bluuebunny/crossref_metadata_2025 huggingface dataset:
The emergence of team resilience: A multilevel conceptual model of facilitating factors
Authors: Gucciardi Daniel F. , Crane Monique , Ntoumanis Nikos , Parker Sharon K. , Thøgersen‐Ntoumani Cecilie , Ducker Kagan J. , Peeling Peter , Chapman Michael T. , Quested Eleanor , Temby Philip
Published: August 2018

With empirical research on team resilience on the rise, there is a need for an integrative conceptual model that delineates the essential elements of this concept and offers a heuristic for the integration of findings across studies. To address this need, we propose a multilevel model of team resilience that originates in the resources of individual team members and emerges as a team‐level construct through dynamic person–situation interactions that are triggered by adverse events. In so doing, we define team resilience as an emergent outcome characterized by the trajectory of a team's functioning, following adversity exposure, as one that is largely unaffected or returns to normal levels after some degree of deterioration in functioning. This conceptual model offers a departure point for future work on team resilience and reinforces the need to incorporate inputs and process mechanisms inherent within dynamic interactions among individual members of a team. Of particular, importance is the examination of these inputs, process mechanisms and emergent states, and outcomes over time, and in the context of task demands, objectives, and adverse events.

Practitioner points

Team resilience as a dynamic, multilevel phenomenon requires clarity on the individual‐ and team‐level factors that foster its emergence within occupational and organizational settings.

An understanding of the nature (e.g., timing, chronicity) of adverse events is key to studying and intervening to foster team resilience within occupational and organizational settings.
Adolescent Psychological Functioning and Membership in Latent Adolescent–Parent Communication Dual Trajectory Classes
Authors: Ohannessian Christine McCauley , Vannucci Anna
Published: August 2018

The primary goal of this study was to examine the relationship between adolescents’ psychological functioning (as indicated by depressive symptoms) and substance use (alcohol and drug use) and membership in adolescent–parent communication trajectory subgroups in a large, diverse community sample of adolescents from the United States (n = 1,057; 53% female; 51% Caucasian; Age: M = 16.15, SD = .75). Adolescents completed questionnaires at three annual assessments. Fit indices from parallel process growth mixture models suggested three dual trajectory classes: (1) Average communication with both parents (Average‐Both); (2) Good adolescent–mother and poor adolescent–father communication (Good‐Mom/Poor‐Dad); and (3) Poor adolescent–mother and good adolescent–father communication (Poor‐Mom/Good‐Dad). The trajectory classes differed by gender. In addition, psychological functioning and substance use were differentially related to the trajectory classes.
Comprehension‐Dependent Cortical Activation During Speech Comprehension Tasks with Multiple Languages: Functional Near‐Infrared Spectroscopy Study
Authors: Lei Miaomei , Miyoshi Toshinori , Niwa Yoshiki , Dan Ippeita , Sato Hiroki
Published: August 2018

In this era of globalization, a second language (which is often English in Japan) has become prevalent and important. To investigate whether cerebral hemodynamics could represent the speech comprehension level of a learned language, we measured the brain activation of 46 non‐fluent Japanese learners of English using functional near‐infrared spectroscopy while performing speech comprehension tasks. Tasks were given in three languages: English (second language), Japanese (native language), and Chinese (unknown language). Analyses of the hemodynamic responses showed that the activated areas for the English task were widely distributed in the bilateral frontal and temporal regions, and this was more evident than for the Japanese and Chinese tasks. This suggests that comprehension of a second language involves more cognitive and/or attentional load. Moreover, particularly in the English tasks, there were significant differences in activations between the cases when participants correctly answered questions and the cases when they did not. These results suggest that the hemodynamic response can provide the information needed to estimate the speech comprehension level of a learned language.
Resolving the predator first paradox: Arthropod predator food webs in pioneer sites of glacier forelands
Authors: Sint Daniela , Kaufmann Ruediger , Mayer Rebecca , Traugott Michael
Published: August 2018

Primary succession on bare ground surrounded by intact ecosystems is, during its first stages, characterized by predator‐dominated arthropod communities. However, little is known on what prey sustains these predators at the start of succession and which factors drive the structure of these food webs. As prey availability can be extremely patchy and episodic in pioneer stages, trophic networks might be highly variable. Moreover, the importance of allochthonous versus autochthonous food sources for these pioneer predators is mostly unknown. To answer these questions, the gut content of 1,832 arthropod predators, including four species of carabid beetles, two lycosid and several linyphiid spider species caught in early and late pioneer stages of three glacier forelands, was screened molecularly to track intraguild and extraguild trophic interactions among all major prey groups occurring in these systems. Two‐thirds of the 2,310 identified food detections were collembolans and intraguild prey, while one‐third were allochthonous flying insects. Predator identity and not successional stage or valley had by far the strongest impact on the trophic interaction patterns. Still, the variability of prey spectra increased significantly from early to late pioneer stage, as did the niche width of the predators. As such the structure of pioneer arthropod food webs in recently deglaciated Alpine habitats seems to be driven foremost by predator identity while site and early successional effects contribute to a lesser extent to food web variability. Our findings also suggest that in these pioneer sites, predatory arthropods depend less on allochthonous aeolian prey but are mainly sustained by prey of local production.
Relations in Creation and Christology: A Response to Porter
Authors: Case Brendan
Published: August 2018

