Publication date: February 2017
Source:Biological Psychology, Volume 123
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Τρίτη 31 Ιανουαρίου 2017
Inside front cover continued (editorial board members)
Editorial board
Source:Biological Psychology, Volume 123
http://ift.tt/2jtYCIJ
The effects of microalloying on the precipitate microstructure at grain boundary regions in an Mg-Zn-based alloy
Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): B. Langelier, G. Sha, A. Korinek, P. Donnadieu, S.P. Ringer, S. Esmaeili
Microalloying additions to Mg-Zn base alloys can refine precipitation and improve hardening, but their effect on the microstructure at the grain boundary regions are seldom analyzed. Here the grain boundary microstructure is examined in an Mg-4Zn (wt.%) alloy, which has been microalloyed with Ce-Ca. This combination of elements has previously been shown to successfully enhance ductility, texture, and precipitation hardening, compared to binary Mg-Zn. Coarse grain boundary precipitates are found with or without microalloying, but precipitate-free zones (PFZs) for β′1 that surround the boundaries are far narrower with Ce-Ca microalloying additions. Furthermore, fine basal precipitates containing Ca are found uniformly distributed up to the boundary, making those zones devoid of β′1 not truly precipitate-free. Electron microscopy and atom probe analysis of early-stage ageing conditions reveals that Ca readily forms clusters with Zn, and forms fine ordered GP zones, while Zn also segregates to the grain boundaries. The tendency of Ca to homogeneously form clusters and precipitates reduces Ca migration to the grain boundaries, which has a beneficial effect on producing the refined precipitate distributions at the grain boundary regions.
Graphical abstract
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Microstructure evolution and mechanical properties of ZnAl2O4-reinforced Al2O3/Al2O3 joints brazed with a bismuth borate zinc glass
Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Wei Guo, Tiesong Lin, Peng He, Tong Wang, Yini Wang
Amorphous bismuth borate zinc glass with a composition of 40Bi2O3–40B2O3–20ZnO (in mol.%) was used as a braze to join 95wt.% purity alumina ceramics (95Al2O3) in air. The interfacial phases in the brazed joints were characterized using scanning electron microscopy, transmission electron microscopy. Zinc aluminate (ZnAl2O4) was identified as the main reaction product in the joints due to the chemical reaction between the Al2O3 substrate and ZnO from the glass. Typical microstructure of the Al2O3/Al2O3 brazed joints was Al2O3 substrate/glassy matrix phase+ZnAl2O4 particles/Al2O3 substrate. The dependence of the microstructure and mechanical properties on brazing temperature was investigated. The size of ZnAl2O4 increased with an increase in brazing temperature. It was found the room lap shear strength of Al2O3/Al2O3 joints firstly increased and then declined with increasing brazing temperature. The maximum lap shear strength of 95MPa was obtained for the samples brazed at 675°C for 30min, which was mainly attributed to the formation of ZnAl2O4.
Graphical abstract
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Self-assembly of quaternized chitosan nanoparticles within nanoclay layers for enhancement of interfacial properties in toughened polymer nanocomposites
Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Omid Zabihi, Mojtaba Ahmadi, Minoo Naebe
Role of montmorillonite nanoclay in self-assembly of quaternized chitosan nanoparticles (QCn) within the clay layers was investigated. Inorganic-organic nanohybrid of clay-chitosan was used as a reactive reinforcing agent in preparation of toughened epoxy nanocomposites. Intercalation of QCn within the clay layers increases d-spacing of clay layers from 1.2nm to 3.6nm, leading to an enhanced exfoliation degree in epoxy nanocomposites. The nanohybrid of clay modified with QCn was then incorporated into an epoxy matrix. It was found that the strong interfacial interactions benefit not only the dispersion of the clay within epoxy but also the effective interfacial stress transfer, leading to significantly improved mechanical properties. Rheological investigations showed that the interfacial interactions between the QCn modified clay and epoxy are dominated by the covalent/hydrogen bondings between the amine/hydroxyl enriched QCn and the epoxy matrix.
Graphical abstract
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Structure-property relationships in ZnO:Al-hydroquinone films grown on flexible substrates by atomic and molecular layer deposition
Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Grzegorz Luka, Lukasz Wachnicki, Bartlomiej S. Witkowski, Rafal Jakiela, Ihor S. Virt
ZnO:Al-hydroquinone (AZO-HQ) films were grown on poly(ethylene terephthalate) (PET) substrates by atomic and molecular layer deposition (ALD/MLD). Organic contents in the films varied from 0 to ≈4vol%. Structural and electrical investigations of the films were carried out. Electrical measurements were performed under film bending. The piezoresistive effect in the films with different organic contents was observed and described. Critical bend radius, critical strain, and piezoresistive coefficient values were related to the film microstructure. The piezoresistivity was found to be enhanced for the deformations of ZnO crystallites along the a-axis whereas higher critical strain was influenced by long crystallites oriented in the deformation direction. AZO-HQ films having 2vol% of the organic content are characterized by the lowest critical bend radius and the highest critical strain among the films under study.
Graphical abstract
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Contribution of image-guided adaptive brachytherapy to pelvic nodes treatment in locally advanced cervical cancer
Source:Brachytherapy
Author(s): Warren Bacorro, Isabelle Dumas, Antonin Levy, Eleonor Rivin Del Campo, Charles-Henri Canova, Tony Felefly, Andres Huertas, Fanny Marsolat, Christine Haie-Meder, Cyrus Chargari, Renaud Mazeron
PurposeWith the increasing use of simultaneous integrated boost in the treatment of cervical cancer, there is a need to anticipate the brachytherapy (BT) contribution at the level of the pathologic pelvic lymph nodes. This study aimed to report the dose delivered at their level during BT.Methods and MaterialsPatients with pelvic nodal involvement and treated with a combination of chemoradiation followed by image-guided adaptive pulsed-dose-rate BT were selected. On per BT three-dimensional images, pelvic lymphadenopathies were delineated, without planning aim. For the purposes of the study, D100, D98, D90, and D50 were reviewed and converted in 2-Gy equivalent doses, using the linear quadratic model with an α/β of 10 Gy.ResultsNinety-one patients were identified, allowing evaluation at the level of 226 lymphadenopathies. The majority of them were external iliac (48%), followed by common iliac (25%), and internal iliac (16%) regions. The 2-Gy equivalent doses D98 were 4.4 ± 1.9 Gy, 5.4 ± 3.1 Gy, and 4.3 ± 2.1 Gy for the obturator, internal iliac, and external iliac, respectively, and 2.8 ± 2.5 Gy for the common iliac. The contribution to the common iliac nodes was significantly lower than the one of external and internal iliac (p < 0.001).ConclusionsBT significantly contributes to the treatment of pelvic nodes at the level of approximately 5 Gy in the internal, external, and obturator areas and 2.5 Gy in the common iliac, allowing the anticipation of nodal boost with the simultaneous integrated boost technique. However, important individual variations have been observed, and evaluation of the genuine BT contribution should be recommended.
http://ift.tt/2jUlFLp
Melanin-concentrating hormone in peripheral circulation in the human
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a well-characterised role in energy homeostasis and emergent roles in diverse physiologic functions such as arousal, mood and reproduction. Work to date has predominantly focused on its hypothalamic functions using animal models; however, little attention has been paid to its role in circulation in humans. The aims of this study were to (a) develop a radioimmunoassay for the detection of MCH in human plasma; (b) establish reference ranges for circulating MCH and (c) characterise the pattern of expression of circulating MCH in humans. A sensitive and specific RIA was developed and cross-validated by RP-HPLC and MS. The effective range was 19.5–1248 pg MCH/mL. Blood samples from 231 subjects were taken to establish a reference range of 19.5–55.4 pg/mL for fasting MCH concentrations. There were no significant differences between male and female fasting MCH concentrations; however, there were correlations between MCH concentrations and BMI in males and females with excess fat (P < 0.001 and P = 0.020) and between MCH concentrations and fat mass in females with excess fat (P = 0.038). Plasma MCH concentrations rose significantly after feeding in a group of older individuals (n = 50, males P = 0.006, females P = 0.023). There were no robust significant correlations between fasting or post-prandial MCH and resting metabolic rate, plasma glucose, insulin or leptin concentrations although there were correlations between circulating MCH and leptin concentrations in older individuals (P = 0.029). These results indicate that the role of circulating MCH may not be reflective of its regulatory hypothalamic role.
