bluuebunny/crossref_metadata_2025 huggingface dataset:
Intelligent Intrusion Detection System Through Combined and Optimized Machine Learning
Authors: Shah Syed Ali Raza , Issac Biju , Jacob Seibu Mary
Published: June 2018

In this paper, an existing rule-based intrusion detection system (IDS) is made more intelligent through the application of machine learning. Snort was chosen as it is an open source software and though it was performing well, it showed false positives (FPs). To find the best performing machine learning algorithms (MLAs) to use with Snort so as to improve its detection, we tested some algorithms on three available datasets. Support vector machine (SVM) was chosen along with fuzzy logic and decision tree based on their accuracy. Combined versions of algorithms through ensemble SVM along with other variants were tried on the generated traffic of normal and malicious packets at 10[Formula: see text]Gbps. Optimized versions of the SVM along with firefly and ant colony optimization (ACO) were also tried, and the accuracy improved remarkably. Thus, the application of combined and optimized MLAs to Snort at 10[Formula: see text]Gbps worked quite well.
A Strength Pareto Evolutionary Algorithm for Optimizing System-On-Chip Test Schedules
Authors: Marrouche Wissam , Farah Rana , Harmanani Haidar M.
Published: June 2018

System-on-chip (SOC) has become a mainstream design practice that integrates intellectual property cores on a single chip. The SOC test scheduling problem maximizes the simultaneous test of all cores by determining the order in which various cores are tested. The problem is tightly coupled with the test access mechanism (TAM) bandwidth and wrapper design. This paper presents a strength Pareto evolutionary algorithm for the SOC test scheduling problem with the objective of minimizing the power-constrained test application time, wrapper design and TAM assignment in flat and hierarchical core-based systems. We demonstrate the effectiveness of the method using the ITC’02 benchmarks.
Modeling Floppy Iris Syndrome and the Impact of Phenylephrine on Iris Buckling
Authors: Qi Nan , Lockington David , Wang Huiming , Hill Nicholas A. , Ramaesh Kanna , Luo Xiaoyu
Published: June 2018

Abnormal iris movement (floppy iris syndrome) during intraocular surgery is associated with an increased risk of intraoperative complications. We have previously investigated this scenario with respect to intracameral air in corneal endothelial transplantation, and described the concept of iris buckling. As a number of clinical interventions are recommended for addressing floppy iris syndrome, we wished to evaluate the impact of intracameral phenylephrine on iris buckling and so refine our mathematical model. We considered the stability of an iris structure under a uniform pressure loading. We performed mathematical and computational simulations to demonstrate iris buckling, and then altered the parameters to assess the impact of phenylephrine on the model. We elucidated a number of buckled iris configurations which become unstable as the intraocular pressure increased, for transversely isotropic iris material properties, and identified a positive correlation between the critical pressure and the iris stiffness. A mechanical analysis with a dilated pupil (mimicking phenylephrine use) was also conducted, and demonstrated a significant increase in the critical pressure required to induce iris buckling. We have shown that iris buckling can arise at lower pressures when the iris stiffness is reduced, as in floppy iris syndrome. The use of phenylephrine was shown to prevent iris movement (buckling) by increasing the required critical pressures. This refined model demonstrates the positive effectiveness of phenylephrine in the management of floppy iris syndrome and gives evidence to the clinical practice of using this as a preventative measure.
Coupled Dynamic Instability Analysis of Thin-Walled Columns Subjected to Harmonic Axial Loading
Authors: Yadav Amit , Panda Sarat Kumar , Dey Tanish
Published: June 2018

This paper presents triply coupled vibrations and instability analysis of thin-walled columns having a non-symmetrical open cross-section. Vlasov’s theory is used to derive the governing differential equations for coupled flexural and torsional vibrations. A numerical method is presented to determine the exact natural frequencies and corresponding mode shapes in terms of real functions. Employing Galerkin’s method, the coupled partial differential equations are reduced to a set of coupled Mathieu type equations. Following Bolotin’s method, the principal instability regions of thin-walled column with a non-symmetrical cross-section having various boundary conditions are determined. Numerical examples are presented to examine the effect of different boundary conditions, aspect ratios, static and dynamic load factors on principal instability regions. The study of response and corresponding phase plot in stable and unstable regions are carried out to identify the dynamic instability behavior.
Particle Size-Dependent Responses of Metal–Ceramic Functionally Graded Plates Under Low-Velocity Impact
Authors: Zhu Bao , Cai Yingjian
Published: June 2018

