gebhart/patrepeval huggingface dataset:
Accelerated Discovery of Novel Ponatinib Analogs with Improved Properties for the Treatment of Parkinson’s Disease (2020)

Parkinson's disease (PD) is a debilitating and common neurodegenerative disease. New insights implicating c-Abl activation as a driving force in PD have opened a new drug development avenue for PD treatment beyond the symptomatic relief by L-DOPA. BCR-Abl inhibitors, which include nilotinib and ponatinib, have been found to inhibit this process, and nilotinib has shown improvement in outcomes in a 12-patient, nonrandomized trial. However, nilotinib is a potent inhibitor of hERG, a cardiac K<sup>+</sup> channel whose inhibition increases risk of sudden death. We used our machine learning approach to predict novel molecules that would inhibit c-Abl while also having minimal liability against hERG. Of our six novel compounds tested, we identified two that had c-Abl potencies comparable to nilotinib, but with significantly improved profiles regarding the hERG channel. Our best compound exhibited a hERG IC<sub>50</sub> of 12.1 μM (compared to nilotinib with an IC<sub>50</sub> of 0.45 μM and ponatinib with IC<sub>50</sub> of 0.767 μM). This work is a step forward for a machine learning enabled, multiparameter optimization of a chemical space and represents a significant advance in the development of novel Parkinson's therapies.
Modeling and Throughput Analysis of FSO Systems using GBN-ARQ and AR Transmission over Atmospheric Turbulence Channels (2018)

This paper addresses the error-control issue in free-space optical (FSO) communications. In particular, we model and analyze the throughput performance of FSO systems over atmospheric fading channel when the go-back-N (GBN) automatic repeat request (ARQ) and adaptive rate (AR) transmission schemes are employed. For this purpose, we first build the model to capture the time-varying behavior in atmospheric fading channels. We then use that channel model to develop the burst error model for GBN-ARQ with AR in order to analytically derive the system throughput. Numerical results quantitatively show the impacts of atmospheric turbulence on the throughput and confirm the effectiveness of the GBN/ARQ. Monte Carlo simulations are also performed to validate the analytical results.
Bacterial Quorum Sensing Signals Self-Assemble in Aqueous Media to Form Micelles and Vesicles: An Integrated Experimental and Molecular Dynamics Study (2020)

Many species of common bacteria communicate and coordinate group behaviors, including toxin production and surface fouling, through a process known as quorum sensing (QS). In Gram-negative bacteria, QS is regulated by <i>N</i>-acyl-l-homoserine lactones (AHLs) that possess a polar homoserine lactone headgroup and a nonpolar aliphatic tail. Past studies demonstrate that AHLs can aggregate in water or adsorb at interfaces, suggesting that molecular self-assembly could play a role in processes that govern bacterial communication. We used a combination of biophysical characterization and atomistic molecular dynamics (MD) simulations to characterize the self-assembly behaviors of 12 structurally related AHLs. We used static light scattering and measurements of surface tension to characterize the assembly of four naturally occurring AHLs (3-oxo-C8-AHL, 3-oxo-C12-AHL, C12-AHL, and C16-AHL) in aqueous media and determine their critical aggregation concentrations (CACs). MD simulations and alchemical free energy calculations were used to predict thermodynamically preferred aggregate structures for each AHL. Those calculations predicted that AHLs with 10 or 12 tail carbon atoms should form spherical micelles and that AHLs with 14 or 16 tail carbon atoms should form vesicles in solution. Characterization of solutions of AHLs using negative stain transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed aggregates with sizes consistent with spherical micelles or small unilamellar vesicles for 3-oxo-C12-AHL and C12-AHL and the formation of large vesicles (∼250 nm) in solutions of C16-AHL. These experimental findings are in general agreement with our simulation predictions. Overall, our results provide insight into processes of self-assembly that can occur in this class of bacterial amphiphiles and, more broadly, provide a potential basis for understanding how AHL structure could influence processes that bacteria use to drive important group behaviors.
The determination of longitudinal crystal moduli in polymers by spectroscopic methods (1985)

