bluuebunny/crossref_metadata_2025 huggingface dataset:
Organocatalyzed Photocontrolled Radical Polymerization of Semifluorinated (Meth)acrylates Driven by Visible Light
Authors: Gong Honghong , Zhao Yucheng , Shen Xianwang , Lin Jun , Chen Mao
Published: November 2017

Fluorinated polymers are important materials that are widely used in many areas. Herein, we report the development of a metal‐free photocontrolled radical polymerization of semifluorinated (meth)acrylates with a new visible‐light‐absorbing organocatalyst. This method enabled the production of a variety of semifluorinated polymers with narrow molar‐weight distributions from semifluorinated trithiocarbonates or perfluoroalkyl iodides. The high performance of “ON/OFF” control and chain‐extension experiments further demonstrate the utility and reliability of this method. Furthermore, to streamline the preparation of semifluorinated polymers, a scalable continuous‐flow approach has been developed. Given the broad interest in fluorinated materials and photopolymerization, we expect that this method will facilitate the development of advanced materials with unique properties.
Internal Peptide Late‐Stage Diversification: Peptide‐Isosteric Triazoles for Primary and Secondary C(sp3)−H Activation
Authors: Bauer Michaela , Wang Wei , Lorion Mélanie M. , Dong Chuan , Ackermann Lutz
Published: November 2017

Secondary C(sp3)−H arylations were accomplished by palladium catalysis with triazoles as peptide bond isosteres. The unique power of this approach is highlighted by the possibility of achieving secondary C(sp3)−H functionalizations on terminal peptides as well as the unprecedented positional‐selective C(sp3)−H functionalization of internal peptide positions, setting the stage for modular peptide late‐stage diversification.
Synthesis and properties of non‐cytotoxic poly(l‐malic acid acetate‐co‐l‐lysine ester)s with thermo‐sensitivity as hydrophobic drug nanocarrier
Authors: Yue Ying , Fan Zhihui , Zheng Chang , Ding Lan , Wang Huiying , Zhang Miao , Deng Kuilin
Published: November 2017

In this investigation, a group of poly(l‐malic acid acetate‐co‐l‐lysine ester)s (PMALs) with excellent thermo‐sensitivity and non‐cytotoxicity were prepared by an optimized synthetic route from natural l‐malic acid and l‐lysine. The structure and properties of PMALs including monomers were systematically characterized by FTIR, 1H NMR, UV, gel permeation chromatograph, scanning electron microscope, contact angle measurement, cell counting kit assess (CCK‐8), and confocal laser scanning microscopy (CLSM). Three PMALs show a reversible lower critical solution temperature of 8–36 °C depending on their chemical structure. The contact angle measurement revealed a considerable discrepancy in the hydrophilicity/hydrophobicity of PMALs and further influence on their thermo‐sensitivity. The viability of HeLa cells exposed to 0.2–100 μg/mL PMALs solution was found to be in a range 80–103% after 24, 48, and 72 h of incubation, indicating no cytotoxicity. Moreover, a spherical nanocarrier with core‐shell structure was facilely fabricated via the thermo‐sensitivity of PMALs and hydrophobicity of drug. CLSM observations manifested that the hydrophobic‐curcumin‐enwrapped nanocarriers can clearly internalize into the cellular inside. The sustained release of curcumin from nanocarriers in vitro provided a possibility of depressing fast hydrolytic degradation at physiological pH or other side‐effects. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 45984.
Alkylation of Ketones Catalyzed by Bifunctional Iron Complexes: From Mechanistic Understanding to Application
Authors: Seck Charlotte , Mbaye Mbaye Diagne , Coufourier Sébastien , Lator Alexis , Lohier Jean‐François , Poater Albert , Ward Thomas R. , Gaillard Sylvain , Renaud Jean‐Luc
Published: November 2017

Cyclopentadienone iron dicarbonyl complexes were applied in the alkylation of ketones with various aliphatic and aromatic ketones and alcohols via the borrowing hydrogen strategy in mild reaction conditions. DFT calculations and experimental works highlight the role of the transition metal Lewis pairs and the base. These iron complexes demonstrated a broad applicability in mild conditions and extended the scope of substrates.
The Intermetalloid Cluster Cation (CuBi8)3+
Authors: Knies Maximilian , Kaiser Martin , Isaeva Anna , Müller Ulrike , Doert Thomas , Ruck Michael
Published: November 2017

Invited for the cover of this issue is the group of Michael Ruck at the Technical University in Dresden. The image depicts the intermetalloid cluster (CuBi8)3+, which features a hitherto unknown bonding mode between bismuth and copper, and crystallizes as an adduct with an [AlCl4]− ion of the applied ionic liquid. Read the full text of the article at 10.1002/chem.201703916.
Degradation of ferrate species produced electrochemically for use in drinking water treatment applications
Authors: Cataldo‐Hernández Macarena , Stewart Mikaela , Bonakdarpour Arman , Mohseni Madjid , Wilkinson David P.
Published: November 2017

