bluuebunny/crossref_metadata_2025 huggingface dataset:
αvβ3 Integrin Is Required for Efficient Infection of Epithelial Cells with Human Adenovirus Type 26
Authors: Nestić Davor , Uil Taco G. , Ma Jiangtao , Roy Soumitra , Vellinga Jort , Baker Andrew H. , Custers Jerome , Majhen Dragomira
Published: October 2018

Adenovirus-based vectors are used today for gene transfer and vaccination. HAdV26 has emerged as a promising candidate vector for development of vaccines due to its relatively low seroprevalence and its ability to induce potent immune responses against inserted transgenes. However, data regarding the basic biology of the virus, like receptor usage or intracellular trafficking, are limited. In this work, we found that efficient infection of human epithelial cell lines by HAdV26 requires the expression of the αvβ3 integrin. By studying intracellular trafficking of fluorescently labeled HAdV26 in a cell clone with stably increased expression of αvβ3 integrin, we observed that HAdV26 colocalizes with αvβ3 integrin and confirmed that αvβ3 integrin expression facilitates efficient HAdV26 internalization. These results will allow further improvement of HAdV26-based vectors for gene transfer and vaccination.
NadA3 Structures Reveal Undecad Coiled Coils and LOX1 Binding Regions Competed by Meningococcus B Vaccine-Elicited Human Antibodies
Authors: Liguori Alessia , Dello Iacono Lucia , Maruggi Giulietta , Benucci Barbara , Merola Marcello , Lo Surdo Paola , López-Sagaseta Jacinto , Pizza Mariagrazia , Malito Enrico , Bottomley Matthew J.
Published: October 2018

The bacterial microbe
Neisseria meningitidis
serogroup B (MenB) is a major cause of devastating meningococcal disease. An approved multicomponent vaccine, 4CMenB, protects against MenB. Neisserial adhesin A (NadA) is a key vaccine antigen and acts in host cell-pathogen interactions. We investigated the 4CMenB vaccine component NadA3 in order to improve the understanding of its immunogenicity, structure, and function and to aid antigen design. We report crystal structures of NadA3, revealing unexpected structural motifs, and other conformational differences from the NadA5 orthologue studied previously. We performed structure-based antigen design to engineer increased NadA3 thermostability. Functional NadA3 residues mediating interactions with the human receptor LOX-1 and vaccine-elicited human antibodies were identified. These antibodies competed binding of NadA3 to LOX-1, suggesting their potential to inhibit host-pathogen colonizing interactions. Our data provide a significant advance in the overall understanding of the 4CMenB vaccine antigen NadA.
A Bacteriophage T4 Nanoparticle-Based Dual Vaccine against Anthrax and Plague
Authors: Tao Pan , Mahalingam Marthandan , Zhu Jingen , Moayeri Mahtab , Sha Jian , Lawrence William S. , Leppla Stephen H. , Chopra Ashok K. , Rao Venigalla B.
Published: October 2018

Following the deadly anthrax attacks of 2001, the Centers for Disease Control and Prevention (CDC) determined that
Bacillus anthracis
and
Yersinia pestis
that cause anthrax and plague, respectively, are two Tier 1 select agents that pose the greatest threat to the national security of the United States. Both cause rapid death, in 3 to 6 days, of exposed individuals. We engineered a virus nanoparticle vaccine using bacteriophage T4 by incorporating key antigens of both
B. anthracis
and
Y. pestis
into one formulation. Two doses of this vaccine provided complete protection against both inhalational anthrax and pneumonic plague in animal models. This dual anthrax-plague vaccine is a strong candidate for stockpiling against a potential bioterror attack involving either one or both of these biothreat agents. Further, our results establish the T4 nanoparticle as a novel platform to develop multivalent vaccines against pathogens of high public health significance.
Suspicious Yersinia granulomatous enterocolitis mimicking appendicitis
Authors: Richardson Tom , Jones Michael , Akhtar Youssaf , Pollard James
Published: October 2018

We present the case of a fit and well 12-year-old boy who presented with signs and symptoms suggestive of appendicitis. On laparoscopy, he was found to have a sinister-looking right iliac fossa mass with associated mesenteric lymphadenopathy. He proceeded to have an oncological right hemicolectomy, while the subsequent histology returned an unexpected result. The aim of this report is to highlight an unusual and complex clinical presentation in a young patient presenting with right iliac fossa pain.
Reappraisal of the suitability of corneas from bacteremic donors for use in corneal transplants
Authors: Chu Hsiao-Sang , Lai Chun-Ting , Hou Yu-Chih , Liu Hsin-Yu , Wang I-Jong , Chen Wei-Li , Shih Chung-Liang , Hu Fung-Rong
Published: October 2018

Background

This study examined whether corneas from bacteremic donors could be used for corneal transplant.

Methods

Corneas donated to the National Eye Bank of Taiwan between 1 January 2014 and 30 June 2017 were included in this study. All the corneas had corneoscleral rim cultures during the retrieval process and were hypothermic preserved in the Optisol-GS storage medium. A microbial work-up flow chart was used for the sterility check of all grafts. Bacteremic donors were defined as those whose last blood culture before corneal donation was positive. The microbial contamination rates, the endothelial cell densities, the tissue utility rates and early complications after transplants were compared between the corneas from bacteremic versus non-bacteremic donors.

