bluuebunny/crossref_metadata_2025_split huggingface dataset:
Security Evaluation of a Banking Fraud Analysis System
Authors: Carminati Michele , Polino Mario , Continella Andrea , Lanzi Andrea , Maggi Federico , Zanero Stefano 
Published: April 2018

The significant growth of banking fraud, fueled by the underground economy of malware, has raised the need for effective detection systems. Therefore, in the last few years, banks have upgraded their security to protect transactions from fraud. State-of-the-art solutions detect fraud as deviations from customers’ spending habits. To the best of our knowledge, almost all existing approaches do not provide an in-depth model’s granularity and security analysis against elusive attacks.
In this article, we examine Banksealer, a decision support system for banking fraud analysis that evaluates the influence on detection performance of the granularity at which spending habits are modeled and its security against evasive attacks. First, we compare user-centric modeling, which builds a model for each user, with system-centric modeling, which builds a model for the entire system, from the point of view of detection performance. Then, we assess the robustness of Banksealer against malicious attackers that are aware of the structure of the models in use. To this end, we design and implement a proof-of-concept attack tool that performs mimicry attacks, emulating a sophisticated attacker that cloaks frauds to avoid detection. We experimentally confirm the feasibility of such attacks, their cost, and the effort required by an attacker in order to perform them. In addition, we discuss possible countermeasures.
We provide a comprehensive evaluation on a large real-world dataset obtained from one of the largest Italian banks.
Computing the Gromov-Hausdorff Distance for Metric Trees
Authors: Agarwal Pankaj K. , Fox Kyle , Nath Abhinandan , Sidiropoulos Anastasios , Wang Yusu 
Published: April 2018

The Gromov-Hausdorff (GH) distance is a natural way to measure distance between two metric spaces. We prove that it is NP-hard to approximate the GH distance better than a factor of 3 for geodesic metrics on a pair of trees. We complement this result by providing a polynomial time
O
(min
n
, √
rn
)-approximation algorithm for computing the GH distance between a pair of metric trees, where
r
is the ratio of the longest edge length in both trees to the shortest edge length. For metric trees with unit length edges, this yields an
O
(√
n
)-approximation algorithm
1
.
Cell type-specific plasticity at parallel fiber synapses onto Purkinje cells in the posterior caudal lobe of the mormyrid fish cerebellum
Authors: Zhang Yueping , Magnus Gerhard , Han Victor Z. 
Published: April 2018

It has been demonstrated that there are two morphological subtypes of Purkinje cells (PCs)—fan-shaped Purkinje cells (fPCs) and multipolar Purkinje cells (mPCs)—in the posterior caudal lobe of the mormyrid fish cerebellum, but whether these cell types are also functionally distinct is unknown. Here, we have used electrophysiological and pharmacological tools in a slice preparation to demonstrate that pairing parallel fiber (PF) and climbing fiber (CF) inputs at a low frequency induces long-term depression (LTD) in fPCs but long-term potentiation (LTP) in mPCs. The induction of plasticity in both cell types required postsynaptic Ca2+ and type 1α metabotropic glutamate receptors. However, the LTD in fPCs was inducted via a calcium/calmodulin-dependent protein kinase II cascade, whereas LTP induction in mPCs required calcineurin. Moreover, the LTD in fPCs and LTP in mPCs were accompanied by changes to the corresponding paired-pulse ratios and their coefficients of variation, suggesting presynaptic modes of expression for the plasticity at PF terminals for both cell types. Hence, the synaptic plasticity at PF synapses onto PCs in the posterior caudal lobe of the mormyrid cerebellum is cell type specific, with both pre- and postsynaptic mechanisms contributing to its induction and expression. NEW & NOTEWORTHY Much has been learnt about the cerebellar long-term depression (LTD) in the cortex. More recent work has shown that long-term potentiation (LTP) is equally important for cerebellar motor learning. Here we report for the first time that plasticity in the mormyrid cerebellum is cell type specific, e.g., following the conventional pairing of parallel and climbing fiber inputs in an in vitro preparation leads to LTD in one Purkinje cell subtype and LTP in another.
Neck muscle biomechanics and neural control
Authors: Fice Jason B. , Siegmund Gunter P. , Blouin Jean-Sébastien 
Published: April 2018

