bluuebunny/crossref_metadata_2025 huggingface dataset:
Sweet sensing, homeostasis and hedonics in the human gut–brain axis
Authors: Stamataki N. S. , McLaughlin J. T.
Published: May 2017

Consumption of added sugars has been associated with excessive energy intake, obesity and its comorbidities, while non‐nutritive sweeteners offer caloric‐free sweet taste and might be helpful in decreasing energy intake. The importance of gut–brain nutrient signalling in the regulation of food intake has recently become a field of extensive research; however, understanding about how nutritive and non‐nutritive sweet tastants affect gut–brain crosstalk is limited. Much of the research has focused on the effects of non‐nutritive sweeteners on gut function, especially after the demonstration that sweet taste receptors are also present in enteroendocrine cells. However, the majority of human studies have not confirmed a physiologically significant biological activity of non‐nutritive sweeteners, nor a role for gut sweet taste receptors in glucose and gut peptide postprandial responses, gastric emptying or appetite. The use of functional and physiological MRI scanning has enabled the investigation of human brain responses to sweet tastants. Imaging studies have demonstrated that the human brain is able to distinguish the sweet taste of caloric sugars from non‐nutritive sweeteners, most likely as a result of nutrient detection in the gut. More studies are required to explore the comparative effects of caloric sugars and non‐nutritive sweeteners on homeostatic, neurophysiological and hedonic signals, which may interact to determine the effects of sweet sensing.
Computational Investigations of Multiword Chunks in Language Learning
Authors: McCauley Stewart M. , Christiansen Morten H.
Published: May 2017

Second‐language learners rarely arrive at native proficiency in a number of linguistic domains, including morphological and syntactic processing. Previous approaches to understanding the different outcomes of first‐ versus second‐language learning have focused on cognitive and neural factors. In contrast, we explore the possibility that children and adults may rely on different linguistic units throughout the course of language learning, with specific focus on the granularity of those units. Following recent psycholinguistic evidence for the role of multiword chunks in online language processing, we explore the hypothesis that children rely more heavily on multiword units in language learning than do adults learning a second language. To this end, we take an initial step toward using large‐scale, corpus‐based computational modeling as a tool for exploring the granularity of speakers' linguistic units. Employing a computational model of language learning, the Chunk‐Based Learner, we compare the usefulness of chunk‐based knowledge in accounting for the speech of second‐language learners versus children and adults speaking their first language. Our findings suggest that while multiword units are likely to play a role in second‐language learning, adults may learn less useful chunks, rely on them to a lesser extent, and arrive at them through different means than children learning a first language.
Analogy Lays the Foundation for Two Crucial Aspects of Symbolic Development: Intention and Correspondence
Authors: Yuan Lei , Uttal David H.
Published: May 2017

We argue that analogical reasoning, particularly Gentner's (1983, 2010) structure‐mapping theory, provides an integrative theoretical framework through which we can better understand the development of symbol use. Analogical reasoning can contribute both to the understanding of others’ intentions and the establishment of correspondences between symbols and their referents, two crucial components of symbolic understanding. We review relevant research on the development of symbolic representations, intentionality, comparison, and similarity, and demonstrate how structure‐mapping theory can shed light on several ostensibly disparate findings in the literature. Focusing on visual symbols (e.g., scale models, photographs, and maps), we argue that analogy underlies and supports the understanding of both intention and correspondence, which may enter into a reciprocal bootstrapping process that leads children to gain the prodigious human capacity of symbol use.
Comparison of laparoscopic‐assisted technique and open laparotomy for gastrointestinal biopsy in cats*
Authors: McClaran Janet Kovak , Skerrett Suzanne C. , Currao Rachael L. , Pavia Philippa R. , Tarvin Kiki M.
Published: May 2017

Objective

To evaluate and compare the complications, postoperative pain, surgical time, hospitalization time, and adequacy of biopsy specimens between laparoscopic assisted (LAP) versus open laparotomy (OPEN) gastrointestinal biopsies in cats.

Study Design

Prospective randomized clinical study.

Sample Population

Twenty‐eight cats with clinical and ultrasonographic evidence of gastrointestinal disease. Fifteen cats in the LAP group and 13 in the OPEN group.

Methods

Signalment, presenting clinical signs, total duration of surgery, operative time, ease of procedure, incision length, postoperative pain scores, complications, and duration of hospitalization were recorded. Quality of gastrointestinal biopsies was compared between techniques.

Results

There was no difference in frequency of intraoperative complications (P = .778), surgical duration (P = .333), postoperative complications (P = .722), or duration of hospitalization (P = .728). Pain scores assigned before (P = .198) or 1 hour after surgery (P = .073) did not differ between groups; however, pain scores were lower at 6 hours (P = .003), 12 hours (P = .001), and 24 hours (P = .005) postoperatively in the LAP group. All cases survived surgery, with one case requiring conversion, and diagnostic biopsies were obtained in all cases.

