gebhart/patrepeval huggingface dataset:
Integrated Assessment of the Clinical Performance of GalNAc 3 -Conjugated 2′- O -Methoxyethyl Chimeric Antisense Oligonucleotides: I. Human Volunteer Experience (2018)

Advances in medicinal chemistry have produced new chemical classes of antisense oligonucleotides (ASOs) with enhanced therapeutic properties. Conjugation of the triantennary N-acetylgalactosamine (GalNAc<sub>3</sub>) moiety to the extensively characterized phosphorothioate (PS)-modified 2'-O-methoxyethyl (2'MOE) ASO exemplifies such an advance. This structure-activity optimized moiety effects receptor-mediated uptake of the ASO prodrug through the asialoglycoprotein receptor 1 to support selective targeting of RNAs expressed by hepatocytes. In this study we report the integrated assessment of data available from randomized placebo-controlled dose-ranging studies of this chemical class of ASOs administered systemically to healthy human volunteers. First, we compare the pharmacokinetic and pharmacodynamic profiles of a subset of the GalNAc<sub>3</sub>-conjugated PS-modified 2'MOE ASOs to the parent PS-modified 2'MOE ASOs for which plasma analytes are available. We then evaluate the safety profile of the full set of GalNAc<sub>3</sub>-conjugated PS-modified 2'MOE ASO conjugates by the incidence of signals in standardized laboratory tests and by the mean laboratory test results as a function of dose level over time. With hepatocyte targeted delivery, the ED<sub>50</sub> for the GalNAc<sub>3</sub>-conjugated PS-modified 2'MOE ASO subset ranges from 4 to 10 mg/week, up to 30-fold more potent than the parent PS-modified 2'MOE ASO. No GalNAc<sub>3</sub>-conjugated PS-modified 2'MOE ASO class effects were identified from the assessment of the integrated laboratory test data across all doses tested with either single or multidose regimens. The increase in potency supports an increase in the safety margin for this new chemical class of ASOs now under broad investigation in the clinic. Although the total exposure is limited in the initial phase 1 trials, ongoing and future investigations in patient populations will support evaluation of the effects of long-term exposure.
Ks0andΛproduction inppinteractions ats=0.9and 7 TeV measured with the ATLAS detector at the LHC (2012)

The production of ${K}_{S}^{0}$ and $\ensuremath{\Lambda}$ hadrons is studied in $pp$ collision data at $\sqrt{s}=0.9$ and 7 TeV collected with the ATLAS detector at the LHC using a minimum-bias trigger. The observed distributions of transverse momentum, rapidity, and multiplicity are corrected to hadron level in a model-independent way within well-defined phase-space regions. The distribution of the production ratio of $\overline{\ensuremath{\Lambda}}$ to $\ensuremath{\Lambda}$ baryons is also measured. The results are compared with various Monte Carlo simulation models. Although most of these models agree with data to within 15% in the ${K}_{S}^{0}$ distributions, substantial disagreements are found in the $\ensuremath{\Lambda}$ distributions of transverse momentum.
Atomic Layer Deposition in a Metal–Organic Framework: Synthesis, Characterization, and Performance of a Solid Acid (2017)

NU-1000, a zirconium-based metal–organic framework (MOF) featuring mesoporous channels, has been postsynthetically metalated via atomic layer deposition in a MOF (AIM) employing dimethylaluminum iso-propoxide ([AlMe2OiPr]2, DMAI), a milder precursor than widely used trimethylaluminum (AlMe3, TMA). The aluminum-modified NU-1000 (Al-NU-1000) has been characterized with a comprehensive suite of techniques that points to the formation of aluminum oxide clusters well dispersed through the framework and stabilized by confinement within small pores intrinsic to the NU-1000 structure. Experimental evidence allows for identification of spectroscopic similarities between Al-NU-1000 and γ-Al2O3. Density functional theory modeling provides structures and simulated spectra, the relevance of which can be assessed via comparison to experimental IR and EXAFS data. The catalytic performance of Al-NU-1000 has been benchmarked against γ-Al2O3, with promising results in terms of selectivity.
1123. EDP-235, A Potent and Once-daily Oral Antiviral, Demonstrates Excellent Penetration into Macrophages and Monocytes, with the Potential for Mitigation of Cytokine Storm in High-Risk COVID-19 Patients (2022)