The mechanics, morphometry, and geometry of our joints, segments, and muscles are fundamental biomechanical properties intrinsic to human neural control. The goal of our study was to investigate whether the biomechanical actions of individual neck muscles predict their neural control. Specifically, we compared the moment direction and variability produced by electrical stimulation of a neck muscle (biomechanics) to the preferred activation direction and variability (neural control). Subjects sat upright with their head fixed to a six-axis load cell and their torso restrained. Indwelling wire electrodes were placed into the sternocleidomastoid (SCM), splenius capitis (SPL), and semispinalis capitis (SSC) muscles. The electrically stimulated direction was defined as the moment direction produced when a current (2–19 mA) was passed through each muscle’s electrodes. Preferred activation direction was defined as the vector sum of the spatial tuning curve built from root mean squared electromyogram when subjects produced isometric moments at 7.5% and 15% of their maximum voluntary contraction (MVC) in 26 three-dimensional directions. The spatial tuning curves at 15% MVC were well defined (unimodal, P < 0.05), and their preferred directions were 23°, 39°, and 21° different from their electrically stimulated directions for the SCM, SPL, and SSC, respectively ( P < 0.05). Intrasubject variability was smaller in electrically stimulated moment directions compared with voluntary preferred directions, and intrasubject variability decreased with increased activation levels. Our findings show that the neural control of neck muscles is not based solely on optimizing individual muscle biomechanics but, as activation increases, biomechanical constraints in part dictate the activation of synergistic neck muscles.NEW & NOTEWORTHY Biomechanics are an intrinsic part of human neural control. In this study, we found that the biomechanics of individual neck muscles cannot fully predict their neural control. Consequently, physiologically based computational neck muscle controllers cannot calculate muscle activation schemes based on the isolated biomechanics of muscles. Furthermore, by measuring biomechanics we showed that the intrasubject variability of the neural control was lower for electrical vs. voluntary activation of the neck muscles.
Neural mechanisms of speed-accuracy tradeoff of visual search: saccade vigor, the origin of targeting errors, and comparison of the superior colliculus and frontal eye field
Authors: Reppert Thomas R. , Servant Mathieu , Heitz Richard P. , Schall Jeffrey D. 
Published: April 2018

Balancing the speed-accuracy tradeoff (SAT) is necessary for successful behavior. Using a visual search task with interleaved cues emphasizing speed or accuracy, we recently reported diverse contributions of frontal eye field (FEF) neurons instantiating salience evidence and response preparation. Here, we report replication of visual search SAT performance in two macaque monkeys, new information about variation of saccade dynamics with SAT, extension of the neurophysiological investigation to describe processes in the superior colliculus (SC), and a description of the origin of search errors in this task. Saccade vigor varied idiosyncratically across SAT conditions and monkeys but tended to decrease with response time. As observed in the FEF, speed-accuracy tradeoff was accomplished through several distinct adjustments in the superior colliculus. In “Accurate” relative to “Fast” trials, visually responsive neurons in SC as in FEF had lower baseline firing rates and later target selection. The magnitude of these adjustments in SC was indistinguishable from that in FEF. Search errors occurred when visual salience neurons in the FEF and the SC treated distractors as targets, even in the Accurate condition. Unlike FEF, the magnitude of visual responses in the SC did not vary across SAT conditions. Also unlike FEF, the activity of SC movement neurons when saccades were initiated was equivalent in Fast and Accurate trials. Saccade-related neural activity in SC, but not FEF, varied with saccade peak velocity. These results extend our understanding of the cortical and subcortical contributions to SAT. NEW & NOTEWORTHY Neurophysiological mechanisms of speed-accuracy tradeoff (SAT) have only recently been investigated. This article reports the first replication of SAT performance in nonhuman primates, the first report of variation of saccade dynamics with SAT, the first description of superior colliculus contributions to SAT, and the first description of the origin of errors during SAT. These results inform and constrain new models of distributed decision making.
Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R–YAP Axis
Authors: Zhu Hong , Wang Dan-Dan , Yuan Tao , Yan Fang-Jie , Zeng Chen-Ming , Dai Xiao-Yang , Chen Zi-bo , Chen Ying , Zhou Tianyi , Fan Guang-Han , Ying Meidan , Cao Ji , Luo Peihua , Liu Xi-Jie , Hu Yuandong , Peng Yong , He Qiaojun , Yang Bo 
Published: April 2018