Stability of ferrate species, produced electrochemically for on‐site treatment of drinking water, has been thoroughly studied for a number of important conditions including: pH, temperature, initial concentration effects, and the presence of impurities, in order to assess the degradation process quantitatively. The limited number of ferrate degradation studies reported to this date have all focused on the chemically‐produced ferrate species and have examined conditions which are unsuitable for drinking water treatment. Degradation of electrochemical ferrates over a wide temperature range of 5 °C to 80 °C shows an Arrhenius‐type reaction behaviour with an activation energy of 27.3 ± 0.6 kJ mol−1. Initial rate analysis of ferrate degradation reveals a reaction order of about 1. The impacts of potential water impurities, such as salts and natural organic matter, and the source water (e.g. tap, deionized, and natural lake) have been studied and are presented. Degradation of ferrates in the pH range of 5 to 13 appears to have a first‐order kinetic behaviour with rate constants ranging from 1.02 × 10−3 s−1 to 6.67 × 10−5 s−1. Understanding the stability properties is important for further development and deployment of on‐site generated ferrates for the purposes of drinking water treatment.
Long‐term, dynamic synaptic reorganization after GABAergic precursor cell transplantation into adult mouse spinal cord
Authors: Llewellyn‐Smith Ida J. , Basbaum Allan I. , Bráz João M.
Published: November 2017

Transplanting embryonic precursors of GABAergic neurons from the medial ganglionic eminence (MGE) into adult mouse spinal cord ameliorates mechanical and thermal hypersensitivity in peripheral nerve injury models of neuropathic pain. Although Fos and transneuronal tracing studies strongly suggest that integration of MGE‐derived neurons into host spinal cord circuits underlies recovery of function, the extent to which there is synaptic integration of the transplanted cells has not been established. Here, we used electron microscopic immunocytochemistry to assess directly integration of GFP‐expressing MGE‐derived neuronal precursors into dorsal horn circuitry in intact, adult mice with short‐ (5–6 weeks) or long‐term (4–6 months) transplants. We detected GFP with pre‐embedding avidin–biotin‐peroxidase and GABA with post‐embedding immunogold labeling. At short and long times post‐transplant, we found host‐derived synapses on GFP‐immunoreactive MGE cells bodies and dendrites. The proportion of dendrites with synaptic input increased from 50% to 80% by 6 months. In all mice, MGE‐derived terminals formed synapses with GFP‐negative (host) cell bodies and dendrites and, unexpectedly, with some GFP‐positive (i.e., MGE‐derived) dendrites, possibly reflecting autoapses or cross talk among transplanted neurons. We also observed axoaxonic appositions between MGE and host terminals. Immunogold labeling for GABA confirmed that the transplanted cells were GABAergic and that some transplanted cells received an inhibitory GABAergic input. We conclude that transplanted MGE neurons retain their GABAergic phenotype and integrate dynamically into host‐transplant synaptic circuits. Taken together with our previous electrophysiological analyses, we conclude that MGE cells are not GABA pumps, but alleviate pain and itch through synaptic release of GABA.
Electrochromism in Polymer‐Electrolyte‐Enabled Nanostructured WO3: Active Layer Thickness and Morphology on Device Performance
Authors: Bathe Suvarna Ravi , Illa Mr. Sivaram , Narayan Ramanuj , Basak Pratyay
Published: November 2017

Herein, we showcase the ease and feasibility of integrating a quasi‐solid semi‐IPN electrolyte supporting Li+‐ion conduction with nanostructured WO3 to achieve a functional electrochromic device with impressive performance and stability. Co‐continuous WO3 electrodes, obtained layer‐by‐layer, reveal interesting changes in morphology from plate‐like structures to nanoparticles. The nanostructured electrodes offer a large surface area and a sufficiently open architecture for realizing effective permeation of the polymeric electrolyte. WO3 films (∼300 nm) achieved with five repetitive deposition‐spin cycles (5 L) provide best coverage, electrolyte wetting and device characteristics. Redox efficiency and reversibility >2000 cycles indicates a stable electrode‐electrolyte interface and device performance. A considerably high coloration efficiency of ∼134 cm2 C−1, an appreciably fast switching response (<2 s), full coloration/bleaching at competitive time scales of 5.9 s and 5.1 s, respectively, along with device reversibility of ≈97 % underline the viability of electrode architecture and polymer electrolyte combination.
Pharmacokinetics, Pharmacodynamics, and Safety of a Long‐Acting Human Growth Hormone (MOD‐4023) in Healthy Japanese and Caucasian Adults
Authors: Kramer William G. , Jaron‐Mendelson Michal , Koren Ronit , Hershkovitz Oren , Hart Gili
Published: November 2017

