gebhart/patrepeval huggingface dataset:
Abstract 1901: Structural basis for selective therapeutic targeting of BFL-1 in cancer by a covalent stapled peptide inhibitor (2018)

Abstract BCL-2 family proteins are master regulators of the mitochondrial apoptotic pathway and dictate whether a cell will live or die in response to stress. Cancer cells hijack the anti-apoptotic arm of this signaling network, overexpressing BCL-2, MCL-1, and BFL-1, to enforce cellular immortality. Whereas BCL-2 has been drugged by the selective small-molecule inhibitor, venetoclax, and new MCL-1 inhibitor molecules have just entered phase I clinical testing, anti-apoptotic BFL-1 remains undrugged. Importantly, the expression of BFL-1 can cause resistance to these molecules and has been independently linked to the pathogenesis and chemoresistance of human cancers, including melanomas and hematologic malignancies. Given the emergence of BCL-2 family proteins as high-priority cancer targets, solving their structures, alone and in complex with their natural BH3 domain ligands, yields important blueprints for drug design. Whereas the structures of numerous “BH3-in-groove” complexes have been solved, the corresponding panel of apo structures remains incomplete. Here, we report the crystal structure of apo BFL-1 at 1.69 Å resolution, revealing similarities and key differences among unliganded anti-apoptotic targets. Unlike all other BCL-2 proteins, apo BFL-1 contains a surface-accessible cysteine within its BH3-binding groove, allowing for selective covalent targeting by BH3-based stapled peptide inhibitors. The crystal structure of a complex between BFL-1 and a cysteine-reactive and stapled NOXA BH3 α-helix demonstrated the sulfhydryl bond and fortuitous interactions between the acrylamide-bearing moiety and a newly formed hydrophobic cavity. Comparison of the apo and BH3-liganded structures further revealed an induced conformational change. The two BFL-1 structures expand our understanding of the surface landscapes available for selective targeting of BFL-1, and inform a new therapeutic strategy for overcoming BFL-1-dependent apoptotic blockades in human cancer. Citation Format: Edward P. Harvey, Hyuk-Soo Seo, Rachel M. Guerra, Gregory H. Bird, Sirano Dhe-Paganon, Loren D. Walensky. Structural basis for selective therapeutic targeting of BFL-1 in cancer by a covalent stapled peptide inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1901.
Real-time GPU rendering of piecewise algebraic surfaces (2006)

We consider the problem of real-time GPU rendering of algebraic surfaces defined by Bézier tetrahedra. These surfaces are rendered directly in terms of their polynomial representations, as opposed to a collection of approximating triangles, thereby eliminating tessellation artifacts and reducing memory usage. A key step in such algorithms is the computation of univariate polynomial coefficients at each pixel; real roots of this polynomial correspond to possibly visible points on the surface. Our approach leverages the strengths of GPU computation and is highly efficient. Furthermore, we compute these coefficients in Bernstein form to maximize the stability of root finding, and to provide shader instances with an early exit test based on the sign of these coefficients. Solving for roots is done using analytic techniques that map well to a SIMD architecture, but limits us to fourth order algebraic surfaces. The general framework could be extended to higher order with numerical root finding.
Production of High-Viscosity Whey Broths by a Lactose-Utilizing <i>Xanthomonas campestris</i> Strain (1985)

Xanthomonas campestris BB-1L was isolated by enrichment and selection by serial passage in a lactose-minimal medium. When BB-1L was subsequently grown in medium containing only 4% whey and 0.05% yeast extract, the lactose was consumed and broth viscosities greater than 500 cps at a 12 s shear rate were produced. Prolonged maintenance in whey resulted in the loss of the ability of BB-1L to produce viscous broths in whey, indicating a reversion to preferential growth on whey protein, like the parent strain.
Attomolar Detection of ssDNA Without Amplification and Capture of Long Target Sequences With Graphene Biosensors (2020)

Graphene-based biosensors can be produced in a scalable manner at reasonable cost, and they show significant promise for sensitive detection of small molecules and biomarkers such as proteins, single strand nucleic acids, and drug targets. Here, we describe an approach that enables a limit of detection of ~1 aM for a ssDNA target without amplification. We also show that a sensor based on a short (20mer) probe complementary to a portion of a longer (100mer) target provides enhanced sensitivity and saturation signal level. Finally, we show that graphene-based DNA biosensors can be repeatedly recycled with consistent sensor responses by melting off bound target strands. These results show the potential utility of this technology in nucleic acid detection for disease diagnostics.
Using acoustic radiation force to probe tissue mechanical properties: Challenges and strategies (2015)

