bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome‐wide mediation analysis of psychiatric and cognitive traits through imaging phenotypes
Authors: Bi Xuan , Yang Liuqing , Li Tengfei , Wang Baisong , Zhu Hongtu , Zhang Heping
Published: May 2017

Heritability is well documented for psychiatric disorders and cognitive abilities which are, however, complex, involving both genetic and environmental factors. Hence, it remains challenging to discover which and how genetic variations contribute to such complex traits. In this article, they propose to use mediation analysis to bridge this gap, where neuroimaging phenotypes were utilized as intermediate variables. The Philadelphia Neurodevelopmental Cohort was investigated using genome‐wide association studies (GWAS) and mediation analyses. Specifically, 951 participants were included with age ranging from 8 to 21 years. Two hundred and four neuroimaging measures were extracted from structural magnetic resonance imaging scans. GWAS were conducted for each measure to evaluate the SNP‐based heritability. Furthermore, mediation analyses were employed to understand the mechanisms in which genetic variants have influence on pathological behaviors implicitly through neuroimaging phenotypes, and identified SNPs that would not be detected otherwise. Our analyses found that rs10494561, located in the intron region within NMNAT2, was associated with the severity of the prodromal symptoms of psychosis implicitly, mediated through the volume of the left hemisphere of the superior frontal region (
). The gene NMNAT2 is known to be associated with brainstem degeneration, and produce cytoplasmic enzyme which is mainly expressed in the brain. Another SNP rs2285351 was found in the intron region of gene IFT122 which may be potentially associated with human spatial orientation ability through the area of the left hemisphere of the isthmuscingulate region (
). Hum Brain Mapp 38:4088–4097, 2017. © 2017 Wiley Periodicals, Inc.
CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers
Authors: Vedeld Hege Marie , Merok Marianne , Jeanmougin Marine , Danielsen Stine A. , Honne Hilde , Presthus Gro Kummeneje , Svindland Aud , Sjo Ole H. , Hektoen Merete , Eknæs Mette , Nesbakken Arild , Lothe Ragnhild A. , Lind Guro E.
Published: May 2017

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5‐markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni‐ and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (<60, 60‐74, ≥75 years). Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31‐2.63] and 1.89 [1.34‐2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P < 0.001), and MSS BRAF mutated tumors (P < 0.001), a finding that persisted in patients with stage II, III or IV disease, and that remained significant in multivariate analysis (P < 0.01). Consistent results were found for all three age groups. To conclude, CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors.
Galectin‐1 promotes an M2 macrophage response to polydioxanone scaffolds
Authors: Abebayehu Daniel , Spence Andrew , Boyan Barbara D. , Schwartz Zvi , Ryan John J. , McClure Michael J.
Published: May 2017

Regulating soft tissue repair to prevent fibrosis and promote regeneration is central to creating a microenvironment conducive to soft tissue development. Macrophages play an important role in this process. The macrophage response can be modulated using biomaterials, altering cytokine and growth factor secretion to promote regeneration. Electrospun polydioxanone (PDO) fiber scaffolds promoted an M2 phenotype when macrophages were cultured on large diameter, highly porous scaffolds, but an M1 phenotype on smaller diameter fibers. In this study, we investigated whether incorporation of galectin‐1, an immunosuppressive protein that enhances muscle regeneration, could promote the M2 response. Galectin‐1 was incorporated into large and small fiber PDO scaffolds during electrospinning. Galectin‐1 incorporation increased arginase‐1 and reduced iNOS and IL‐6 production in mouse bone‐marrow derived macrophages compared with PDO alone for both scaffold types. Inhibition of ERK mitogen‐activated protein kinase did not alter galectin‐1 effects on arginase‐1 and iNOS expression, but reversed IL‐6 suppression, indicating that IL‐6 is mediated by a different mechanism. Our results suggest that galectin‐1 can be used to modulate macrophage commitment to a pro‐regenerative M2 phenotype, which may positively impact tissue regeneration when using small diameter PDO scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2562–2571, 2017.
Mechanical properties, structure, bioadhesion, and biocompatibility of pectin hydrogels
Authors: Markov Pavel A. , Krachkovsky Nikita S. , Durnev Eugene A. , Martinson Ekaterina A. , Litvinets Sergey G. , Popov Sergey V.
Published: May 2017

