gebhart/patrepeval huggingface dataset:
Natural Product Splicing Inhibitors: A New Class of Antibody–Drug Conjugate (ADC) Payloads (2016)

There is a considerable ongoing work to identify new cytotoxic payloads that are appropriate for antibody-based delivery, acting via mechanisms beyond DNA damage and microtubule disruption, highlighting their importance to the field of cancer therapeutics. New modes of action will allow a more diverse set of tumor types to be targeted and will allow for possible mechanisms to evade the drug resistance that will invariably develop to existing payloads. Spliceosome inhibitors are known to be potent antiproliferative agents capable of targeting both actively dividing and quiescent cells. A series of thailanstatin-antibody conjugates were prepared in order to evaluate their potential utility in the treatment of cancer. After exploring a variety of linkers, we found that the most potent antibody-drug conjugates (ADCs) were derived from direct conjugation of the carboxylic acid-containing payload to surface lysines of the antibody (a "linker-less" conjugate). Activity of these lysine conjugates was correlated to drug-loading, a feature not typically observed for other payload classes. The thailanstatin-conjugates were potent in high target expressing cells, including multidrug-resistant lines, and inactive in nontarget expressing cells. Moreover, these ADCs were shown to promote altered splicing products in N87 cells in vitro, consistent with their putative mechanism of action. In addition, the exposure of the ADCs was sufficient to result in excellent potency in a gastric cancer xenograft model at doses as low as 1.5 mg/kg that was superior to the clinically approved ADC T-DM1. The results presented herein therefore open the door to further exploring splicing inhibition as a potential new mode-of-action for novel ADCs.
Quantitative falls risk estimation through multi-sensor assessment of standing balance (2012)

Falls are the most common cause of injury and hospitalization and one of the principal causes of death and disability in older adults worldwide. Measures of postural stability have been associated with the incidence of falls in older adults. The aim of this study was to develop a model that accurately classifies fallers and non-fallers using novel multi-sensor quantitative balance metrics that can be easily deployed into a home or clinic setting. We compared the classification accuracy of our model with an established method for falls risk assessment, the Berg balance scale. Data were acquired using two sensor modalities--a pressure sensitive platform sensor and a body-worn inertial sensor, mounted on the lower back--from 120 community dwelling older adults (65 with a history of falls, 55 without, mean age 73.7 ± 5.8 years, 63 female) while performing a number of standing balance tasks in a geriatric research clinic. Results obtained using a support vector machine yielded a mean classification accuracy of 71.52% (95% CI: 68.82-74.28) in classifying falls history, obtained using one model classifying all data points. Considering male and female participant data separately yielded classification accuracies of 72.80% (95% CI: 68.85-77.17) and 73.33% (95% CI: 69.88-76.81) respectively, leading to a mean classification accuracy of 73.07% in identifying participants with a history of falls. Results compare favourably to those obtained using the Berg balance scale (mean classification accuracy: 59.42% (95% CI: 56.96-61.88)). Results from the present study could lead to a robust method for assessing falls risk in both supervised and unsupervised environments.
Synthetic Studies of Neoclerodane Diterpenes from <i>Salvia divinorum</i>: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor (2020)

Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-opioid receptor (MOR) agonist, kurkinorin (<b>1</b>), derived from salvinorin A. In an effort to further probe the physiological effects induced upon activation of MORs with this nonmorphine scaffold, a variety of analogues were synthesized and evaluated <i>in vitro</i> for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-arrestin-2 recruitment or biased toward G-protein activation have been identified. One such compound, <b>25</b>, has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively, <b>25</b> is over 100× more potent than morphine and over 5× more potent than fentanyl <i>in vitro</i> and elicits antinociception with limited tolerance development <i>in vivo</i>. This is especially significant given that <b>25</b> lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.
A Novel Surface NMR Pulse Sequence for Improved Estimation of Longitudinal T1 Relaxation Times (2012)