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Binding of the chemokine CXCL12α to its natural extracellular matrix ligand heparan sulfate enables myoblast adhesion and facilitates cell motility
Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Dhruv Thakar, Fabien Dalonneau, Elisa Migliorini, Hugues Lortat-Jacob, Didier Boturyn, Corinne Albiges-Rizo, Liliane Coche-Guerente, Catherine Picart, Ralf P. Richter
The chemokine CXCL12α is a potent chemoattractant that guides the migration of muscle precursor cells (myoblasts) during myogenesis and muscle regeneration. To study how the molecular presentation of chemokines influences myoblast adhesion and motility, we designed multifunctional biomimetic surfaces as a tuneable signalling platform that enabled the response of myoblasts to selected extracellular cues to be studied in a well-defined environment. Using this platform, we demonstrate that CXCL12α, when presented by its natural extracellular matrix ligand heparan sulfate (HS), enables the adhesion and spreading of myoblasts and facilitates their active migration. In contrast, myoblasts also adhered and spread on CXCL12α that was quasi-irreversibly surface-bound in the absence of HS, but were essentially immotile. Moreover, co-presentation of the cyclic RGD peptide as integrin ligand along with HS-bound CXCL12α led to enhanced spreading and motility, in a way that indicates cooperation between CXCR4 (the CXCL12α receptor) and integrins (the RGD receptors). Our findings reveal the critical role of HS in CXCL12α induced myoblast adhesion and migration. The biomimetic surfaces developed here hold promise for mechanistic studies of cellular responses to different presentations of biomolecules. They may be broadly applicable for dissecting the signalling pathways underlying receptor cross-talks, and thus may guide the development of novel biomaterials that promote highly specific cellular responses.
http://ift.tt/2kbRBZT
Limiting the protein corona: A successful strategy for in vivo active targeting of anti-HER2 nanobody-functionalized nanostars
Source:Biomaterials, Volume 123
Author(s): Antoine D'Hollander, Hilde Jans, Greetje Vande Velde, Charlotte Verstraete, Sam Massa, Nick Devoogdt, Tim Stakenborg, Serge Muyldermans, Liesbet Lagae, Uwe Himmelreich
Gold nanoparticles hold great promise as anti-cancer theranostic agents against cancer by actively targeting the tumor cells. As this potential has been supported numerously during in vitro experiments, the effective application is hampered by our limited understanding and control of the interactions within complex in vivo biological systems. When these nanoparticles are exposed to a biological environment, their surfaces become covered with proteins and biomolecules, referred to as the protein corona, reducing the active targeting capabilities. We demonstrate a chemical strategy to overcome this issue by reducing the protein corona's thickness by blocking the active groups of the self-assembled monolayer on gold nanostars. An optimal blocking agent, 2-mercapto ethanol, has been selected based on charge and length of the carbon chain. By using a nanobody as a biological ligand of the human epidermal growth factor 2 receptor (HER2), the active targeting is demonstrated in vitro and in vivo in an experimental tumor model by using darkfield microscopy and photoacoustic imaging. In this study, we have established gold nanostars as a conceivable theranostic agent with a specificity for HER2-positive tumors.
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Selective transduction of astrocytic and neuronal CNS subpopulations by lentiviral vectors pseudotyped with Chikungunya virus envelope
Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Ioanna Eleftheriadou, Michael Dieringer, Xuan Ying Poh, Julia Sanchez-Garrido, Yunan Gao, Argyro Sgourou, Laura E. Simmons, Nicholas D. Mazarakis
Lentiviral vectors are gene delivery vehicles that integrate into the host genome of dividing and non-dividing mammalian cells facilitating long-term transgene expression. Lentiviral vector versatility is greatly increased by incorporating heterologous viral envelope proteins onto the vector particles instead of the native envelope, conferring on these pseudotyped vectors a modified tropism and host range specificity. We investigated the pseudotyping efficiency of HIV-1 based lentiviral vectors with alphaviral envelope proteins from the Chikungunya Virus (CHIKV-G) and Sindbis Virus (SINV-G). Following vector production optimisation, titres for the CHIKV-G pseudotype were comparable to the VSV-G pseudotype but those for the SINV-G pseudotype were significantly lower. High titre CHIKV-G pseudotyped vector efficiently transduced various human and mouse neural cell lines and normal human astrocytes (NHA) in vitro. Although transduction was broad, tropism for NHAs was observed. In vivo stereotaxic delivery in striatum, thalamus and hippocampus respectively in the adult rat brain revealed localised transduction restricted to striatal astrocytes and hippocampal dentate granule neurons. Transduction of different subtypes of granule neurons from precursor to post-mitotic stages of differentiation was evident in the sub-granular zone and dentate granule cell layer. No significant inflammatory response was observed, but comparable to that of VSV-G pseudotyped lentiviral vectors. Robust long-term expression followed for three months post-transduction along with absence of neuroinflammation, coupled to the selective and unique neuron/glial tropism indicates that these vectors could be useful for modelling and gene therapy studies in the CNS.
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IOP-details
Source:International Journal of Psychophysiology, Volume 113
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Editorial Board
Source:International Journal of Psychophysiology, Volume 113
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Instructions to Authors
Publication date: March 2017
Source:International Journal of Psychophysiology, Volume 113
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Biocompatibility of polymer-infiltrated-ceramic-network (PICN) materials with Human Gingival Keratinocytes (HGKs)
Publication date: Available online 31 January 2017
Source:Dental Materials
Author(s): Charlotte Grenade, Marie-Claire De Pauw-Gillet, Catherine Pirard, Virginie Bertrand, Corinne Charlier, Alain Vanheusden, Amélie Mainjot
ObjectiveBiocompatibility of polymer-infiltrated-ceramic-network (PICN) materials, a new class of CAD–CAM composites, is poorly explored in the literature, in particular, no data are available regarding Human Gingival Keratinocytes (HGK). The first objective of this study was to evaluate the in vitro biocompatibility of PICNs with HGKs in comparison with other materials typically used for implant prostheses. The second objective was to correlate results with PICN monomer release and indirect cytotoxicity.MethodsHGK attachment, proliferation and spreading on PICN, grade V titanium (Ti), yttrium zirconia (Zi), lithium disilicate glass-ceramic (eM) and polytetrafluoroethylene (negative control) discs were evaluated using a specific insert-based culture system. For PICN and eM samples, monomer release in the culture medium was quantified by high performance liquid chromatography and indirect cytotoxicity tests were performed.ResultsTi and Zi exhibited the best results regarding HGK viability, number and coverage. eM showed inferior results while PICN showed statistically similar results to eM but also to Ti regarding cell number and to Ti and Zi regarding cell viability. No monomer release from PICN discs was found, nor indirect cytotoxicity, as for eM.SignificanceThe results confirmed the excellent behavior of Ti and Zi with gingival cells. Even if polymer based, PICN materials exhibited intermediate results between Ti–Zi and eM. These promising results could notably be explained by PICN high temperature–high pressure (HT–HP) innovative polymerization mode, as confirmed by the absence of monomer release and indirect cytotoxicity.
Graphical abstract
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Crystal orientation of poly(ε-caprolactone) chains confined in lamellar nanodomains: Effects of chain-ends tethering to nanodomain interfaces
Publication date: Available online 31 January 2017
Source:Polymer
Author(s): Shintaro Nakagawa, Yuki Yoneguchi, Takashi Ishizone, Shuichi Nojima, Kazuo Yamaguchi, Seiichi Nakahama
We have examined the crystal orientation of poly (ε-caprolactone) (PCL) chains covalently tethered to nanodomain interfaces at both chain-ends (T2-PCL), one chain-end (T1-PCL), and no chain-end (PCL homopolymers, T0-PCL) all confined in an identical lamellar nanodomain (nanolamella). In order to prepare these PCL chains, we synthesized two kinds of lamella-forming polystyrene-block-PCL-block-polystyrene (PS-b-PCL-b-PS) triblock copolymers with photocleavable o-nitrobenzyl groups (ONB) at either or both of block junctions. The chain-ends tethering significantly affected the tilt angle φ between the c axis of PCL crystals and the normal of nanolamella interfaces (ND). That is, the c axis of T2-PCL crystals oriented almost perpendicular to ND (φ ≥ 70°), whereas that of T0-PCL crystals took completely parallel orientation against ND (φ ∼ 0°) at high crystallization temperatures (>32 °C). The T1-PCL crystal showed an intermediate orientation between T2-PCL and T0-PCL crystals (35° < φ < 55°), which depended moderately on the crystallization temperature. The difference in crystal orientation was discussed in terms of a delicate balance between the heterogeneous nucleation rate and subsequent crystal growth rate by considering the difference in chain mobility based on the state of chain-ends tethering.
Graphical abstract
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High-strength silk fibroin scaffolds with anisotropic mechanical properties
Publication date: Available online 31 January 2017
Source:Polymer
Author(s): Berkant Yetiskin, Oguz Okay
In contrast to isotropic morphologies of synthetic hydrogels, many biological tissues possess anisotropic hierarchical morphologies leading to extraordinary mechanical properties that cannot be mimicked by synthetic materials. Here, we report preparation of anisotropic silk fibroin cryogels and scaffolds exhibiting a Young's modulus in the range of MPa that sustain up to 20 MPa compressive stresses. The cryogels were prepared by a combined directional freezing – cryogelation process starting from an aqueous 4.2 wt% fibroin solution containing butanediol diglycidyl ether cross-linker and N,N,N′,N′-tetramethylethylenediamine. In the first step, the reactor containing the aqueous solution of fibroin, cross-linker, and TEMED was immersed into liquid nitrogen at a controlled rate to create a directionally frozen ice template. In the second step, cryogelation reactions were conducted in this frozen solution at −18 °C whereby the cryo-concentrated fibroin in the unfrozen microzones of the reaction system forms a 3D fibroin network. The scaffolds exhibit anisotropic microstructure and hence anisotropic mechanical properties, e.g., the Young's modulus is 3.4 ± 0.5 MPa and 0.8 ± 0.3 MPa when measured along the directions parallel and vertical to the freezing direction, respectively. All the cryogels could completely be compressed due to squeezing out of water from their pores. Upon removal of the load, the compressed cryogels immediately recover their original dimensions and mechanical properties by absorbing the released water into their pores.
