bluuebunny/crossref_metadata_2025 huggingface dataset:
PRIGSA: Protein repeat identification by graph spectral analysis
Authors: Chakrabarty Broto , Parekh Nita
Published: October 2014

Repetition of a structural motif within protein is associated with a wide range of structural and functional roles. In most cases the repeating units are well conserved at the structural level while at the sequence level, they are mostly undetectable suggesting the need for structure-based methods. Since most known methods require a training dataset, de novo approach is desirable. Here, we propose an efficient graph-based approach for detecting structural repeats in proteins. In a protein structure represented as a graph, interactions between inter- and intra-repeat units are well captured by the eigen spectra of adjacency matrix of the graph. These conserved interactions give rise to similar connections and a unique profile of the principal eigen spectra for each repeating unit. The efficacy of the approach is shown on eight repeat families annotated in UniProt, comprising of both solenoid and nonsolenoid repeats with varied secondary structure architecture and repeat lengths. The performance of the approach is also tested on other known benchmark datasets and the performance compared with two repeat identification methods. For a known repeat type, the algorithm also identifies the type of repeat present in the protein. A web tool implementing the algorithm is available at the URL http://bioinf.iiit.ac.in/PRIGSA/ .
Quantum random state generation with predefined entanglement constraint
Authors: Daskin Anmer , Grama Ananth , Kais Sabre
Published: October 2014

Entanglement plays an important role in quantum communication, algorithms, and error correction. Schmidt coefficients are correlated to the eigenvalues of the reduced density matrix. These eigenvalues are used in von Neumann entropy to quantify the amount of the bipartite entanglement. In this paper, we map the Schmidt basis and the associated coefficients to quantum circuits to generate random quantum states. We also show that it is possible to adjust the entanglement between subsystems by changing the quantum gates corresponding to the Schmidt coefficients. In this manner, random quantum states with predefined bipartite entanglement amounts can be generated using random Schmidt basis. This provides a technique for generating equivalent quantum states for given weighted graph states, which are very useful in the study of entanglement, quantum computing, and quantum error correction.
Chronic Wasting Disease of Cervids: Current Knowledge and Future Perspectives
Authors: Haley Nicholas J. , Hoover Edward A.
Published: October 2014

A naturally occurring transmissible spongiform encephalopathy (TSE) of mule deer was first reported in Colorado and Wyoming in 1967 and has since spread to other members of the cervid family in 22 states, 2 Canadian provinces, and the Republic of Korea. Chronic wasting disease (CWD), caused by exposure to an abnormally folded isoform of the cellular prion protein, is characterized by progressive neurological disease in susceptible natural and experimental hosts and is ultimately fatal. CWD is thought to be transmitted horizontally in excreta and through contaminated environments, features common to scrapie of sheep, though rare among TSEs. Evolving detection methods have revealed multiple strains of CWD and with continued development may lead to an effective antemortem test. Managing the spread of CWD, through the development of a vaccine or environmental cleanup strategies, is an active area of interest. As such, CWD represents a unique challenge in the study of prion diseases.
Animal Phylogeny and Its Evolutionary Implications
Authors: Dunn Casey W. , Giribet Gonzalo , Edgecombe Gregory D. , Hejnol Andreas
Published: October 2014

In recent years, scientists have made remarkable progress reconstructing the animal phylogeny. There is broad agreement regarding many deep animal relationships, including the monophyly of animals, Bilateria, Protostomia, Ecdysozoa, and Spiralia. This stability now allows researchers to articulate the diminishing number of remaining questions in terms of well-defined alternative hypotheses. These remaining questions include relationships at the base of the animal tree, the position of Xenacoelomorpha, and the internal relationships of Spiralia. Recent progress in the field of animal phylogeny has important implications for our understanding of the evolution of development, morphology, genomes, and other characters. A remarkable pattern emerges—there is far more homoplasy for all these characters than had previously been anticipated, even among many complex characters such as segmentation and nervous systems. The fossil record dates most deep branches of the animal tree to an evolutionary radiation in the early Cambrian with roots in the Late Neoproterozoic.
Trophic Cascades in a Multicausal World: Isle Royale and Yellowstone
Authors: Peterson Rolf O. , Vucetich John A. , Bump Joseph M. , Smith Douglas W.
Published: October 2014

