gebhart/patrepeval huggingface dataset:
EXTH-43. DIFFERENTIATED PHARMACOLOGY OF THE IMIPRIDONE ONC201, THE FIRST SELECTIVE DRD2/3 ANTAGONIST IN CLINICAL NEURO-ONCOLOGY (2017)

ONC201, founding member of the imipridone class of compounds, has demonstrated evidence of tumor shrinkage along with exceptional safety in recurrent glioblastoma patients. In this study, we identified and characterized a previously unknown binding target of ONC201. BANDIT – a machine learning-based drug target identification platform – predicted that ONC201 would bind with high selectivity to the G-protein coupled receptors (GPCRs) dopamine receptor D2(DRD2) and D3 (DRD3). DRD2 is overexpressed in glioblastoma, controls pro-survival mechanisms, and its antagonism causes pro-apoptotic effects in malignant cells. PathHunter® β-arrestin and cAMP assays determined that ONC201 selectively antagonizes DRD2 and DRD3. Consistent with BANDIT and in contrast to DRD2 blocking antipsychotics, ONC201 did not antagonize other dopamine receptors or other closely related GPCRs with identified endogenous ligands. Schild analyses and radioligand competition assays revealed DRD2 affinities that were consistent with those identified for ONC201 anticancer activity. In accordance with superior selectivity, ONC201 exhibited a wider therapeutic window compared to other antipsychotics. In support of the hypothesis that selectively targeting D2-like receptors yields superior anti-cancer efficacy, combined DRD2/DRD1 inhibition was found to be inferior to DRD2 inhibition alone. ONC201 exhibited a very slow association rate for DRD2 relative to antipsychotics, whereas the dissociation rate was similar to atypical antipsychotics that are better tolerated clinically. Shotgun mutagenesis across 350 amino acids of DRD2 identified 8 residues critical for ONC201-mediated antagonism of DRD2-induced calcium flux. Several residues were not conserved among other dopamine receptors, suggesting a potential role in conferring ONC201 selectivity. Consistent with competitive inhibition, several mutated residues were within the orthosteric binding site (OBS), however, two distal residues were identified outside of the OBS suggesting a secondary binding pocket. In summary, receptor pharmacology of ONC201, the first selective DRD2/3 antagonist in clinical neuro-oncology, may explain its unique selectivity, safety, and anti-cancer activity in clinical trials.
A novel tau‐tubulin kinase from bovine brain (1995)

During purification of tau protein kinase I and II from the bovine brain extract, a new tau protein kinase was detected and purified with phosphocellulose, gel filtration, S-Sepharose and AF-Heparin column chromatography. The molecular mass of the enzyme was determined to be 32 kDa by gel filtration and activity staining on SDS-PAGE. The enzyme is a Ser/Thr protein kinase phosphorylating tau, beta-tubulin, MAP2 and alpha-casein. Employing many synthetic peptides, the recognition site of this enzyme appears to be -SR-. The enzyme requires no second messenger and is inhibited with high concentration of heparin, but not by inhibitors of CKI. These results indicate that this enzyme, tau-tubulin kinase is novel and distinct from TPKI, II and CKI, II.
Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS‐induced acute lung injury (2016)

Acute inflammatory diseases are the leading causes of mortality in intensive care units. Myeloid differentiation 2 (MD-2) is required for recognizing lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and represents an attractive therapeutic target for LPS-induced inflammatory diseases. In this study, we report a chalcone derivative, L2H21, as a new MD2 inhibitor, which could inhibit LPS-induced inflammation both in vitro and in vivo. We identify that L2H21 as a direct inhibitor of MD-2 by binding to Arg<sup>90</sup> and Tyr<sup>102</sup> residues in MD-2 hydrophobic pocket using a series of biochemical experiments, including surface plasmon response, molecular docking and amino acid mutation. L2H21 dose dependently inhibited LPS-induced inflammatory cytokine expression in primary macrophages. In mice with LPS intratracheal instillation, L2H21 significantly decreased LPS-induced pulmonary oedema, pathological changes in lung tissue, protein concentration increase in bronchoalveolar lavage fluid, inflammatory cells infiltration and inflammatory gene expression, accompanied with the decrease in pulmonary TLR4/MD-2 complex. Meanwhile, administration with L2H21 protects mice from LPS-induced mortality at a degree of 100%. Taken together, this study identifies a new MD2 inhibitor L2H21 as a promising candidate for the treatment of acute lung injury (ALI) and sepsis, and validates that inhibition of MD-2 is a potential therapeutic strategy for ALI.
Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas (2016)

Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10-3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10-5).
Nicotine and the nicotinic cholinergic system in COVID‐19 (2020)

There is an urgent need to address the devastating pandemic, COVID-19, caused by SARS-CoV-2. The efforts to understand the details of this disease in hope of providing effective treatments are commendable. It is clear now that the virus can cause far more damage in patients with comorbid conditions-particularly in those with respiratory, cardiovascular, or immune-compromised system-than in patients without such comorbidities. Drug use can further exacerbate the condition. In this regard, the ill effects of smoking are amply documented, and no doubt can be a confounding factor in COVID-19 progression. Although conflicting hypotheses on the potential role of nicotine in COVID-19 pathology have recently been offered, we believe that nicotine itself, through its interaction with the nicotinic cholinergic system, as well as ACE2, may not only be of use in a variety of neuropsychiatric and neurodegenerative diseases, but may also be of potential use in COVID-19. Thus, on one hand, while we strongly support smoking cessation as a means of harm reduction associated with COVID-19, on the other hand, we support a potential therapeutic role for nicotine, nicotinic agonists, or positive allosteric modulators of nicotinic cholinergic receptors in COVID-19, owing to their varied effects including mood regulation, anti-inflammatory, and purported interference with SARS-CoV-2 entry and/or replication.
New structural and functional defects in polyphosphate deficient bacteria: A cellular and proteomic study (2010)

The results obtained suggest that during polyP deficiency energy metabolism and particularly nucleoside triphosphate (NTP) formation were affected and that bacterial cells overcame this problem by increasing the flux of energy-generating metabolic pathways such as tricarboxilic acid (TCA) cycle, beta-oxidation and oxidative phosphorylation and by reducing energy-consuming ones such as active transporters and amino acid biosynthesis. Furthermore, our results suggest that a general stress response also took place in the cell during polyP deficiency.
Insulin-Like Growth Factor-I and -II Messenger RNA Expression in Muscle, Heart, and Liver of Streptozotocin-Diabetic Swine* (1990)

We have investigated the effects of streptozotocin-diabetes and fasting in juvenile swine by monitoring IGF-I and -II gene expression in muscle, heart, and liver tissues. In diabetic pigs, IGF-I messenger RNAs (mRNA) were decreased by 50% in muscle and liver tissues, and by 70% in heart. The imposition of fasting on diabetic animals tended to further decrease IGF-I mRNA levels, and fasting alone also decreased IGF-I mRNA abundance in the three tissues (P less than 0.05). Insulin therapy restored IGF-I mRNA levels to normal in muscle and livers but was less effective in hearts of diabetic pigs. Relative IGF-I mRNA expression in heart and muscle tissues was 2-fold and 4-fold higher, respectively, than in liver tissues under normal conditions in these animals. Serum IGF-I concentrations and tissue extractable immunoreactive IGF-I levels were also measured. Serum IGF-I was markedly decreased in the diabetic state, dropping to 70% below control levels (P less than 0.01). Extractable IGF-I in liver declined by 50% with diabetes (P less than 0.01), and by 30% in muscle with diabetes and fasting (P less than 0.05), but no significant changes in heart levels of IGF-I protein were detected. Expression levels of IGF-II mRNAs in the three tissues were unaffected by diabetes or fasting. These results are consistent with earlier observations in rat liver and further demonstrate that IGF-I expression in muscle and heart is altered by diabetes and fasting, whereas IGF-II mRNAs do not change.
Ru–B nanoparticles on metal–organic frameworks as excellent catalysts for hydrogenation of benzene to cyclohexane under mild reaction conditions (2015)

Ru–B/MIL-53(AlCr) affords an exceptionally high turnover frequency (TOF) of 6.4 s<sup>−1</sup>for hydrogenation of benzene to cyclohexane under mild reaction conditions.
N-dimensional N-microphone sound source localization (2013)