Graphical abstract
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Sequence distribution and elastic properties of propylene-based elastomers
Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Andy H. Tsou, Alexander I. Norman, Yonglai Lu, Joseph A. Throckmorton, Benjamin S. Hsiao
Three iso-specific organometallic catalysts for ethylene and propylene copolymerization with varying r1r2 parameters, i.e., the products of ethylene and propylene reactivity ratios, were utilized to synthesize equal-molecular-weight propylene-based elastomers (PBEs) of alternating, random, and blocky backbone sequences. To compensate for the variations in catalyst iso-specificity and thus to maintain a constant amount of 50% isotactic propylene trimer concentration, the ethylene content of PBEs was varied between 11 wt % and 16 wt %. Although all three PBEs have an equal amount of crystallizable sequences, the high-C2 (high-ethylene) blocky PBE was found to have the highest crystallinity and crystallization rate, while the low-C2 alternating PBE possesses the lowest crystallinity and rate. This suggests that the backbone sequence distribution of a PBE affects its rate and degree of crystallization. The polypropylene (PP) crystallite width and perfection were enlarged and improved in the order of random, alternating, and blocky PBE, as measured by crystalline peak widths using the wide-angle X-ray scattering (WAXS) method. In addition, their crystals, cross-hatched lamellae web and embryonic axialites, which are the assembly of PP crystallites, are largest in the alternating PBE, followed by the random PBE as indicated by bimodal atomic force microscopy (AFM). A limited crystallite assembly was noted in the blocky PBE. Increasing crystallite assembly may have led to lowering the crosslink density (less crosslinks) and elasticity erosion. As a result of the wider and more perfect PP crystallites and the lack of assembly of these crystallites in the blocky PBE, it may have the highest crosslink density and strongest crosslinks and, hence, the best elasticity, as measured by set, hysteresis and retractive force, among the three, followed by the random PBE, and then the alternating PBE.
Graphical abstract
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Synthesis of polymeric ionic liquids with unidirectional chain topology by AB step growth polymerization
Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): M. Suckow, M. Roy, K. Sahre, L. Häußler, N. Singha, B. Voit, F. Böhme
Poly(ionic liquid)s with alkyl imidazolium moieties in the main chain were synthesized by step growth addition polymerization of the AB monomers 1-(4-chlorobutyl)-1H-imidazole, 1-(6-chlorohexyl)-1H-imidazole, and 1-(6-bromohexyl)-1H-imidazole in the melt. The molar masses of the polymers were controlled by adding 1-butyl-1H-imidazole as monofunctional chain stopper. The bromine containing monomer polymerized spontaneously at room temperature whereas the chlorine containing monomers were sufficiently stable up to 40 °C. This could be evidenced by DSC measurements which showed a broad exothermal peak above 40 °C caused by the polymerization. MALDI-TOF investigations proved that dissociation of the alkyl imidazolium groups which might disturb the expected directional chain topology (AB-AB-AB…) did not occur. This is an important precondition for the intended cross-linking free grafting reactions of the AB monomers on halide containing polymers without any danger of gelation. Additionally, the results of the MALDI-TOF investigations indicated partial complexation of the polymer with the matrix and structural rearrangements during the measurements which converted the ionic imidazolium moieties into neutral moieties. The thermal behavior of the poly(ionic liquid)s has proved to be dependent on the length of the alkyl linking group between the imidazolium moieties and the type of counter ion.
Graphical abstract
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Radiochemical “degelation” of polymethyl methacrylate networks
Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Pierre Gilormini, Emmanuel Richaud, Jacques Verdu
Methyl methacrylate-ethylene glycol dimethacrylate networks were synthetized and submitted to radiochemical degradation, with ageing monitored by means of sol-gel analysis. The networks were shown to undergo chain scission predominantly, which leads to their degelation, i.e., the recovery of a thermoplastic-like behavior with loss of all elastically active chains. The degelation dose was shown to increase with crosslink density and the corresponding critical conversion ratio was discussed regarding a recent and general statistical theory that covers radiochemical as well as chemical chain scissions.
Graphical abstract
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Nanofiltration properties of asymmetric membranes prepared by phase inversion of sulfonated nitro-polyphenylsulfone
Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Matan V. Brami, Yoram Oren, Charles Linder, Roy Bernstein
This study is a systematic investigation of preparation and characteristics of membranes, made from sulfonated nitro-polyphenylsulfone (SPPS-NO2) with different degrees of sulfonation and prepared by non-solvent–induced phase separation in different immersion baths (deionized water, 0.1 M HCl, or 1 M NaCl).Following nitration, the PPS-NO2 was sulfonated with different amounts of chlorosulfonic acid to achieve polymers with different ion exchange capacities (IECs), from 0 to 2.2 meq/g.The cross-sectional membrane morphology changed from porous to dense following sulfonation as seen by scanning electron microscopy. The phase inversion of the polymer solution was studied using the cloud-point method, light microscopy, and Langmuir isotherm. It was found that the liquid-liquid demixing of the polymer solution changed due to the increase in the IEC. This was mainly attributed to an increase in polymer miscibility in the aqueous non-solvent bath with an increasing degree of sulfonation. In addition, the phase-inversion properties of the ionic polymers were influenced by changing the aqueous composition of the immersion baths, probably due to partial protonation of the ionic sulfonic groups (in the case of HCl as the non-solvent) or to solvation effect (when NaCl was the non-solvent).Changing the morphology and of the membrane influenced its performance. Increasing the IEC increased the salt rejection and decreased flux. However, the permeability was improved without a large loss of selectivity by changing the non-solvent to aqueous NaCl. In addition, the new membrane showed high chlorine resistance due to the addition of a nitro group to the polymer backbone, and high acid resistance property.
Graphical abstract
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Neutron diffraction study of conducting polyaniline doped with (±) camphorsulfonic acid
Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Tomasz Kozik, Maciej Śniechowski, Wojciech Łużny, Adam Proń, David Djurado
Fully hydrogenated and partially deuterated free standing films of polyaniline doped with (±) camphorsulfonic acid (PANIh5/CSA and PANId4/CSA) are subjected to neutron diffraction study. Obtained results are analyzed and compared with X-ray diffraction measurements. The very distinct differences observed between the two neutron diffraction profiles are described in detail. Making use of the recently published new model of the crystalline structure of the PANI/CSA system, the neutron diffraction curves for the analogous structures are calculated. The two calculated neutron diffraction patterns exhibit similar differences as those obtained in experiment. This fully confirms the validity of the refined molecular model elaborated for this still important material for applications as synthetic metals or organic thermoelectrics.
Graphical abstract
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Cross-linked, polyurethane-based, ammonium poly(ionic liquid)/ionic liquid composite films for organic vapor suppression and ion conduction
Publication date: Available online 31 January 2017
Source:Polymer
Author(s): Dylan I. Mori, Rhia M. Martin, Richard D. Noble, Douglas L. Gin
A series of ammonium-diol and -triol ionic liquid (IL) monomers were synthesized and used in step-growth polymerization with the commercial di-isocyanate monomer, toluene-di-isocyanate (TDI), in the presence of free ammonium IL to form new curable ammonium-based polymerized ionic liquid/ionic liquid (PIL/IL) composite film coatings. The use of polyurethane chemistry allows for the near-complete curing of the alcohol and isocyanate monomers to yield solid, homogeneous, cross-linked polyurethane-based PIL/IL composite materials with no volatile side product formation. The physical properties and curing rates of these PIL/IL films were altered by tailoring the structures of the ammonium-alcohol IL monomers, the ratio of the linear vs. cross-linking IL monomers employed, and the amount of free IL in the curing reactions. Although ammonium-based PILs have been reported to be less thermally and electrochemically stable than their imidazolium counterparts in the literature, TGA results indicated a Tonset of up to 300 °C under air for the ammonium PIL/IL composites prepared in this study. These new PIL/IL materials were also tested as curable coatings in a toxic industrial chemical (TIC) vapor suppression and liquid uptake assay using o-dichlorobenzene (o-DCB) as a simulant for polychlorinated biphenyls. The curable PIL/IL coatings were found to suppress 88% of the o-DCB vapor on o-DCB-contaminated painted steel substrates and 79% of the o-DCB vapor on o-DCB-contaminated rubber substrates, relative to uncoated control samples. However, although effective for TIC vapor suppression, these ammonium PIL/IL coatings only sorbed less than 50% of the applied liquid o-DCB from the same test substrates, making them slightly less effective for this latter application than previously reported imidazolium-based curable PIL/IL coatings. These materials exhibited comparable ionic conductivity values to other types of PIL/IL systems previously reported in the literature. However, it was found that the more heavily cross-linked ammonium-based PIL/IL films were more prone to free IL leach-out at higher temperatures, leading to their unexpectedly higher ionic conductivity at elevated temperatures.
Graphical abstract
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Investigation into dielectric behaviour and electromagnetic interference shielding effectiveness of conducting styrene butadiene rubber composites containing ionic liquid modified MWCNT
Publication date: Available online 31 January 2017
Source:Polymer
Author(s): Jiji Abraham, Mohammed Arif P, Priti Xavier, Suryasarathi Bose, Soney C. George, Nandakumar Kalarikkal, Sabu Thomas
Designing new conducting materials with a promise for electromagnetic shielding applications attracted a wide spread interest in recent years. Styrene-butadiene rubber (SBR) is a widely used low cost synthetic rubber for a large number of applications. However, their use in providing an effective barrier for electromagnetic radiations is limited by its poor electrical conductivity. Herein we report a facile synthesis of conducting polymer nanocomposite by incorporating non-covalently functionalized Multiwalled Carbon Nanotube (MWCNT) with ionic liquid into SBR matrix and achieve a shielding efficiency of ca.35.06 dB @ 18 GHz (i.e ∼99.99% shielding attenuation). Importantly, ionic liquid embedded MWCNT makes it dispersible facilitated through cation–π interaction. A synergy between ionic liquid and MWCNT was well understood by analysing the dielectric behaviour and ac conductivity of composites in the frequency range of 100–20 MHz. A 5 mm thick soft rubber shielding material is fabricated and the shielding performance is analysed by vector network analyser for a frequency range of 2 GHz–18 GHz. A significant enhancement in the shielding effectiveness of the polymer nanocomposite with different amounts of f-MWCNT loading is observed. Electron microscopy analysis (TEM and FESEM) clearly illustrate the excellent dispersion state and microstructural development of MWCNTs within the SBR matrix which in turn accounts for the increase in the shielding performance of the polymer nanocomposite. This work opens up new paradigm for EMI shielding applications based on soft elastomer with the aid of a sustainable and simplified methodology.
