gebhart/patrepeval huggingface dataset:
Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings (2023)

ABSTRACT Targeted protein degradation (TPD) of neo-substrates with proteolysis targeting chimeras (PROTACs) or molecular glues has emerged as a key modality in exploring new biology as well as designing new drug candidates where catalytic inhibition is neither efficacious nor an option. TPD is mediated through harnessing E3 ligases and redirecting them to ubiquitinate de novo target proteins for subsequent proteasomal degradation. Until recently, E3 ligase chemical matter available for mediating TPD has been limited to a relatively low number of ligases, considering that over 600 E3 ligases are encoded by the human genome. In addition, the most utilized ligase for TPD approaches, CRBN, has been observed to be downregulated in settings of acquired resistance to immunomodulatory inhibitory drugs (IMiDs). IMiDs are molecular glues that target IKZF transcription factors to CRBN for degradation. Resistance is potentially accelerated by non-essentiality of CRBN for cell viability. Here we investigated if the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a potent, non-covalent DCAF1 binder. We show that this binder, selective for the CRL4 DCAF1 E3 ligase complex, can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirm specific degradation via the CRL4 DCAF1 E3 ligase. We further highlight the versatility of DCAF1 for TPD by developing a DCAF1-dasatininb PROTAC targeting multiple cytosolic and membrane bound tyrosine kinases. We expand these findings towards Bruton’s tyrosine kinase (BTK) selective PROTACs and through extensive optimization and characterization efforts share key observations that led to a potent and selective DCAF1-BTK PROTAC (DBt-10). Finally, with this PROTAC DBt-10, we show rescue of BTK degradation in a BTK-dependent, CRBN-degradation-resistant cell line and provide a rationale for E3 ligase swap to overcome CRBN mediated resistance.
Figure S1 from Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer (2023)

&lt;p&gt;Chemoresistant cell lines&lt;/p&gt;
CMH-Small Molecule Docks into SIRT1, Elicits Human IPF-Lung Fibroblast Cell Death, Inhibits Ku70-deacetylation, FLIP and Experimental Pulmonary Fibrosis (2020)

Regenerative capacity in vital organs is limited by fibrosis propensity. Idiopathic pulmonary fibrosis (IPF), a progressive lung disease linked with aging, is a classic example. In this study, we show that in flow cytometry, immunoblots (IB) and in lung sections, FLIP levels can be regulated, in vivo and in vitro, through SIRT1 activity inhibition by CMH (4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide), a small molecule that, as we determined here by structural biology calculations, docked into its nonhistone substrate Ku70-binding site. Ku70 immunoprecipitations and immunoblots confirmed our theory that Ku70-deacetylation, Ku70/FLIP complex, myofibroblast resistance to apoptosis, cell survival, and lung fibrosis in bleomycin-treated mice, are reduced and regulated by CMH. Thus, small molecules associated with SIRT1-mediated regulation of Ku70 deacetylation, affecting FLIP stabilization in fibrotic-lung myofibroblasts, may be a useful strategy, enabling tissue regeneration.
Simulation of Nanostructural Formation in Cathode Catalyst Layer of a PEM Fuel Cell (2007)

Abstract not Available.
Consequences of rock layers and interfaces on hydraulic fracturing and well production of unconventional reservoirs (2018)