Obtaining estimates of permeability from NMR methods requires the ability to measure relaxation time parameters that are most sensitive to pore geometry. While surface‐NMR (SNMR) measurements can reliably quantify the effective transverse relaxation time T2*, transverse relaxation times are sometimes dominated by the influence of magnetic geology. The longitudinal relaxation time T1 is known to provide a more robust link to pore geometry, but previous attempts to measure T1 by SNMR, have shown mixed success due to fundamental limitations the commonly applied “pseudo‐saturation recovery” (PSR) experiment. Recognizing a need for improved measurements, we have developed a new paradigm of experiments for quantifying T1, which we refer to as the “crush recovery” (CR) sequence. The CR sequence utilizes two pulses: a first pulse of fixed amplitude and a second smaller pulse with an amplitude that is varied between measurements. The first pulse of the CR sequence is not intended to generate saturation with 90 degree tip angles, as in the PSR sequence; rather, the initial pulse acts to crush or decoherently scatter the magnetization orientation, leaving an effectively saturated condition of zero net longitudinal magnetization over a range of shallow to intermediate depths. A second pulse, applied after a short delay, is then used to probe the magnetization that recovers by T1 between the two pulses. The amplitude of the second pulse is varied to provide depth resolution of T1 recovery within the “crushed” zone. Fixing the amplitude of the initial pulse provides constant initial conditions, such that the data measured after the second pulse can be inverted using the standard SNMR imaging kernel. Inversion of a CR dataset for a single delay time yields depth‐separated free induction decay signals where the amplitude of the signal components are linearly weighted by the observed T1 recovery at each depth. Given a complete set of CR data acquired with multiple delay times, the inversion provides estimates of both T1 and T2* as a function of depth. Further, the covariance of the observed signal with T2* and T1, provides the opportunity to estimate a two‐dimensional distributions of T2* versus T1 at each depth. We illustrate the success and advantages of this new approach though a combination of synthetic and real field data examples.
Design and Simulation of All-Optical AND Gate using XGM in Semiconductor Optical Amplifiers without Input Additional Beam (2006)

Design and simulation of an all-optical AND gate that utilize a XGM in semiconductor optical amplifiers is demonstrated at 10 Gbps using only input signals A and B. In the AND (AB) gate, Boolean AB is firstly obtained by using signal B as a pump beam and signal A as a probe beam in SOA-1. By passing signal A as a probe beam and AB as a pump beam through SOA-2, Boolean AB is acquired.
Flexible instruction processors (2000)

This paper introduces the notion of a Flexible Instruction Processor (FIP) for systematic customisation of instruction processor design and implementation. The features of our approach include: (a) a modular framework based on “processor templates” that capture various instruction processor styles, such as stack-based or register-based styles; (b) enhancements of this framework to improve functionality and performance, such as hybrid processor templates and superscalar operation; (c) compilation strategies involving standard compilers and FIP-specific compilers, and the associated design flow; (d) technology-independent and technology-specific optimisations, such as techniques for ecient resource sharing in FPGA implementations. Our current implementation of the FIP framework is based on a highlevel parallel language called Handel-C, which can be compiled into hardware. Various customised Java Virtual Machines and MIPS style processors have been developed using existing FPGAs to evaluate the eectiveness and promise of this approach.
Efficient floating-point polynomial evaluation on FPGAS (2013)

Many applications require the evaluation of polynomials having floating-point coefficients - one example is rational polynomial approximation, often used to implement some special functions. The most resource efficient polynomial evaluation scheme (Horner) is costly to implement on FPGAs due to the high cost associated with floating-point arithmetic. Floating-point adders are particularly costly due to their alignment stages requiring large barrel shifters. In this work we present a novel FPGA-specific technique for evaluating polynomials using the Horner scheme. Our technique removes the majority of alignment shifters present in floating-point adders by building a fused evaluation operator. It pushes the possible alignment values of the monomials into tables containing multiple shifted coefficient instances which are selected using the exponent of the input argument. Compared to operator assembly this work reduces circuit latency by 30-50% and logic consumption by 40-60%. Our work can be easily extended to other polynomial evaluation methods.
Purified 60-kilodalton Legionella protein antigen with Legionella-specific and nonspecific epitopes (1987)