Conclusion

Laparoscopic‐assisted gastrointestinal biopsy technique provided diagnostic specimens and decreased postoperative pain compared to open surgical techniques. No difference was detected in surgical duration, complications, or duration of hospitalization.
Impacts of the Problem-based Learning Pedagogy on English Learners’ Reading Comprehension, Strategy Use, and Active Learning Attitudes
Authors: Lin Lu-Fang
Published: May 2017

This study investigated whether an English reading course integrated with the problem-based learning approach could foster foreign language learners’ reading comprehension ability, strategy use, and their active learning attitudes. The pedagogy was featured with the small group scaffolding. Two intact English classes in a Taiwanese university were randomly assigned to the experimental and control treatment conditions. The experimental group received problem-based learning instruction, whereas the control group did not. The reading comprehension pre- and post-tests and the English active learning questionnaire were employed to collect the data. The Independent Samples t test yielded a significant difference between the 2 groups in the total score of the reading comprehension post-test, indicating that the PBL approach significantly improved the participants’ reading comprehension ability, and the PBL participants’ strategy use for identifying the subject matter and supportive details was better than that of their counterparts. The t-test results of the questionnaire showed that the PBL participants exhibited a significantly higher degree of active English learning attitude than the non-PBL participants in terms of motivation intensity and desire to learn English. There was a significantly positive correlation between reading comprehension ability and English learning attitude. Finally, instructional recommendations are presented.
Differences in Need for Instruction: Dynamic Testing in Children with Arithmetic Difficulties
Authors: Bosma Tirza , Stevenson Claire E. , Resing Wilma C. M.
Published: May 2017

In this paper we investigated the contribution of a dynamic testing procedure, including multiple graduated prompts protocols, in identifying differences in need for instruction of second grade children (N = 120) with arithmetic difficulties. The training was adaptive and prompts were provided according to one of six protocols, each focusing on a different problem solving step. Results showed that based on the number of prompts required from each protocol different patterns of problem solving could be identified, and further four profiles of instructional needs could be distinguished. The results provide starting points for individualized instruction and support the use of dynamic testing procedures in educational settings.
Characterization of the root and soil mycobiome associated with invasive Microstegium vimineum in the presence and absence of a native plant community
Authors: North Brittany A. , Torzilli Albert P.
Published: May 2017

The potential role of fungal root endophytes (including mycorrhizae) in the invasiveness of Microstegium vimineum (Trin.) A. Camus, was researched using automated ribosomal intergenic spacer analysis (ARISA) and brightfield microscopy. Fungal communities of roots from two native plants (Onoclea sensibilis L. and Amphicarpaea bracteata (L.) Fernald) were compared with those found in Microstegium. Fungal communities from the bulk soils also were examined in terms of their potential influence on the root mycobiomes. All three plants occurred in natural communities as monocultures and together in one mixed community in Northern Virginia where Microstegium has recently invaded. Principal coordinate analysis of ARISA data identified fungal communities unique to roots from each monoculture. When the three plants co-occurred in a mixed setting, Microstegium was found to maintain its distinct fungal community while the fungal communities of the two native plants overlapped. In contrast, soil fungal communities showed no specific plant associations. Brightfield microscopy confirmed the presence of endophytic fungi in all three plants. The results recorded here suggest a positive contribution by the root mycobiome in promoting the invasive ability of Microstegium, providing a basis for future experiments testing this hypothesis.
Magnetic alginate beads with high basic dye removal potential and excellent regeneration ability
Authors: Elwakeel K.Z. , El-Bindary A.A. , El-Sonbati A.Z. , Hawas A.R.
Published: May 2017

The adsorption of crystal violet (CV) dye onto magnetic alginate (MAlg) composite from aqueous solutions was studied. Experiments were carried out as function of contact time, dosage, temperature, pH, and CV concentration in the solutions. Optimum CV uptake was observed at equilibrium pH 7 and most of the CV was sorbed within 30 min. The equilibrium adsorption data were analyzed using two common adsorption models: Langmuir and Freundlich. The results revealed that Langmuir isotherm fit the experimental results well. The maximum adsorption capacity obtained from Langmuir isotherm equation was 0.113 mmol g−1at 298 ± 1 K. The kinetics adsorption of CV onto MAlg composite was investigated using the pseudo first-order and pseudo second-order kinetic models. The results showed that the adsorption of CV onto MAlg composite followed pseudo second-order kinetic model. Thermodynamic data indicated that the adsorption process is an endothermic and spontaneous reaction. Due to its outstanding adsorption capacities, MAlg composite is an excellent adsorbent for the removal of CV. The composite regeneration was greater than 98.6% with 0.01 mol/L HCl, and MAlg composite could be repeatedly utilized for CV removal with negligible loss in sorption capacity.
Target-based catch-per-unit-effort standardization in multispecies fisheries
Authors: Okamura Hiroshi , Morita Shoko H. , Funamoto Tetsuichiro , Ichinokawa Momoko , Eguchi Shinto
Published: May 2017