Hydraulic fracturing is a fundamental condition for economic production of hydrocarbons from unconventional reservoirs. Hydrocarbon production is proportional to the propped surface area that is in contact with the reservoir and remains connected to the wellbore. Yet, the propped surface area controlling production appears to be considerably smaller than the surface area created during pumping. Somehow hydraulic fractures are disconnected, truncated, and reduced during production. One important mechanism causing this segmentation is the shear displacement of weak interfaces between rock layers. Shear stresses are generated in response to abrupt changes in material properties and changes in bed orientation, in relation to the orientation of the existing principal stresses. If the layered rocks are strongly laterally heterogeneous, they provide a high potential for shear failures and fracture segmentation along the interfaces between layers. The induced shear stress and shear slip also depend on the current geologic structure and following in situ stress loading, the stress alteration and fluid leakoff during hydraulic fracturing, and the existence of wells. We conducted numerical simulations using the finite-element method on layered and discontinuous rocks, and specifically in organic-rich mudstones and carbonate sequences. Our work was part of a field study. Three different layered rock models were simulated and compared: laterally homogeneous, laterally heterogeneous, and strongly laterally heterogeneous. For the latter, the heterogeneity was introduced by randomly varying the elastic rock properties of each layer. Our results indicate that localized shear stresses develop along interfaces between materials with contrasting properties and along the wellbore walls. This includes the generation of localized shear in planes that were principal in the homogeneous model. It was also seen that rock shear and slip, along interfaces between layers, may occur when the planes of weakness are pressurized (e.g., during hydraulic fracturing).
A RISK BASED COST MODEL OF A SHELL-AND-TUBE HEAT EXCHANGER SUBJECT TO FOULING (2023)

Fouling may be defined as the deposition of unwanted material on heat transfer equipment that reduces heat-transfer and increases the resistance to fluid flow. Once the thermal-hydraulic performance decreases to a minimum acceptable level, cleaning of the equipment has to be done to restore the performance. The decision regarding periodic off-line maintenance of the heat exchangers is generally based on a thermoeconomic performance of the process. In this paper, we discuss a maintenance model by incorporating the risk level and scatter parameter of the four random fouling growth models, namely linear, power law, falling rate and asymptotic models, which are integrated in the dimensionless cost model for a heat exchanger used in a crude oil preheat train.
Genome-Wide Mapping of DNA Strand Breaks (2011)

Determination of cellular DNA damage has so far been limited to global assessment of genome integrity whereas nucleotide-level mapping has been restricted to specific loci by the use of specific primers. Therefore, only limited DNA sequences can be studied and novel regions of genomic instability can hardly be discovered. Using a well-characterized yeast model, we describe a straightforward strategy to map genome-wide DNA strand breaks without compromising nucleotide-level resolution. This technique, termed "damaged DNA immunoprecipitation" (dDIP), uses immunoprecipitation and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL) to capture DNA at break sites. When used in combination with microarray or next-generation sequencing technologies, dDIP will allow researchers to map genome-wide DNA strand breaks as well as other types of DNA damage and to establish a clear profiling of altered genes and/or intergenic sequences in various experimental conditions. This mapping technique could find several applications for instance in the study of aging, genotoxic drug screening, cancer, meiosis, radiation and oxidative DNA damage.
Nanostructural evidence of mechanical aging and performance loss in ballistic fibers Part B Polymer physics (2017)

It is understood that the ballistic resistance of aromatic polyamide fibers is related to the fiber's ultimate tensile strength, strain‐to‐failure, and Young's modulus. Ideal high‐performance ballistic materials maximize these properties while minimizing material density. Equally important is long‐term mechanical and chemical stability: the fibers should not exhibit performance loss over their lifetime. However, less is known quantitatively about their modes of degradation, and experimental methods to quantify the aging and degradation in these fibers are critical. Multiple variations of next generation high‐performance fibers have been investigated under chemical and mechanical accelerated aging conditions. Performance losses have been empirically correlated to chemical degradation of the polymer chain and nanostructural changes in the fiber morphology through X‐ray photoelectron spectroscopy (XPS). Here, we introduce positron annihilation lifetime spectroscopy measurements as a sensitive method to quantify the early onset of damage in the flexed fibers as quantified through changes in the nanoscale void structure in the material. Published 2017.† J. Polym. Sci., Part B: Polym. Phys. 2017, 55, 1711–1717
Inside Back Cover: Suzuki–Miyaura Diversification of Amino Acids and Dipeptides in Aqueous Media (ChemCatChem 14/2015) (2015)

