Miracle-dz/UniFAR-FTUs huggingface dataset:
Application of HC-AFW1 Hepatocarcinoma Cells for Mechanistic Studies: Regulation of Cytochrome P450 2B6 Expression by Dimethyl Sulfoxide and Early Growth Response 1

Various exogenous compounds, for example, the drugs bupropione and propofol, but also various cytostatics, are metabolized in the liver by the enzyme cytochrome P450 (P450) CYP2B6. Transcription from the CYP2B6 gene is regulated mainly via the transcription factors constitutive androstane receptor (CAR) and pregnane-X-receptor (PXR). Most hepatic cell lines express no or only low levels of CYP2B6 because of loss of these two regulators. Dimethyl sulfoxide (DMSO) is frequently used in liver cell cultivation and is thought to affect the expression of various P450 isoforms by inducing or preserving cellular differentiation. We studied the effects of up to 1.5% of DMSO as cell culture medium supplement on P450 expression in hepatocarcinoma cells from line HC-AFW1. DMSO did not induce differentiation of the HC-AFW1 cell line, as demonstrated by unaltered levels of selected mRNA markers important for hepatocyte differentiation, and also by the lack of a DMSO effect on a broader spectrum of P450s. By contrast, CYP2B6 mRNA was strongly induced by DMSO. This process was independent of CAR or PXR activation. Interestingly, elevated transcription of CYP2B6 was accompanied by a simultaneous induction of early growth response 1 (EGR1), a transcription factor known to influence the expression of CYP2B6. Expression of wild-type EGR1 or of a truncated, dominant-negative EGR1 mutant was able to mimic or attenuate the DMSO effect, respectively. These findings demonstrate that EGR1 is involved in the regulation of CYP2B6 by DMSO in HC-AFW1 cells.
Nitrogen-Induced Enhancement of Synaptic Weight Reliability in Titanium-Oxide-based Resistive Artificial Synapse and Demonstration of Reliability Effect on Neuromorphic System.

With the significant technological developments in recent times, the neuromorphic system has been receiving considerable attention owing to its parallel arithmetic, low power consumption, and high scalability. However, the low reliability of artificial synapse devices disturbs calculations and causes inaccurate results in neuromorphic systems. In this paper, we propose a stable resistive artificial synapse (RAS) device with nitrogen-doped titanium oxide (TiOx:N)-based resistive switching (RS) memory. The TiOx:N-based RAS, compared to the TiOx-based RAS, demonstrates more stable RS characteristics in current-voltage (I-V) and pulse measurements. In terms of resistance variability, the TiOx:N-based RAS demonstrates five times lower resistance variability at 1.38%, compared to 6.68% with the TiOx-based RAS. In addition, we verified the relation between the neuromorphic system and the resistance reliability of the synapse device for the first time. The pattern recognition simulation is performed using an artificial neural network (ANN) consisting of artificial synapse devices using the Modified National Institute of Standards and Technology dataset. In the simulation, the ANN with the TiOx:N-based RAS exhibited significant pattern recognition accuracy of 64.41%, while the ANN with TiOx-based RAS demonstrated only low recognition accuracy of 22.07%. According to the results of subsequent simulations, the pattern recognition accuracy exponentially decreases when the resistance variability exceeds 5%. Therefore, for implementing a stable neuromorphic system, the synapse device in the neuromorphic system has to maintain low resistance variability. The proposed nitrogen-doped synapse device is suitable for neuromorphic systems because a reliable resistance variability can be obtained with only simple process steps.
A New Rapid In Vitro Assay for Assessing Reactivity of Acyl Glucuronides

Idiosyncratic drug toxicity is a major challenge for the pharmaceutical industry since complex and multifactorial steps are involved, the dose-dependency is unclear, and its occurrence is not reliably predictable. Whereas the exact mechanisms leading to idiosyncratic toxicity remain elusive in many cases, there are often hints at the involvement of reactive metabolites, such as acyl glucuronides formed by conjugation of carboxylic acids with glucuronic acid. Because the patient-related susceptibilities leading to idiosyncratic toxicity are not sufficiently understood, the best option for the pharmaceutical industry is to minimize drug-related risk factors such as potential acyl glucuronide formation. Here, we describe a rapid in vitro assay for the assessment of the reactivity of acyl glucuronides, on the basis of acyl glucuronide migration, that can support the selection of low-risk drug candidates in the drug discovery phase. Twenty marketed compounds with a wide range of half-lives were tested, their acyl glucuronide migration rates were determined and compared with the half-lives of the respective acyl glucuronides. Ranking of acyl glucuronide stability using this method compared well with the results from existing methodologies. With this method, migration rates >20% would indicate higher risk of reactivity. This simpler approach using the acyl glucuronide migration rate is not dependent on authentic standards, therefore eliminating the requirement for either lengthy chemical synthesis or in vitro biosynthesis and purification of the 1-O-β-glucuronide. This methodology provides a rapid in vitro assay to assess acyl glucuronide stability and reactivity that is well suited for use early in the drug discovery phase.
Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia–rearranged and integrase interactor-1–deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.
Synthesis of Sandwich-liked Nanostructure Fillers and Their Use in Different Types of Thermal Composites.