Standardized catch per unit effort (CPUE) is a fundamental component of fishery stock assessment. In multispecies fisheries, catchability can differ depending on which species is being targeted, and so the yearly trend extracted from the standardized CPUE is likely to be biased. We have, therefore, developed a method for predicting the unobserved variable related to targeted species from among multispecies composition data using a mixture regression model for the transformed residuals. In contrast with traditional methods, the proposed method predicts the target variable in CPUE standardization without removing a subset of the data. Keeping the entire data set avoids information loss, and so CPUE standardization with the predicted target variable should yield an unbiased estimate of the yearly trend. Simple simulation tests demonstrate that our method outperforms traditional methods. We illustrate the use of our method by applying it to CPUE data on arabesque greenling (Pleurogrammus azonus) caught in multispecies trawl fisheries in Hokkaido, Japan.
Thinning effect on understory community and photosynthetic characteristics in a subtropical Pinus massoniana plantation
Authors: Cheng Chuanpeng , Wang Yidong , Fu Xiaoli , Xu Mingjie , Dai Xiaoqin , Wang Huimin
Published: May 2017

Thinning forest stands changes biotic and abiotic conditions, subsequently altering understory communities including their photosynthetic characteristics. We investigated the effects of thinning (25% basal area decrease) in a subtropical Pinus massoniana Lamb. plantation at two post-thinning times: 0.5 years (PT0.5) and 2.5 years (PT2.5). Thinning (PT0.5 and PT2.5) significantly increased understory density (+104.9% and +142.4%, respectively), aboveground biomass (+191.1% and +239.2%, respectively), the Shannon–Wiener index, and the Pielou index and decreased the Simpson index (p < 0.05). Species richness significantly increased at PT0.5 and decreased at PT2.5 (p < 0.05). Photosynthetic characteristics of new and old leaves of three dominant species (Woodwardia japonica (Linn. f.) Sm., Dryopteris championii (Benth.) C. Chr., and Dicranopteris dichotoma (Thunb.) Bernh.) showed different variations at 0.5 and 2.5 years after thinning, depending on their various adaptive strategies. Generally, thinning improved leaf carbon fixation capacity of these dominant plants (except W. japonica old leaves). Leaf photosynthetic characteristics of these species exhibited some common changes with respect to leaf morphological attributes and chlorophyll content. Thinning increased new-leaf length (or width) and reduced old-leaf chlorophyll b concentration at PT0.5 but reduced new-leaf length, specific leaf area, and all-leaf chlorophyll concentration at PT2.5. In conclusion, thinning is a useful tool for increasing understory abundance and carbon fixation capacity of some fern species.
Variants of stability of discontinuous groups for Euclidean motion groups
Authors: Baklouti Ali , Bejar Souhail
Published: May 2017

Let [Formula: see text] be a Lie group, [Formula: see text] a closed subgroup of [Formula: see text] and [Formula: see text] a discontinuous group for the homogeneous space [Formula: see text]. Given a deformation parameter [Formula: see text], the deformed subgroup [Formula: see text] may fail to act properly discontinuously on [Formula: see text]. To understand this phenomenon in the case when [Formula: see text] stands for an Euclidean motion group [Formula: see text], we compare the notion of stability for discontinuous groups (cf. [T. Kobayashi and S. Nasrin, Deformation of properly discontinuous action of [Formula: see text] on [Formula: see text], Int. J. Math. 17 (2006) 1175–1193]) with its variants. We prove that the defined stability variants hold when [Formula: see text] turns out to be a crystallographic subgroup of [Formula: see text].
Nonradial oscillations of neutron stars and emitted gravitational waves: Computing strongly damped normal modes
Authors: Geroyannis V. S. , Tzelati E. E. , Karageorgopoulos V. G.
Published: May 2017

In this paper, we compute eigenfrequencies of strongly damped normal modes arising from the coupling of the nonradial oscillations of a neutron star to the oscillations of the space-time metric, so-called “w-modes”, by integrating all involved differential equations in the complex plane. Regarding the interior of the star, we use the so-called “complex-plane strategy”. Specifically, we integrate the differential equations of the nonradial fluid oscillations of a general-relativistic polytropic model, simulating the star, along a straight-line contour placed parallel to the real axis and at small imaginary distance from it, thus avoiding a singularity at the stellar center. Regarding the exterior of the star, we use a method proposed by Andersson, Kokkotas and Schutz, following a slightly different terminating procedure. Specifically, (i) we integrate the equations along a straight-line contour lying parallel to the so-called “anti-Stokes lines”, on which the exponential divergence of the solution is drastically suppressed, so that the outgoing and ingoing waves become comparable; and (ii) we carry out one final integration up to a “common reference point”, thus comparing all results at this point. We verify the reliability and accuracy of the method by comparing our numerical results to corresponding ones appearing in the bibliography.
Evolution of pedestrian evacuation considering different human behaviors
Authors: Guan Junbiao , Wang Kaihua , Chen Fangyue , Feng Zhaosheng
Published: May 2017