Graphical abstract
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Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells.
Publication date: Available online 31 January 2017
Source:Peptides
Author(s): Terry W. Moody, Irene Ramos-Alvarez, Paola Moreno Perez, Samuel A. Mantey, Lisa Ridnour, David Wink, Robert T. Jensen
Endothelin (ET)-1 is an important peptide in cancer progression stimulating cellular proliferation, tumor angiogenesis and metastasis. ET-1 binds with high affinity to the ETA receptor (R) and ETBR on cancer cells. High levels of tumor ET-1 and ETAR are associated with poor survival of lung cancer patients. Here the effects of ET-1 on epidermal growth factor (EGF)R and HER2 transactivation were investigated using non-small cell lung cancer (NSCLC) cells. ETAR mRNA was present in all 10 NSCLC cell lines examined. Addition of ET-1 to NCI-H838 or H1975 cells increased EGFR, HER2 and ERK tyrosine phosphorylation within 2min. The increase in EGFR and HER2 transactivation caused by ET-1 addition to NSCLC cells was inhibited by lapatinib (EGFR and HER2 tyrosine kinase inhibitor (TKI)), gefitinib (EGFR TKI), ZD4054 or BQ-123 (ETAR antagonist), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor) or Tiron (superoxide scavenger). ET-1 addition to NSCLC cells increased cytosolic Ca2+ and reactive oxygen species. ET-1 increased NSCLC clonal growth, whereas BQ123, ZD4054, lapatinib or gefitinib inhibited proliferation. The results indicate that ET-1 may regulate NSCLC cellular proliferation in an EGFR- and HER2-dependent manner.
http://ift.tt/2keEK9y
A Near-peer Point-of-care Ultrasound Elective for Medical Students: Impact on Anatomy Knowledge, Perceptions About Ultrasound, and Self-reported Skill Level
Source:Academic Radiology
Author(s): Jacqueline T. DesJardin, Santo K. Ricceri, Stephen D. Brown, Emily M. Webb, David M. Naeger, Nathan A. Teismann
Rationale and ObjectivesWe aimed to assess the impact of our institution's recently created point-of-care ultrasound (POCUS) course for preclinical medical students by examining its effect on first–year-level medical knowledge, self-reported skill level, and beliefs regarding the importance of ultrasound in future clinical practice.Materials and MethodsA total of 18 first-year medical students completed a 5-month near–peer-led training program in POCUS consisting of 3-hour teaching sessions (7), 4-hour clinical sessions (10–12), and an independent study. Students completed pre- and postprogram assessments examining (1) student perceptions about ultrasound and its importance to future careers, (2) students' self-reported skill level with ultrasound, and (3) performance on an anatomy and physiology knowledge quiz. Scores and responses were compared to 20 controls.ResultsThe majority of students believed that ultrasound was useful for learning anatomy and would be important in their future clinical practice. Students who completed our training program tended to perform better than controls on a test of medical knowledge. Despite reporting far fewer hours of formal ultrasound training, control students rated their skill level comparably to POCUS-trained students.ConclusionsThis study provides evidence that ultrasound is well received by medical students and may be useful for teaching basic anatomy concepts.
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Antibiotic therapy in critically ill patients: expert opinion of the European Society of Anaesthesia Intensive Care Scientific Subcommittee: A narrative review.
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Intraoperative monitoring of analgesia using nociceptive reflexes correlates with delayed extubation and immediate postoperative pain: A prospective observational study.
http://ift.tt/2kSEr34
Editorial Board
Source:American Journal of Infection Control, Volume 45, Issue 2
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APIC Masthead
Source:American Journal of Infection Control, Volume 45, Issue 2
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Knowledge of Ebola virus disease among a university population: A cross-sectional study
Publication date: 1 February 2017
Source:American Journal of Infection Control, Volume 45, Issue 2
Author(s): Muhammad Salman, Naureen Shehzadi, Khalid Hussain, Fahad Saleem, Muhammad Tanveer Khan, Nauman Asif, Maria Yousaf, Maham Rafique, Rushda Bedar, Sonia Tariq, Usman AbuBakar, Syed Azhar Syed Sulaiman
This cross-sectional study aimed to evaluate the knowledge of a Pakistani university population (students and employees) regarding Ebola virus disease. A total of 2,200 individuals were approached and 1,647 were enrolled in the study. We observed that the vast majority of study participants (91.8%) had inadequate knowledge of Ebola virus disease (knowledge score ≤ 12). Our findings highlight the need to increase the knowledge of Ebola virus disease by using multidimensional approach involving awareness campaigns, print, electronic, and social media.
http://ift.tt/2kpo5lI
Information for Readers
Publication date: 1 February 2017
Source:American Journal of Infection Control, Volume 45, Issue 2
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Information for Authors
Source:American Journal of Infection Control, Volume 45, Issue 2
http://ift.tt/2kpj8JH
Updated resource: The APIC/JCR Infection Prevention and Control Workbook, Third Edition
Publication date: 1 February 2017
Source:American Journal of Infection Control, Volume 45, Issue 2
http://ift.tt/2kSEv33
Table of Contents
Source:American Journal of Infection Control, Volume 45, Issue 2
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Longitudinal assessment of reprocessing effectiveness for colonoscopes and gastroscopes: Results of visual inspections, biochemical markers, and microbial cultures
Source:American Journal of Infection Control, Volume 45, Issue 2
Author(s): Cori L. Ofstead, Harry P. Wetzler, Otis L. Heymann, Ellen A. Johnson, John E. Eiland, Michael J. Shaw
BackgroundFlexible endoscopes are currently reused following cleaning and high-level disinfection. Contamination has been found on endoscopes, and infections have been linked to gastrointestinal, respiratory, and urologic endoscopes.MethodsThis longitudinal study involved visual inspections with a borescope, microbial cultures, and biochemical tests for protein and adenosine triphosphate to identify endoscopes in need of further cleaning or maintenance. Three assessments were conducted over a 7-month period. Control group endoscopes reprocessed using customary practices were compared with intervention group endoscopes subjected to more rigorous reprocessing.ResultsAt final assessment, all endoscopes (N = 20) had visible irregularities. Researchers observed fluid (95%), discoloration, and debris in channels. Of 12 (60%) endoscopes with microbial growth, 4 had no growth until after 48 hours. There were no significant differences in culture results by study group, assessment period, or endoscope type. Similar proportions of control and intervention endoscopes (~20%) exceeded postcleaning biochemical test benchmarks. Adenosine triphosphate levels were higher for gastroscopes than colonoscopes (P = .014). Eighty-five percent of endoscopes required repair due to findings.ConclusionsMore rigorous reprocessing was not consistently effective. Seven-day incubation allowed identification of slow-growing microbes. These findings bolster the need for routine visual inspection and cleaning verification tests recommended in new reprocessing guidelines.
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The new frontier of diagnostics: Molecular assays and their role in infection prevention and control
Publication date: 1 February 2017
Source:American Journal of Infection Control, Volume 45, Issue 2
Author(s): Sanchita Das, Dena R. Shibib, Michael O. Vernon
Recent advances in technology over the last decade have propelled the microbiology laboratory into a pivotal role in infection prevention and control. The rapid adaptation of molecular technologies to the field of clinical microbiology now greatly influences infectious disease management and significantly impacts infection control practices. This review discusses recent developments in molecular techniques in the diagnosis of infectious diseases. It describes the basic concepts of molecular assays, discusses their advantages and limitations, and characterizes currently available commercial assays with respect to cost, interpretive requirements, and clinical utility.
http://ift.tt/2kSEtYZ
Infection control in the new age of genomic epidemiology
Publication date: 1 February 2017
Source:American Journal of Infection Control, Volume 45, Issue 2
Author(s): Patrick Tang, Matthew A. Croxen, Mohammad R. Hasan, William W.L. Hsiao, Linda M. Hoang
With the growing importance of infectious diseases in health care and communicable disease outbreaks garnering increasing attention, new technologies are playing a greater role in helping us prevent health care–associated infections and provide optimal public health. The microbiology laboratory has always played a large role in infection control by providing tools to identify, characterize, and track pathogens. Recently, advances in DNA sequencing technology have ushered in a new era of genomic epidemiology, where traditional molecular diagnostics and genotyping methods are being enhanced and even replaced by genomics-based methods to aid epidemiologic investigations of communicable diseases. The ability to analyze and compare entire pathogen genomes has allowed for unprecedented resolution into how and why infectious diseases spread. As these genomics-based methods continue to improve in speed, cost, and accuracy, they will be increasingly used to inform and guide infection control and public health practices.
