Miracle-dz/UniFAR-FTUs huggingface dataset:
Daclatasvir: potential role in hepatitis C

Chronic hepatitis C virus (HCV) infection is responsible for the development of liver cirrhosis and hepatocellular carcinoma. It has been a tremendous burden on global health care systems. With the advent of a number of new direct-acting and host-targeting antiviral agents, current interferon-α- and ribavirin-based HCV therapy has started to move towards an interferon-sparing or even interferon-free strategy. In this regard, a recently identified NS5A inhibitor, daclatasvir, showed a great promise in clinical trials as another new class of direct-acting anti-HCV therapeutics, with a distinct mechanism of action. In this review, a variety of preclinical as well as clinical proof-of-concept studies of daclatasvir, including the studies of its discovery, mechanism of action, viral resistance, and host polymorphism profiles are reviewed. In addition, a role of daclatasvir in the future therapy for HCV patients is discussed briefly.
Rigidity and flexibility of biological networks

The network approach became a widely used tool to understand the behaviour of complex systems in the last decade. We start from a short description of structural rigidity theory. A detailed account on the combinatorial rigidity analysis of protein structures, as well as local flexibility measures of proteins and their applications in explaining allostery and thermostability is given. We also briefly discuss the network aspects of cytoskeletal tensegrity. Finally, we show the importance of the balance between functional flexibility and rigidity in protein-protein interaction, metabolic, gene regulatory and neuronal networks. Our summary raises the possibility that the concepts of flexibility and rigidity can be generalized to all networks.
Polyphonic Score Retrieval Using Polyphonic Audio Queries: A Harmonic Modeling Approach

This paper extends the familiar “query by humming” music retrieval framework into the polyphonic realm. As humming in multiple voices is quite difficult, the task is more accurately described as “query by audio example,” onto a collection of scores. To our knowledge, we are the first to use polyphonic audio queries to retrieve from polyphonic symbolic collections. Furthermore, as our results will show, we will not only use an audio query to retrieve a known item symbolic piece, but we will use it to retrieve an entire set of real-world composed variations on that piece, also in the symbolic format. The harmonic modeling approach which forms the basis of this work is a new and valuable technique which has both wide applicability and future potential.
Probabilistic movement modeling for intention inference in human–robot interaction

Intention inference can be an essential step toward efficient human–robot interaction. For this purpose, we propose the Intention-Driven Dynamics Model (IDDM) to probabilistically model the generative process of movements that are directed by the intention. The IDDM allows the intention to be inferred from observed movements using Bayes’ theorem. The IDDM simultaneously finds a latent state representation of noisy and high-dimensional observations, and models the intention-driven dynamics in the latent states. As most robotics applications are subject to real-time constraints, we develop an efficient online algorithm that allows for real-time intention inference. Two human–robot interaction scenarios, i.e. target prediction for robot table tennis and action recognition for interactive humanoid robots, are used to evaluate the performance of our inference algorithm. In both intention inference tasks, the proposed algorithm achieves substantial improvements over support vector machines and Gaussian processes.
Analysis of Heat-Spreading Thermal Management Solutions for Lithium-Ion Batteries

The analysis and optimization of thermal performance of Li-ion battery packs are topics of great interest today. Most Li-ion batteries for motive, vehicular, backup power and utility energy storage applications are fitted with a microprocessor-controlled thermal management system including an array of temperature and voltage sensors and an active cooling system. However, as the complexity of the thermal management system increases, so does its weight, volume and parasitic power consumption, all factors that adversely affect the vehicle’s performance. In this sense, an improved thermal management system based on including passive solutions such as phase change materials or heat spreading technologies could decrease the load on active components and ultimately the weight and costs of the system. This paper describes an experimental and simulation study aimed at evaluating the effectiveness of flexible graphite materials for heat spreaders in battery thermal management systems. A commercial Li-ion battery pack for power tools applications was adopted as a case study. The electro-thermal behavior of the battery pack was characterized through combined experimental investigation and 3D FEM modeling to determine the heat generation rate of the battery cells during utilization and to evaluate the thermal behavior of the battery pack. A thermal management solution based on flexible graphite heat spreading material was then designed and implemented. The paper presents a comparative study conducted in simulation to evaluate the improvements in the pack thermal behavior.Copyright © 2011 by ASME
Characterization of piezoelectric paint and its refinement for structural health monitoring applications