The analysis of impact response for metal–ceramic functionally graded materials is important for the design of advanced impact resistance structures in aerospace, nuclear and mechanical industries. Here, we propose a dislocation-based continuum model to analyze elasto-plastic deformation of metal–ceramic functionally graded plates under low-velocity impact. The dislocation-based continuum model explicitly accounts for strengthening effects due to geometrically necessary dislocations and plastic strain gradient in impact analysis of metal–ceramic functionally graded plates by combining Taylor dislocation model and Tamura–Tomota–Ozowa (TTO) model. In the dislocation-based model, we describe the effective linear elastic properties of the metal–ceramic functionally graded plates based on the Mori–Tanaka scheme. We show from finite element simulations that particle-size-dependent elasto-plastic properties play important roles in determining the impact behavior of metal–ceramic functionally graded plates and provide a good prediction of diameters of after-impact impression compared to experiments on SiC/Al functionally graded circular plates.
Dynamic Response and Stability of Un-Reinforced and Reinforced Rock Slopes Against Planar Sliding Subjected to Ground Shaking
Authors: Aydan Ö. , Takahashi Y. , Iwata N. , Kiyota R. , Adachi K.
Published: June 2018

The authors have been performing some scaled model tests to investigate the response and stability of rock slopes against planar sliding. In these tests, rockbolts/rockanchors are modeled and their reinforcement effects on rock slopes against planar sliding during ground shaking are investigated. These model tests are also used to check the reliability of the numerical simulations. The authors present the outcomes of both model experiments and numerical simulations and compare their implications on actual rock slopes.
Estimation of Surface Fault Displacement by High Performance Computing
Authors: Sawada Masataka , Haba Kazumoto , Hori Muneo
Published: June 2018

Reliable estimation of surface fault displacements is crucial to the safety of nuclear power plant facilities. It is necessary to develop a numerical method for the estimation. In the study, we develop a finite element method in which the following two functions are implemented: (1) a symplectic time integration of an explicit scheme to properly conserve the energy of the system; and (2) rigorously formulated joint elements of high order. The finite element method is enhanced with parallel computing capability. We apply the developed method to solve simple three-dimensional models of faults embedded in a rock mass. It includes a comparison of results from quasi-static and dynamic simulations and investigation of the sensitivity of results to the shear stiffness on faults. In the study, we propose capacity computing with a quasi-static simulation for uncertainty quantification.
Source Modeling for Predicting Ground Motions and Permanent Displacements Very Close to the Fault Trace
Authors: Ikutama Shinya , Kawasato Takeshi , Kawakami Yosuke , Nosho Masahiro , Oana Atsuko , Dan Kazuo , Torita Haruhiko , Okada Yasuo
Published: June 2018

A conventional “recipe” for strong ground motion prediction has been applied to the seismic fault (deep fault; located within seismogenic layer). In order to perform assessments of strong ground motions and permanent displacements at sites very close to the fault trace, we proposed the method of modeling that takes the entire ruptured fault from the ground surface to the seismic fault into account. Our approach was validated by the simulation of observed records obtained at stations very close to the fault trace of the mainshock of the 2016 Kumamoto Japan, earthquake (Mw7.1). Also, through the ground motion assessment performed for a hypothetical strike-slip fault with a 90[Formula: see text] dip angle, we found that adding the shallow fault had virtually no effect on acceleration time history, but it had a clear effect on the fault-parallel component of velocity and displacement time histories in the area close to the fault trace.
Effects of Earthquake Faulting on Civil Engineering Structures
Authors: Aydan Ömer , Nasiry Nasir Zia , Ohta Yoshimi , Ulusay Reşat
Published: June 2018

Ground motion characteristics, deformation and surface breaks of earthquakes depend upon the causative faults. Their effects on the seismic design of engineering structures are almost not considered in the present codes of design although there are attempts to include in some countries (i.e. USA, Japan, Taiwan, and Turkey). In this study, the authors first describe ground motions, crustal deformation and surface break observations caused by earthquakes having different faulting mechanism. Then some laboratory experiments were carried out to simulate the motions during normal and thrust faulting and their effects on model structures. And then, the effects of surface ruptures and deformations due to earthquake faulting on the response and stability engineering structures through observations in recent great earthquakes are presented. Finally, some recommendations for the design of structures with the consideration of permanent ground deformation in addition to ground shaking, which may be used in the development of seismic codes incorporating the effect of permanent deformation on structures, are proposed.
The Implementation of the Gradual Movement of Sliding Blocks to a New Method for Evaluating the Seismic Stability of Slopes Reinforced by Geotextile
Authors: Kawai Tadashi , Ishimaru Makoto
Published: June 2018

