scholarly journals Improved Electrophile Design for Exquisite Covalent Molecule Selectivity

2021 ◽  
Author(s):  
José Montaño ◽  
Brian Wang ◽  
Regan Volk ◽  
Virginia Garda ◽  
Balyn Zaro
Keyword(s):  
Shotgun Proteomics ◽  
Response To Treatment ◽  
Protein Targets ◽  
New Approach ◽  
Covalent Inhibitors ◽  
Order Of Magnitude ◽  
Inhibitor Selectivity ◽  
Btk Inhibitor ◽  
Covalent Probes ◽  
Magnitude Increase

Covalent inhibitors continue to show therapeutic promise. However, off-target reactivity challenges the field. Extensive efforts have been exerted to solve this issue by varying the reactivity attributes of electrophilic warheads, with features such as reversibility or metabolic vulnerability. Here we report the development of a new approach to increase the selectivity of covalent probes and small molecule inhibitors that is independent of warhead reactivity features and can be used in concert with already-existing methods. Using the Bruton’s Tyrosine Kinase (BTK) inhibitor Ibrutinib scaffold for our proof-of-concept, we reasoned that increasing the steric bulk of fumarate-based electrophiles on Ibrutinib should improve selectivity via the steric exclusion of off-targets but ideally retain rates of cysteine reactivity comparable to that of an acrylamide. Using chemical proteomic techniques, we demonstrate that elaboration of the electrophile to a tert-Butyl (t-Bu) fumarate ester significantly decreases time-dependent off-target reactivity and abolishes time-independent off-target reactivity but retains BTK target engagement. While an alkyne-bearing probe analog of Ibrutinib has 247 protein targets, our t-Bu fumarate Ibrutinib probe analog has only 7 protein targets. Of these 7 targets, BTK is the only time-independent target. This 2-order-of-magnitude increase in selectivity is also conferred to the t-Bu inhibitor itself. By shotgun proteomics, we investigated the consequences of treatment with Ibrutinib and our t-Bu analog and discovered that only 8 proteins are downregulated in response to treatment with the t-Bu analog compared to 107 with Ibrutinib. Of these 8 proteins, 7 are also downregulated by Ibrutinib and a majority of these targets are associated with BTK biology. Taken together, these findings reveal a previously-unappreciated opportunity to increase cysteine-reactive covalent inhibitor selectivity through electrophilic structure optimization.

scholarly journals Improved Electrophile Design for Exquisite Covalent Molecule Selectivity

2021 ◽  
Author(s):  
José Montaño ◽  
Brian Wang ◽  
Regan Volk ◽  
Virginia Garda ◽  
Balyn Zaro
Keyword(s):  
Shotgun Proteomics ◽  
Response To Treatment ◽  
Protein Targets ◽  
New Approach ◽  
Covalent Inhibitors ◽  
Order Of Magnitude ◽  
Inhibitor Selectivity ◽  
Btk Inhibitor ◽  
Covalent Probes ◽  
Magnitude Increase

Covalent inhibitors continue to show therapeutic promise. However, off-target reactivity challenges the field. Extensive efforts have been exerted to solve this issue by varying the reactivity attributes of electrophilic warheads, with features such as reversibility or metabolic vulnerability. Here we report the development of a new approach to increase the selectivity of covalent probes and small molecule inhibitors that is independent of warhead reactivity features and can be used in concert with already-existing methods. Using the Bruton’s Tyrosine Kinase (BTK) inhibitor Ibrutinib scaffold for our proof-of-concept, we reasoned that increasing the steric bulk of fumarate-based electrophiles on Ibrutinib should improve selectivity via the steric exclusion of off-targets but ideally retain rates of cysteine reactivity comparable to that of an acrylamide. Using chemical proteomic techniques, we demonstrate that elaboration of the electrophile to a tert-Butyl (t-Bu) fumarate ester significantly decreases time-dependent off-target reactivity and abolishes time-independent off-target reactivity but retains BTK target engagement. While an alkyne-bearing probe analog of Ibrutinib has 247 protein targets, our t-Bu fumarate Ibrutinib probe analog has only 7 protein targets. Of these 7 targets, BTK is the only time-independent target. This 2-order-of-magnitude increase in selectivity is also conferred to the t-Bu inhibitor itself. By shotgun proteomics, we investigated the consequences of treatment with Ibrutinib and our t-Bu analog and discovered that only 8 proteins are downregulated in response to treatment with the t-Bu analog compared to 107 with Ibrutinib. Of these 8 proteins, 7 are also downregulated by Ibrutinib and a majority of these targets are associated with BTK biology. Taken together, these findings reveal a previously-unappreciated opportunity to increase cysteine-reactive covalent inhibitor selectivity through electrophilic structure optimization.