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Editorial Board
Source:Cancer Treatment Reviews, Volume 53
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Association of Facebook Use With Compromised Well-Being: A Longitudinal Study
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Face-to-face social interactions enhance well-being. With the ubiquity of social media, important questions have arisen about the impact of online social interactions. In the present study, we assessed the associations of both online and offline social networks with several subjective measures of well-being. We used 3 waves (2013, 2014, and 2015) of data from 5,208 subjects in the nationally representative Gallup Panel Social Network Study survey, including social network measures, in combination with objective measures of Facebook use. We investigated the associations of Facebook activity and real-world social network activity with self-reported physical health, self-reported mental health, self-reported life satisfaction, and body mass index. Our results showed that overall, the use of Facebook was negatively associated with well-being. For example, a 1-standard-deviation increase in "likes clicked" (clicking "like" on someone else's content), "links clicked" (clicking a link to another site or article), or "status updates" (updating one's own Facebook status) was associated with a decrease of 5%–8% of a standard deviation in self-reported mental health. These associations were robust to multivariate cross-sectional analyses, as well as to 2-wave prospective analyses. The negative associations of Facebook use were comparable to or greater in magnitude than the positive impact of offline interactions, which suggests a possible tradeoff between offline and online relationships.</span>
http://ift.tt/2jTdfUs
Indoor Tanning and Melanoma Risk: Long-Term Evidence From a Prospective Population-Based Cohort Study
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Indoor tanning is associated with increased risk of melanoma, but most evidence comes from case-control studies. Using data from the Norwegian Women and Cancer Study, a large prospective cohort study, we investigated the associations of age at initiation of indoor tanning, duration of tanning-device use, and dose response with melanoma risk and examined the role of indoor tanning in age at melanoma diagnosis. We used Poisson regression to estimate relative risks and 95% confidence intervals for the relationship of indoor tanning to melanoma risk and linear regression to examine age of indoor tanning initiation in relation to age at diagnosis. During follow-up of 141,045 women (1991–2012; mean duration follow-up = 13.7 years), 861 women were diagnosed with melanoma. Melanoma risk increased with increasing cumulative number of tanning sessions (for highest tertile of use vs. never use, adjusted relative risk = 1.32, 95% confidence interval (CI): 1.08, 1.63); <span style="font-style:italic;">P</span>-trend = 0.006. Age at initiation <30 years was associated with a higher risk in comparison with never use (adjusted relative risk = 1.31, 95% CI: 1.07, 1.59). Moreover, women who started indoor tanning prior to 30 years of age were 2.2 years (95% CI: 0.9, 3.4) younger at diagnosis, on average, than never users. This cohort study provides strong evidence of a dose-response association between indoor tanning and risk of melanoma and supports the hypothesis that vulnerability to the harmful effects of indoor tanning is greater at a younger age.</span>
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Invited Commentary: Indoor Tanning—A Melanoma Accelerator?
<span class="paragraphSection"><div class="boxTitle">Abstract</div>In this issue of the <span style="font-style:italic;">Journal</span>, Ghiasvand et al. (<span style="font-style:italic;">Am J Epidemiol.</span> 2017;185(3):147–156) present results from a longitudinal study of the association between indoor tanning and melanoma in a large cohort of Norwegian women. These new data further support previous findings on the damaging effects of tanning bed exposure on women, particularly young women. The authors present compelling evidence that early exposure to tanning beds advances the date of diagnosis of melanoma by at least 2 years. With a strong design and a large cohort followed for a mean of 13.7 years, this study lends additional support to previous evidence of the negative effects of tanning beds and provides further justification for stronger policy initiatives designed to reduce tanning bed use among young women.</span>
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A Comprehensive Model of Colorectal Cancer by Risk Factor Status and Subsite Using Data From the Nurses’ Health Study
<span class="paragraphSection"><div class="boxTitle">Abstract</div>We expanded and updated our colon cancer risk model to evaluate colorectal cancer (CRC) and whether subsite-specific risk models are warranted. Using data from 1980–2010 for 90,286 women enrolled in the Nurses' Health Study, we performed competing-risks regression and tests for subsite heterogeneity (proximal colon: <span style="font-style:italic;">n</span> = 821; distal colon: <span style="font-style:italic;">n</span> = 521; rectum: <span style="font-style:italic;">n</span> = 376). Risk factors for CRC were consistent with those in our colon cancer model. Processed meat consumption was associated with a higher risk of distal (hazard ratio (HR) = 1.45; <span style="font-style:italic;">P</span> = 0.02) but not proximal (HR = 0.95; <span style="font-style:italic;">P</span> = 0.72) colon cancer. Smoking was associated with both colon (HR = 1.21) and rectal (HR = 1.27) cancer and was more strongly associated with proximal (HR = 1.31) than with distal (HR = 1.04) colon cancer (<span style="font-style:italic;">P</span> = 0.029). We observed a significant trend of cancer risk for smoking in subsites from the cecum (HR = 1.41) to the proximal colon (excluding the cecum; HR = 1.27) to the distal colon (HR = 1.04; <span style="font-style:italic;">P</span> for trend = 0.040). The <span style="font-style:italic;">C</span> statistics for colorectal (<span style="font-style:italic;">C</span> = 0.607), colon (<span style="font-style:italic;">C</span> = 0.603), and rectal (<span style="font-style:italic;">C</span> = 0.639) cancer were similar, although <span style="font-style:italic;">C</span> was slightly higher for rectal cancer. Despite evidence for site-specific differences for several risk factors, overall our findings support the application of risk prediction models for colon cancer to CRC.</span>
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Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006–2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005–2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.</span>
http://ift.tt/2jTg2wY
Prevalence of Masked Hypertension Among US Adults With Nonelevated Clinic Blood Pressure
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Masked hypertension (MHT), defined as nonelevated blood pressure (BP) in the clinic setting and elevated BP assessed by ambulatory monitoring, is associated with increased risk of target organ damage, cardiovascular disease, and mortality. Currently, no estimate of MHT prevalence exists for the general US population. After pooling data from the Masked Hypertension Study (<span style="font-style:italic;">n</span> = 811), a cross-sectional clinical investigation of systematic differences between clinic BP and ambulatory BP (ABP) in a community sample of employed adults in the New York City metropolitan area (2005–2012), and the National Health and Nutrition Examination Survey (NHANES; 2005–2010; <span style="font-style:italic;">n</span> = 9,316), an ongoing nationally representative US survey, we used multiple imputation to impute ABP-defined hypertension status for NHANES participants and estimate MHT prevalence among the 139 million US adults with nonelevated clinic BP, no history of overt cardiovascular disease, and no use of antihypertensive medication. The estimated US prevalence of MHT in 2005–2010 was 12.3% of the adult population (95% confidence interval: 10.0, 14.5)—approximately 17.1 million persons aged ≥21 years. Consistent with prior research, estimated MHT prevalence was higher among older persons, males, and those with prehypertension or diabetes. To our knowledge, this study provides the first estimate of US MHT prevalence—nearly 1 in 8 adults with nonelevated clinic BP—and suggests that millions of US adults may be misclassified as not having hypertension.</span>
http://ift.tt/2jTbwOJ
Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Few studies have assessed the association of sedentary time with leukocyte telomere length (LTL). In a cross-sectional study conducted in 2012–2013, we examined associations of accelerometer-measured and self-reported sedentary time with LTL in a sample of 1,481 older white and African-American women from the Women's Health Initiative and determined whether associations varied by level of moderate- to vigorous-intensity physical activity (MVPA). The association between sedentary time and LTL was evaluated using multiple linear regression models. Women were aged 79.2 (standard deviation, 6.7) years, on average. Self-reported sedentary time was not associated with LTL. In a model adjusting for demographic characteristics, lifestyle behaviors, and health-related factors, among women at or below the median level of accelerometer-measured MVPA, those in the highest quartile of accelerometer-measured sedentary time had significantly shorter LTL than those in the lowest quartile, with an average difference of 170 base pairs (95% confidence interval: 4, 340). Accelerometer-measured sedentary time was not associated with LTL in women above the median level of MVPA. Findings suggest that, on the basis of accelerometer measurements, higher sedentary time may be associated with shorter LTL among less physically active women.</span>
http://ift.tt/2kOjXcV
Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.</span>
http://ift.tt/2jTk4Fn
Maternal Concentrations of Perfluoroalkyl Substances and Fetal Markers of Metabolic Function and Birth Weight The Maternal-Infant Research on Environmental Chemicals (MIREC) Study
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Perfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals that have been widely used in the production of common household and consumer goods for their nonflammable, lipophobic, and hydrophobic properties. Inverse associations between maternal or umbilical cord blood concentrations of perfluorooctanoic acid and perfluorooctanesulfonate and birth weight have been identified. This literature has primarily examined each PFAS individually without consideration of the potential influence of correlated exposures. Further, the association between PFAS exposures and indicators of metabolic function (i.e., leptin and adiponectin) has received limited attention. We examined associations between first-trimester maternal plasma PFAS concentrations and birth weight and cord blood concentrations of leptin and adiponectin using data on 1,705 mother-infant pairs from the Maternal Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada birth cohort study that recruited women between 2008 and 2011. Bayesian hierarchical models were used to quantify associations and calculate credible intervals. Maternal perfluorooctanoic acid concentrations were inversely associated with birth weight <span style="font-style:italic;">z</span> score, though the null value was included in all credible intervals (log<sub>10</sub> β = −0.10, 95% credible interval: −0.34, 0.13). All associations between maternal PFAS concentrations and cord blood adipocytokine concentrations were of small magnitude and centered around the null value. Follow-up in a cohort of children is required to determine how the observed associations manifest in childhood.</span>
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Tracing a Path to the Past: Exploring the Use of Commercial Credit Reporting Data to Construct Residential Histories for Epidemiologic Studies of Environmental Exposures
<span class="paragraphSection"><div class="boxTitle">Abstract</div>Large-scale environmental epidemiologic studies often rely on exposure estimates based on linkage to residential addresses. This approach, however, is limited by the lack of residential histories typically available for study participants. Our objective was to evaluate the feasibility of using address data from LexisNexis (a division of RELX, Inc., Dayton, Ohio), a commercially available credit reporting company, to construct residential histories for participants in the California Teachers Study (CTS), a prospective cohort study initiated in 1995–1996 to study breast cancer (<span style="font-style:italic;">n</span> = 133,479). We evaluated the degree to which LexisNexis could provide retrospective addresses prior to study enrollment, as well as the concordance with existing prospective CTS addresses ascertained at the time of the completion of 4 self-administered questionnaires. For approximately 80% of CTS participants, LexisNexis provided at least 1 retrospective address, including nearly 25,000 addresses completely encompassed by time periods prior to enrollment. This approach more than doubled the proportion of the study population for whom we had an address of residence during the childbearing years—an important window of susceptibility for breast cancer risk. While overall concordance between the prospective addresses contained in these 2 data sources was good (85%), it was diminished among black women and women under the age of 40 years.</span>
http://ift.tt/2jTti4D
Novel molecular insights into the function and the antioxidative stress response of a Peroxiredoxin Q protein from Cyanobacteria
Publication date: Available online 31 January 2017
Source:Free Radical Biology and Medicine
Author(s): Vijay Tailor, Anand Ballal
The PeroxiredoxinQ (PrxQ) proteins are thiol-based peroxidases that are important for maintaining redox homeostasis in several organisms. Activity of PrxQs is mediated by two cysteines, peroxidatic (Cp) and resolving (Cr), in association with a reducing partner. A PrxQ, Alr3183, from the cyanobacterium, Anabaena PCC 7120, was characterized in this study. Alr3183, which required thioredoxin A (TrxA) for peroxidase activity, was an intramolecular disulfide bond-containing monomeric protein. However, Alr3183 lacking Cp (Alr3183C46S) or Cr (Alr3183C51S) formed intermolecular disulphide linkages and was dimeric. Alr3183C46S was completely inactive, while Alr3183C51S required higher concentration of TrxA for peroxidase activity. Surface plasmon resonance analysis showed that unlike Alr3183 or Alr3183C46S, Alr3183C51S bound rather poorly to TrxA. Also, compared to the oxidized protein, the DTT-treated (reduced) Alr3183 displayed decreased interaction with TrxA. In vivo, Alr3183 was found to be induced in response to γ-radiation. On exposure to H2O2, Anabaena strain over-expressing Alr3183 showed reduced formation of ROS, intact photosynthetic pigments and consequently better survival than the wild-type, whereas overproduction of Alr3183C46S did not provide any protection. Significantly, this study (1) reveals the importance of Cr for interaction with thioredoxins and (2) demonstrates that over-expression of PrxQs can protect cyanobacteria from oxidative stresses.