Abstract Experimental methods for determining longitudinal crystal moduli of polymers were evaluated in light of recent proceesing methods that produced macroscopic Young's moduli which exceeded ultimate values as found by the x‐ray diffraction method. The spectroscopic techniques of Raman and coherent inelastic neutron scattering yielded higher longitudinal crystal moduli than x‐ray diffraction, and from calculations described herein it is concluded that these spectroscopic values are better estimates of the maximum Young's moduli in fully aligned and crystalline polymeric materials.
Investigations on Thermal Stresses of a Graded Ti(C,N) Coating Deposited on WC-Co Hardmetal (2014)

We investigated the stress behaviour of Ti(C,N) coatings deposited on WC-Co substrates during an individual thermal cycle. The stress analyses were performed in-situ by energy dispersive X-ray diffraction using a white synchrotron beam. The stresses were determined using the sin 2 ψ method combined with scattering vector measurements at the strain-free ψ-tilt, in order to avoid the effect of the chemical C/N gradient on the strain distributions over sin 2 ψ. It was found that compressive stresses induced by top blasting on the coating are released after the individual thermal cycle. During heating and cooling, part of the Ti(C,N) coating was oxidized into a TiO 2 rutile phase. Stress analysis was also performed in this phase in order to evaluate the influence of oxidation on the residual stress of the coating. The obtained results can support the design of coated tools with improved properties at interrupted cutting operations by understanding the role of thermal cycling on the stresses of Ti(C,N) coatings.
Evaluating the Large Electromigration Resistance of Copper Interconnects Employing a Newly Developed Accelerated Life‐Test Method (1993)

An accelerated electromigration life‐test method has been developed to evaluate the large electromigration resistance of Cu interconnects in a very short period of test time. The essence of the acceleration technique employed here is to use stress current more than 107 A/cm2 and to utilize the self‐heating of the test interconnect for giving temperature stress. Moreover, to avoid uncontrollable thermal runaway and resultant interconnect melting, we adopted an efficient cooling technique that immediately removes the joule heat and keeps the interconnect temperature constant. As a result, it has been demonstrated that large grain copper interconnects created by a low‐kinetic‐energy particle process and the thermal annealing that follows exhibit approximately three orders of magnitude larger electromigration lifetime at 300 K than Al‐alloy interconnects formed by a conventional sputtering process. Additionally, a new expression for electromigration lifetime was proposed based on Black's equation through the comparative studies of electromigration endurance of various materials.
Somatic mutation in the ACK1 ubiquitin association domain enhances oncogenic signaling through EGFR regulation in renal cancer derived cells (2010)

Activated Cdc42-associated Kinase, ACK1, is a non-receptor tyrosine kinase with numerous interacting partners, including Cdc42 and EGFR. Gene amplification and overexpression of ACK1 were found in many cancer types such as those of the lung and prostate. Previously, we identified both somatic- and germ line missense mutations in the ACK1 coding sequence, by surveying 261 cancer cell lines and 15 control tissues. Here, we verified and characterized the non-synonymous mutation, ACK-S985 N, located in the ubiquitin association domain of the protein. Both overexpression and silencing experiments in MCF7 and A498 cells, respectively, demonstrated a role of the ACK1 S985 N mutation in enhancing cell proliferation, migration and anchorage-independent growth as well as the epithelial-mesenchymal transition. Further, we showed that the ACK1 S985 N mutant is unable to bind ubiquitin, unlike the wild type kinase. This contributed to ACK1 protein stability and stabilized EGFR after EGF stimulation, thereby prolonging mitogenic signaling in cancer cells. In addition, the ACK1 S985 N-EGFR interaction is enhanced, but not the ubiquitination of the receptor. Intriguingly, silencing of ACK1 in A498 cells sensitized the renal carcinoma cells to gefitinib, against which they are otherwise resistant. The work demonstrates that other than gene amplification, a single somatic mutation in ACK1 can result in extended protein stability enabling the oncoprotein to exert its oncogenic function in tumor progression. It also provides a rationale to target ACK1 in combination with other chemotherapeutic drugs, such as EGFR inhibitors, to potentiate therapeutic action against resistant tumors.
Development of a Hydrophobically Modified Water-Soluble Polymer as a Selective Bullhead System for Water-Production Problems (2003)