Abstract Background Macrophages, including lung alveolar macrophages (AM), and monocytes are the first lines of defense against SARS-CoV-2. Several reports have suggested that SARS-CoV-2 can hijack AM and monocytes for replication and viral spread, which may, in turn, drive the cytokine storm associated with severe COVID-19. Herein, we describe one of many advantageous features that EDP-235, a novel and potent SARS-CoV-2 3C-like protease (3CLpro) inhibitor under development as a once-daily oral antiviral therapy for COVID-19, displays - excellent penetration into macrophages and monocytes. Methods Intracellular uptake of EDP-235 was tested side-by-side with nirmatrelvir in rat lung AM, human monocytes and human macrophages. To determine the in vivo drug distribution into lung AM, rats were dosed orally with 25 mg/kg of EDP-235 or nirmatrelvir and plasma and AM drug levels were analyzed by LC/MS/MS. Results The ratios of intracellular to extracellular concentrations of EDP-235 in rat lung AM, human monocytes and human macrophages were 22.8, 22.7 and 30.5, respectively. In contrast, nirmatrelvir had ratios of 1.2 to 1.5 in these cells. Consistent with the in vitro observations, EDP-235 showed favorable rat AM penetration with an AUC0-24 ratio of 28.4 (AM over plasma), and nirmatrelvir had much less rat AM penetration with an AUC0-24 ratio of 0.5 (AM over plasma). EDP-235 had respective AUC0-24 values of 9.6 and 271.9 h·μg/mL in rat plasma and AM, while the AUC0-24 values of nirmatrelvir in rat plasma and AM were 2.7 and 1.2 h·μg/mL, respectively. Conclusion EDP-235, a novel and potent SARS-CoV-2 3CL protease inhibitor, demonstrated excellent penetration into monocytes and macrophages, including lung AM. EDP-235 has the potential to eliminate the viral replication of SARS-CoV-2 in these critical immune cells, thus mitigating macrophage-mediated cytokine storm in high-risk COVID-19 patients. Clinical trials with EDP-235 for COVID-19 treatment and prevention are ongoing. Disclosures All Authors: No reported disclosures.
GABAergic modulation in central sensitization in humans (2015)

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.
2-Methyl-6-nitrobenzoic Anhydride (MNBA) (2009)

[434935-69-0] C16H12N2O7 (MW 344.28) InChI = 1S/C16H12N2O7/c1-9-5-3-7-11(17(21)22)13(9)15(19)25-16(20)14-10(2)6-4-8-12(14)18(23)24/h3-8H,1-2H3 InChIKey = YEKPNMQQSPHKBP-UHFFFAOYSA-N (reagent used as a coupling promoter to produce esters, lactones, amides, and peptides) Physical Data: mp 178–180 °C. Solubility: sol alcohol, ether, and most organic solvents. Form Supplied in: a white solid; commercially available (TCI, Aldrich). Analysis of Reagent Purity: IR (KBr): 1759, 1820 cm−1; 1H NMR (CDCl3): δ 2.57 (6H, s), 7.53 (2H, dd, J = 7.6, 8.1 Hz), 7.64 (2H, d, J = 7.6 Hz), 8.06 (2H, d, J = 8.1 Hz); 13C NMR (CDCl3) δ 19.1, 121.7, 127.5, 130.5, 136.6, 137.9, 145.1, 160.3; anal calcd for C16H12N2O7: C, 55.82; H, 3.51; N, 8.14; found: C, 55.81; H, 3.39; N, 8.07. Preparative Methods: A solution of 2-methyl-6-nitrobenzoic acid (5.00 g, 27.6 mmol) and thionyl chloride (20.1 mL, 276 mmol) in dichloromethane (50 mL) was stirred for 15 h at room temperature (eq 1). The solvent and thionyl chloride were distilled under reduced pressure at 50 °C and then dichloromethane (40 mL), 2-methyl-6-nitrobenzoic acid (5.00 g, 27.6 mmol), and pyridine (2.40 mL, 30.4 mmol) were successively added at 0 °C. After the reaction mixture had been stirred for 24 h at room temperature, cooled water (100 mL) was added at 0 °C. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated aqueous copper(II) sulfate, saturated aqueous sodium hydrogen carbonate, cold water, and brine, and dried over sodium sulfate. Filtration of the mixture and evaporation of the solvent under reduced pressure produced 8.80 g of the crude 2-methyl-6-nitrobenzoic anhydride (MNBA). The first recrystallization of the crude product from dichloromethane (ca. 90 mL) at 0 °C gave 7.70 g (81%) of pure MNBA as a white solid. (1) Purification: usable after recrystallization. Handling, Storage, and Precautions: stable after recrystallization under argon or nitrogen atmosphere.
Fluctuation Effects on a Strongly Pinned Vortex Lattice in a Thin Type-II Superconducting Wire (1995)

