bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonally resolved environmental reconstructions using fish otoliths
Authors: Izzo Christopher , Doubleday Zoë A. , Grammer Gretchen L. , Disspain Morgan C.F. , Ye Qifeng , Gillanders Bronwyn M.
Published: June 2016

Exploiting the chemical and growth properties of otoliths, this study demonstrates how environmental archives with high temporal resolution can be developed. Elemental profiles (Ba:Ca and Sr:Ca) of fish otoliths (ear bones) from the estuarine species Acanthopagrus butcheri (black bream) were related to growth increments on a seasonal time scale. A series of mixed effects models were used to investigate biological, temporal, and environmental factors influencing seasonal otolith elemental profiles. Resultant seasonally resolved chemical chronologies were correlated with environmental data (i.e., salinity) to develop an element–salinity regression function, which when fit to an independently derived chemical chronology showed strong agreement between reconstructed and recorded salinities. Support for the element–salinity regression function through independent verification provided confidence in environmental reconstructions derived from an archaeological otolith. This suggests otoliths can be used to reconstruct past environmental conditions over decadal and centennial time scales. Moreover, the application of mixed effect models to develop chemical chronologies also provides information on drivers of elemental profiles and allows a range of ecological questions to be addressed. This approach may be further adapted and employed across a broader range of taxonomic groups and environments.
Positive L1-gain filter design for positive Markovian jump systems with time-varying delay and incomplete transition rates
Authors: Qi Wenhai , Gao Xianwen , Kao Yonggui
Published: June 2016

This paper deals with the problem of positive L1-gain filter design for positive Markovian jump systems with time-varying delay and incomplete transition rates. By implying an appropriate co-positive type Lyapunov function and free-connection weighting vectors, sufficient conditions for stochastic stability of the filtering error system are established. Then, the L1-gain performance is analyzed. Based on the obtained results, a positive full-order filter is designed to ensure that the corresponding filtering error system is positive and stochastically stable with L1-gain performance. All the conditions are derived in linear programming. Finally, the obtained theoretical results are demonstrated by a numerical example.
Protective effects ofZygophyllum albumextract against deltamethrin-induced hyperglycemia and hepato-pancreatic disorders in rats
Authors: Feriani Anouar , Hachani Rafik , Kaabi Belhassen , Ncir Marwa , El Feki Abdelfattah , Allagui Mohamed Salah
Published: June 2016

The current study was designed to investigate the possible mechanism involved in hyperglycemia induced by chronic exposure to deltamethrin (DLM) in rat and to assess whether this damage is amenable to modulation by Zygophyllum album. DLM, a synthetic pyrethroid pesticide, was administrated at a dose of 4 mg/kg body mass, during 60 days. Compared with control, DLM showed a significant increase of blood glucose (p ≤ 0.01) and glycosylated hemoglobin levels (p ≤ 0.01) and a clear decrease (p ≤ 0.01) of insulin and total hemoglobin levels. In addition, hepatic glycogen content and the activity of hexokinase decreased (p ≤ 0.01), whereas the activities of glucose-6-phosphatase and glycogen phosphorylase were significantly increased (p ≤ 0.01). Moreover, pancreatic lipid peroxidation (TBARS level) was higher (p ≤ 0.01) and oxidative stress biomarkers (SOD, CAT, GPx, and GSH) were altered owing to DLM toxicity. However, Z. album, when combined with DLM, significantly ameliorated almost all the hepato-pancreatic disorders induced by DLM alone. Furthermore, Z. album supplement was found to be effective in preserving the normal histological appearance of hepatic and pancreatic tissue. In conclusion, this study suggested that, owing to its antioxidant effects, methanolic extract of Z. album (MEZAL) can potentially prevent the hyperglycemia observed in DLM-treated group.
Necessary but challenging: Multiple disciplinary approaches to solving conservation problems
Authors: Dick Melissa , Rous Andrew M. , Nguyen Vivian M. , Cooke Steven J.
Published: June 2016

Contemporary conservation problems are typically positioned at the interface of complex ecological and human systems. Traditional approaches aiming to compartmentalize a phenomenon within the confines of a single discipline and failing to engage non-science partners are outmoded and cannot identify solutions that have traction in the social, economic, and political arenas in which conservation actions must operate. As a result, conservation science teams must adopt multiple disciplinary approaches that bridge not only academic disciplines but also the political and social realms and engage relevant partners. Five reasons are presented that outline why conservation problems demand multiple disciplinary approaches in order to move forward because: (i) socio-ecological systems are complex, (ii) multiple perspectives are better than one, (iii) the results of research must influence practice, (iv) the heterogeneity of scale necessitates it, and (v) conservation involves compromise. Presenting reasons that support multiple disciplinarity demands a review of the barriers that impede this process, as we are far from attaining a model or framework that is applicable in all contexts. Two challenges that impede multiple disciplinarity are discussed, in addition to pragmatic solutions that conservation scientists and practitioners can adopt in their work. Overall, conservation researchers and practitioners are encouraged to explore the multiple disciplinary dimensions of their respective realms to more effectively solve problems in biodiversity and sustainability.
A quantitative protocol for DNA metabarcoding of springtails (Collembola)
Authors: Saitoh Seikoh , Aoyama Hiroaki , Fujii Saori , Sunagawa Haruki , Nagahama Hideki , Akutsu Masako , Shinzato Naoya , Kaneko Nobuhiro , Nakamori Taizo
Published: June 2016