In a recent, provocative essay (“Inheriting Wittgenstein's Augustine,” New Blackfriars (February, 2018)), Philip Porter criticizes Augustine's habit of drawing analogies between the embodiment of concepts in language and the Incarnation of the Word as Jesus of Nazareth, suggesting that his distinctions encourage us to drive a wedge between God the Son and the human being, Jesus, whom he is. Porter worries that Augustine succumbs to the linguistic and then theological fantasy that we might peel away the word's flesh, to attain to the Word beneath. He proposes to dissolve this fantasy by way of a Wittgensteinian revision of Augustine's linguistic Christology, eschewing the distinction between the “verbum mentis” and the “verbum vocis,” the better to safeguard the unity of Christ. In what follows, I suggest that while Augustine is indeed tempted toward Christological error by an inappropriate extension of the linguistic analogy, Porter's proposed corrective both neglects important resources from the developed Chalcedonian tradition, and has as its unhappy outcome that “God is robbed of his transcendence, and creation of its true gratuity.”
A predictive model of suicidal ideation in Korean college students
Authors: Kim Geunmyun , Cha Sunkyung
Published: August 2018

Objective

The study was conducted to develop a theoretical model to comprehensively explain suicidal ideation in Korean college students by including resilience, belongingness, and college life adjustment in addition to depression and stress.

Design and Sample

This study was a descriptive survey with 291 college students.

Measures

Structural equation modeling was used to the hypotheses on this study.

Results

Belongingness and depression showed a statistically significant direct effect, and college life stress and belongingness showed a statistically significant indirect effect. Belongingness was the most influential, and all the predictors in combination had an explanatory power of 37% for suicidal ideation in college students.

Conclusions

Findings suggest a model of suicidal ideation focused on perspective, protective factors; previous research provided a negative perspective with focus on risk factors for suicidal ideation. Findings can be used to develop diverse programs to decrease suicidal ideation in college students and help them to adjust to college life.
Common and well‐documented HLA alleles of German stem cell donors by haplotype frequency estimation
Authors: Eberhard Hans‐Peter , Schmidt Alexander H. , Mytilineos Joannis , Fleischhauer Katharina , Müller Carlheinz R.
Published: August 2018

We present a catalog of common and well‐documented (CWD) alleles of the German population for the six HLA loci A, B, C, DRB1, DQB1, and DPB1. This study is based on a sample of over 5 million volunteer adult hematopoietic stem cell donors from the 26 German donor centers. To establish the catalog, allele and haplotype frequencies were estimated with a validated implementation of the expectation‐maximization algorithm. CWD criteria similar to existing CWD catalogs were applied in order to be able to put our findings into the context of relevant existing references. Overall, 2155 HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, and ‐DPB1 alleles were identified as CWD in the German donor population representing about 20% of the HLA alleles at two‐field resolution in the IPD‐IMGT/HLA Database release v3.25.0 from July 2016 for these six loci. We found a substantial concordance of CWD alleles between the three catalogs and showed the contribution of the German donor population to the CWD alleles domain. In conclusion, the definition of CWD criteria that allow interoperability, scalability, and flexibility will be crucial for the development of a worldwide CWD catalog.
TBL10 is required for O‐acetylation of pectic rhamnogalacturonan‐I in Arabidopsis thaliana
Authors: Stranne Maria , Ren Yanfang , Fimognari Lorenzo , Birdseye Devon , Yan Jingwei , Bardor Muriel , Mollet Jean‐Claude , Komatsu Takanori , Kikuchi Jun , Scheller Henrik V. , Sakuragi Yumiko
Published: August 2018

O‐Acetylated pectins are abundant in the primary cell wall of plants and growing evidence suggests they have important roles in plant cell growth and interaction with the environment. Despite their importance, genes required for O‐acetylation of pectins are still largely unknown. In this study, we showed that TRICHOME BIREFRINGENCE LIKE 10 (AT3G06080) is involved in O‐acetylation of pectins in Arabidopsis (Arabidopsis thaliana). The activity of the TBL10 promoter was strong in tissues where pectins are highly abundant (e.g. leaves). Two homozygous knock‐out mutants of Arabidopsis, tbl10‐1 and tbl10‐2, were isolated and shown to exhibit reduced levels of wall‐bound acetyl esters, equivalent of ~50% of the wild‐type level in pectin‐enriched fractions derived from leaves. Further fractionation revealed that the degree of acetylation of the pectin rhamnogalacturonan‐I (RG‐I) was reduced in the tbl10 mutant compared to the wild type, whereas the pectin homogalacturonan (HG) was unaffected. The degrees of acetylation in hemicelluloses (i.e. xyloglucan, xylan and mannan) were indistinguishable between the tbl10 mutants and the wild type. The mutant plants contained normal trichomes in leaves and exhibited a similar level of susceptibility to the phytopathogenic microorganisms Pseudomonas syringae pv. tomato DC3000 and Botrytis cinerea; while they displayed enhanced tolerance to drought. These results indicate that TBL10 is required for O‐acetylation of RG‐I, possibly as an acetyltransferase, and suggest that O‐acetylated RG‐I plays a role in abiotic stress responses in Arabidopsis.
Thylakoid proteome modulation in pea plants grown at different irradiances: quantitative proteomic profiling in a non‐model organism aided by transcriptomic data integration
Authors: Albanese Pascal , Manfredi Marcello , Re Angela , Marengo Emilio , Saracco Guido , Pagliano Cristina
Published: August 2018

