversible (e.g. diazomethylketone, acyloxymethyl ketone, o-acyl hydroxamic acid and vinyl sulfone) or reversible (e.g. semicarbazide, nitrile and cyanamide) electrophilic warheads. While potent and highly selective, the best inhibitors described to date still have poor stability and/or rodent pharmacokinetics, likely resulting from their peptidic nature. The lack of selective compounds with appropriate rodent pharmacokinetic properties has hampered the assessment of the effects of Cat C inhibitors on the activation of disease-relevant proteases in vivo and the full evaluation of the therapeutic utility of Cat C inhibitors.

Design and synthesis of dipeptidyl nitriles as potent, selective, and reversible inhibitors of cathepsin C.

A series of dipeptide nitriles with a thienyl alanine in P2 were identified as potent and selective cathepsin C inhibitors. Incorporation of a substituted cyclopropyl moiety in P1 effectively protects these derivatives against hydrolase activity in whole blood.

Optimization and structure-activity relationship of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides: identification of MK-0873, a potent and effective PDE4 inhibitor.

A SAR study of a series of 1-phenyl-1,8-naphthyridin-4-one-3-carboxamides is described. Optimization of the series was based on in vitro potency against PDE4, inhibition of the LPS-induced production of TNF-alpha in human whole blood and minimizing affinity for the hERG potassium channel. From these studies, compounds 18 and 20 (MK-0873) were identified as optimized PDE4 inhibitors with good overall in vitro and in vivo profiles and selected as development candidates.