Mixed Valence {Ni²⁺Ni¹⁺} Clusters as Models of Acetyl Coenzyme ASynthase Intermediates

Acetyl coenzyme A synthase (ACS) catalyzes the formation and deconstruction of the key biological metabolite, acetyl coenzyme A (acetyl-CoA). The active site of ACS features a {NiNi} cluster bridged to a [Fe4S4]n+ cubane known as the A-cluster. The mechanism by which the A-cluster functions is debated, with few model complexes able to replicate the oxidation states, coordination features, or reactivity proposed in the catalytic cycle. In this work, we isolate the first bimetallic models of two hypothesized intermediates on the paramagnetic pathway of the ACS function. The heteroligated {Ni2+Ni1+} cluster, [K(12-crown-4)2][1], effectively replicates the coordination number and oxidation state of the proposed “Ared” state of the A-cluster. Addition of carbon monoxide to [1]− allows for isolation of a dinuclear {Ni2+Ni1+(CO)} complex, [K(12-crown-2)n][2] (n = 1–2), which bears similarity to the “ANiFeC” enzyme intermediate. Structural and electronic properties of each cluster are elucidated by X-ray diffraction, nuclear magnetic resonance, cyclic voltammetry, and UV/vis and electron paramagnetic resonance spectroscopies, which are supplemented by density functional theory (DFT) calculations. Calculations indicate that the pseudo-T-shaped geometry of the three-coordinate nickel in [1]– is more stable than the Y-conformation by 22 kcal mol–1, and that binding of CO to Ni1+ is barrierless and exergonic by 6 kcal mol–1. UV/vis absorption spectroscopy on [2]− in conjunction with time-dependent DFT calculations indicates that the square-planar nickel site is involved in electron transfer to the CO π*-orbital. Further, we demonstrate that [2]− promotes thioester synthesis in a reaction analogous to the production of acetyl coenzyme A by ACS

Unraveling the Steric Link to Copper Precursor Decomposition: A Multi-Faceted Study for the Printing of Flexible Electronics

The field of printed electronics strives for lower processing temperatures to move toward flexible substrates that have vast potential: from wearable medical devices to animal tagging. Typically, ink formulations are optimized using mass screening and elimination of failures; as such, there are no comprehensive studies on the fundamental chemistry at play. Herein, findings which describe the steric link to decomposition profile: combining density functional theory, crystallography, thermal decomposition, mass spectrometry, and inkjet printing, are reported. Through the reaction of copper(II) formate with excess alkanolamines of varying steric bulk, tris-co-ordinated copper precursor ions: "[CuL3 ]," each with a formate counter-ion (1-3) are isolated and their thermal decomposition mass spectrometry profiles are collected to assess their suitability for use in inks (I1-3 ). Spin coating and inkjet printing of I1,2 provides an easily up-scalable method toward the deposition of highly conductive copper device interconnects (ρ = 4.7-5.3 × 10-7 Ω m; ≈30% bulk) onto paper and polyimide substrates and forms functioning circuits that can power light-emitting diodes. The connection among ligand bulk, coordination number, and improved decomposition profile supports fundamental understanding which will direct future design

An ultrasound based platform for image-guided radiotherapy in canine bladder cancer patients

Background and purpose: Ultrasound (US) is a non-invasive, non-radiographic imaging technique with high spatial and temporal resolution that can be used for localizing soft-tissue structures and tumors in real-time during radiotherapy (RT) (inter- and intra-fraction). A comprehensive approach incorporating an in-house 3D-US system within RT is presented. This system is easier to adopt into existing treatment protocols than current US based systems, with the aim of providing millimeter intra-fraction alignment errors and sensitivity to track intra-fraction bladder movement. Materials and methods: An in-house integrated US manipulator and platform was designed to relate the computed tomographic (CT) scanner, 3D-US and linear accelerator coordinate systems. An agar-based phantom with measured speed of sound and densities consistent with tissues surrounding the bladder was rotated (0-45°) and translated (up to 55 mm) relative to the US and CT coordinate systems to validate this device. After acquiring and integrating CT and US images into the treatment planning system, US-to-US and US-to-CT images were co-registered to re-align the phantom relative to the linear accelerator. Results: Statistical errors from US-to-US registrations for various patient orientations ranged from 0.1 to 1.7 mm for x, y, and z translation components, and 0.0-1.1° for rotational components. Statistical errors from US-to-CT registrations were 0.3-1.2 mm for the x, y and z translational components and 0.1-2.5° for the rotational components. Conclusions: An ultrasound-based platform was designed, constructed and tested on a CT/US tissue-equivalent phantom to track bladder displacement with a statistical uncertainty to correct and track inter- and intra-fractional displacements of the bladder during radiation treatments