Daily injections of growth hormone (GH) as replacement therapy in GH‐deficient (GHD) patients may cause poor compliance and inconvenience. C‐terminal peptide–modified human GH (MOD­4023) has been developed for once­weekly administration in GHD adults and children. In the present study, the pharmacokinetics (PK) and pharmacodynamics (PD) of a single subcutaneous dose of MOD­4023 were evaluated in healthy Caucasian and Japanese adults, using a phase 1 double‐blind, vehicle‐controlled, randomized study design. The study was conducted in 42 healthy Japanese (n = 21) and Caucasian (n = 21) men receiving either MOD‐4023 at a dose of 2.5, 7.5, or 15 mg or vehicle. In the 2.5‐ and 7.5‐mg cohorts, no differences in mean MOD‐4023 serum concentration were found between Japanese and Caucasian subjects. A comparison of PK parameters in the 15‐mg group suggests a slower absorption rate of MOD‐4023 in Japanese subjects. PD analysis showed no apparent differences in IGF‐1 and IGFBP‐3 plasma concentrations between the Japanese and Caucasian subjects and indicated that a dose of 15 mg achieved the maximal effect in both ethnic groups. MOD‐4023 demonstrated a favorable safety profile and local tolerance following single‐dose subcutaneous administration. This study provides additional support for the development of MOD‐4023 as a long‐acting human growth hormone formulation for once‐weekly administration.
On the Performance of Hybrid Functionals for Non‐linear Optical Properties and Electronic Excitations in Chiral Molecular Crystals: The Case of Butterfly‐Shaped Dicinnamalacetone
Authors: da Silva Pedro S. Pereira , Martín‐Ramos Pablo , Domingos Sérgio R. , Bota de Sousa Maria do Carmo , Arranja Cláudia T. , Sobral Abílio J. F. N. , Ramos Silva Manuela
Published: November 2017

Purely organic chiral molecular assemblies in the solid state hold great potential for non‐linear optical applications. Herein, a newly synthesised molecular system is reported, namely, dicinnamalacetone, an otherwise planar molecule that crystallises in a disordered non‐centrosymmetric form with four different conformations having an overall predominance of a particular helicity. A combined experimental and theoretical approach, including single‐crystal X‐ray diffraction, Kurtz–Perry and ab initio methods, is employed to characterise the system and benchmark the performance of hybrid functionals for the prediction of non‐linear optical properties and electronic excitations. Comparison of experiment and theory points to a particular set of hybrid functionals that provides an optimal description of this molecular system.
First‐in‐Human Study With the Inhaled TLR9 Oligonucleotide Agonist AZD1419 Results in Interferon Responses in the Lung, and Is Safe and Well‐Tolerated
Authors: Jackson Sam , Candia Albert F. , Delaney Stephen , Floettmann Simone , Wong Clifford , Campbell John D. , Kell Sariah , Lum Jeremy , Hessel Edith M. , Traquina Paula , McHale Mark , Robinson Ian , Bell John , Fuhr Rainard , Keeling David , Coffman Robert L.
Published: November 2017

Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll‐like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long‐term disease modification. We present the nonclinical data and phase I clinical profile of an inhaled TLR9 agonist, AZD1419, a C‐type CpG designed to induce interferon in the lung. In healthy volunteers, AZD1419 was found to be safe and well‐tolerated. Target engagement in the lung was demonstrated at all dose levels tested. No evidence of tolerization or amplification of responses was evident on repeated dosing and 15.4 mg was defined as the maximum tolerated dose. AZD1419 clinical data supports its continued development as a potentially disease‐modifying therapeutic in asthma.
Elucidating Anion‐Dependent Formation and Conversion of Pd2L4 and Pd3L6 Metal–Organic Cages by Complementary Techniques
Authors: Yu Hui‐Juan , Liu Zhi‐Min , Pan Mei , Wu Kai , Wei Zhang‐Wen , Xu Yao‐Wei , Fan Ya‐Nan , Wang Hai‐Ping , Su Cheng‐Yong
Published: November 2017

The fast development of the design, construction, and application of metal–organic materials including infinite metal–organic frameworks (MOFs) and discrete metal–organic cages (MOCs) has not only propelled the advance of modern supramolecular syntheses to an unprecedented level, but also burgeoned various kinds of detection and characterization technologies. Herein, complementary techniques, including diversified NMR and ESI‐MS spectrometry, solid‐state crystallography, and theoretical simulation are exploited to elucidate the structural evolution of a dynamic supramolecular coordination system involving PdII–MOCs of different compositions. The combination of various kinds of modern techniques verifies the anion template effect, which leads to the preferred formation and further conversion of Pd2L4 or Pd3L6 cages.
Development and Application of a Voltammetric Biosensor Based on Polypyrrole/uricase/graphene for Uric Acid Determination
Authors: de Fátima Giarola Juliana , Mano Valdir , Pereira Arnaldo César
Published: November 2017

In the present paper a voltammetric biosensor based on platinum electrode and polypyrrole / uricase / graphene composite, named Pt‐PPy/UOx/Grap has been successfully prepared and validated for uric acid (UA) determination in real samples. The electrochemical behavior has been evaluated by employing cyclic voltammetric. The charge transfer coefficient, α, and the charge transfer rate constant, κs, for electron transfer between PPy/UOx/Grap and Pt were calculated as 0.71, in average, and 48.3 s−1, respectively. Under optimized conditions for the composite (2.5 U mL−1 of UOx, 0.3 mg mL−1 of Grap and 2.9 mmol L−1 of pyrrole) and for the analysis (pH 7.0 in 0.1 mol L−1 phosphate buffer) the method was validated for UA determination at human urine and showed good linearity to UA from 2 up to 24 nmol L−1 (r=0.993) with limits of detection and quantification of 0.541 and 1.805 nmol L−1, respectively. The results obtained for the UA determination at urine presented a relative error lower than 5 %, showing the good performance of the method developed and potential application in UA clinical analysis.
Recent Advances in Flexible Electrochromic Devices: Prerequisites, Challenges, and Prospects
Authors: Eh Alice Lee‐Sie , Tan Alvin Wei Ming , Cheng Xing , Magdassi Shlomo , Lee Pooi See
Published: November 2017