We developed a novel protocol with superior quantitative analysis results for DNA metabarcoding of Collembola, a major soil microarthropod order. Degenerate PCR primers were designed for conserved regions in the mitochondrial cytochrome c oxidase subunit I (mtCOI) and 16S ribosomal RNA (mt16S) genes based on published collembolan mitogenomes. The best primer pair was selected based on its ability to amplify each gene, irrespective of the species. DNA was extracted from 10 natural communities sampled in a temperate forest (with typically 25–30 collembolan species per 10 soil samples) and 10 mock communities (with seven cultured collembolan species). The two gene regions were then amplified using the selected primers, ligated with adapters for 454 technology, and sequenced. Examination of the natural community samples showed that 32 and 36 operational taxonomic units (defined at a 90% sequence similarity threshold) were recovered from the mtCOI and mt16S data, respectively, which were comparable to the results of the microscopic identification of 25 morphospecies. Further, sequence abundances for each collembolan species from the mtCOI and mt16S data of the mock communities, after normalization by using a species as the internal control, showed good correlation with the number of individuals in the samples (R = 0.91–0.99), although relative species abundances within a mock community sample estimated from sequences were skewed from community composition in terms of the number of individuals or biomass of the species. Thus, this protocol enables the comparison of collembolan communities in a quantitative manner by metabarcoding.
Some Characterizations of a Normal Subgroup of a Group and Isotopic Classes of Transversals
Authors: Kakkar Vipul , Shukla R. P.
Published: June 2016

Let G be a group and H be a subgroup of G which is either finite or of finite index in G. In this paper, we give some characterizations for the normality of H in G. As a consequence we get a very short and elementary proof of the main theorem of a paper of Lal and Shukla, which avoids the use of the classification of finite simple groups. Further, we study the isotopy between the transversals in some groups and determine the number of isotopy classes of transversals of a subgroup of order 2 in D2p, the dihedral group of order 2p, where p is an odd prime and the isotopism classes are formed with respect to induced right loop structures.
Quasitriangular Turaev Group Coalgebras and Radford's Biproduct
Authors: Guo Shuangjian , Wang Shuanhong
Published: June 2016

In this paper, we construct a new example of Hopf group coalgebras by considering Radford's biproduct Hopf algebra in the Turaev category. Furthermore, we find some sufficient and necessary conditions for such Radford's biproduct Hopf algebra to admit quasitriangular structures in the sense of Turaev group coalgebras.
The Derivation Algebra and Automorphism Group of the Twisted N = 2 Superconformal Algebra
Authors: Fa Huanxia , Han Jianzhi , Yue Xiaoqing
Published: June 2016

In this paper, the derivation algebra and the automorphism group of the twisted N=2 superconformal algebra are completely determined.
Cohen-Macaulay and Gorenstein Path Ideals of Trees
Authors: Saeedi Madani Sara , Kiani Dariush
Published: June 2016

Let R=k[x1,…,xn], where k is a field. The path ideal (of length t ≥ 2) of a directed graph G is the monomial ideal, denoted by It(G), whose generators correspond to the directed paths of length t in G. Let Γ be a directed rooted tree. We characterize all such trees whose path ideals are unmixed and Cohen-Macaulay. Moreover, we show that R/It(Γ) is Gorenstein if and only if the Stanley-Reisner simplicial complex of It(Γ) is a matroid.
On the Normality of One-fibered Monomial Ideals
Authors: Beddani Charef , Messirdi Wahiba
Published: June 2016

This paper presents a generalization to the higher-dimensional situation of the main results of the first author about the normality of one-fibered monomial ideals [2, Théorèmes 2.4 and 3.8]. Precisely, we show that if I is a monomial ideal of R = k[x1,x2,…,xd], then I is normal one-fibered if and only if for all positive integers n and all x, y in R such that xy ∈ I2n, either x or y belongs to In.
Differential Evolution-Based Synthesis of Dynamic Quantizers with Fixed-Structures
Authors: Minami Yuki , Muromaki Takao
Published: June 2016

In the discrete-valued input control of dynamical systems, quantizers, which convert continuous-valued signals into discrete-valued ones, play an important role. This paper focuses on the design problem of dynamic quantizers with fixed-structures such as a fixed-order and a decentralized structure. It is known to be difficult to solve the problem since it is NP-hard. Therefore, in order to solve the problem in practical steps, we adopt differential evolution (DE) which is one of the evolutionary computation algorithms. We first propose a DE-based design method of quantizers with fixed structures. Then, the effectiveness of the proposed method is verified by examples in the discrete-valued input control of dynamical systems. Moreover, we compare the performance of the proposed DE-based method with that of a particle swarm optimization (PSO)-based method, and show that DE is an easy-to-use and reliable tool for quantizer design problem.
Dyke–brittle shear relationships in the Western Deccan Strike-slip Zone around Mumbai (Maharashtra, India)
Authors: Misra Achyuta Ayan , Mukherjee Soumyajit
Published: June 2016