Piezoelectric paint is a composite piezoelectric material, due to its outstanding properties consisting of flexibility and conformability, it has been a great interest in structural health monitoring applications recently. The normal piezoelectric ceramics offer high piezoelectric properties, but are difficult to adhere on curly structural surfaces. For normal polymers, it offers high flexibility but missing the ability to transform the mechanical energy into the electrical energy, and vice versa. The piezoelectric paint combines the features of both, so it could be distributed on both even and uneven structural surface, as a sensor or actuator. This work starts with the development of the piezoelectric paint, followed by a systematic characterization of its mechanical and piezoelectric properties, which includes microstructure, Young's modulus, sensitivity and piezoelectric charge constant da1. The characterization results helps to understand the performance of the piezoelectric paint more deeply. Finally, a refinement method is demonstrated to improve the piezoelectricity of the paint. The results showed that the piezoelectricity was greatly improved and therefore its applications in structural health monitoring is widely expanded.
Gramicidin‐perforated patch revealed depolarizing effect of GABA in cultured frog melanotrophs

1 In frog pituitary melanotrophs, GABA induces a transient stimulation followed by prolonged inhibition of hormone secretion. This biphasic effect is inconsistent with the elevation of cytosolic calcium and the inhibition of electrical activity also provoked by GABA in single melanotrophs. In the present study, standard patch‐clamp configurations and gramicidin‐perforated patches were used to investigate the physiological GABAA receptor‐mediated response and intracellular chloride concentration ([Cl−]i) in cultured frog melanotrophs. 2 In the gramicidin‐perforated patch configuration, 1 μM GABA caused a depolarization associated with an action potential discharge and a slight fall of membrane resistance. In contrast, at a higher concentration (10 μm) GABA elicited a depolarization accompanied by a transient volley of action potentials, followed by a sustained inhibitory plateau and a marked fall of membrane resistance. Isoguvacine mimicked the GABA‐evoked responses, indicating a mediation by GABAA receptors. 3 In gramicidin‐perforated cells, the depolarizing excitatory effect of 1 μm GABA was converted into a depolarizing inhibitory action when 0.4 μm allopregnanolone was added to the bath solution. 4 After gaining the whole‐cell configuration, the amplitude and/or direction of the GABA‐evoked current (IGABA) rapidly changed before stabilizing. After stabilization, the reversal potential of IGABA followed the values predicted by the Nernst equation for chloride ions when [Cl−]i was varied. 5 In gramicidin‐perforated cells, the steady‐state I–V relationships of 10 μm GABA‐ or isoguvacine‐evoked currents yielded reversal potentials of −37.5 ± 1.6 (n= 17) and −38.6 ± 2.0 mV (n= 8), respectively. These values were close to those obtained by using a voltage‐ramp protocol in the presence of Na+, K+ and Ca2+ channel blockers. The current evoked by 1 μm GABA also reversed at these potentials. 6 We conclude that, in frog pituitary melanotrophs, chloride is the exclusive charge carrier of IGABA. In intact cells, the reversal potential of IGABA is positive to the resting potential because of a relatively high [Cl−]i (26.5 mm). Under these conditions, GABA induces a chloride efflux responsible for a depolarization triggering action potentials. However, GABA at a high concentration or in the presence of the potentiating steroid allopregnanolone exerts a concomitant shunting effect leading to a rapid inhibition of the spontaneous firing.
Two distinct neuronal mechanisms underlying high frequency power changes in human local field potential recordings

1Neuroscience Graduate Group and 2Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104 3Princeton Neuroscience Institute and 4Department of Computer Science, Princeton University, Princeton, NJ 08540 5School of Biomedical Engineering, Sciences, and Health Systems, Drexel University, Philadelphia, PA 19104 6Division of Neurosurgery and 7Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095 8Functional neurosurgery unit, Tel-Aviv Medical Center and 9Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
The Effect of Hostile Acquisition Threats on the Equity Value and Firm Value

This paper studies the effect of hostile acquisition threats on the manager's effort, equity value, operation value and firm value, under the separation of ownership and control. We analyze the optimal ratio of the acquisition premium that the shareholder will determine. At last, we use numerical methods to compare the manager's effort and firm value under non acquisition threats and acquisition threats, and to reveal the effect of takeover efficiency on the firm value. We find that acquisition threats can enhance the manager's effort, increase the equity value and firm value, but will reduce the return of manager, and reduce the operation value when the takeover efficiency is high.
Early Vocal Development in a Normally Hearing Infant and a Young Cochlear Implant Recipient