The surface structure, biocompatibility, textural, and adhesive properties of calcium hydrogels derived from 1, 2, and 4% solutions of apple pectin were examined in this study. An increase in the pectin concentration in hydrogels was shown to improve their stability toward elastic and plastic deformation. The elasticity of pectin hydrogels, measured as Young's modulus, ranged from 6 to 100 kPa. The mechanical properties of the pectin hydrogels were shown to correspond to those of soft tissues. The characterization of surface roughness in terms of the roughness profile (Ra) and the root‐mean‐square deviation of the roughness profile (Rq) indicated an increased roughness profile for hydrogels depending on their pectin concentration. The adhesion of AU2% and AU4% hydrogels to the serosa abdominal wall, liver, and colon was higher than that of the AU1% hydrogel. The adhesion of macrophages and the non‐specific adsorption of blood plasma proteins were found to increase as the pectin concentration in the hydrogels increased. The rate of degradation of all hydrogels was higher in phosphate buffered saline (PBS) than that in DMEM and a fibroblast cell monolayer. The pectin hydrogel was also found to have a low cytotoxicity. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2572–2581, 2017.
Engineering muscle cell alignment through 3D bioprinting
Authors: Mozetic Pamela , Giannitelli Sara Maria , Gori Manuele , Trombetta Marcella , Rainer Alberto
Published: May 2017

Processing of hydrogels represents a main challenge for the prospective application of additive manufacturing (AM) to soft tissue engineering. Furthermore, direct manufacturing of tissue precursors with a cell density similar to native tissues has the potential to overcome the extensive in vitro culture required for conventional cell‐seeded scaffolds seeking to fabricate constructs with tailored structural and functional properties. In this work, we present a simple AM methodology that exploits the thermoresponsive behavior of a block copolymer (Pluronic®) as a means to obtain good shape retention at physiological conditions and to induce cellular alignment. Pluronic/alginate blends have been investigated as a model system for the processing of C2C12 murine myoblast cell line. Interestingly, C2C12 cell model demonstrated cell alignment along the deposition direction, potentially representing a new avenue to tailor the resulting cell histoarchitecture during AM process. Furthermore, the fabricated constructs exhibited high cell viability, as well as a significantly improved expression of myogenic genes vs. conventional 2D cultures. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2582–2588, 2017.
Population Pharmacokinetics and Exposure Response Assessment of CC‐292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia
Authors: Li Yan , Ramírez‐Valle Francisco , Xue Yongjun , Ventura Judith I. , Gouedard Olivier , Mei Jay , Takeshita Kenichi , Palmisano Maria , Zhou Simon
Published: May 2017

CC‐292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B‐cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC‐292 and assess the influence of demographics and disease‐related covariates on CC‐292 exposure and to assess the exposure‐response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2‐compartment base model conducted in NONMEM. Categorical exposure‐response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC‐292 pharmacokinetic disposition is similar between healthy subjects and patients. CC‐292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC‐292, clearance from blood occurs faster than distribution into deep tissues and organs. CC‐292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure‐response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice‐daily dose regimen showed higher overall response rate as compared to once‐daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases.
Decomposing Weighted Graphs
Authors: Ban Amir
Published: May 2017

We solve the following problem: Can an undirected weighted graph G be partitioned into two nonempty induced subgraphs satisfying minimum constraints for the sum of edge weights at vertices of each subgraph? We show that this is possible for all constraints satisfying , for every vertex x, where are, respectively, the sum and maximum of incident edge weights.
Graph properties, graph limits, and entropy
Authors: Hatami Hamed , Janson Svante , Szegedy Balázs
Published: May 2017

We study the relation between the growth rate of a graph property and the entropy of the graph limits that arise from graphs with that property. In particular, for hereditary classes we obtain a new description of the coloring number, which by well‐known results describes the rate of growth. We study also random graphs and their entropies. We show, for example, that if a hereditary property has a unique limiting graphon with maximal entropy, then a random graph with this property, selected uniformly at random from all such graphs with a given order, converges to this maximizing graphon as the order tends to infinity.
Exponentially many 4‐list‐colorings of triangle‐free graphs on surfaces
Authors: Kelly Tom , Postle Luke
Published: May 2017

Thomassen proved that every planar graph G on n vertices has at least distinct L‐colorings if L is a 5‐list‐assignment for G and at least distinct L‐colorings if L is a 3‐list‐assignment for G and G has girth at least five. Postle and Thomas proved that if G is a graph on n vertices embedded on a surface Σ of genus g, then there exist constants such that if G has an L‐coloring, then G has at least distinct L‐colorings if L is a 5‐list‐assignment for G or if L is a 3‐list‐assignment for G and G has girth at least five. More generally, they proved that there exist constants such that if G is a graph on n vertices embedded in a surface Σ of fixed genus g, H is a proper subgraph of G, and ϕ is an L‐coloring of H that extends to an L‐coloring of G, then ϕ extends to at least distinct L‐colorings of G if L is a 5‐list‐assignment or if L is a 3‐list‐assignment and G has girth at least five. We prove the same result if G is triangle‐free and L is a 4‐list‐assignment of G, where , and .
Mild cognitive impairment and structural brain abnormalities in a sexagenarian with a history of childhood traumatic brain injury
Authors: Van Horn John Darrell , Irimia Andrei , Torgerson Carinna M. , Bhattrai Avnish , Jacokes Zachary , Vespa Paul M.
Published: May 2017