Evaluating the seismic stability of a rock slope typically involves searching for the minimum value of calculated safety factors (SF) for each supposed sliding block. Because only the transient equilibrium is evaluated, the likelihood of any slope failure can be deemed negligible if all the calculated SFs are greater than unity. However, even if some of the calculated SF are less than unity, it cannot be assumed that the slope will collapse. Recently, in the wake of extremely large earthquakes in Japan, the design earthquake standards for nuclear power plants (NPP) have been extended. After the experience of the 2011 off the Pacific coast of Tohoku Earthquake, the designer is expected to consider beyond design basis earthquakes to determine whether more can reasonably be done to reduce the potential for damage, especially where major consequences may ensue [IAEA (2011). IAEA international fact finding expert mission of the Fukushima dai-ichi NPP accident following the Great East Japan Earthquake and Tsunami, Mission report, IAEA]. With this in mind, the method employed to evaluate the seismic performance of the slope surrounding an NPP needs to be capable of doing more than determining the likelihood of failure: it must also consider the process toward failure in the event of an earthquake beyond the design basis. In this paper, a new evaluation flow which considers the failure process is proposed to evaluate the seismic performance of slopes surrounding an NPP. This is followed by confirming the validity of the concepts in the proposed flow chart by re-evaluating centrifuge tests in past literature and the numerical simulations designed for those tests.
Stability of a CD4+ T cell viral infection model with diffusion
Authors: Xu Zhiting , Xu Youqing
Published: June 2018

This paper is devoted to the study of the stability of a CD[Formula: see text] T cell viral infection model with diffusion. First, we discuss the well-posedness of the model and the existence of endemic equilibrium. Second, by analyzing the roots of the characteristic equation, we establish the local stability of the virus-free equilibrium. Furthermore, by constructing suitable Lyapunov functions, we show that the virus-free equilibrium is globally asymptotically stable if the threshold value [Formula: see text]; the endemic equilibrium is globally asymptotically stable if [Formula: see text] and [Formula: see text]. Finally, we give an application and numerical simulations to illustrate the main results.
THE AGGREGATION DILEMMA IN CLIMATE CHANGE POLICY EVALUATION
Authors: SCHUMACHER INGMAR
Published: June 2018

We show that a policy maker who ignores regional data and instead relies on aggregated integrated assessment models is likely underestimating the carbon price and thus the required climate policy. Based on a simple theoretical model, we give conditions under which the Aggregation Dilemma is expected to play a role in climate change cost-benefit analysis. We then study the importance of the Aggregation Dilemma with the integrated assessment model RICE [Nordhaus and Boyer, (2000) Warning the World: Economic Models of Global Warming. MA: MIT Press]. Aggregating all regions of the RICE-99 model into one region yields a 40% lower social cost of carbon than the RICE model itself predicts. Based on extrapolating the results, a country-level integrated assessment model would give a more than eight times higher social cost of carbon compared to a fully aggregated model. We suggest that these tentative results require researchers to rethink the aggregation level used in integrated assessment models and to develop models at much lower levels of aggregation than currently available.
Robotic intelligence and computational creativity
Authors: Augello Agnese , Infantino Ignazio , Maniscalco Umberto , Pilato Giovanni , Rizzo Riccardo , Vella Filippo
Published: June 2018

The paper illustrates a cognitive architecture for computational creativity based on the Psi model and the mechanisms inspired by dual-process theories of reasoning and rationality. In particular, three applications of computational creativity will be summed up: (a) a robot capable of executing creative paintings through a multilayer mechanism that implements an associative memory and is capable to properly mix elements belonging to different domains; (b) a robot aimed at producing a collage formed by a mix of photo-montage and digital collage: the artwork is created after a visual and verbal interaction with a human user; and (c) a humanoid robot capable of improvising a dancing choreography in real-time according to the listened music. First results in computational creativity show a set of potentialities to be explored that can shed light on human and artificial creativities and artificial intelligent systems.
Triiodothyronine and leptin repletion in humans similarly reverse weight-loss-induced changes in skeletal muscle
Authors: Rosenbaum Michael , Goldsmith Rochelle L. , Haddad Fadia , Baldwin Kenneth M. , Smiley Richard , Gallagher Dympna , Leibel Rudolph L.
Published: June 2018