The developmental progress before expressing the first words is rarely assessed for Germanspeaking children. For this reason two single-case studies were performed to investigate the early vocal development of a normal hearing female infant and a young female cochlear implant (CI) recipient. Longitudinal data were collected by performing monthly audio- and video-recordings of one-hour mother-child-interactions over one year. Implementation of the Stark Assessment of Early Vocal Development - Revised (SAEVD-R) allowed the classification of children's utterances and the assessment of developmental progress in both children. Results show a decrease of early vocalizations and an increase of adult-like vocalizations for the normal hearing infant as well as for the implanted toddler over the first year. In the first six months of life and respectively of hearing experience the children almost exclusively produced vocalizations assigned to the early developmental levels 1-3 of SAEVD-R. An increase of vocalizations assigned to the more mature levels 4 and 5 of SAEVD-R containing true vowels and consonants was observed in the second half of the first year. Overall the CI recipient showed a slightly faster progress of development than the normal hearing infant with respect to hearing age. Interrater- and intrarater-reliability using the SAEVD-R were satisfying.
Cavitation development in the lubricant film of a reciprocating piston-ring assembly

Abstract The onset and development of cavitation in the lubrication film present throughout the stroke between the piston ring and the cylinder liner in a reciprocating test rig was visualized by a charge-coupled device (CCD) camera and monitored by a miniature pressure sensor. Various transient cavitation patterns were identified during the stroke, ranging from developing fern-shaped cavities to string cavities extending gradually up to the trailing edge of the piston ring. Both the onset and the development of these cavities seem to be affected by piston speed and load; at higher speeds cavities appear later in the stroke and are larger in size, while at higher loads they appear earlier, are more numerous and, thus, smaller in size.
First-in-Human Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma

Purpose: TGFβ signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGFβ signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer. Experimental Design: Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria. Results: In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ≥6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events. Conclusions: On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation. Clin Cancer Res; 21(3); 553–60. ©2014 AACR.
Reduction in Ki-67 in Benign Breast Tissue of High-Risk Women with the Lignan Secoisolariciresinol Diglycoside

Preclinical and correlative studies suggest reduced breast cancer with higher lignan intake or blood levels. We conducted a pilot study of modulation of risk biomarkers for breast cancer in premenopausal women after administration of the plant lignan secoisolariciresinol given as the diglycoside (SDG). Eligibility criteria included regular menstrual cycles, no oral contraceptives, a >3-fold increase in 5-year risk, and baseline Ki-67 of ≥2% in areas of hyperplasia in breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) during the follicular phase of the menstrual cycle. SDG (50 mg/d) was given for 12 months, followed by repeat RPFNA. The primary end point was change in Ki-67. Secondary end points included change in cytomorphology, mammographic breast density, serum bioavailable estradiol and testosterone insulin-like growth factor-I and IGF-binding protein-3, and plasma lignan levels. Forty-five of 49 eligible women completed the study with excellent compliance (median = 96%) and few serious side effects (4% grade 3). Median plasma enterolactone increased ∼9-fold, and total lignans increased 16-fold. Thirty-six (80%) of the 45 evaluable subjects showed a decrease in Ki-67, from a median of 4% (range, 2-16.8%) to 2% (range, 0-15.2%; P < 0.001, Wilcoxon signed rank test). A decrease from baseline in the proportion of women with atypical cytology (P = 0.035) was also observed. Based on favorable risk biomarker modulation and lack of adverse events, we are initiating a randomized trial of SDG versus placebo in premenopausal women. Cancer Prev Res; 3(10); 1342–50. ©2010 AACR.
A novel disease-modifying osteoarthritis drug candidate targeting Runx1

Objectives To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy. Methods We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays. Results TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue. Conclusions Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.
A Data-driven Investigation of Corrective Feedback on Subject Omission Errors in First Language Acquisition

We investigate implicit corrections in the form of contrastive discourse in childadult interaction, which have been argued to contribute to language learning. In contrast to previous work in psycholinguistics, we adopt a data-driven methodology, using comparably large amounts of data and leveraging computational methods. We conduct a corpus study on the use of parental corrective feedback and show that its presence in child directed speech is associated with a reduction of child subject omission errors in English.
Maternal Caffeine Intake Has Minor Effects on Adenosine Receptor Ontogeny in the Rat Brain

