gebhart/patrepeval huggingface dataset:
Characterization of novel selective positive allosteric modulators (PAMS) of the M4 muscarinic acetylcholine receptor (mAChR) (2008)

Resent clinical studies have revealed that the M 1 /M 4 preferring mAChR agonist xanomeline induces a robust antipsychotic effect in schizophrenic patients, suggesting that mAChR agonists may be efficacious in reducing psychotic symptoms in patients suffering from a variety of neurodegenerative and psychiatric disorders. Nevertheless, a lack of highly selective compounds has made it impossible to conclusively verify whether one or both of these receptor subtypes is responsible for mediating these observed clinical effects. Previous compounds developed to selectively activate mAChR receptors have failed in clinical development due to a lack of true specificity and adverse effects associated with activation of peripheral M 2 and M 3 mAChR subtypes. Here we report characterization of a series of novel, selective M4 PAMs which do not activate the receptor directly, but dramatically potentiate activation of the receptor by its natural agonist, acetylcholine. These novel M 4 ‐selective agents can now be utilized as tools to ascertain whether selective potentiation of the M4 mAChR will mimic the in vivo effects of traditional orthosteric agonists and, more importantly, to rigorously test the hypothesis that activation of M 4 has effects in animal models predictive of antipsychotic efficacy in humans. This work supported by NIMH grants MH073676‐01A1,1 F32 MH079678‐01, 1 F31 MH80559‐01 and 5T90DA022873‐02.
Chlorination of 3,4,5‐trichloropyridazin‐6‐one and synthesis of 3,4,5‐trichloro‐1‐(4,5,6‐trichloropyridazin‐3‐yl)pyridazin‐6‐one (2000)

Abstract This paper presents the chlorination of 3,4,5‐trichloropyridazin‐6‐one and the synthesis of 3,4,5‐trichloro‐1‐(4,5,6‐trichloropyridazin‐3‐yl)pyridazin‐6‐one.
Current CRISPR gene drive systems are likely to be highly invasive in wild populations (2018)

Recent reports have suggested that self-propagating CRISPR-based gene drive systems are unlikely to efficiently invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption for population alteration drives. Our models show that although resistance prevents spread to fixation in large populations, even the least effective drive systems reported to date are likely to be highly invasive. Releasing a small number of organisms will often cause invasion of the local population, followed by invasion of additional populations connected by very low rates of gene flow. Hence, initiating contained field trials as tentatively endorsed by the National Academies report on gene drive could potentially result in unintended spread to additional populations. Our mathematical results suggest that self-propagating gene drive is best suited to applications such as malaria prevention that seek to affect all wild populations of the target species.
Organocatalytic Enantioselective Aminosulfenylation of α,β‐Unsaturated Aldehydes (2008)

Dominotheorie: Eine einfache, hoch enantioselektive organokatalytische Aminosulfenylierung von α,β-ungesättigten Aldehyden liefert in hohen Ausbeuten und mit 93 bis >99 % ee orthogonal geschützte β-Amino-α-mercaptoaldehyde (siehe Schema). Diese katalytischen Umsetzungen belegen, dass es möglich ist, alle Komponenten eines Elektrophils, das ein Nucleofug enthält, effizient in organokatalytischen Dominoreaktionen mit Enalen zu nutzen. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
AASERT-93: New High-Pressure Diagnostic Technique (1994)

As we outlined in our submitted proposal, progress towards making DFWM spectroscopy quantitative has been achieved. This work makes explicit how the magnitude of the DFWM signal depends on the polarizations of the three incident beams under the weak and strong-field limits. We have been using DFWM to investigate acetylene (C2H2) and methyl radical (CH3) molecules in an atmospheric pressure flame and in a low-pressure hot-filament reactor. To calibrate the measurement, acetylene is measured in the free flow of a C2H2/O2 mixture, and also in the pre-reaction zone of a C2H2/O2 flame-both with a fast flow rate of 40-50 m/s at the nozzle outlet of the mixture. The DFWM signal falls in the weak field limit (far from saturation), which means the DFWM signal is proportional to the products of the three incident beam intensities (IfIbIp).
Thermal probe nanolithography: in-situ inspection, high-speed, high-resolution, 3D (2013)