Results

697 corneas from 356 donors were analysed, 70 of which were from bacteremic donors. The microbial contamination rates of the corneas from bacteremic and non-bacteremic donors (7.1% vs 9.1%)(p=0.30) were close. None of the contaminated corneas grew the same bacterial strains as those from their blood cultures. The corneas from bacteremic donors and non-bacteremic donors have similar endothelial cell densities (2931±297 cells/mm2 vs 2903 ± 470 cells/mm2) (p=0.63). Corneas from bacteremic and non-bacteremic donors shared a similar utility rate (98.6% vs 99.4%)(p=0.41). None of the corneas caused infectious complications after transplants.

Conclusion

Our study showed that corneas from bacteremic and non-bacteremic donors have equally low contamination rates and are of the same quality in terms of endothelial cell density and safety.
Cardiovascular biomarkers predict fragility fractures in older adults
Authors: Johansson Madeleine , Ricci Fabrizio , Di Martino Giuseppe , Rogmark Cecilia , Sutton Richard , Hamrefors Viktor , Melander Olle , Fedorowski Artur
Published: October 2018

Objective

To assess the role of four biomarkers of neuroendocrine activation and endothelial dysfunction in the longitudinal prediction of fragility fractures.

Methods

We analysed a population-based prospective cohort of 5415 community-dwelling individuals (mean age, 68.9±6.2 years) enrolled in the Malmö Preventive Project followed during 8.1±2.9 years, and investigated the longitudinal association between C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), the mid-regional fragments of pro-adrenomedullin (MR-proADM) and pro-atrial natriuretic peptide (MR-proANP), and incident vertebral, pelvic and extremity fractures.

Results

Overall, 1030 (19.0%) individuals suffered vertebral, pelvic or extremity fracture. They were older (70.7±5.8 vs 68.4±6.3 years), more likely women (46.9% vs 26.3%), had lower body mass index and diastolic blood pressure, were more often on antihypertensive treatment (44.1% vs 38.4%) and had more frequently history of fracture (16.3% vs 8.1%). Higher levels of MR-proADM (adjusted HR (aHR) per 1 SD: 1.51, 95% CI 1.01 to 2.28, p<0.001) and MR-proANP (aHR: 1.23, 95% CI 1.05 to 1.45, p<0.001) were independently associated with increased risk of any fracture. The fracture risk increased linearly across MR-proANP quartiles. Individuals who were in the top quartile of all four biomarkers had a significant higher risk of fracture at any site (aHR: 2.32, 95% CI 1.86 to 2.91), vertebral fracture (aHR: 3.16, 95% CI 1.97 to 5.07) and femoral fracture (aHR: 2.35, 95% CI 1.64 to 3.36).

Conclusions

Elevated levels of MR-proADM and MR-proANP independently predict fragility fractures in older adults. In subjects with top quartile levels of all four biomarkers there is a twofold to threefold increase in risk of vertebral and femoral fractures.
Association between cytokine gene polymorphisms and ankylosing spondylitis susceptibility: a systematic review and meta-analysis
Authors: Xia Yi , Liang Yan , Guo Shi , Yu Jie-Gen , Tang Meng-Sha , Xu Peng-Hui , Qin Fen-Dui , Wang Guo-Pin
Published: October 2018

Purpose of the study

The aim of this study was to perform a meta-analysis to derive precise estimation of the association of interleukin-23 receptor (IL-23R), IL-1 receptor 2 (IL-1R2), IL-12 beta (IL-12B), IL-10 and tumour necrosis factor (TNF)-α polymorphisms with ankylosing spondylitis (AS) susceptibility.

Study design

A systematic literature search was conducted to identify the relevant studies. Pooled OR with 95% CI was calculated to assess the strength of the association in a fixed or random-effects model.

Results

A total of 13 917 cases and 19 849 controls in 43 eligible studies were included in the meta-analysis. Seventeen single-nucleotide polymorphisms (SNPs) in the abovementioned five cytokine genes were evaluated. The results indicate that the nine SNPs (rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs11209032, rs1495965, rs7517847, rs2201841) of IL-23R are associated with AS susceptibility in all study subjects in the allelic model. Moreover, stratification by ethnicity identified a significant association between seven SNPs of IL-23R and AS susceptibility in Europeans and Americans, but not in Asians. In addition, the IL-10–819  C/T and TNF-α−857 C/T polymorphisms also confer susceptibility to AS, especially in Asian population.