Maternal caffeine intake has been suggested to influence the offspring. We have studied the effects of maternal caffeine intake on adenosine and GABA receptors, targets for caffeine, during development of the rat brain. Caffeine (0.3 g/L) was added to the drinking water of rat dams during pregnancy and early postnatal life. Adenosine A1 and A2A and GABAA receptor development was studied using receptor autoradiography and in situ hybridization. Pups were examined on embryonic d 14 (E14), E18, E21, 2 h after birth (P2h), P24h, postnatal d 3 (P3), P7, P14, and P21. Adenosine A1 receptor mRNA was detected at E14 and receptors at E18. A1 mRNA levels increased from the level reached at E18 between P3 and P14 (maximally a doubling), whereas A1 receptors, studied by [3H]-1,3-dipropyl-8-cyclopentyl xanthine binding, increased later and to a much larger extent (about 10-fold) postnatally. Caffeine treatment had no significant effect on adenosine A1 receptors or on A1 receptor mRNA. A2A mRNA had reached adult levels by E18, whereas receptor levels were low or undetectable before birth and increased dramatically until P14. Caffeine did not influence A2A receptors or A2A receptor mRNA at any stage during development. [3H]-flunitrazepam binding, representing GABAA receptors, showed large regional variations during ontogeny, but there were no clear differences between the caffeine-exposed and the nonexposed pups. Thus, exposure to a low dose of caffeine during gestation and postnatal life had only minor effects on development of adenosine A1 and A2A receptors and GABAA receptors in the rat brain.
Enhanced Oil Recovery

What is enhanced oil recovery? Enhanced oil recovery (EOR)2 is the most common oil recovery practice in the U.S., accounting for an estimated 60% of total crude oil production. Despite its prevalence, EOR is largely unknown to the public, poses threats to groundwater, and lacks adequate oversight from state and federal regulators. EOR involves the injection of fluids underground to increase the flow of oil and gas to the surface. There are four primary types of EOR:
Spina bifida occulta in homozygous Patch mouse embryos

In normal embryos, mRNA encoding platelet‐derived growth factor A (PDGF A) and the platelet‐derived growth factor receptor α (PDGFRα) are found within and adjacent to the site of vertebral development, the sclerotome. These patterns of expression are consistent with PDGF action on the developing sclerotome and dermis. Homozygous Patch (Ph) mutant mouse embryos lack the receptor gene (Pdgfra) due to an extensive deletion at that locus. Consistent with the spatial pattern of Pdgfra expression, striking deformities are found in the spine and ribcage of Ph/Ph embryos. In particular, we show that late‐gestation Ph/Ph embryos have occult spina bifida involving the entire spinal column. We have analyzed the progression of the axial defects in homozygous Patch embryos in detail. By late gestation it appears that the components of the vertebrae are present, yet the neural arches of the spine are misshapen. We propose that PDGF A is required for proper positioning of the neural arch condensation at all axial levels. Furthermore, since the neural tube appears to close normally, we suggest that spina bifida in the Ph homozygote is caused primarily by a somitic mesoderm abnormality rather than a neural tube defect. Dev. Dyn. 209:105–116, 1997. © 1997 Wiley‐Liss, Inc.
Packaging of Host mY RNAs by Murine Leukemia Virus May Occur Early in Y RNA Biogenesis

ABSTRACT Moloney murine leukemia virus (MLV) selectively encapsidates host mY1 and mY3 RNAs. These noncoding RNA polymerase III transcripts are normally complexed with the Ro60 and La proteins, which are autoantigens associated with rheumatic disease that function in RNA biogenesis and quality control. Here, MLV replication and mY RNA packaging were analyzed using Ro60 knockout embryonic fibroblasts, which contain only ∼3% as much mY RNA as wild-type cells. Virus spread at the same rate in wild-type and Ro knockout cells. Surprisingly, MLV virions shed by Ro60 knockout cells continued to package high levels of mY1 and mY3 (about two copies of each) like those from wild-type cells, even though mY RNAs were barely detectable within producer cells. As a result, for MLV produced in Ro60 knockout cells, encapsidation selectivity from among all cell RNAs was even higher for mY RNAs than for the viral genome. Whereas mY RNAs are largely cytoplasmic in wild-type cells, fractionation of knockout cells revealed that the residual mY RNAs were relatively abundant in nuclei, likely reflecting the fact that most mY RNAs were degraded shortly after transcription in the absence of Ro60. Together, these data suggest that these small, labile host RNAs may be recruited at a very early stage of their biogenesis and may indicate an intersection of retroviral assembly and RNA quality control pathways.