Graphical abstract
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Combined p16 and p53 expression in cervical cancer of unknown primary and other prognostic parameters
Abstract
Background and purpose
Cervical cancer of unknown primary (CUP) represents an uncommon and heterogeneous subentity of head and neck cancer. However, both optimal diagnostics and therapy remain unclear. An improved understanding of the underlying pathology is essential to enable future tailored therapies and optimized outcomes.
Materials and methods
We retrospectively analyzed 53 patients with head and neck CUP and 48 available cervical lymph node specimens. All patients have received radiotherapy between 2007 and 2015. Preradiotherapy involved lymph node specimens were analyzed for p16 and p53 immunoreactivity. The prognostic relevance of the combined p16 and p53 status and other clinical parameters were examined by univariate and multivariate analyses.
Results
Median patient age was 61.5 years and median irradiation dose to the involved nodal levels was 66 Gy. Of the 48 evaluated specimens, 13 (27%) were p16-positive and 31 (64.6%) p53-positive. After a median follow up of 32.9 months, patients with p16-negative and simultaneously p53-positive tumors showed a significantly inferior tumor-specific survival (TSS) compared to those with either p16+/p53−, p16+/p53+, or p16−/p53− (univariate: p = 0.055, multivariate: p = 0.038). Other factors with an adverse impact on TSS in the univariate analysis were smoking history (p = 0.032) and nodal stage (p = 0.038).
Conclusions
The combined p16- and p53-expression status in cervical metastases of CUP may represent a simple method for risk stratification. Further validation of these biomarkers in large prospective trials is essential to design rational trials for CUP treatment optimization.
http://ift.tt/2kRA9Jy
Functional evaluation of the restored mucosa after nasal reconstruction with a forehead-galea flap
Abstract
Background
Recovery of the internal mucosal lining is the most problematic step in nasal reconstruction. Restoration of both aesthetic and functional components should be the goal to be pursued. For this purpose, we performed a study for functional evaluation of the restored mucosa after nasal reconstruction.
Methods
From April 2009 to May 2016, 10 patients in whom the galea was used to reconstruct the nasal lining were selected from our casuistic of nasal reconstruction. In order to visualize the nasal and nasopharyngeal cavity, an antero-posterior rhinoendoscopy was performed in all patients. Additionally, patients were asked to complete a visual analogue scale (VAS) evaluation regarding nasal obstruction. Active anterior rhinomanometry analysis, olfactometry analysis and a cytologic examination were also conducted.
Results
Near-normal results in nasal obstruction evaluation were reported subjectively by patients. Near-normal inspiratory values were obtained using rhinomanometry. Average values of TDI (threshold, discrimination and identification), a comprehensive olfactometric parameter, were essentially normal. Cytological sampling examination did not reveal any substantial abnormal variation.
Conclusions
Based on our morphological and functional results, we can assert that the forehead flap in association with galea for lining is a safe and practical surgical technique in total nasal reconstruction.
Level of Evidence: Level V, prognostic study
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Molecular cloning, characterization and expression analysis of Tim-3 and Galectin-9 in the woodchuck model
Source:Molecular Immunology, Volume 83
Author(s): Yanan Liu, Junzhong Wang, Lu Wang, Baoju Wang, Shangqing Yang, Qin Wang, Jinzhuo Luo, Xuemei Feng, Xuecheng Yang, Yinping Lu, Michael Roggendorf, Mengji Lu, Dongliang Yang, Jia Liu
In recent years, a critical role for T cell immunoglobulin mucin domain 3 (Tim-3) and its ligand Galectin-9 (Gal-9) has emerged in infectious disease, autoimmunity and cancer. Manipulating this immune checkpoint may have immunotherapeutic potential and could represent an alternative approach for improving immune responses to viral infections and cancer. The woodchuck (Marmot monax) infected by woodchuck hepatitis virus (WHV) represents an informative animal model to study HBV infection and HCC. In the current study, the cDNA sequences of woodchuck Tim-3 and Gal-9 were cloned, sequenced and characterized. The extracellular domain of Tim-3 cDNA sequence consisted of 576bp coding sequence (CDS) that encoded 192 amino acids. The 1076bp full-length Gal-9 cDNA sequence consisted of 1059bp coding sequence (CDS) that encoded 352 amino acids with a molecular weight of 39.7kDa. The phylogenetic tree analysis revealed that the woodchuck Tim-3 and Gal-9 had the closest genetic relationship with Ictidomys tridecemlineatus. The result of quantification PCR analysis showed that ubiquitous expression of Gal-9 but not Tim-3 in different tissues of naive woodchucks. Elevated liver Gal-9 expression was observed in woodchucks with chronic WHV infection. Moreover, a polyclonal antibody against the extracellular domain of woodchuck Tim-3 were generated and identified by flow cytometry. Our results serve as a foundation for further insight into the role of Tim-3/Galectin-9 signaling pathway in viral hepatitis and HCC in the woodchuck model.
http://ift.tt/2jzLa18
DnaJ (hsp40) of Streptococcus pneumoniae is involved in bacterial virulence and elicits a strong natural immune reaction via PI3K/JNK
Source:Molecular Immunology, Volume 83
Author(s): Jin Cui, Chenyu Ma, Guo Ye, Yong Shi, Wenchun Xu, Liang Zhong, Jian Wang, Yibing Yin, Xuemei Zhang, Hong Wang
As a heat shock protein, DnaJ plays an important role in the pathogenesis of pneumococcal infection. However, how the virulence factor-DnaJ elicits host natural immunity still remains unclear. In this study, we investigated the effects of dnaJ deficiency in Streptococcus pneumoniae (S. pneumoniae) on bacterial virulence, and further explored the related molecular mechanisms in vivo and in vitro. By generating dnaJ deficient mutant (ΔdnaJ), the virulence and colonization were detected in murine pneumonia and sepsis models in vivo. Compared with wild-type parent strain, the abilities of rapid colonization and induction of inflammatory responses of ΔdnaJ in mouse lungs were significantly impaired. Simultaneously, recombinant DnaJ purified from E. coli expression system (rDnaJ) induced macrophage strain RAW264.7 to secrete IL-6 by activation of PI3K and JNK signal pathways, which were confirmed by the specific signaling inhibitors. In conclusion, DnaJ, a novel virulence protein, was essential for the virulence and colonization of S. pneumoniae and induced pro-inflammatory cytokine production in macrophages through PI3K/JNK.
http://ift.tt/2knK6Sv
Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-κB activation
Publication date: March 2017
Source:Molecular Immunology, Volume 83
Author(s): Annegret Bitzer, Michael Basler, Daniel Krappmann, Marcus Groettrup
Activation of the pro-inflammatory transcription factor NF-κB requires signal-induced proteasomal degradation of the inhibitor of NF-κB (IκB) in order to allow nuclear translocation. Most cell types are capable of expressing two types of 20S proteasome core particles, the constitutive proteasome and immunoproteasome. Inducible under inflammatory conditions, the immunoproteasome is mainly characterized through an altered cleavage specificity compared to the constitutive proteasome. However, the question whether immunoproteasome subunits affect NF-κB signal transduction differently from constitutive subunits is still up for debate. To study the effect of immunoproteasomes on LPS- or TNF-α-induced NF-κB activation, we used IFN-γ stimulated peritoneal macrophages and mouse embryonic fibroblasts derived from mice deficient for the immunoproteasome subunits low molecular mass polypeptide (LMP) 2, or LMP7 and multicatalytic endopeptidase complex-like 1 (MECL-1). Along the canonical signaling pathway of NF-κB activation no differences in the extent and kinetic of IκB degradation were observed. Neither the nuclear translocation and DNA binding of NF-κB nor the production of the NF-κB dependent cytokines TNF-α, IL-6, and IL-10 differed between immunoproteasome deficient and proficient cells. Hence, we conclude that immunoproteasome subunits have no specialized function for canonical NF-κB activation.