In a previous study, all convalescent-phase sera from patients with culture-confirmed legionellosis reacted on immunoblots with a Legionella genus-wide 58-kilodalton (kDa) protein antigen (J.S. Sampson, B.B. Plikaytis, and H.W. Wilkinson, J. Clin. Microbiol. 23:92-99, 1986). The present study was done to immunologically characterize and determine the diagnostic relevance of this purified antigen. The antigen was precipitated from enriched cell extracts with ammonium sulfate and purified by high-pressure liquid chromatography. High-titered rabbit antiserum produced to the purified protein was used to show its presence on immunoblots in the 60-kDa range in 38 Legionella serogroups, representing 23 species, and in 39 non-Legionella bacteria. The antiserum was made specific for Legionella strains by sequential absorptions with Bordetella pertussis, Pseudomonas aeruginosa, and Pseudomonas fluorescens whole cells. Serum from legionellosis patients reacted with both specific and nonspecific epitopes. Results of indirect immunofluorescence experiments showed that neither specific nor nonspecific epitopes of the 60-kDa protein were surface exposed on Legionella cells and that cross-reactive epitopes were variably exposed on non-Legionella bacteria. The 60-kDa protein antigen should be useful in diagnostic tests for legionellosis if care is taken to expose cryptic epitopes and if the tests use or measure only the Legionella-specific epitopes.
Three-dimensional Migration of Neurites Is Mediated by Adhesion Site Density and Affinity (2000)

Three-dimensional neurite outgrowth rates within fibrin matrices that contained variable amounts of RGD peptides were shown to depend on adhesion site density and affinity. Bi-domain peptides with a factor XIIIa substrate in one domain and a RGD sequence in the other domain were covalently incorporated into fibrin gels during coagulation through the action of the transglutaminase factor XIIIa, and the RGD-dependent effect on neurite outgrowth was quantified, employing chick dorsal root ganglia cultured two- and three-dimensionally within the modified fibrin. Two separate bi-domain peptides were synthesized, one with a lower binding affinity linear RGD domain and another with a higher binding affinity cyclic RGD domain. Both peptides were cross-linked into fibrin gels at concentrations up to 8.2 mol of peptide/mol of fibrinogen, and their effect on neurite outgrowth was measured. Both two- and three-dimensional neurite outgrowth demonstrated a bi-phasic dependence on RGD concentration for both the linear and cyclic peptide, with intermediate adhesion site densities yielding maximal neurite extension and higher densities inhibiting outgrowth. The adhesion site density that yielded maximal outgrowth depended strongly on adhesion site affinity in both two and three dimensions, with lower densities of the higher affinity ligand being required (0.8-1.7 mol/mol for the linear peptide versus 0.2 mol/mol for the cyclic peptide yielding maximum neurite outgrowth rates in three-dimensional cultures).
High-capacity assay to quantify the clonal heterogeneity in potency of mesenchymal stem cells (2011)

Background The regenerative capacity of mesenchymal stem cells (MSCs) is contingent on their content of multipotent progenitors [1]. Despite its importance to the efficacy of MSC therapies, the clonal heterogeneity of MSCs remains poorly defined. To address this deficiency, the current study presents a novel high-capacity assay to quantify the clonal heterogeneity in MSC potency and demonstrates its utility to resolve regenerative properties as a function of potency. Human bone marrow was the source of MSCs in this study. The versatility and accessibility of marrow-derived MSCs make them a standard for many therapeutic applications.
Abstract P1-07-16: Galectin-7 increases resistance of breast cancer cells to drug-induced apoptosis and promotes tumor escape by killing T cells (2015)