The Inside Back Cover picture shows palladium-catalyzed derivatisations of halogenated phenylalanine and tryptophan and dipeptide substrates containing these entities in view of the optimization of lead peptide ligands for improved receptor interactions. A wide scope of substrates is presented to highlight the tolerated peptide functionality during the application of the Suzuki-Miyaura reaction in aqueous media. In their Full Paper, T. Willemse et al. investigate the influence of unprotected peptide functionalities on the progress of the Pd-catalyzed reaction. In the background, the collaboration between the Maes and Ballet laboratories is emphasized by the skylines of Antwerp and Brussels. The article highlighted by this cover can be found on p. 2055 ff. of Issue 14, 2015.
Cytolytic thymus-derived lymphocytes specific for allogeneic stimulator cells crossreact with chemically modified syngeneic cells. (1977)

Mouse spleen cells cocultured with irradiated allogeneic stimulator cells develop cytolytic effector cells capable of lysing 51Cr-labeled syngeneic trinitrophenyl-derivatized tumor or spleen targets and to a lesser degree unconjugated tumor cells in addition to the allogeneic stimulator cells. Lysis of trinitrophenyl-syngeneic targets was inhibited competitively by cold trinitrophenyl-syngeneic tumor or spleen targets as well as by cells bearing the allogeneic stimulator H-2 haplotype demonstrating the immunological specificity of the interaction. Allogeneic H-2 specificities may, therefore, be considered variants of modified autologous H-2 specificities against which cytolytic thymus-derived clones potentially exist that are capable of exerting immunological surveillance.
A Streamlined Ribosome Profiling Protocol for the Characterization of Microorganisms (2015)

Ribosome profiling is a powerful tool for characterizing in vivo protein translation at the genome scale, with multiple applications ranging from detailed molecular mechanisms to systems-level predictive modeling. Though highly effective, this intricate technique has yet to become widely used in the microbial research community. Here we present a streamlined ribosome profiling protocol with reduced barriers to entry for microbial characterization studies. Our approach provides simplified alternatives during harvest, lysis, and recovery of monosomes and also eliminates several time-consuming steps, in particular size-selection steps during library construction. Furthermore, the abundance of rRNAs and tRNAs in the final library is drastically reduced. Our streamlined workflow enables greater throughput, cuts the time from harvest to the final library in half (down to 3-4 days), and generates a high fraction of informative reads, all while retaining the high quality standards of the existing protocol.
<title>Adaptive phased-array radar processing using photorefractive crystals</title> (1990)

An unconstrained, adaptive, null-steering phased-array optical processor that utilizes a photorefractive crystal to time-integrate the adaptive weights, and null out correlated jammers is described. A passive processor is presented, where it is assumed that it is only known a priori that the signal is broad-band and the jammers are narrow-band. The passive processor computes the angle(s) of arrival of the jammers and extinguishes them. Also presented is an active processor in which the temporal waveform of the desired signal is known, but the look direction is not. The processor computes the angle(s) of arrival of the desired signal and steers the array to look in that direction while nulling any narrow-band jammers. These are two embodiments of a class of processors which use the angular selectivity of volume holograms to form the nulls and look directions in an adaptive phased array radar antenna pattern
Detection in a nonstationary waveguide using orthogonal codes to measure the invariants of the time reversal operator (2006)

In underwater acoustics, time reversal (TR) techniques using an array of acoustic sources are commonly known for their efficiency in applications such as communication and detection. However, as TR methods assume stationary conditions, they are clearly affected by fluctuations of the medium. Among them, the decomposition of the time reversal operator (DORT method), although highly efficient for separating the echo from two close targets through a complex medium, suffers from the long acquisition time required. Indeed the whole interelement responses are needed meaning that N signals are acquired for an N-transducer array. The measurement is then at least N times longer than travel time. To reduce the acquisition time, orthogonal codes can be used [Folgot et al., J. Acoust. Soc. Am. 117, 3757–3765 (2005)]. These codes are tested in a laboratory detection experiment: a small-scale model of a shallow-water wave guide in which we add artificial surface waves of different frequencies and different amplitudes. The perturbations induced by the surface waves on the invariant of the time reversal operator are analyzed. Different methods which greatly reduce the acquisition time like Kasami and AIRS codes are compared.
Possible role of steady streaming flows in fish hearing. (2009)