Conclusion

The results suggested that the genetic susceptibility for AS is associated with the nine SNPs of IL-23R in overall population. In the subgroup analysis, significant associations were shown in European and American population, but not in Asian population. Our results also suggest that IL-10–819  C/T and TNF-α−857 C/T polymorphism might be associated with AS risk, especially in Asian population.
Long QT syndrome masquerading as epilepsy
Authors: Galtrey Clare M , Levee Viva , Arevalo Jan , Wren Damian
Published: October 2018

The diagnosis of epilepsy is incorrect in up to 20% of cases so should be revisited if attacks are not responding to treatment. We present a case of long QT syndrome that remained undiagnosed in the epilepsy clinic for 15 years until a near-fatal arrhythmia revealed the diagnosis and allowed effective treatment of her attacks. We hope this near miss raises awareness of long QT syndrome as a potentially fatal, rare but treatable condition that neurologists must consider in people with a label of refractory epilepsy. We provide practical pointers to increase the chance of early diagnosis and explore the impact of a late diagnosis for the patient and her family.
Southeast Anatolian Orogenic Belt revisited (geology and evolution)
Authors: Yılmaz Yücel
Published: October 2018

The Southeast Anatolian Orogenic Belt consists of the Arabian Platform, a zone of imbrication, and a nappe zone. The Arabian Platform is represented by a thick marine succession. The zone of imbrication is a narrow belt sandwiched between the Arabian Platform and the nappes. The nappes are the highest tectonic unit. They consist of two continental slivers separated by ophiolitic associations representing oceanic environments. They were involved in the orogenic development and formed two metamorphic belts. The oceanic environment survived by the end of Middle Eocene. A northward subduction began in this ocean and generated the Elbistan–Yüksekova arc built above the Göksun ophiolite. Development of the Southeastern Anatolian Orogenic Belt began in the north, where the Binboğa–Malatya metamorphic massif, collided with the Elbistan volcanic arc to the end of Early Eocene period. Later new tectonic entities were accreted to this progressively growing and southerly transporting nappe stack. In the lower plate, the southern continental sliver that was attached to the oceanic slab subducted together and underwent high-pressure metamorphism. The subducting oceanic slab retreated. Asthenospheric inflow caused high-temperature metamorphism, which superimposed on the previous high-pressure metamorphism. The oceanic and continental fragments formed the Bitlis Massif and the Berit metaophiolite when exhumed. A younger volcanic arc was built on the ocean floor to the south. Accretion of the volcanic arc to the nappe pile occurred during the Late Eocene period. The orogenic belt was formed when the nappes collided with the Arabian plate during the Late Miocene.
The influence of illumination on two-photon absorption of quantum dots
Authors: Zhou Zhiqiang , Cong Jiawei , Yao Hongbing , Fu Yonghong , Ren Naifei
Published: October 2018

The influence of illumination with 365[Formula: see text]nm ultraviolet light on two-photon absorption (TPA) of aqueous Co[Formula: see text] doped CdTe (CdTe:Co) quantum dots (QDs) is studied. The results show that with the increase of illumination time, the TPA cross section of the CdTe:Co QDs increases. The experimental results suggest that this enhancement is due to the reduction of surface nonradiative traps which is consistent with the formation of CdS shell on the surface of CdTe:Co QDs. Meanwhile, the results indicate that aqueous CdTe:Co QDs have good optical limiting and optical stabilization performances. This provides a strategy of TPA enhancement by illumination.
A geometric Hamilton–Jacobi theory on a Nambu–Jacobi manifold
Authors: de León M. , Sardón C.
Published: October 2018

In this paper, we propose a geometric Hamilton–Jacobi (HJ) theory on a Nambu–Jacobi (NJ) manifold. The advantage of a geometric HJ theory is that if a Hamiltonian vector field [Formula: see text] can be projected into a configuration manifold by means of a one-form [Formula: see text], then the integral curves of the projected vector field [Formula: see text] can be transformed into integral curves of the vector field [Formula: see text] provided that [Formula: see text] is a solution of the HJ equation. This procedure allows us to reduce the dynamics to a lower-dimensional manifold in which we integrate the motion. On the other hand, the interest of a NJ structure resides in its role in the description of dynamics in terms of several Hamiltonian functions. It appears in fluid dynamics, for instance. Here, we derive an explicit expression for a geometric HJ equation on a NJ manifold and apply it to the third-order Riccati differential equation as an example.
Research Progress on Surface Coating Layers on the Positive Electrode for Lithium Ion Batteries
Authors: Hao Zhen Dong , Xu Xiaolong , Wang Hao , Liu Jingbing , Yan Hui
Published: October 2018

Lithium ion batteries (LIBs) are one of the most promising secondary batteries due to their advantages including long cycle life, high energy density, limited self-discharge, high operating voltage and environmental friendliness. The development of electrode materials is crucial for the further application of LIBs. There are many effective ways to enhance the performance of positive electrode materials of LIBs such as surface coating, ion doping, preparation of composite materials and nanosized materials and so forth. Among them, surface coating is considered to be a promising way to improve the electrochemical performance of LIBs. Surface coating can normally form a physical barrier or a doped surface layer to play favorable roles for the electrode materials, such as hindering side reactions between positive electrode materials and the electrolyte. In this paper, different kinds of surface coating layers will be discussed according to previous research, including carbon materials, metal oxides, metal fluorides, metal phosphates, nonmetal oxides, electrode materials coating layer, hybrid coating layer, polymer and so forth. In addition, the mechanism of these coating materials will be summarized, and the future development will be discussed in this paper.
Seismic Assessment and Retrofitting of a Heritage Brick Masonry Building Using FRP
Authors: Tomar Anshu , Paul Dilip Kumar , Agarwal Pankaj
Published: October 2018