Questions of whether trophic cascades occur in Isle Royale National Park (IRNP) or Yellowstone National Park's northern range (NR) cannot lead to simple, precise, or definitive answers. Such answers are limited especially by multicausality in the NR and by complex temporal variation in IRNP. Spatial heterogeneity, contingency, and nonequilibrium dynamics also work against simple answers in IRNP and NR. The existence of a trophic cascade in IRNP and NR also depends greatly on how it is defined. For example, some conceive of trophic cascades as entailing essentially any indirect effect of predation. This may be fine, but the primary intellectual value of such a conception may be to assess an important view in community ecology that most species are connected to most other species in a food web through a network of complicated, albeit weak, indirect effects. These circumstances that work against simple answers likely apply to many ecosystems. Despite the challenges of assessing the existence of trophic cascades in IRNP and NR, such assessments result in considerable insights about a more fundamental question: What causes population abundance to fluctuate?
On the Nature and Evolutionary Impact of Phenotypic Robustness Mechanisms
Authors: Siegal Mark L. , Leu Jun-Yi
Published: October 2014

Biologists have long observed that physiological and developmental processes are insensitive, or robust, to many genetic and environmental perturbations. A complete understanding of the evolutionary causes and consequences of this robustness is lacking. Recent progress has been made in uncovering the regulatory mechanisms that underlie environmental robustness in particular. Less is known about robustness to the effects of mutations, and indeed the evolution of mutational robustness remains a controversial topic. The controversy has spread to related topics, in particular the evolutionary relevance of cryptic genetic variation. This review aims to synthesize current understanding of robustness mechanisms and to cut through the controversy by shedding light on what is and is not known about mutational robustness. Some studies have confused mutational robustness with nonadditive interactions between mutations (epistasis). We conclude that a profitable way forward is to focus investigations (and rhetoric) less on mutational robustness and more on epistasis.
Gecko Adhesion as a Model System for Integrative Biology, Interdisciplinary Science, and Bioinspired Engineering
Authors: Autumn Kellar , Niewiarowski Peter H. , Puthoff Jonathan B.
Published: October 2014

Geckos possess a superlative climbing adaptation in the form of hierarchical arrays of adhesive nanostructures on the underside of their toes. These structures permit rapid, robust, and reliable adhesion to nearly any substrate during full-speed locomotion. We review the fundamental principles and properties of this system, describe its ecological and evolutionary aspects, and offer our assessment of the field alongside suggestions for future research in this direction.
Biodiversity and Ecosystem Functioning
Authors: Tilman David , Isbell Forest , Cowles Jane M.
Published: October 2014

Species diversity is a major determinant of ecosystem productivity, stability, invasibility, and nutrient dynamics. Hundreds of studies spanning terrestrial, aquatic, and marine ecosystems show that high-diversity mixtures are approximately twice as productive as monocultures of the same species and that this difference increases through time. These impacts of higher diversity have multiple causes, including interspecific complementarity, greater use of limiting resources, decreased herbivory and disease, and nutrient-cycling feedbacks that increase nutrient stores and supply rates over the long term. These experimentally observed effects of diversity are consistent with predictions based on a variety of theories that share a common feature: All have trade-off-based mechanisms that allow long-term coexistence of many different competing species. Diversity loss has an effect as great as, or greater than, the effects of herbivory, fire, drought, nitrogen addition, elevated CO2, and other drivers of environmental change. The preservation, conservation, and restoration of biodiversity should be a high global priority.
Ecological Restoration of Streams and Rivers: Shifting Strategies and Shifting Goals
Authors: Palmer Margaret A. , Hondula Kelly L. , Koch Benjamin J.
Published: October 2014