For many years, bullhead systems have received a great deal of attention from the oil and gas industry. Because of the completion techniques used in many wells, protecting the hydrocarbon interval effectively during a water control treatment is not always practical or cost-effective. Bullhead systems offer the option of a treatment without zonal isolation and are designed to decrease water production with little or no decrease in oil or gas production. This paper describes the laboratory development of a new polymer that shows promise as a bullhead system.The material falls into the class of hydrophobically modified water-soluble polymers; that is, a water-soluble polymer into which water-insoluble moieties have been introduced. The unique associative and adsorptive properties of this class of polymers are well documented, but they have not been commercially exploited to a great extent in oil field applications.These materials offer improvements over the hydrophilic polymers traditionally used for permeability modifications. For example, hydrophobic modification appears to improve cleanup of the polymer that penetrates an oil saturated core, resulting in less risk of damage to oil permeability. Hydrophobic modification, depending on the structural features, also increases reduction to water flow in comparison to the unmodified polymer. This paper includes a general description of hydrophobically modified polymers and their properties, as well as detailed descriptions of the development and laboratory testing of the new system.
Successful Acid-Fracturing in Adverse Conditions: Lessons Learnt and Integrated Evaluation in the Kharyaga Field (2006)

Abstract The Kharyaga field is located in Timan-Petchora region of Northern Russia, 60 km North of the Arctic Polar Circle. The field is producing principally from a Devonian age carbonate reservoir, this limestone formation having an average porosity of 8 to 12% and permeabilities ranging from 1 to 200 mD. The wells are completed as cased-hole, with a 7inch liner through the reservoir section. The perforated intervals range from 30 to 80 m in length and the wells were traditionally matrix-acid stimulated following perforation. The wells produced initially unassisted then later on, a work-over campaign was launched in order to equip the well with electrical submersible pumps (ESP). Work-over operations were taken as an opportunity to re-stimulate lower-performing wells of the field. Several options were considered for this purpose from mechanically-diverted acid squeeze to propped hydraulic-fracturing or acid-fracturing this later option being ultimately selected. However, the rather adverse conditions existing both downhole and at surface rendered such an operation quite challenging. In the first place, the tectonically active nature of this region (West of Ural) led to anticipate significantly high fracturing gradients and difficulties to initiate a fracturing regime. Secondly, the weather conditions, with surface temperatures ranging from +20°C in summer to -50°C in winter and logistical issues necessitated adjustments to the fracturing fluids and job design. Finally other factors such as a high tendency of the Khariaga crude to precipitate wax, the presence of H2S or the flow-back through the ESP called for additional precautions. In this paper we will show that despite these rather adverse conditions successful acid-fracturing treatments can be implemented in this region; we will discuss some of the key parameters that helped base the choice of treatment type and we will describe the lessons learnt during such treatments. In addition, as the data-set available for this acid-fracturing treatment is unusually comprehensive with image logs, production profiles, pre and post-frac thermal logs, bottom-hole gauges and extended post-frac decline, an integrated evaluation of the treatment will be proposed.
Using R&D portfolio management to deal with dynamic risk (2008)

We develop a theoretical framework for understanding why firms adopt specific approaches for the management of innovation project portfolios. Our theory focuses on a key contingency factor for innovation, namely the dynamics of competitive environments. We use four dimensions to characterize the patterns of environmental dynamics: velocity, turbulence, growth and instability. The paper then proposes the concept of dynamic risk as a determinant of portfolio management processes. Dynamic risk results from second‐order learning by a firm confronted with a specific dynamic pattern in its environment. This learning concerns the likely nature of threats and the required updating of cognitive frameworks in such environments. Attempts to deal with dynamic risk enable various actors inside the firm to understand what kind of dynamic capabilities are needed in their innovation portfolio management processes. As a result of this diffuse learning, firms tend to favor certain common characteristics in their concrete portfolio management activities. To advance the theorizing of these characteristics, the paper also proposes four dimensions of portfolio management: structure, commitment, emergence and integration. Based on arguments inspired by the dynamic capability and related literatures, we advance a series of hypotheses, that relate environmental dynamics dimensions and portfolio management dimensions. These hypotheses are tested based on a survey of 795 firms in a variety of sectors and on four continents, using original scales and structural equation modeling methods. The results show, among other findings, that high‐velocity environments favor structured as well as integrated portfolio management approaches, while high‐growth environments favor approaches that are structured but commit significant resources to each project as well. Turbulent environments favor approaches that are emergent, but also, contrary to our expectations, have high resource commitment levels. Finally, firms in unstable environments have a marginal preference for emergent approaches. Results could help advance the dynamic contingency theoretical perspective on dynamic capabilities, as well as improve the practice of innovation portfolio management.
RF Shimming Capabilities at 9.4 Tesla using a 16-channel Dual-Row Array (2013)