Uttarakhand in the foothills of Himalayas is considered to be one of the most tectonically active regions of northern India as it had experienced several destructive earthquakes such as Pithoragarh (1980), Uttarkashi (1991), Chamoli (1999) and Gopeshwar (2005). The state of Uttar Pradesh (now Uttarakhand) being the center of activity during British regime is having numerous historical brick masonry structures such as churches, missionaries, hospitals, administrative building and educational institutions required to be safeguarded against catastrophic future earthquakes. One such building: Forest Research Institute Dehradun which suffered extensive damages during the Uttarkashi earthquake has been considered for seismic vulnerability assessment and achieving a generalized retrofitting strategy for the region which can be extrapolated globally. Structural assessment by non-linear static analysis has been carried out for FRP retrofitted and an un-retrofitted building using FEM. Different types of FRP has been modeled numerically as wrapped around the piers of huge brick masonry structure and analyzed under site specific earthquake loading which reported in an improved performance of strengthened structure.
Cosserat crystal plasticity with dislocation-driven grain boundary migration
Authors: Ask Anna , Forest Samuel , Appolaire Benoit , Ammar Kais
Published: October 2018

This paper discusses a coupled mechanics–phase-field model that can predict microstructure evolution in metallic polycrystals and in particular evolution of lattice orientation due to either deformation or grain boundary migration. The modeling framework relies on the link between lattice curvature and geometrically necessary dislocations and connects a micropolar or Cosserat theory with an orientation phase-field model. Some focus is placed on the underlying theory and in particular the theory of dislocations within a continuum single crystal plasticity setting. The model is finally applied to the triple junction problem for which there is an analytic solution if the grain boundary energies are known. The attention is drawn on the evolution of skew–symmetric stresses inside the grain boundary during migration.
Social Media, the Internet, and Trial by Jury
Authors: Hoffmeister Thaddeus , Watts Ann Charles
Published: October 2018

This review starts with a historical overview of trial by jury and then moves to a discussion of media and communication. This is followed by an examination of the advantages and disadvantages associated with jurors and digital technology. The heart of the article is a review of six scholarly studies that attempt to explain why jurors use the Internet, as well as methods for combating such use. The article concludes with recommendations for future areas of research.
The Politics of Professionalism: Reappraising Occupational Licensure and Competition Policy
Authors: Vaheesan Sandeep , Pasquale Frank
Published: October 2018

Elite economists and lawyers contend that occupational licensure raises consumer prices and unemployment. Billed as a bipartisan boost to market competition, this technocratic policy agenda rests on thin empirical foundations. Studies of the wage effects of licensing rarely couple this analysis of its putative costs with convincing analysis of the benefits of the professional or vocational education validated via licensure. While some licensing rules may be onerous and excessive, licensing rules are inadequate or underenforced in other labor markets. Furthermore, by limiting labor market entry, occupational licensing rules, like minimum wage and labor laws, can help stabilize working- and middle-class wages. Although current antitrust law provides an ideological framework for technocratic attacks on licensing, it is fundamentally unsuited for evaluation of labor markets. Contemporary antitrust law's arcane concept of efficiency reflects neither the legislative objectives animating the antitrust statutes nor popular understanding of what competition policy should do.
Anisotropic Quintessence Strange Stars in f(T) Gravity with Modified Chaplygin Gas
Authors: Saha Pameli , Debnath Ujjal
Published: October 2018

In this paper, we study the existence of strange star in the background of f(T) modified gravity where T is a scalar torsion. In KB metric space, we derive the equations of motion using anisotropic property within the spherically strange star with modified Chaplygin gas in the framework of modified f(T) gravity. Then we obtain many physical quantities to describe the physical status such as anisotropic behavior, energy conditions, and stability. By the matching condition, we calculate the unknown parameters to evaluate the numerical values of mass, surface redshift, etc., from our model to make comparison with the observational data.
Family of Bistable Attractors Contained in an Unstable Dissipative Switching System Associated to a SNLF
Authors: Echenausía-Monroy J. L. , García-López J. H. , Jaimes-Reátegui R. , López-Mancilla D. , Huerta-Cuellar G.
Published: October 2018

This work presents a multiscroll generator system, which addresses the issue by the implementation of 9‐level saturated nonlinear function, SNLF, being modified with a new control parameter that acts as a bifurcation parameter. By means of the modification of the newly introduced parameter, it is possible to control the number of scrolls to generate. The proposed system has richer dynamics than the original, not only presenting the generation of a global attractor; it is capable of generating monostable and bistable multiscrolls. The study of the basin of attraction for the natural attractor generation (9‐scroll SNLF) shows the restrictions in the initial conditions space where the system is capable of presenting dynamical responses, limiting its possible electronic implementations.
Research on Workshop‐Based Positioning Technology Based on Internet of Things in Big Data Background
Authors: Liu FengChun , Liu YaLou , Jin DongHao , Jia XueYong , Wang TingTing
Published: October 2018