Ecological restoration has grown rapidly and now encompasses not only classic ecological theory but also utilitarian concerns, such as preparedness for climate change and provisioning of ecosystem services. Three dominant perspectives compete to influence the science and practice of river restoration. A strong focus on channel morphology has led to approaches that involve major Earth-moving activities, such as channel reconfiguration with the unmet assumption that ecological recovery will follow. Functional perspectives of river restoration aim to regain the full suite of biogeochemical, ecological, and hydrogeomorphic processes that make up a healthy river, and though there is well-accepted theory to support this, research on methods to implement and assess functional restoration projects is in its infancy. A plethora of new studies worldwide provide data on why and how rivers are being restored as well as the project outcomes. Measurable improvements postrestoration vary by restoration method and measure of outcome.
Cancer: Evolution Within a Lifetime
Authors: Gerlinger Marco , McGranahan Nicholas , Dewhurst Sally M. , Burrell Rebecca A. , Tomlinson Ian , Swanton Charles
Published: October 2014

Subclonal cancer populations change spatially and temporally during the disease course. Studies are revealing branched evolutionary cancer growth with low-frequency driver events present in subpopulations of cells, providing escape mechanisms for targeted therapeutic approaches. Despite such complexity, evidence is emerging for parallel evolution of subclones, mediated through distinct somatic events converging on the same gene, signal transduction pathway, or protein complex in different subclones within the same tumor. Tumors may follow gradualist paths (microevolution) as well as major shifts in evolutionary trajectories (macroevolution). Although macroevolution has been subject to considerable controversy in post-Darwinian evolutionary theory, we review evidence that such nongradual, saltatory leaps, driven through chromosomal rearrangements or genome doubling, may be particularly relevant to tumor evolution. Adapting cancer care to the challenges imposed by tumor micro- and macroevolution and developing deeper insight into parallel evolutionary events may prove central to improving outcome and reducing drug development costs.
How Nature Meets Nurture: Universal Grammar and Statistical Learning
Authors: Lidz Jeffrey , Gagliardi Annie
Published: October 2014

Evidence of children’s sensitivity to statistical features of their input in language acquisition is often used to argue against learning mechanisms driven by innate knowledge. At the same time, evidence of children acquiring knowledge that is richer than the input supports arguments in favor of such mechanisms. This tension can be resolved by separating the inferential and deductive components of the language learning mechanism. Universal Grammar provides representations that support deductions about sentences that fall outside of experience. In addition, these representations define the evidence that learners use to infer a particular grammar. The input is compared with the expected evidence to drive statistical inference. In support of this model, we review evidence of (a) children’s sensitivity to the environment, (b) mismatches between input and intake, (c) the need for learning mechanisms beyond innate representations, and (d) the deductive consequences of children’s acquired syntactic representations.
Therapeutic Applications of Extracellular Vesicles: Clinical Promise and Open Questions
Authors: György Bence , Hung Michelle E. , Breakefield Xandra O. , Leonard Joshua N.
Published: October 2014

This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury.
DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility
Authors: Urban Daniel J. , Roth Bryan L.
Published: October 2014

In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein–coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.
Alternative Paradigms for Ion Channelopathies: Disorders of Ion Channel Membrane Trafficking and Posttranslational Modification
Authors: Curran Jerry , Mohler Peter J.
Published: October 2014

Channelopathies are a diverse set of disorders associated with defects in ion channel (and transporter) function. Although the vast majority of channelopathies are linked with inherited mutations that alter ion channel biophysical properties, another group of similar disorders has emerged that alter ion channel synthesis, membrane trafficking, and/or posttranslational modifications. In fact, some electrical and episodic disorders have now been identified that are not defects in the ion channel but instead reflect dysfunction in an ion channel (or transporter) regulatory protein. This review focuses on alternative paradigms for physiological disorders associated with protein biosynthesis, folding, trafficking, and membrane retention. Furthermore, the review highlights the role of aberrant posttranslational modifications in acquired channelopathies.
Reduced uterine perfusion pressure induces hypertension in the pregnant mouse
Authors: Intapad Suttira , Warrington Junie P. , Spradley Frank T. , Palei Ana C. , Drummond Heather A. , Ryan Michael J. , Granger Joey P. , Alexander Barbara T.
Published: October 2014

