Miracle-dz/UniFAR-FTUs huggingface dataset:
Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences

Abstract Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene. The initial sequence used for this ‘oligonucleotide-linked topoisomerase inhibitor’ (OTI) was identified as part of the translocation breakpoint of a patient with acute promyelocytic leukemia (APL). Subsequent OTI sequences were derived from the observed APL breakpoint between PML and RARA. Results indicate that OTIs can be used to direct the sites of etoposide-induced DNA cleavage mediated by topoisomerase IIα and topoisomerase IIβ. OTIs increased levels of enzyme-mediated cleavage by inhibiting DNA ligation, and cleavage complexes induced by OTIs were as stable as those induced by free etoposide. Finally, OTIs directed against the PML-RARA breakpoint displayed cleavage specificity for oligonucleotides with the translocation sequence over those with sequences matching either parental gene. These studies demonstrate the feasibility of using oligonucleotides to direct topoisomerase II-mediated DNA cleavage to specific sites in the genome.
Using Program Shaping and Algorithmic Skeletons to Parallelise an Evolutionary Multi-Agent System in Erlang

This paper considers how to use program shaping and algorithmic skeletons to parallelise a multi-agent system that is written in Erlang. Program shaping is the process of transforming a program to better enable the introduction of parallelism. Whilst algorithmic skeletons abstract away the low-level aspects of parallel programming that often plague traditional techniques, it is not always easy to introduce them into an arbitrary program, especially one that has not been written with parallelism in mind. Amongst other issues, data may not always be in a compatible format, function calls may need to be replicated to support alternative uses, side-effects may need to be isolated, or there may be dependencies between functions and data that obstruct the introduction of parallelism. Program shaping can be used to transform such code to a form that allows skeletons to be more easily introduced. In this paper, we present a series of generic program shaping rewrite rules, provide their implementation as refactorings, and show how they can be used to parallelise an Evolutionary Multi-Agent System (MAS) written in Erlang. We show that we can significantly speed up this application, obtaining super-linear speedups of over 70 times the original sequential performance on a 64-core shared-memory machine.
An Efficient I/O-Redirection-Based Reconstruction Scheme for Erasure-Coded Storage Clusters

This paper addresses an I/O interference problem encountered in on-line reconstruction of erasure-coded storage clusters, where user I/Os compete with reconstruction I/Os for both disk and network bandwidth. We propose a redirection scheme called `RAM-RS' to minimize the I/O interference among user and reconstruction requests. RAM-RS redirects user read/writes targeted at failed nodes to an RS-coded RAM region, which is formed by pre-allocated main memory in surviving nodes in the RS-coding manner. The RS-coded RAM region quickly serves all user read/write misses; therefore, a rebuilding node can devote its disk and network bandwidths to the node reconstruction. The RAM region substantially reduces the amount of data rebuilt by the rebuilding node, because (1) missed writes are buffered in the RAM region and (2) missed reads are satisfied by using surviving nodes to co-rebuild failed blocks. We build two Markov models to estimate the reliability of the RAM-RS system. Modeling results demonstrate that the MTTDL of RS-coded RAM region in a storage cluster is larger than that of the same cluster comprised of surviving nodes. We implement both RAM-RS and the traditional Redirection schemes in an erasure-coded storage cluster, on which real-world I/O traces are replayed. Experimental results show that compared with the Redirection scheme running on a 9-node storage cluster, RAM-RS improves system performance in terms of both user response time and reconstruction time by a factor of 1.78 and 1.20, respectively.
Exploiting Recurrent Neural Networks and Leap Motion Controller for the Recognition of Sign Language and Semaphoric Hand Gestures

Hand gesture recognition is still a topic of great interest for the computer vision community. In particular, sign language and semaphoric hand gestures are two foremost areas of interest due to their importance in human–human communication and human–computer interaction, respectively. Any hand gesture can be represented by sets of feature vectors that change over time. Recurrent neural networks (RNNs) are suited to analyze this type of set thanks to their ability to model the long-term contextual information of temporal sequences. In this paper, an RNN is trained by using as features the angles formed by the finger bones of the human hands. The selected features, acquired by a leap motion controller sensor, are chosen because the majority of human hand gestures produce joint movements that generate truly characteristic corners. The proposed method, including the effectiveness of the selected angles, was initially tested by creating a very challenging dataset composed by a large number of gestures defined by the American sign language. On the latter, an accuracy of over 96% was achieved. Afterwards, by using the Shape Retrieval Contest (SHREC) dataset, a wide collection of semaphoric hand gestures, the method was also proven to outperform in accuracy competing approaches of the current literature.
Amorphous indium gallium zinc oxide thin film grown by pulse laser deposition technique