Subjects maintaining a ≥10% dietary weight loss exhibit decreased circulating concentrations of bioactive thyroid hormones and increased skeletal muscle work efficiency largely due to increased expression of more-efficient myosin heavy chain (MHC) isoforms (MHC I) and significantly mediated by the adipocyte-derived hormone leptin. The primary purpose of this study was to examine the effects of triiodothyronine (T3) repletion on energy homeostasis and skeletal muscle physiology in weight-reduced subjects and to compare these results with the effects of leptin repletion. Nine healthy in-patients with obesity were studied at usual weight (Wtinitial) and following a 10% dietary weight loss while receiving 5 wk of a placebo (Wt−10%placebo) or T3 (Wt−10%T3) in a single-blind crossover design. Primary outcome variables were skeletal muscle work efficiency and vastus lateralis muscle mRNA expression. These results were compared with the effects of leptin repletion in a population of 22 subjects, some of whom participated in a previous study. At Wt−10%placebo, skeletal muscle work efficiency and relative expression of the more-efficient/less-efficient MHC I/MHC II isoforms were significantly increased and the ratio of the less-efficient to the more-efficient sarco(endo)plasmic reticulum Ca2+-ATPase isoforms (SERCA1/SERCA2) was significantly decreased. These changes were largely reversed by T3 repletion to a degree similar to the changes that occurred with leptin repletion. These data support the hypothesis that the effects of leptin on energy expenditure in weight-reduced individuals are largely mediated by T3 and suggest that further study of the possible role of thyroid hormone repletion as adjunctive therapy to help sustain weight loss is needed.
Analysis of short-term treatment with the phosphodiesterase type 5 inhibitor tadalafil on long bone development in young rats
Authors: Wang Luqiang , Jia Haoruo , Tower Robert J. , Levine Michael A. , Qin Ling
Published: June 2018

Cyclic GMP (cGMP) is an important intracellular regulator of endochondral bone growth and skeletal remodeling. Tadalafil, an inhibitor of the phosphodiesterase (PDE) type 5 (PDE5) that specifically hydrolyzes cGMP, is increasingly used to treat children with pulmonary arterial hypertension (PAH), but the effect of tadalafil on bone growth and strength has not been previously investigated. In this study, we first analyzed the expression of transcripts encoding PDEs in primary cultures of chondrocytes from newborn rat epiphyses. We detected robust expression of PDE5 as the major phosphodiesterase hydrolyzing cGMP. Time-course experiments showed that C-type natriuretic peptide increased intracellular levels of cGMP in primary chondrocytes with a peak at 2 min, and in the presence of tadalafil the peak level of intracellular cGMP was 37% greater ( P < 0.01) and the decline was significantly attenuated. Next, we treated 1-mo-old Sprague Dawley rats with vehicle or tadalafil for 3 wk. Although 10 mg·kg−1·day−1 tadalafil led to a significant 52% ( P < 0.01) increase in tissue levels of cGMP and a 9% reduction ( P < 0.01) in bodyweight gain, it did not alter long bone length, cortical or trabecular bone properties, and histological features. In conclusion, our results indicate that PDE5 is highly expressed in growth plate chondrocytes, and short-term tadalafil treatment of growing rats at doses comparable to those used in children with PAH has neither obvious beneficial effect on long bone growth nor any observable adverse effect on growth plate structure and trabecular and cortical bone structure.
Time course of fractional gluconeogenesis after meat ingestion in healthy adults: a D2O study
Authors: Gaudichon Claire , Ta Hai-Yen , Khodorova Nadezda V. , Oberli Marion , Breton Isabelle , Benamouzig Robert , Tomé Daniel , Godin Jean-Philippe
Published: June 2018

In the postprandial state, glucose homeostasis is challenged by macronutrient intake, including proteins that trigger insulin secretion and provide glucose precursors. However, little is known about the postprandial response of gluconeogenesis to a protein meal. We aimed to quantify the evolution of fractional gluconeogenesis after a meat meal. Thirteen healthy subjects received oral doses of D2O. After fasting overnight, they ingested a steak (120 g). Glycemia, insulinemia, and 2H enrichments in glucose and plasma water were measured for 8 h after the meal. Fractional gluconeogenesis was assessed using the average method. Glucose was stable for 5 h and then decreased. There was a slight increase of insulin 1 h after the meal. 2H enrichment in the carbon 5 position of glucose (C5) increased after 2 h, whereas it decreased in plasma water. Consequently, fractional gluconeogenesis increased from 68.2 ± 7.2% before the meal to 75.5 ± 5.8% 8 h after the meal, the latter corresponding to 22 h without a glucose supply. These values are consistent with the exhaustion of glycogen stores after 24 h but represent the highest among values in the literature. The impact of methodological conditions is discussed.
A Delamination Propagation Model for Fiber Reinforced Laminated Composite Materials
Authors: Aveiga David , Ribeiro Marcelo L.
Published: June 2018