Despite preeclampsia being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for its pathogenesis have yet to be fully elucidated. Growing evidence indicates that reduced uteroplacental perfusion and the resulting placental ischemia triggers the cascade of events leading to this maternal disorder. While the well-established rat model of reduced uterine perfusion pressure (RUPP) is providing invaluable insight into the etiology of preeclampsia, the aim of this study was to develop a mouse model of reduced uterine perfusion to expand mechanistic investigation by incorporation with novel gene-targeted mice. To accomplish this aim, a sham surgical procedure or a restriction of blood flow at the abdominal aorta and the ovarian arteries was initiated at day 13 of gestation in C57BL/6J mice. Mean arterial pressure measured in conscious, chronically instrumented mice was significantly elevated in the RUPP (120 ± 4 mmHg) compared with the sham (104 ± 4 mmHg) mice at day 18 of gestation ( P < 0.01). Placental ischemia reduced fetal weights (0.95 ± 0.04 and 0.80 ± 0.02 g; RUPP vs. Sham, respectively; P < 0.02) and increased circulating levels of antiangiogenic soluble fms-related tyrosine kinases (sFlt)-1 ( P < 0.05) in the RUPP at day 18 of gestation. Plasma concentrations of sFlt-1 are increased in preeclamptic patients and in response to reduced uterine perfusion in the rat. Thus, these results suggest that the mouse model of reduced uterine perfusion is applicable to facilitate novel mechanistic investigation into the etiology of hypertension that results from placental ischemia during pregnancy.
Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat
Authors: Jansen Nico A. , Giesler Glenn J.
Published: October 2014

We tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek were characterized for their responses to graded mechanical and thermal stimuli and intradermal injections of pruritogens (serotonin, chloroquine, and β-alanine), partial pruritogens (histamine and capsaicin), and an algogen (mustard oil). All pruriceptive VcPbT neurons were responsive to mechanical stimuli, and more than half were additionally responsive to thermal stimuli. The majority of VcPbT neurons were activated by injections of serotonin, histamine, capsaicin, and/or mustard oil. A subset of neurons were inhibited by injection of chloroquine. The large majority of VcPbT neurons projected to the ipsilateral and/or contralateral external lateral parabrachial and Kölliker-Fuse nuclei, as evidenced by antidromic mapping techniques. Analyses of mean responses and spike-timing dynamics of VcPbT neurons suggested clear differences in firing rates between responses to noxious and pruritic stimuli. Comparisons between the present data and those previously obtained from trigeminothalamic tract (VcTT) neurons demonstrated several differences in responses to some pruritogens. For example, responses of VcPbT neurons to injection of serotonin often endured for nearly an hour and showed a delayed peak in discharge rate. In contrast, responses of VcTT neurons endured for roughly 20 min and no delayed peak of firing was noted. Thus the longer duration responses to 5-HT and the delay in peak firing of VcPbT neurons better matched behavioral responses to stimulation in awake rats than did those of VcTT neurons. The results indicate that VcPbT neurons may have important roles in the signaling of itch as well as pain.
Benthic Macroinvertebrates along the Haraz Downstream in Southern Caspian Sea Basin: In Gradient of the Physicochemical Parameters
Authors: Ghasemi Amir Faraz , Kamali Morteza
Published: October 2014

The Haraz River is one of the most important rivers in the Caspian Sea basin. In order to investigate changes in the taxa abundance composition and feeding groups of the benthic macroinvertebrates, twelve-time sampling was carried out at nine stations along three different sites: (1) before, (2) into, and (3) after Amol City. Results showed impacts of anthropogenic activities caused by the urbanization and development on the occurrence of benthic macroinvertebrates taxa. Families, Hydropsychidae and Heptageniidae at site 1 and Tipulidae at sites 2 and 3, were significantly dominant. The feeding groups of gathering collectors and predators increased from site 1 to site 3, while the filtering collectors and scrapers decreased. Consequently, our data supported the use of the bioindicator concept for Haraz River. Some sensitive (Hydropsychidae, Heptageniidae, Baetidae, and Leuctridae) and tolerant families (Tipulidae and Naididae/Tubificidae) are introduced as potential bioindicators of clean and disturbed river’s area, respectively.
Total Knee Arthroplasty Designed to Accommodate the Presence or Absence of the Posterior Cruciate Ligament
Authors: Harman Melinda K. , Bonin Stephanie J. , Leslie Chris J. , Banks Scott A. , Hodge W. Andrew
Published: October 2014