Plant thylakoid membranes contain hundreds of proteins that closely interact to cope with ever‐changing environmental conditions. We investigated how Pisum sativum L. (pea) grown at different irradiances optimizes light‐use efficiency through the differential accumulation of thylakoid proteins. Thylakoid membranes from plants grown under low (LL), moderate (ML) and high (HL) light intensity were characterized by combining chlorophyll fluorescence measurements with quantitative label‐free proteomic analysis. Protein sequences retrieved from available transcriptomic data considerably improved thylakoid proteome profiling, increasing the quantifiable proteins from 63 to 194. The experimental approach used also demonstrates that this integrative omics strategy is powerful for unravelling protein isoforms and functions that are still unknown in non‐model organisms. We found that the different growth irradiances affect the electron transport kinetics but not the relative abundance of photosystems (PS) I and II. Two acclimation strategies were evident. The behaviour of plants acclimated to LL was compared at higher irradiances: (i) in ML, plants turn on photoprotective responses mostly modulating the PSII light‐harvesting capacity, either accumulating Lhcb4.3 or favouring the xanthophyll cycle; (ii) in HL, plants reduce the pool of light‐harvesting complex II and enhance the PSII repair cycle. When growing at ML and HL, plants accumulate ATP synthase, boosting both cyclic and linear electron transport by finely tuning the ΔpH across the membrane and optimizing protein trafficking by adjusting the thylakoid architecture. Our results provide a quantitative snapshot of how plants coordinate light harvesting, electron transport and protein synthesis by adjusting the thylakoid membrane proteome in a light‐dependent manner.
Response rate to a single dose of vinblastine administered to dogs with treatment‐naive multicentric lymphoma
Authors: Harding K. , Bergman N. , Smith A. , Lindley S. , Szivek A. , Milner R. , Brawner W. , Lejeune A.
Published: August 2018

Vincristine is included in vincristine, cyclophosphamide, doxorubicin and prednisone (CHOP) chemotherapy protocols, which are the gold‐standard treatment for high‐grade canine lymphoma. Vincristine can result in relatively high rates of gastrointestinal toxicity, whereas vinblastine is generally well tolerated and thus may represent an under‐utilized and minimally toxic alternative to vincristine. Our objective was to determine the response rate and toxicity associated with a single dose of vinblastine administered to dogs with treatment‐naïve, intermediate to large‐cell, multicentric lymphoma. Twenty client‐owned dogs were enrolled with signed owner consent. A Simon's minimax, phase II, two‐stage trial was performed to test the efficacy of vinblastine administered at 2 mg/m2 IV followed by a pilot trial of vinblastine at 2.5 mg/m2. No dogs were administered concurrent steroids or other chemotherapy. One out of 14 dogs receiving vinblastine at 2 mg/m2 demonstrated a partial response. Three out of five dogs demonstrated a partial response to vinblastine at 2.5 mg/m2. Gastrointestinal toxicity was infrequent and low grade for both groups. The majority of dogs (80%) in the 2.5 mg/m2 dosing group developed neutropenia 1‐week post administration. Vinblastine was well tolerated but minimally efficacious at a dose of 2 mg/m2 IV in dogs with treatment‐naive, multicentric lymphoma. Because of poor response rates, treatment at this dose is not recommended. A small subset of dogs administered 2.5 mg/m2 had significantly improved response rates (P = 0.04), suggesting that higher doses may have improved efficacy, although further research is indicated to confirm these preliminary findings.
A pilot study evaluating adaptive closed‐loop fluid resuscitation during states of absolute and relative hypovolemia in dogs
Authors: Gholami Behnood , Haddad Wassim M. , Bailey James M. , Geist Beth , Ueyama Yukie , Muir William W.
Published: August 2018

Objective

To evaluate and determine the performance of a partially automated as well as a fully automated closed‐loop fluid resuscitation system during states of absolute and relative hypovolemia.

Design

Prospective experimental trial.

Setting

Research laboratory.

Animals

Five adult Beagle dogs.

Methods

Isoflurane anesthetized mechanically ventilated dogs were subjected to absolute hypovolemia (controlled: 2 trials; uncontrolled: 3 trials), relative hypovolemia (2 trials), and the combination of relative and absolute controlled hypovolemia (2 trials). Controlled and uncontrolled hypovolemia were produced by withdrawing blood from the carotid or femoral artery. Relative hypovolemia was produced by increasing the isoflurane concentration (1 trial) or by infusion of intravenous sodium nitroprusside (1 trial). Relative hypovolemia combined with controlled absolute hypovolemia was produced by increasing the isoflurane concentration (1 trial) and infusion of IV sodium nitroprusside (1 trial). Hemodynamic parameters including stroke volume variation (SVV) were continuously monitored and recorded in all dogs. A proprietary closed‐loop fluid administration system based on fluid distribution and compartmental dynamical systems administered a continuous infusion of lactated Ringers solution in order to restore and maintain SVV to a predetermined target value.