Dykes are abundant in the Deccan Large Igneous Province, and those to the west are referred to as the ‘coastal swarm’. Most of the coastal swarm dykes appear in the Western Deccan Strike-slip Zone (WDSZ). Faults with N–S, NE–SW and NW–SE trends (brittle shears) have been reported in the WDSZ around Mumbai. However, details of their relationships with Deccan dykes, which can easily be studied at sub-horizontal outcrops, have remained unknown. Previous authors have classified dykes in the WDSZ according to their isotopic ages as group I (
c.
65.6 Ma), group II (
c.
65 Ma) and group III (64–63 Ma). Dykes have also been categorized on the basis of field observations; group I dykes were found to pre-date deformation related to the separation of Seychelles and India, whereas group II and III dykes post-date this event. Our field studies reveal group I dykes to be faulted/sheared and lacking a uniform trend, whereas group II and III dykes have approximately N–S, NW–SE and NE–SW trends and intrude brittle shears/fault planes. We have also found evidence of syn-deformation intrusion in the group II and III dykes: e.g. P-planes along the dyke margins and grooves in the baked zone of dykes. These two groups of dykes match the trends of dominantly sinistral brittle shears. Of the 43 dykes studied, only ten belong to group I, and we conclude that a large proportion of the dykes in the WDSZ belong to groups II and III. It is erroneous to interpret the Seychelles–India rifting as simple near-E–W extension at
c.
63–62 Ma from the general approximately N–S trend of the dykes; the direction of brittle extension must instead be deduced from brittle shears/fault planes.

Supplementary material:
Stereo plots and reduced stress tensors for all faults and brittle shears are available at
https://doi.org/10.6084/m9.figshare.c.3259627
An empirical reexamination of global DNS behavior
Authors: Gao Hongyu , Yegneswaran Vinod , Chen Yan , Porras Phillip , Ghosh Shalini , Jiang Jian , Duan Haixin
Published: June 2016

The performance and operational characteristics of the DNS protocol are of deep interest to the research and network operations community. In this paper, we present measurement results from a unique dataset containing more than 26 billion DNS query-response pairs collected from more than 600 globally distributed recursive DNS resolvers. We use this dataset to reaffirm findings in published work and notice some significant differences that could be attributed both to the evolving nature of DNS traffic and to our differing perspective. For example, we find that although characteristics of DNS traffic vary greatly across networks, the resolvers within an organization tend to exhibit similar behavior. We further find that more than 50% of DNS queries issued to root servers do not return successful answers, and that the primary cause of lookup failures at root servers is malformed queries with invalid TLDs. Furthermore, we propose a novel approach that detects malicious domain groups using temporal correlation in DNS queries. Our approach requires no comprehensive labeled training set, which can be difficult to build in practice. Instead, it uses a known malicious domain as anchor, and identifies the set of previously unknown malicious domains that are related to the anchor domain. Experimental results illustrate the viability of this approach, i.e. , we attain a true positive rate of more than 96%, and each malicious anchor domain results in a malware domain group with more than 53 previously unknown malicious domains on average.
Full duplex radios
Authors: Bharadia Dinesh , McMilin Emily , Katti Sachin
Published: June 2016

This paper presents the design and implementation of the first in-band full duplex WiFi radios that can simultaneously transmit and receive on the same channel using standard WiFi 802.11ac PHYs and achieves close to the theoretical doubling of throughput in all practical deployment scenarios. Our design uses a single antenna for simultaneous TX/RX (i.e., the same resources as a standard half duplex system). We also propose novel analog and digital cancellation techniques that cancel the self interference to the receiver noise floor, and therefore ensure that there is no degradation to the received signal. We prototype our design by building our own analog circuit boards and integrating them with a fully WiFi-PHY compatible software radio implementation. We show experimentally that our design works robustly in noisy indoor environments, and provides close to the expected theoretical doubling of throughput in practice.
On HTTP live streaming in large enterprises
Authors: Roverso Roberto , El-Ansary Sameh , Högqvist Mikael
Published: June 2016

In this work, we present a distributed caching solution which addresses the problem of efficient delivery of HTTP live streams in large private networks. With our system, we have conducted tests on a number of pilot deployments. The largest of them, with 3000 concurrent viewers, consistently showed that our system saves more than 90% of traffic towards the source of the stream while providing the same quality of user experience of a CDN. Another result is that our solution was able to reduce the load on the bottlenecks in the network by an average of 91.6%.
Security risks evaluation toolbox for smart grid devices
Authors: Liu Yang , Liu Jiahe , Liu Ting , Guan Xiaohong , Sun Yanan
Published: June 2016

Numerous smart devices are deployed in smart grid for state measurement, decision-making and remote control. The security issues of smart devices attract more and more attention. In our work, the communication protocol, storage mechanism and authentication of smart devices are analyzed and a toolbox is developed to evaluate the security risks of smart devices. In this demo, our toolbox is applied to scan 3 smart meters/power monitor systems. A potential risk list is generated and the vulnerabilities are further verified.
The contagion of malicious behaviors in online games
Authors: Woo Jiyoung , Kang Ah Reum , Kim Huy Kang
Published: June 2016

This article investigates whether individual users are more likely to display malicious behavior after receiving social reinforcement from friends in their online social networks. We analyze the dynamics of game bot diffusion on the basis of real data supplied by a major massively multiplayer online role-playing game company. We find that the social reinforcement, measured by the ratio of bot friends over total friends, affects the likelihood of game bot adoption and the commitment in terms of usage time.
Thermotherapy reduces blood pressure and circulating endothelin-1 concentration and enhances leg blood flow in patients with symptomatic peripheral artery disease
Authors: Neff Dustin , Kuhlenhoelter Alisha M. , Lin Chen , Wong Brett J. , Motaganahalli Raghu L. , Roseguini Bruno T.
Published: June 2016