In this report, we present a case study involving an older, female patient with a history of pediatric traumatic brain injury (TBI). Magnetic resonance imaging and diffusion tensor imaging volumes were acquired from the volunteer in question, her brain volumetrics and morphometrics were extracted, and these were then systematically compared against corresponding metrics obtained from a large sample of older healthy control (HC) subjects as well as from subjects in various stages of mild cognitive impairment (MCI) and Alzheimer disease (AD). Our analyses find the patient's brain morphometry and connectivity most similar to those of patients classified as having early‐onset MCI, in contrast to HC, late MCI, and AD samples. Our examination will be of particular interest to those interested in assessing the clinical course in older patients having suffered TBI earlier in life, in contradistinction to those who experience incidents of head injury during aging.
Comparison of 2 versus 3 dimensional fracture mapping strategies for 3 dimensional computerized tomography reconstructions of scapula neck and body fractures
Authors: Dugarte Anthony J. , Tkany Luisa , Schroder Lisa K. , Petersik Andreas , Cole Peter A.
Published: May 2017

Fracture mapping has been used in the understanding of injury patterns in different bones. To our knowledge, there are no applications of this technique using three‐dimensional (3D) morphologic fracture characteristics. Previously, scapula fractures were mapped by transferring information from 3D computed tomography to a two‐dimensional (2D) template. Cole et al. determined that 3D Computerized Tomography (CT) scans were more reliable compared to plain radiographs in terms of scapular angulation, translation, and glenopolar angle measurements. Thus, we hypothesized that if there is a difference between fracture lines drawn in 3D and in 2D, then the 3D mapping would yield more accurate fracture patterns. We completed a retrospective, comparative study (evidence level III) utilizing CT imaging from a single center scapular registry. We studied ten patients with scapula fractures in whom bilateral CT scans were obtained. Fractures were mapped both two and three‐dimensionally, and we measured deviations between the fracture lines that were drawn with each approach. The measured deviations ranged from 10.4 mm to 28.0 mm when comparing 2D versus 3D techniques, with the mean deviation being 4.0 mm and 10.4 mm, respectively. Half of the 2D renderings possessed hidden fracture lines that were later revealed on 3D imaging. Three‐dimensional renderings were more accurate when compared to 2D fracture mapping methods. This more accurate technique will allow for better understanding of 3D morphology and provide a basis for future fracture mapping in any bone. Accurate mapping is important because surgical approach, reduction, fixation, and implant design and selection are based on fracture patterns. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:265–271, 2018.
Exoanal Imaging of the Anal Sphincters
Authors: Dietz Hans Peter
Published: May 2017

Since its introduction in the early 1990s, endoanal sonography has become the mainstay of morphologic assessment of the anal canal and sphincter, especially for obstetric anal sphincter trauma. Lack of availability of suitable systems and the invasive nature of the method have limited uptake and clinical utility. More recently, exoanal or transperineal/translabial tomographic imaging has been developed as a noninvasive alternative. This pictorial overview aims to introduce the reader to this new diagnostic modality and to demonstrate common findings in asymptomatic and symptomatic women.
Longest sage‐grouse migratory behavior sustained by intact pathways
Authors: Newton Rebecca E. , Tack Jason D. , Carlson John C. , Matchett Marc R. , Fargey Pat J. , Naugle David E.
Published: May 2017

Expanding human footprints across the globe are affecting animal migrations by altering their use of traditional routes and exposing them to increased costs of travel. Sustaining migratory behavior among populations requires knowledge of animal movement and space use during this critical life stage. We studied the migratory movements in a population of greater sage‐grouse (Centrocercus urophasianus), an imperiled species endemic to the North American sagebrush steppe, with the longest‐known obligate and annual migration for a grouse: a 240‐km journey between Saskatchewan, Canada, and north central Montana, USA. Remote tracking revealed that stepping‐stone behavior in sage‐grouse is analogous to that of migratory big game populations, which frequent stopover sites along varied and individual routes. Within migratory routes, sage‐grouse chose pathways with gently rolling grasslands and sagebrush flats. Sage‐grouse avoided cropland, making punctuated movements across a 6‐km river valley dominated by cropland and trees. During autumn migration (Oct–Nov), individuals typically spent a day at an average of 9 different stopovers while traveling 41–126 km in 14 days. Sage‐grouse were faithful to winter ranges and timing of autumn migration but demonstrated adaptive behavior in response to heavy snowfalls with no effect on survival. Birds made a mass exodus north in spring (Mar–Apr) to their respective breeding ranges, traveling up to 160 km in 18 days. Migratory pathways were stitched together by an array of public and private lands, with large and intact landscapes composed of native vegetation forming the common thread. Conservation easements and public lands policy that preclude temperate grasslands from being fragmented will be critical in maintaining the largest migratory event observed among gallinaceous species. © 2017 The Wildlife Society.
Cell line dependent expression of EpCAM influences the detection of circulating tumor cells with CellSearch
Authors: Lindgren Gustaf , Wennerberg Johan , Ekblad Lars
Published: May 2017