Over the last five years, the authors have studied the time-independent portion, or the steady streaming, of flows near model otoliths and determined that these flows encode both the direction and frequency of incident sounds. This talk summarizes these findings and discusses whether the fish ear can detect the displacements due to these flows. Although the results for a model cod otolith indicate that information relating to the direction of the local sound field is indeed contained within the flow patterns in the vicinity of the sensory macula, the threshold for the detectability of these directional cues appears to be much higher than published thresholds for directionalization in fish. There is some evidence, however, that the observed thresholds may have been underestimated. While these studies indicate that steady streaming flows may be insufficient to explain directionalization in fish, the results suggest that steady streaming may provide a mechanism for fish to hear ultrasound. [Work supported by ONR.]
Electron beam induced annealing of defects in GaAs (1977)

It has recently been shown that minority-carrier injection greatly increases the annealing rate of 1-MeV electron damage in GaAs. Energy deposited during nonradiative recombination at the radiation damage defects has been shown by Kimerling and Lang to be responsible for this effect. We have confirmed this effect in experiments in which carrier injection was achieved by 15–45-keV electron irradiation. The annealing process was monitored during irradiation by measurement of the charge collected at a p-n junction within the material. Carrier lifetime improvements of 100% were observed, and could be produced at rates 100 times faster than those reported by Kimerling and Lang when focused electron beam annealing was employed. Dislocations were observed to act as sinks for the defects. Focused electron beam annealing was employed to ’’write’’ annealed patterns in GaAs.
Integrated coherent Ising machines for next-generation optimization accelerators (2021)

Coherent Ising machines have been proposed as a promising platform for combinatorial optimization. Initial fiber-based, FPGA-assisted instantiations experimentally outperform quantum annealers based on superconducting qubits in speed and energy-efficiency due their ability to have programmable all-to-all connectivity between the Ising nodes. Since then, multiple flavors of coherent Ising machines have been proposed based on silicon photonics. In this talk, we will compare and contrast these integrated Ising machines with their table-top setup counterparts and their upcoming competitors in digital and analog electronics. Moreover, we will explain how large-scale problems can be mapped to small-scale integrated Ising cores.
Aprepitant for Symptoms of Gastroparesis and Related Disorders: The APRON Randomized Clinical Trial (2016)

Introduction: There is a paucity of treatments for patients with gastroparesis (Gp) and related syndromes associated with chronic nausea and vomiting. Here we report on the effects of the neurokinin-1 receptor antagonist aprepitant, on symptoms in these patients. Methods: The APRON (Aprepitant for the Relief of Nausea) was a 4-week multicenter, parallel-group, double-masked, randomized clinical trial comparing aprepitant (125 mg orally daily) with placebo for symptomatic relief of patients with nausea and vomiting of suspected gastric dysfunction. As in aprepitant trials for chemotherapy, a patient-reported visual analog scale (VAS 0-100) for nausea was chosen as the primary outcome, with improvement defined as either a ≥25 mm reduction in 4-week mean VAS or attaining a 4-week mean VAS < 25 mm. Other measures included the Gastroparesis Cardinal Symptom Index (GCSI) and global Gastrointestinal Symptom Rating Scale (GSRS). Results: (Table) 126 patients were randomized to either aprepitant (n=63) or placebo (n=63) of which 72 (57%) patients had delayed gastric emptying (Gp) and the rest had normal or rapid emptying with symptoms of Gp. Diabetes was present in 37 (29%) patients. There was no difference amongst the treatment groups in the proportion of patients achieving the primary outcome of improvement of nausea (46% [29/63] with aprepitant vs. 40% [25/63] with placebo; RIR=1.2, 95% CI: 0.8-1.7; P=0.43). Compared with placebo, aprepitant use resulted in a greater decline in mean 4-week daily hours of nausea (-2.5 vs. -1.2 hrs; P=0.03), mean 4-week GCSI score (-1.3 vs -0.7; P=0.001), and greater improvement in multiple other PAGI-SYM and GSRS measures (Table). 20 patients (31.7%) in the aprepitant group and 10 patients (15.9%) in the placebo group experienced at least one adverse effect (P=0.10). Most adverse effects were of mild to moderate severity and expected; none were serious.Figure 1Conclusion: While the pre-specified primary outcome defined by a nausea VAS was not achieved, more commonly used Gp measures showed statistically significant benefits with aprepitant including overall symptom relief (4-week GCSI), and GCSI scores for nausea, vomiting, postprandial fullness, bloating, and abdominal pain. These data suggest that aprepitant has high potential for effective and safe improvement of a variety of symptoms in Gp and related disorders. Our results encourage further trials with attention to the sensitivity of outcome metrics to treatment effects.
Selectin Ligand Sialyl-Lewis x Antigen Drives Metastasis of Hormone-Dependent Breast Cancers (2011)