Heated tips offer the possibility to create arbitrary high-resolution nanostructures by local decomposition and evaporation of resist materials. Turnaround times of minutes are achieved with this patterning method due to the high-speed direct-write process and an in-situ imaging capability. Dense features with 10 nm half-pitch can be written into thin films of organic resists such as self-amplified depolymerization (SAD) polymers or molecular glasses. The patterning speed of tSPL has been increased far beyond usual scanning probe lithography (SPL) technologies and approaches the speed of Gaussian shaped electron beam lithography (EBL) for &lt;30 nm resolution. A single tip can write complex patterns with a pixel rate of 500 kHz and a linear scan speed of 20 mm/s. Moreover, a novel scheme for stitching was developed to extend the patterning area beyond the &le;100 &mu;m range of the piezo stages. A stitching accuracy of 10 nm is obtained without the use of markers. Furthermore, the patterning depth can be controlled independently and accurately (~1 nm) at each position. Thereby, arbitrary 3D structures can be written in a single step. Finally, we demonstrated an all-dry tri-layer pattern transfer concept to create high aspect ratio structures in silicon. Dense fins and trenches with 27 nm half-pitch and a line edge roughness (LER) below 3nm (3&sigma;) have been fabricated.
Etude des premiers stades de l’insertion d’hélium dans le tungstène : apport du couplage entre simulation numérique et caractérisation NRA/PAS des échantillons implantés (2018)

International audience
On the problem of predicting inflationary perturbations (1997)

We examine the theoretical foundations of standard methods for computing density perturbations in inflationary models. We find that: (1) the time-delay formalism (introduced by Guth and Pi [Phys. Rev. Lett. 49 (1982) 1110]) is only valid when inflation is well-described by the de Sitter solution and the equation-of-state is nearly unchanging; and, (2) the horizon-crossing/Bessel approximation extends to non-exponential inflation, but only if the equation-of-state is changing slowly. Integration of the gauge-invariant perturbation equations mode-by-mode is the only method reliable for general models. For models with rapidly varying equation-of-state, the correction leads to significantly different predictions for the microwave background anisotropy. An important corollary is that methods proposed for “reconstruction” of the inflaton potential from anisotropy data are unreliable for general models.
Impact of composition and structure of Al alloy electrodes to power durability of SAW devices (2014)

This paper reviews power durability of SAW filters in terms of its dependence on temperature and input power, and discusses how composition and structure of Al alloy electrodes affect power durability. First, the time to fail (TF) measurement is discussed. It is shown that change of the frequency response must be taken into account for the acceleration test. This is because excess temperature causes shift of the passband. Difference of the chip temperature with the environment must be also considered. Two types of four layer electrodes (AlMgCu/Ti/AlMgCu/Ti and AlScCu/Ti/AlScCu/Ti) are used for the discussion. Series of power durability tests are performed for 800 MHz and 1.9 GHz SAW devices, and we reveal how choice of the additives, their content and layer thicknesses influence behavior of the Al migration and affect the TF performances.
X-Ray determination of the molecular structure of a 3-o-chlorophenylisoxazoline derivative of pyrethrosin (1971)

The structure of pyrethrosine is deduced from an X-ray study of the adduct formed between pyrethrosin and o-chlorobenzonitrile oxide.
Diagnosis and treatment of dementia: 2. Diagnosis (2008)

The diagnosis of dementia remains clinically integrative based on history, physical examination and brief cognitive testing. A number of core laboratory tests are also recommended. Structural neuroimaging is advised in selected cases. Other diagnostic approaches, including functional neuroimaging, neuropsychological testing and measurement of biomarkers, have shown promise but are not yet recommended for routine use by family physicians.
The Use of Human Adipose‐Derived Stem Cells in the Treatment of Physiological and Pathological Vulvar Dystrophies (2016)