Objectives

The existence of circulating tumor cells has emerged as an important factor for prognosis and survival. The CellSearch method is the only circulating tumor cell detection method approved by the US Food and Drug Administration for clinical use. It relies on the detection of EpCAM (epithelial cell adhesion molecule) and is approved for colon cancer, breast cancer and prostate cancer. We now investigated whether CellSearch can be used to quantify circulating tumor cells in head and neck squamous cell cancer.

Study Design and Methods

In this study, we investigated the expression of EpCAM in 12 head and neck squamous cell cancer cell lines using Western blot and how this affected their detectability with CellSearch in peripheral blood.

Results

We found a great variation in the expression of EpCAM between our head and neck squamous cell cancer cell lines. This was accompanied by variations in counting efficiency.

Conclusion

We suggest that for reliable quantification of circulating tumor cells in blood from patients with head and neck squamous cell cancer cell, an epitope independent method is preferable.

Level of Evidence

NA
Large differences between carbon and nutrient loss rates along the land to ocean aquatic continuum—implications for energy:nutrient ratios at downstream sites
Authors: Weyhenmeyer Gesa A. , Conley Daniel J.
Published: May 2017

The balance between the availability of energy and nutrients is decisive for the growth and survival of organisms. Here, we evaluated how energy, in this study expressed as total carbon (TC), is lost along the land to ocean aquatic continuum (LOAC) in relation to nutrients, i.e., total phosphorus (TP), total nitrogen (TN), total iron (TFe), and dissolved silica (DSi). For the evaluation, we used data from 4774 lakes, 149 streams, and 52 river mouths from the boreal region. We found that the loss of all chemical variables followed a first order decay function along the LOAC with shortest half‐lives for TFe and DSi (410 d and 568 d, respectively). The half‐life of TC was more than twice as long as for TFe and DSi, resulting in rapidly increasing TC:TFe and TC:DSi ratios along the LOAC. In contrast, TC:TP and TC:TN ratios decreased along the LOAC. The TC and TFe concentration declines along the LOAC were quantitatively similar to the TC and TFe concentration declines from winter to summer, indicating that similar drivers are responsible for spatial and seasonal TC and TFe losses in inland waters. We conclude that the energy:nutrient ratio rapidly changes along the LOAC with an increasing surplus of energy in relation to TFe and DSi the longer water stays in the landscape. These findings have implications for the growth of aquatic organisms along the LOAC, where organisms are likely to become increasingly iron and silica limited with increasing water retention in the landscape.
High‐speed optical imaging of liquid film flow and liquid macro‐slip over free surfaces with different surface energies
Authors: Polajnar M. , Bizjan B. , Širok B. , Kalin M.
Published: May 2017

High‐speed optical imaging is introduced as a visualization method to investigate the film‐flow properties of liquids with different surface tensions and viscosities (water, poly‐alpha‐olefin oil, and glycerol) over free rotating surfaces with different surface energies and polarities (steel, and two different diamond‐like‐carbon ‐ DLC coatings, i.e. DLC, and F‐DLC). It was found that the polar surface energy strongly influences the structural dynamics of the liquid film's flow and the film's slip. Namely, a decrease in the polar surface energy results in a less stable film with de‐wetting areas and breakups into streams, as well as in a larger amount of film slip, which was most clearly expressed by the F‐DLC. It was also found that the combination of a high surface tension and a low viscosity provides the largest amount of liquid slip, with the most obvious breakup of the liquid film being observed with water, which clearly exhibits these properties.
Application of Bottlebrush Block Copolymers as Photonic Crystals
Authors: Liberman‐Martin Allegra L. , Chu Crystal K. , Grubbs Robert H.
Published: May 2017

Brush block copolymers are a class of comb polymers that feature polymeric side chains densely grafted to a linear backbone. These polymers display interesting properties due to their dense functionality, low entanglement, and ability to rapidly self‐assemble to highly ordered nanostructures. The ability to prepare brush polymers with precise structures has been enabled by advancements in controlled polymerization techniques. This Feature Article highlights the development of brush block copolymers as photonic crystals that can reflect visible to near‐infrared wavelengths of light. Fabrication of these materials relies on polymer self‐assembly processes to achieve nanoscale ordering, which allows for the rapid preparation of photonic crystals from common organic chemical feedstocks. The characteristic physical properties of brush block copolymers are discussed, along with methods for their preparation. Strategies to induce self‐assembly at ambient temperatures and the use of blending techniques to tune photonic properties are emphasized.