Electrochromic (EC) technology has progressed tremendously in recent years. Rigid EC devices have advanced to offer additional attractive physical attributes such as flexibility, stretchability, and foldability. These features are appealing for wearable and futuristic technologies, and hence serve to revolutionize EC applications toward deformable electronics. In this review, the essential prerequisites of each component of the flexible EC devices are delineated, such that each component is mechanically flexible to maintain the structural integrity of the device. The recent progress in flexible EC performance is discussed, from flexible to stretchable and the foldable device being the latest trend in deformable electronics. Next, we address the pertinent challenges often encountered in the fabrication of flexible EC devices and outline the adopted strategies from the literature to this point. Finally, the concept of the multifunctional EC device is discussed for achieving versatile emerging applications. We envision that this review will shed light on the properties of flexible ECs and shape the new milestones to be set for realizing a more versatile multifunctional EC device.
A taxonomic revision of Scutellaria sect. Lupulinaria subsect. Lupulinaria (Lamiaceae) in Iran
Authors: Ranjbar Massoud , Mahmoudi Chonour
Published: November 2017

A taxonomic revision of Scutellaria L. sect. Lupulinaria subsect. Lupulinaria (Lamiaceae) for Iran is presented. The present study is based on morphological characters of the specimens from the authors’ expeditions and other herbarium collections. A new species is described and one subspecies is elevated to the species rank. In addition, Scutellaria chorassanica Bunge is treated as a distinct species. With this treatment the number of species in subsect. Lupulinaria in the country is increased to 25 taxa (21 species and 4 subspecies) enumerated here. Lectotypes are also designated for S. araxensis, S. litwinowii, S. luteocaerulea, S. mianensis, S. persica, S. theobromina and S. tomentosa. Finally, a key to all species of the section is provided.
Biofuel production and soil GHG emissions after land‐use change to switchgrass and giant reed in the U.S. Southeast
Authors: Nocentini Andrea , Field John , Monti Andrea , Paustian Keith
Published: November 2017

United States mandated the production of biofuel from lignocellulosic feedstocks. Nonetheless, the cultivation of these feedstocks may produce debates, as agricultural land is scarce and it is primarily needed for food production and grazing. Thus, it is thought that biofuel production should be placed on land with low economical value (i.e., marginal land). At the same time, depending on what land is considered marginal and therefore available for lignocellulosic crops, different greenhouse gas impacts will be generated upon land use change. Here, we attempted to estimate the biomass production and soil greenhouse gas emissions of the cultivation of switchgrass (Panicum virgatum L.) and giant reed (Arundo donax L.) in the U.S. Southeast, when converting distinct former land uses. We employed the NLCD and the SSURGO databases to select grasslands, shrublands, and marginal croplands and to then allocate switchgrass and giant reed on this land basing on biophysical parameters included in the Land Capability Classification. After calibration, the DAYCENT model was employed to simulate 15‐year cultivation of both crops in the U.S. Southeast. Florida, Georgia, Mississippi and South Carolina were the States with the highest availability of land, thus the highest potential for biofuel production. Among scenarios, the one converting poor grazing land and marginal croplands yielded the greatest benefits: converting 3.6 Mha of land, 44 Mt/year of dry biomass could be produced, storing 0.05 Mt/year of soil organic C at the same time. In this scenario, considering 80‐km supply areas, nineteen biorefineries could deliver 7,124 Ml/year of advanced ethanol across the region. When minimizing giant reed invasion risks through reallocating giant reed outside flooded areas, 4,695 Ml/year of advanced ethanol could be still delivered from thirteen biorefineries, but the scenario turned in a biogenic greenhouse gas source (3.2 Mt CO2eq/year).
Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury
Authors: van Tilborg Erik , de Theije Caroline G. M. , van Hal Maurik , Wagenaar Nienke , de Vries Linda S. , Benders Manon J. , Rowitch David H. , Nijboer Cora H.
Published: November 2017