Measurements and Main Results

A total of 9 experiments were performed on 5 dogs. Hemodynamic parameters deteriorated and SVV increased during controlled or uncontrolled hypovolemia, relative hypovolemia, and during relative hypovolemia combined with controlled hypovolemia. Stroke volume variation was restored to baseline values during closed‐loop fluid infusion.

Conclusions

Closed‐loop fluid administration based on IV fluid distribution and compartmental dynamical systems can be used to provide goal directed fluid therapy during absolute or relative hypovolemia in mechanically ventilated isoflurane anesthetized dogs.
A synthetic microRNA‐92a inhibitor (MRG‐110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds
Authors: Gallant‐Behm Corrie L. , Piper Joseph , Dickinson Brent A. , Dalby Christina M. , Pestano Linda A. , Jackson Aimee L.
Published: August 2018

There is a strong unmet need for new therapeutics to accelerate wound healing across both chronic and acute indications. It is well established that local tissue hypoxia, vascular insufficiency, and/or insufficient angiogenesis contribute to inadequate wound repair in the context of diabetic foot ulcers as well as to other chronic wounds such as venous stasis and pressure ulcers. microRNA‐92a‐3p (miR‐92a) is a potent antiangiogenic miRNA whose inhibition has led to increases in angiogenesis in multiple organ systems, resulting in an improvement in function following myocardial infarction, limb ischemia, vascular injury, and bone fracture. Due to their pro‐angiogenic effects, miR‐92a inhibitors offer potential therapeutics to accelerate the healing process in cutaneous wounds as well. This study investigated the effect of a development stage locked nucleic acid‐modified miR‐92a inhibitor, MRG‐110, in excisional wounds in db/db mice and in normal pigs. In both acute and chronic wounds, MRG‐110 increased granulation tissue formation as assessed by histology, angiogenesis as assessed by immunohistochemistry and tissue perfusion, and wound healing as measured by time to closure and percent closure over time. The effects of MRG‐110 were greater than those that were observed with the positive controls rhVEGF‐165 and rhPDGF‐BB, and MRG‐110 was at least additive with rhPDGF‐BB when co‐administered in db/db mouse wounds. MRG‐110 was found to up‐regulate expression of the pro‐angiogenic miR‐92a target gene integrin alpha 5 in vitro in both human vascular endothelial cells and primary human skin fibroblasts and in vivo in mouse skin, demonstrating its on‐target effects in vitro and in vivo. Additional safety endpoints were assessed in both the mouse and pig studies with no safety concerns noted. These studies suggest that MRG‐110 has the potential to accelerate both chronic and acute wound healing and these data provide support for future clinical trials of MRG‐110.
Growth and mechanical properties of 111-oriented V0.5Mo0.5Nx/Al2O3(0001) thin films
Authors: Kindlund Hanna , Lu Jun , Broitman Esteban , Petrov Ivan , Greene J. E. , Birch Jens , Hultman Lars
Published: August 2018

Pseudobinary V0.5Mo0.5Nx(111) alloys with the B1-NaCl crystal structure are grown on Al2O3(0001) substrates in an ultra-high-vacuum system by reactive magnetron sputter deposition in mixed Ar/N2 atmospheres at temperatures Ts between 100 and 900 °C. Nitrogen-to-metal, N/(V + Mo), fractions x vary monotonically from 0.9 ± 0.1 with Ts = 100 °C to 0.4 ± 0.1 at Ts = 900 °C. Nitrogen loss at higher growth temperatures leads to a corresponding decrease in the relaxed lattice parameter ao from 4.21 ± 0.01 Å at Ts = 300 °C to 4.125 ± 0.005 Å with Ts = 900 °C. Scanning electron micrographs of cube-corner nanoindents extending into the substrate show that the films are relatively ductile, exhibiting material pile-up (plastic flow) around the indent edges. Nanoindentation hardnesses H and elastic moduli E, obtained using a calibrated Berkovich tip, of V0.5Mo0.5Nx(111) layers increase with increasing Ts (decreasing x) from 15 ± 1 and 198 ± 5 GPa at 100 °C to 23 ± 2 and 381 ± 11 GPa at 900 °C. These values are lower than the corresponding results obtained for the 001-oriented V0.5Mo0.5Nx films. In addition, film wear resistance increases with increasing Ts, while the coefficient of friction, under 1000 μN loads, is 0.09 ± 0.01 for all layers.
Multivalent binding of herpesvirus to living cells is tightly regulated during infection
Authors: Delguste Martin , Zeippen Caroline , Machiels Bénédicte , Mast Jan , Gillet Laurent , Alsteens David
Published: August 2018