The acoustic radiation force phenomenon provides a highly flexible instrument with which to probe the mechanical properties of tissue. The ability to shape the applied force both in time and space, combined with the high sensitivity of ultrasound motion tracking, enables a multitude of techniques for the estimation of tissue mechanical properties. A present challenge is to reduce the measurement variance of these properties so as to better distinguish subtle variations associated with disease stage. Shear wave tracking is the starting point for many of these techniques, and can be used to characterize tissue in terms of group velocity, as well in terms of tissue constitutive model parameters. This talk will discuss sources of error in shear wave velocity and tissue parameter estimation and strategies for their avoidance or compensation. Time-domain estimation of viscoelastic parameters using a wave propagation model and maximum likelihood estimator will be described, along with challenges due to non-ideal source geometries.
Tracking controlled chaos: Theoretical foundations and applications (1997)

Tracking controlled states over a large range of accessible parameters is a process which allows for the experimental continuation of unstable states in both chaotic and non-chaotic parameter regions of interest. In algorithmic form, tracking allows experimentalists to examine many of the unstable states responsible for much of the observed nonlinear dynamic phenomena. Here we present a theoretical foundation for tracking controlled states from both dynamical systems as well as control theoretic viewpoints. The theory is constructive and shows explicitly how to track a curve of unstable states as a parameter is changed. Applications of the theory to various forms of control currently used in dynamical system experiments are discussed. Examples from both numerical and physical experiments are given to illustrate the wide range of tracking applications. (c) 1997 American Institute of Physics.
Benzoyl-Substituted Ferrocenes:  An Attractive New Class of Anionic Photoinitiators (2000)

Spectroscopic, photochemical, and photoinitiation studies are reported for a series of monobenzoylferrocenes and 1,1‘-dibenzoylferrocenes. These nonionic metallocene complexes absorb strongly in the ultraviolet and visible wavelength regions owing to electronic transitions of mixed ligand field/charge-transfer character. Irradiation of the complexes in methanol results in ring−metal cleavage to yield a benzoyl-substituted cyclopentadienide carbanion and the corresponding half-sandwich iron(II) complex. This process occurs with an appreciable quantum efficiency (>0.30 at 546 nm) for 1,1‘-dibenzoylferrocenes; in contrast, monobenzoylferrocenes are appreciably less photosensitive. When the solvent is neat ethyl α-cyanoacrylate, the photogenerated carbanion initiates rapid anionic polymerization of this electrophilic monomer. Several factors that can influence the performance of benzoyl-substituted ferrocenes as anionic photoinitiators are considered.
Abstract 4414: EC0531: A potent folate-targeted tubulysin conjugate (2010)

Abstract Our lab is focused on the discovery and development of highly potent chemotherapeutic agents that target folate receptor (FR) expressing malignancies. One such compound, EC0305, represents a folate-tubulysin B construct capable of specifically eradicating well-established, FR-positive subcutaneous tumors from mice [Cancer Res (2008) 68:9839]. Recently, multiple polar carbohydrate segments (e.g. 1-amino-1-deoxy-glucitolyl–glutamate) were placed in-between the folate and tubulysin B moieties (i.e. the spacer region) of EC0305 to create a new compound with more desirable biological properties. When tested in culture, this novel agent, herein referred to as EC0531, was found to specifically inhibit the growth of FR-positive cells (IC50 of ∼ 2 nM) in a dose-dependent manner. Its cytotoxic activity was blocked in the presence of an excess of folic acid, and no activity was observed against FR-negative cells, thereby demonstrating this compound's target specificity. EC0531′s potency was confirmed againstin a human KB xenograft-nu/nu mice cancer model. Here, EC0531 therapy displayed remarkable anti-tumor activity (5/5 cures) with dose levels that did not cause weight loss or major organ tissue degeneration. In contrast, the anti-tumor activity was completely abolished (0/5 remissions) in EC0531-treated animals that were co-dosed with a benign folate-containing analog. The advantage provided by folate conjugation was further proven by the un-targeted free drug, which was found to be completely inactive (0/5 remissions) at both tolerable and highly toxic dose levels. Collectively, these results show that this potent anti-proliferative tubulysin compound can be specifically delivered to FR-positive tumors to provide substantial therapeutic benefit using well tolerated dosing regimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4414.
Recent Moisture Separator Reheater Design Technologies (2010)

