bluuebunny/crossref_metadata_2025 huggingface dataset:
Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle
Authors: Grossi Mario , Bhattachariya Anirban , Nordström Ina , Turczyńska Karolina M. , Svensson Daniel , Albinsson Sebastian , Nilsson Bengt‐Olof , Hellstrand Per
Published: December 2016

Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage‐dependent toward voltage‐independent regulation of the intracellular calcium level, and inhibition of non‐voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium‐dependent signaling is the FAK‐family non‐receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium‐dependent manner. We used the Pyk2 inhibitor PF‐4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF‐BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long‐term (24–96 hr) treatment with PF‐4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L‐type calcium channel and large‐conductance calcium‐activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store‐operated calcium influx were reduced after Pyk2 inhibition of growth‐stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions.
Smoothened‐antagonists reverse homogentisic acid‐induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria
Authors: Gambassi Silvia , Geminiani Michela , Thorpe Stephen D. , Bernardini Giulia , Millucci Lia , Braconi Daniela , Orlandini Maurizio , Thompson Clare L. , Petricci Elena , Manetti Fabrizio , Taddei Maurizio , Knight Martin M. , Santucci Annalisa
Published: December 2016

Alkaptonuria (AKU) is an ultra‐rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignaling and Hedgehog signaling pathways. Hedgehog signaling has been demonstrated to be activated in osteoarthritis (OA) and to drive cartilage degeneration in vivo. The numerous similarities between OA and AKU suggest that primary cilia Hedgehog signaling may also be altered in AKU. Thus, we characterized an AKU cellular model in which healthy chondrocytes were treated with HGA (66 µM) to replicate AKU cartilage pathology. We investigated the degree of activation of the Hedgehog signaling pathway and how treatment with inhibitors of the receptor Smoothened (Smo) influenced Hedgehog activation and primary cilia structure. The results obtained in this work provide a further step in the comprehension of the pathophysiological features of AKU, suggesting a potential therapeutic approach to modulate AKU cartilage degradation processes through manipulation of the Hedgehog pathway.
Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling
Authors: Gerdøe‐Kristensen Stine , Lund Viktor K. , Wandall Hans H. , Kjaerulff Ole
Published: December 2016

Receptor tyrosine kinase (RTK) signaling controls key aspects of cellular differentiation, proliferation, survival, metabolism, and migration. Deregulated RTK signaling also underlies many cancers. Glycosphingolipids (GSL) are essential elements of the plasma membrane. By affecting clustering and activity of membrane receptors, GSL modulate signal transduction, including that mediated by the RTK. GSL are abundant in the nervous system, and glial development in Drosophila is emerging as a useful model for studying how GSL modulate RTK signaling. Drosophila has a simple GSL biosynthetic pathway, in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3‐kinase (PI3K). However, to what extent this effect involves changes in upstream signaling events is unresolved. We show here that glial overgrowth in egh is strongly linked to increased activation of Insulin and fibroblast growth factor receptors (FGFR). Glial hypertrophy is phenocopied when overexpressing gain‐of‐function mutants of the Drosophila insulin receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of insulin and fibroblast growth factor receptors in Drosophila glia.
Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End‐Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects
Authors: Dymond Angela W. , Martin Paul , So Karen , Huang Yifan , Severin Paul , Holmes Victoria , Mariani Gabriella , Marbury Thomas
Published: December 2016

Two phase I open‐label studies were conducted to investigate the pharmacokinetics (PK), safety, and tolerability of single oral doses of selumetinib in subjects with end‐stage renal disease (ESRD) undergoing hemodialysis and subjects with varying degrees of hepatic impairment; both studies included a matched control group comprised of healthy individuals. In the renal impairment study, subjects received single doses of selumetinib 50 mg; those with ESRD received selumetinib before and after dialysis (with a between‐treatment washout period of ≥7 days). In the hepatic impairment study, subjects received varying single doses of selumetinib (20‐50 mg) depending on liver dysfunction (mild, moderate, or severe as per Child‐Pugh classification). PK, safety, and tolerability data were collected from both studies. Overall, 24 subjects were included in the renal impairment study (ESRD, N = 12; healthy subjects, N = 12). Selumetinib exposure (AUC and Cmax) was not increased in the ESRD group vs healthy subjects. Selumetinib exposure was lower when selumetinib was dosed before vs after dialysis, although individual exposure was variable. Overall, 32 subjects were included in the hepatic impairment study (mild, moderate, and severe impairment, N = 8 per group; healthy subjects, N = 8). Generally, dose‐normalized total selumetinib exposure was increased by 25% to 59% in subjects with moderate and severe hepatic impairment compared with healthy subjects. Increasing Child‐Pugh score, decreasing serum albumin, and increasing prothrombin time correlated with increasing unbound selumetinib exposure. In both studies, selumetinib was well tolerated with no new safety concerns. These studies will inform dose adjustment considerations in patients.
Process flowsheet analysis of pervaporation‐based hybrid processes in the production of ethyl tert‐butyl ether
Authors: Norkobilov Adham , Gorri Daniel , Ortiz Inmaculada
Published: December 2016

BACKGROUND

The manufacturing process of ethyl tert‐butyl ether (ETBE) involves the separation of ETBE, mixed C4 hydrocarbons and unreacted ethanol. Unfortunately, the unreacted ethanol forms azeotropic mixtures with ETBE that are difficult to separate by distillation. One of the alternative methods to overcome this limitation is the application of hybrid distillation–pervaporation processes with alcohol‐selective membranes.