scholarly journals Hydraulic transmissivity inferred from ice-sheet relaxation following Greenland supraglacial lake drainages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ching-Yao Lai ◽  
Laura A. Stevens ◽  
Danielle L. Chase ◽  
Timothy T. Creyts ◽  
Mark D. Behn ◽  
...  
Keyword(s):  
Laboratory Experiments ◽  
Ice Sheet ◽  
Drainage System ◽  
Greenland Ice Sheet ◽  
Field Observations ◽  
Surface Uplift ◽  
Drainage Networks ◽  
Order Of Magnitude ◽  
Lake Drainage ◽  
Magnitude Increase

AbstractSurface meltwater reaching the base of the Greenland Ice Sheet transits through drainage networks, modulating the flow of the ice sheet. Dye and gas-tracing studies conducted in the western margin sector of the ice sheet have directly observed drainage efficiency to evolve seasonally along the drainage pathway. However, the local evolution of drainage systems further inland, where ice thicknesses exceed 1000 m, remains largely unknown. Here, we infer drainage system transmissivity based on surface uplift relaxation following rapid lake drainage events. Combining field observations of five lake drainage events with a mathematical model and laboratory experiments, we show that the surface uplift decreases exponentially with time, as the water in the blister formed beneath the drained lake permeates through the subglacial drainage system. This deflation obeys a universal relaxation law with a timescale that reveals hydraulic transmissivity and indicates a two-order-of-magnitude increase in subglacial transmissivity (from 0.8 ± 0.3 $${\rm{m}}{{\rm{m}}}^{3}$$ m m 3 to 215 ± 90.2 $${\rm{m}}{{\rm{m}}}^{3}$$ m m 3 ) as the melt season progresses, suggesting significant changes in basal hydrology beneath the lakes driven by seasonal meltwater input.

scholarly journals Review of the soft-X-ray laser research at CEL-V

1991 ◽  
Vol 9 (2) ◽  
pp. 493-499
Author(s):  
D. Naccache ◽  
J-L. Bourgade ◽  
P. Combis ◽  
C. J. Keane ◽  
J-P. Le Breton ◽  
...  
Keyword(s):  
Atomic Number ◽  
Collisional Excitation ◽  
X Ray ◽  
Order Of Magnitude ◽  
Laser Experiments ◽  
Magnitude Increase

We present some significant results of collisional excitation X-ray laser experiments in plasmas produced by a laser. We studied the amplification in Ne- and Ni-like ions by varying both the nature and the thickness of targets, the irradiation, and the wavelength of the driving laser. Some potentially interesting scalings as a function of the atomic number of the lasing element are demonstrated in the Ne-like system. An order-of-magnitude increase in gain in the Ni-like experiments was determined.

Critical current density and microstructure variations in YBa2Cu3O7−x + BaSnO3 films with different concentrations of BaSnO3

2008 ◽  
Vol 23 (12) ◽  
pp. 3363-3369 ◽  
Author(s):  
C.V. Varanasi ◽  
J. Burke ◽  
L. Brunke ◽  
H. Wang ◽  
J.H. Lee ◽  
...  
Keyword(s):  
Critical Current Density ◽  
Critical Current ◽  
Current Density ◽  
Gradual Increase ◽  
Critical Transition ◽  
Critical Transition Temperature ◽  
Transmission Electron ◽  
Order Of Magnitude ◽  
High Fields ◽  
Magnitude Increase