This paper first analyzes the data collection and data management of the workshop, obtains the data of the workshop changes with time, and accumulates the data. There are bottleneck problems such as big data being difficult to be fully used. Then, the concept of the Internet of Things was introduced into the workshop positioning to realize the comprehensive use of the big data in the workshop. Finally, aiming at the positioning problem of manufacturing workshop items, the ZigBee positioning algorithm, the received signal strength indication algorithm RSSI and the trilateration algorithm, is applied, and the trilateral positioning algorithm is applied to the CC2430 wireless MCU, and the positioning node is designed and implemented. The three‐sided localization algorithm was used to locate and simulate the horizontal and vertical comparisons of six groups of workshop terminals. The results showed that the difference between the simulated position and the actual position did not exceed 1m, which was in line with the positioning requirements of the workshop.
Integrated Berth Allocation and Time-Variant Quay Crane Scheduling with Tidal Impact in Approach Channel
Authors: Jiao Xiaogang , Zheng Feifeng , Liu Ming , Xu Yinfeng
Published: October 2018

This paper addresses the integrated problem of dynamic continuous berth allocation and time-variant quay crane scheduling in container terminals and introduces the factor of tidal impacts into the problem. We mainly consider the impact of tides on the transport capacity of an approach channel that connects quay and anchorage. An integer linear programming model is developed, and then three heuristic algorithms, Genetic Algorithm, Hybrid Particle Swarm Optimization, and Hybrid Simulated Annealing, are proposed to solve the model. Numerical experiments are conducted to verify the efficient performances of the proposed heuristics. Moreover, experimental results also demonstrate the nonignorable impact of tides on the vessel turnaround time and the utilization of berth and quay cranes.
Feature Recognition of Crop Growth Information in Precision Farming
Authors: Sun Hanqing , Zhang Xiaohui , Yu Zhou , Xi Gang
Published: October 2018

To identify plant electrical signals effectively, a new feature extraction method based on multiwavelet entropy and principal component analysis is proposed. The wavelet energy entropy, wavelet singular entropy, and the wavelet variance entropy of plants’ electrical signals are extracted by a wavelet transformation to construct the combined features. Principal component analysis (PCA) is applied to treat the constructed features and eliminate redundant information among those features and extract features which can reflect signal type. Finally, the classification method of BP neural network is used to classify the obtained feature vectors. The experimental results show that this method can acquire comparatively high recognition rate, which proposed a new efficient solution for the identification of plant electrical signals.
Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer
Authors: Redaelli Sara , Ceccon Monica , Zappa Marina , Sharma Geeta G. , Mastini Cristina , Mauri Mario , Nigoghossian Marion , Massimino Luca , Cordani Nicoletta , Farina Francesca , Piazza Rocco , Gambacorti-Passerini Carlo , Mologni Luca
Published: October 2018

Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third-generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors. In this study, we utilize lorlatinib-resistant anaplastic large cell lymphoma (ALCL), non–small cell lung cancer (NSCLC), and neuroblastoma cell lines in vitro and in vivo to investigate the acquisition of resistance and its underlying mechanisms. ALCL cells acquired compound ALK mutations G1202R/G1269A and C1156F/L1198F in vitro at high drug concentrations. ALCL xenografts selected in vivo showed recurrent N1178H (5/10 mice) and G1269A (4/10 mice) mutations. Interestingly, intracellular localization of NPM/ALKN1178H skewed toward the cytoplasm in human cells, possibly mimicking overexpression. RNA sequencing of resistant cells showed significant alteration of PI3K/AKT and RAS/MAPK pathways. Functional validation by small-molecule inhibitors confirmed the involvement of these pathways in resistance to lorlatinib. NSCLC cells exposed in vitro to lorlatinib acquired hyperactivation of EGFR, which was blocked by erlotinib to restore sensitivity to lorlatinib. In neuroblastoma, whole-exome sequencing and proteomic profiling of lorlatinib-resistant cells revealed a truncating NF1 mutation and hyperactivation of EGFR and ErbB4. These data provide an extensive characterization of resistance mechanisms that may arise in different ALK-positive cancers following lorlatinib treatment.

Significance:

High-throughput genomic, transcriptomic, and proteomic profiling reveals various mechanisms by which multiple tumor types acquire resistance to the third-generation ALK inhibitor lorlatinib.
Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer
Authors: Garrido Marine F. , Martin Nicolas J.-P. , Bertrand Matthieu , Gaudin Catherine , Commo Frédéric , El Kalaany Nassif , Al Nakouzi Nader , Fazli Ladan , Del Nery Elaine , Camonis Jacques , Perez Franck , Lerondel Stéphanie , Le Pape Alain , Compagno Daniel , Gleave Martin , Loriot Yohann , Désaubry Laurent , Vagner Stéphan , Fizazi Karim , Chauchereau Anne
Published: October 2018

Purpose:

Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance.