RESULTS

Simulation tasks were carried out with the process simulation software Aspen Plus and the results of alternative process flowsheets that result from the relative location of the separation technologies (for a target product purity) have been compared on the basis of the required membrane area and energy consumption. Thus, in the case study analyzed seven pervaporation modules located on a sidestream withdrawal, with a total membrane area of 210 m2, are required to obtain 6420 kg h−1 of ETBE with a purity of 95.2 wt%. The retentate stream is returned to the column while the permeate stream, with a high ethanol content, is recycled back to feed the reactors

CONCLUSION

Incorporating pervaporation modules in the process flowsheet for production of ETBE allows unloading of the main separation unit (debutanizer column), thereby reducing energy consumption and operating costs and increasing throughput. © 2016 Society of Chemical Industry
Regeneration of arsenic spent adsorbents by Fe/MgO nanoparticles
Authors: Simeonidis Konstantinos , Martinez‐Boubeta Carlos , Rivera-Gil Pilar , Ashraf Sumaira , Samaras Theodoros , Angelakeris Makis , Tresintsi Sofia , Mitrakas Manassis , Parak Wolfgang J , Monty Claude , Balcells Lluis
Published: December 2016

BACKGROUND

Over recent decades, there has been increasing global concern over public health impacts related to water pollution with arsenic. With the development of nanotechnology, nanomaterials are being proposed as alternative agents for water treatment. This study focuses on the use of core‐shell nanoparticles as secondary receptors able to operate under intense conditions and perform efficient yet environmentally friendly regeneration of conventional adsorbents.

RESULTS

Hybrid MgO‐coated Fe nanoparticles are proposed, optimized to achieve maximum arsenic uptake under a strong alkaline environment, such as the NaOH stream used to regenerate a typical oxy‐hydroxide adsorption column. The magnetic response of these nanocomposites enables their recovery and recirculation by means of an external magnetic field. A scalable laboratory continuous flow system was designed as a proof‐of‐concept to provide maximum efficiency of the recirculating nanoparticles, as well as complete reuse of the alkaline washing solution. A risk assessment scheme was conducted to evaluate the potential environmental impact of nanoparticle residues by testing the toxicity of arsenic‐loaded materials in RTgill‐W1 cells and their inertization into concrete building blocks.

CONCLUSION

The presented methodology illustrates a way to incorporate nanoparticles in water technology taking advantage of their surface activity and magnetic separation potential. © 2016 Society of Chemical Industry
Evaluation of neonatal brain myelination using the T1‐ and T2‐weighted MRI ratio
Authors: Soun Jennifer E. , Liu Michael Z. , Cauley Keith A. , Grinband Jack
Published: December 2016

Purpose

To validate the T1‐ and T2‐weighted (T1w/T2w) MRI ratio technique in evaluating myelin in the neonatal brain.

Materials and Methods

T1w and T2w MR images of 10 term neonates with normal‐appearing brain parenchyma were obtained from a single 1.5 Tesla MRI and retrospectively analyzed. T1w/T2w ratio images were created with a postprocessing pipeline and qualitatively compared with standard clinical sequences (T1w, T2w, and apparent diffusion coefficient [ADC]). Quantitative assessment was also performed to assess the ratio technique in detecting areas of known myelination (e.g., posterior limb of the internal capsule) and very low myelination (e.g., optic radiations) using linear regression analysis and the Michelson Contrast equation, a measure of luminance contrast intensity.

Results

The ratio image provided qualitative improvements in the ability to visualize regional variation in myelin content of neonates. Linear regression analysis demonstrated a significant inverse relationship between the ratio intensity values and ADC values in the posterior limb of the internal capsule and the optic radiations (R2 = 0.96 and P < 0.001). The Michelson Contrast equation showed that contrast differences between these two regions for the ratio images were 1.6 times higher than T1w, 2.6 times higher than T2w, and 1.8 times higher than ADC (all P < 0.001). Finally, the ratio improved visualization of the corticospinal tract, one of the earliest myelinated pathways.

Conclusion

The T1w/T2w ratio accentuates contrast between myelinated and less myelinated structures and may enhance our diagnostic ability to detect myelination patterns in the neonatal brain.

Level of Evidence: 2

Technical Efficacy: Stage2

J. MAGN. RESON. IMAGING 2017;46:690–696
A novel surrogate to identify anatomical changes during radiotherapy of head and neck cancer patients
Authors: Gros Sébastien A.A. , Xu William , Roeske John C. , Choi Mehe , Emami Bahman , Surucu Murat
Published: December 2016

Purpose

To develop a novel method to monitor external anatomical changes in head and neck cancer patients in order to triage possible adaptive radiotherapy needs.