Thermally conductive yet electrically insulating two-dimensional boron nitride nanosheet (BNNS) has been an ideal choice of the enhanced filler for improving thermal properties of polymer-based composites. As a nanofiller with ultra-high aspect ratio, BNNS results in a conspicuous stacking along the planar direction in the preparation of composites, which results in a strong anisotropy of heat transfer and suppresses out-plane thermal dissipation. Thus, it is necessary to facilitate the out-plane heat transfer by building favorable microstructure. Focusing on the structural design of nanofillers itself, here we have fabricated a novel three-dimensional nanofiller with improved out-plane connections. Carbon nanotubes (CNTs) have been grown in-situ on the surface of BNNSs using chemical vapor deposition (CVD). Utilizing this BNNS/CNT as fillers in composites, we have assembled diverse sorts of composites, such as the flexible films, scleroid 3D mats, painted ink, and viscous grease. Simultaneously, their thermal and insulating properties have been evaluated. The results indicate that the BNNS/CNT filler has superior thermal performance over the original BNNS while maintaining a satisfactory electrical resistivity to avoid short-circuits in high-power electronics. Furthermore, the prepared grease used as a thermal interface material shows an impressive heat dissipation performance when being applied on a computer running.
Prevalence of Non–Cytochrome P450–Mediated Metabolism in Food and Drug Administration–Approved Oral and Intravenous Drugs: 2006–2015

In recent years, claims of increased involvement of non–cytochrome P450 (non-P450) enzymes in the metabolism of drugs have appeared in the literature. However, no temporal summaries of the contribution of non-P450 enzymes to the metabolism of drugs have been published. Using data from human radiolabeled absorption, distribution, metabolism, and excretion studies available for a set of 125 orally or intravenously administered small-molecule drugs approved by the United States Food and Drug Administration from 2006 to 2015, the contributions of P450 and non-P450 enzymes to the formation of major metabolites (≥10% of dose) were assessed and tabulated. Over this time frame, the involvement of P450 versus non-P450 enzymes in the formation of major metabolites is compared, and the individual non-P450 enzymes responsible are described. This analysis indicates that non-P450 enzymes contribute significantly to the metabolism of the 125 drugs analyzed. Approximately 30% of the metabolism of these drugs is carried out by non-P450 enzymes, with the predominant non-P450 enzymes identified being glucuronosyltransferases (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and aldehyde oxidase (1.1%). Although significant, the relative contribution of non-P450 enzymes to drug metabolism does not appear to have increased dramatically over the last 10 years. As the current evaluation involves drugs which emerged from the discovery phase >10 years ago, this evaluation may not reflect the current or evolving situation in some research organizations; therefore, additional monitoring and assessment of the involvement of non-P450 enzymes in the metabolism of drugs will be conducted in the future.
ASCARIS LUMBRICOIDES INFESTATION WITH EXTREME ANEMIA

A fairly comprehensive search of medical textbooks does not reveal the association of Ascaris lumbricoides infestation with extreme anemia. It is noted, however, in Strumpell's Textbook of Medicine that "when Bothriocephalus latus or occasionally a taenia is present in the intestines there will often be an extremely severe anemia, quite like pernicious anemia. " In a case seen recently in a child, this pernicious anemia-like type of blood picture accompanying the ascaris infestation was so marked that it seems worthy of attention. R. W. , a 7 year old boy, puny in stature, of American parents of German descent, whose life had been spent in Milwaukee, had had only one outstanding illness prior to the present trouble, namely, a mild attack of measles, and a moderately severe attack of pertussis six months before coming under my observation. Because of his poor development, anemic appearance, repeated attacks of nosebleed, and
N,N′-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity

The current study evaluated a new series of N,N′-alkane-diyl-bis-3-picolinium (bAPi) analogs with C6–C12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [3H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity, and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for α4β2* (* indicates putative nAChR subtype assignment) and α7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C6, all analogs inhibited nicotine-evoked [3H]DA overflow (IC50 = 2 nM–6 μM; Imax = 54–64%), with N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; C12) being most potent. bPiDDB did not inhibit electrically evoked [3H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [3H]DA overflow. To determine whether bPiDDB interacts with α-conotoxin MII-sensitive α6β2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and α-conotoxin MII (1 nM). Inhibition of nicotine-evoked [3H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with α6β2-containing nAChRs. C7, C8, C10, and C12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although none of the analogs altered the discriminative stimulus effect of nicotine, C8, C9, C10, and C12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted.
A database accelerator for energy-efficient query processing and optimization

Data processing on a continuously growing amount of information and the increasing power restrictions have become an ubiquitous challenge in our world today. Besides parallel computing, a promising approach to improve the energy efficiency of current systems is to integrate specialized hardware. This paper presents a Tensilica RISC processor extended with an instruction set to accelerate basic database operators frequently used in modern database systems. The core was taped out in a 28 nm SLP CMOS technology and allows energy-efficient query processing as well as query optimization by applying selectivity estimation techniques. Our chip measurements show an 1000x energy improvement on selected database operators compared to state-of-the-art systems.
Sensor-based Planning for a Rod-shaped Robot in Three Dimensions: Piecewise Retracts of R3 × S2

We present a new roadmap for a rod-shaped robot operating in a three-dimensional workspace, whose configuration space is diffeomorphic to R 3 × S 2. This roadmap is called the rod hierarchical generalized Voronoi graph (rod-HGVG) and can be used to find a path between any two points in an unknown configuration space using only the sensor data. More importantly, the rod-HGVG serves as a basis for an algorithm to explore an unknown configuration space without explicitly constructing it. Once the rod-HGVG is constructed, the planner can use it to plan a path between any two configurations. One of the challenges in defining the roadmap revolves around a homotopy theory result, which asserts that there cannot be a one-dimensional deformation retract of a non-contractible space with dimension greater than two. Instead, we define an exact cellular decomposition on the free configuration space and a deformation retract in each cell (each cell is contractible). Next, we “connect” the deformation retracts of each of the cells using a roadmap of the workspace. We call this roadmap a piecewise retract because it comprises many deformation retracts. Exploiting the fact that the rod-HGVG is defined in terms of workspace distance measurements, we prescribe an incremental procedure to construct the rod-HGVG that uses the distance information that can be obtained from conventional range sensors.
On the Benefits of Using Multipath TCP and Openflow in Shared Bottlenecks

This paper focuses on evaluating the use of MPTCP to forward sub flows in Open Flow networks. MPTCP is a network protocol designed to forward sub flows through disjointed paths. Modern networks commonly use Equal-Cost Multipath Protocol (ECMP) to split flows through distinct paths. However, even with ECMP enabled, sub flows may be forwarded through the same path. MPTCP improves the multipath routing by setting sub flows to be forwarded through distinct paths. As a consequence, the amount of sub flows must be considered to evaluate the network throughput. In this paper, we design Multiflow to use MPTCP in Open Flow networks. Our proposal is to improve the throughput in shared bottlenecks by forwarding sub flows from a same MPTCP connection through multiple paths. We validate our approach in a test bed where shared bottlenecks occur in the link at the endpoints. The Multiflow improvement of the network performance is evaluated in experiments about resilience and end-to-end throughput.
Special Issue on the Seventh International Workshop on Algorithmic Foundations of Robotics

Algorithms are a fundamental component of robotic systems – they control or reason about motion and perception in the physical world, they receive input from noisy sensors, consider geometric and physical constraints, and operate on the world through imprecise actuators. Increasingly, robotics algorithms are finding use in areas far beyond the traditional scope of robots such as computer animation and gaming, virtual environments, sensor networks, manufacturing, medical robotics, and computational biology. The International Workshop on the Algorithmic Foundations of Robotics (WAFR) is a multi-disciplinary single-track workshop with submitted and invited papers on advances on algorithmic problems in robotics. WAFR has been held every other year since 1994 and has an established reputation as one of the most important venues for presenting algorithmic work related to robotics. Previous WAFRs have been held at Zeist, The Netherlands (2004), Nice, France (2002), Hanover, NH, USA (2000), Houston, TX, USA (1998), Toulouse, France (1996), and Stanford, CA, USA (1994). This special issue contains expanded versions of 12 papers that were presented at the Seventh WAFR which was held at the Tribeca Grand Hotel in New York City in July 2006. WAFR 2006 had a record number of submissions and attendees, and a very strong and interesting technical program with six stellar invited speakers – James Gimzewski (UCLA), Jessica Hodgins (CMU), Jean-Claude Latombe (Stanford), Tomas Lozano-Perez (MIT), Jacob Schwartz (NYU), and Sebastian Thrun (Stanford) – and 32 contributed papers, each of which underwent a rigorous selection process where each submission was reviewed by at least three members of the program committee. The authors of some of the best and most interesting papers were invited to submit expanded versions of their WAFR 2006 papers to this special issue. These papers underwent the rigorEditorial
Regulation of Somatostatin Release by Adenosine in the Mouse Stomach