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Intrinsic functional connectivity alterations in progressive supranuclear palsy: Differential effects in frontal cortex, motor, and midbrain networks
Authors: Rosskopf Johannes , Gorges Martin , Müller Hans‐Peter , Lulé Dorothée , Uttner Ingo , Ludolph Albert C. , Pinkhardt Elmar , Juengling Freimut D. , Kassubek Jan
Published: May 2017

Background:

The topography of functional network changes in progressive supranuclear palsy can be mapped by intrinsic functional connectivity MRI. The objective of this study was to study functional connectivity and its clinical and behavioral correlates in dedicated networks comprising the cognition‐related default mode and the motor and midbrain functional networks in patients with PSP.

Methods:

Whole‐brain‐based “resting‐state” functional MRI and high‐resolution T1‐weighted magnetic resonance imaging data together with neuropsychological and video‐oculographic data from 34 PSP patients (22 with Richardson subtype and 12 with parkinsonian subtype) and 35 matched healthy controls were subjected to network‐based functional connectivity and voxel‐based morphometry analysis.

Results:

After correction for global patterns of brain atrophy, the group comparison between PSP patients and controls revealed significantly decreased functional connectivity (P < 0.05, corrected) in the prefrontal cortex, which was significantly correlated with cognitive performance (P = 0.006). Of note, midbrain network connectivity in PSP patients showed increased connectivity with the thalamus, on the one hand, whereas, on the other hand, lower functional connectivity within the midbrain was significantly correlated with vertical gaze impairment, as quantified by video‐oculography (P = 0.004). PSP Richardson subtype showed significantly increased functional motor network connectivity with the medial prefrontal gyrus.

Conclusions:

PSP‐associated neurodegeneration was attributed to both decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (ie, dementia severity and gaze palsy), whereas the pattern of increased functional connectivity may be a potential adaptive mechanism. © 2017 International Parkinson and Movement Disorder Society
Improved image quality and reduced power deposition in the spine at 3 T using extremely high permittivity materials
Authors: Koolstra Kirsten , Börnert Peter , Brink Wyger , Webb Andrew
Published: May 2017

Purpose

To explore the effect of using extremely high permittivity (εr∼1,000) materials on image quality and power requirements of spine imaging at 3 T.

Theory and Methods

A linear array of high permittivity dielectric blocks made of lead zirconate titanate (PZT) was designed and characterized by electromagnetic simulations and experiments. Their effect on the transmit efficiency, receive sensitivity, power deposition, and diagnostic image quality was analyzed in vivo in 10 healthy volunteers.

Results

Simulation results showed that for quadrature mode excitation, the PZT blocks improve the transmit efficiency by 75% while reducing the maximum 10g average specific absorption rate (SAR10) by 20%. In vivo experiments in 10 healthy volunteers showed statistically significant improvements for the transmit efficiency, and image quality. Compared to active radiofrequency shimming, image quality was similar, but the required system input power was significantly lower for quadrature excitation using the PZT blocks.

Conclusion

For single‐channel transmit systems, using high permittivity PZT blocks offer a way to improve transmit efficiency and image quality in the spine. Results show that the effect, and therefore optimal design, is body mass index and sex specific. Magn Reson Med 79:1192–1199, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Single‐commodity stochastic network design under demand and topological uncertainties with insufficient data
Authors: Shen Siqian , You Mingdi , Ma Yintai
Published: May 2017

Stochastic network design is fundamental to transportation and logistic problems in practice, yet faces new modeling and computational challenges resulted from heterogeneous sources of uncertainties and their unknown distributions given limited data. In this article, we design arcs in a network to optimize the cost of single‐commodity flows under random demand and arc disruptions. We minimize the network design cost plus cost associated with network performance under uncertainty evaluated by two schemes. The first scheme restricts demand and arc capacities in budgeted uncertainty sets and minimizes the worst‐case cost of supply generation and network flows for any possible realizations. The second scheme generates a finite set of samples from statistical information (e.g., moments) of data and minimizes the expected cost of supplies and flows, for which we bound the worst‐case cost using budgeted uncertainty sets. We develop cutting‐plane algorithms for solving the mixed‐integer nonlinear programming reformulations of the problem under the two schemes. We compare the computational efficacy of different approaches and analyze the results by testing diverse instances of random and real‐world networks. © 2017 Wiley Periodicals, Inc. Naval Research Logistics 64: 154–173, 2017
PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS
Authors: Almeida Gilberto S. , Bawn Carlo M. , Galler Martin , Wilson Ian , Thomas Huw D. , Kyle Suzanne , Curtin Nicola J. , Newell David R. , Maxwell Ross J.
Published: May 2017

Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (1H‐MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD+) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild‐type (WT) and PARP1 knock‐out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. 1H‐MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD+ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD+ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD+ levels in the temozolomide‐treated group. The combination of rucaparib and temozolomide did not prevent the NAD+ depletion caused by temozolomide treatment. The 1H‐MRS results show that NAD+ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD+ would be valuable.
Chemical‐exchange‐sensitive MRI of amide, amine and NOE at 9.4 T versus 15.2 T
Authors: Chung Julius Juhyun , Choi Wonmin , Jin Tao , Lee Jung Hee , Kim Seong‐Gi
Published: May 2017

Chemical exchange (CE)‐sensitive MRI benefits greatly from stronger magnetic fields; however, field effects on CE‐sensitive imaging have not yet been studied well in vivo. We have compared CE‐sensitive Z‐spectra and maps obtained at the fields of 9.4 T and 15.2 T in phantoms and rats with off‐resonance chemical‐exchange‐sensitive spin lock (CESL), which is similar to conventional chemical exchange saturation transfer. At higher fields, the background peak at water resonance has less spread and the exchange rate relative to chemical shift decreases, thus CESL intensity is dependent on B0. For the in vivo amide and nuclear Overhauser enhancement (NOE) composite resonances of rat brains, intensities were similar for both magnetic fields, but effective amide proton transfer and NOE values obtained with three‐point quantification or a curve fitting method were larger at 15.2 T due to the reduced spread of attenuation at the direct water resonance. When using intermediate exchange‐sensitive irradiation parameters, the amine proton signal was 65% higher at 15.2 T than at 9.4 T due to a reduced ratio of exchange rate to chemical shift. In summary, increasing magnetic field provides enhancements to CE‐sensitive signals in the intermediate exchange regime and reduces contamination from background signals in the slow exchange regime. Consequently, ultrahigh magnetic field is advantageous for CE‐sensitive MRI, especially for amine and hydroxyl protons.
White matter biomarkers from fast protocols using axially symmetric diffusion kurtosis imaging
Authors: Hansen Brian , Khan Ahmad R. , Shemesh Noam , Lund Torben E. , Sangill Ryan , Eskildsen Simon F. , Østergaard Leif , Jespersen Sune N.
Published: May 2017

White matter tract integrity (WMTI) can characterize brain microstructure in areas with highly aligned fiber bundles. Several WMTI biomarkers have now been validated against microscopy and provided promising results in studies of brain development and aging, as well as in a number of brain disorders. Currently, WMTI is mostly used in dedicated animal studies and clinical studies of slowly progressing diseases, and has not yet emerged as a routine clinical tool. To this end, a less data intensive experimental method would be beneficial by enabling high resolution validation studies, and ease clinical applications by speeding up data acquisition compared with typical diffusion kurtosis imaging (DKI) protocols utilized as part of WMTI imaging.

Here, we evaluate WMTI based on recently introduced axially symmetric DKI, which has lower data demand than conventional DKI. We compare WMTI parameters derived from conventional DKI with those calculated analytically from axially symmetric DKI. We employ numerical simulations, as well as data from fixed rat spinal cord (one sample) and in vivo human (three subjects) and rat brain (four animals). Our analysis shows that analytical WMTI based on axially symmetric DKI with sparse data sets (19 images) produces WMTI metrics that correlate strongly with estimates based on traditional DKI data sets (60 images or more). We demonstrate the preclinical potential of the proposed WMTI technique in in vivo rat brain (300 μm isotropic resolution with whole brain coverage in a 1 h acquisition). WMTI parameter estimates are subject to a duality leading to two solution branches dependent on a sign choice, which is currently debated. Results from both of these branches are presented and discussed throughout our analysis. The proposed fast WMTI approach may be useful for preclinical research and e.g. clinical evaluation of patients with traumatic white matter injuries or symptoms of neurovascular or neuroinflammatory disorders.
Thermal and Sensitivity Study of Dihydroxyl Ammonium 5,5′‐Bistetrazole‐1,1′‐diolate (TKX‐50)‐based Melt Cast Explosive Formulations
Authors: Badgujar Dilip , Talawar Mahadev
Published: May 2017

Dihydroxyl ammonium 5,5′‐bistetrazole‐1,1′‐diolate (TKX‐50) is a promising energetic material with predicted performance similar to RDX as well as to CL‐20. In the present study, TKX‐50 was evaluated as a possible replacement for RDX in TNT‐based, aluminized as well as non‐aluminized melt cast formulations. Thermal analysis reveals the compatibility of TKX‐50 with benchmark explosives like RDX and TNT in explosive formulations. This paper describes the thermal and sensitivity study of TKX‐50 with RDX and TNT‐based melt cast explosives. The result indicated that TKX‐50 can be effectively used as a RDX replacement in melt cast explosive formulations. TKX‐50/TNT‐based aluminized composition shows more thermal stability than RDX/TNT based composition, which clearly indicated the usefulness of TKX‐50 in melt cast explosive formulations.
The structural flexibility of the human copper chaperone Atox1: Insights from combined pulsed EPR studies and computations
Authors: Levy Ariel R. , Turgeman Meital , Gevorkyan‐Aiapetov Lada , Ruthstein Sharon
Published: May 2017