Methods

The presented approach aims to provide information on internal anatomical changes based on variations observed in external anatomy. Setup Cone Beam Computed Tomography (CBCT) images are processed to produce an accurate external contour of the patient's skin. After registering the CBCTs to the reference planning CT, the external contours from each CBCT are transferred to the initial — first week — CBCT. Contour radii, defined as the distances between an external contour and the isocenter projection in each CBCT slice, are calculated for each scan over the full 360 degrees. The changes in external anatomy are then quantified by the difference in radial distance between the external contours of any secondary CBCT relative to the initial CBCT. Finally, the radial difference is displayed in cylindrical coordinates as a 2D intensity map to highlight regions of interests with significant changes. Weekly CBCT scans from 15 head and neck patients were retrospectively analyzed to demonstrate the utility of this approach as a proof of principle. External changes suggested by the 2D radial difference map of an example patient after 23 fractions were then correlated with the changes in the gross tumor volumes and organs at risks. The resulting dosimetric effects were evaluated. An interactive standalone software application has been developed to facilitate the generation and the interpretation of the 2D intensity map.

Results

The 2D radial difference maps provided qualitative and quantitative information, such as the location and the magnitude of external contour changes and the rate at which these deviations occur. Out of the 15 patients, 10 presented clear evidence of general external volume shrinkage due to weight loss, and nine patients had at least one site of local shrinkage. Only two patients showed no signs of anatomical change during their entire treatment course. For the example patient, the mean (±σ) radial difference was 6.7 (±3.0) mm for the left parotid and 7.3 (±2.5) mm for the right parotid. The mean dose to the left and right parotids increased from 20.1 Gy to 30 Gy and from 16.3 Gy to 29.6 Gy, respectively.

Conclusion

This novel method provides an efficient tool to visualize 3D external anatomical changes on a single 2D map. It quickly pinpoints the location of differences in anatomy during the course of radiotherapy, which can help physicians determine if a treatment plan needs to be adapted. The interactive graphic user interface developed in this study will be evaluated in an adaptive radiotherapy workflow for head and neck patients in a future prospective trial.
The relative accuracy of 4D dose accumulation for lung radiotherapy using rigid dose projection versus dose recalculation on every breathing phase
Authors: Valdes Gilmer , Lee Chul , Tenn Stephen , Lee Percy , Robinson Clifford , Iwamoto Keisuke , Low Daniel , Lamb James M.
Published: December 2016

Purpose

To investigate the accuracy of 4D dose accumulation using projection of dose calculated on the end‐exhalation, mid‐ventilation, or average intensity breathing phase CT scan, versus dose accumulation performed using full Monte Carlo dose recalculation on every breathing phase.

Methods

Radiotherapy plans for 10 patients with stage I–II lung cancer were analyzed. All patients had respiratory‐correlated computed tomography (4D‐CT) performed as part of an IRB‐approved research protocol. Stereotactic body radiotherapy (SBRT) plans were optimized using the dose calculated by a commercially available Monte Carlo algorithm on the end‐exhalation 4D‐CT phase. 4D dose accumulations using deformable registration were performed with a commercially available tool that projected the planned dose onto every breathing phase without recalculation, as well as with a Monte Carlo recalculation of the dose on all breathing phases. The 3D planned dose (3D‐EX), the 3D dose calculated on the average intensity image (3D‐AVE), and the 4D accumulations of the dose calculated on the end‐exhalation phase CT (4D‐PR‐EX), the mid‐ventilation phase CT (4D‐PR‐MID), and the average intensity image (4D‐PR‐AVE), respectively, were compared against the accumulation of the Monte Carlo dose recalculated on every phase. Plan evaluation metrics relating to target volumes and critical structures relevant for lung SBRT were analyzed.

Results

Plan evaluation metrics tabulated using 4D‐PR‐EX, 4D‐PR‐MID, and 4D‐PR‐AVE differed from those tabulated using Monte Carlo recalculation on every phase by an average of 0.14 ± 0.70 Gy, −0.11 ± 0.51 Gy, and 0.00 ± 0.62 Gy, respectively. Plan evaluation metrics calculated from 3D‐EX and 3D‐AVE were acceptably accurate for target volumes and most critical structures, however, deviations of between 8 and 13 Gy were observed for the proximal bronchial trees of three patients.

Conclusions

The accuracy of 4D dose accumulated by projecting the dose calculated on the end‐exhale, mid‐ventilation, and average intensity images has been presented for 10 lung cancer SRBT plans. These methods involving projection without recalculation may be sufficiently accurate compared to 4D dose accumulated from Monte Carlo recalculation on every phase, depending on institutional protocols. Projection of the dose calculated on the mid‐ventilation scan was found to be statistically significantly more accurate than projection of the dose calculated on end‐exhalation when considering target volume dose metrics. Use of 4D dose accumulation should be considered when evaluating normal tissue complication probabilities as well as in clinical situations where target volumes are directly inferior to mobile critical structures.
Nuclear paramagnetism‐induced MR frequency shift and its implications for MR‐based magnetic susceptibility measurement
Authors: Park Jinil , Lee Jeongtaek , Park Jang‐Yeon , Lee Seung‐Kyun
Published: December 2016

Purpose

To investigate the 1H spin contribution (0.004 parts per million (ppm)) to the water magnetic susceptibility and discuss its implications for high‐precision phase mapping and tissue susceptibility measurement.