Experimental Design: We established 4 chemoresistant prostate cancer cell lines and used image-based high-content siRNA functional screening, based on gene-expression signature, to explore mechanisms of chemoresistance and identify new potential targets with potential roles in taxane resistance. The functional role of a new target was assessed by in vitro and in vivo silencing, and mass spectrometry analysis was used to identify its downstream effectors.

Results:

We identified FKBP7, a prolyl-peptidyl isomerase overexpressed in docetaxel-resistant and in cabazitaxel-resistant prostate cancer cells. This is the first study to characterize the function of human FKBP7 and explore its role in cancer. We discovered that FKBP7 was upregulated in human prostate cancers and its expression correlated with the recurrence observed in patients receiving docetaxel. FKBP7 silencing showed that FKBP7 is required to maintain the growth of chemoresistant cell lines and chemoresistant tumors in mice. Mass spectrometry analysis revealed that FKBP7 interacts with eIF4G, a component of the eIF4F translation initiation complex, to mediate the survival of chemoresistant cells. Using small-molecule inhibitors of eIF4A, the RNA helicase component of eIF4F, we were able to kill docetaxel- and cabazitaxel-resistant cells.

Conclusions:

Targeting FKBP7 or the eIF4G-containing eIF4F translation initiation complex could be novel therapeutic strategies to eradicate taxane-resistant prostate cancer cells.
Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy
Authors: Panditharatna Eshini , Kilburn Lindsay B. , Aboian Mariam S. , Kambhampati Madhuri , Gordish-Dressman Heather , Magge Suresh N. , Gupta Nalin , Myseros John S. , Hwang Eugene I. , Kline Cassie , Crawford John R. , Warren Katherine E. , Cha Soonmee , Liang Winnie S. , Berens Michael E. , Packer Roger J. , Resnick Adam C. , Prados Michael , Mueller Sabine , Nazarian Javad
Published: October 2018

Purpose:

Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy.

Experimental Design:

We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data.

Results:

H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients.

Conclusions:

Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.
Regional Variation in Fundamental Frequency of American English Vowels
Authors: Jacewicz Ewa , Fox Robert Allen
Published: October 2018

We examined whether the fundamental frequency (f0) of vowels is influenced by regional variation, aiming to (1) establish how the relationship between vowel height and f0 (“intrinsic f0”) is utilized in regional vowel systems and (2) determine whether regional varieties differ in their implementation of the effects of phonetic context on f0 variations. An extended set of acoustic measures explored f0 in vowels in isolated tokens (experiment 1) and in connected speech (experiment 2) from 36 women representing 3 different varieties of American English. Regional differences were found in f0 shape in isolated tokens, in the magnitude of intrinsic f0 difference between high and low vowels, in the nature of f0 contours in stressed vowels, and in the completion of f0 contours in the context of coda voicing. Regional varieties utilize f0 control in vowels in different ways, including regional f0 ranges and variation in f0 shape.
Antiplatelet Therapy in Primary Spontaneous and Oral Anticoagulation–Associated Intracerebral Hemorrhage
Authors: Sprügel Maximilian I. , Kuramatsu Joji B. , Gerner Stefan T. , Sembill Jochen A. , Beuscher Vanessa D. , Hagen Manuel , Roeder Sebastian S. , Lücking Hannes , Struffert Tobias , Dörfler Arnd , Schwab Stefan , Huttner Hagen B.
Published: October 2018

Background and Purpose—

This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), vitamin K antagonist (VKA)- and non–VKA oral anticoagulant-associated ICH.

Methods—

Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume.

Results—

A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non–VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0–3; APT, 48/202 [23.8%] versus no APT, 187/587 [31.9%];
P
=0.030) and higher mortality (APT, 103/202 [51.0%] versus no APT, 237/587 [40.4%];
P
=0.009), whereas no significant differences were present in primary spontaneous ICH and non–VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 [7.4–61.4] versus 15.7 [5.7–44.5] mL;
P
=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 [1.20–2.70];
P
=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients.

Conclusions—

APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.
Oxidized Low-Density Lipoprotein to High-Density Lipoprotein Ratio Predicts Recurrent Stroke in Minor Stroke or Transient Ischemic Attack
Authors: Wang Anxin , Li Shiyu , Zhang Nan , Dai Liye , Zuo Yingting , Wang Yilong , Meng Xia , Wang Yongjun
Published: October 2018

Background and Purpose—

Oxidized low-density lipoprotein (oxLDL) level is thought to be associated with recurrent stroke. We aimed to investigate the association between oxLDL to high-density lipoprotein (HDL) ratio and recurrent stroke in patients with minor stroke or transient ischemic attack.

Methods—

The study included 3019 patients with minor ischemic stroke or high-risk transient ischemic attack from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events). Baseline oxLDL and HDL levels were measured. The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The association between oxLDL/HDL and recurrent stroke was analyzed by using Cox proportional hazards.