We report on transport properties of the vortex lattice in fine, round NbTi wires fabricated by a novel wire-drawing process. The voltage onset in the isothermal $I\ensuremath{-}V$ characteristic is sharp for thick wires ($d\ensuremath{\ge}1$ \ensuremath{\mu}m) at 4.2 K and 6 T, but is rounded for thinner wires. The thinnest wires also display an Ohmic resistivity at low current densities. This linear resistivity decreases exponentially with temperature near ${T}_{c}(H)$ and approaches a constant value at low temperatures. We explain our results as finite size effects of the thermal and quantum collective creep of vortex lines.
Endomicroscopie d'autofluorescence appliquée à l'exploration bronchique et alvéolaire photoniques (2010)

International audience
Lesion Detection in Breast Ultrasound Images Using Tissue Transition Analysis (2014)

Breast cancer is one of the leading cause of cancer related deaths in women and early detection is crucial for reducing mortality rates. In this paper, we present a novel and fully automated approach based on tissue transition analysis for lesion detection in breast ultrasound images. Every candidate pixel is classified as belonging to the lesion boundary, lesion interior or normal tissue based on its descriptor value. The tissue transitions are modeled using a Markov chain to estimate the likelihood of a candidate lesion region. Experimental evaluation on a clinical dataset of 135 images show that the proposed approach can achieve high sensitivity (95 %) with modest (3) false positives per image. The approach achieves very similar results (94 % for 3 false positives) on a completely different clinical dataset of 159 images without retraining, highlighting the robustness of the approach.
22nm node ArF lithography performance improvement by utilizing mask 3D topography: controlled sidewall angle (2011)

To improve lithography performance, resolution enhancement technique (RET) such as source mask optimization (SMO) will be applied to 22 nm node and beyond. We examine if lithography performance is improved by altering mask 3D topography. In this paper, we report that we have confirmed what topography is effective for lithography performance improvement in the dense region of 22nm technology node. Since shadowing effect is strong at the dense region, we focus on sidewall angle that decreases shadowing effect. As a basic analysis, we evaluate maximum exposure latitude (EL) and mask error enhancement factor (MEEF) of mask 3D topographic patterns that have various sidewall angles by 3D rigorous simulator. This result shows the increasing of maximum exposure latitude when changing sidewall angle. As a next step, we fabricate a test mask which has optimized sidewall angle and the exposure is performed on NA1.30 immersion scanner (Nikon NSR-S610C). Then we compare wafer printing results and simulation results. These results induce that the optimization of mask 3D topography has a potential to improve lithographic performance.
Bend ribbon-forming tetrahydrofuran amino acidsThis is one of a number of contributions from the current members of the Dyson Perrins Laboratory to mark the end of almost 90 years of organic chemistry research in that building, as all its current academic staff move across South Parks Road to a new purpose-built laboratory. (2003)

Short oligomeric chains of C-glycosyl beta-D-arabinofuranose configured tetrahydrofuran amino acids (where the C-2 and C-5 substituents of the tetrahydrofuran ring are cis to each other) exhibit a well-defined repeating turn secondary structure stabilised by (i, i - 2) inter-residue hydrogen bonds. This is in contrast to the epimeric alpha-D-arabinofuranose oligomer (where the C-2 and C-5 substituents of the tetrahydrofuran ring are trans to each other) in which there is no indication of any secondary structure in solution.
A Monoterpene Glucoside and Three Megastigmane Glycosides from Juniperus communis var. depressa (2005)

A new monoterpene glucoside (1) and three new natural megastigmane glycosides (2-4) were isolated along with a known megastigmane glucoside (5) from twigs with leaves of Juniperus communis var. depressa (Cupressaceae) collected in Oregon, U.S.A., and their structures were determined on the basis of spectral and chemical evidence. In addition, the antibacterial activities of the isolated components against Helicobacter pylori were also investigated.
Trefoil Factor–2 Reverses Airway Remodeling Changes in Allergic Airways Disease (2012)

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.
Metal-carbonyl syntheses. 9. Carbon monoxide - a six-electron ligand? Synthesis and structural characterization of the unusual carbonylniobium cluster heptacarbonyltris(.eta.5-cyclopentadienyl)triniobium (1981)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMetal-carbonyl syntheses. 9. Carbon monoxide - a six-electron ligand? Synthesis and structural characterization of the unusual carbonylniobium cluster heptacarbonyltris(.eta.5-cyclopentadienyl)triniobiumWolfgang A. Herrmann, Helmut Biersack, Manfred L. Ziegler, Klaus Weidenhammer, Rolf Siegel, and Dieter RehderCite this: J. Am. Chem. Soc. 1981, 103, 7, 1692–1699Publication Date (Print):April 1, 1981Publication History Published online1 May 2002Published inissue 1 April 1981https://doi.org/10.1021/ja00397a018Request reuse permissionsArticle Views431Altmetric-Citations104LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-Alertsclose Get e-Alerts
Generation of a Tumor-Specific Chemokine Gradient Using Oncolytic Vesicular Stomatitis Virus Encoding CXCL9 (2019)