Pedestrian evacuation becomes more complicated when different human behaviors are considered. In this paper, pedestrian evacuation considering two different kinds of human behaviors is studied by using a cellular automaton (CA) model. Two types of evacuees, cooperators and defectors, are initially randomly distributed in a square room with one exit and they interact with their neighbors following the snowdrift game theory (characterized by the parameter “[Formula: see text]”) during the evacuation process. Cooperators and defectors are mutually changed according to two typically different kinds of evacuees’ judgements, namely, judgement based on neighbors’ strategies (we call it herding behavior) and judgement based on neighbors’ payoffs (we call it independent behavior), which leads to the corresponding evacuee clusters. It is found from a large amount of numerical simulations that the proportions of the corresponding evacuee clusters are evolved to respectively consistent states despite 11 typically different initial evacuee cluster ratios, largely owing to self-organization effect. Moreover, for other 200 randomly chosen initial evacuee cluster ratios, Monte-Carlo simulations show that the proportions of the corresponding evacuee clusters are evolved stably, without any oscillation, and when the initial number of pedestrians of two different kinds of behaviors are comparable, the proportions are evolved to respectively consistent states despite different initial evacuee cluster ratios, indicating that some regular phenomena occur during the evacuation process. Furthermore, it is found that the moderate values of [Formula: see text] is necessary for short evacuation time, and for the fixed values of [Formula: see text], the initial ratio of pedestrians of herding behavior has a great influence on the final evacuation time.
Clustering-based link prediction in scientific coauthorship networks
Authors: Ma Yang , Cheng Guangquan , Liu Zhong , Liang Xingxing
Published: May 2017

Link prediction in social networks has become a growing concern among researchers. In this paper, the clustering method was used to exploit the grouping tendency of nodes, and a clustering index (CI) was proposed to predict potential links with characteristics of scientific cooperation network taken into consideration. Results showed that CI performed better than the traditional indices for scientific coauthorship networks by compensating for their disadvantages. Compared with traditional algorithms, this method for a specific type of network can better reflect the features of the network and achieve more accurate predictions.
Nano-Scale Silicon Quantum Dot-Based Single-Electron Transistors and Their Application to Design of Analog-to-Digital Convertors at Room Temperature
Authors: Aminzadeh Hamed , Dashti Mohammad Ali , Miralaei Mohammad
Published: May 2017

Room-temperature analog-to-digital converters (ADCs) based on nanoscale silicon (Si) quantum dot (QD)-based single-electron transistors (SETs) can be very attractive for high-speed processors embedded in future generation nanosystems. This paper focuses on the design and modeling of advanced single-electron converters suited for operation at room temperature. In contrast to conventional SETs with metallic QD, the use of sub-10-nm Si QD results in stable operation at room temperature, as the observable Coulomb blockade regime covers effectively the higher temperature range. Si QD-based SETs are also fully compatible with advanced CMOS technology and they can be manufactured using routine nanofabrication steps. At first, we present the principles of operation of Si SETs used for room-temperature operation. Possible flash-type ADC architectures are then investigated and the design considerations of possible Coulomb oscillation regimes are addressed. A modified design procedure is then introduced for [Formula: see text]-bit SET-based ADCs, and validated through simulation of a 3-bit ADC with a sampling frequency of 5 GS/s. The ADC core is comprised from a capacitive signal divider followed by three periodic symmetric functions (PSFs). Simulation results demonstrate the stability of output signals at the room-temperature range.
A Perturbation Based Chaotic System Exploiting the Quasi-Newton Method for Global Optimization
Authors: Tatsumi Keiji , Tanino Tetsuzo
Published: May 2017

The chaotic system has been exploited in metaheuristic methods of solving continuous global optimization problems. Recently, the gradient method with perturbation (GP) was proposed, which was derived from the steepest descent method for the problem with additional perturbation terms, and it was reported that chaotic metaheuristics with the GP have good performances of solving some benchmark problems. Moreover, the sufficient condition of its parameter values was theoretically shown under which its updating system is chaotic. However, the sufficient condition of its chaoticity and the width of strange attractor around each local minimum, which are important properties for exploiting the chaotic system in optimization, deeply depend on the eigenvalues of the Hessian matrix of the objective function at the local minimum. Thus, if the eigenvalues of different local minima are widely different from each other, or if it is different in different problems, such properties can cause the difficulty of selecting appropriate parameter values for an effective search. Therefore, in this paper, we propose modified GPs based on the quasi-Newton method instead of the steepest descent method, where their chaoticities and the width of strange attractor do not depend on the eigenvalue of the Hessian matrix at any local minimum due to the scale invariant of the quasi-Newton method. In addition, we empirically demonstrate that the parameter selection of the proposed methods is easier than the original GP, especially with respect to the step-size, and the chaotic metaheuristics with the proposed methods can find better solutions for some multimodal functions.
Bifurcation Analysis of the Oblique Shock Wave in the Supersonic Flow Over a Wedge from a Calculus of Variation Approach
Authors: Wang Zhuopu , Zhang Jiazhong , Wang Le , Liu Yan
Published: May 2017