Leg thermotherapy (TT) application reduces blood pressure (BP) and increases both limb blood flow and circulating levels of anti-inflammatory mediators in healthy, young humans and animals. The purpose of the present study was to determine the impact of TT application using a water-circulating garment on leg and systemic hemodynamics and on the concentrations of circulating cytokines and vasoactive mediators in patients with symptomatic peripheral artery disease (PAD). Sixteen patients with PAD and intermittent claudication (age: 63 ± 9 yr) completed three experimental sessions in a randomized order: TT, control intervention, and one exercise testing session. The garment was perfused with 48°C water for 90 min in the TT session and with 33°C water in the control intervention. A subset of 10 patients also underwent a protocol for the measurement of blood flow in the popliteal artery during 90 min of TT using phase-contrast MRI. Compared with the control intervention, TT promoted a significant reduction in systolic (∼11 mmHg) and diastolic (∼6 mmHg) BP ( P < 0.05) that persisted for nearly 2 h after the end of the treatment. The serum concentration of endothelin-1 (ET-1) was significantly lower 30 min after exposure to TT (Control: 2.3 ± 0.1 vs. TT: 1.9 ± 0.09 pg/ml, P = 0.026). In addition, TT induced a marked increase in peak blood flow velocity (∼68%), average velocity (∼76%), and average blood flow (∼102%) in the popliteal artery ( P < 0.01). These findings indicate that TT is a practical and effective strategy to reduce BP and circulating ET-1 concentration and enhance leg blood flow in patients with PAD.
Eggshell and Bacterial Cellulose Composite Membrane as Absorbent Material in Active Packaging
Authors: Ummartyotin S. , Pisitsak P. , Pechyen C.
Published: June 2016

Bacterial cellulose and eggshell composite was successfully developed. Eggshell was mixed with bacterial cellulose suspension and it was casted as a composite film. CaCO3derived from eggshell was compared with its commercial availability. It can be noted that good dispersion of eggshell particle was prepared. Eggshell particle was irregular in shape with a variation in size. It existed in bacterial cellulose network. Characterization on composite was focused on thermal and mechanical properties. It showed that flexibility and thermal stability of composite were enhanced. No significant effect of mechanical properties was therefore observed. The thermal stability of composite was stable up to 300°C. The adsorption experiment on water and vegetable oil capacity was performed. The enhancement on adsorption was due to the existence of eggshell in bacterial cellulose composite. It exhibited the potential to be a good candidate for absorbent material in active packaging.
A Comparative Study of Microleakage on Dental Surfaces Bonded with Three Self-Etch Adhesive Systems Treated with the Er:YAG Laser and Bur
Authors: Sanhadji El Haddar Youssef , Cetik Sibel , Bahrami Babak , Atash Ramin
Published: June 2016

Aim. This study sought to compare the microleakage of three adhesive systems in the context of Erbium-YAG laser and diamond bur cavity procedures. Cavities were restored with composite resin.Materials and Methods. Standardized Class V cavities were performed in 72 extracted human teeth by means of diamond burs or Er-YAG laser. The samples were randomly divided into six groups of 12, testing three adhesive systems (Clearfil s3Bond Plus, Xeno® Select, and Futurabond U) for each method used. Cavities were restored with composite resin before thermocycling (methylene blue 2%, 24 h). The slices were prepared using a microtome. Optical microscope photography was employed to measure the penetration.Results. No statistically significant differences in microleakage were found in the use of bur or laser, nor between adhesive systems. Only statistically significant values were observed comparing enamel with cervical walls (p<0.001).Conclusion. It can be concluded that the Er:YAG laser is as efficient as diamond bur concerning microleakage values in adhesive restoration procedures, thus constituting an alternative tool for tooth preparation.
Canadian Association of Gastroenterology Indicators of Safety Compromise following Colonoscopy in Clinical Practice
Authors: Borgaonkar Mark R. , Pace David , Lougheed Muna , Marcoux Curtis , Evans Bradley , Hickey Nikita , O’Leary Meghan , McGrath Jerry
Published: June 2016

In 2012 the Canadian Association of Gastroenterology published 19 indicators of safety compromise. We studied the incidence of these indicators by reviewing all colonoscopies performed in St. John’s, NL, between January 1, 2012, and June 30, 2012.Results. A total of 3235 colonoscopies were included. Adverse events are as follows.Medication-relatedincludes use of reversal agents 0.1%, hypoxia 9.9%, hypotension 15.4%, and hypertension 0.9%. No patients required CPR or experienced allergic reactions or laryngospasm/bronchospasm. The indicator, “sedation dosages in patients older than 70,” showed lower usage of fentanyl and midazolam in elderly patients.Procedure-related immediateincludes perforation 0.2%, immediate postpolypectomy bleeding 0.3%, need for hospital admission or transfer to the emergency department 0.1%, and severe persistent abdominal pain proven not to be perforation 0.4%. Instrument impaction was not seen.Procedure-related delayedincludes death within 14 days 0.1%, unplanned health care visit within 14 days of the colonoscopy 1.8%, unplanned hospitalization within 14 days of the colonoscopy 0.6%, bleeding within 14 days of colonoscopy 0.2%, infection 0.03%, and metabolic complication 0.03%.Conclusions. The most common adverse events were mild and sedation related. Rates of serious adverse events were in keeping with published reports.
Effects of Aeration Treatment onγ-Aminobutyric Acid Accumulation in Germinated Tartary Buckwheat (Fagopyrum tataricum)
Authors: Guo Yuanxin , Zhu Yunhui , Chen Chunxu , Chen Xiaoman
Published: June 2016