Abstract Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 was recently shown to be specifically expressed in basal-like and HER-2 positive but not in luminal subtypes of human breast cancer. Galectin-7 also increases the metastatic behavior of breast cancer cells since overexpression of this protein in poorly metastatic breast cancer cells increases their ability to metastasize to the bone and to the lung. This pro-tumoral activity of galectin-7 in breast cancer is surprising since galectin-7 had been previously associated with activation of p53 and breast cancer cells often harbor a transcriptionally inactive form of p53. We have recently reconcile this apparent contradiction by showing that elevated levels of galectin-7 in breast cancer cells occurs via a gain-of-function mechanism of mutant p53. In p53-null breast cancer cells, we have shown that C/EBPβ-2 (also known as LAP2), the most transcriptionally active of the C/EBPβ isoforms, is responsible for the upregulation of galectin-7. How galectin-7 contributes to the progression of breast cancer remains unclear. Up to now, regulation of apoptosis by intracellular galectins has been largely attributed to their ability to translocate to mitochondria, possibly following their interaction with bcl-2. Here, we report that a mutant of galectin-7 that is unable to translocate to mitochondria induces resistance of human breast cancer cells to apoptosis induced by etoposide or by hypoxia-mimicking conditions. Surprisingly, this mutant and the wild-type form of galectin-7 bind equally well to bcl-2 in vitro and in vivo. Interestingly, both forms decreases the translocation of p53 to the nucleus and reduce the expression of p21 following treatment with doxorubicin. We also found that galectin-7 was released by breast cancer cells and that recombinant galectin-7 increased apoptosis of monocytes, T CD4+ and T CD8+ cells. This suggests that galectin-7 contributes to the establishment of an immunosuppressive tumor microenvironment by killing helper and effector T cells. Taken together, these results challenges the current paradigm that mitochondrial galectins are important for resistance to apoptosis and call for a greater focus on the role of galectin-7 in breast cancer. They also indicate that targeting both cytosolic and extracellular galectin-7 could improve the efficacy of anti-cancer drugs for the treatment of aggressive forms of breast cancer. Citation Format: Yves St-Pierre, Andrée-Anne Grosset, Marilyne Labrie, Donald Gagné, Maria-Claudia Vladoiu, Louis Gaboury, Nicolas Doucet. Galectin-7 increases resistance of breast cancer cells to drug-induced apoptosis and promotes tumor escape by killing T cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-16.
Low-temperature silicon epitaxy using low pressure chemical vapor deposition with and without plasma enhancement (1984)

Specular epitaxial silicon films have been deposited at 775 °C using a low pressure chemical vapor deposition process both with and without plasma enhancement. This is the lowest silicon epitaxial deposition temperature reported for thermally driven chemical vapor deposition. It was found that the predeposition in situ cleaning of the surface, rather than any plasma effects during the deposition, was essential for achieving epitaxial growth at this low temperature. Surface cleaning in these experiments was done by sputtering the wafer in an argon plasma at 775 °C with a dc bias applied to the susceptor. This is the lowest pre-epitaxial cleaning temperature reported for thermally driven chemical vapor deposition.
Plasma technology for tail pipe reduction of NO{sub x} in diesel exhaust (1998)

In the conventional application of plasmas to the treatment of power plant flue gases, the plasma is used to oxidize NO{sub x} to nitric acid; the final product us ammonium nitrate, which is obtained by addition of ammonia. A critical issue in the application of plasmas to cars and trucks is whether the plasma can remove the NO{sub x} by direct chemical reduction to N{sub 2}. We have found that gas-phase reactions in the plasma alone cannot lead to true chemical reduction of NO{sub x}. Any reduction of NO{sub x}to N{sub 2} can only be accomplished through heterogeneous reactions of NO{sub 2} with surfaces or particulates. This paper discusses how the plasma oxidation of NO to NO{sub 2} can be utilized to enhance the heterogeneous catalytic reduction of NO{sub x} to N{sub 2}. Plasma- assisted heterogeneous catalysis can enhance the NO{sub x} reduction under conditions that normally make it difficult for either the plasma or the catalyst to function by itself. The combination of a plasmas with a catalyst opens the opportunity for a new class of catalysts that are potentially more durable, more active, more selective and more sulfur-tolerant compared to conventional lean-NO{sub x} catalysts.
Linear astigmatism of confocal off-axis reflective imaging systems and its elimination (2006)