Previous work on YBa2Cu3O7−x (YBCO) + BaSnO3 (BSO) films with a single composition showed significant critical current density (Jc) improvements at higher fields but lowered Jc in low fields. A detailed study on BSO concentrations provided here demonstrates that significant Jc enhancement can occur even up to 20 mol% BSO inclusion, where typical particulate inclusions in these concentrations degrade the YBCO performance. YBCO + BSO films were processed on (100) LaAlO3 substrates using premixed targets of YBa2Cu3O7-x (YBCO) with additions of 2, 4, 10, and 20 mol% BSO. The critical transition temperature Tc of the films remained high (>87 K), even with large amounts (20 mol%) of BSO. YBCO + BSO films showed a gradual increase in Jc at high fields as the amount of BSO was increased. More than an order of magnitude increase in Jc was measured in YBCO + BSO samples as compared to regular YBCO at 4 T. YBCO + 10 mol% BSO films showed overall improvement at all the field ranges while YBCO + 20 mol% BSO was better only at high fields. Transmission electron microscopy revealed the presence of ∼7–8-nm-diameter BSO nanocolumns, the density of which increased with increasing BSO content correlating well with the observed improvements in Jc.

Half division two-dimensional method for simple sinusoidal quantities parameters accurate measurement

2021 ◽  
pp. 16-21
Author(s):  
Kirill Yu. Solomentsev ◽  
Vyacheslav I. Lachin ◽  
Aleksandr E. Pasenchuk
Keyword(s):  
Measuring Instruments ◽  
Measured Signal ◽  
Two Dimensional ◽  
Measuring Device ◽  
New Approach ◽  
Precision Measuring ◽  
Useful Signal ◽  
Midpoint Method ◽  
Order Of Magnitude ◽  
Current Measuring

Several variants of half division two-dimensional method are proposed, which is the basis of a fundamentally new approach for constructing measuring instruments for sinusoidal or periodic electrical quantities. These measuring instruments are used in the diagnosis of electric power facilities. The most general variant, called midpoint method, is considered. The proposed midpoint method allows you to measure much smaller than using widespread methods, alternating currents or voltages, especially when changing the amplitude of the measured signal in very wide ranges, by 1–2 orders of magnitude. It is shown that using the midpoint method it is possible to suppress sinusoidal or periodic interference in the measuring path, in particular, to measure small alternating current when sinusoidal or periodic interference is 1–2 orders of magnitude higher than the useful signal. Based on the results of comparative tests, it was found that the current measuring device implementing the midpoint method is an order of magnitude more sensitive than the currently used high-precision measuring instruments.

scholarly journals Large-area printing of ferroelectric surface and super-domains for efficient solar water splitting

2020 ◽  
Author(s):  
Yu Tian ◽  
Yaqing Wei ◽  
Minghui Pei ◽  
Rongrong Cao ◽  
Zhenao Gu ◽  
...  
Keyword(s):  
Water Splitting ◽  
Electric Fields ◽  
Electronic Structures ◽  
Active Sites ◽  
Large Area ◽  
Solar Water Splitting ◽  
High Efficient ◽  
Catalytic Sites ◽  
Order Of Magnitude ◽  
Magnitude Increase

Abstract Surface electronic structures of the photoelectrodes determine the activity and efficiency of the photoelectrochemical water splitting, but the controls of their surface structures and interfacial chemical reactions remain challenging. Here, we use ferroelectric BiFeO3 as a model system to demonstrate an efficient and controllable water splitting reaction by large-area constructing the hydroxyls-bonded surface. The up-shift of band edge positions at this surface enables and enhances the interfacial holes and electrons transfer through the hydroxyl-active-sites, leading to simultaneously enhanced oxygen and hydrogen evolutions. Furthermore, printing of ferroelectric super-domains with microscale checkboard up/down electric fields separates the distribution of reduction/oxidation catalytic sites, enhancing the charge separation and giving rise to an order of magnitude increase of the photocurrent. This large-area printable ferroelectric surface and super-domains offer an alternative platform for controllable and high-efficient photocatalysis.

scholarly journals Hydrodechlorination of CHClF2 (HCFC-22) over Pd-Pt catalysts supported on thermally modified activated carbon. Beneficial effect of catalyst oxidation.