To explore the optimum condition ofγ-aminobutyric acid (GABA) accumulation in germinated tartary buckwheat, effects of some factors including aeration treatment, physiological indexes, air flow rate, culture temperature, and pH value of cultivating solution under hypoxia on GABA in germinated tartary buckwheat were investigated. The results showed that the dark cultures with distilled water at 30°C, 2 days, and aeration stress with 1.0 L/min air flow rate at 30°C were optimal for GABA accumulation. Under these conditions, the predicted content of GABA was up to 371.98 μg/g DW. The analysis of correlation indicated that there was a significant correlation (P<0.01) between GABA accumulation and physiological indexes. Box-Behnken experimental analysis revealed that optimal conditions with aeration treatment for GABA accumulation in germinated tartary buckwheat were air flow rate of 1.04 L/min, culture temperature of 31.25°C, and a pH value of 4.21. Under these conditions, the GABA content was predicted as high as 386.20 μg/g DW, which was close to the measured value (379.00±9.30 μg/g DW). The variance analysis and validation test suggested that this established regression model could predict GABA accumulation in tartary buckwheat during germination.
Anti-VEGF in a Marathon Runner’s Retinopathy Case
Authors: Soon Alexander Kahjun , Oliveira Paulo Ricardo Chaves de , Chow David Robert
Published: June 2016

Central retinal vein occlusion (CRVO) is one of the most common retinal vascular disorders. Intense exercise associated CRVO have been described in otherwise healthy young patients. We describe a case of a young male ultramarathoner who presented with a CRVO, presumably associated with dehydration, making part of a marathon runner’s retinopathy. Resolution of macular edema and subretinal fluid, with visual acuity improvement, was observed after 3 monthly injections of ranibizumab. Our case suggests that dehydration could be involved in the mechanism of CRVO in healthy young patients and ranibizumab may be an effective treatment option for marathon runner’s retinopathy.
Magnesium Attenuates Phosphate-Induced Deregulation of a MicroRNA Signature and Prevents Modulation of Smad1 and Osterix during the Course of Vascular Calcification
Authors: Louvet Loïc , Metzinger Laurent , Büchel Janine , Steppan Sonja , Massy Ziad A.
Published: June 2016

Vascular calcification (VC) is prevalent in patients suffering from chronic kidney disease (CKD). High phosphate levels promote VC by inducing abnormalities in mineral and bone metabolism. Previously, we demonstrated that magnesium (Mg2+) prevents inorganic phosphate- (Pi-) induced VC in human aortic vascular smooth muscle cells (HAVSMC). As microRNAs (miR) modulate gene expression, we investigated the role of miR-29b, -30b, -125b, -133a, -143, and -204 in the protective effect of Mg2+on VC. HAVSMC were cultured in the presence of 3 mM Pi with or without 2 mM Mg2+chloride. Total RNA was extracted after 4 h, 24 h, day 3, day 7, and day 10. miR-30b, -133a, and -143 were downregulated during the time course of Pi-induced VC, whereas the addition of Mg2+restored (miR-30b) or improved (miR-133a, miR-143) their expression. The expression of specific targets Smad1 and Osterix was significantly increased in the presence of Pi and restored by coincubation with Mg2+. As miR-30b, miR-133a, and miR-143 are negatively regulated by Pi and restored by Mg2+with a congruent modulation of their known targets Runx2, Smad1, and Osterix, our results provide a potential mechanistic explanation of the observed upregulation of these master switches of osteogenesis during the course of VC.
Lower Limb Reconstruction with Tibia Allograft after Resection of Giant Aneurysmal Bone Cyst
Authors: Soares do Brito Joaquim , Teixeira Joana , Portela José
Published: June 2016

Aneurysmal bone cysts (ABCs) are benign, expansible, nonneoplastic lesions of the bone, characterized by channels of blood and spaces separated by fibrous septa, which occur in young patients and, occasionally, with aggressive behavior. Giant ABC is an uncommon pathological lesion and can be challenging because of the destructive effect of the cyst on the bones and the pressure on the nearby structures, especially on weight-bearing bones. In this scenario,en blocresection is the mainstay treatment and often demands complex reconstructions. This paper reports a difficult case of an unusual giant aneurysmal bone cyst, which required extensive resection and a knee fusion like reconstruction with tibia allograft.
Unusual Ventilatory Response to Exercise in Patient with Arnold-Chiari Type 1 Malformation after Posterior Fossa Decompression
Authors: Smith Keely , Gomez-Rubio Ana M. , Harris Tomika S. , Brooks Lauren E. , Mosquera Ricardo A.
Published: June 2016