Evidence for selecting the same total knee arthroplasty prosthesis whether the posterior cruciate ligament (PCL) is retained or resected is rarely documented. This study reports prospective midterm clinical, radiographic, and functional outcomes of a fixed-bearing design implanted using two different surgical techniques. The PCL was completely retained in 116 knees and completely resected in 43 knees. For the entire cohort, clinical knee(96±7)and function(92±13)scores and radiographic outcomes were good to excellent for 84% of patients after 5–10 years in vivo. Range of motion averaged124˚±9˚, with 126 knees exhibiting≥120°flexion. Small differences in average knee flexion and function scores were noted, with the PCL-resected group exhibiting an average of 5° more flexion but an average function score that was 7 points lower compared to the PCL-retained group. Fluoroscopic analysis of 33 knees revealed stable tibiofemoral translations. This study demonstrates that a TKA articular design with progressive congruency in the lateral compartment can provide for femoral condyle rollback in maximal flexion activities and achieve good clinical and functional performance in patients with PCL-retained and PCL-resected TKA. This TKA design proved suitable for use with either surgical technique, providing surgeons with the choice of maintaining or sacrificing the PCL.
Photoelastic Analysis of Fixed Partial Prosthesis Crown Height and Implant Length on Distribution of Stress in Two Dental Implant Systems
Authors: Figueirêdo Evandro Portela , Sigua-Rodriguez Eder Alberto , Pimentel Marcele Jardim , Oliveira Moreira Ana Regina , Nóbilo Mauro Antônio de Arruda , de Albergaria-Barbosa José Ricardo
Published: October 2014

The aim of this study was to evaluate by photoelastic analysis stress distribution on short and long implants of two dental implant systems with 2-unit implant-supported fixed partial prostheses of 8 mm and 13 mm heights. Sixteen photoelastic models were divided into 4 groups: I: long implant (5×11 mm) (Neodent), II: long implant (5×11 mm) (Bicon), III: short implant (5×6 mm) (Neodent), and IV: short implants (5×6 mm) (Bicon). The models were positioned in a circular polariscope associated with a cell load and static axial (0.5 Kgf) and nonaxial load (15°, 0.5 Kgf) were applied to each group for both prosthetic crown heights. Three-way ANOVA was used to compare the factors implant length, crown height, and implant system (α=0.05). The results showed that implant length was a statistically significant factor for both axial and nonaxial loading. The 13 mm prosthetic crown did not result in statistically significant differences in stress distribution between the implant systems and implant lengths studied, regardless of load type (P>0.05). It can be concluded that short implants showed higher stress levels than long implants. Implant system and length was not relevant factors when prosthetic crown height were increased.
Lipoid Pneumonia in a Gas Station Attendant
Authors: Yampara Guarachi Gladis Isabel , Barbosa Moreira Valeria , Santos Ferreira Angela , Sias Selma M. De A. , Rodrigues Cristovão C. , Teixeira Graça Helena M. do C.
Published: October 2014

The exogenous lipoid pneumonia, uncommon in adults, is the result of the inhalation and/or aspiration of lipid material into the tracheobronchial tree. This is often confused with bacterial pneumonia and pulmonary tuberculosis due to a nonspecific clinical and radiologic picture. It presents acutely or chronically and may result in pulmonary fibrosis. We describe here a case of lipoid pneumonia in a gas station attendant who siphoned gasoline to fill motorcycles; he was hospitalized due to presenting with a respiratory infection that was hard to resolve. The patient underwent bronchoscopy with bronchoalveolar lavage, which, on cytochemical (oil red O) evaluation, was slightly positive for lipid material in the foamy cytoplasm of alveolar macrophages. Due to his occupational history and radiographic abnormalities suggestive of lipoid pneumonia, a lung biopsy was performed to confirm the diagnosis. The patient was serially treated with segmental lung lavage and showed clinical, functional, and radiological improvement.
Event-Related Potentials Related to Anxiety in Emotion-Attention Interaction
Authors: Seo Ssanghee , Kim Bonghyun
Published: October 2014