"Vulvar dystrophy" is characterized by chronic alterations of vulvar trophism, occurring in both physiological (menopause) and pathological (lichen sclerosus, vulvar graft-versus-host disease) conditions. Associated symptoms are itching, burning, dyspareunia and vaginal dryness. Current treatments often do not imply a complete remission of symptoms. Adipose-Derived Stem Cells (ADSCs) injection represents a valid alternative therapy to enhance trophism and tone of dystrophic tissues. We evaluated efficacy of ADSCs-based therapy in the dystrophic areas. From February to April 2013 we enrolled 8 patients with vulvar dystrophy. A biopsy specimen was performed before and after treatment. Digital photographs were taken at baseline and during the follow-up. Pain was detected with Visual Analogue Scale and sexual function was evaluated with Female Sexual Function Index. All patients received 2 treatments in 3 months. Follow-up was at 1 week , 1 and 3 months, and 1 and 2 years. We obtained a significant vulvar trophism enhancement in all patients, who reported pain reduction and sexual function improvement. Objective exam with speculum was easy to perform after treatment. We believe ADSCs-based therapy finds its application in the treatment of vulvar dystrophies, since ADSCs could induce increased vascularization due to their angiogenic properties and tissue trophism improvement thanks to their eutrophic effect.
Assigning channels by link directionality in a medium access control protocol for IEEE 802.11 ad hoc networks (2009)

This study attempts to exploit the potential of link directionality to increase the achievable capacities of ad hoc networks. When an IEEE 802.11 ad hoc network achieves capacity C by using a single channel, the targeted capacity by using two channels should be 2C. However, most of the dual-channel 802.11 protocols proposed in the literature appear only to be able to achieve less than 60% of the 2C targeted capacity. The authors thus propose a link-directionality-based dual-channel medium access control protocol in an attempt to double the capacities of networks using the single-channel IEEE 802.11 protocol. The main idea is to assign channels according to link directionality to allow a link to transmit simultaneously within the carrier-sensing region of another link provided that these transmissions do not interfere with each other. Simulations show that our proposed scheme can achieve more than 85% of our targeted capacities, 0.85×2C=1.7C, in large-scale random topologies. In lattice and irregular topologies, the throughput is boosted up to 2.83C and 2.13C, respectively. An approach for capacity analysis is also introduced to determine the throughput improvements that can be achieved by our proposed protocol. We believe using link directionality for channel allocations is a key step that yields significant potential for multiplying the capacity of ad hoc networks.
Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432 (2022)

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (<b>41</b>) as an oral candidate quality molecule.
SLGAN (2022)

There are five features to consider when using generative adversarial networks to apply makeup to photos of the human face. These features include (1) facial components, (2) interactive color adjustments, (3) makeup variations, (4) robustness to poses and expressions, and the (5) use of multiple reference images. To tackle the key features, we propose a novel style- and latent-guided makeup generative adversarial network for makeup transfer and removal. We provide a novel, perceptual makeup loss and a style-invariant decoder that can transfer makeup styles based on histogram matching to avoid the identity-shift problem. In our experiments, we show that our SLGAN is better than or comparable to state-of-the-art methods. Furthermore, we show that our proposal can interpolate facial makeup images to determine the unique features, compare existing methods, and help users find desirable makeup configurations.
Shared Services Transformation: Conceptualization and Valuation from the Perspective of Real Options (2009)