Methods

Free induction decay (FID) signals were acquired at 3 Tesla (T) and 9.4T from thin square phantoms at a range of tip angles. The FID frequency shift was examined at a high resolution ( < 0.01 Hz) for different phantom orientations relative to the main magnetic field (B0). B0 maps on an axial and a coronal slice of a spherical phantom were obtained at 3T to examine the tip angle and orientation dependence at the 0.001 ppm level.

Results

A frequency shift of about 0.3 Hz was observed between tip angles of 10 ° and 90 ° when the thin phantom was normal to B0 at 3T, whereas the shift changed sign and was halved in magnitude when the phantom's face was parallel to B0. At 9.4T, the effect size increased proportionately. The orientation‐dependent frequency shift was also observed in the B0 map experiment. These observations agree with theoretical frequency shift due to longitudinal 1H spin polarization.

Conclusion

Magnetic susceptibility contribution from the nuclear paramagnetism should be taken into account in the interpretation of high‐precision phase and susceptibility mapping in MRI. Magn Reson Med 77:848–854, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Intelligent and automatic in vivo detection and quantification of transplanted cells in MRI
Authors: Afridi Muhammad Jamal , Ross Arun , Liu Xiaoming , Bennewitz Margaret F. , Shuboni Dorela D. , Shapiro Erik M.
Published: December 2016

Purpose

Magnetic resonance imaging (MRI)‐based cell tracking has emerged as a useful tool for identifying the location of transplanted cells, and even their migration. Magnetically labeled cells appear as dark contrast in T2*‐weighted MRI, with sensitivities of individual cells. One key hurdle to the widespread use of MRI‐based cell tracking is the inability to determine the number of transplanted cells based on this contrast feature. In the case of single cell detection, manual enumeration of spots in three‐dimensional (3D) MRI in principle is possible; however, it is a tedious and time‐consuming task that is prone to subjectivity and inaccuracy on a large scale. This research presents the first comprehensive study on how a computer‐based intelligent, automatic, and accurate cell quantification approach can be designed for spot detection in MRI scans.

Methods

Magnetically labeled mesenchymal stem cells (MSCs) were transplanted into rats using an intracardiac injection, accomplishing single cell seeding in the brain. T2*‐weighted MRI of these rat brains were performed where labeled MSCs appeared as spots. Using machine learning and computer vision paradigms, approaches were designed to systematically explore the possibility of automatic detection of these spots in MRI. Experiments were validated against known in vitro scenarios.

Results

Using the proposed deep convolutional neural network (CNN) architecture, an in vivo accuracy up to 97.3% and in vitro accuracy of up to 99.8% was achieved for automated spot detection in MRI data.

Conclusion

The proposed approach for automatic quantification of MRI‐based cell tracking will facilitate the use of MRI in large‐scale cell therapy studies. Magn Reson Med 78:1991–2002, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Robustness of spatio‐temporal regularization in perfusion MRI deconvolution: An application to acute ischemic stroke
Authors: Giacalone Mathilde , Frindel Carole , Robini Marc , Cervenansky Frédéric , Grenier Emmanuel , Rousseau David
Published: December 2016

Purpose

The robustness of a recently introduced globally convergent deconvolution algorithm with temporal and edge‐preserving spatial regularization for the deconvolution of dynamic susceptibility contrast perfusion magnetic resonance imaging is assessed in the context of ischemic stroke.

Theory and Methods

Ischemic tissues are not randomly distributed in the brain but form a spatially organized entity. The addition of a spatial regularization term allows to take into account this spatial organization contrarily to the sole temporal regularization approach which processes each voxel independently. The robustness of the spatial regularization in relation to shape variability, hemodynamic variability in tissues, noise in the magnetic resonance imaging apparatus, and uncertainty on the arterial input function selected for the deconvolution is addressed via an original in silico validation approach.

Results

The deconvolution algorithm proved robust to the different sources of variability, outperforming temporal Tikhonov regularization in most realistic conditions considered. The limiting factor is the proper estimation of the arterial input function.

Conclusion

This study quantified the robustness of a spatio‐temporal approach for dynamic susceptibility contrast‐magnetic resonance imaging deconvolution via a new simulator. This simulator, now accessible online, is of wide applicability for the validation of any deconvolution algorithm. Magn Reson Med 78:1981–1990, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Noninvasive measurement of pressure gradient across a coronary stenosis using phase contrast (PC)‐MRI: A feasibility study
Authors: Deng Zixin , Fan Zhaoyang , Lee Sang‐Eun , Nguyen Christopher , Xie Yibin , Pang Jianing , Bi Xiaoming , Yang Qi , Choi Byoung‐Wook , Kim Jung‐Sun , Berman Daniel , Chang Hyuk‐Jae , Li Debiao
Published: December 2016

Purpose

To investigate the feasibility of blood pressure difference measurement, ΔP, across the coronary artery using phase contrast (PC)‐MRI for potential noninvasive assessment of the functional significance of coronary artery stenosis.