The stability of the oblique shock in the supersonic flow over a wedge is investigated from a calculus of variation approach. By taking the nonequilibrium effects inside the shock wave into consideration, a higher order term of bulk viscosity is introduced into the Euler equation, and the resulting system has two smooth solutions corresponding to the two possible attached shock waves, respectively. Additionally, the new system admits a variational formulation, and the stability of the two possible shock waves can then be determined by the second variation of each shock solution. Due to the parameter dependence of the functional, there is a stability transition at the intersection point of the two solution branches, and this gives a new explanation of the fact that only one of the two possible shock waves is physically observable. It is then shown that the critical solution with maximum deflection angle corresponds to a fold bifurcation point.
Chaos in the Sense of Devaney for Two-Dimensional Time-Varying Generalized Symbolic Dynamical Systems
Authors: Tian Chuanjun
Published: May 2017

This paper studies chaos in the sense of Devaney for a class of two-dimensional time-varying generalized symbol systems of the form [Formula: see text] where [Formula: see text] for [Formula: see text], [Formula: see text] is an integer, [Formula: see text] and [Formula: see text] are two well-defined functions. By introducing a more restrictive concept of chaos in the sense of Devaney, some sufficient conditions for this system to be completely chaotic in the sense of Devaney are derived.
On Harsanyi Dividends and Asymmetric Values
Authors: Dehez Pierre
Published: May 2017

The concept of dividend in transferable utility games was introduced by Harsanyi [1959], offering a unifying framework for studying various valuation concepts, from the Shapley value to the different notions of values introduced by Weber. Using the decomposition of the characteristic function used by Shapley to prove uniqueness of his value, the idea of Harsanyi was to associate to each coalition a dividend to be distributed among its members to define an allocation. Many authors have contributed to that question. We offer a synthesis of their work, with a particular attention to restrictions on dividend distributions, starting with the seminal contributions of Vasil’ev, Hammer, Peled and Sorensen and Derks, Haller and Peters, until the recent papers of van den Brink, van der Laan and Vasil’ev.
A computational study of the main degradation product of antitumor drug imexon
Authors: Kheffache Djaffar , Ouamerali Ourida
Published: May 2017

We theoretically study, from the thermodynamic point of view, the possibility of the two degradation pathways of antitumor drug of imexon. According to the theoretical results obtained at DFT level in both gas and aqueous phases, the two degradation pathways of imexon are characterized by negative reaction Gibbs free energies. It has been found that 4-imino-5-methylene-imidazolidin-2-one is the favored degradation product of imexon.

Herein, the focus of this work has been on calculating the geometries, relative energies and electronic properties of all possible prototropic tautomers of 4-imino-5-methylene-imidazolidin-2-one using the DFT and MP2 levels. The bulk water environment has been simulated by continuum model using Solvation Model based on Density (SMD). The UV spectra of two dominant tautomers of 4-imino-5-methylene-imidazolidin-2-one are also predicted using time-dependent density functional theory and the results are compared with the available experimental data. The comparison of the simulated and the experimental absorption spectra has allowed us to accurately characterize the predominant tautomer of the degradation product in aqueous medium.
A cross-layer flow schedule with dynamical grouping for mitigating larger-scale TCP incast
Authors: Tseng Hsueh-Wen , Chang Wan-Chi , Peng I-Hsuan , Chen Pei-Shan
Published: May 2017

Data center network (DCN), a type of network featuring low delays and high bandwidths, exchanges information rapidly through high-performance network switches. Currently, DCN provides various distributed services to satisfy user requirements. However, the size of buffers in the switches of DCNs is limited, thus causing throughput collapse when transmission control protocol (TCP) is used for multiple-to-one transmissions. Dropped packets result in additional retransmission costs and cause a substantial decrease in the efficient use of network bandwidths. Such a decrease in network performance is called a TCP incast problem. Previous studies have typically focused on modifying the original TCP or increasing additional switch hardware costs; rarely have studies focused on the existing DCN environments. Therefore, this study proposes using a cross-layer flow schedule with dynamical grouping (CLFS-DG) scheme to reduce the effect of TCP incast in DCNs. In CLSF-DG, data transmission schedules are organized by a receiver using application-level information. Multiple data flows are then grouped for simultaneously transmission to improve TCP throughput and satisfy deadline requirements. CLFS-DG can be applied to inexpensive switches without extra hardware support, substantially reducing hardware costs. The simulation result indicated that CLFS-DG can effectively prevent TCP incast occurrence and ensure the quality of service in both local networks and fat-tree topologies typically applied in the DCN. A realistic multiple-to-one transmission in the one-hop local network scenario had been set up and tested. The average error rate of the simulation results and actual experimental results is small and about 4.6%. The results show that CLFS-DG can actually be applied to real large networks.
Of content, context, and conveyance
Authors: Amant Kirk St.
Published: May 2017