Infants born prematurely are at high risk to develop white matter injury (WMI), due to exposure to hypoxic and/or inflammatory insults. Such perinatal insults negatively impact the maturation of oligodendrocytes (OLs), thereby causing deficits in myelination. To elucidate the precise pathophysiology underlying perinatal WMI, it is essential to fully understand the cellular mechanisms contributing to healthy/normal white matter development. OLs are responsible for myelination of axons. During brain development, OLs are generally derived from neuroepithelial zones, where neural stem cells committed to the OL lineage differentiate into OL precursor cells (OPCs). OPCs, in turn, develop into premyelinating OLs and finally mature into myelinating OLs. Recent studies revealed that OPCs develop in multiple waves and form potentially heterogeneous populations. Furthermore, it has been shown that myelination is a dynamic and plastic process with an excess of OPCs being generated and then abolished if not integrated into neural circuits. Myelination patterns between rodents and humans show high spatial and temporal similarity. Therefore, experimental studies on OL biology may provide novel insights into the pathophysiology of WMI in the preterm infant and offers new perspectives on potential treatments for these patients.
Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models
Authors: Latta‐Mahieu Martine , Elmer Bradford , Bretteville Alexis , Wang Yaming , Lopez‐Grancha Mati , Goniot Philippe , Moindrot Nicolas , Ferrari Paul , Blanc Véronique , Schussler Nathalie , Brault Emmanuel , Roudières Valérie , Blanchard Véronique , Yang Zhi‐Yong , Barneoud Pascal , Bertrand Philippe , Roucourt Bart , Carmans Sofie , Bottelbergs Astrid , Mertens Liesbeth , Wintmolders Cindy , Larsen Peter , Hersley Caroline , McGathey Tyler , Racke Margaret M. , Liu Ling , Lu Jirong , O'Neill Michael J. , Riddell David R. , Ebneth Andreas , Nabel Gary J. , Pradier Laurent
Published: November 2017

Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death‐1 (PD1) checkpoint inhibition produces an IFN‐γ‐dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135–137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid‐β pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti‐PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte‐derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (): Nature Medicine, 22:135–137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.
Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism
Authors: Vogel Ciernia Annie , Careaga Milo , LaSalle Janine M. , Ashwood Paul
Published: November 2017

Dysregulation in immune responses during pregnancy increases the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive, and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome‐wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.
Cortical hemispheric asymmetries are present at young ages and further develop into adolescence
Authors: Yamazaki Hiroshi , Easwar Vijayalakshmi , Polonenko Melissa Jane , Jiwani Salima , Wong Daniel D. E. , Papsin Blake Croll , Gordon Karen Ann
Published: November 2017

Specialization of the auditory cortices for pure tone listening may develop with age. In adults, the right hemisphere dominates when listening to pure tones and music; we thus hypothesized that (a) asymmetric function between auditory cortices increases with age and (b) this development is specific to tonal rather than broadband/non‐tonal stimuli. Cortical responses to tone‐bursts and broadband click‐trains were recorded by multichannel electroencephalography in young children (5.1 ± 0.8 years old) and adolescents (15.2 ± 1.7 years old) with normal hearing. Peak dipole moments indicating activity strength in right and left auditory cortices were calculated using the Time Restricted, Artefact and Coherence source Suppression (TRACS) beamformer. Monaural click‐trains and tone‐bursts in young children evoked a dominant response in the contralateral right cortex by left ear stimulation and, similarly, a contralateral left cortex response to click‐trains in the right ear. Responses to tone‐bursts in the right ear were more bilateral. In adolescents, peak activity dominated in the right cortex in most conditions (tone‐bursts from either ear and to clicks from the left ear). Bilateral activity was evoked by right ear click stimulation. Thus, right hemispheric specialization for monaural tonal stimuli begins in children as young as 5 years of age and becomes more prominent by adolescence. These changes were marked by consistent dipole moments in the right auditory cortex with age in contrast to decreases in dipole activity in all other stimulus conditions. Together, the findings reveal increasingly asymmetric function for the two auditory cortices, potentially to support greater cortical specialization with development into adolescence.
Reduced IL‐6 levels and tumor‐associated phospho‐STAT3 are associated with reduced tumor development in a mouse model of lung cancer chemoprevention with myo‐inositol
Authors: Unver Nese , Delgado Oliver , Zeleke Kirubel , Cumpian Amber , Tang Ximing , Caetano Mauricio S. , Wang Hong , Katayama Hiroyuki , Yu Hua , Szabo Eva , Wistuba Ignacio I. , Moghaddam Seyed Javad , Hanash Samir M. , Ostrin Edwin J.
Published: November 2017

Several promising chemopreventive agents have for lung cancer emerged in preclinical models and in retrospective trials. These agents have been shown to modulate pathways altered in carcinogenesis and reduce markers of carcinogenesis in animal and cell culture models. Cancer‐prone transgenic mice with oncogenic Kras expressed in the airway epithelium (CcspCre/+; KrasLSL‐G12D/+) were raised on diets compounded with myo‐inositol. These animals form lung premalignant lesions in a stereotypical fashion over the ten weeks following weaning. Mice raised on myo‐inositol containing diets showed potent reduction in the number, size, and stage of lesions as compared to those raised on control diets. myo‐inositol has previously been reported to inhibit phosphoinositide 3‐kinase (PI3K) signaling. However, in mice raised on myo‐inositol, total PI3K signaling was largely unaffected. Proteomic and cytokine analyses revealed large reduction in IL‐6 related pathways, including STAT3 phosphorylation. This effect was not due to direct inhibition of IL‐6 production and autocrine signaling within the tumor cell, but rather through alteration in macrophage recruitment and in phenotype switching, with an increase in antitumoral M1 macrophages.
Thyroid‐associated genetic polymorphisms in relation to breast cancer risk in the Malmö Diet and Cancer Study
Authors: Brandt Jasmine , Borgquist Signe , Almgren Peter , Försti Asta , Huss Linnea , Melander Olle , Manjer Jonas
Published: November 2017