Metallochaperones are responsible for shuttling metal ions to target proteins. Thus, a metallochaperone's structure must be sufficiently flexible both to hold onto its ion while traversing the cytoplasm and to transfer the ion to or from a partner protein. Here, we sought to shed light on the structure of Atox1, a metallochaperone involved in the human copper regulation system. Atox1 shuttles copper ions from the main copper transporter, Ctr1, to the ATP7b transporter in the Golgi apparatus. Conventional biophysical tools such as X‐ray or NMR cannot always target the various conformational states of metallochaperones, owing to a requirement for crystallography or low sensitivity and resolution. Electron paramagnetic resonance (EPR) spectroscopy has recently emerged as a powerful tool for resolving biological reactions and mechanisms in solution. When coupled with computational methods, EPR with site‐directed spin labeling and nanoscale distance measurements can provide structural information on a protein or protein complex in solution. We use these methods to show that Atox1 can accommodate at least four different conformations in the apo state (unbound to copper), and two different conformations in the holo state (bound to copper). We also demonstrate that the structure of Atox1 in the holo form is more compact than in the apo form. Our data provide insight regarding the structural mechanisms through which Atox1 can fulfill its dual role of copper binding and transfer.
A computational study of monolayer hexagonal WTe2 to metal interfaces
Authors: So Chol , Zhang Han , Wang Yangyang , Ye Meng , Pan Yuanyuan , Quhe Ruge , Li Jing Zhen , Zhang Xiuying , Zhou Yunsong , Lu Jing
Published: May 2017

Monolayer (ML) hexagonal (2H) WTe2 is predicted to be the best channel material of tunnel field effect transistor (TFET) and metal–oxide–semiconductor field effect transistor (MOSFET) among ML transition‐metal dichalcogenides. Actual devices based on 2H WTe2 typically have a contact with metal. We explore for the first time the interfacial properties between ML 2H WTe2 and Sc, Ti, Pd, Pt, Ag, and Au by using ab initio electronic structure calculation and ab initio quantum transport simulations. The energy bands of ML 2H WTe2 on Sc, Ti, Pd, and Pt substrates are destroyed strongly due to strong adhesion of ML 2H WTe2 with metal substrates, and ML 2H WTe2–Sc, −Ti, −Pd, and −Pt systems are regarded as new metallic materials. Weak adhesion is formed between ML 2H WTe2 and the Ag and Au surfaces, with the electronic energy band of ML 2H WTe2 being identifiable. Ag and Au form n‐type Schottky contact with ML 2H WTe2 at the vertical direction with electron Schottky barrier height (SBH) of 0.24 and 0.49 eV, respectively. In contrast, Pd, Pt, and Ti form p‐type Schottky contact with ML 2H WTe2 in the lateral direction with hole SBH of 0.26, 0.40, and 0.63 eV, respectively. Our study not only presents a theoretical insight into the ML 2H WTe2–metal interfaces but also help in ML 2H WTe2 based device design.
Raman spectra of CuGa3Te5 ordered‐defect compound
Authors: Rincón C. , Wasim S. M. , Marín G. , Delgado J. M. , Sánchez‐Pérez G. , Essaleh L. , Galibert J.
Published: May 2017

Raman spectra of CuGa3Te5 that has a chalcopyrite‐related structure with space group P2c were obtained at room temperature from measurements performed under parallel (z|xx|z) and perpendicular (z|xy|z) polarization dependent configurations. A tentative assignment of the observed lines was made by comparison with the reported phonon modes for ZnTe, which is the binary analogue of CuGaTe2, and also by using theoretical models reported in the literature for multinary compounds. The main lines observed at 129, 144, and 187 cm−1 were assigned to the three A1‐symmetry modes for P2c ternary compounds predicted by group theory, and other lines at 91 and 277–285 cm−1 to the B1 modes. Also, lines at 55, 64, 102, 172, 224, 265–269, and 333–334 cm−1 and lines at 78, 172, 224, 205–209, 242–249, and 342 cm−1 were assigned to E and B2 modes, respectively. The higher‐phonon frequencies observed at 291–297, 303–310, and 319–323 cm−1 are attributed to an overtone of the A1 mode at 144 cm−1, and a combination of A1 and E modes, respectively.
An investigation into the two‐stage meta‐analytic copula modelling approach for evaluating time‐to‐event surrogate endpoints which comprise of one or more events of interest
Authors: Dimier Natalie , Todd Susan
Published: May 2017

Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter‐term surrogate endpoints as substitutes for costly long‐term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long‐term endpoint. A number of statistical methods to evaluate this prediction have been proposed; this paper uses a simulation study to explore one such method in the context of time‐to‐event surrogates for a time‐to‐event true endpoint. This two‐stage meta‐analytic copula method has been extensively studied for time‐to‐event surrogate endpoints with one event of interest, but thus far has not been explored for the assessment of surrogates which have multiple events of interest, such as those incorporating information directly from the true clinical endpoint. We assess the sensitivity of the method to various factors including strength of association between endpoints, the quantity of data available, and the effect of censoring. In particular, we consider scenarios where there exist very little data on which to assess surrogacy. Results show that the two‐stage meta‐analytic copula method performs well under certain circumstances and could be considered useful in practice, but demonstrates limitations that may prevent universal use.
An adaptive degradation‐based maintenance model taking into account both imperfect adjustments and AGAN replacements
Authors: Letot Christophe , Dehombreux Pierre , Fleurquin Guillaume , Lesage Arnaud
Published: May 2017

This paper presents an adaptive maintenance model for equipment that can be adjusted (minor preventive maintenance, imperfect state) or replaced (major preventive maintenance, as good as new) at specific scheduled times based on degradation measurements. An initial reliability law that uses a degradation‐based model is built from the collection of hitting times of a failure threshold. Inspections are performed to update the reliability, the remaining useful life, and the optimum time for preventive maintenance. The case of both as good as new replacements and imperfect adjustments is considered. The proposed maintenance model is based on the optimization of the long‐term expected cost per unit of time. The model is then tested on a numerical case study to assess its effectiveness. This results in an improvement for the occurrences of maintenance tasks that minimizes the mean cost per unit of time as well as an optimized number of adjustments that can be considered before replacing an item. The practical application is a decision aid support to answer the 2 following questions: Should we intervene now or wait for the next inspection? For each intervention, should we adjust or replace the item of equipment? The originality is the presence of 2 criteria that help the maintainer to decide to postpone or not the preventive replacement time depending on the measured degradation and to decide whether the item should be adjusted or replaced.
Weighted‐average ℓ1 filtering for switched positive systems
Authors: Ren Yu , Sun Guanghui , Feng Zhiguang , Er Meng Joo , Wu Shiqian
Published: May 2017

In this paper, the filtering problem for a class of switched positive systems with dwell time is investigated. A novel weighted‐average technique is proposed for filter design such that the final estimate of the unmeasurable outputs of the considered system is more accurate than that of traditional approaches. The main contributions of this paper are summarized as follows: By exploiting the positivity and characteristics of switched positive systems with dwell time, a candidate linear copositive Lyapunov function, which is both quasi‐time‐dependent and mode‐dependent, is presented to establish the closed‐loop stability of the considered systems. Upon the established closed‐loop stability, less conservative bounded positive filters (both upper‐bound and lower‐bound filter) with ℓ1 disturbance attenuation performance are designed for the considered system. By introducing a proper weight, a weighted‐average approach, which is more general than the bounded filter design method, is proposed for filter design. The worst ℓ1 disturbance attenuation performance of the novel developed filter is evaluated. Both the bounded filters and the weighted‐average filter are designed by solving standard linear programming problems. A numerical example illustrates the effectiveness of the proposed approach. Copyright © 2017 John Wiley & Sons, Ltd.
Dissolving Microneedle Arrays for Transdermal Delivery of Amphiphilic Vaccines
Authors: An Myunggi , Liu Haipeng
Published: May 2017

Amphiphilic vaccine based on lipid‐polymer conjugates is a new type of vaccine capable of self‐delivering to the immune system. When injected subcutaneously, amphiphilic vaccines efficiently target antigen presenting cells in the lymph nodes (LNs) via a unique albumin‐mediated transport and uptake mechanism and induce potent humoral and cellular immune responses. However, whether this new type of vaccine can be administrated via a safe, convenient microneedle‐based transdermal approach remains unstudied. For such skin barrier‐disruption systems, a simple application of microneedle arrays (MNs) is desired to disrupt the stratum corneum, and for rapid and pain‐free self‐administration of vaccines into the skin, the anatomic place permeates with an intricate mesh of lymphatic vessels draining to LNs. Here the microneedle transdermal approach is combined with amphiphilic vaccines to create a simple delivery approach which efficiently traffic molecular vaccines into lymphatics and draining LNs. The rapid release of amphiphilic vaccines into epidermis upon application of dissolving MNs to the skin of mice generates potent cellular and humoral responses, comparable or superior to those elicited by traditional needle‐based immunizations. The results suggest that the amphiphilic vaccines delivered by dissolving MNs can provide a simple and safer vaccination method with enhanced vaccine efficacy.