Content
is about ideas: It involves the thoughts, concepts, and perspectives we wish to convey to others.
Context
is what gives it form. If we know the setting in which we wish to convey information, we can present content in a manner that enhances the chances our ideas will be received (and understood as intended) by an audience. Of course, how we perceive a given context and how our users perceive it can be two different things. We thus need to know what individuals look for in a given context to guide how to design content for that setting.
Designing online writing classes to promote multimodal literacies
Authors: Bourelle Tiffany , Clark-Oates Angela , Bourelle Andrew
Published: May 2017

In this entry, we argue that to promote multimodal literacy in online writing classes, instructors should address the following five practices in their course design:

• Incorporate multimodal assignments and appropriate scaffolding tools;

• Use multimodal instructional tools to teach and model multimodal composition;

• Provide multimodal feedback to students' compositions;

• "Teach" technology through the use of media labs;

• Encourage reflection as a significant part of students' learning process.

In so doing, we discuss each practice in depth, addressing the reasons and benefits for incorporating each, as well as advice about how to implement them. By implementing these practices in their online courses, instructors can successfully design classes that promote multimodal literacy.
The data shadow
Authors: Rogerson Simon
Published: May 2017

This hypothetical story is about personal data which resides on the internet. It has its foundation in things which have happened. It raises serious questions about whether we should be more wary of, and whether there are things organisations and individuals could do to reduce the risks associated with data shadows.
Abstract B44: Protein interactions involving LARP1 in chemotherapy resistant ovarian cancer cells
Authors: Stavraka Chara , Mura Manuela , Fischer Roman , Thezenas Marie-Laetitia , Maghami Sadaf Ghaem , Chettle James , Buluwela Laki , Kessler Benedikt , Blagden Sarah P.
Published: May 2017

Ovarian cancer (OC) is the most lethal gynecological malignancy accounting for 152,000 deaths annually worldwide. Due to the lack of a validated diagnostic tool, patients usually present with disseminated disease and the majority will develop resistance to platinum chemotherapy. Resensitizing OC to cisplatin-based chemotherapy is an unmet clinical need. The RNA-binding protein LARP1 is highly expressed in OC and is a post-transcriptional regulator of cell survival and tumorigenesis. LARP1 depletion using RNA interference (RNAi) restores platinum sensitivity in cisplatin-resistant OC cell lines and shows a synergistic anti-tumour effect with cisplatin. We explored the effect of this resensitization on the efficiency of protein translation using the Surface Sensing of Translation (SUnSET) method. Whilst cisplatin-induced genotoxic stress attenuated de novo protein synthesis in platinum sensitive OVCAR3 cells, this was not observed in platinum-resistant OVCAR8 cells where residual protein synthesis was maintained. However this residual translation was completely abolished after RNAi to LARP1 suggesting that, in the OVCAR8 cells, LARP1 maintains protein synthesis during genotoxic stress. Although LARP1 is known to bind Poly A binding protein (PABP) we questioned whether other interacting partners might also regulate this response. Using immunoprecipitation followed by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) in OVCAR3 and OVCAR8 cells before and after cisplatin treatment, we identified PABPC1, PABPC4 and YB-1 as strong interactors with LARP1. By western blotting, Duolink Proximity Ligation Assay and Immunofluorescence we then confirmed these candidates as being complexed with LARP1. We are currently elucidating the functional role of these interactions on the LARP1-mediated genotoxic stress response with the overall aim of identifying therapeutic strategies to overcome platinum-resistance in ovarian cancer.

Citation Format: Chara Stavraka, Manuela Mura, Roman Fischer, Marie-Laetitia Thezenas, Sadaf Ghaem Maghami, James Chettle, Laki Buluwela, Benedikt Kessler, Sarah P. Blagden. Protein interactions involving LARP1 in chemotherapy resistant ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B44.
Abstract B45: Endometrial cancer microbiome signature and its implications for carcinogenesis
Authors: Walther-Antonio Marina , Chen Jun , Multinu Francesco , Hokenstad Alexis , Distad Tammy , Cheek Heidi , Keeney Gary , Creedon Douglas , Nelson Heidi , Mariani Andrea , Chia Nicholas
Published: May 2017

Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. Because of the inflammatory display in endometrial cancer, we set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer. We undertook a pilot study of the microbiome in 238 samples taken from different locations along the entire female reproductive tract in hysterectomy patients with endometrial cancer (n=17), patients with endometrial hyperplasia (n=4) and patients afflicted with a benign uterine condition (n=10). Samples were collected aseptically both in the operating room and the pathology laboratory. Following DNA extraction, the 16S rDNA (V3-V5 region) microbial gene was amplified and sequenced to identify the microbiota present. The microbiome sequencing revealed a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases (p=0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes (Anaerostipes, ph2, Dialister, Peptoniphilus, 1-68, Ruminococcus, and Anaerotruncus), Spirochaetes (Treponema), Actinobacteria (Atopobium), Bacteroidetes (Bacteroides and Porphyromonas), and Proteobacteria (Arthrospira). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99% match to P.somerae) were found to be predictive of the disease status (sensitivity 73-93%; specificity 67-90%, AUC 0.918). Sensitivity is increased to 100% if combined with a high vaginal pH (>4.5), although specificity is decreased to 60%. Although our numbers are low, the microbiome signature of hyperplasia was even more distinct from benign disease than endometrial cancer itself. This is suggestive of an early microbiome role in the disease. Given the pathogenic profile of the identified microorganisms these findings raise the possibility of a microbiome role in the etiology or progression of endometrial cancer that should be further investigated.

Citation Format: Marina Walther-Antonio, Jun Chen, Francesco Multinu, Alexis Hokenstad, Tammy Distad, Heidi Cheek, Gary Keeney, Douglas Creedon, Heidi Nelson, Andrea Mariani, Nicholas Chia. Endometrial cancer microbiome signature and its implications for carcinogenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B45.
Abstract IA08: Therapeutic resistance and feedback loops
Authors: Zhao Jean J.
Published: May 2017

Therapeutic resistance is a major obstacle in the clinic. Utilizing our novel genetically engineered mouse models (GEMMs) of breast cancer driven by inducible expression of PIK3CAH1047R or a wildtype HER2, coupled with pharmacological approaches, we identified a number of significant resistance mechanisms to PI3K- or HER2-targeted therapy. For example, we found spontaneous focal amplification of Met and Myc, recurrent mutations in Ras and β-catenin, and compensatory activation of the MAPK pathway render resistance to PI3K inhibition. We recently identified Cyclin D1-CDK4 mediated resistance to HER2-targeted therapy through a signaling feedback loop. More importantly, our results led to the design of a randomized phase II trial examining a CDK4/6 inhibitor plus trastuzumab as a regimen for patients with metastatic, refractory HER2+ breast cancer. In addition to GEMMs, we have led the efforts at DFCI to establish and characterize novel breast cancer patient-derived xenograft (PDX) models, with an emphasis on brain metastases, an emerging clinical challenge. I will discuss how we have used these models to discover a therapeutic strategy that overcomes resistance and yields durable remission of brain metastases of HER2+ breast cancer in animals.

Citation Format: Jean J. Zhao. Therapeutic resistance and feedback loops. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA08.
Abstract IA15: Novel approaches for targeting MYC
Authors: Tansey William
Published: May 2017

The MYC family (c-, L-, and N-MYC) is one of the most important groups of proteins in human cancer. More than 50% of all malignancies overexpress at least one MYC family member, and estimates suggest that upwards of 100,000 Americans die from cancer every year as a result of inappropriate MYC expression or activity. Preclinical mouse models have demonstrated that perturbing MYC function in preexisting cancers promotes frank tumor regression, establishing MYC proteins as bonafide and high-value targets for discovery of broadly effective anti-cancer therapies.

Despite the potential of MYC inhibitors to impact cancer therapy, efforts to discover MYC inhibitors are stymied by numerous factors, including an absence of MYC interaction partners with characteristics that make them amenable to drug discovery efforts. The best understood MYC interaction partner, MAX, is required for MYC to assemble a competent DNA-binding module and would theoretically be a superb target for anti-MYC therapies. The MYC–MAX interaction, however, encompasses more that 1800 Å2 of buried protein surface, making it difficult to effectively disrupt by a small molecule with drug-like properties. Breaking the stalemate in drugging MYC requires a fresh perspective on how MYC functions and where the vulnerabilities in its molecular mechanisms of action lie.

Structure-function studies have delineated a potent activation domain at the amino-terminus of MYC and a DNA-binding domain at the carboxy-terminus, but the central portion between these domains has not been studied in detail. To rectify this deficit, we recently initiated screens to identify proteins that bind to the central portion of MYC, with the idea that these proteins would reveal new aspects of MYC regulation or function; some of which may expose new ways to target MYC activity. One novel MYC-interaction partner to emerge from this screen was WDR5.

WDR5 is a chromatin-associated protein that co-binds with MYC at a majority of its target genes. MYC binds weakly to WDR5 by engaging a structured hydrophobic cleft on one side of the WDR5 protein. Mutations in MYC that disrupt interaction with WDR5 block the ability of MYC to bind chromatin and disable its tumorigenic properties in mice, demonstrating that WDR5 is a critical co-factor for MYC. These studies led to a revised model for target gene recognition by MYC in which WDR5 facilitates the recruitment of MYC/MAX complexes to chromatin, and revealed that the MYC–WDR5 interface is a tractable surface for small molecule inhibition. In collaboration with the laboratory of Dr. Stephen Fesik we seek to discover and validate drug-like molecules that disrupt the MYC–WDR5 interaction and explore their utility in cell and animal-based models of cancer.