We probe herpesvirus binding to living cells using atomic force microscopy.
Epstein-Barr Virus Nuclear Antigen 3C Inhibits Expression of
COBLL1
and the
ADAM28-ADAMDEC1
Locus via Interaction with the Histone Lysine Demethylase KDM2B
Authors: Gillman Adam C. T. , Parker Gillian , Allday Martin J. , Bazot Quentin
Published: August 2018

EBV is a virus associated with human cancers and is well known for its ability to transform B lymphocytes into continuously proliferating lymphoblastoid cell lines. EBNA3C is considered an oncoprotein and has been shown to be essential for B cell transformation by EBV. EBNA3C is well characterized as a viral transcription factor, but very little is known about its mechanisms of action. In the present study, we demonstrate that removal of the activating histone mark H3K4me3 and deposition of the repressive mark H3K27me3 by EBNA3C on
COBLL1
are achieved by at least two distinct mechanisms. Furthermore, we discovered that EBNA3C interacts with the lysine demethylase KDM2B and that this interaction is important for its transcriptional repressive function. The findings in this study provide new insights into the mechanism used by the oncoprotein EBNA3C to repress cellular target genes.
Staphylococcal Biofilms
Authors: Otto Michael
Published: August 2018

Staphylococci, with the leading speciesStaphylococcus aureusandStaphylococcus epidermidis, are the most frequent causes of infections on indwelling medical devices. The biofilm phenotype that those bacteria adopt during device-associated infection facilitates increased resistance to antibiotics and host immune defenses. This review presents and discusses the molecular mechanisms contributing to staphylococcal biofilm development and their in-vivo importance. Furthermore, it summarizes current strategies for the development of therapeutics against staphylococcal biofilm-associated infection.
Variability in the ocular phenotype in mucopolysaccharidosis
Authors: Sornalingam Krishanthy , Javed Ahmed , Aslam Tariq , Sergouniotis Panagiotis , Jones Simon , Ghosh Arunabha , Ashworth Jane
Published: August 2018

Purpose

Mucopolysaccharidoses (MPSs) are a heterogeneous group of lysosomal storage disorders. Ocular complications (such as corneal clouding, retinopathy and optic neuropathy) are common. Notably, there is a paucity of data on the effect of genotype and systemic treatments (enzyme replacement therapy or haematopoietic stem cell transplantation) on the ocular phenotype in MPS. We prospectively studied the ocular features of patients with MPSI (Hurler/Hurler-Scheie/Scheie), MPSIV (Morquio) and MPSVI (Maroteaux-Lamy), to evaluate the effect of different therapeutic interventions and to correlate the findings with genetic and biomarker data.

Methods

Prospective observational cohort study. Study participants underwent detailed ocular examination including visual acuity; assessment of corneal clouding (Iris camera Corneal Opacification Measure score and Pentacam densitometry) and retinal and optic nerve imaging (optical coherence tomography and wide-field fundus imaging). Data on genotype, biomarkers and delivered therapies (type and length of treatment) were also collected for each patient where available.

Results

Overall, 21 patients with MPSI, 4 patients with MPSIV and 3 patients with MPSVI were recruited. Corneal clouding scores were higher in MPSI compared with MPSIV and MPSVI. Retinopathy was evident in patients with MPSI only. Association was observed between corneal clouding and biomarkers in MPSI, MPSIV and MPSVI. However, no clear association was seen between genotype or treatment type and ocular phenotype.

Conclusions

The ocular phenotype in MPS is variable, with corneal clouding occurring in MPSI, MPSIV and MPSVI, and retinopathy in MPSI only. There was an association between corneal clouding and efficacy of systemic treatment as measured by biomarkers.
Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM)
Authors: Wang Kun , Zhao Sen , Liu Bowen , Zhang Qianqian , Li Yaqi , Liu Jiaqi , Shen Yan , Ding Xinghuan , Lin Jiachen , Wu Yong , Yan Zihui , Chen Jia , Li Xiaoxin , Song Xiaofei , Niu Yuchen , Liu Jian , Chen Weisheng , Ming Yue , Du Renqian , Chen Cong , Long Bo , Zhang Yisen , Tong Xiangjun , Zhang Shuyang , Posey Jennifer E , Zhang Bo , Wu Zhihong , Wythe Joshua D , Liu Pengfei , Lupski James R , Yang Xinjian , Wu Nan
Published: August 2018

Background

Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10–18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM.

Methods

We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model.

Results

We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene,ENG, and three damaging variants in novel candidate genes:PITPNM3,SARSandLEMD3, which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (TIMP3,SCUBE2, MAP4K4, CDH2, IL17RD, PREX2, ZFYVE16andEGFR) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance (MAP4K4withENG,RASA1withTIMP3andSCUBE2withENG) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-β) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM.