Exploration potenzieller Barrieren für die Akzeptanz eines interdisziplinären sektorenübergreifenden Versorgungsnetzwerkes für Patient*innen mit Morbus Parkinson

Hintergrund Mit dem ParkinsonNetzwerk Ostsachsen (PANOS) soll ein intersektorales, pfadbasiertes und plattformunterstütztes Versorgungskonzept etabliert werden, um trotz steigender Behandlungszahlen eine flächendeckende Parkinson-Versorgung mit adäquaten Therapien zu unterstützen. Fragestellung Welche Barrieren könnten die Akzeptanz und eine erfolgreiche Verstetigung des PANOS-Behandlungspfades gefährden? Methode Implementierungsbarrieren wurden über eine selektive Literaturrecherche identifiziert und in einer Onlinebefragung von 36 projektassoziierten Neurolog*innen und Hausärzt*innen priorisiert. Die Auswertung der Ergebnisse erfolgte anonymisiert und deskriptiv. Ergebnisse Dreizehn mögliche Implementierungsbarrieren wurden identifiziert. Es nahmen 11 Neurolog*innen und 7 Hausärzt*innen an der Onlineumfrage teil. Die befragten Neurolog*innen sahen in Doppeldokumentationen sowie in unzureichender Kommunikation und Kooperation zwischen den Leistungserbringenden die größten Hindernisse für eine Akzeptanz von PANOS. Hausärzt*innen beurteilten u. a. die restriktiven Verordnungs- und Budgetgrenzen und den möglicherweise zu hohen Zeitaufwand für Netzwerkprozesse als hinderlich. Diskussion Doppeldokumentationen von Patienten- und Behandlungsdaten sind zeitintensiv und fehleranfällig. Die Akzeptanz kann durch adäquate finanzielle Kompensation der Leistungserbringenden erhöht werden. Das hausärztliche Verordnungsverhalten könnte durch die Verwendung interventionsbezogener Abrechnungsziffern positiv beeinflusst werden. Die Ergebnisse zeigen u. a. einen Bedarf an integrativen technischen Systemlösungen und sektorenübergreifenden Dokumentationsstrukturen, um den Mehraufwand für Leistungserbringende zu reduzieren. Schlussfolgerung Eine Vorabanalyse der Einflussfaktoren von PANOS sowie die Sensibilisierung aller mitwirkenden Akteure für potenzielle Barrieren sind entscheidend für die Akzeptanz des Versorgungsnetzwerkes. Gezielte Maßnahmen zur Reduzierung und Vermeidung identifizierter Barrieren können die anwenderseitige Akzeptanz erhöhen und die Behandlungsergebnisse optimieren.Introduction The ParkinsonNetwork Eastern Saxony (PANOS) aims to establish an intersectoral, path-based and platform-supported care concept in order to support comprehensive care with adequate therapies despite the increasing number of patients to be treated. Objective Which barriers may limit the acceptance and successful implementation of PANOS? Methods Implementation barriers were identified through a selective literature review and prioritized in an online survey of 36 project-associated neurologists and general practitioners. The results were analyzed anonymously and descriptively. Results Thirteen potential implementation barriers were identified. Eleven neurologists and seven general practitioners participated in the online survey. The surveyed neurologists assessed double documentation and inadequate communication and cooperation between the service providers as the biggest obstacles to the acceptance of PANOS. General practitioners rated the restrictions for prescription and budget and the potentially high time expenditure required for network activities as barriers. Discussion Double documentation of patient and treatment data is time consuming and prone to errors. Adequate financial compensation could increase service providers’ willingness to participate in such measures. In addition, the prescribing behavior of general practitioners may be influenced positively by the use of intervention-related accounting numbers. The results indicate a need for integrative technical system solutions and intersectoral documentation structures in order to reduce the additional effort for service providers. Conclusion Analyzing the influencing factors of the PANOS network, and raising the awareness of all participating service providers to potential barriers, are decisive measures for the acceptance of the care network. Targeted measures to reduce and avoid identified barriers can increase user acceptance and optimize treatment results

Hybrid Organic-Inorganic Coordination Complexes as Tunable Optical Response Materials.