The glycome acts as an essential interface between cells and the surrounding microenvironment. However, changes in glycosylation occur in nearly all breast cancers, which can alter this interaction. Here, we report that profiles of glycosylation vary between ER-positive and ER-negative breast cancers. We found that genes involved in the synthesis of sialyl-Lewis x (sLe(x); FUT3, FUT4, and ST3GAL6) are significantly increased in estrogen receptor alpha-negative (ER-negative) tumors compared with ER-positive ones. SLe(x) expression had no influence on the survival of patients whether they had ER-negative or ER-positive tumors. However, high expression of sLe(x) in ER-positive tumors was correlated with metastasis to the bone where sLe(x) receptor E-selectin is constitutively expressed. The ER-positive ZR-75-1 and the ER-negative BT20 cell lines both express sLe(x) but only ZR-75-1 cells could adhere to activated endothelial cells under dynamic flow conditions in a sLe(x) and E-selectin-dependent manner. Moreover, L/P-selectins bound strongly to ER-negative MDA-MB-231 and BT-20 cell lines in a heparan sulfate (HS)-dependent manner that was independent of sLe(x) expression. Expression of glycosylation genes involved in heparan biosynthesis (EXT1 and HS3ST1) was increased in ER-negative tumors. Taken together, our results suggest that the context of sLe(x) expression is important in determining its functional significance and that selectins may promote metastasis in breast cancer through protein-associated sLe(x) and HS glycosaminoglycans.
Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling (2017)

A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.
Remarkable Enhancement of Enantioselectivity in the Asymmetric Conjugate Addition of Dimethylzinc to (Z)‐Nitroalkenes with a Catalytic [(MeCN)4Cu]PF6–Hoveyda Ligand Complex (2014)

Abstract An enantioselective copper‐catalyzed asymmetric conjugate addition of Me 2 Zn to (Z)‐nitroalkenes led to the formation of all‐carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN) 4 Cu]PF 6 in conjunction with the Hoveyda ligand L1 and the use of (Z)‐nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)‐selective nitroalkene synthesis.
Bonfire (2009)

We present Bonfire, a self-contained mobile computing system that uses two laptop-mounted laser micro-projectors to project an interactive display space to either side of a laptop keyboard. Coupled with each micro-projector is a camera to enable hand gesture tracking, object recognition, and information transfer within the projected space. Thus, Bonfire is neither a pure laptop system nor a pure tabletop system, but an integration of the two into one new nomadic computing platform. This integration (1) enables observing the periphery and responding appropriately, e.g., to the casual placement of objects within its field of view, (2) enables integration between physical and digital objects via computer vision, (3) provides a horizontal surface in tandem with the usual vertical laptop display, allowing direct pointing and gestures, and (4) enlarges the input/output space to enrich existing applications. We describe Bonfire's architecture, and offer scenarios that highlight Bonfire's advantages. We also include lessons learned and insights for further development and use.