The moisture separator reheater (MSR) is a key piece of equipment in reheat systems in nuclear steam turbines that use saturated main steam, where it helps improve turbine efficiency and suppress flow-accelerated corrosion. Fundamental to achieving a compact, reliable MSR design are methods for predicting mist separator vane performance and suppressing tube drainage instability. First, we devised a method for predicting separator performance based on the observation of mist separation behavior under an air-water test. We then developed a method for predicting performance under steam conditions from air-water test data and verified it by means of a comparison with the actual results of a steam condition test. The instability of tube drainage associated with both subcooling and temperature oscillation at turbine partial load, which might adversely affect the seal welding of the tubes to the tube sheet due to thermal fatigue, was measured on an existing unit to clarify the behavior. We then developed a technique for increasing venting steam, which had been operating at a constant flow rate, to suppress instability and verified its effectiveness. Both methods were applied to current MSR models, which were adopted for nuclear power plant turbines commercially placed in service from 1984 to 2009, and the effectiveness of the methods was demonstrated. The separator vane mist carryover rate was less than 0.1%, and tube drainage instability was suppressed, demonstrating the effectiveness of the simple design concept of a two-flow U-tube instead of the prevailing four-flow U-tube design. We put forth a new concept in the design of MSRs for 1700 MW class advanced pressurized water reactor (APWR) units based on associated technologies, along with advanced technology for the compact design of pressure vessels and multidisciplinary optimum design for evaluating heat exchanger tube bundles.
Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections (2021)

Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity <i>in vitro</i>, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into <i>in vivo</i> nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further <i>in vitro</i> evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, <i>in vivo</i> efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.
New fusion protein systems designed to give soluble expression inEscherichia coli (1999)

Three native E. coli proteins—NusA, GrpE, and bacterioferritin (BFR)—were studied in fusion proteins expressed in E. coli for their ability to confer solubility on a target insoluble protein at the C-terminus of the fusion protein. These three proteins were chosen based on their favorable cytoplasmic solubility characteristics as predicted by a statistical solubility model for recombinant proteins in E. coli. Modeling predicted the probability of soluble fusion protein expression for the target insoluble protein human interleukin-3 (hIL-3) in the following order: NusA (most soluble), GrpE, BFR, and thioredoxin (least soluble). Expression experiments at 37°C showed that the NusA/hIL-3 fusion protein was expressed almost completely in the soluble fraction, while GrpE/hIL-3 and BFR/hIL-3 exhibited partial solubility at 37°C. Thioredoxin/hIL-3 was expressed almost completely in the insoluble fraction. Fusion proteins consisting of NusA and either bovine growth hormone or human interferon-γ were also expressed in E. coli at 37°C and again showed that the fusion protein was almost completely soluble. Starting with the NusA/hIL-3 fusion protein with an N-terminal histidine tag, purified hIL-3 with full biological activity was obtained using immobilized metal affinity chromatography, factor Xa protease cleavage, and anion exchange chromatography. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 65: 382–388, 1999.
Active Digital Cancellation of Transmitter Induced Modulated Spur Interference in 4G LTE Carrier Aggregation Transceivers (2016)

Mobile user equipments supporting Long Term Evolution (LTE) - carrier aggregation (CA) face several new unpredicted issues when operating in frequency division duplex mode. This paper addresses the transmit (Tx) modulated spur problem, a new issue, that appears in LTE-CA transceivers. Due to the presence of several mixers and dividers to support different bands and CA scenarios, many harmonics are generated on the chip. Unavoidable crosstalk between these harmonics can generate an unwanted continuous wave spur around the Tx frequency. Once this spur appears at the chip area where the receive (Rx) local oscillator resides, it downconverts the undesired portion of the Tx signal which leaked through the duplexer to the Rx baseband. This interference, referred to as Tx modulated spur, causes a severe degradation of the signal-to-noise ratio (SNR) of the wanted signal. To mitigate such, we propose an active digital cancellation architecture which utilizes the known information of the Tx signal. An equivalent baseband model of the Tx modulated spur is presented from which the digital cancellation architecture is derived. Simulations show that the proposed architecture cancels the Tx interference and improves the SNR of the wanted signal significantly.
Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin (2007)

The exact molecular mechanism of how endostatin inhibits angiogenesis and tumor growth remains uncharacterized. Here, we report that endostatin specifically binds to the cell surface nucleolin with high affinity. Blockage of nucleolin by a neutralizing antibody or knockdown of nucleolin by the RNA interference results in loss of antiendothelial activities of endostatin. Importantly, a neutralizing antinucleolin antibody abrogates the antiangiogenic and antitumor activities of endostatin in vivo. Nucleolin and endostatin are colocalized on the cell surface of endothelial cells of angiogenic blood vessels in the tumor environment. Finally, we found that endostatin is internalized and transported into cell nuclei of endothelial cell via nucleolin. In the nucleus, the phosphorylation of nucleolin, which is critical for cell proliferation, can be inhibited by endostatin. Our studies demonstrate that nucleolin is a novel functional receptor for endostatin, and mediates the antiangiogenic and antitumor activities of endostatin. These findings also provide mechanistic insights of how endostatin specifically inhibits proliferating endothelial cell growth and angiogenesis.
A Synthesis of 3′,4′-Dideoxykanamycin B (1977)