To identify neurological characteristics in accordance with anxiety under the interaction between emotion and attention, this study examines major ERP components when participants identify a target number by inhibiting task-irrelevant emotional face distractors. Experiments were conducted once per day at the same time for two days with 19 healthy adult men and women as required to study emotion-attention interaction. In this study, a variety of ERP components such as P100, N200, and P300 during experiment are significant. The amplitude and latency of the N200 component reflect both state and trait anxiety at all positions. This characteristic specially is prominently featured at Cz. Also, the latency of the late P300 component reflects the trait anxiety rather than state anxiety. The result of this study can help our understanding of the neurological responses related to anxiety during attentional control.
Dynamical Adaptive Integral Sliding Backstepping Control of Nonlinear Nontriangular Uncertain Systems
Authors: Pervaiz Mahmood , Khan Qudrat , Bhatti Aamer Iqbal , Malik Shahzad Ahmed
Published: October 2014

We present a control strategy for nonlinear nontriangular uncertain systems. The proposed control method is a synergy between the dynamic adaptive backstepping (DAB) and integral sliding mode (ISM) and is referred to as DAB‐ISMC. Our main objective is to find a recursive procedure to transform a nontriangular system into an implementable form that enables designing a control law which almost eliminates the reaching‐phase. The proposed method further facilitates minimization of chattering which is believed to be a shortcoming of the sliding mode control. In this methodology, the ISM, as an integrated subsystem of DAB, is introduced at the final stage of backstepping. This strategy works very well to obtain a system that is robust against model imperfections, matching and unmatching uncertainties. The DAB‐ISMC method is applied on a continuous stirred tank reactor (CSTR) and simulation results obtained on Matlab are found to be very promising.
X-Ray Fluorescence Analysis of XII–XIV Century Italian Gold Coins
Authors: Baldassarri Monica , Cavalcanti Gildo de Holanda , Ferretti Marco , Gorghinian Astrik , Grifoni Emanuela , Legnaioli Stefano , Lorenzetti Giulia , Pagnotta Stefano , Marras Luciano , Violano Eleonora , Lezzerini Marco , Palleschi Vincenzo
Published: October 2014

An extensive analytical study has been performed on a large number of gold coins (Norman-Swabian Augustale and Tarì, Grosso of Lucca, Florin of Florence) minted in Italy from the end of XII century to XIV century. The X-ray fluorescence (XRF) technique was used for verifying the composition of the coins. XRF is a nondestructive technique particularly suited for in situ quantitative analysis of gold and minor elements in the precious alloy. The Florins turned out to have a gold content very close to 24 carats (pure gold) although in a couple of cases we observed relatively high concentrations of iron (around 2%) or lead (around 1%). The Grosso of Lucca has a similar composition, with a measured gold content around 97% due to a higher silver percentage (about 2%), with respect to the average Florin. The Augustali analyzed showed, on average, a gold content around 89%. The average gold content of the Tarì analysed is around 72%, with a relatively large variability. The analysis revealed the use of native gold for the coinage of the Florins, excluding the possibility of recycling gold coming from other sources. On the other hand, the variability observed in the compositions of the Tarì and Augustali could suggest the reuse of Islamic and North African gold. The study could shed some light on the sudden diffusion of gold coins in Italy around the first half of XIII century, allowing hypotheses on the provenience of the gold used for a coinage that dominated the economic trades from then on.
Experimental Investigation of Phase Change inside a Finned-Tube Heat Exchanger
Authors: Rahimi M. , Ranjbar A. A. , Ganji D. D. , Sedighi K. , Hosseini M. J.
Published: October 2014

An experimental study is conducted in order to investigate melting and solidification processes of paraffin RT35 as phase change materials in a finned-tube. Therefore the effect of using fins in this study as well as some operational parameters is considered. The motivation of this study is to design and construct a novel storage unit and to compare it with a finless heat exchanger. A series of experiments are conducted to investigate the effect of increasing the inlet temperature and flow rate on the charging and discharging processes of the phase change material. It is shown that, using fins in phase change process enhances melting and solidification procedures. The trend of this variation is different for the heat exchangers; increasing the inlet temperature for the bare tube heat exchanger more effectively lowers melting time. Similarly, flow rate variation varies the solidification time more intensely for the bare tube heat exchanger.
Functional Aromatic Poly(1,3,4-Oxadiazole-Ether)s with Benzimidazole Pendants: Synthesis, Thermal and Dielectric Studies
Authors: Ganesh Shimoga D. , Pai Vasantakumar K. , Kariduraganavar Mahadevappa Y. , Jayanna Madhu B.
Published: October 2014