Previous studies have suggested that thyroid function is associated with breast cancer risk, which could have an important clinical impact, as one in eight women will develop a thyroid disorder during her lifetime. However, the underlying pathomechanism behind the association is still unknown. We used the Malmö Diet and Cancer Study (a population‐based prospective study consisting of 17,035 women) to examine 17 single nucleotide polymorphisms (SNPs) previously related to levels of free thyroxine (free T4) and thyroid peroxidase antibodies (TPO‐Ab) as potential genetic risk factors for breast cancer. A baseline examination including free T4 and TPO‐Ab levels was conducted at the time of inclusion. Genotyping was performed on 901 breast cancer patients and 3335 controls. Odds ratios (95% confidence intervals) for high free T4, TPO‐Ab positivity, and breast cancer were calculated by logistic regression and adjusted for confounders. We identified one free T4‐related SNP (rs2235544, D101 gene) that was significantly associated with both free T4 level and breast cancer risk. There was a suggested association between rs11675434 (TPO gene) and TPO‐Ab level, and TPO‐Ab‐related rs11675434 (TPO), rs3094228 (HCP5), rs1033662 (no registered gene), and rs301806 (RERE) were associated with breast cancer risk. There was an indicated interaction between rs6485050 (no registered gene) and free T4 level in regards to breast cancer risk. This is the first study to suggest an association between thyroid‐related SNPs and breast cancer risk. All SNPs have a biological plausibility of being associated with breast cancer risk, and may contribute to the genetic predisposition to breast cancer.
Acyclic Cucurbit[n]uril‐type Receptors: Preparation, Molecular Recognition Properties and Biological Applications
Authors: Ganapati Shweta , Isaacs Lyle
Published: November 2017

This article traces the development of acyclic cucurbit[n]uril‐type receptors with a focus on work from the Isaacs group. First, we describe the synthesis of methylene bridged glycoluril dimers capped with aromatic sidewalls which allowed us to probe the interconversion of the S‐ and C‐shaped dimers which is a fundamental step in CB[n] formation. The C‐shaped compounds were found to undergo discrete self‐assembly (dimerization) in both water and organic solvents which lead us to investigate multicomponent self‐sorting systems. We supressed the self‐association of 8 by electrostatic repulsion in the putative dimer which allowed expression of its innate molecular recognition properties toward methylene blue and related planar cationic dyes. Longer glycoluril oligomers (trimer‐hexamer, acyclic decamer) were prepared by starving the CB[n]‐forming reaction of formaldehyde. The longer oligomers (e. g. 15 and 16) bind to alkylammonium ions in water ≈100‐fold weaker than macrocyclic CB[n] highlighting the high preorganization of the acyclic but polycyclic framework. We prepared a wide variety of acyclic CB[n] compounds (wall variants, solubilizing group variants, linker variants) based on glycoluril trimer and tetramer. In particular, 26 and 27 have been shown to possess a wide variety of chemically and biologically interesting functions. For example, 26 was used to formulate the insoluble drug Albendazole and treat mice bearing SK‐OV‐3 xenograft tumors. Compound 27 binds tightly to the neuromuscular blocking agents rocuronium, vecuronium, and cisatracurium and acts as an in vivo reversal agent for these compounds in anesthetized rats. Container 27 was also found to modulate the hyperlocomotive effect of rats that had been treated with methamphetamine. Finally, 38 has been used as a cross reactive component of sensor arrays that are capable of classifying and quantifying cancer related nitroamine and a range of over the counter drugs. Overall, the work demonstrates that acyclic CB[n]‐type compounds are nicely pre‐organized and therefore retain the essential aspects of the recognition properties of macrocyclic CB[n] but allow for more straightforward tailoring of structure and solubility that enables a variety of chemically and biologically important applications.
Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review
Authors: Nguyen Hanh H , van de Laarschot Denise M , Verkerk Annemieke JMH , Milat Frances , Zillikens M Carola , Ebeling Peter R
Published: November 2017

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long‐term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate‐naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand‐searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X‐linked osteoporosis (PLS3), osteopetrosis, X‐linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate‐naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X‐linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole‐exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well‐phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Comparison of the anticancer properties of a novel valproic acid prodrug to leading histone deacetylase inhibitors
Authors: Tarasenko Nataly , Chekroun‐Setti Hanna , Nudelman Abraham , Rephaeli Ada
Published: November 2017