Multi-row arrays offer improved coverage in z-direction along with the capability to control the B1+ field in all spatial dimensions for high-field applications. This can be used to trade B1+ homogeneity against power efficiency in arbitrary volumes, depending on the desired application. However, numerical simulations must be provided to assess local SAR. In this work, we demonstrate the RF phase shimming capability of an inductively decoupled dual-row array for 9.4 T neuroimaging using time-domain simulations together with circuit co-simulation as well as RF shimmed, in vivo TSE and MP2RAGE images.
Carbonylchlorohydridotris(triphenylphosphine)ruthenium(II) (2014)

[16971-33-8] C55H46ClOP3Ru (MW 954.23) InChI = 1S/3C18H15P.CO.ClH.Ru.H/c3*1-4-10-16(11-5-1)19(17-12-6-2-7-13-17)18-14-8-3-9-15-18;1-2;;;/h3*1-15H;;1H;;/q;;;;;-2;/p+2 InChIKey = QZLKVTMGHSURLT-UHFFFAOYSA-P (ruthenium complex; used as a catalyst for (a) hydrogenation, (b) transfer hydrogenation, (c) transfer hydrogenative CC bond-forming reaction, (d) α-alkylation of ketones with primary alcohols, (e) used as a precursor of pincer ruthenium carbonyl catalysts for hydrogenation) Physical Data: (mp 204–206°C, decomposition starts just above the mp) Solubility: very insoluble in water, ethanol, and DMSO, sparingly soluble in benzene and acetone (about 0.4 g per 100 g), and slightly soluble in chloroform. Form Supplied in: tan powder; widely available. Preparative Method: this complex is obtained from the homogeneous reaction of triphenylphosphine, ruthenium trichloride, and aqueous formaldehyde in boiling 2-methoxyethanol.
The Ino80 complex prevents invasion of euchromatin into silent chromatin (2015)

Here we show that the Ino80 chromatin remodeling complex (Ino80C) directly prevents euchromatin from invading transcriptionally silent chromatin within intergenic regions and at the border of euchromatin and heterochromatin. Deletion of Ino80C subunits leads to increased H3K79 methylation and noncoding RNA polymerase II (Pol II) transcription centered at the Ino80C-binding sites. The effect of Ino80C is direct, as it blocks H3K79 methylation by Dot1 in vitro. Heterochromatin stimulates the binding of Ino80C in vitro and in vivo. Our data reveal that Ino80C serves as a general silencing complex that restricts transcription to gene units in euchromatin.
Induction and Evasion of Type-I Interferon Responses during Influenza A Virus Infection (2020)

Influenza A viruses (IAVs) are contagious pathogens and one of the leading causes of respiratory tract infections in both humans and animals worldwide. Upon infection, the innate immune system provides the first line of defense to neutralize or limit the replication of invading pathogens, creating a fast and broad response that brings the cells into an alerted state through the secretion of cytokines and the induction of the interferon (IFN) pathway. At the same time, IAVs have developed a plethora of immune evasion mechanisms in order to avoid or circumvent the host antiviral response, promoting viral replication. Herein, we will review and summarize already known and recently described innate immune mechanisms that host cells use to fight IAV viral infections as well as the main strategies developed by IAVs to overcome such powerful defenses during this fascinating virus-host interplay.
Surface plasmon resonance in metallic nanocylinder array (2005)