We present a case of a 17-year-old Hispanic male with Arnold-Chiari Type 1 [AC-Type 1] with syringomyelia, status post decompression, who complains of exercise intolerance, headaches, and fatigue with exertion. The patient was found to have diurnal hypercapnia and nocturnal alveolar hypoventilation. Cardiopulmonary testing revealed blunting of the ventilatory response to the rise in carbon dioxide (CO2) resulting in failure of the parallel correlation between increased CO2levels and ventilation; the expected vertical relationship between PETCO2and minute ventilation during exercise was replaced with an almost horizontal relationship. No new pathology of the brainstem was discovered by MRI or neurological evaluation to explain this phenomenon. The patient was placed on continuous noninvasive open ventilation (NIOV) during the day and CPAP at night for a period of 6 months. His pCO2level decreased to normal limits and his symptoms improved; specifically, he experienced less headaches and fatigue during exercise. In this report, we describe the abnormal response to exercise that patients with AC-Type 1 could potentially experience, even after decompression, characterized by the impairment of ventilator response to hypercapnia during exertion, reflecting a complete loss of chemical influence on breathing with no evidence of abnormality in the corticospinal pathway.
Resistance Status to the Insecticides Temephos, Deltamethrin, and Diflubenzuron in BrazilianAedes aegyptiPopulations
Authors: Bellinato Diogo Fernandes , Viana-Medeiros Priscila Fernandes , Araújo Simone Costa , Martins Ademir J. , Lima José Bento Pereira , Valle Denise
Published: June 2016

Insecticides are still largely applied in public health to control disease vectors. In Brazil, organophosphates (OP) and pyrethroids (PY) are used againstAedes aegyptifor years. Since 2009 Insect Growth Regulators (IGR) are also employed in the control of larvae. We quantified resistance to temephos (OP), deltamethrin (PY), and diflubenzuron (IGR) ofA. aegyptisamples from 12 municipalities distributed throughout the country, collected between 2010 and 2012. High levels of resistance to neurotoxic insecticides were detected in almost all populations: RR95to temephos varied between 4.0 and 27.1; the lowest RR95to deltamethrin was 13.1, and values higher than 70.0 were found. In contrast, all samples were susceptible to diflubenzuron (RR95< 2.3). Biochemical tests performed with larvae and adults discarded the participation of acetylcholinesterase, the OP target, and confirmed involvement of the detoxifying enzymes esterases, mixed function oxidases, and glutathione-S-transferases. The results obtained were discussed taking into account the public chemical control component and the increase in the domestic use of insecticides during dengue epidemic seasons in the evaluated municipalities.
Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition
Authors: Yu Xiaocong , Duval Mark , Gawron Melissa , Posner Marshall R. , Cavacini Lisa A.
Published: June 2016

Innovative strategies are necessary to maximize the clinical application of HIV neutralizing antibodies. To this end, bispecific constructs of human antibody F240, reactive with well-conserved gp41 epitope and antibody 14A8, reactive with the IgA receptor (CD89) on effector cells, were constructed. A F240 × 14A8 bispecific single chain variable region (scFv) molecule was constructed by linking two scFvs using a conventional GGGGS linker. Despite immunoreactivity with HIV gp41 and neutrophils, this bispecific scFv failed to inhibit HIV infection. This is in sharp contrast to viral inhibition using a chemical conjugate of the Fab of these two antibodies. Therefore, we constructed two novel Fab-like bispecific antibody molecules centered on fusion of the IgG1 CH1 domain or CH1-hinge domain to the C-terminus of F240scFv and fusion of the kappa chain CL domain to the C-terminus of 14A8scFv. Both Bi-Fab antibodies showed significant ADCVI activity for multiple clade B and clade C isolates by arming the neutrophils to inhibit HIV infection. The approach presented in this study is unique for HIV immunotherapy in that the impetus of neutralization is to arm and mobilize PMN to destroy HIV and HIV infected cells.
Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma
Authors: Cadamuro Massimiliano , Spagnuolo Gaia , Sambado Luisa , Indraccolo Stefano , Nardo Giorgia , Rosato Antonio , Brivio Simone , Caslini Chiara , Stecca Tommaso , Massani Marco , Bassi Nicolò , Novelli Eugenio , Spirli Carlo , Fabris Luca , Strazzabosco Mario
Published: June 2016

Nuclear expression of the calcium-binding protein S100A4 is a biomarker of increased invasiveness in cholangiocarcinoma, a primary liver cancer with scarce treatment opportunities and dismal prognosis. In this study, we provide evidence that targeting S100A4 nuclear import by low-dose paclitaxel, a microtubule-stabilizing agent, inhibits cholangiocarcinoma invasiveness and metastatic spread. Administration of low-dose paclitaxel to established (EGI-1) and primary (CCA-TV3) cholangiocarcinoma cell lines expressing nuclear S100A4 triggered a marked reduction in nuclear expression of S100A4 without modifying its cytoplasmic levels, an effect associated with a significant decrease in cell migration and invasiveness. While low-dose paclitaxel did not affect cellular proliferation, apoptosis, or cytoskeletal integrity, it significantly reduced SUMOylation of S100A4, a critical posttranslational modification that directs its trafficking to the nucleus. This effect of low-dose paclitaxel was reproduced by ginkolic acid, a specific SUMOylation inhibitor. Downregulation of nuclear S100A4 by low-dose paclitaxel was associated with a strong reduction in RhoA and Cdc42 GTPase activity, MT1-MMP expression, and MMP-9 secretion. In an SCID mouse xenograft model, low-dose metronomic paclitaxel treatment decreased lung dissemination of EGI-1 cells without significantly affecting their local tumor growth. In the tumor mass, nuclear S100A4 expression by cholangiocarcinoma cells was significantly reduced, whereas rates of proliferation and apoptosis were unchanged. Overall, our findings highlight nuclear S100A4 as a candidate therapeutic target in cholangiocarcinoma and establish a mechanistic rationale for the use of low-dose paclitaxel in blocking metastatic progression of cholangiocarcinoma. Cancer Res; 76(16); 4775–84. ©2016 AACR.
T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer
Authors: Ikeda Yuji , Park Jae-Hyun , Miyamoto Takashi , Takamatsu Naofumi , Kato Taigo , Iwasa Akiko , Okabe Shuhei , Imai Yuichi , Fujiwara Keiichi , Nakamura Yusuke , Hasegawa Kosei
Published: June 2016

Background: We aimed to clarify the clinical significance of TOPK (T-lymphokine–activated killer cell–originated protein kinase) expression in ovarian cancer and evaluate the possible effect of TOPK inhibitors, OTS514 and OTS964, on ovarian cancer cells.