Methods

Three‐directional velocities in the coronary arteries acquired using 2D‐PC‐MRI were used with the Navier‐Stokes equations to derive ΔP. Repeat phantom studies were performed to assess the reproducibility of flow velocity and ΔP. ΔP derived using PC‐MRI (ΔPMR) and that obtained using pressure transducer (ΔPPT) were compared. Reproducibility of coronary flow velocity was assessed in healthy controls (n = 11). Patients with suspected coronary artery disease (n = 6) were studied to evaluate the feasibility of ΔPMR measurement across a coronary stenosis.

Results

Phantom: Good overall reproducibility of flow velocity and ΔP measurements and excellent correlation (ΔPMR vs ΔPPT) was observed: intraclass correlation (ICC) of 0.95(Vz), 0.72(Vx), 0.73(Vy), and 0.87(ΔPMR) and R2 = 0.94, respectively. Human: Good reproducibility of coronary flow velocity was observed: ICC of 0.94/0.95(Vz), 0.76/0.74(Vx), and 0.80/0.77(Vy) at cardiac phase 1/2. Significant (p = 0.025) increase in ΔPMR was observed in patients (6.40 ± 4.43 mmHg) versus controls (0.70 ± 0.57 mmHg).

Conclusion

ΔPMR in the coronary arteries is feasible. Upon further validation using the invasive measure, ΔPMR has the potential for noninvasive assessment of coronary artery stenosis. Magn Reson Med 77:529–537, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Contrast mechanisms associated with neuromelanin‐MRI
Authors: Trujillo Paula , Summers Paul E. , Ferrari Emanuele , Zucca Fabio A. , Sturini Michela , Mainardi Luca T. , Cerutti Sergio , Smith Alex K. , Smith Seth A. , Zecca Luigi , Costa Antonella
Published: December 2016

Purpose

To investigate the physical mechanisms associated with the contrast observed in neuromelanin MRI.

Methods

Phantoms having different concentrations of synthetic melanins with different degrees of iron loading were examined on a 3 Tesla scanner using relaxometry and quantitative magnetization transfer (MT).

Results

Concentration‐dependent T1 and T2 shortening was most pronounced for the melanin pigment when combined with iron. Metal‐free melanin had a negligible effect on the magnetization transfer spectra. On the contrary, the presence of iron‐laden melanins resulted in a decreased magnetization transfer ratio. The presence of melanin or iron (or both) did not have a significant effect on the macromolecular content, represented by the pool size ratio.

Conclusion

The primary mechanism underlying contrast in neuromelanin‐MRI appears to be the T1 reduction associated with melanin‐iron complexes. The macromolecular content is not significantly influenced by the presence of melanin with or without iron, and thus the MT is not directly affected. However, as T1 plays a role in determining the MT‐weighted signal, the magnetization transfer ratio is reduced in the presence of melanin‐iron complexes. Magn Reson Med 78:1790–1800, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Multiparametric estimation of brain hemodynamics with MR fingerprinting ASL
Authors: Su Pan , Mao Deng , Liu Peiying , Li Yang , Pinho Marco C. , Welch Babu G. , Lu Hanzhang
Published: December 2016

Purpose

Assessment of brain hemodynamics without exogenous contrast agents is of increasing importance in clinical applications. This study aims to develop an MR perfusion technique that can provide noncontrast and multiparametric estimation of hemodynamic markers.

Methods

We devised an arterial spin labeling (ASL) method based on the principle of MR fingerprinting (MRF), referred to as MRF‐ASL. By taking advantage of the rich information contained in MRF sequence, up to seven hemodynamic parameters can be estimated concomitantly. Feasibility demonstration, flip angle optimization, comparison with Look‐Locker ASL, reproducibility test, sensitivity to hypercapnia challenge, and initial clinical application in an intracranial steno‐occlusive process, Moyamoya disease, were performed to evaluate this technique.

Results

Magnetic resonance fingerprinting ASL provided estimation of up to seven parameters, including
, tissue T1, cerebral blood flow (CBF), tissue bolus arrival time (BAT), pass‐through arterial BAT, pass‐through blood volume, and pass‐through blood travel time. Coefficients of variation of the estimated parameters ranged from 0.2 to 9.6%. Hypercapnia resulted in an increase in CBF by 57.7%, and a decrease in BAT by 13.7 and 24.8% in tissue and vessels, respectively. Patients with Moyamoya disease showed diminished CBF and lengthened BAT that could not be detected with regular ASL.