Citation Format: William Tansey. Novel approaches for targeting MYC. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA15.
Abstract IA27: Protein methyltransferase inhibitors as precision cancer therapeutics: From bench to bedside to bench
Authors: Copeland Robert A.
Published: May 2017

The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example, gene amplification, chromosomal translocations, point mutations and synthetic lethal relationships. The enzyme EZH2 provides a representative example of altered PMTs that act as genetic drivers of specific human cancers. Point mutations of EZH2 are found in a subset of non-Hodgkins lymphoma patients; the enzymatic activity of both wild type and mutant EZH2 are required for pathogenesis in these patients. Also, deletion of the INI1 or SMARCA4 subunit of the SWI/SNF chromatin-remodeling complex occur in a number of cancer types. For example, INI1 is deleted in nearly all malignant rhabdoid tumors (MRTs), a cancer found mainly in children that carries a particularly poor prognosis. Similarly, the SMARCA4 subunit of SWI/SNF is deleted, for example, in malignant rhabdoid tumor of the ovary (MRTO, also referred to as small cell carcinoma of the ovary hypercalcemic type), an aggressive cancer affecting young women. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the INI1 deletion. MRTs and other INI1- or SMARCA4-negative cancers therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation, and we have shown that MRT cells deficient in INI1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models. Drug discovery efforts have yielded a potent, selective inhibitor of EZH2, tazemetostat (EPZ-6438), that has now transitioned into phase 2 clinical trials. This inhibitor affects the appropriate histone methyl marks in cells, leads to selective cell killing that is dependent on genetic lesions associated with EZH2 activity and effects tumor growth inhibition in xenograft models. Combining tazemetostat with other treatment modalities for non-Hodgkins lymphoma results in dramatic synergy of anti-proliferative activity in preclinical models. Results of preclinical and phase 1 clinical studies of tazemetostat will be presented.

Citation Format: Robert A. Copeland. Protein methyltransferase inhibitors as precision cancer therapeutics: From bench to bedside to bench. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA27.
Does Transfer Capacitive Resistive Energy Has a Therapeutic Effect on Peyronie's Disease? Randomized, Single-Blind, Sham-Controlled Study on 96 Patients: Fast Pain Relief
Authors: Pavone Carlo , Romeo Salvatore , D'Amato Francesco , Usala Manuela , Letizia Mauro Giulia , Caruana Giovanni , Caruana Giovanni
Published: May 2017

Background/Aims/Objectives: We have investigated the clinical and physiological effects of Transfer Capacitive Resistive Energy (TCARE) therapy on men with Peyronie's disease (PD). Methods: Ninety-six men with PD have been randomized in a 2:1 ratio to receive 3 sessions of TCARE therapy or sham therapy. Pain, penile curvature and erectile function have been assessed before the first treatment and up to 9 months after the end of treatment, using the Visual Analogue Scale for the pain, a goniometer to measure the degree of curvature using at-home photography and an International Index of Erectile Function (IIEF-5) questionnaire. Results: A significant pain reduction at the end of the treatment in 51 (79.6%) patients (p < 0.01) of the treated group was observed. No significant improvements in the sham group (p = 0.23) have been observed. No statistical differences in the degree of curvature have been observed in both groups. No statistical improvements have been observed in the IIEF-5 questionnaire. Adverse events have not been reported. Conclusion: This is, to our knowledge, the first randomized, single-blind, sham-controlled study that shows that TCARE has a positive short-term clinical effect on pain in patients with PD. The feasibility and tolerability of this treatment produce an attractive new therapeutic option for men with PD.
Non-Melanoma Skin Cancers of the Fronto-Temporal Area Preferentially Localize in the Proximity of Arterial Blood Vessels
Authors: Kuonen François , Gilliet Michel , Perrier Patrick
Published: May 2017

Background: Squamous cell carcinomas and basal cell carcinomas are both induced by chronic UV exposure. However, their predilection for specific areas of the face remains unexplained. Regional factors such as arterial blood flow may explain specific tumor localization. Objective: To determine whether in the fronto-temporal area of the face there is a preferential localization of non-melanoma skin cancer (NMSC) at sites of arterial blood vessels. Methods: Twenty-two patients with NMSC of the fronto-temporal area were selected for this study. The clinical tumor margins were demarked based on clinical examination. Arterial colocalization was determined using both sonography and histological analysis. Results: Echo-Doppler analysis revealed the colocalization of NMSC with an arterial branch in 59% of the patients. Histologically, colocalization between NMSC and artery was found in 68% of the patients. When combining echo-Doppler and histological results, colocalization of NMSC and arteries were found in 82% of the patients. Conclusion: In this study, we found an unexpectedly high colocalization of NMSC with arterial branches in the fronto-temporal area of the face. These results suggest that in addition to UV exposure, pulsatile arterial blood flow may represent an additional factor determining the precise facial localization of NMSC.