The HDAC inhibitory activity of valproic acid (VPA) has led to on‐going evaluation of it as an anticancer agent. The histone deacetylase (HDAC) inhibitor AN446, a prodrug of VPA, releases the acid upon metabolic degradation. AN446 is >60‐fold more potent than VPA in killing cancer cells in vitro. Herein, we compare the activities of AN446, as an anticancer agent, to those of representative types from each of the four major classes of HDAC inhibitors (HDACIs): vorinostat, romidepsin, entinostat, and VPA. AN446 exhibited the greatest selectivity and HDAC inhibitory activity against cancer cells. In glioblastoma cells only AN446, and in MDA‐MB‐231 cells only AN446 and VPA interacted in synergy with doxorubicin (Dox). AN446 was superior to the studied HDACIs in inducing DNA‐damage in cancer cells, while in normal astrocytes and cardiomyoblasts AN446 was the least toxic. AN446 was the only HDACI tested that exhibited selective HDAC inhibitory activity that was high in cancer cells and low in noncancerous cells. This discriminating inhibition correlated with the toxicity of the HDACIs, suggesting that their effects could be attributed to HDAC inhibition. In cardiomyoblasts, the HDACIs tested, except for AN446, hampered DNA repair by reducing the level of Rad 51. VPA and AN446 were the most effective HDACIs in inhibiting in vitro migration and invasion. The advantages of AN446 shown here, position it as a potentially improved HDACI for treatment of glioblastoma and triple negative breast cancer.
Brompheniramine and Chlorpheniramine Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years
Authors: Pathirana Sudam , Jayawardena Shyamalie , Meeves Suzanne , Thompson Gary A.
Published: November 2017

Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age‐/weight‐based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high‐pressure liquid chromatography–tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression. Results indicated that for brompheniramine and chlorpheniramine, Cmax was similar across age groups, although it tended to occur earlier in the youngest group. AUC was ∼15% to 30% higher in the oldest age group. As expected, CLo and Vz/F increased with age; however, following allometric scaling, no age‐related differences existed. Because the increase with age for both parameters was similar, no age‐related differences in t1/2,z existed (∼15 hours). Overall, the single doses were well tolerated. Sedation was the most common reported AE and appeared to be more prevalent in the 2‐ to 5‐year‐old group. Overall, these results indicate that an age/weight dosing nomogram using a 4‐fold range of doses achieves similar Cmax and AUC.
ATR‐FTIR spectroscopy and μ‐EDXRF spectrometry monitoring of enamel erosion caused by medicaments used in the treatment of respiratory diseases
Authors: Gomes Raimundo Nonato Silva , Bhattacharjee Tanmoy T. , Carvalho Luis Felipe C. S. , Soares Luís Eduardo Silva
Published: November 2017

Medicaments essential for alleviation of diseases may sometime adversely affect dental health by eroding the enamel, owing to their acidic nature. It is therefore highly desirable to be able to detect these effects quickly and reliably. In this study, we evaluated the erosive capacity of four most commonly prescribed respiratory disease syrup medicaments on enamel using micro‐energy‐dispersive X‐ray fluorescence spectrometry (µ‐EDXRF) and attenuated total reflection Fourier transform infrared spectroscopy (ATR‐FTIR). Fifty‐five enamel fragments obtained from 30 bovine teeth were treated with artificial saliva (S), acebrofilin hydrochloride (AC), ambroxol hydrochloride (AM), bromhexine hydrochloride (BR), and salbutamol sulfate (SS); by immersing in 3 mL of respective solutions for 1 min, three times a day at intervals of 1 hr, for 5 days. µ‐EDXRF analysis of enamel surface did not reveal significant erosion caused by the medications. However, ATR‐FTIR showed a detectable shift in the phosphate (PO4) antisymmetric stretching mode (ν3) at ∼985 cm−1for AM, BR, and SS, indicating erosion. Multivariate statistical analysis showed that AC, AM, SS, and BR could be classified with 70%, 80%, 100%, and 100% efficiency from S (control), further highlighting the ability of ATR‐FTIR to identify degree of erosion. This suggests ATR‐FTIR may be used to rapidly and nondestructively investigate erosive effects of medicaments.
Can MR enterography screen for perianal disease in pediatric inflammatory bowel disease?
Authors: AlSabban Zehour , Carman Nicholas , Moineddin Rahim , Lo Ryan T. , King Sebastian K. , Langer Jacob C. , Walters Thomas D. , Griffiths Anne M. , Church Peter C. , Greer Mary‐Louise C.
Published: November 2017

Background

Pediatric Crohn's disease is associated with perianal disease (PAD). Magnetic resonance enterography (MRE) assesses small bowel involvement in pediatric inflammatory bowel disease (PIBD). Pelvic MRI (P‐MRI) is the gold standard for assessing PAD.

Purpose

To determine if MRE can accurately detect PAD in PIBD, distinguishing perianal fistulae (PAF) from perianal abscesses (PAA), referenced against P‐MRI.

Study Type

Retrospective.

Population

Seventy‐seven PIBD patients, 27 females (mean age 14.1 years), with P‐MRI and MRE within 6 months.

Field Strength/Sequence

1.5T and 3T; P‐MRI: sagittal fat suppressed (FS) T2 fast spin‐echo (FSE), coronal short tau inversion recovery, axial T1 FSE, coronal and axial postcontrast FS T1 FSE; MRE: coronal balanced steady‐state free‐precession (SSFP), coronal cine SSFP, coronal and axial single‐shot T2 FS, axial SSFP, coronal ultrafast 3D T1‐weighted gradient echo FS (3D T1 GE), axial diffusion‐weighted imaging, coronal and axial postcontrast 3D T1 GE FS.