2021 ◽  
Author(s):  
Monika Radlik ◽  
Wojciech Juszczyk ◽  
Wioletta Raróg-Pilecka ◽  
Magdalena Zybert ◽  
Zbigniew Karpiński
Keyword(s):  
Alloy Composition ◽  
Active Surface ◽  
Metal Particles ◽  
Pt Catalysts ◽  
Modified Activated Carbon ◽  
Palladium Surface ◽  
Order Of Magnitude ◽  
Carbon Burning ◽  
Magnitude Increase ◽  
Catalyst Oxidation

Pd-Pt catalysts supported on carbon preheated to 1600°C have been reinvestigated in CHFCl2 hydrodechlorination. An additionally adopted catalyst oxidation at 350-400°C produced an order of magnitude increase in the catalytic activity of Pd/C. This increase is not caused by changes in metal dispersion or possible decontamination of the Pd surface from superficial carbon, but rather by unlocking the active surface, originally inaccessible in metal particles tightly packed in the pores of carbon. Burning carbon from the pore walls attached to the metal changes the pore structure, providing easier access for the reactants to the entire palladium surface. As upon calcination the performance of the rest of the Pd-Pt/C catalysts changes less than for Pd/C, the relation between the turnover frequency and alloy composition does not confirm the Pd-Pt synergy invoked in our previous work. The use of even higher-preheated carbon (1800°C), completely free of micropores, results in a Pd/C catalyst that does not need to be oxidized to achieve high activity and excellent selectivity up to CH2F2 (>90%).

scholarly journals TOXIFY: a deep learning approach to classify animal venom proteins

2019 ◽  
Author(s):  
T Jeffrey Cole ◽  
Michael S Brewer
Keyword(s):  
Protein Sequence ◽  
Software Package ◽  
Shotgun Proteomics ◽  
Learning Approach ◽  
The Novel ◽  
Venom Protein ◽  
Order Of Magnitude ◽  
Gated Recurrent Units ◽  
Venom Proteins ◽  
Generation Sequencing

In the era of Next-Generation Sequencing and shotgun proteomics, the sequences of animal toxigenic proteins are being generated at rates exceeding the pace of traditional means for empirical toxicity verification. To facilitate the automation of toxin identification from protein sequences, we trained Recurrent Neural Networks with Gated Recurrent Units on publicly available datasets. The resulting models are available via the novel software package TOXIFY, allowing users to infer the probability of a given protein sequence being a venom protein. TOXIFY is more than 20X faster and uses over an order of magnitude less memory than previously published methods. Additionally, TOXIFY is more accurate, precise, and sensitive at classifying venom proteins. Availability: https://www.github.com/tijeco/toxify

scholarly journals Optbayesexpt: Sequential Bayesian Experiment Design for Adaptive Measurements

2021 ◽  
Vol 126 ◽  
Author(s):  
Robert D. McMichael ◽  
Sean M. Blakley ◽  
Sergey Dushenko
Keyword(s):  
Lower Cost ◽  
Adaptive Algorithms ◽  
Efficient Estimation ◽  
Function Parameter ◽  
Model Function ◽  
Measurement Results ◽  
Adaptive Measurements ◽  
Order Of Magnitude ◽  
Magnitude Increase ◽  
Python Package

Optbayesexpt is a public domain, open-source python package that provides adaptive algorithms for efficient estimation/measurement of parameters in a model function. Parameter estimation is the type of measurement one would conventionally tackle with a sequence of data acquisition steps followed by fitting. The software is designed to provide data-based control of experiments, effectively learning from incoming measurement results and using that information to select future measurement settings live and online as measurements progress. The settings are chosen to have the best chances of improving the measurement results. With these methods optbayesexpt is designed to increase the efficiency of a sequence of measurements, yielding better results and/or lower cost. In a recent experiment, optbayesexpt yielded an order of magnitude increase in speed for measurement of a few narrow peaks in a broad spectral range.

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