Methods: TOPK expression was examined by immunohistochemistry using 163 samples with epithelial ovarian cancer (EOC). TOPK protein level and FOXM1 transcriptional level in ovarian cancer cell lines were examined by Western blot and RT-PCR, respectively. Half-maximum inhibitory concentration (IC50) values against TOPK inhibitors were examined by the MTT assay. Using the peritoneal dissemination model of ES-2 ovarian cancer cells, we examined the in vivo efficacy of OTS514. In addition, the cytotoxic effect of OTS514 and OTS964 on 31 patient-derived primary ovarian cancer cells was examined.

Results: TOPK was expressed very highly in 84 (52%) of 163 EOC tissues, and high TOPK expression was significantly associated with poor progression-free survival and overall survival in early-stage cases of EOC (P = 0.008 and 0.006, respectively). Both OTS514 and OTS964 showed significant growth-inhibitory effect on ovarian cancer cell lines with IC50 values of 3.0 to 46 nmol/L and 14 to 110 nmol/L, respectively. TOPK protein and transcriptional levels of FOXM1 were reduced by TOPK inhibitor treatment. Oral administration of OTS514 significantly elongated overall survival in the ES-2 abdominal dissemination xenograft model, compared with vehicle control (P < 0.001). Two drugs showed strong growth-inhibitory effect on primary ovarian cancer cells regardless of tumor sites or histological subtypes.

Conclusions: Our results demonstrated the clinical significance of high TOPK expression and potential of TOPK inhibitors to treat ovarian cancer. Clin Cancer Res; 22(24); 6110–7. ©2016 AACR.
A Tet-On Inducible System for Controlling CD19-Chimeric Antigen Receptor Expression upon Drug Administration
Authors: Sakemura Reona , Terakura Seitaro , Watanabe Keisuke , Julamanee Jakrawadee , Takagi Erina , Miyao Kotaro , Koyama Daisuke , Goto Tatsunori , Hanajiri Ryo , Nishida Tetsuya , Murata Makoto , Kiyoi Hitoshi
Published: June 2016

T cells genetically modified with a CD19 chimeric antigen receptor (CD19CAR) are remarkably effective against B-cell malignancies in clinical trials. However, major concerns remain regarding toxicities, such as hypogammaglobulinemia, due to B-cell aplasia or severe cytokine release syndrome after overactivation of CAR T cells. To resolve these adverse events, we aimed to develop an inducible CAR system by using a tetracycline regulation system that would be activated only in the presence of doxycycline (Dox). In this study, the second-generation CD19CAR was fused into the third-generation Tet-On vector (Tet-CD19CAR) and was retrovirally transduced into primary CD8+ T cells. Tet-CD19CAR T cells were successfully generated and had minimal background CD19CAR expression without Dox. Tet-CD19CAR T cells in the presence of Dox were equivalently cytotoxic against CD19+ cell lines and had equivalent cytokine production and proliferation upon CD19 stimulation, compared with conventional CD19CAR T cells. The Dox(+) Tet-CD19CAR T cells also had significant antitumor activity in a xenograft model. However, without Dox, Tet-CD19CAR T cells lost CAR expression and CAR T-cell functions in vitro and in vivo, clearly segregating the “On” and “Off” status of Tet-CD19CAR cells by Dox administration. In addition to suicide-gene technology, controlling the expression and the functions of CAR with an inducible vector is a potential solution for CAR T-cell therapy–related toxicities, and may improve the safety profile of CAR T-cell therapy. This strategy might also open the way to treat other malignancies in combination with other CAR or TCR gene–modified T cells. Cancer Immunol Res; 4(8); 658–68. ©2016 AACR.

See related Spotlight by June, p. 643.
Strategies for Prevention of Gastric Cancer: Progress from Mass Eradication Trials
Authors: Sugano Kentaro
Published: June 2016

Background:Helicobacter pylori infection is the cause of the majority of gastric cancer. Meta-analyses on several interventional trials, irrespective of the target population, unanimously demonstrated the benefit of eradication therapy in reducing the occurrence of gastric cancer. Based on the evidence for the preventive effects on gastric cancer by eradication therapy in the general population, the International Agency for Research on Cancer advocated eradication of H. pylori as the primary preventive strategy for gastric cancer. Consensus reports on H. pylori gastritis by experts also recommended eradication of H. pylori as the strategy for prevention of gastric cancer. Key Messages:H. pylori is responsible for the majority of gastric cancer. As the eradication of the infection has been shown to reduce subsequent development of gastric cancer, a number of large-scale controlled trials involving a large number of subjects are currently underway in various countries to further verify the feasibility and effects of H. pylori eradication on gastric cancer prevention. However, such studies might be considered unethical as we already knew that the criminal role of H. pylori in gastric carcinogenesis. In Japan, rather than conducting clinical trials, the government adopted insurance coverage for H. pylori gastritis irrespective of symptoms. This policy brought about a massive surge in eradication therapy, which will ensue in a drastic reduction in the prevalence of H. pylori by 2030 as well as gastric cancer. Conclusions: Primary prevention of gastric cancer is now moving into implementation phase in Japan and will be spreading in other counties where long-term clinical trials have started.
Improving the Outcome of Acute Pancreatitis
Authors: Bruno Marco J. ,   on behalf of the Dutch Pancreatitis Study Group
Published: June 2016