Highly electrically conducting and transparent in visible light IGZO thin film were grown on glass substrate at substrate temperature of 400 C by a pulse laser deposition techniques. Structural, surface, electrical, and optical properties of IGZO thin films were investigated at room temperature. Smooth surface morphology and amorphous nature of the film has been confirmed from the AFM and GIXRD analysis. A resistivity down to 7.7×10−3 V cm was reproducibly obtained while maintaining optical transmission exceeding 70% at wavelengths from 340 to 780 nm. The carrier densities of the film was obtain to the value 1.9×1018 cm3, while the Hall mobility of the IGZO thin film was 16 cm2 V−1S−1.
Hydrophobic patches on SMAD2 and SMAD3 determine selective binding to cofactors

Multiple hydrophobic patches on the surfaces of SMAD2 and SMAD3 mediate their interactions with cofactors. The SMAD cofactor code SMADs are transcription factors that execute the transcriptional outputs of transforming growth factor–β (TGF-β) signaling. SMAD2 and SMAD3 form complexes with SMAD4 that translocate into the nucleus. Whether these complexes stimulate or repress the expression of target genes depends on cofactors that interact with the SMADs; therefore, the underlying mechanism is critical for the appropriate response to TGF-β signaling. Miyazono et al. determined the crystal structures of SMAD2 in complex with the transcriptional corepressor SKI and SMAD3 in complex with the transcription factor FOXH1. The authors identified multiple hydrophobic patches on the surfaces of SMAD2 and SMAD3 that mediated the interactions with these cofactors. The cofactors interacted with the SMADs through different subsets of these patches, suggesting that cooperation and competition between cofactors determine which cofactors bind to the SMADs in vivo. The transforming growth factor–β (TGF-β) superfamily of cytokines regulates various biological processes, including cell proliferation, immune responses, autophagy, and senescence. Dysregulation of TGF-β signaling causes various diseases, such as cancer and fibrosis. SMAD2 and SMAD3 are core transcription factors involved in TGF-β signaling, and they form heterotrimeric complexes with SMAD4 (SMAD2-SMAD2-SMAD4, SMAD3-SMAD3-SMAD4, and SMAD2-SMAD3-SMAD4) in response to TGF-β signaling. These heterotrimeric complexes interact with cofactors to control the expression of TGF-β–dependent genes. SMAD2 and SMAD3 may promote or repress target genes depending on whether they form complexes with other transcription factors, coactivators, or corepressors; therefore, the selection of specific cofactors is critical for the appropriate activity of these transcription factors. To reveal the structural basis by which SMAD2 and SMAD3 select cofactors, we determined the crystal structures of SMAD3 in complex with the transcription factor FOXH1 and SMAD2 in complex with the transcriptional corepressor SKI. The structures of the complexes show that the MAD homology 2 (MH2) domains of SMAD2 and SMAD3 have multiple hydrophobic patches on their surfaces. The cofactors tether to various subsets of these patches to interact with SMAD2 and SMAD3 in a cooperative or competitive manner to control the output of TGF-β signaling.
Left ventricular function and remodeling after myocardial infarction in aging rats.

- Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/d t, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/d t, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocardial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.
Evolutionary Gradient Search Revisited Dirk

Evolutionary gradient search (EGS) is an approach to optimization that combines features of gradient strategies with ideas from evolutionary computation. Recently, several modifications to the algorithm have been proposed with the goal of improving its robustness in the presence of noise and its suitability for implementation on parallel computers. In this paper, the value of the proposed modifications is studied analytically. A scaling law is derived that describes the performance of the algorithm on the noisy sphere model and allows comparing it with competing strategies. The comparisons yield insights into the interplay of mutation, multirecombination, and selection. Then, the covariance matrix adaptation mechanism originally formulated for evolution strategies is adapted for use with EGS in order to make the algorithm competitive on objective functions with large condition numbers of their Hessians. The resulting strategy is evaluated experimentally on a number of convex quadratic test functions.
Crystallographic conditions for the initiation of cavitation erosion in CuMn11Al11 bronze