Abstract 3′,4′-Dideoxykanamycin B was prepared from kanamycin B via 4″,6″-O-cyclohexylidenation, N-benzyloxycarbonylation, 3′,4′,2″-tri-O-benzylsulfonylation, double bond formation at C-3′,4′, removal of the cyclohexylidene group, simultaneous removal of the N,O-protecting groups with sodium metal in liquid ammonia and hydrogenation of the resulting 3′,4′-dideoxy-3′-eno-kanamycin B.
Clinical significance of scintillation camera electronics capable of high processing rates. (1977)

The use of larger scintillation detectors with high-efficiency converging collimators has greatly increased the photon input rate to the crystals of scintillation cameras in many clinical studies. To process these high-count-rate data accurately, modifications have been made by some manufacturers in the electronics of scintillation cameras. Cameras with new electronic design were compared with earlier models with respect to count rate processing capability and the effect of high input rate on spatial resolution, pulse-pair pileup, image size, and instability of the amplification of energy pulses. The improvements with the new electronic design result in shorter imaging times, better preservation of resolution, increased statistical reliability, and reduced distortion of dynamic tracer curves used for quantitative analysis.
Epigenetics in idiopathic pulmonary fibrosis (2015)

Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disorder with no effective treatment and a prognosis worse than that of lung cancer. Despite extensive research efforts, its etiology and pathogenesis still remain largely unknown. Current experimental evidence has shifted the disease paradigm from chronic inflammation towards the premise of abnormal epithelial wound repair in response to repeated epigenetic injurious stimuli in genetically predisposed individuals. Epigenetics is defined as the study of heritable changes in gene function by factors other than an individual's DNA sequence, providing valuable information regarding adaption of genes to environmental changes. Although cancer is the most studied disease with relevance to epigenetic modifications, recent data support the idea that epigenomic alterations may lead to variable disease phenotypes, including fibroproliferative lung disorders such as IPF. This review article summarizes the latest experimental and translational epigenetic studies in the research field of chronic lung disorders, mainly focusing on IPF, highlights current methodology limitations, and underlines future directions and perspectives.
Cell manipulation in microsystems for clinical and biological applications (2008)

The mission of the center is to develop and promote living-cell-based microdevices as key technologies in medicine and biological sciences. By integrating engineering methods and biological research into novel microsystem technologies, we aim to provide unique capabilities to biomedical investigators to probe, manipulate, engineer, and analyze biological cells for diagnostic, prognostic and therapeutic advances and basic biology discovery. This brief review describes our recent work in microchips for blood analysis, microfabricated living cell arrays, and microfluidic gradient generators for studies of cellular chemotaxis.
Preparation and Properties of Bonding Glass for Amorphous Magnetic Head (1992)

A new bonding glass which can be worked at a low temperature (480°C) and is resistant to water has been prepared. The glass is composed of SiO2-B2O3-PbO-ZnO-Al2O3-CdO with a low softening point (below 410°C) and a thermal expansion coefficient of (90-100)×10-7/°C comparable with that of a ferrite substrate. The composition of the glass with a high durability against water is as follows: SiO2=4wt%, B2O3=9wt%, PbO=75wt%, Al2O3=0-3wt%, ZnO=2-6wt%, CdO=5-12wt%.
Lock-free transactional support for large-scale storage systems (2011)

In this paper, we introduce ReTSO, a reliable and efficient design for transactional support in large-scale storage systems. ReTSO uses a centralized scheme and implements snapshot isolation, a property that guarantees that read operations of a transaction read a consistent snapshot of the data stored. The centralized scheme of ReTSO enables a lock-free commit algorithm that prevents unre-leased locks of a failed transaction from blocking others. We analyze the bottlenecks in a single-server implementation of transactional logic and propose solutions for each. The experimental results show that our implementation can service up to 72K transaction per second (TPS), which is an order of magnitude larger than the maximum achieved traffic in similar data storage systems. Consequently, we do not expect ReTSO to be a bottleneck even for current large distributed storage systems.
A Selective Decision-Feedback Detector for Space-Time Block Code with Combined Diversity and Spatial Multiplexing (2007)

Selective decision feedback detection (SDFD) is investigated for decoding the space-time block code which provides both diversity gain and spatial multiplexing gain. In SDFD, the system matrices are formulized with the real and imaginary parts decoupled before the channel matrix is Q-R decomposed (QRD). With a column permutation of the channel matrix, two candidates for the solution are obtained. The candidate with the lesser mean square error is selected as the detector output. SDFD is simpler than the sphere detector, while the error performance in certain conditions is very close to that provided by the optimum detector.