Acute pancreatitis (AP) is the most common indication for hospital admission and its incidence is rising. It has a variable prognosis, which is mainly dependent upon the development of persistent organ failure and infected necrotizing pancreatitis. In the past few years, based on large-scale multicenter randomized trials, some novel insights regarding clinical management have emerged. In patients with infected pancreatic necrosis, a step-up approach of percutaneous catheter drainage followed by necrosectomy only when the patient does not improve, reduces new-onset organ failure and prevents the need for necrosectomy in about a third of patients. A randomized pilot study comparing surgical to endoscopic necrosectomy in patients with infected necrotizing pancreatitis showed a striking reduction of the pro-inflammatory response following endoscopic necrosectomy. These promising results have recently been tested in a large multicenter randomized trial whose results are eagerly awaited. Contrary to earlier data from uncontrolled studies, a large multicenter randomized trial comparing early (within 24 h) nasoenteric tube feeding compared with an oral diet after 72 h, did not show that early nasoenteric tube feeding was superior in reducing the rate of infection or death in patients with AP at high risk for complications. Although early ERCP does not have a role in the treatment of predicted mild pancreatitis, except in the case of concomitant cholangitis, it may ameliorate the disease course in patients with predicted severe pancreatitis. Currently, a large-scale randomized study is underway and results are expected in 2017.
Microbiota as Therapeutic Targets
Authors: Xavier Ramnik J.
Published: June 2016

Background: Inflammatory bowel disease (IBD) represents a family of diseases including Crohn's disease and ulcerative colitis. IBD has garnered significant attention in recent years due to successes in 2 areas of basic science: complex human genetics and host-microbe interactions. Advances in understanding the genetics of IBD, mainly driven by genome-wide association studies, have identified more than 160 genetic loci that modulate the risk of disease. Notably, several of these genes have pointed to alterations in host-microbe interactions as being critical factors in pathogenesis. Investigations into the microbial communities of the gastrointestinal tract (or the ‘gut microbiome') in IBD have yielded important insights into several aspects of interactions between microbiota and the host immune system, including how alterations to microbial community composition and function have important consequences for immune homeostasis. Key Messages: The anatomy of the gastrointestinal tract plays a role in defining not only intestinal function, but also the microbial ecosystem that lives within the gut. Careful investigations into the composition and function of these microbial communities have suggested that patients with IBD have an imbalance in their gut microbiota, termed dysbiosis. These studies, as well as studies using samples from healthy individuals, have begun to uncover mechanisms of crosstalk between particular microbes (and microbial products) and immunomodulatory pathways, alterations which may drive immune diseases such as IBD. Conclusions: Investigations into the role of the microbiome in IBD have provided important clues to potential pathogenic mechanisms. Harnessing this knowledge to develop therapeutics and identify biomarkers is currently a major translational goal, holding great promise for clinically meaningful progress.
New Developments on the Treatment of Liver Fibrosis
Authors: Koyama Yukinori , Xu Jun , Liu Xiao , Brenner David A.
Published: June 2016

Liver fibrosis results from many chronic injuries and often progresses to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis. Therefore, new strategies for anti-fibrotic therapy are required. Various kinds of hepatocyte damage result in inflammation, which leads to the activation of hepatic stellate cells (HSCs), which are the major source of myofibroblasts in the liver. Myofibroblasts proliferate in response to various kinds of cytokines, chemokines, and growth factors and produce extracellular matrix proteins, which forms the fibrous scar. Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here we describe our current knowledge of targeting the steps in HSC activation as therapeutic target for liver fibrosis.
Rap-Interacting Proteins are Key Players in the Rap Symphony Orchestra
Authors: Guo Xiao-Xi , An Su , Yang Yang , Liu Ying , Hao Qian , Xu Tian-Rui
Published: June 2016

Rap, a member of the Ras-like small G-protein family, is a key node among G-protein coupled receptors (GPCR), receptor tyrosine kinases (RTKs), ion channels and many other downstream pathways. Rap plays a unique role in cell morphogenesis, adhesion, migration, exocytosis, proliferation, apoptosis and carcinogenesis. The complexity and diversity of Rap functions are tightly regulated by Rap-interacting proteins such as GEFs, GAPs, Rap effectors and scaffold proteins. These interacting proteins decide the subcellular localization of Rap, the interaction modes with downstream Rap effectors and tune Rap as an atypical molecular conductor, coupling extra- and intracellular signals to various pathways. In this review, we summarize four groups of Rap-interacting proteins, highlight their distinctions in Rap-binding properties and interactive modes and discuss their contribution to the spatiotemporal regulation of Rap as well as the implications of targeting Rap-interacting proteins in human cancer therapy.