Conclusions

Our study highlights the specific role of BMP/TGF-β and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.
Influence of stress path on stress memory and stress fracturing in brittle rocks
Authors: Bahrani Navid , Valley Benoît , Kaiser Peter K.
Published: August 2018

A two-dimensional numerical model based on the distinct element method, previously calibrated to the laboratory properties of undamaged and damaged Lac du Bonnet (LdB) granite, was used to investigate the influence of stress path on the development of stress memory and stress fracturing in brittle rocks. Various cycles of loading and unloading, similar to those imposed during Kaiser effect tests, were first applied to undamaged numerical specimens of LdB granite. The results of Kaiser effect test simulations were found to be consistent with those of published laboratory and numerical investigations. Further simulations were conducted to investigate the influence of stress path resulting from the excavation of a tunnel on the depth of stress fracturing around the excavation boundary. For this purpose, the stress paths at points on and near the tunnel wall, obtained from a continuum finite element model, were applied to the calibrated numerical specimen. It was found that the amount of damage in the numerical specimens decreases rapidly with increasing distance from the excavation wall. The findings of this research shed some light on the influence of stress path and grain-scale heterogeneity on stress memory in brittle rocks and stress fracturing around underground openings.
Geology and geochemistry of pillow basalt in the Huilvshan region (west Junggar, China): implications for magma source and tectonic setting
Authors: Zhang Huichao , Zhu Yongfeng
Published: August 2018

Geological characteristics and geochemical analyses are reported for the early Carboniferous pillow basalt in the Huilvshan region (west Junggar, Northwest China), with the aim to indicate its petrogenesis, magma source characteristics, and tectonic implication. This pillow basalt consists of clinopyroxene and plagioclase with trace amounts of magnetite, apatite, and chromian spinel. It is tholeiitic in composition with low concentrations of Na2O + K2O (1.52–4.74 wt.%). Similar to the N-MORB, the samples of this pillow basalt have nearly flat chondrite-normalized REE patterns ((La/Yb)N = 0.87–1.47) with insignificant Eu anomalies (Eu/Eu* = 0.84–1.18), and show no obvious enrichments of LILEs and insignificant depletions in HFSEs. Petrology and geochemical characteristics suggest that this pillow basalt is the product of MORB-like magma derived from a depleted mantle corresponding to ≤4% partial melting of spinel lherzolite. SIMS analysis of the zircons separated from tuff interlayered with basalt gives a weighted average U–Pb age of 328 ± 3 Ma (MSWD = 1.4), which represents the magma eruption time in the Huilvshan region. From these observations, in combination with the previous work, we conclude that an extensional tectonic regime dominated the tectonic activity of west Junggar during early Carboniferous.
Mechanism research of negative resistance oscillations characteristics of the silicon magnetic sensitive transistor with long base region
Authors: Bai Yunjia , Zhao Xiaofeng , Hao Jiandong , Wen Dianzhong
Published: August 2018

A silicon magnetic sensitive transistor (SMST) with the negative resistance oscillation phenomenon is presented in this paper. The SMST of cubic structure is composed of three regions and three electrodes (E, C and B). Two of the regions (collector region and base region) are designed on the top surface of the SMST, and the emitter region is designed at the bottom of the SMST. Using microelectromechanical system (MEMS) technology, the chip is fabricated on [Formula: see text] orientation p-type silicon (near intrinsic) wafer and packaged on printed circuit board (PCB). When collector voltage (V[Formula: see text]) and the base injecting current (I[Formula: see text]) are a certain value, the experimental results show that the collector current (I[Formula: see text]) attains negative resistance oscillation phenomenon and it is influenced by the external magnetic field (B) and temperature (T). Based on the effect of deep-level impurities on the carrier net recombination rate, theoretical analysis demonstrates that the deep-level impurities are the main factors of the appearance for oscillations phenomenon.
Quantum symmetry of graph C∗-algebras associated with connected graphs
Authors: Joardar Soumalya , Mandal Arnab
Published: August 2018

We define a notion of quantum automorphism groups of graph [Formula: see text]-algebras for finite, connected graphs. Under the assumption that the underlying graph does not have any multiple edge or loop, the quantum automorphism group of the underlying directed graph in the sense of Banica [Quantum automorphism groups of homogeneous graphs, J. Funct. Anal. 224 (2005) 243–280] (which is also the symmetry object in the sense of [S. Schmidt and M. Weber, Quantum symmetry of graph [Formula: see text]-algebras, arXiv:1706.08833 ] is shown to be a quantum subgroup of quantum automorphism group in our sense. Quantum symmetries for some concrete graph [Formula: see text]-algebras have been computed.
IDENTIFYING FACTORS INFLUENCING THE PRICE OF TECHNOLOGY LICENSES: A FRAMEWORK GROUNDED IN NEGOTIATION RESEARCH
Authors: FRATTINI FEDERICO , BIANCHI MATTIA , FRANZÓ SIMONE
Published: August 2018

This paper focusses on the issue of pricing in technology licensing transactions, by developing a framework grounded in negotiation research which identifies the factors affecting the price of a technology license. The different components of the framework are illustrated by using several examples of technology licensing deals from the bio-pharmaceutical industry. The paper contributes to licensing research by shedding light on the mechanisms underlying the formation of price in the market for technologies. It has also interesting practical implications because it helps licensing managers and chief technology officers gain an overarching view on the pricing of technology license, which will hopefully help them in this delicate stage of the licensing process.
Abstract A015: Intrapatient heterogeneity of multiple myeloma is evenly distributed in multiple myeloma lesions
Authors: Mishima Yuji , Terui Yasuhito , Hatake Kiyohiko
Published: August 2018