Abstract This paper investigates real-time N -dimensional wideband sound source localization in outdoor (far-field) and low-degree reverberation cases, using a simple N -microphone arrangement. Outdoor sound source localization in different climates needs highly sensitive and high-performance microphones, which are very expensive. Reduction of the microphone count is our goal. Time delay estimation (TDE)-based methods are common for N -dimensional wideband sound source localization in outdoor cases using at least N + 1 microphones. These methods need numerical analysis to solve closed-form non-linear equations leading to large computational overheads and a good initial guess to avoid local minima. Combined TDE and intensity level difference or interaural level difference (ILD) methods can reduce microphone counts to two for indoor two-dimensional cases. However, ILD-based methods need only one dominant source for accurate localization. Also, using a linear array, two mirror points are produced simultaneously (half-plane localization). We apply this method to outdoor cases and propose a novel approach for N -dimensional entire-space outdoor far-field and low reverberation localization of a dominant wideband sound source using TDE, ILD, and head-related transfer function (HRTF) simultaneously and only N microphones. Our proposed TDE-ILD-HRTF method tries to solve the mentioned problems using source counting, noise reduction using spectral subtraction, and HRTF. A special reflector is designed to avoid mirror points and source counting used to make sure that only one dominant source is active in the localization area. The simple microphone arrangement used leads to linearization of the non-linear closed-form equations as well as no need for initial guess. Experimental results indicate that our implemented method features less than 0.2 degree error for angle of arrival and less than 10% error for three-dimensional location finding as well as less than 150-ms processing time for localization of a typical wideband sound source such as a flying object (helicopter).
Effects of Laser Illumination on Superconducting Circuits for Quantum Transduction (2021)

Decoherence and noise from optical absorption in superconducting circuits hinder development of microwave to optical quantum transducers. Addressing these issues, we fabricate niobium-based resonators and qubits, and study them under laser illumination at milliKelvin temperatures.
A Bayes tour of inversion: A tutorial (2001)

Abstract It is unclear whether one can (or should) write a tutorial about Bayes. It is a little like writing a tutorial about the sense of humor. However, this tutorial is about the Bayesian approach to the solution of the ubiquitous inverse problem. Inasmuch as it is a tutorial, it has its own special ingredients. The first is that it is an overview; details are omitted for the sake of the grand picture. In fractal language, it is the progenitor of the complex pattern. As such, it is a vision of the whole. The second is that it does, of necessity, assume some ill-defined knowledge on the part of the reader. Finally, this tutorial presents our view. It may not appeal to, let alone be agreed to, by all.
Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer (2008)

The imprinted insulin-like growth factor 2 (IGF2) gene is expressed predominantly from the paternal allele. Loss of imprinting (LOI) associated with hypomethylation at the promoter proximal sequence (DMR0) of the IGF2 gene was proposed as a predisposing constitutive risk biomarker for colorectal cancer. We used pyrosequencing to assess whether IGF2 DMR0 methylation is either present constitutively prior to cancer or whether it is acquired tissue-specifically after the onset of cancer. DNA samples from tumour tissues and matched non-tumour tissues from 22 breast and 42 colorectal cancer patients as well as peripheral blood samples obtained from colorectal cancer patients [SEARCH (n=case 192, controls 96)], breast cancer patients [ABC (n=case 364, controls 96)] and the European Prospective Investigation of Cancer [EPIC-Norfolk (n=breast 228, colorectal 225, controls 895)] were analysed. The EPIC samples were collected 2-5 years prior to diagnosis of breast or colorectal cancer. IGF2 DMR0 methylation levels in tumours were lower than matched non-tumour tissue. Hypomethylation of DMR0 was detected in breast (33%) and colorectal (80%) tumour tissues with a higher frequency than LOI indicating that methylation levels are a better indicator of cancer than LOI. In the EPIC population, the prevalence of IGF2 DMR0 hypomethylation was 9.5% and this correlated with increased age not cancer risk. Thus, IGF2 DMR0 hypomethylation occurs as an acquired tissue-specific somatic event rather than a constitutive innate epimutation. These results indicate that IGF2 DMR0 hypomethylation has diagnostic potential for colon cancer rather than value as a surrogate biomarker for constitutive LOI.
Residues of ampicillin in blood of cultured olive flounder by oral, injection and dipping administration (2012)