Abstract
Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.
Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995–4006. ©2018 AACR.
Targeting Merkel Cell Carcinoma by Engineered T Cells Specific to T-Antigens of Merkel Cell Polyomavirus
Authors: Gavvovidis Ioannis , Leisegang Matthias , Willimsky Gerald , Miller Natalie , Nghiem Paul , Blankenstein Thomas 
Published: April 2018

Abstract
Purpose: The causative agent of most cases of Merkel cell carcinoma (MCC) has been identified as the Merkel cell polyomavirus (MCV). MCV-encoded T antigens (Tag) are essential not only for virus-mediated tumorigenesis but also for maintaining MCC cell lines in vitro. MCV Tags are thus an appealing target for viral oncoprotein-directed T-cell therapy for MCC. With this study, we aimed to isolate and characterize Tag-specific T-cell receptors (TCR) for potential use in gene therapy clinical trials.
Experimental Design: T-cell responses against MCV Tag epitopes were investigated by immunizing transgenic mice that express a diverse human TCR repertoire restricted to HLA-A2. Human lymphocytes genetically engineered to express Tag-specific TCRs were tested for specific reactivity against MCC cell lines. The therapeutic potential of Tag-specific TCR gene therapy was tested in a syngeneic cancer model.
Results: We identified naturally processed epitopes of MCV Tags and isolated Tag-specific TCRs. T cells expressing these TCRs were activated by HLA-A2–positive cells loaded with cognate peptide or cells that stably expressed MCV Tags. We showed cytotoxic potential of T cells engineered to express these TCRs in vitro and demonstrated regression of established tumors in a mouse model upon TCR gene therapy.
Conclusions: Our findings demonstrate that MCC cells can be targeted by MCV Tag-specific TCRs. Although recent findings suggest that approximately half of MCC patients benefit from PD-1 pathway blockade, additional patients may benefit if their endogenous T-cell response can be augmented by infusion of transgenic MCV-specific T cells such as those described here. Clin Cancer Res; 24(15); 3644–55. ©2018 AACR.
Crosstalk Between Apoptosis and Autophagy Is Regulated by the Arginylated BiP/Beclin-1/p62 Complex
Authors: Song Xinxin , Lee Dae-Hee , Dilly Ashok-Kumar , Lee Young-Sun , Choudry Haroon Asif , Kwon Yong Tae , Bartlett David L. , Lee Yong J. 
Published: April 2018

Abstract
Emerging evidence demonstrates that autophagy and apoptosis are interconnected and their interplay greatly affects cell death. However, the key regulators in this crosstalk remain elusive. Therefore, the role of N-terminal arginylated BiP (R-BiP)/Beclin-1/p62 complex was examined in the crosstalk between apoptosis and autophagy during combination chemotherapy with mitomycin C and bortezomib using immunoblot, immunoprecipitation, and cellular imaging assays in wild-type (WT) and genetically engineered colorectal cancer cells. In addition, the tumoricidal efficacy of the combinatorial treatment in a nude mouse tumor xenograft model of colorectal cancer was assessed. Bortezomib combined with mitomycin C synergistically induced cytotoxicity and apoptosis rather than autophagy. Mechanistically, this combination inactivated Akt and subsequently induced Beclin-1 (BECN1) dephosphorylation at Ser 234/295. Dephosphorylation of Beclin-1 resulted in increased cleavage of Beclin-1 and disruption of the R-BiP/Beclin-1/p62 complex, which led to switching autophagy to the synergistic induction of apoptosis. Importantly, the combination significantly suppressed LS174T intraperitoneal xenograft tumor growth, induced Akt inactivation and Beclin-1 cleavage, and decreased autophagy in vivo. Moreover, the tumoricidal efficacy of the combinatorial treatment was less effective, in vitro and in vivo, in HCT116 tumors harboring a Beclin-1 caspase 8 cleavage site mutant knock-in.
Implications: This study uncovers that the R-BiP/Beclin-1/p62 complex has an important role in the crosstalk between apoptosis and autophagy. The results also propose how mono-drug resistance can be overcome using potent combinations to improve anticancer therapy. Mol Cancer Res; 16(7); 1077–91. ©2018 AACR.
Recognition of Recurrent Protein Expression Patterns in Pediatric Acute Myeloid Leukemia Identified New Therapeutic Targets
Authors: Hoff Fieke W. , Hu Chenyue W. , Qiu Yihua , Ligeralde Andrew , Yoo Suk-Young , Mahmud Hasan , de Bont Eveline S.J.M. , Qutub Amina A. , Horton Terzah M. , Kornblau Steven M. 
Published: April 2018