Background: We previously reported that circulating tumor cells (CTCs) from myeloma patients and clonal plasma cells from the BM biopsy of the same patients have quite similar clonal structures (Cell Rep. 2017;19(1):218). Specifically, overall, 90% of CTC mutations were present in BM tumors and 93% of BM mutations were present in CTC samples, and upon analyzing the mutational variants by nucleotide change, we found that the percentages of each change in BM myeloma PCs and CTCs were concordant. This finding suggests the possibility that multiple lesions of a multiple myeloma patient basically share similar clonal structure. Methods: To examine this hypothesis, we performed xenograft dissemination model of multiple myeloma using DNA-barcoded cell library. Briefly, two million human multiple myeloma cell lines barcoded with 12mer-DNA tags were inoculated into the bone chips harvested from syngeneic donor mice and the tumor-bearing bone chips were implanted to recipient mice. After the implanted myeloma cells were disseminated to murine host bone marrow via hematogenous dissemination, tumor cells were harvested from multiple BM sites and peripheral blood then analyzed the clonal structure by next-generation sequencing. Results: The clonal structures of tumor cells were highly concordant between left and right femur bone marrow from same mice. In addition, the clonal structures of tumor in host murine bone marrow were also highly concordant with those of CTCs harvested from same mice as we observed in clinical samples previously. Discussion: Recent studies of massive parallel sequencing of tumor cells obtained from the BM of patients with MM have demonstrated significant intrapatient clonal heterogeneity. Most patients have both clonal and subclonal variants even in single biopsy site. In a previous study, we have shown that the variant landscapes of tumors were highly concordant between CTCs and single BM biopsy specimen in same patients. Together with these findings, the result of our xenograft model may indicate that the tumor lesions of myeloma patients basically consist of heterogeneous but highly shared tumor cell population across the multiple lesions. The concordance of clonal structures among the multiple BM lesions is thought to be due to the fact that the clonal structure of BM myeloma tumors reflects that of CTC. Together, this study supports validity of the CTC for genetic profiling.

Citation Format: Yuji Mishima, Yasuhito Terui, Kiyohiko Hatake. Intrapatient heterogeneity of multiple myeloma is evenly distributed in multiple myeloma lesions [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A015.
Abstract A038: Establishing ubiquitylation pattern in tissues and cells efficient method to monitor cancer drug function and biomarkers
Authors: Lu Xiaolong , Singh Rajesh , Song Chengcheng , Foote Peter
Published: August 2018

The cell regulates its function by altering ubiquitylation status of many key proteins, especially oncoproteins. As a result, these ubiquitin proteasome system (UPS) substrates and the relevant UPS enzymes have been identified as attractive anticancer targets. However, to date, the only effective way to measure these effects has been by immunoprecipitation coupled with immunoblot analysis (IP/IB) or by mass spectrometry methods, which are either insensitive, low throughput, or highly intensive. Here, we describe two Tandem Ubiquitin Binding Entity (TUBE)-based assays, UbiQuant S and UbiTest, that provide a platform to efficiently detect ubiquitylation of anticancer targets. UbiQuant S is a high-throughput assay to quantify ubiquitylation status in a cell or tissue. Ubiquitylated proteins and the nature poly-ubiquitin are identified by energy transfer between tagged TUBE and antibody against the target protein that is poly-ubiquitylated. Interaction between TUBE and antibody is registered in a label-free manner in a solution. In case the level of ubiquitylated protein is extremely low or cannot be detected by antibody, ubiquitylated proteins can be affinity purified by TUBEs attached to agarose or magnetic beads and FRET or alphaLISA experiment is repeated. Furthermore, we have extended the technology to identify K63- and K48-linked poly-ubiquitin proteins by poly-ubiquitin chain selective TUBEs. UbiTest is an immunoblot-based assay, which can be used to verify the result of UbiQuant S. Compared to traditional ubiquitin IP/IB, this assay avoids epitope masking of antibodies caused by ubiquitin modification. Several important therapeutic targets have been used to verify these assays, including Cbl-b and USP7 immune oncology drug targets. The high efficiency and sensitivity of these assays have wide applications in drug discovery targeting ubiquitylation-dependent signaling pathways. Examples from DUBs and ubiquitin ligase inhibitors will illustrate the power of this system. These novel technologies will equip researchers with versatile tools to better understand the role of ubiquitylation in cancer treatment and monitoring biomarkers in response to drug action.