Conclusion

Magnetic resonance fingerprinting ASL is a promising technique for noncontrast, multiparametric perfusion assessment. Magn Reson Med 78:1812–1823, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
In situ catalyzed and reinforced high‐temperature flexible crosslinked ZnO nano‐whisker/polyarylene ether nitriles composite dielectric films
Authors: Yang Ruiqi , Xiao Qian , You Yong , Wei Renbo , Liu Xiaobo
Published: December 2016

Zinc oxide nano‐whiskers (ZnO‐nws) with the aspect ratio of about 30 are prepared via hydrothermal method and characterized by XRD and SEM. Then, the ZnO‐nws are doped into polyarylene ether nitriles terminated with phthalonitrile (PEN‐Ph) to fabricate the ZnO‐nws/PEN‐Ph crosslinked composite films. The crosslinking density, thermo‐stability, dielectric property, microstructure and mechanical property are investigated in detail. According to the DSC test, the ZnO‐nws can be served as catalyst for the crosslinking reaction of phthalonitrile. Under the same condition, the crosslinking density of the composites is determined by the weight content of ZnO‐nws, and is 5.45 × 10−2 mol/cm3 when 4 wt% of ZnO‐nws is incorporated. The TGA and DSC results show that the ZnO‐nws/PEN‐Ph crosslinked composite films are endowed with excellent thermo‐stability and operating temperature. With the ZnO‐nws incorporated, the dielectric constant of the composite is improved from 3.4 to 6.2 at 1 kHz when the ZnO‐nws weight content is 16 wt%. The mechanical property test shows that the tensile strength increases with the increasing weight content of ZnO‐nws. The cross‐sectional micromorphology of the composites is determined by SEM and it shows that the ZnO‐nws is uniformly dispersed in PEN‐Ph matrix. These results indicate that the ZnO‐nws act both as catalyst and reinforce element for PEN‐Ph to obtain high performance crosslinked composite films. POLYM. COMPOS., 39:2801–2811, 2018. © 2016 Society of Plastics Engineers
Encapsulation of imidazole with synthesized copolymers for latent curing of epoxy resin
Authors: Shin Young Jae , Shin Min Jae , Shin Jae Sup
Published: December 2016

Anisotropic conductive film (ACF) is an essential component in the manufacture of liquid crystal displays, and an imidazole–epoxy resin system that exhibits a latent behavior is generally used as an adhesive in the ACF. In this study, a new copolymer was synthesized using methacrylic acid and dodecyl methacrylate, and this copolymer was used to encapsulate an imidazole curing agent to endow the ACF with latent behavior. A spray‐drying method was used in the encapsulation process, and this encapsulated imidazole was mixed with epoxy resin to form an imidazole–epoxy resin system. A comparison with our previous results showed that a smaller amount of polymeric material could be used in the encapsulating process, and a superior latent behavior could be obtained. © 2016 Society of Chemical Industry
Synthesis and conjugation of a triiodohydroxylamine for the preparation of highly X‐ray opaque poly(ε‐caprolactone) materials
Authors: Van Horn Brooke A. , Davis Lundy L. , Nicolau Samantha E. , Burry Emma E. , Bailey Victoria O. , Guerra Fernanda D. , Alexis Frank , Whitehead Daniel C.
Published: December 2016

To address a need for highly X‐ray opaque biodegradable materials, a series of poly(ε‐caprolactone) derivatives were prepared using oxime post‐polymerization modification to conjugate two different iodinated hydroxylamines. These materials were synthesized with up to 32 wt. % iodine content and demonstrated improved X‐ray contrast relative to both the ketone precursors and previously reported monoiodinated materials. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 787–793
The prospective relationship between satisfaction with information and symptoms of depression and anxiety in breast cancer: A structural equation modeling analysis
Authors: Faller Hermann , Strahl André , Richard Matthias , Niehues Christiane , Meng Karin
Published: December 2016

Objective

Previous research has demonstrated associations between satisfaction with information and reduced emotional distress in cancer patients. However, as most studies were cross‐sectional, the direction of this relationship remained unclear. We therefore aimed to test whether information satisfaction predicted subsequent depression and anxiety levels, and, reciprocally, depression and anxiety levels predicted subsequent information satisfaction, thus clarifying the direction of impact.

Methods

We performed a secondary analysis of a prospective cohort study with 436 female breast cancer patients (mean age 51 years). We measured information satisfaction with 2 self‐developed items, symptoms of depression with the 2‐item Patient Heath Questionnaire and symptoms of anxiety with the 2‐item Generalized Anxiety Disorder Scale. We created 2 structural equation models, 1 for depression and 1 for anxiety, that examined the prediction of 1‐year depression (or anxiety) levels by baseline information satisfaction and, in the same model, 1‐year information satisfaction by baseline depression (or anxiety) levels (cross‐lagged panel analysis).

Results

Baseline information satisfaction predicted 1‐year levels of both depression (beta = −0.17, P < .01) and anxiety (beta = −0.13, P < .01), adjusting for the baseline scores of the outcome variables. Conversely, baseline levels of depression (beta = −0.12, P < .05) and anxiety (beta = −0.16, P < .01) predicted 1‐year information satisfaction, adjusting for its baseline score.