Linear astigmatism of a confocal off-axis reflective imaging system when the object plane is tilted and located at a finite distance from the imaging system is derived. We show that linear astigmatism can be eliminated by proper configuration of the parent mirror axes in confocal off-axis two-mirror systems. The tilt angle of the image plane is also derived. The developed theory is verified by ray-tracing analysis of an example system.
Abstract 19056: Discovery of Potent and Selective Neprilysin Inhibitors Exhibiting Sustained Pharmacodynamic Activity and Non-renal Elimination in Rats (2015)

Introduction: Neprilysin (NEP) inhibitors in combination with angiotensin-II receptor antagonists (ARNIs) have demonstrated benefits in patients with hypertension and chronic heart failure (CHF). A significant population of patients with cardiorenal diseases (e.g., CHF, chronic kidney disease and diabetic nephropathy) exhibit moderate to severe levels of renal impairment. Sacubitril (NEP inhibitor component of LCZ696) is extensively cleared by the kidney and systemic exposures are increased in patients with renal dysfunction thus potentially limiting its therapeutic utility. We aimed to identify potent and selective NEP inhibitors that exhibit non-renal excretion in order to discover agents that may provide optimal therapy in patients with renal dysfunction. Methods: In vitro enzyme activity assays at human NEP were used to assess inhibitory potencies and half-lives of the enzyme-inhibitor complexes. In vivo potentiation of ANP-induced plasma cGMP was evaluated after PO dosing in Sprague Dawley rats. Blood pressure was monitored in conscious Dahl Salt-Sensitive (Dahl/SS) hypertensive rats surgically implanted with telemetry transmitters. Urinary and biliary excretion was evaluated in bile-duct cannulated rats. Results: Selective NEP inhibitors (THRX-213068, THRX-134025, and THRX-124283) were identified with increased potency relative to LBQ657 (active moiety of sacubitril) at NEP (pKi 9.4, 9.3, 9.3 versus 8.2) and displayed longer enzyme residence time (T1/2 = 25, 145, and 190 versus 3 min). All three NEP inhibitors potentiated cGMP to a greater extent than LBQ657 in rat plasma after PO dosing (10 mg/kg). Sustained lowering of mean arterial pressure also was observed in Dahl/SS rats after PO dosing (24 hr average change -17 to -45 mm Hg). Negligible renal excretion was observed for all NEP inhibitors in rats after IV or PO dosing [< 5% of dose relative to 40% (IV) for LBQ657]. Conclusions: Novel, potent, and selective NEP inhibitors were identified that exhibit sustained potentiation of cGMP and BP-lowering in rodent models. Negligible levels of renal excretion were observed in rats suggesting the possibility of providing consistent dosing in patients with cardiorenal diseases across various levels of renal dysfunction.
Development of oxygen and pH sensors for aqueous systems. Final report (1994)

Corrosion science has long recognized that two of the most important parameters in characterizing the corrosivity of an aqueous environment are oxygen chemical potential and pH. These parameters not only determine the thermodynamic driving forces for various corrosion reactions, but also characterize the rates of these reactions and hence the lifetime of a particular component. The primary goal of this project is to develop an electrochemical oxygen and pH sensor for continuous use in the cycle chemistry control of power plants. In the past year, electrochemical sensors with a metal/metal oxide or metal/metal hydride internal reference electrode and a fluoride-based electrolyte tube have been developed and tested in this laboratory. The corrosion tests showed that the LaF{sub 3}-based solid electrolyte was very stable both chemically and physically in water. Furthermore, its electrical conductivity is 4 to 5 orders of magnitude higher than that of stabilized zirconia below 573 K (300{degree}C), which is the main advantage of a fluoride-based electrolyte at low temperatures. With this electrolyte and the selected internal oxygen reference electrode (Ag/Ag{sub 2}O), the electrochemical probe demonstrated Nernstian responses to the oxygen chemical potential and pH of the aqueous solution with good reproducibility. A similar cell with Zr/ZrH{sub 1+x}more » as the internal hydrogen reference electrode showed promising pH sensing characteristics. It is proposed that these two cells be combined to form a double-headed electrochemical probe to determine oxygen chemical potential and pH in the solution simultaneously.« less