Miracle-dz/UniFAR-FTUs huggingface dataset:
Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of 14C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods

Inclusion of a microdose of 14C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated.
Concept and design of a lightweight biped robot for walking on rough terrain

Long-term evolvement enables human to achieve various locomotion on different terrains. But it is still a challenge for biped robots to walk stably on rough terrain. The purpose of this paper is to develop a lightweight biped robot adaptable to uneven ground, by integrating the inspirations obtained from human into its structure design and realization. The main design concepts of the biped robot include compliance, combination of active and passive actuation, as well as electric-pneumatic hybrid actuation. On this basis, a prototype of the biped robot which is composed of hip joints with unidirectional series elastic actuator, biomimetic knee joints, semi-passive ankle joints and stiffness adjustable feet is developed. Walking experiments on the biped robot shows that it has the ability to adapt to uneven ground with small-sized bumps in maximum height of 8 mm.
A Gain-of-Function Mutation in the α9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity

Gain control of the auditory system operates at multiple levels. Cholinergic medial olivocochlear (MOC) fibers originate in the brainstem and make synaptic contacts at the base of the outer hair cells (OHCs), the final targets of several feedback loops from the periphery and higher-processing centers. Efferent activation inhibits OHC active amplification within the mammalian cochlea, through the activation of a calcium-permeable α9α10 ionotropic cholinergic nicotinic receptor (nAChR), functionally coupled to calcium activated SK2 potassium channels. Correct operation of this feedback requires careful matching of acoustic input with the strength of cochlear inhibition (Galambos, 1956; Wiederhold and Kiang, 1970; Gifford and Guinan, 1987), which is driven by the rate of MOC activity and short-term facilitation at the MOC–OHC synapse (Ballestero et al., 2011; Katz and Elgoyhen, 2014). The present work shows (in mice of either sex) that a mutation in the α9α10 nAChR with increased duration of channel gating (Taranda et al., 2009) greatly elongates hair cell-evoked IPSCs and Ca2+ signals. Interestingly, MOC–OHC synapses of L9′T mice presented reduced quantum content and increased presynaptic facilitation. These phenotypic changes lead to enhanced and sustained synaptic responses and OHC hyperpolarization upon high-frequency stimulation of MOC terminals. At the cochlear physiology level these changes were matched by a longer time course of efferent MOC suppression. This indicates that the properties of the MOC–OHC synapse directly determine the efficacy of the MOC feedback to the cochlea being a main player in the “gain control” of the auditory periphery. SIGNIFICANCE STATEMENT Plasticity can involve reciprocal signaling across chemical synapses. An opportunity to study this phenomenon occurs in the mammalian cochlea whose sensitivity is regulated by efferent olivocochlear neurons. These release acetylcholine to inhibit sensory hair cells. A point mutation in the hair cell's acetylcholine receptor that leads to increased gating of the receptor greatly elongates IPSCs. Interestingly, efferent terminals from mutant mice present a reduced resting release probability. However, upon high-frequency stimulation transmitter release facilitates strongly to produce stronger and far longer-lasting inhibition of cochlear function. Thus, central neuronal feedback on cochlear hair cells provides an opportunity to define plasticity mechanisms in cholinergic synapses other than the highly studied neuromuscular junction.
RoMo: An efficient strategy for functional mosaic analysis via stochastic Cre recombination and gene targeting in the ROSA26 locus

Functional mosaic analysis allows for the direct comparison of mutant cells with differentially marked control cells in the same organism. While this offers a powerful approach for elucidating the role of specific genes or signalling pathways in cell populations of interest, genetic strategies for generating functional mosaicism remain challenging. We describe a novel and streamlined approach for functional mosaic analysis, which combines stochastic Cre/lox recombination with gene targeting in the ROSA26 locus. With the RoMo strategy a cell population of interest is randomly split into a cyan fluorescent and red fluorescent subset, of which the latter overexpresses a chosen transgene. To integrate this approach into high‐throughput gene targeting initiatives, we developed a procedure that utilizes Gateway cloning for the generation of new targeting vectors. RoMo can be used for gain‐of‐function experiments or for altering signaling pathways in a mosaic fashion. To demonstrate this, we developed RoMo‐dnGs mice, in which Cre‐recombined red fluorescent cells co‐express a dominant‐negative Gs protein. RoMo‐dnGs mice allowed us to inhibit G protein‐coupled receptor activation in a fraction of cells, which could then be directly compared to differentially marked control cells in the same animal. We demonstrate how RoMo‐dnGs mice can be used to obtain mosaicism in the brain and in peripheral organs for various cell types. RoMo offers an efficient new approach for functional mosaic analysis that extends the current toolbox and may reveal important new insights into in vivo gene function.
Involvement of microRNA miR‐2b‐3p in regulation of metabolic resistance to insecticides in Plutella xylostella