The employment of composite materials in the aerospace industry has been gradually considered due to the fundamental lightweight and strength characteristics that this type of materials has. The science material and technological progress reached matched perfectly with the requirements for high-performance materials in aircraft and aerospace structures; thus, the development of primary structure elements applying composite materials became something very convenient. It is extremely important to pay attention to the failure modes that influence composite materials performances, since these failures lead to a loss of stiffness and strength of the laminate. Delamination is a failure mode present in most of the damaged structures and can be ruinous, considering that the evolution of interlaminar defects can carry the structure to a total failure followed by its collapse. The present work aims at the development of a delamination propagation model to estimate a progressive interlaminar delamination failure in laminated composite materials and to allow the prediction of material’s degradation due to delamination phenomenon. Experimental data, available at literature, was considered to determine some model parameters, like the strain energy release rate, using GFRPs laminated composites. This new delamination propagation model was implemented as subroutines in FORTRAN language (UMAT-User Material Subroutine) with formulations based on the Fracture Mechanics and Continuum Damage Mechanics. Finally, the UMAT subroutine was complemented with an intralaminar model and compiled beside the commercial Finite Element (FE) software ABAQUS™.
A Bee Evolutionary Algorithm for Multiobjective Vehicle Routing Problem with Simultaneous Pickup and Delivery
Authors: Gong Guiliang , Deng Qianwang , Gong Xuran , Zhang Like , Wang Haibin , Xie He
Published: June 2018

A new closed-loop supply chain logistics network of vehicle routing problem with simultaneous pickups and deliveries (VRPSPD) dominated by remanufacturer is constructed, in which the customers are originally divided into three types: distributors, recyclers, and suppliers. Furthermore, the fuel consumption is originally added to the optimization objectives of the proposed VRPSPD. In addition, a bee evolutionary algorithm guiding nondominated sorting genetic algorithm II (BEG-NSGA-II) with a two-stage optimization mechanism is originally designed to solve the proposed VRPSPD model with three optimization objectives: minimum fuel consumption, minimum waiting time, and the shortest delivery distance. The proposed BEG-NSGA-II could conquer the disadvantages of traditional nondominated sorting genetic algorithm II (NSGA-II) and algorithms with a two-stage optimization mechanism. Finally, the validity and feasibility of the proposed model and algorithm are verified by simulating an engineering machinery remanufacturing company’s reverse logistics and another three test examples.
Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes
Authors: Borghardt Jens Markus , Kloft Charlotte , Sharma Ashish
Published: June 2018

The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.
Validation of Activity Tracking Procedures in Elderly Patients after Operative Treatment of Proximal Femur Fractures
Authors: Schmal Hagen , Holsgaard-Larsen Anders , Izadpanah Kaywan , Brønd Jan Christian , Madsen Carsten Fladmose , Lauritsen Jens
Published: June 2018

Background. Early postoperative physical activity in elderly patients suffering from proximal femoral fractures may reduce mortality. We hypothesized that activity trackers can reliably and objectively monitor the in-hospital mobilization, correlating with functional independence and quality of life. Methods. Three different tracker types (Fitbit™ flex, Misfit™ Shine, and Axivity AX3) at three locations (wrist, ankle, and femur) recorded steps and signal vector magnitudes (SVM) in 22 patients. They were 81±8 years old, were equally distributed between the sexes, and had an ASA score of 2.5±0.6. Single protocoled activity events (n=191) were clinically categorized into 4 levels and correlated with the monitored signals. Additionally, 2±1 and 8±3 days after the operation, the EuroQol-5D and the Barthel-20 index supplemented this data. Results. All measurements at the wrist (Fitbit, Misfit) resulted in unacceptable accuracy; however, sensitivity and specificity reached around 90% using the Misfit at the ankle. Applying this combination, the correlation between real and measured steps (R2 = 0.99) and the category discrimination were statistically significant (p<0.002). A discriminant analysis featured the calculation of four activity levels based on SVM measurements using the Axivity tracker at the femur. A cluster analysis showed a 100% agreement between the clinically observed and the calculated activity levels. The amount of active minutes or periods and both the EuroQol-5D and the Barthel-20 indices significantly increased between the analyzed time points after the operation. However, only the Barthel-20 was associated with the measured activity levels (p<0.01). Conclusion. The Misfit and the Axivity trackers can reliably monitor activity in elderly patients after operative treatment of proximal femur fractures. However, the wear location is decisive. Objectively measured activity correlated with functional independence and quality of life.
Effect of Doping Metals on the Structure of PEO Coatings on Titanium
Authors: Sakhnenko Nykolay D. , Ved’ Maryna V. , Karakurkchi Ann V.
Published: June 2018