Results—

Patients in the highest oxLDL/HDL quartile had a higher risk of recurrent stroke within 90 days (hazards ratio, 1.50; 95% CI, 1.08–2.08) compared with the lowest quartile after adjusting relevant confounding factors (
P
=0.02). Similar results were found for secondary outcomes (
P
<0.05 for all). There were no significant interaction between oxLDL/HDL and use of statins agents.

Conclusions—

Higher serum oxLDL/HDL level in minor stroke or transient ischemic attack was associated with increased risk of recurrent stroke in 90 days and 1 year. OxLDL/HDL may act as a powerful indicator of recurrent stroke in patients with minor stroke or transient ischemic attack.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00979589.
Induced Hypertension in Preventing Cerebral Infarction in Delayed Cerebral Ischemia After Subarachnoid Hemorrhage
Authors: Haegens N. Marlou , Gathier Celine S. , Horn Janneke , Coert Bert A. , Verbaan Dagmar , van den Bergh Walter M.
Published: October 2018

Background and Purpose—

Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage. If clinical signs of DCI occur, induced hypertension is a plausible but unproven therapeutic intervention. There is clinical equipoise if the use of hypertension induction is useful or not with the consequence that this strategy is irregularly used. We explored the effect of blood pressure augmentation in preventing cerebral infarction in patients with clinical signs of DCI.

Methods—

We performed a retrospective observational study, totaling 1647 patients with aneurysmal subarachnoid hemorrhage admitted at 3 academic hospitals in the Netherlands between 2006 and 2015. To study the primary outcome DCI related cerebral infarcts, we only included patients with no cerebral infarct at the time of onset of clinical signs of DCI. Cox regression was used to test the association between induced hypertension after onset of clinical signs of DCI and the occurrence of DCI related cerebral infarcts. Logistic regression was used to relate hypertension induction with poor outcome after 3 months, defined as a modified Rankin score >3. Results were adjusted for treatment center and baseline characteristics.

Results—

Clinical signs of DCI occurred in 479 (29%) patients of whom 300 without cerebral infarction on computed tomography scan at that time. Of these 300 patients, 201 (67%) were treated with hypertension induction and 99 were not. Of the patients treated with hypertension induction, 41 (20%) developed a DCI related cerebral infarct compared with 33 (33%) with no induced hypertension: adjusted hazard ratio, 0.59; 95% CI, 0.35 to 0.99. Hypertension induction also prevented poor outcome: adjusted odds ratio, 0.27; 95% CI, 0.14 to 0.55.

Conclusions—

Hypertension induction seems an effective strategy for preventing DCI related cerebral infarcts if not already present at the time of onset of clinical signs of DCI. This may lead to a reduction in poor clinical outcome.
C-Reactive Protein, Plasma Amyloid-β Levels, and Their Interaction With Magnetic Resonance Imaging Markers
Authors: Hilal Saima , Ikram M. Arfan , Verbeek Marcel M. , Franco Oscar H. , Stoops Erik , Vanderstichele Hugo , Niessen Wiro J. , Vernooij Meike W.
Published: October 2018

Background and Purpose—

Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers.

Methods—

We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1–38, Aβ1–40, and Aβ1–42 were assessed using ELISA.

Results—

Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00–0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19–2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00–1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00–1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1–42, a strong association was observed between CRP and lacunar (
P
interaction, 0.004), enlarged perivascular spaces (
P
interaction, 0.002), and microbleed counts (
P
interaction, <0.001). Similarly, among persons in higher tertile of Aβ1–38, a strong association was observed between CRP and microbleed counts (
P
interaction, 0.004).

Conclusions—

Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.
PETROL FİYATLARI VE İSTİHDAM İLİŞKİSİ: G7 ÜLKELERİ ÖRNEKLEMİNDE PANEL VERİ ANALİZİ
Authors: SARAÇ Şenay , YAĞLIKARA Aykut
Published: October 2018

Bu

çalışmanın amacı petrol fiyatları ile istihdam arasındaki ilişkiyi her biri net

petrol ithalatçısı olan G7 ülkeleri örnekleminde panel veri analiz yöntemiyle

incelemektir. Bu kapsamda 1986-2014 dönemine ait yıllık ham petrol fiyatları ve

istihdam verileri kullanılarak gerçekleştirilen analizde söz konusu ülkeler

için petrol fiyatları ile istihdam oranları arasında eşbütünleşme ve

nedensellik ilişkisinin varlığı tespit edilmiştir.