The diamondback moth, Plutella xylostella, has developed extremely high levels of resistance to chlorantraniliprole and other classes of insecticides in the field. As microRNAs (miRNAs) play important roles in various biological processes through gene regulation, we examined the miRNA profile of P. xylostella in response to chlorantraniliprole exposure. RNA sequencing analysis showed that insecticide treatment caused significant changes in the abundance of some miRNAs. Increasing exposure time and insecticide concentration induced more dysregulated miRNAs in P. xylostella larvae. We also screened potential target genes for some of the differentially expressed miRNAs (such as miR‐2b‐3p, miR‐14b‐5p and let‐7‐5p), which may play important roles in insecticide resistance development. Exposure of P. xylostella larvae to chlorantraniliprole caused considerable overexpression in the transcript levels of potential target genes cytochrome P450 9f2 (CYP9F2) and 307a1 (CYP307a1). Application of miR‐2b‐3p and miR‐14b‐5p mimics significantly suppressed the relative transcript levels of CYP9F2 and CYP307a1, respectively, in a P. xylostella cell line. Furthermore, enrichment of P. xylostella diet with miR‐2b‐3p mimics significantly increased mortality in deltamethrin‐resistant larvae when exposed to deltamethrin. The results suggest that miR‐2b‐3p may suppress CYP9F2 transcript levels in P. xylostella and consequently inhibit larval detoxification pathways. The findings provide an insight into possible role of miRNAs in regulation of metabolic resistance of insects to insecticides.
Maternal RNA regulates Aurora C kinase during mouse oocyte maturation in a translation-independent fashion†

Abstract During oocyte meiotic maturation, Aurora kinase C (AURKC) is required to accomplish many critical functions including destabilizing erroneous kinetochore–microtubule (K-MT)attachments and regulating bipolar spindle assembly. How localized activity of AURKC is regulated in mammalian oocytes, however, is not fully understood. Female gametes from many species, including mouse, contain stores of maternal transcripts that are required for downstream developmental events. We show here that depletion of maternal RNA in mouse oocytes resulted in impaired meiotic progression, increased incidence of chromosome misalignment and abnormal spindle formation at metaphase I (Met I), and cytokinesis defects. Importantly, depletion of maternal RNA perturbed the localization and activity of AURKC within the chromosomal passenger complex (CPC). These perturbations were not observed when translation was inhibited by cycloheximide (CHX) treatment. These results demonstrate a translation-independent function of maternal RNA to regulate AURKC-CPC function in mouse oocytes. Summary Sentence Maternal RNA contained in mouse oocytes regulates localized AURKC-CPC activity independent of its role in translation to support meiotic maturation.
Hardware design of cryptographic accelerator

The goal of this paper is representation of computing unit focused on implementation hardware cryptography accelerator. After analysis of assigned problem, there are next chapters dedicated to available solutions, comparison of them, the issues of cryptography and computer security, FPGA device in which the designed solution is verified and tested, the chapters dedicated to cryptography algorithm RSA. Chapters of synthesis have the specifically implemented and designed solution in programming languages of lower and higher level. In evaluation and conclusion chapter there are measurements on software and hardware level and comparison among them.
Background Subtraction via Robust Dictionary Learning

We propose a learning-based background subtraction approach based on the theory of sparse representation and dictionary learning. Our method makes the following two important assumptions: (1) the background of a scene has a sparse linear representation over a learned dictionary; (2) the foreground is "sparse" in the sense that majority pixels of the frame belong to the background. These two assumptions enable our method to handle both sudden and gradual background changes better than existing methods. As discussed in the paper, the way of learning the dictionary is critical to the success of background modeling in our method. To build a correct background model when training samples are not foreground-free, we propose a novel robust dictionary learning algorithm. It automatically prunes foreground pixels out as outliers at the learning stage. Experiments in both qualitative and quantitative comparisons with competing methods demonstrate the obtained robustness against background changes and better performance in foreground segmentation.
Backhaul-Aware Caching Placement for Wireless Networks