Conclusion

Our results suggest a bidirectional relationship between information satisfaction and symptoms of depression and anxiety. Thus, provision of information may reduce subsequent depression and anxiety, while reducing depression and anxiety levels may increase satisfaction with received information. Combining the provision of information with emotional support may be particularly beneficial.
Biomarker discovery by proteomics‐based approaches for early detection and personalized medicine in colorectal cancer
Authors: Corbo Claudia , Cevenini Armando , Salvatore Francesco
Published: December 2016

About one million people per year develop colorectal cancer (CRC) and approximately half of them die. The extent of the disease (i.e. local invasion at the time of diagnosis) is a key prognostic factor. The 5‐year survival rate is almost 90% in the case of delimited CRC and 10% in the case of metastasized CRC. Hence, one of the great challenges in the battle against CRC is to improve early diagnosis strategies. Large‐scale proteomic approaches are widely used in cancer research to search for novel biomarkers. Such biomarkers can help in improving the accuracy of the diagnosis and in the optimization of personalized therapy. Herein, we provide an overview of studies published in the last 5 years on CRC that led to the identification of protein biomarkers suitable for clinical application by using proteomic approaches. We discussed these findings according to biomarker application, including also the role of protein phosphorylation and cancer stem cells in biomarker discovery. Our review provides a cross section of scientific approaches and can furnish suggestions for future experimental strategies to be used as reference by scientists, clinicians and researchers interested in proteomics for biomarker discovery.
The long path towards implementation of clinical proteomics: Exemplified based on CKD273
Authors: Nkuipou‐Kenfack Esther , Zürbig Petra , Mischak Harald
Published: December 2016

Clinical proteomics aims at the development and the implementation of novel biomarkers that demonstrate a clear clinical benefit in the management of diseases. However, though the attention in the field is increasing and multiple articles on biomarker research are published, clinical implementation of these biomarkers is scarce. In this paper, we aim towards identifying the hurdles on the path towards implementation, and present one successful approach, based on capillary electrophoresis coupled with mass spectrometry. A panel of biomarkers identified and assessed using this approach, termed CKD273, has recently received a Letter‐of‐Support from the US‐Food and Drug Administration (FDA), and is now implemented in the (early) management of chronic kidney disease. Based on this experience in the process towards implementation of CKD273, issues associated with implementation and suggestions how to meet these challenges are given.
Novel product specificity toward erlose and panose exhibited by multisite engineered mutants of amylosucrase
Authors: Vergès Alizée , Cambon Emmanuelle , Barbe Sophie , Moulis Claire , Remaud‐Siméon Magali , André Isabelle
Published: December 2016

A computer‐aided engineering approach recently enabled to deeply reshape the active site of N. polysaccharea amylosucrase for recognition of non‐natural acceptor substrates. Libraries of variants were constructed and screened on sucrose allowing the identification of 17 mutants able to synthesize molecules from sole sucrose, which are not synthesized by the parental wild‐type enzyme. Three of the isolated mutants as well as the new products synthesized were characterized in details. Mutants contain between 7 and 11 mutations in the active site and the new molecules were identified as being a sucrose derivative, named erlose (α‐d‐glucopyranosyl‐(1→4)‐α‐d‐glucopyranosyl‐(1→2)‐β‐d‐Fructose), and a new malto‐oligosaccharide named panose (α‐d‐glucopyranosyl‐(1→6)‐α‐d‐glucopyranosyl‐(1→4)‐α‐d‐Glucose). These product specificities were never reported for none of the amylosucrases characterized to date, nor their engineered variants. Optimization of the production of these trisaccharides of potential interest as sweeteners or prebiotic molecules was carried out. Molecular modelling studies were also performed to shed some light on the molecular factors involved in the novel product specificities of these amylosucrase variants.
Structural analysis of oligomeric and protofibrillar Aβ amyloid pair structures considering F20L mutation effects using molecular dynamics simulations
Authors: Lee Myeongsang , Chang Hyun Joon , Baek Inchul , Na Sungsoo
Published: December 2016

Aβ amyloid proteins are involved in neuro‐degenerative diseases such as Alzheimer's, Parkinson's, and so forth. Because of its structurally stable feature under physiological conditions, Aβ amyloid protein disrupts the normal cell function. Because of these concerns, understanding the structural feature of Aβ amyloid protein in detail is crucial. There have been some efforts on lowering the structural stabilities of Aβ amyloid fibrils by decreasing the aromatic residues characteristic and hydrophobic effect. Yet, there is a lack of understanding of Aβ amyloid pair structures considering those effects. In this study, we provide the structural characteristics of wildtype (WT) and phenylalanine residue mutation to leucine (F20L) Aβ amyloid pair structures using molecular dynamics simulation in detail. We also considered the polymorphic feature of F20L and WT Aβ pair amyloids based on the facing β‐strand directions between the amyloid pairs. As a result, we were able to observe the varying effects of mutation, polymorphism, and protofibril lengths on the structural stability of pair amyloids. Furthermore, we have also found that opposite structural stability exists on a certain polymorphic Aβ pair amyloids depending on its oligomeric or protofibrillar state, which can be helpful for understanding the amyloid growth mechanism via repetitive fragmentation and elongation mechanism. Proteins 2017; 85:580–592. © 2016 Wiley Periodicals, Inc.
Why was resistance to shorter‐acting pre‐emergence herbicides slower to evolve?
Authors: Somerville Gayle J , Powles Stephen B , Walsh Michael J , Renton Michael
Published: December 2016