Poly(1,3,4-oxadiazole-ether) with reactive carboxylic acid pendants was synthesized from solution polymerization via nucleophilic displacement polycondensation among 2,5-bis(4-fluorophenyl)-1,3,4-oxadiazole (BFPOx) and 4,4′-bis(4-hydroxyphenyl) valeric acid (BHPA). Without altering the polymeric segments, benzimidazole modified poly(1,3,4-oxadiazole-ether)s were prepared by varying stoichiometric ratios of 1,2-phenylenediamine. The molecular structural characterization of these polymers was achieved by, FT-IR, NMR, TGA, elemental analysis, and analytical techniques. The weight-average molecular weight of virgin polymer with carboxylic acid functionality was determined by gel permeation chromatography (GPC) and was found to be 22400 (Mw/Mn=2.07). All the synthesized polyethers were compressed into pellets and electrical contacts were established to perform dielectric properties.
The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations
Authors: Patel Yesha M. , Stram Daniel O. , Wilkens Lynne R. , Park Sung-Shim L. , Henderson Brian E. , Le Marchand Loic , Haiman Christopher A. , Murphy Sharon E.
Published: October 2014

Background: The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism.

Methods: We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined.

Results: Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5×10−8). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 × 10−155). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 × 10−43) was in high LD (r2 = 0.99) with rs115765562.

Conclusions: Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose.

Impact: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk. Cancer Epidemiol Biomarkers Prev; 24(1); 119–27. ©2014 AACR.
Doxorubicin Synergizes with 34.5ENVE to Enhance Antitumor Efficacy against Metastatic Ovarian Cancer
Authors: Bolyard Chelsea , Yoo Ji Young , Wang Pin-Yi , Saini Uksha , Rath Kellie S. , Cripe Timothy P. , Zhang Jianying , Selvendiran Karuppaiyah , Kaur Balveen
Published: October 2014

Purpose: Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here, we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell–specific nestin promoter, and encoding for antiangiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer.

Experimental Design: Antitumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites–derived tumor cells, and primary patient ascites–derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a Transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou–Talalay synergy analysis. Viral replication, herpes simplex virus receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer.

Results: Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites–derived and patient ascites–derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors.

Conclusions: This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer. Clin Cancer Res; 20(24); 6479–94. ©2014 AACR.
Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
Authors: Choi Seongmin , Kim Hyeong Ryul , Sung Chang Ohk , Kim Jongkyu , Kim Sukjun , Ahn Sung-Min , Choi Chang-min , Chun Sung-Min , Choi Eun Kyung , Kim Sang-We , Kim Yong-Hee , Lee Ji-Young , Song Joon Seon , Kim Deokhoon , Haq Farhan , Lee Sun Young , Lee Jong-eun , Jung Wang-rim , Jang Hye Yoon , Yang Eunho , Lee Charles , Yu Eunsil , Kong Gu , Baek Daehyun , Jang Se Jin
Published: October 2014

Purpose: To better understand the complete genomic architecture of lung adenocarcinoma.

Experimental Design: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes.

Results: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma.

Conclusions: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients. Clin Cancer Res; 21(11); 2613–23. ©2014 AACR.

See related commentary by Collisson, p. 2418
Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression
Authors: Sucker Antje , Zhao Fang , Real Birgit , Heeke Christina , Bielefeld Nicola , Maβen Stefan , Horn Susanne , Moll Iris , Maltaner Raffaela , Horn Peter A. , Schilling Bastian , Sabbatino Francesco , Lennerz Volker , Kloor Matthias , Ferrone Soldano , Schadendorf Dirk , Falk Christine S. , Griewank Klaus , Paschen Annette
Published: October 2014

Purpose: CD8+ T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells.

Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell–stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor–T-cell interaction.

Results: Metastases Ma-Mel-48a and Ma-Mel-48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell–stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I–negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel-48b cells, pointing to an early acquired genetic event predisposing to development of β2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second β2m-deficient melanoma model.

Conclusion: Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell–based immunotherapy. Clin Cancer Res; 20(24); 6593–604. ©2014 AACR.
MHC Class I Loss Is a Frequent Mechanism of Immune Escape in Papillary Thyroid Cancer That Is Reversed by Interferon and Selumetinib TreatmentIn Vitro
Authors: Angell Trevor E. , Lechner Melissa G. , Jang Julie K. , LoPresti Jonathan S. , Epstein Alan L.
Published: October 2014

Purpose: To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines.

Experimental Design: MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production.

Results: Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3+, CD8+, CD16+) and suppressor (FoxP3+) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25+ of CD3+) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment.

Conclusions: MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC. Clin Cancer Res; 20(23); 6034–44. ©2014 AACR.
T-Cell Levels Are Prognostic in Mantle Cell Lymphoma
Authors: Nygren Lina , Wasik Agata M. , Baumgartner-Wennerholm Stefanie , Jeppsson-Ahlberg Åsa , Klimkowska Monika , Andersson Patrik , Buhrkuhl Daren , Christensson Birger , Kimby Eva , Wahlin Björn E. , Sander Birgitta
Published: October 2014

Purpose: The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL).

Experimental Design: Cell populations were investigated using flow cytometry in diagnostic MCL (n = 153) and reactive (n = 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters.

Results: MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4+ T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P = 0.007; P = 0.003) and in the diffuse compared with the nodular subtype (P = 0.022; P = 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P = 0.003). Higher levels of CD3+ and CD4+ T cells and higher CD4:CD8 ratios were associated with indolent disease (P = 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P = 0.023).

Conclusion: CD3+, CD8+, and particularly CD4+ T-cell levels are higher in indolent MCL and decrease with more aggressive histology as reflected by a diffuse growth pattern. High CD4:CD8 ratio correlated independently of other high-risk prognostic factors with longer OS, suggesting a prognostic role for T cells in MCL. Clin Cancer Res; 20(23); 6096–104. ©2014 AACR.
Identification of Recurrent FGFR3–TACC3 Fusion Oncogenes from Lung Adenocarcinoma
Authors: Capelletti Marzia , Dodge Michael E. , Ercan Dalia , Hammerman Peter S. , Park Seung-Il , Kim Jhingook , Sasaki Hidefumi , Jablons David M. , Lipson Doron , Young Lauren , Stephens Phil J. , Miller Vincent A. , Lindeman Neal I. , Munir Kiara J. , Richards William G. , Jänne Pasi A.
Published: October 2014

Purpose: Targetable oncogenic alterations are detected more commonly in patients with non–small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC to define additional treatment options.

Experimental Design: We analyzed 576 lung adenocarcinomas from patients of Asian and Caucasian ethnicity. We identified a subset of cancers that did not harbor any known oncogenic alteration. We performed targeted next-generation sequencing (NGS) assay on 24 patients from this set with >75% tumor cell content.

Results: EGFR mutations were the most common oncogenic alteration from both Asian (53%) and Caucasian (41.6%) patients. No known oncogenic alterations were present in 25.7% of Asian and 31% of Caucasian tumor specimens. We identified a FGFR3–TACC3 fusion event in one of 24 patients from this subset using targeted NGS. Two additional patients harboring FGFR3–TACC3 were identified by screening our entire cohort (overall prevalence, 0.5%). Expression of FGFR3–TACC3 led to IL3 independent growth in Ba/F3 cells. These cells were sensitive to pan-fibroblast growth factor receptor (pan-FGFR) inhibitors but not the epidermal growth factor (EGFR) inhibitor gefitinib.

Conclusions: FGFR3–TACC3 rearrangements occur in a subset of patients with lung adenocarcinoma. Such patients should be considered for clinical trials featuring FGFR inhibitors. Clin Cancer Res; 20(24); 6551–8. ©2014 AACR.