Assessment

Two radiologists independently, then by consensus, assessed randomized MRI exams, recording PAF number, location, and length; and PAA number, location, length, and volume. Sensitivity analysis used clinical disease as the gold standard, calculated separately for P‐MRI and MRE.

Statistical Tests

Comparing MRE and P‐MRI consensus data, sensitivity, specificity, positive, and negative predictive values (P/NPV) were calculated. Inter‐ and intrareader reliability were assessed using kappa statistics.

Results

P‐MRI and MRE were paired, detecting PAD in 73 patients, PAF in 63, and PAA in 31 P‐MRI. MRE sensitivities, specificities, PPV, and NPV were: PAD 82%, 100%, 100%, 23%; PAF 74%, 71%, 92%, 38%; PAA 51%, 85%, 69%, 72%; clinical 82%, 22%, 37%, 69%; clinical P‐MRI 96%, 8%, 37%, 80%. MRE interreader agreement for PAD was moderate (kappa = 0.51 [0.29–0.73]), fair for PAF and PAA.

Data Conclusion

Using a standard technique, MRE can detect PAD with high specificity and moderate sensitivity in PIBD, missing some PAF and small PAA.

Level of Evidence: 3

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;47:1638–1645.
Prospective studies of the efficacy and safety of the picosecond 755, 1,064, and 532 nm lasers for the treatment of infraorbital dark circles
Authors: Vanaman Wilson Monique J. , Jones Isabela T. , Bolton Joanna , Larsen Lisa , Wu Douglas C. , Goldman Mitchel P.
Published: November 2017

Background

Infraorbital dark circles result from a combination of factors. The fractionated picosecond 755 nm alexandrite laser and dual wavelength picosecond Nd:YAG laser have not been examined as a method of addressing infraorbital hyperpigmentation.

Objective

To determine the efficacy and safety of treatment of infraorbital dark circles using fractionated picosecond 755 nm and dual wavelength picosecond Nd:YAG laser.

Methods and Materials

These trials did not utilize a comparative design; rather, these were separate, prospective, open‐label, evaluator‐blinded trials utilizing two treatment regimens: (i) 19 adult subjects were treated in a single session with the dual wavelengths of 532 nm and 1,064 nm in consecutive passes using the fractionated lens; (ii) 10 adult subjects were treated using the picosecond 755 nm laser via the fractionated lens in three treatment sessions at 3 week intervals. Subjects in both studies were followed‐up for blinded‐investigator assessment of infraorbital hyperpigmentation, adverse events, and improvement compared to baseline.

Results

The dual wavelength picosecond Nd:YAG laser, blinded‐investigator assessment did not demonstrate a significant improvement in infraorbital hyperpigmentation at day 60 (P = 0.16). The picosecond 755 nm alexandrite laser significantly improved infraorbital hyperpigmentation by day 42, with improvement maintained through day 132 (P = 0.07 and 0.00001, respectively). Adverse events were mild and temporary.

Conclusion

A single treatment with the fractionated picosecond 1,064/532 nm lasers did not produce a significant improvement in infraorbital hyperpigmentation. A series of three treatments with the fractionated picosecond 755 nm laser resulted in significant improvement in hyperpigmentation. Lasers Surg. Med. 50:45–50, 2018. © 2017 Wiley Periodicals, Inc.
Maintenance of Cartilaginous Gene Expression of Serially Subcultured Chondrocytes on Poly(2‐Methoxyethyl Acrylate) Analogous Polymers
Authors: Hoshiba Takashi , Maruyama Hiroka , Sato Kazuhiro , Endo Chiho , Kawazoe Naoki , Chen Guoping , Tanaka Masaru
Published: November 2017

Chondrocytes are important for cartilage tissue engineering. However, dedifferentiation during chondrocyte subculture prevents the application of cartilage tissue engineering. Therefore, prevention of this dedifferentiation is required. Here, the possibility of poly(2‐methoxyethyl acrylate) (PMEA) and its analogous polymers, poly(tetrahydrofurfuryl acrylate) (PTHFA) and poly(2‐(2‐methoxyethoxy) ethyl acrylate‐co‐butyl acrylate) (PMe2A), for chondrocyte subculture without dedifferentiation is examined. Chondrocytes spread on PTHFA and polyethylene terephthalate (PET), whereas their spreading is delayed on PMEA and PMe2A. When primary chondrocytes are subcultured on these polymers, the expression levels of cartilaginous genes are higher on PMEA and PMe2A than on PET and PTHFA. Integrin contribution to the initial cell adhesion is lower on PMEA and PMe2A than on PTHFA and PET. This low level of integrin contribution to cell adhesion may cause a delay in cell spreading and the maintenance of cartilaginous gene expression. These results indicate that PMEA and PMe2A may be favorable substrates for chondrocyte subculture and cartilage tissue engineering.