Purpose: The basic aim of this paper is to examine and present specific destruction processes connected with cavitation erosion of multi-component Cu-Mn-Al bronzes. In technical operational conditions these processes are ‘masked’ by the effects of electrochemical corrosion phenomena. However, these destructive processes may significantly accelerate the destruction of flow devices and marine propulsion systems. The essential phenomena occurring during these processes are incubation and propagation of brittle cracks in the planes of cleavage planes of the ordered phase β (Cu3Mn2Al) that occurs in the examined group of alloys. Additional purpose is the assessment of possible applications of alloys with single-phase structure of intermetallic phases as model materials for research into erosion-cavitation resistance. Design/methodology/approach: This work presents research results concerning erosion cavitation resistance of a model alloy examined at a cavitation jet stand. The destructed areas were examined by gravimetric methods and those using scanning microscopy combined with computer image analysis. As the test materials used were single phase model alloys with the composition simulating selected phase components of Cu-Mn-Al bronzes, it was possible to examine erosion cavitation phenomena in the conditions of minimized effect of electrochemical phenomena. Findings: It has been found that at the initial period of destruction of the phase β in multi-component Mn-Al bronzes the prevailing form of destruction was a classical attack along grain boundaries, starting from the grain boundary junctions while in cases where the Cu3Mn2Al superstructure was present, the major mechanism of the incubation of erosion cavitation damage in the phase β is brittle cracking along cleavage planes {001} oriented at 45° angle to the exposed surface. Research limitations/implications: An essential problem is the verification of the results obtained using the computer-based image analysis by other methods. It seems purposeful to carry out micro-diffraction examination by the EBSP method and making a ’map’ of lattice orientation of particular grains on the surface of a specimen, followed by a series of cavitation tests. Practical implications: The observed phenomena can be regarded as the basic explanation of observed accelerated wear of marine propellers that had been repaired by casting and welding methods. Originality/value: The value of this work is that cavitation erosion was examined in the conditions of minimized influence of electrochemical factors.
Cumulative toxicity of neonicotinoid insecticide mixtures to Chironomus dilutus under acute exposure scenarios

Extensive agricultural use of neonicotinoid insecticide products has resulted in the presence of neonicotinoid mixtures in surface waters worldwide. Although many aquatic insect species are known to be sensitive to neonicotinoids, the impact of neonicotinoid mixtures is poorly understood. In the present study, the cumulative toxicities of binary and ternary mixtures of select neonicotinoids (imidacloprid, clothianidin, and thiamethoxam) were characterized under acute (96‐h) exposure scenarios using the larval midge Chironomus dilutus as a representative aquatic insect species. Using the MIXTOX approach, predictive parametric models were fitted and statistically compared with observed toxicity in subsequent mixture tests. Single‐compound toxicity tests yielded median lethal concentration (LC50) values of 4.63, 5.93, and 55.34 μg/L for imidacloprid, clothianidin, and thiamethoxam, respectively. Because of the similar modes of action of neonicotinoids, concentration‐additive cumulative mixture toxicity was the predicted model. However, we found that imidacloprid–clothianidin mixtures demonstrated response‐additive dose‐level–dependent synergism, clothianidin–thiamethoxam mixtures demonstrated concentration‐additive synergism, and imidacloprid–thiamethoxam mixtures demonstrated response‐additive dose‐ratio–dependent synergism, with toxicity shifting from antagonism to synergism as the relative concentration of thiamethoxam increased. Imidacloprid–clothianidin–thiamethoxam ternary mixtures demonstrated response‐additive synergism. These results indicate that, under acute exposure scenarios, the toxicity of neonicotinoid mixtures to C. dilutus cannot be predicted using the common assumption of additive joint activity. Indeed, the overarching trend of synergistic deviation emphasizes the need for further research into the ecotoxicological effects of neonicotinoid insecticide mixtures in field settings, the development of better toxicity models for neonicotinoid mixture exposures, and the consideration of mixture effects when setting water quality guidelines for this class of pesticides. Environ Toxicol Chem 2017;36:3091–3101. © 2017 SETAC
Deficient Major Histocompatibility Complex-Linked Innate Murine Cytomegalovirus Immunity in MA/My.L-H2b Mice and Viral Downregulation of H-2k Class I Proteins

ABSTRACT NK cells are key effectors of innate immunity and host survival during cytomegalovirus (CMV) infection. Innate murine CMV (MCMV) resistance in MA/My mice requires Ly49H/m157-independent H-2k-linked NK cell control. Here we show that replacement of MA/My H-2k with C57L H-2b susceptibility genes led to a remarkable loss of innate virus immunity, though NK gamma interferon was induced in H-2b and H-2k strains shortly after infection. Thus, H-2b genes expressed in C57L or MA/My.L-H2b are sufficient in alerting NK cells to intrusion but fail to support NK restraint of viral infection. In addition, novel H-2 recombinant strains were produced and utilized in a further refinement of a critical genetic interval controlling innate H-2k-linked MCMV resistance. Importantly, this analysis excluded the gene interval from Kk class I through class II. The responsible gene(s) therefore resides in an interval spanning Dk class Ia and more-distal major histocompatibility complex (MHC) nonclassical class Ib genes. Recently, the NK activation receptor Ly49P and MHC class I Dk proteins were genetically implicated in MCMV resistance, in part because Ly49P-expressing reporter T cells could specifically bind Dk molecules on MCMV-infected mouse embryonic fibroblasts (MEFs). However, as we found that H-2k innate resistance differs in the C57L or MA/My backgrounds and because MCMV very efficiently downregulates H-2k class I proteins in L929 cells and primary MEFs shortly after infection, a Ly49P/Dk model should not fully explain H-2k-linked MCMV resistance.
Streptococcus equi Infections in Horses: Guidelines for Treatment, Control, and Prevention of Strangles—Revised Consensus Statement