The structure and properties of the oxide films formed on titanium alloys by means of plasma-electrolytic oxidizing in alkali electrolytes based on pyrophosphates, borates, or acetates of alkali metals with the addition of dopants’ oxides or oxoanions of varying composition have been studied. Anodic polarization in the spark discharge (microarc) mode at application of interelectrode potential 90 to 160 V has been used to obtain mixed-oxide systems TiOx·WOy, TiOx·MoOy, TiOx·ZrO2, and TiOx·V2O5. The possibility to obtain the oxide layers containing the alloying elements by the modification of the composition of electrolytes has been stated. The chemical and phase composition as well as the topography, the microstructure, and the grain size of the formed layers depend on the applied current, interelectrode voltage, and the layer chemical composition. The effect of formed films composition on the resistance of titanium to corrosion has been discussed. Catalytic activity of mixed-oxide systems was determined in the model reaction of methyl orange dye MO photodestruction.
Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia
Authors: Qin Yanhua , Hu Weiming , Yang Yang , Hu Zhiying , Li Weiyun , Fang Marong
Published: June 2018

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.
Neurotoxicity of Inhalation Anesthetics in the Neonatal Rat Brain: Effects on Behavior and Neurodegeneration in the Piriform Cortex
Authors: O’Farrell Rachel A. , Foley Andrew G. , Buggy Donal J. , Gallagher Helen C.
Published: June 2018

There is concern that clinical use of anesthetic drugs may cause neurotoxicity in the developing brain and subsequent abnormal neurobehavior. We therefore evaluated neurotoxic effects of inhalation anesthetics in the neonatal rat brain, using in vivo histological and neurobehavioral outcomes. Wistar rats (n=79, postnatal day 15) were subjected to a clinically relevant single exposure of urethane, isoflurane, sevoflurane, or placebo, without surgery. At 48 h and 96 h, behavioral parameters were recorded and the animals were sacrificed. In cryosectioned brains, total cells and dying cells in layer II of the piriform cortex were counted using unbiased stereology. At 48 h, cell numbers in layer II of the piriform cortex of all drug-treated animals were reduced versus controls (p=0.01). The effect persisted at 96 h in isoflurane- and urethane-exposed animals. Piriform cortical layer II neurons undergoing degeneration, detected histologically by pyknotic nuclei and eosinophilic cytoplasm, were increased in the animals treated with isoflurane (1.9 ± 0.7 at 96 h) and urethane (2.4 ± 0.8 at 96 h) versus sevoflurane (0.8 ± 0.3 at 96 h) and controls (0.9 ± 0.2 at 96 h). Sevoflurane- and isoflurane-treated animals exhibited increased activity and decreased suckling compared with controls, and sevoflurane-exposed animals also displayed increased rearing behavior at both timepoints.
MST1 Suppression Reduces Early Brain Injury by Inhibiting the NF-κB/MMP-9 Pathway after Subarachnoid Hemorrhage in Mice
Authors: Qu Jie , Zhao Hengli , Li Qiang , Pan Pengyu , Ma Kang , Liu Xin , Feng Hua , Chen Yujie
Published: June 2018

Background. Mammalian sterile 20-like kinase 1 (MST1), the key component of the Hippo-YAP pathway, exhibits an important role in the pathophysiological process of various neurological disorders, including ischemic stroke and spinal cord injury. However, during subarachnoid hemorrhage, the involvement of MST1 in the pathophysiology of early brain injury remains unknown. Methods. We employed intravascular filament perforation to establish the subarachnoid hemorrhage (SAH) mouse model. The MST1 inhibitor XMU-MP-1 was intraperitoneally injected at 1 h after SAH, followed by daily injections. MST1 in vivo knockdown was performed 3 weeks prior to SAH via intracerebroventricular injection of adeno-associated virus (AAV) packaged with MST1 shRNA. The SAH grade, behavioral deficits, TUNEL staining, Evans blue dye extravasation and fluorescence, brain water content, protein and cytokine expressions by Western blotting, immunofluorescence, and proteome cytokine array were evaluated. Results. Following SAH, the phosphorylation level of MST1 was upregulated at 12 h, with a peak at 72 h after SAH. It was colocalized with the microglial marker Iba1. Both XMU-MP-1 and MST1 shRNA alleviated the neurological deficits, blood-brain barrier (BBB) disruption, brain edema, neuroinflammation, and white matter injury, which were induced by SAH in association with nuclear factor- (NF-) κB p65 and matrix metallopeptidase-9 (MMP-9) activation and downregulated endothelial junction protein expression. Conclusions. The current findings indicate that MST1 participates in SAH-induced BBB disruption and white matter fiber damage via the downstream NF-κB-MMP-9 signaling pathway. Therefore, MST1 antagonists may serve as a novel therapeutic target to prevent early brain injury in SAH patients.
Comparison of Machine-Learning Classification Models for Glaucoma Management
Authors: An Guangzhou , Omodaka Kazuko , Tsuda Satoru , Shiga Yukihiro , Takada Naoko , Kikawa Tsutomu , Nakazawa Toru , Yokota Hideo , Akiba Masahiro
Published: June 2018