As the capacity demand of mobile applications keeps increasing, the backhaul network is becoming a bottleneck to support high quality of experience (QoE) in next-generation wireless networks. Content caching at base stations (BSs) is a promising approach to alleviate the backhaul burden and reduce user-perceived latency. In this paper, we consider a wireless caching network where all the BSs are connected to a central controller via backhaul links. In such a network, users can obtain the required data from candidate BSs if the data are pre-cached. Otherwise, the user data need to be first retrieved from the central controller to local BSs, which introduces extra delay over the backhaul. In order to reduce the download delay, the caching placement strategy needs to be optimized. We formulate such a design problem as the minimization of the average download delay over user requests, subject to the caching capacity constraint of each BS. Different from existing works, our model takes BS cooperation in the radio access into consideration and is fully aware of the propagation delay on the backhaul links. The design problem is a mixed integer programming problem and is highly complicated, and thus we relax the problem and propose a low-complexity algorithm. Simulation results will show that the proposed algorithm can effectively determine the near-optimal caching placement and provide significant performance gains over conventional caching placement strategies.
Application of Fiber Bragg Grating to Determine the Terfenol-D Magnetostriction Characteristics for Sensor Development

The magnetic bodies present deformation in the direction of the magnetic field and this phenomenon is called magnetostriction. Electric current sensors based on magnetostriction have been reported in several papers. In common these previous papers use i¬ber Bragg grating (FBG) to perform the direct measurement of strain caused by the magnetostrictive material. However, magnetostriction sensors present few disadvantages often neglected, such as the temperature dependence. In this paper a Terfenol-D rod (a giant magnetostrictive material-GMM) is used as well as two multiplexed FBGs for simultaneous strain and temperature measurement. One of them is encapsulated in an alumina tube and it is subjected to temperature variation. The i¬rst result presents unipolar characteristics of Terfenol-D magnetostriction. Other experiments determine the Terfenol-D response for different temperatures. The Terfenol-D sensitivity increases when the temperature increases, however the saturation of the material occurs for small i¬eld values. The issues presented in this paper must be taken into account on the development of magnetostrictive sensors.
Speaker Idiosyncratic Intensity Variability in the Speech Signal

presented at Phonetik & Phonologie 10, Konstanz, Germany. http://ling.uni-konstanz.de/pages/conferences/pp10/abstracts/He_pp10. pdf Klatt, D. H. (1980). Software for a cascade/parallel formant synthesizer, Journal of the Acoustical Society of America 67: 971-995. Klatt, D. H. and Klatt, L. C. (1990). Analysis, synthesis, and perception of voice quality variations among female and male talkers, Journal of the Acoustical Society of America 82: 820-857. Lee, C. S. and Todd, N. P. M. (2004). Towards an auditory account of speech rhythm: application of a model of the auditory “primal sketch” to two multilanguage corpora, Cognition 93: 225-254. Leemann, A. , Kolly, M. -J. and Dellwo, V. (2014). Speech-individuality in suprasegmental temporal features: implications for forensic voice comparison, Forensic Science International 238: 59-67. Leemann, A. and Kolly, M. -J. (2015). Speaker-invariant suprasegmental temporal features in normal and disguised speech, Speech Communication 75: 97-122.
Edge detection method on thermal wave images for skin-core disbonds in carbon fiber reinforced honeycomb material

The infrared thermal wave nondestructive evaluation technology is one kind of fast, effective and intuitionistic methods, which can detect skin-core disbonds in carbon fiber reinforced honeycomb material. The quantitative measure is feasible on experiment research. It is easy to figure out flaw depth based on formula derived from the principle of thermal wave. The flaw size is detected by two methods and compared. The results show that image edge detection with Canny operator can improve performance of edge detection and visibility of shape of defects and flaws, and it may be regarded as a reference to measure the flaw size under the surface of the material.
SEVENTEEN YEARS STORAGE OF JUNIPER AND SPINACH LEAVES IN ALCOHOLS: EFFECTS ON DNA

Propanol appeared better than ethanol for the long-term storage of spinach leaves, followed by hexanol and pentanol. The lowest molecular weight and yields of DNA came from spinach stored in methanol and ethanol. In an experiment with spinach leaves stored in 100, 95, 70, 50 and 25% ethanol, the 50% ethanol stored leaves appeared to yield more and higher molecular weight DNA than any other treatment. In contrast, juniper leaves stored in 100 and 95% ethanol yielded more and higher molecular weight DNA than 70, 50 or 25% ethanol. The different manner that these two very differnet leaves respond to storage in ethanol solutions may reflect the herbaceous nature of spinach leaves versus the woody nature of juniper leaves, as well as differences in secondary compounds. Phytologia 93(3): 283292 (December 1, 2010).
Pairwise Operator Learning for Patch-Based Single-Image Super-Resolution