Citation Format: Xiaolong Lu, Rajesh Singh, Chengcheng Song, Peter Foote. Establishing ubiquitylation pattern in tissues and cells efficient method to monitor cancer drug function and biomarkers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A038.
Abstract A042: Genomic predictors of chemotherapy efficacy in gastric cancer in the GC0301/TOP002 phase III trial
Authors: Das Kakoli , Taguri Masataka , Tsuburaya Akira , Tan Patrick
Published: August 2018

Recent gastric cancer (GC) clinical trials have aimed to establish the efficacy of combination therapy over monotherapy; however, a role for genomic biomarkers in these trials has remained largely unexplored. Here, using the NanoString expression platform, we analyzed 105 gastric tumors from a randomized phase III Japanese clinical trial (GC0301/TOP002) testing efficacy of irinotecan plus S-1 over S-1 chemotherapy. We found that previously established proliferative subtype signatures were associated with older patients (>65 years) and liver metastasis, while mesenchymal subtype signatures were associated with younger patients (≤65 years) and peritoneal metastasis. Genes associated with the tumor microenvironment (CD14, DPYD), oncogenic signaling (Wnt5A, PTRF), and chemokines (CCL5, CXCL12, CCL19) were significantly associated with patient age, Lauren’s histologic classification, tumor status, measurable lesions, and metastasis. We identified Wnt5A downregulation as a candidate predictor of improved progression-free survival (PFS) (>8 weeks) in fluorouracil (S-1) monotherapy-treated patients, but not in irinotecan plus S-1 (IRI-S) combined treatment. Although not achieving statistical significance, we observed a trend for mesenchymal subtype showing a treatment interaction with IRI-S for efficacy. These findings highlight promising genomic markers that could be useful predictors of chemotherapy efficacy for better prognosis and survival outcome in gastric cancer.

Citation Format: Kakoli Das, Masataka Taguri, Akira Tsuburaya, Patrick Tan. Genomic predictors of chemotherapy efficacy in gastric cancer in the GC0301/TOP002 phase III trial [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A042.
Abstract A069: Increasing replication stress by reducing nucleoside levels sensitizes melanomas and non-small cell lung cancers to CHK1 inhibitor in vitro and in vivo
Authors: Oo Zay Yar , Proctor Martina , Stevenson Alexander , Larsen Jill , Gabrielli Brian G.
Published: August 2018

CHK1 inhibitors are being investigated as chemosensitizing agents with agents that increase replication stress. Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors as single agents in melanoma and as combinations with subclinical doses of hydroxyurea in melanoma and non-small cell lung cancer (NSCLC). We have found that sensitivity in vitro and in vivo to single agent CHK1 inhibitor is associated with defective S phase cell cycle checkpoint response to low dNTP levels. Loss of checkpoint response by overexpressing components of the checkpoint or inhibition of Wee1, convert CHK1 inhibitor insensitive cells to sensitive, and similarly depletion of CDC25A reduces CHK1 inhibitor sensitivity in sensitive lines. The increased DNA damage found with CHK1 inhibitor treatment is not sufficient to induce cell death, and cell death was triggered without entry into mitosis. We have found that about 20% of melanomas are sensitive to CHK1 inhibitor as a single agent, but we show that >70% of melanomas and NSCLCs are sensitive to combination with subclinical doses of hydroxyurea. The mechanism of cell death in the combination appears identical to CHK1 inhibitor alone in inhibitor-sensitive melanomas, with cells dying without entering mitosis. In half the cell melanomas tested, the combination produced a complete loss of viability; in the other half, the viable population after treatment was incapable of further proliferation in the absence in drug. The sensitivity to the combination is independent of other known risk factors, suggesting a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.

Citation Format: Zay Yar Oo, Martina Proctor, Alexander Stevenson, Jill Larsen, Brian G. Gabrielli. Increasing replication stress by reducing nucleoside levels sensitizes melanomas and non-small cell lung cancers to CHK1 inhibitor in vitro and in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A069.
Abstract A103: ATM inhibitor AZD0156 in combination with irinotecan: the use of mathematical modeling to predict efficacious doses and schedules from preclinical data
Authors: Cadogan Elaine
Published: August 2018

AZD0156 is a first- and only-in-class, potent, and selective ATM inhibitor. It is being investigated in clinical ascending dose studies in combination with olaparib or irinotecan. Preclinical data on the AZD0156 irinotecan combination have been used to determine which doses and schedules should be investigated to maximize efficacy. The effects of AZD0156 and irinotecan in combination on the distribution of cell cycle phases have been investigated in vitro by flow cytometry. Cell population growth and DNA damage response biomarkers such as pATM foci, gH2AX foci, and micronuclei were described in detail using high-throughput immunofluorescence imaging. In vivo, preclinical xenograft studies have been carried out to examine the effects on pharmacodynamics and tumor growth from different doses and schedules of both agents. These in vitro and in vivo data have been integrated into a mechanistic mathematical model that supports the combination hypothesis, and allows prediction of pharmacodynamic and tumor volume responses under different doses and schedules. In particular, the effects of clinical doses and schedules can be predicted by taking into account differences between mouse and human pharmacokinetics for the co-agents. It can be challenging to identify the optimum schedule during clinical ascending dose studies, especially in combination cases with multiple variables, such as the doses of each agent, time gaps between doses, and times without dosing between cycles. Preclinical information, together with mathematical modeling, can be used to guide the prioritization of clinical experiments.

Citation Format: Elaine Cadogan. ATM inhibitor AZD0156 in combination with irinotecan: the use of mathematical modeling to predict efficacious doses and schedules from preclinical data [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A103.