This study develops an objective machine-learning classification model for classifying glaucomatous optic discs and reveals the classificatory criteria to assist in clinical glaucoma management. In this study, 163 glaucoma eyes were labelled with four optic disc types by three glaucoma specialists and then randomly separated into training and test data. All the images of these eyes were captured using optical coherence tomography and laser speckle flowgraphy to quantify the ocular structure and blood-flow-related parameters. A total of 91 parameters were extracted from each eye along with the patients’ background information. Machine-learning classifiers, including the neural network (NN), naïve Bayes (NB), support vector machine (SVM), and gradient boosted decision trees (GBDT), were trained to build the classification models, and a hybrid feature selection method that combines minimum redundancy maximum relevance and genetic-algorithm-based feature selection was applied to find the most valid and relevant features for NN, NB, and SVM. A comparison of the performance of the three machine-learning classification models showed that the NN had the best classification performance with a validated accuracy of 87.8% using only nine ocular parameters. These selected quantified parameters enabled the trained NN to classify glaucomatous optic discs with relatively high performance without requiring color fundus images.
Stochastic C-GNet Environment Modeling and Path Planning Optimization in a Narrow and Long Space
Authors: Yang Jianjian , Tang Zhiwei , Wang Xiaolin , Wang Zirui , Yin Biaojun , Wu Miao
Published: June 2018

This study proposes a novel method of optimal path planning in stochastic constraint network scenarios. We present a dynamic stochastic grid network model containing semienclosed narrow and long constraint information according to the unstructured environment of an underground or mine tunnel. This novel environment modeling (stochastic constraint grid network) computes the most likely global path in terms of a defined minimum traffic cost for a roadheader in such unstructured environments. Designing high-dimensional constraint vector and traffic cost in nodes and arcs based on two- and three-dimensional terrain elevation data in a grid network, this study considers the walking and space constraints of a roadheader to construct the network topology for the traffic cost value weights. The improved algorithm of variation self-adapting particle swarm optimization is proposed to optimize the regional path. The experimental results both in the simulation and in the actual test model settings illustrate the performance of the described approach, where a hybrid, centralized-distributed modeling method with path planning capabilities is used.
Epithelial–Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression
Authors: Kolijn Kimberley , Verhoef Esther I. , Smid Marcel , Böttcher René , Jenster Guido W. , Debets Reno , van Leenders Geert J.L.H.
Published: June 2018

Cancer invasion and metastasis are driven by epithelial–mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in patients with prostate cancer. We performed laser capture microdissection of matched N-cadherin–positive and -negative prostate cancer areas from patient samples (n = 8), followed by RNA sequencing. N-cadherin expression was significantly associated with an immune-regulatory signature including profound upregulation of indoleamine 2,3-dioxygenase (IDO1; log2-fold change = 5.1; P = 2.98E-04). Fluorescent immunostainings of patient samples confirmed expression of IDO1 protein and also its metabolite kynurenine in primarily N-cadherin–positive areas. N-cadherin–positive areas also exhibited a local decrease of intraepithelial cytotoxic (CD8+) T cells and an increase of immunosuppressive regulatory T cells (CD4+/FOXP3+). In conclusion, EMT in clinical prostate cancer is accompanied by upregulated expression of IDO1 and an increased number of regulatory T cells. These data indicate that EMT, which is an important step in tumor progression, can be protected from effective immune control in patients with prostate cancer.