ABSTRACT In today's volatile global economy, where many organizations face severe pressure to downsize, the “shared services” model, in which a firm merges common functions performed by multiple units into a single service delivery organization, provides an innovative approach to make business more efficient and effective. To successfully implement shared services, firms need to strategically decide whether and how to pursue various service transformation alternatives such as simplification, standardization, consolidation, insourcing, or outsourcing. In this study, we develop the notion of real options into a unique theoretical lens for conceptualizing service organizations and their transformation in an uncertain business environment. Specifically, we view service organization as a set of strategic options that give the firm preferential access to future transformation opportunities. We create a taxonomy of these options, and introduce a decision methodology for valuing alternative shared services transformation approaches. We illustrate this methodology by applying it in a real business case to justify a global firm's decision regarding the transformation of its finance organization.
Cascade Reactions for Sustainable Conversion of Fatty Acid Methyl Esters (2010)

verdampfung lsst sich Heizdampf erzeugen, mit dem sich die Mehreffektverdampfung (MED), auch in der Verfahrensvariante mit thermischer Brdenverdichtung (MED-TVC), betreiben lsst. Alternativ kann die
Single image shadow removal via detection-free spatially adaptive denormalization (2021)

Removing shadows in a single image has been a challenging problem because shadows can appear in various forms due to complex physical situations, influenced by many factors such as light sources and the material’s transparency. In order to remove shadows precisely, most previous works utilized shadow mask information, which indicates the shadow region in a given image using binary representation. However, shadow mask utilization inevitably induces multiple problems, including shadow removal performance dependency and additional shadow detection process requirements. To solve these problems, the proposed algorithm is based on an image-to-image translation algorithm, which does not require additional shadow mask information. In this deep neural network , the convergence of fast learning is induced by utilizing various normalization layers. However, in a case that is very sensitive to various spatial features of an input image, such as shadow removal, the normalization process causes a problem of losing a large amount of information existing in the input image data. So, we utilize spatially adaptive denormalization(SPADE) to prevent loss of spatial features of input image data. Therefore, not only does it fundamentally solve the problem that various feature information constituting the input image is lost in the normalization process, but also enables precise shadow region removal by combining the feature map of multi-resolutions with the feature map of the decoder. In evaluation, the proposed algorithm shows that it exceeds the existing approach by about 20~30% in both PSNR and RMSE based on the ISTD large data set.
Crafting plaster through continuous mobile robotic fabrication on-site (2020)

Abstract Industrialization of architectural components and technological advances have had a significant impact on how we design and build. These developments, resulting in mass-produced and panelized architectural components, have rationalized building construction. However, they often do not reveal the true potential of the inherent qualities of malleable materials. This research investigates the bespoke design potentials of combining a cementitious plaster, with a robotic spraying and forming process, and proposes an adaptive thin-layer additive manufacturing method for plasterwork. Research goals address an on-site construction system that is capable of performing continuous robotic plaster spraying on building elements. To support the understanding of the complex-to-simulate material behavior in this process, systematic studies and physical testing are proposed to be conducted to collect empirical knowledge and data. The goal is to explore bespoke surface qualities, with minimal waste, moving away from the modular and standardized form of the material. The paper presents the preliminary results and findings of the method that aims addressing the challenge of an adaptive construction system capable of performing continuous fabrication, for which mobile robots are proposed to be deployed.
Dimerization of the Conserved N-Terminal Domain of a Spider Silk Protein Controls the Self-Assembly of the Repetitive Core Domain (2017)

Spider silk proteins comprise a repetitive core domain with polyalanine and glycine/proline-rich stretches flanked by highly conserved nonrepetitive N- and C-terminal domains. The termini are responsive to assembly triggers, sensing changes in the ionic (H<sup>+</sup>, phosphate) and mechanical (shear stress) environment along the spinning duct. The N-terminal domain dimerizes in a pH-dependent manner induced by protonation of conserved acidic residues. To date, dimerization of N-terminal spider silk domains has been individually investigated in the absence of large core domains. In this work, the impact of an engineered 50 kDa (AQ) core domain was studied on N-terminal dimerization by circular dichroism, fluorescence and absorbance spectroscopy, multiangle light scattering, as well as scanning electron and transmission electron microscopy. Although the core domain showed no apparent influence on the dimerization behavior of the N-terminal domain, the N-terminal domain in contrast influenced the behavior of the core domain: the monomeric state enhanced (AQ)'s solubility, and dimer formation triggered self-assembly. The monomer-dimer equilibrium was influenced by using several previously established mutants, confirming these results. This work thereby provides molecular insights into how key residues of the N-terminal domain control the dimerization-mediated transformation of soluble spidroins into fibrillary assemblies.
Safety and activity of CLN-081 (TAS6417) in NSCLC with EGFR Exon 20 insertion mutations (Ins20). (2021)