BACKGROUND

Across several agricultural systems the evolution of herbicide resistance has occurred more rapidly to post‐emergence than pre‐emergence herbicides; however, the reasons for this are not clear. We used a new simulation model to investigate whether interactions between differences in order of application and weed cohorts affected could explain this historically observed difference between the herbicide groups.

RESULTS

A 10 year delay in resistance evolution was predicted for a shorter‐acting residual pre‐emergence (cf. post‐emergence), when all other parameters were identical. Differences in order of application between pre‐ and post‐emergence herbicides had minimal effect on rates of resistance evolution when similar weed cohorts were affected.

CONCLUSION

This modelling suggested that the historically observed lower levels of resistance to pre‐emergence herbicides are most likely to be due to the smaller number of weed cohorts affected by many pre‐emergence herbicides. The lower number of weed cohorts affected by pre‐emergence herbicides necessitated the use of additional, effective control measures, thereby reducing resistance evolution. This study highlights the advantages of applying multiple control measures to each weed cohort. © 2016 Society of Chemical Industry
Interaction of transgenic and natural insect resistance mechanisms against Spodoptera littoralis in cotton
Authors: Hagenbucher Steffen , Eisenring Michael , Meissle Michael , Romeis Jörg
Published: December 2016

BACKGROUND

Insect‐resistant transgenic plants that express insecticidal Cry proteins from Bacillus thuringiensis (Bt) are grown on millions of hectares worldwide. While these proteins are efficient in controlling key lepidopteran pests, not all pests are affected and the development of resistance in target pests is always a concern. These shortcomings could be addressed by exploiting the natural insect resistance of cotton, especially inducible terpenoids such as gossypol.

RESULTS

To assess the potential of gossypol in supplementing Cry proteins as a resistance trait, we conducted a range of feeding assays with Spodoptera littoralis using artificial diet with defined amounts of Cry proteins and gossypol. This was supplemented by assays with leaf discs of induced and uninduced non‐Bt and Bt cotton (expressing Cry1Ac and Cry2Ab). Additionally, we quantified Cry proteins and cotton terpenoids to describe the interactions in planta. We found that gossypol can increase the efficacy of Cry proteins in artificial diet in an additive way. Induced production of gossypol and other cotton terpenoids, however, did not increase the efficacy of Bt cotton owing to the strong impact of the Bt trait.

CONCLUSION

Cotton terpenoids may offer the chance to supplement the insect resistance of Bt cotton in cases were the pest is not strongly affected by the Cry proteins. © 2016 Society of Chemical Industry
Target‐site mutations conferring resistance to glyphosate in feathertop Rhodes grass (Chloris virgata) populations in Australia
Authors: Ngo The D , Krishnan Mahima , Boutsalis Peter , Gill Gurjeet , Preston Christopher
Published: December 2016

BACKGROUND

Chloris virgata is a warm‐season, C4, annual grass weed affecting field crops in northern Australia that has become an emerging weed in southern Australia. Four populations with suspected resistance to glyphosate were collected in South Australia, Queensland and New South Wales, Australia, and compared with one susceptible (S) population to confirm glyphosate resistance and elucidate possible mechanisms of resistance.

RESULTS

Based on the rate of glyphosate required to kill 50% of treated plants (LD50), glyphosate resistance (GR) was confirmed in four populations of C. virgata (V12, V14.2, V14.16 and V15). GR plants were 2–9.7‐fold more resistant and accumulated less shikimate after glyphosate treatment than S plants. GR and S plants did not differ in glyphosate absorption and translocation. Target‐site EPSPS mutations corresponding to Pro‐106‐Leu (V14.2) and Pro‐106‐Ser (V15, V14.16 and V12) substitutions were found in GR populations. The population with Pro‐106‐Leu substitution was 2.9–4.9‐fold more resistant than the three other populations with Pro‐106‐Ser substitution.

CONCLUSION

This report confirms glyphosate resistance in C. virgata and shows that target‐site EPSPS mutations confer resistance to glyphosate in this species. The evolution of glyphosate resistance in C. virgata highlights the need to identify alternative control tactics. © 2016 Society of Chemical Industry
p16INK4a, a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV‐Infected Subjects
Authors: Dumond JB , Collins JW , Cottrell ML , Trezza CR , Prince HMA , Sykes C , Torrice C , White N , Malone S , Wang R , Patterson KB , Sharpless NE , Forrest A
Published: December 2016

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)‐infected patients. Ninety‐one HIV‐infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a, a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.