Genetically modified vesicular stomatitis virus (VSV) is an attractive agent for cancer treatment due to rapid intratumoral replication and observed clinical responses. Although VSV selectively kills malignant cells and can boost antitumor immunity, limited induction of intratumoral immune infiltration remains a barrier to efficacy in some cancer models. Here we engineered the oncolytic VSV platform to encode the T cell chemokine CXCL9, which is known to mediate the recruitment of activated CD8<sup>+</sup> cytotoxic T cells and CD4<sup>+</sup> T helper cells, and demonstrates conserved protein function between mice and humans. Chemotactic activity of the virally encoded chemokine was confirmed <i>in vitro</i>. Intratumoral concentration of CXCL9 was shown to increase after VSV therapy in three different cancer models, but to a much greater degree after VSV-CXCL9 therapy as compared with VSV control viruses. Despite a steep chemokine gradient from the tumor to the bloodstream, tumor trafficking of adoptively transferred and endogenous T cells was not measurably increased following VSV-CXCL9 therapy. Our results indicate that oncolytic VSV infection promotes release of CXCL9 in the tumor microenvironment, but further boosting of the functional chemokine gradient through virus engineering has little incremental impact on intratumoral immune cell infiltration in mouse and human tumor models.
High quality factor and high confinement silicon resonators using etchless process (2012)

We demonstrate high quality factor and high confinement in a silicon ring resonator fabricated by a thermal oxidation process. We fabricated a 50 μm bending radius racetrack resonator, with a 5 μm coupling region. We achieved an intrinsic quality factor of 760,000 for the fundamental TM mode, which corresponds to a propagation loss of 0.9 dB/cm. Both the fundamental TE and TM modes are highly confined in the waveguide, with effective indices of 3.0 for the TE mode and 2.9 for the TM mode.
Effect of basal epicardial tone on endothelium‐independent coronary flow reserve measurement (1998)

Increased basal epicardial tone may attenuate the coronary flow reserve (CFR) by causing vasodilatation of resistance vessels. We examined the effect of basal epicardial tone on the endothelium-independent CFR measurements in subjects with nonobstructive coronary disease. Patients underwent evaluation of endothelium-independent CFR using adenosine (18-36 microg) and endothelium-dependent CFR using acetylcholine (10(-6) M-10(-4) M), both administered intracoronary. CFR to adenosine, presented as the ratio of Doppler flow velocities post- and pre-adenosine, was measured at baseline and after intracoronary nitroglycerin (200 microg). Nitroglycerin increased the coronary artery diameter by 19.7 +/- 2.5%, and decreased the coronary vascular resistance from 3.0 +/- 0.2 mm Hg/ml/min to 1.8 +/- 0.1 mm Hg/ml/min (p < 0.0001). The response to adenosine at baseline and after nitroglycerin was similar (CFR ratio of 2.52 +/- 0.09 and 2.57 +/- 0.10, respectively, p = NS). The effect of nitroglycerin on the response to adenosine did not correlate with coronary endothelial function (r2 = 0.06, p = 0.13). The basal epicardial tone does not affect CFR measurements in patients with angina and nonobstructive coronary disease.
Plasma Wakefield Effects On High-current Relativistic Electron Beam Transport In The Ion Focus Regime (1991)

A relativistic electron beam injected into a preionized plasma channel immersed in a low density background plasma causes both channel electrons and plasma electrons to be ejected by the electrostatic force of the beam head out to the charge neutralization radius. Typically the ejected electrons will overshoot this radius and the resulting charge imbalance causes them to oscillate at a frequency near that of the electron plasma frequency of the low-density background plasma. These radial plasma oscillations produce an electrostatic wakefield with electric field components that lead to beam energy and current modulation. In the experiment, a 1. 7 MeV, 6 kA, 30 ns electron beam produced by a Febetron 705 is passed through a beam risetime sharpener and matched onto a laser produced IFR channel. The risetime sharpener cell uses a single magnetic lens to preferentially focus the high energy portion of the beam at an aperture. This results in a 1 kA electron beam exiting the risetime sharpening cell with a 5 ns risetime and a 13 ns flattop. This beam is matched onto a KrF laser ionized IFR channel in TMA. The channel provides a fractional charge neutralization, f<>e ≈ 0.8, sufficient to efficiently propagate the electron beam in the absence of a background plasma.