Adenosine inhibits gastric acid secretion, either directly by acting on acid-secreting parietal cells or indirectly by stimulating the release of the acid inhibitor, somatostatin. The present study examined the role of adenosine on somatostatin release in an isolated vascularly perfused mouse stomach model. Concentrations of exogenous adenosine ≥ 1.0 μM stimulated gastric release of somatostatin-like immunoreactivity (SLI), and this effect was blocked by the A2A receptor antagonist ZM 241385 [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol]. The A2A receptor agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride] augmented SLI release in a concentration-dependent manner, suggesting that A2A receptor activation is involved in the stimulatory effect of adenosine on SLI release. Conversely, SLI release was inhibited by the A1 receptor agonists N6-cyclopentyladenosine and 2-chloro-N6-cyclopentyladenosine and lower concentration of adenosine (0.01 μM). The involvement of specific adenosine receptors in controlling the release of gastric SLI was also examined using A2A receptor knockout (A2AR-KO) mice. In these mice, adenosine (10 μM) inhibited SLI release, and the effect was abolished by the selective A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, suggesting a link between the selective A1 activation and inhibition of SLI release. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride augmented SLI release in wild-type controls but not in the presence of ZM 241385 or in A2AR-KO mice. We conclude that adenosine has dual actions on regulating mouse gastric SLI release: stimulatory at higher concentrations through the A2A receptor and inhibitory at lower concentrations through the A1 receptor, whereas A2B and A3 receptors have a minimal role.
Effect of CO2 pneumoperitoneum on ventilation‐perfusion relationships during laparoscopic cholecystectomy

Background: Previous studies have shown that pneumoperitoneum transiently reduces venous admixture as assessed by a calculation based on the shunt formula, and increases arterial oxygen tension (PaO2) in patients without heart or lung disease. The aim of the present study was to further explore the relationship between ventilation‐perfusion (V˙A/Q˙) before and during pneumoperitoneum by using the multiple inert gas technique.
QUANTITATIVE DETERMINATION OF EIGHT ORGANOCHLORINE PESTICIDES IN SERUM BY GC COUPLED TO TANDEM MASS SPECTROMETRY

Abstract The pathogenic role of exposure to organochlorine pesticides residues is a matter of controversy. Some of them were recently suspected to be associated with neurodegenerative diseases (Parkinson, Alzheimer, …), especially α-hexachlorocyclohexane (α-HCH), β-HCH, γ-HCH, p,p′-1,1-dichloro-2,2- bis(p-chlorophenyl)ethylene (p,p′-DDE), o,p′-DDE, dieldrin, p,p′-dichlorodiphenyltrichloroethane (p,p′-DDT) and o,p′-DDT. Since these organochlorine products are prohibited in Europe and USA, the blood concentrations found in general population are usually lower than 1μg/L for each compound. To allow quantification of very low concentrations, the analytical method needs to be as sensitive as possible. A gas chromatography coupled to tandem mass spectrometry method has been developed for the simultaneous determination of the eight residues, and has been validated in order to check its suitability with our objectives. Sample preparation included a double liquid-liquid extraction of the serum with a mixture of petroleum ether and diethyl ether followed by a solid phase extraction on Bond Elut LRC-Certify cartridges (130mg, Varian). Extracted sample was injected onto the gas chromatography analyzer (Agilent, 7890A). The chromatographic separation was done on a HP-5MS column (30m × 0.25mm, 0.25μm, Agilent) and compounds were then analyzed in the tandem mass spectrometer (Agilent, Triple Quad, 7000A). Two transitions were studied by molecule. The method was validated using total error approach. The linearity of the method was acceptable in the validated range of concentrations for the eight pesticides. The bias was lower than 10%, the relative standard deviations are lower than 10% for repeatability (n=3) and than 15% for intermediate precision (k=3). Lower and upper β-expectation tolerance limits did not exceed the acceptance limits of 20%. The limit of quantitation was about 0. 5μg/L for all compounds. The gas chromatography coupled to tandem mass spectrometry (GC-MSMS) technology was fully convenient for the detection and the quantitative determination of 8 organochlorine residues in serum. The method had been applied to the identification and quantification of the products in blood samples obtained from patients suffering from neurodegenerative disorders.