This consensus statement update reflects our current published knowledge and opinion about clinical signs, pathogenesis, epidemiology, treatment, complications, and control of strangles. This updated statement emphasizes varying presentations in the context of existing underlying immunity and carrier states of strangles in the transmission of disease. The statement redefines the “gold standard” for detection of possible infection and reviews the new technologies available in polymerase chain reaction diagnosis and serology and their use in outbreak control and prevention. We reiterate the importance of judicious use of antibiotics in horses with strangles. This updated consensus statement reviews current vaccine technology and the importance of linking vaccination with currently advocated disease control and prevention programs to facilitate the eradication of endemic infections while safely maintaining herd immunity. Differentiation between immune responses to primary and repeated exposure of subclinically infected animals and responses induced by vaccination is also addressed.
Performance of In Silico Models for Mutagenicity Prediction of Food Contact Materials

In silico methodologies, such as (quantitative) structure-activity relationships ([Q]SARs), are available to predict a wide variety of toxicological properties and biological activities for structurally diverse substances. To obtain insights in the scientific value of these predictions, the capacity of the prediction models to generate (sufficiently) reliable results for a particular type of compounds needs to be evaluated. In the current study, performance parameters to predict the endpoint "bacterial mutagenicity" were calculated for a battery of common (Q)SAR tools, namely Toxtree, Derek Nexus, VEGA Consensus, and Sarah Nexus. Printed paper and board food contact material (FCM) constituents were chosen as study substances because many of these lack experimental data, making them an interesting group for in silico screening. Accuracy, sensitivity, specificity, positive predictivity, negative predictivity, and Matthews correlation coefficient for the individual models and for the combination of VEGA Consensus and Sarah Nexus were determined and compared. Our results demonstrate that performance varies among the four models, but can be increased by applying a combination strategy. Furthermore, the importance of the applicability domain is illustrated. Limited performance to predict the mutagenic potential of substances that are new to the model (ie, not included in the training set) is reported. In this context, the generally poor sensitivity for these new substances is also addressed.
On Large-Scale Graph Generation with Validation of Diverse Triangle Statistics at Edges and Vertices

Researchers developing implementations of distributed graph analytic algorithms require graph generators that yield graphs sharing the challenging characteristics of real-world graphs (small-world, scale-free, heavy-tailed degree distribution) with efficiently calculable ground-truth solutions to the desired output. Reproducibility for current generators [1] used in benchmarking are somewhat lacking in this respect due to their randomness: the output of a desired graph analytic can only be compared to expected values and not exact ground truth. Nonstochastic Kronecker product graphs [2] meet these design criteria for several graph analytics. Here we show that many flavors of triangle participation can be cheaply calculated while generating a Kronecker product graph. Given two medium-sized scale-free graphs with adjacency matrices A and B, their Kronecker product graph has adjacency matrix C = A ? B. Such graphs are highly compressible: |E| edges are represented in O(|? |^1/2) memory and can be built in a distributed setting from small data structures, making them easy to share in compressed form. Many interesting graph calculations have worst-case complexity bounds O(|? |^p) and often these are reduced to O(|? |^p/2) for Kronecker product graphs, when a Kronecker formula can be derived yielding the sought calculation on C in terms of related calculations on A and B. We focus on deriving formulas for triangle participation at vertices, tC, a vector storing the number of triangles that every vertex is involved in, and triangle participation at edges, ? _C, a sparse matrix storing the number of triangles at every edge. When factors A and B are undirected, C is also undirected. In the case when both factors have no self loops we show t_C = 2 t_A ? t_B, ? _C = ? _A ? _B. Moreover, we derive the respective formulas when A and B have self loops, which boosts the triangle counts for the associated vertices/edges in C. We additionally demonstrate strong assumptions on B that allow the truss decomposition of C to be derived cheaply from the truss decomposition of A. We extend these results and show Kronecker formulas for triangle participation in both directed graphs and undirected, vertex-labeled graphs. In these classes of graphs each vertex / edge can participate in many different types of triangles.