9077 Background: NSCLC with EGFR ins20 represents a significant area of unmet need, with no approved targeted therapies. While several agents targeting EGFR ins20 are in development, wild-type (WT) EGFR-related adverse events (AEs) have been common and challenging to manage. CLN-081 is a novel oral EGFR TKI with broad activity against clinically relevant EGFR mutations, including ins20, and has attenuated activity against WT EGFR relative to EGFR ins20 in vitro, suggesting that CLN-081 may have a more favorable clinical therapeutic window. We present interim results of a multicenter, Phase (Ph) 1/2a trial evaluating CLN-081 in advanced, EGFR ins20 NSCLC (NCT04036682). Methods: Patients (pts) with EGFR ins20 previously treated with platinum-based therapy (tx) were eligible to enroll. Ph 1 dose escalation in this adaptive trial began with an accelerated titration (AT) design, and converted to a rolling six design based upon pre-specified safety criteria or at clinically active doses. Cohort expansion in Ph 1 occurred at any dose where responses were seen. Transition from Ph 1 to 2a was based on a Simon-Two Stage design. Prior tx with EGFR ins20-specific inhibitors was allowed in AT cohorts only. CLN-081 was dosed twice daily (BID) in 21-day cycles. Results: As of 10 November 2020, 37 pts [median age 64 years (44-82); median 2 (1-9) prior lines of tx] received CLN-081 at doses of 30 mg (n = 8), 45 mg (1), 65 mg (12), 100 mg (13), and 150 mg (3) BID. The most common all-grade (gr) treatment-related AEs (TRAEs) were rash (49%), diarrhea (24%), paronychia (16%), nausea (14%), stomatitis (14%), and dry skin (11%). Gr 3 TRAEs included anemia (5%), diarrhea (3%), and increased alkaline phosphatase (ALP) (3%). There was 1 DLT, gr 3 diarrhea at 150 mg BID. No gr ≥ 3 rash or gr 4/5 TRAEs were reported. Four pts (11%) required dose reductions for rash (2), diarrhea (1), and increased ALP (1). Two pts (5%) discontinued tx due to TRAEs of gr 2 hypersensitivity reaction (1) and gr 2 pneumonitis (1); the latter also experienced pneumonitis while receiving prior osimertinib. Among the 25 response evaluable pts (RECIST 1.1), 10 (40 %) had a partial response (PR) (6 confirmed, 2 pending confirmation, 2 unconfirmed), 14 (56%) had stable disease (SD), and 1 (4%) had progressive disease as best response. Of the 4 pts that received prior EGFR ins20 inhibitors, 2 had PR and 2 SD. Of pts with SD or PR as best response, 20/24 (83 %) experienced tumor regression [median regression: -18 % (-100 to +3)]. Enrollment is ongoing and updated data will be presented. Conclusions: CLN-081 has an acceptable safety profile, including diarrhea in &lt; 25% of pts treated to date. CLN-081 has demonstrated encouraging preliminary anti-tumor activity across the full dose range tested, in multiple distinct EGFR ins20 variants, and in heavily pre-treated pts that are either naïve or refractory to other EGFR ins20 inhibitors. Since the time of the data cut, a Ph 2a expansion has been initiated at 100 mg BID. Clinical trial information: NCT04036682.