Abstract
Heterogeneity in the genetic landscape of pediatric acute myeloid leukemia (AML) makes personalized medicine challenging. As genetic events are mediated by the expression and function of proteins, recognition of recurrent protein patterns could enable classification of pediatric AML patients and could reveal crucial protein dependencies. This could help to rationally select combinations of therapeutic targets. To determine whether protein expression levels could be clustered into functionally relevant groups, custom reverse-phase protein arrays were performed on pediatric AML (n = 95) and CD34+ normal bone marrow (n = 10) clinical specimens using 194 validated antibodies. To analyze proteins in the context of other proteins, all proteins were assembled into 31 protein functional groups (PFG). For each PFG, an optimal number of protein clusters was defined that represented distinct transition states. Block clustering analysis revealed strong correlations between various protein clusters and identified the existence of 12 protein constellations stratifying patients into 8 protein signatures. Signatures were correlated with therapeutic outcome, as well as certain laboratory and demographic characteristics. Comparison of acute lymphoblastic leukemia specimens from the same array and AML pediatric patient specimens demonstrated disease-specific signatures, but also identified the existence of shared constellations, suggesting joint protein deregulation between the diseases.
Implication: Recognition of altered proteins in particular signatures suggests rational combinations of targets that could facilitate stratified targeted therapy. Mol Cancer Res; 16(8); 1275–86. ©2018 AACR.
See related article by Hoff et al., p. 1263
Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression
Authors: Chiang David Y. , Alsina Katherina M. , Corradini Eleonora , Fitzpatrick Martin , Ni Li , Lahiri Satadru K. , Reynolds Julia O. , Pan Xiaolu , Scott Larry , Heck Albert J.R. , Wehrens Xander H.T. 
Published: April 2018

Background:
Heart failure (HF) is a complex disease with a rising prevalence despite advances in treatment. Protein phosphatase 1 (PP1) has long been implicated in HF pathogenesis, but its exact role is both unclear and controversial. Most previous studies measured only the PP1 catalytic subunit (PP1c) without investigating its diverse set of interactors, which confer localization and substrate specificity to the holoenzyme. In this study, we define the PP1 interactome in cardiac tissue and test the hypothesis that this interactome becomes rearranged during HF progression at the level of specific PP1c interactors.

Methods:
Mice were subjected to transverse aortic constriction and grouped on the basis of ejection fraction into sham, hypertrophy, moderate HF (ejection fraction, 30%–40%), and severe HF (ejection fraction <30%). Cardiac lysates were subjected to affinity purification with anti-PP1c antibodies followed by high-resolution mass spectrometry. PP1 regulatory subunit 7 (Ppp1r7) was knocked down in mouse cardiomyocytes and HeLa cells with adeno-associated virus serotype 9 and siRNA, respectively. Calcium imaging was performed on isolated ventricular myocytes.

Results:
Seventy-one and 98 PP1c interactors were quantified from mouse cardiac and HeLa lysates, respectively, including many novel interactors and protein complexes. This represents the largest reproducible PP1 interactome data set ever captured from any tissue, including both primary and secondary/tertiary interactors. Nine PP1c interactors with changes in their binding to PP1c were strongly associated with HF progression, including 2 known (Ppp1r7 and Ppp1r18) and 7 novel interactors. Within the entire cardiac PP1 interactome, Ppp1r7 had the highest binding to PP1c. Cardiac-specific knockdown in mice led to cardiac dysfunction and disruption of calcium release from the sarcoplasmic reticulum.