Motivated by the fact that image patches could be inherently represented by matrices, single-image super-resolution is treated as a problem of learning regression operators in a matrix space in this paper. The regression operators that map low-resolution image patches to high-resolution image patches are generally defined by the left and right multiplication operators. The pairwise operators are, respectively, used to extract the raw and column information of low-resolution image patches for recovering high-resolution estimations. The patch-based regression algorithm possesses three favorable properties. First, the proposed super-resolution algorithm is efficient during both training and testing, because image patches are treated as matrices. Second, the data storage requirement of the optimal pairwise operator is far less than most popular single-image super-resolution algorithms, because only two small sized matrices need to be stored. Last, the super-resolution performance is competitive with most popular single-image super-resolution algorithms, because both raw and column information of image patches is considered. Experimental results show the efficiency and effectiveness of the proposed patch-based single-image super-resolution algorithm.
Target-Oriented High-Resolution SAR Image Formation via Semantic Information Guided Regularizations

Sparsity-regularized synthetic aperture radar (SAR) imaging framework has shown its remarkable performance to generate a feature-enhanced high-resolution image, in which a sparsity-inducing regularizer is involved by exploiting the sparsity priors of some visual features in the underlying image. However, since the simple prior of low-level features is insufficient to describe different semantic contents in the image, this type of regularizer will be incapable of distinguishing between the target of interest and unconcerned background clutters. As a consequence, the features belonging to the target and clutters are simultaneously affected in the generated image without concerning their underlying semantic labels. To address this problem, we propose a novel semantic information guided generative framework for target-oriented SAR image formation, which aims at enhancing the interested target scatters while suppressing the background clutters. First, we develop a new semantics-specific regularizer for image formation by exploiting the statistical properties of different semantic categories in a target scene SAR image. In order to infer the semantic label for each pixel in an unsupervised way, we moreover induce a novel high-level prior-driven regularizer and some semantic causal rules from the prior knowledge. Finally, our regularized framework for image formation is further derived as a simple iteratively reweighted $\ell _{1}$ minimization problem that can be conveniently solved by many off-the-shelf solvers. Experimental results demonstrate the effectiveness and superiority of our framework for SAR image formation in terms of target enhancement and clutters suppression, compared with the state of the arts. Additionally, the proposed framework opens a new direction of devoting some machine learning strategies to image formation, which can benefit the subsequent decision-making tasks.
Viscoelasticity in Biological Systems: A Special Focus on Microbes

Over billions of years of evolution, living organisms have developed into complex biosystems, of which the basic unit is the cell. Cells have a complex molecular structure with a certain level of rigidity. Living cells, whether isolated or part of a larger collective, live under constant mechanical stress from their external environments. Cells have developed adaptive mechanisms to maintain homeostasis and viability, which interestingly follow the basic principles of classical mechanics.
Phosphomimetic S3D cofilin binds but only weakly severs actin filaments

Many biological processes, including cell division, growth, and motility, rely on rapid remodeling of the actin cytoskeleton and on actin filament severing by the regulatory protein cofilin. Phosphorylation of vertebrate cofilin at Ser-3 regulates both actin binding and severing. Substitution of serine with aspartate at position 3 (S3D) is widely used to mimic cofilin phosphorylation in cells and in vitro. The S3D substitution weakens cofilin binding to filaments, and it is presumed that subsequent reduction in cofilin occupancy inhibits filament severing, but this hypothesis has remained untested. Here, using time-resolved phosphorescence anisotropy, electron cryomicroscopy, and all-atom molecular dynamics simulations, we show that S3D cofilin indeed binds filaments with lower affinity, but also with a higher cooperativity than wild-type cofilin, and severs actin weakly across a broad range of occupancies. We found that three factors contribute to the severing deficiency of S3D cofilin. First, the high cooperativity of S3D cofilin generates fewer boundaries between bare and decorated actin segments where severing occurs preferentially. Second, S3D cofilin only weakly alters filament bending and twisting dynamics and therefore does not introduce the mechanical discontinuities required for efficient filament severing at boundaries. Third, Ser-3 modification (i.e. substitution with Asp or phosphorylation) “undocks” and repositions the cofilin N terminus away from the filament axis, which compromises S3D cofilin's ability to weaken longitudinal filament subunit interactions. Collectively, our results demonstrate that, in addition to inhibiting actin binding, Ser-3 modification favors formation of a cofilin-binding mode that is unable to sufficiently alter filament mechanical properties and promote severing.