Graphical abstract
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Relationship between the change of language symptoms and the change of regional cerebral blood flow in the recovery process of two children with acquired aphasia
Source:Brain and Development
Author(s): Junko Kozuka, Akira Uno, Hiroshi Matsuda, Yoshiya Toyoshima, Shin-ichiro Hamano
ObjectiveThis study aimed to investigate the relationship between the change of language symptoms and the change of regional cerebral blood flow (rCBF) in the recovery process of two children with acquired aphasia caused by infarctions from Moyamoya disease with an onset age of 8years.MethodsWe compared the results for the Standard Language Test of Aphasia (SLTA) with rCBF changes in 7 language regions in the left hemisphere and their homologous regions in the right hemisphere at 4 time points from 3weeks for up to 5years after the onset of aphasia, while controlling for the effect of age.ResultsIn both cases, strong correlations were seen within a hemisphere between adjacent regions or regions that are connected by neuronal fibers, and between some language regions in the left hemisphere and their homologous regions in the right hemisphere. Conversely, there were differences between the two cases in the time course of rCBF changes during their recovery process.ConclusionConsistent with previous studies, the current study suggested that both hemispheres were involved in the long-term recovery of language symptoms in children with acquired aphasia. We suggest that the differences between both cases during their recovery process might be influenced by the brain states before aphasia, by which hemisphere was affected, and by the timing of the surgical revascularization procedure. However, the changes were observed in the data obtained for rCBF with strong correlations with the changes in language performance, so it is possible that rCBF could be used as a biomarker for language symptom changes.
http://ift.tt/2jzDwDG
Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Mathew Van de Pette, Allifia Abbas, Amelie Feytout, Gráinne McNamara, Ludovica Bruno, Wilson K. To, Andrew Dimond, Alessandro Sardini, Zoe Webster, James McGinty, Eleanor J. Paul, Mark A. Ungless, Paul M.W. French, Dominic J. Withers, Anthony Uren, Anne C. Ferguson-Smith, Matthias Merkenschlager, Rosalind M. John, Amanda G. Fisher
Imprinted genes are regulated according to parental origin and can influence embryonic growth and metabolism and confer disease susceptibility. Here, we designed sensitive allele-specific reporters to non-invasively monitor imprinted Cdkn1c expression in mice and showed that expression was modulated by environmental factors encountered in utero. Acute exposure to chromatin-modifying drugs resulted in de-repression of paternally inherited (silent) Cdkn1c alleles in embryos that was temporary and resolved after birth. In contrast, deprivation of maternal dietary protein in utero provoked permanent de-repression of imprinted Cdkn1c expression that was sustained into adulthood and occurred through a folate-dependent mechanism of DNA methylation loss. Given the function of imprinted genes in regulating behavior and metabolic processes in adults, these results establish imprinting deregulation as a credible mechanism linking early-life adversity to later-life outcomes. Furthermore, Cdkn1c-luciferase mice offer non-invasive tools to identify factors that disrupt epigenetic processes and strategies to limit their long-term impact.
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Van de Pette et al. use sensitive allele-specific reporters to longitudinally image imprinted Cdkn1c expression in mice and show that expression is modulated by environmental factors encountered in utero. These results establish imprinting deregulation as a mechanism linking early-life adversity to later-life outcomes and provide tools to detect imprinting changes in vivo.http://ift.tt/2kMPJXo
Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Daniel A. Nagode, Xiangying Meng, Daniel E. Winkowski, Ed Smith, Hamza Khan-Tareen, Vishnupriya Kareddy, Joseph P.Y. Kao, Patrick O. Kanold
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as "patches" of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD.
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It has been hypothesized that dysfunction of subplate neurons is an early event in autism pathology, but never directly tested. Nagode et al. demonstrate spatially restricted increases in excitatory and inhibitory connectivity to subplate in the VPA autism model. These results provide direct evidence of subplate dysfunction in autism.http://ift.tt/2kN2YaD
Autonomous CaMKII Activity as a Drug Target for Histological and Functional Neuroprotection after Resuscitation from Cardiac Arrest
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Guiying Deng, James E. Orfila, Robert M. Dietz, Myriam Moreno-Garcia, Krista M. Rodgers, Steve J. Coultrap, Nidia Quillinan, Richard J. Traystman, K. Ulrich Bayer, Paco S. Herson
The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling, but its role in pathological glutamate signaling (excitotoxicity) remains less clear, with indications for both neuro-toxic and neuro-protective functions. Here, the role of CaMKII in ischemic injury is assessed utilizing our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). CaMKII inhibition (with tatCN21 or tatCN19o) at clinically relevant time points (30 min after resuscitation) greatly reduces neuronal injury. Importantly, CaMKII inhibition also works in combination with mild hypothermia, the current standard of care. The relevant drug target is specifically Ca2+-independent "autonomous" CaMKII activity generated by T286 autophosphorylation, as indicated by substantial reduction in injury in autonomy-incompetent T286A mutant mice. In addition to reducing cell death, tatCN19o also protects the surviving neurons from functional plasticity impairments and prevents behavioral learning deficits, even at extremely low doses (0.01 mg/kg), further highlighting the clinical potential of our findings.
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Deng et al. find that CaMKII and its phospho-T286-induced autonomous activity are a promising therapeutic drug target for global cerebral ischemia (induced by cardiac arrest followed by CPR in a mouse model). Pharmacological inhibition or T286A mutation leads to neuroprotection and improves synaptic and functional recovery following cardiac arrest.http://ift.tt/2kMIOxq
Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa Katsuno, Gen Sobue
Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio. Normalization of this increased ratio by 4R-T-specific silencing results in recovery of the normal phenotype. These findings suggest a biological link among FUS/SFPQ, tau isoform alteration, and phenotypic expression, which may function in the early pathomechanism of FTLD.
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Ishigaki et al. investigate the functions of Fused in sarcoma (FUS) and its binding partner proline- and glutamine-rich (SFPQ) in regulation of Mapt splicing. The authors show how loss of interaction between FUS and SFPQ causes altered expression ratio of tau isoforms and leads to a neurodegenerative phenotype similar to FTLD. Normalization of this ratio can reduce phenotypic abnormalities in the mouse model of disease.http://ift.tt/2kMIy1z
Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson’s Disease
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Li Song, Yijing He, Jiayao Ou, Yongbo Zhao, Ruoyu Li, Jingjing Cheng, Chin-Hsien Lin, Margaret S. Ho
Parkinson's disease (PD) is a common neurodegenerative disorder that exhibits motor and non-motor symptoms, as well as pathological hallmarks, including dopaminergic (DA) neuron death and formation of α-synuclein (α-Syn) Lewy bodies. Cyclin-G-associated kinase (GAK), a PD susceptibility gene identified through genome-wide association studies (GWAS), is a ubiquitous serine/threonine kinase involved in clathrin uncoating, though its PD-related function remains elusive. Here, we implicate the Drosophila GAK homolog, auxilin (aux), in a broad spectrum of parkinsonian-like symptoms. Downregulating aux expression leads to progressive loss of climbing ability, decreased lifespan, and age-dependent DA neuron death similar to α-Syn overexpression. Reduced aux expression further enhances and accelerates α-Syn-mediated DA neuron loss. Flies with reduced aux expression are more sensitive to the toxin paraquat, suggesting that genetic and environmental factors intertwine. Taken together, these findings decipher a pivotal role for GAK/aux and suggest mechanisms underlying PD.
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Parkinson's disease (PD) is a neurodegenerative disorder that exhibits motor symptoms and neuron loss. Song et al. implicate Drosophila cyclin-G-associated kinase (GAK) in fly phenotypes reminiscent of PD.http://ift.tt/2kMJUJP
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Inês Milagre, Thomas M. Stubbs, Michelle R. King, Julia Spindel, Fátima Santos, Felix Krueger, Martin Bachman, Anne Segonds-Pichon, Shankar Balasubramanian, Simon R. Andrews, Wendy Dean, Wolf Reik
Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here, we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global demethylation requires activation-induced cytidine deaminase (AID)-mediated downregulation of UHRF1 protein, and abolishing demethylation leaves thousands of hypermethylated regions in the iPSC genome. Independently of AID and global demethylation, regulatory regions, particularly ESC enhancers and super-enhancers, are specifically targeted for hypomethylation in association with transcription of the pluripotency network. Our results show that global and targeted DNA demethylation are conserved and distinct reprogramming processes, presumably because of their respective roles in epigenetic memory erasure and in the establishment of cell identity.