Significance: These findings demonstrate EMT is linked to an immunosuppressive environment in clinical prostate cancer, suggesting that patients with prostate cancer can potentially benefit from combinatorial drug therapy. Cancer Res; 78(16); 4671–9. ©2018 AACR.
Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence
Authors: Pallavicini Gianmarco , Sgrò Francesco , Garello Francesca , Falcone Mattia , Bitonto Valeria , Berto Gaia E. , Bianchi Federico T. , Gai Marta , Chiotto Alessandra M.A. , Filippi Miriam , Cutrin Juan C. , Ala Ugo , Terreno Enzo , Turco Emilia , Cunto Ferdinando Di
Published: June 2018

Medulloblastoma is the most common malignant brain tumor in children. Current treatment for medulloblastoma consists of surgery followed by irradiation of the whole neuraxis and high-dose multiagent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting medulloblastoma growth without disturbing brain development is needed. Citron kinase protein (CITK), encoded by primary microcephaly gene MCPH17, is required for normal proliferation and survival of neural progenitors. Constitutive loss of CITK leads to cytokinesis failure, chromosome instability, and apoptosis in the developing brain, but has limited effects on other tissues. On this basis, we hypothesized that CITK could be an effective target for medulloblastoma treatment. In medulloblastoma cell lines DAOY and ONS-76, CITK knockdown increased both cytokinesis failure and DNA damage, impairing proliferation and inducing cell senescence and apoptosis via TP53 or TP73. Similar effects were obtained in the NeuroD-SmoA1 transgenic mouse model, in which CITK deletion increased apoptotic cells and senescence markers such as P21CIP1, P27KIP1, and P16INK4A. Most importantly, CITK deletion decreased tumor growth and increased overall survival in these mice, with no apparent side effects. These results suggest that CITK can be a useful molecular target for medulloblastoma treatment.

Significance: In vitro and in vivo proof of concept identifies citron kinase protein as a suitable target for medulloblastoma treatment.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4599/F1.large.jpg. Cancer Res; 78(16); 4599–612. ©2018 AACR.
Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation
Authors: Osumi Tomoo , Tsujimoto Shin-ichi , Tamura Moe , Uchiyama Meri , Nakabayashi Kazuhiko , Okamura Kohji , Yoshida Masanori , Tomizawa Daisuke , Watanabe Akihiro , Takahashi Hiroyuki , Hori Tsukasa , Yamamoto Shohei , Hamamoto Kazuko , Migita Masahiro , Ogata-Kawata Hiroko , Uchiyama Toru , Kizawa Hiroe , Ueno-Yokohata Hitomi , Shirai Ryota , Seki Masafumi , Ohki Kentaro , Takita Junko , Inukai Takeshi , Ogawa Seishi , Kitamura Toshio , Matsumoto Kimikazu , Hata Kenichiro , Kiyokawa Nobutaka , Goyama Susumu , Kato Motohiro
Published: June 2018

Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL.

Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.
Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment
Authors: Kato Takuya , Noma Kazuhiro , Ohara Toshiaki , Kashima Hajime , Katsura Yuki , Sato Hiroaki , Komoto Satoshi , Katsube Ryoichi , Ninomiya Takayuki , Tazawa Hiroshi , Shirakawa Yasuhiro , Fujiwara Toshiyoshi
Published: June 2018

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression.

Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.

Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3+ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues.

Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820–33. ©2018 AACR.
Prognostic Value of Methylator Phenotype in Stage III Colon Cancer Treated with Oxaliplatin-based Adjuvant Chemotherapy
Authors: Gallois Claire , Taieb Julien , Le Corre Delphine , Le Malicot Karine , Tabernero Josep , Mulot Claire , Seitz Jean-François , Aparicio Thomas , Folprecht Gunnar , Lepage Côme , Mini Enrico , Van Laethem Jean-Luc , Emile Jean-François , Laurent-Puig Pierre
Published: June 2018

Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen.

Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3. Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 ± cetuximab).

Results: CIMP status was successfully determined in 1,867 patients (97.9%): 275 (14.7%) tumors were CIMP+. Compared with CIMP− patients, CIMP+ patients were more frequently older (P = 0.002), females (P = 0.04), with right-sided (P < 0.0001), grade 3–4 (P < 0.0001), pN2 (P = 0.001), dMMR (P < 0.0001), BRAF mutated (P < 0.0001), and RAS wild-type (P < 0.0001) tumors. In multivariate analysis, CIMP+ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02–1.94; P = 0.04] and SAR [HR, 1.76; 95% CI, 1.20–2.56; P < 0.0004]; but not DFS [HR, 1.15; 95% CI, 0.86–1.54; P = 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMP+ tumors for OS, DFS, and SAR.

Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMP+ phenotype is associated with a shorter OS and SAR but not to DFS. Clin Cancer Res; 24(19); 4745–53. ©2018 AACR.