Günümüz

koşullarında sanayi üretiminin en önemli girdisi enerji tüketiminden

kaynaklanan maliyetler olup petrol fiyatları bu maliyetlerin ortaya konmasında

önemli bir gösterge niteliği taşımaktadır. Bu nedenle petrol fiyatları ile

makroekonomik değişkenler arasındaki ilişki birçok çalışmada ele alınmıştır. 
BİREYSEL EMEKLİLİK ARACILIĞI VE VERGİ KANUNLARI KARŞISINDAKİ DURUMU
Authors: ACUNER Serkan
Published: October 2018

Bireysel emeklilik sigortası yaşlılık riskini bertaraf etmek üzere bireysel emeklilik şirketlerince emeklilere sağlanan özel bir himayedir. Bireysel emeklilik şirketleri bu sigorta türünün tanıtımı, pazarlanması yahut satışı konusundaki ihtiyacını, uzman meslek erbaplarını istihdam etmek suretiyle giderir. Burada belirtilen uzman meslek erbabı, Emeklilik Gözetim Merkezi Anonim Şirketi’nce yetkilendirilmiş bireysel emeklilik aracılarıdır. Bireysel emeklilik aracılığı mesleğinin kendine özgü bir yapısı bulunmaktadır ve diğer aracılık mesleklerinden ayrılmaktadır. Yeterliliği sınanmış gerçek kişilerce yürütülen meslek kolu, kurumsal bir çatı altında, emeklilik şirketleri ile çağrı merkezleri, acente ve bankalarda icra edilebilir. Bu çalışmayla bir işverene tabi ve ona bağlı olarak çalışan bireysel emeklilik aracılarının vergi kanunları karşısındaki durumlarına açıklık getirilmiştir.  Gerçek kişi bireysel emeklilik aracılarının elde ettikleri ücretler Gelir Vergisi Kanunu’nun genel hükümlerine göre vergilendirilir. Ayrıca aracılık hizmetini şirketle acentelik sözleşmesi akdetmek suretiyle ifa eden acente yahut bankaların aracılıktan elde ettikleri gelirlerin vergi kanunları karşısındaki durumu ele alınmıştır. Bireysel emeklilik aracılarının istihdam edildiği kurumlar, hangi ticaret unvanı altında kurulduklarına bağlı olarak ya Gelir Vergisi Kanunu ya da Kurumlar Vergisi Kanunu’nun genel hükümlerine tabidirler. Bu çalışmada, ilgili kanun hükümleri lafzi yöntemle yorumlanmış ve sistematik literatür tarama yöntemi kullanılmıştır.
DÖNÜŞTÜRÜCÜ LİDERLİĞİN İÇ GİRİŞİMCİLİK DAVRANIŞINA ETKİSİ: BOLU İLİNDE BİR ARAŞTIRMA
Authors: BÜYÜKYILMAZ Ozan , KAYIŞ Musa
Published: October 2018

Bu çalışmada dönüştürücü

liderlik ile iç girişimcilik arasındaki ilişki incelenmektedir. Çalışmanın

amacı, dönüştürücü liderlik uygulamalarının çalışanların iç girişimcilik

davranışları üzerindeki etkisini belirleyebilmektir. Çalışmada dönüştürücü

liderliğin dört boyutunun (idealleştirerek etkileme, ilham verme, entelektüel

teşvik ve bireysel ilgi) iç girişimcilik davranışlarını (risk alma,

yenilikçilik, proaktiflik, özerklik ve bireysel ağ genişletme) etkileme

derecesi araştırılmaktadır. Bu amaç için Bolu ilinde faaliyet gösteren dört

farklı işletmedeki 313 çalışan üzerinde bir araştırma gerçekleştirilmiştir.

Araştırmada kullanılan veriler anket yöntemi kullanılarak elde edilmiştir.

Hipotezler ise regresyon analizi ile test edilmiştir. Çalışmanın sonucunda,

dönüştürücü liderliğin idealleştirerek etkileme, entelektüel teşvik ve bireysel

ilgi boyutlarının farklı iş girişimcilik boyutlarını olumlu yönde etkilediği

belirlenmiştir. Buna karşılık dönüştürücü liderliğin ilham verme boyutunun iç

girişimcilik davranışları üzerinde bir etkisi bulunamamıştır.
Action Planning Modulates Peripersonal Space
Authors: Patané Ivan , Cardinali Lucilla , Salemme Romeo , Pavani Francesco , Farnè Alessandro , Brozzoli Claudio
Published: October 2018

Peripersonal space is a multisensory representation relying on the processing of tactile and visual stimuli presented on and close to different body parts. The most studied peripersonal space representation is perihand space (PHS), a highly plastic representation modulated following tool use and by the rapid approach of visual objects. Given these properties, PHS may serve different sensorimotor functions, including guidance of voluntary actions such as object grasping. Strong support for this hypothesis would derive from evidence that PHS plastic changes occur before the upcoming movement rather than after its initiation, yet to date, such evidence is scant. Here, we tested whether action-dependent modulation of PHS, behaviorally assessed via visuotactile perception, may occur before an overt movement as early as the action planning phase. To do so, we probed tactile and visuotactile perception at different time points before and during the grasping action. Results showed that visuotactile perception was more strongly affected during the planning phase (250 msec after vision of the target) than during a similarly static but earlier phase (50 msec after vision of the target). Visuotactile interaction was also enhanced at the onset of hand movement, and it further increased during subsequent phases of hand movement. Such a visuotactile interaction featured interference effects during all phases from action planning onward as well as a facilitation effect at the movement onset. These findings reveal that planning to grab an object strengthens the multisensory interaction of visual information from the target and somatosensory information from the hand. Such early updating of the visuotactile interaction reflects multisensory processes supporting motor planning of actions.