암피실린 (ampicillin, AM) 을 넙치 (평균체중 300g, <TEX>$20{\pm}1.0^{\circ}C$</TEX>) 에 1일 1회 경구 (10, 20, 40mg/kg), 근육주사(5, 10, 20mg/kg), 약욕 (10, 20, 40ppm; 1시간) 한 다음, 경시적 (1시간~360시간) 으로 혈장 내 AM의 잔류량을 HPLC로써 분석하였다. 10, 20 및 40mg/kg로 경구 투여한 경우, 최대혈중농도가 모두 10시간째 각각 <TEX>$3.62{\pm}0.97$</TEX>, <TEX>$5.20{\pm}0.70$</TEX> 및 <TEX>$11.18{\pm}0.87{\mu}g/ml$</TEX>로 나타났으며, 이들은 각각 144, 360 및 360시간째 검출되지 않았다. 5, 10 및 20mg/kg의 농도로 근육주사한 경우, 최대 혈중농도가 모두 5시간째 <TEX>$6.92{\pm}1.29$</TEX>, <TEX>$9.89{\pm}2.22$</TEX> 및 <TEX>$19.85{\pm}2.97{\mu}g/ml$</TEX>를 나타내었으며, 이들은 각각 216, 264 및 264시간째 혈중에서 검출되지 않았다. 10, 20 및 40ppm의 농도로 약욕한 경우, 최대혈중농도가 모두 3시간째 <TEX>$4.39{\pm}1.10$</TEX>, <TEX>$9.57{\pm}1.51$</TEX> 및 <TEX>$11.61{\pm}1.92{\mu}g/ml$</TEX>로 나타났으며, 이들은 각각 264, 264 및 360시간째 혈중에서 검출되지 않았다. 이로써 경구, 주사 및 약욕 투약에 의한 넙치 혈액 중 분포와 배설정도는 투약량에 의존적 경향이라는 것을 알 수 있었다. The residue levels of ampicillin (AM) in cultured olive flounder, Paralichthys olivaceus (average 300g) at <TEX>$20{\pm}1.0^{\circ}C$</TEX> were studied by oral, intramuscular and dipping administration (routes). The concentrations of AM in the plasma were determined by HPLC-UV detector. The average recoveries of AM in spiked samples between 0.01~10 ppm were ranging from 84.45% to 91.26% for plasma. The limit of detection for AM was 0.05 ppm by using this method. Plasma concentrations of AM were determined after oral dosage (10, 20 and 40 mg/kg body weight), intramuscular injection (5, 10 and 20 mg/kg body weight) and dipping (10, 20 and 40 ppm; 1 h). Samples were taken at 1, 3, 5, 10, 15, 24, 30, 48, 96, 144, 216, 264 and 360 h post-administration. In oral dosage of 10, 20 and 40 mg/kg, it's peak concentrations were <TEX>$3.62{\pm}0.97$</TEX>, <TEX>$5.20{\pm}0.70$</TEX> and <TEX>$11.18{\pm}0.87{\mu}g/ml$</TEX>, respectively at 10 h post-administration, but AM was not measurable at 144, 360 and 360 h post-administration, respectively. In intramuscular injection of 5, 10 and 20 mg/kg, it's peak concentrations were <TEX>$6.92{\pm}1.29{\mu}g/m1$</TEX>, <TEX>$9.89{\pm}2.22{\mu}g/ml$</TEX> and <TEX>$19.85{\pm}2.97{\mu}g/ml$</TEX>, respectively at 5 h post-administration, but AM was not measurable at 216, 264 and 264 h post-administration, respectively. In dipping of 10, 20 and 40 ppm, it's peak concentrations were <TEX>$4.39{\pm}1.10$</TEX>, <TEX>$9.57{\pm}1.51$</TEX> and <TEX>$11.61{\pm}1.92{\mu}g/ml$</TEX>, respectively at 3 h post-administration, but AM was not measurable at 264, 264 and 360 h post-administration, respectively. Therefore, the plasma distribution and elimination levels of AM in olive flounder were dosage-dependant manner in all administration routes.
Carbon Nanotubes: An Example of Multiscale Development—A Mechanistic View from the Subnanometer to the Meter Scale (2013)

We summarize the catalytic synthesis of multiwall carbon nanotubes (MWCNTs). The current understanding of the reaction mechanism is presented, in particular the catalyst design for the CCVD process is analyzed. To complement that, kinetics and reaction engineering aspects are discussed along with the impact of the reaction and reactor operation on the product properties. All these issues are analyzed from the perspective of the industrial synthesis and implications for the application of carbon nanotubes. Carbon-nanotube technology is a perfect example of multi-scale development and covers challenges from the nanometer to the meter scale. Problems, methods, and solutions characteristic for different scales will be highlighted. The Co/Mn catalyst is used as reference as one of the first commercially used technologies for the scalable production of multiwall carbon nanotubes.
Underwater sound radiation from a spherical bubble cloud encapsulated by a thin spherical shell (1997)