Novel lead and bismuth dipyrido complexes have been synthesized and characterized by single-crystal X-ray diffraction, which shows their structures to be directed by highly oriented π-stacking of planar fully conjugated organic ligands. Optical band gaps are influenced by the identity of both the organic and inorganic component. Density functional theory calculations show optical excitation leads to exciton separation between inorganic and organic components. Using UV-vis, photoluminescence, and X-ray photoemission spectroscopies, we have determined the materials' frontier energy levels and show their suitability for photovoltaic device fabrication by use of electron- and hole-transport materials such as TiO2 and spiro-OMeTAD respectively. Such organic/inorganic hybrid materials promise greater electronic tunability than the inflexible methylammonium lead iodide structure through variation of both the metal and organic components

An L Band Spectrum of the Coldest Brown Dwarf

The coldest brown dwarf, WISE 0855, is the closest known planetary-mass, free-floating object and has a temperature nearly as cold as the solar system gas giants. Like Jupiter, it is predicted to have an atmosphere rich in methane, water, and ammonia, with clouds of volatile ices. WISE 0855 is faint at near-infrared wavelengths and emits almost all its energy in the mid-infrared. Skemer et al. 2016 presented a spectrum of WISE 0855 from 4.5-5.1 micron (M band), revealing water vapor features. Here, we present a spectrum of WISE 0855 in L band, from 3.4-4.14 micron. We present a set of atmosphere models that include a range of compositions (metallicities and C/O ratios) and water ice clouds. Methane absorption is clearly present in the spectrum. The mid-infrared color can be better matched with a methane abundance that is depleted relative to solar abundance. We find that there is evidence for water ice clouds in the M band spectrum, and we find a lack of phosphine spectral features in both the L and M band spectra. We suggest that a deep continuum opacity source may be obscuring the near-infrared flux, possibly a deep phosphorous-bearing cloud, ammonium dihyrogen phosphate. Observations of WISE 0855 provide critical constraints for cold planetary atmospheres, bridging the temperature range between the long-studied solar system planets and accessible exoplanets. JWST will soon revolutionize our understanding of cold brown dwarfs with high-precision spectroscopy across the infrared, allowing us to study their compositions and cloud properties, and to infer their atmospheric dynamics and formation processes.Comment: 19 pages, 21 figures. Accepted for publication in Ap

Inter-professional perspectives of dementia services and care in England: Outcomes of a focus group study

© The Author(s) 2014. Many people living with dementia are supported at home using a variety of health and social care services. This paper reports the findings from a focus group study undertaken with staff in community mental health teams to explore areas for improvement in relation to national policies and recommendations for dementia care. Two focus groups were held with staff (n = 23) in 2011 to discuss topics including service delivery, information and communication, and provision of health and community care for people with dementia. Respondents identified problems with information sharing and incompatible electronic systems; inflexibility in home care services; and poor recognition of dementia in hospital settings. General practitioners had developed a greater awareness of the disease and some community services worked well. They felt that budgetary constraints and a focus on quality indicators impeded good dementia care. Key areas suggested by staff for improvements in dementia care included the implementation of more flexible services, dementia training for health and social care staff, and better quality care in acute hospital settings

Association of Killer Cell Immunoglobulin-Like Receptor Genes with Hodgkin's Lymphoma in a Familial Study

BACKGROUND: Epstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study. METHODOLOGY: We included 90 families with 90 HL index cases (age 16–35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families. PRINCIPAL FINDINGS: Five KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23–0.85] and 0.42[0.21–0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18–71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells. CONCLUSIONS: This work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. METHOD: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. DISCUSSION: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. TRIAL REGISTRATION: Current controlled trials ISRCTN49545035.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Uniform Atmospheric Retrieval Analysis of Ultracool Dwarfs II : Properties of 11 T-dwarfs

Accepted ApJ. Supplemental material including full posteriors will be included through the link in the published ApJ article © 2017 The American Astronomical Society. All rights reserved.Brown dwarf spectra are rich in information revealing of the chemical and physical processes operating in their atmospheres. We apply a recently developed atmospheric retrieval tool to an ensemble of late T-dwarf (600-800K) near infrared spectra. With these spectra we are able to place direct constraints the molecular abundances of H$_2$O, CH$_4$, CO, CO$_2$, NH$_3$, H$_2$S, and Na+K, gravity, thermal structure (and effective temperature), photometric radius, and cloud optical depths. We find that ammonia, water, methane, and the alkali metals are present and well constrained in all 11 objects. From the abundance constraints we find no significant trend in the water, methane, or ammonia abundances with temperature, but find a very strong ($>$25$\sigma$) increasing trend in the alkali metal abundances with effective temperature, indicative of alkali rainout. We also find little evidence for optically thick clouds. With the methane and water abundances, we derive the intrinsic atmospheric metallicity and carbon-to-oxygen ratios. We find in our sample, that metallicities are typically sub solar and carbon-to-oxygen ratios are somewhat super solar, different than expectations from the local stellar population. We also find that the retrieved vertical thermal profiles are consistent with radiative equilibrium over the photospheric regions. Finally, we find that our retrieved effective temperatures are lower than previous inferences for some objects and that our radii are larger than expectations from evolutionary models, possibly indicative of un-resolved binaries. This investigation and methodology represents a paradigm in linking spectra to the determination of the fundamental chemical and physical processes governing cool brown dwarf atmospheres.Peer reviewe