Localized surface plasmon resonances of noble-metal nanoparticles lead to high enhancements of local electromagnetic fields near the nanoparticle surface and play a key role in surface-enhanced Raman scattering, surface-enhanced fluorescence, near-field microscopy, and plasmonic devices. Recently, research results have shown that electromagnetic energy can transfer along a metallic nanoparticle chain because of coupled plasmon modes. In this paper, finite-difference time-domain method was used to study the surface plasmon resonances in coupled silver nanocylinder (nanopar-ticle) arrays and slab-like periodic modulation structures. From the far-field transmittance and reflectance, three different resonance modes were excited for the periodic nanocylinder arrays and only one resonance was excited for the periodic modulation structure. The near-field intensity dis-tributions exhibited highly enhanced fields at the center of the gaps for nanoparticle arrays and at the caves of the periodic modulation structure.
On the time-optimal trajectory planning and control of robotic manipulators along predefined paths (2013)

In this paper we study the problem of time-optimal trajectory planning and control of robotic manipulators along predefined paths. An algorithm that generates dynamically feasible time-optimal trajectories and controls is presented, which considers the complete dynamic model with both Coulomb and viscous friction. Even though the effects of viscous friction for fast motions become more significant than Coulomb friction, in previous formulations viscous friction was ignored. We propose a formulation that naturally leads to a convex relaxation which solves exactly the original non-convex formulation. In order to numerically solve the proposed formulation, a discretization scheme is also developed. Through simulation and experimental studies on the resulting tracking errors, applied torques, and accelerometer readings for a 6-axis manipulator, we emphasize the significance of penalizing a measure of total jerk. The importance of imposing acceleration constraints at the initial and final transitions of the trajectory is also studied.
Long-Distance QKD with Superconducting Single-Photon Detectors (2008)

Email Share Share with Facebook Tweet This Post on reddit Share with LinkedIn Add to CiteULike Add to Mendeley Add to BibSonomy Get Citation Copy Citation Text R. Hughes, "Long-Distance QKD with Superconducting Single-Photon Detectors," in Frontiers in Optics 2008/Laser Science XXIV/Plasmonics and Metamaterials/Optical Fabrication and Testing, OSA Technical Digest (CD) (Optica Publishing Group, 2008), paper FWA1. Export Citation BibTex Endnote (RIS) HTML Plain Text Citation alert Save article
Thermally curable adhesive tapes with complex catalyst system for fabricating semiconductor packages (2009)

Abstract Thermal curing of adhesive films was investigated to facilitate the fabrication of a reliable bonding for semiconductors. The formulated adhesive films contained acrylic polymer, epoxy resins, phenol resin, and an imidazole derivative that was the catalyst for curing the epoxy resins with phenol resin. The solubility, thermally latent characteristics, mechanical and adhesive properties of 2‐methylimidazole/boron trifluoride (2MZ/BF3), and 2MZ/aluminum trisacetylacetonate (AlAC) were investigated. It was found that 2MZ/BF3 and 2MZ/AlAC had excellent solubility in adhesive materials and they had excellent latent characteristics as thermal curing catalysts for epoxy resins, whereas conventional catalysts (2MZ and 2‐phenyl‐4, 5‐dihydroxymethylimidazole (2PHZ)) could not achieve both excellent solubility and thermally latent characteristics. The mechanical and adhesive properties of the post‐thermal‐cured adhesive film that contained 2MZ/BF3 or 2MZ/AlAC were comparable to those of the post‐thermal‐cured adhesive films that contained conventional catalysts. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Supplementary Methods, References, Figures 1-4, Tables 1-3 from A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors (2023)

&lt;p&gt;Supplementary Methods Supplementary References Supplementary Figure 1. Effect of acquired resistance mutations on TRK inhibitor activity. Supplementary Figure 2. Further characterization of LOXO-195 inhibitory activity against acquired resistance mutations. Supplementary Figure 3. LOXO-195 is selectively cytotoxic to TRK-fusion cell lines. Supplementary Figure 4. Identification of a clonal NTRK1 (TRKA)-G595R mutation after larotrectinib treatment. Supplementary Table 1. LOXO-195 ADME properties. Supplementary Table 2. Selectivity of LOXO-195 for 228 kinases. Supplementary Table 3. Summary of LOXO-195 PK parameters for each patient during intra-patient dose escalation.&lt;/p&gt;