Conclusions:
PP1 is best studied at the level of its interactome, which undergoes significant rearrangement during HF progression. The 9 key interactors that are associated with HF progression may represent potential targets in HF therapy. In particular, Ppp1r7 may play a central role in regulating the PP1 interactome by acting as a competitive molecular “sponge” of PP1c.
Genetic and Environmental Contributions to the Covariation Between Cardiometabolic Traits
Authors: Chen Xu , Kuja‐Halkola Ralf , Chang Zheng , Karlsson Robert , Hägg Sara , Svensson Per , Pedersen Nancy L. , Magnusson Patrik K. E. 
Published: April 2018

Background

The variation and covariation for many cardiometabolic traits have been decomposed into genetic and environmental fractions, by using twin or single‐nucleotide polymorphism (
SNP
) models. However, differences in population, age, sex, and other factors hamper the comparison between twin‐ and
SNP
‐based estimates.

Methods and Results

Twenty‐four cardiometabolic traits and 700,000 genotyped
SNP
s were available in the study base of 10 682 twins from TwinGene cohort. For the 27 highly correlated pairs (absolute phenotypic correlation coefficient ≥0.40), twin‐based bivariate structural equation models were performed in 3870 complete twin pairs, and
SNP
‐based bivariate genomic relatedness matrix restricted maximum likelihood methods were performed in 5779 unrelated individuals. In twin models, the model including additive genetic variance and unique/nonshared environmental variance was the best‐fitted model for 7 pairs (5 of them were between blood pressure traits); the model including additive genetic variance, common/shared environmental variance, and unique/nonshared environmental variance components was best fitted for 4 pairs, but estimates of shared environment were close to zero; and the model including additive genetic variance, dominant genetic variance, and unique/nonshared environmental variance was best fitted for 16 pairs, in which significant dominant genetic effects were identified for 13 pairs (including all 9 obesity‐related pairs). However,
SNP
models did not identify significant estimates of dominant genetic effects for any pairs. In the paired
t
test, twin‐ and
SNP
‐based estimates of additive genetic correlation were not significantly different (both were 0.67 on average), whereas the nonshared environmental correlations from these 2 models differed slightly from each other (on average, twin‐based estimate=0.64 and SNP‐based estimate=0.68).

Conclusions
Beside additive genetic effects and nonshared environment, nonadditive genetic effects (dominance) also contribute to the covariation between certain cardiometabolic traits (especially for obesity‐related pairs); contributions from the shared environment seem to be weak for their covariation in TwinGene samples.
A Dynamically Consistent, Multivariable Ocean Climatology
Authors: Fukumori Ichiro , Heimbach Patrick , Ponte Rui M. , Wunsch Carl 
Published: April 2018

AbstractA dynamically consistent 20-yr average ocean climatology based on monthly values during the years 1994–2013 has been produced from the most recent state estimate of the Estimating the Circulation and Climate of the Ocean (ECCO) project, globally, top to bottom. The estimate was produced from a least squares fit of a free-running ocean general circulation model to almost all available near-global data. Data coverage in space and time during this period is far more homogeneous than in any earlier interval and includes CTD, elephant seal, and Argo temperature and salinity profiles; sea ice coverage; full altimetric and gravity-field coverage; satellite sea surface temperatures; and the initializing meteorological coverage from the European Centre for Medium-Range Weather Forecasts (ECMWF) interim reanalysis (ERA-Interim). Dominant remaining data inhomogeneity arises from increasing coverage from the Argo profiles from about 2000 to the present. The state estimate exactly satisfies the primitive equations of the free-running Massachusetts Institute of Technology General Circulation Model (MITgcm) at all times and hence produces values satisfying the fundamental conservation laws of energy, freshwater, and so forth, permitting its use for climate change studies. Quantities such as calculated heat content depend upon all observations, not just temperature, for example, altimetric height and meteorological exchanges. Output files are publicly available in Network Common Data Form (netCDF) and MATLAB form and include hydrographic variables, three components of velocity, and pressure at all depths, as well as other variables, including inferred air–sea momentum and buoyancy fluxes, 3D mixing parameters, and sea ice cover.