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Milagre et al. find that two modes of DNA demethylation occur during primary iPSC reprogramming. Global DNA demethylation, more pronounced in female cells, is regulated by AID through UHRF1 and occurs transiently at intermediate-late stages of reprogramming. Targeted DNA demethylation, by contrast, is important in establishing hypomethylation at enhancers of pluripotency genes and occurs similarly in female and male cells.http://ift.tt/2kMRhRi
Serotonin Signaling through Prefrontal Cortex 5-HT1A Receptors during Adolescence Can Determine Baseline Mood-Related Behaviors
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Alvaro L. Garcia-Garcia, Qingyuan Meng, Sarah Canetta, Alain M. Gardier, Bruno P. Guiard, Christoph Kellendonk, Alex Dranovsky, E. David Leonardo
Lifelong homeostatic setpoints for mood-related behaviors emerge during adolescence. Serotonin (5-HT) plays an important role in refining the formation of brain circuits during sensitive developmental periods. In rodents, the role of 5-HT1A receptors in general and autoreceptors in particular has been characterized in anxiety. However, less is known about the role of 5-HT1A receptors in depression-related behavior. Here, we show that whole-life suppression of heteroreceptor expression results in a broad depression-like behavioral phenotype accompanied by physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper (mPFC-DRN) circuitry. These changes include increased basal 5-HT in a mPFC that is hyporesponsive to stress and decreased basal 5-HT levels and firing rates in a DRN hyperactivated by the same stressor. Remarkably, loss of heteroreceptors in the PFC at adolescence is sufficient to recapitulate this depression-like behavioral syndrome. Our results suggest that targeting mPFC 5-HT1A heteroreceptors during adolescence in humans may have lifelong ramifications for depression and its treatment.
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Garcia-Garcia et al. use transgenic and viral approaches to demonstrate that signaling through 5-HT1A heteroreceptors in the medial prefrontal cortex during adolescence is critical in establishing baseline mood setpoints.http://ift.tt/2kMQIan
Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Giorgia Bartolini, Juan Antonio Sánchez-Alcañiz, Catarina Osório, Manuel Valiente, Cristina García-Frigola, Oscar Marín
Neural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3) as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.
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The integration of interneurons in the developing cerebral cortex depends on signals generated by pyramidal cells. In this study, Bartolini et al. identify Neuregulin 3 as a developmentally regulated factor that controls the migration of interneurons into the cortical plate and influences their final laminar distribution.http://ift.tt/2kMIL4W
miR-182 Regulates Slit2-Mediated Axon Guidance by Modulating the Local Translation of a Specific mRNA
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Anaïs Bellon, Archana Iyer, Simone Bridi, Flora C.Y. Lee, Cesaré Ovando-Vázquez, Eloina Corradi, Sara Longhi, Michela Roccuzzo, Stephanie Strohbuecker, Sindhu Naik, Peter Sarkies, Eric Miska, Cei Abreu-Goodger, Christine E. Holt, Marie-Laure Baudet
During brain wiring, cue-induced axon behaviors such as directional steering and branching are aided by localized mRNA translation. Different guidance cues elicit translation of subsets of mRNAs that differentially regulate the cytoskeleton, yet little is understood about how specific mRNAs are selected for translation. MicroRNAs (miRNAs) are critical translational regulators that act through a sequence-specific mechanism. Here, we investigate the local role of miRNAs in mRNA-specific translation during pathfinding of Xenopus laevis retinal ganglion cell (RGC) axons. Among a rich repertoire of axonal miRNAs, miR-182 is identified as the most abundant. Loss of miR-182 causes RGC axon targeting defects in vivo and impairs Slit2-induced growth cone (GC) repulsion. We find that miR-182 targets cofilin-1 mRNA, silencing its translation, and Slit2 rapidly relieves the repression without causing miR-182 degradation. Our data support a model whereby miR-182 reversibly gates the selection of transcripts for fast translation depending on the extrinsic cue.
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Bellon et al. examine how specific mRNAs are selected for cue-induced local protein synthesis during axon guidance and find that miR-182 reversibly regulates the selective translation of a specific transcript to facilitate fast growth cone steering and axon guidance.http://ift.tt/2kMP1JJ
Mechanism of β-actin mRNA Recognition by ZBP1
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Giuseppe Nicastro, Adela M. Candel, Michael Uhl, Alain Oregioni, David Hollingworth, Rolf Backofen, Stephen R. Martin, Andres Ramos
Zipcode binding protein 1 (ZBP1) is an oncofetal RNA-binding protein that mediates the transport and local translation of β-actin mRNA by the KH3-KH4 di-domain, which is essential for neuronal development. The high-resolution structures of KH3-KH4 with their respective target sequences show that KH4 recognizes a non-canonical GGA sequence via an enlarged and dynamic hydrophobic groove, whereas KH3 binding to a core CA sequence occurs with low specificity. A data-informed kinetic simulation of the two-step binding reaction reveals that the overall reaction is driven by the second binding event and that the moderate affinities of the individual interactions favor RNA looping. Furthermore, the concentration of ZBP1, but not of the target RNA, modulates the interaction, which explains the functional significance of enhanced ZBP1 expression during embryonic development.
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The interaction of β-actin mRNA with the RNA-binding protein ZBP1 regulates mRNA transport and translation and is necessary for neuronal development. Using NMR and biophysics, Nicastro et al. have shown that the interaction is driven by RNA looping and regulated by the protein, rather than the RNA, concentration.http://ift.tt/2kMSU1x
Visualization of Chromatin Decompaction and Break Site Extrusion as Predicted by Statistical Polymer Modeling of Single-Locus Trajectories
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Assaf Amitai, Andrew Seeber, Susan M. Gasser, David Holcman
Chromatin moves with subdiffusive and spatially constrained dynamics within the cell nucleus. Here, we use single-locus tracking by time-lapse fluorescence microscopy to uncover information regarding the forces that influence chromatin movement following the induction of a persistent DNA double-strand break (DSB). Using improved time-lapse imaging regimens, we monitor trajectories of tagged DNA loci at a high temporal resolution, which allows us to extract biophysical parameters through robust statistical analysis. Polymer modeling based on these parameters predicts chromatin domain expansion near a DSB and damage extrusion from the domain. Both phenomena are confirmed by live imaging in budding yeast. Calculation of the anomalous exponent of locus movement allows us to differentiate forces imposed on the nucleus through the actin cytoskeleton from those that arise from INO80 remodeler-dependent changes in nucleosome organization. Our analytical approach can be applied to high-density single-locus trajectories obtained in any cell type.
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Amitai et al. present a robust analytical workflow for the analysis of single-particle trajectories. The extracted biophysical parameters allow accurate modeling of chromatin dynamics. The authors predict and show that, at double-strand breaks, chromatin decompacts and induces break relocation, while nuclear oscillation arises from cytoskeleton forces.http://ift.tt/2kMP1tj
Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Maria E. Gonzalez, Emily E. Martin, Talha Anwar, Caroline Arellano-Garcia, Natasha Medhora, Arjun Lama, Yu-Chih Chen, Kevin S. Tanager, Euisik Yoon, Kelley M. Kidwell, Chunxi Ge, Renny T. Franceschi, Celina G. Kleer
Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.
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By isolating human mesenchymal stem cells from breast cancer metastasis, Gonzalez et al. identify a pathway initiated by stromal DDR2, a unique receptor tyrosine kinase activated by fibrillar collagen, that mediates DDR2 activation in breast cancer cells and induces metastasis.http://ift.tt/2kMQ9NQ
Regulation of Serine-Threonine Kinase Akt Activation by NAD+-Dependent Deacetylase SIRT7
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Jia Yu, Bo Qin, Fengying Wu, Sisi Qin, Somaira Nowsheen, Shan Shan, Jacqueline Zayas, Huadong Pei, Zhenkun Lou, Liewei Wang
The Akt pathway is a central regulator that promotes cell survival in response to extracellular signals. Depletion of SIRT7, an NAD+-dependent deacetylase that is the least-studied sirtuin, is known to significantly increase Akt activity in mice through unknown mechanisms. In this study, we demonstrate that SIRT7 depletion in breast cancer cells results in Akt hyper-phosphorylation and increases cell survival following genotoxic stress. Mechanistically, SIRT7 specifically interacts with and deacetylates FKBP51 at residue lysines 28 and 155 (K28 and K155), resulting in enhanced interactions among FKBP51, Akt, and PHLPP, as well as Akt dephosphorylation. Mutating both lysines to arginines abolishes the effect of SIRT7 on Akt activity through FKBP51 deacetylation. Finally, energy stress strengthens SIRT7-mediated effects on Akt dephosphorylation through FKBP51 and thus sensitizes cancer cells to cytotoxic agents. These results reveal a direct role of SIRT7 in Akt regulation and raise the possibility of using the glucose analog 2-deoxy-D-glucose (2DG) as a chemo-sensitizing agent.
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Yu et al. reveal a direct role of SIRT7 in regulating Akt activation and affecting cancer cell responses to chemotherapies under energy stress.http://ift.tt/2kMIPkY
The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism
Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Jonathan Matalonga, Estibaliz Glaria, Mariana Bresque, Carlos Escande, José María Carbó, Kerstin Kiefer, Ruben Vicente, Theresa E. León, Susana Beceiro, Mónica Pascual-García, Joan Serret, Lucía Sanjurjo, Samantha Morón-Ros, Antoni Riera, Sonia Paytubi, Antonio Juarez, Fernando Sotillo, Lennart Lindbom, Carme Caelles, Maria-Rosa Sarrias, Jaime Sancho, Antonio Castrillo, Eduardo N. Chini, Annabel F. Valledor
Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.
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Macrophages constitute a preferential niche for intracellular bacteria to replicate. Matalonga et al. identified an antibacterial circuit mediated by pharmacological targeting of the liver X receptor (LXR) pathway that impacts intracellular NAD metabolism and interferes with macrophage cytoskeletal rearrangements subverted by invasive bacteria.http://ift.tt/2kMW9pR
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