Measurements of sound transmission versus frequency are performed (in the Rickover Hall Hydrodynamics Tow Tank Facility) for a submerged spherical bubble cloud that is encapsulated by a thin spherical shell. The bubble cloud is driven by a miniature spherical PZT transducer unit that is suspended in the center. A theoretical model has been developed which predicts the resonant frequencies for the case where the shell thickness has negligible effect. Therefore, the resonances will depend on the radius of the cloud and the sound speed in the bubbly media (which is a function of the air volume void fraction). A shell of urethane elastomer is molded as a single piece by using the ‘‘lost wax technique.’’ Hemispherical molds are used. The first set is for making the ‘‘inner’’ spherical wax ball. The second set forms the ‘‘outer’’ boundary of the casting for the spherical shell with filling ports on the north and south poles. The shell’s inner wax material is then melted out to complete the process. The shell is nearly acoustically transparent since ρ=1.03 g/cm3, clong∼1450 m/s and ctran∼70 m/s. The bubbly fluid consists of castor oil that has been whipped in a microblender.
DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge (2017)

Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.
Mechanism of murine epidermal maintenance: Cell division and the voter model (2008)

The dynamics of a genetically labeled cell population may be used to infer the laws of cell division in mammalian tissue. Recently, we showed that in mouse tail skin, where proliferating cells are confined to a two-dimensional layer, cells proliferate and differentiate according to a simple stochastic model of cell division involving just one type of proliferating cell that may divide both symmetrically and asymmetrically. Curiously, these simple rules provide excellent predictions of the cell population dynamics without having to address the cells' spatial distribution. Yet, if the spatial behavior of cells is addressed by allowing cells to diffuse at random, one deduces that density fluctuations destroy tissue confluence, implying some hidden degree of spatial regulation of cell division. To infer the mechanism of spatial regulation, we consider a two-dimensional model of cell fate that preserves the overall population dynamics. By identifying the resulting behavior with a three-species variation of the voter model, we predict that proliferating cells in the basal layer should cluster. Analysis of empirical correlations of cells stained for proliferation activity confirms that the expected clustering behavior is indeed seen in nature. As well as explaining how cells maintain a uniform two-dimensional density, these findings present an interesting experimental example of voter-model statistics in biology.
Studies on Antibiotics and Related Substances. III. Oxazolidines Derived from Some α-Hydroxy Schiff Bases and a Synthesis of Dl-threo-1-p-Nitrophenyl-2-amino-1,3-propanediol (1956)

Abstract 1) When Erlenmeyer’s β-phenylserine ethyl ester was reduced with Raney nickel catalyst, Dl-threo-1-phenyl-2-benzylideneamino-1, 3-propanediol (a Schiff base) was obtained as a main product. The structure was demonstrated by means of its infrared and ultraviolet absorption spectra. 2) It was found that Dl-threo-1-phenyl-2-benzylideneamino-1, 3-propanediol gave Dl-threo-N-acetyl-2-phenyl-4-(α-hydroxybenzyl) oxazolidine on acetylation with acetic anhydride. 3) The condensation products of Dl-threo-1-phenyl-2-amino-1, 3-propanediol and Dl-threo-1-p-nitrophenyl-2-amino-1, 3-propanediol with benzaldehyde, o-, m- and p-nitrobenzaldehyde were prepared and acetylated to give corresponding oxazolidine derivatives, which failed to hydrolyze under Kunz’s conditions. Infrared and ultraviolet absorption spectra of some of these compounds were observed. Acetylated derivatives failed to show the characteristic absorption of (Remark: Graphics omitted.) bond in the 1660–1610 cm−1 region. 4) Dl-Chloramphenicol was synthesized from Dl-threo-N-acetyl-2-phenyl-4-(α-hydroxybenzyl)oxazolidine.
Toward Mid-Infrared Ultra-Short Pulse Generation in a Gas-Filled Hollow-Core Photonic Crystal fiber (2021)

We numerically show that when a gas filled hollow-core photonic crystal fiber is pumped by two-color pulses, an ultra-short pulse can be generated in the mid-infrared. This phenomenon is due to the cascaded nonlinear phenomenon starting from a spectral broadening of the two pulses combined with an induced phase-matched four wave-mixing lying in the mid-infrared, with a dispersive wave. By selecting the mid-infrared band with a bandpass filter, we demonstrate the generation of 60 fs pulses at 3-4 µm and an ultra-short pulse duration of 20 fs can be reached with additional phase compensator.