gebhart/patrepeval huggingface dataset:
Data from RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy (2023)

&lt;div&gt;Abstract&lt;p&gt;&lt;i&gt;PIK3CA&lt;/i&gt; is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with &lt;i&gt;PIK3CA&lt;/i&gt;-mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer.&lt;/p&gt;Significance:&lt;p&gt;The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in &lt;i&gt;PIK3CA&lt;/i&gt;-mutant tumors.&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-21-1411" target="_blank"&gt;See related commentary by Vanhaesebroeck et al., p. 20&lt;/a&gt;.&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;i&gt;&lt;a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-1-ITI" target="_blank"&gt;This article is highlighted in the In This Issue feature, p. 1&lt;/a&gt;&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;
Kisspeptin Modulates Mitochondrial Metabolic State and Potentiates Glucose Stimulated Insulin Secretion in INS 832/3 Cells and Pseudo-Islets (2023)

Glucagon Like Peptide-1 (GLP-1) and Kisspeptin (KP) receptors are co-expressed on pancreatic β-cells, and activation of both receptors potentiates glucose-stimulated insulin secretion (GSIS). Due to their roles in enhancing GSIS, GLP-1 and KP represent targets for controlling blood glucose in patients with diabetes. Unlike GLP-1, KP has a low affinity for receptor activation (EC50 GLP-1 ~20 nM vs KP ~1 μM) making it difficult to use as a therapeutic agent. GLP-1 has been shown to potentiate insulin secretion via cAMP dependent pathways. Conversely, previous studies in isolated rat islets of Langerhans indicated that KP potentiation of GSIS was not dependent on cAMP and may be related to changes in beta cell metabolism (Schwetz TA, et al., Differential Stimulation of Insulin Secretion by GLP-1 and Kisspeptin-10. PLoS ONE 9: e113020, 2014). In the current studies, we evaluated KP signaling in comparison to GLP-1, in order to determine if there are unique components to target in the KP signaling pathway. The effects of GLP-1 and a 10 amino acid analog of KP (KP10) on insulin secretion and cell signaling were compared in insulinoma INS 832/3 cells. As previously described, KP had no effect on insulin secretion in the absence of glucose. In the presence of stimulatory glucose (15.5 mM), KP10 (10 μM) doubled insulin secretion (GSIS without KP10= 471.3 +/- 83.8, GSIS with KP10 = 865.0 +/- 23.8 pgm/min; +/- SEM) with an EC50 of ~5-10 μM. At saturating doses, KP10 (100 μm) and GLP-1 (100 nM) had similar effects on GSIS. Importantly, in combination, they had an additive effect (GLP-1 = 612.5 +/- 25.0, GLP-1 + KP-10 = 739.8 +/- 70.0 pgm/min) consistent with activation of independent downstream signaling pathways. GLP-1 increased cAMP production (165.0 +/- 17.4% over control), whereas KP-10 had no effect. Neither GLP-1 nor KP-10 altered intracellular Ca2+ levels at basal or activating glucose concentrations. Conversely, the addition of KP-10 enhanced glucose-stimulated oxygen consumption (% change over baseline O_2 consumption= 221.2 +/- 44.2%) from INS 832/3 pseudo-islets (Hart et al. Insulinoma-derived pseudo-islets for diabetes research. Am. J. Physio. 321, C247-C256, 2021) which was correlated with a sustained increase in mitochondrial NADH fluorescence. Our findings indicate that KP modulation of mitochondrial metabolic state is related to its ability to potentiate GSIS. Moreover, the KP induced potentiation is synergistic with that promoted by GLP-1 indicating the potential for targeting the KP activated metabolic pathway to further enhance GLP-1 therapeutic effectiveness. Funded by the Juvenile Diabetes Research Foundation (2-SRA-2018-685-S-B), and Procyon Technologies LLC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy (2021)

The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.
Molecular defect (Gla+ 14----Lys) and its functional consequences in a hereditary factor X deficiency (factor X" Vorarlberg"). (2021)

Factor X (FX) "Vorarlberg" is a congenital FX deficiency characterized clinically by a mild bleeding tendency. Homozygous individuals have a FX activity of less than 10% in the extrinsic system and 25% in the intrinsic system. FX antigen is 20%. Using molecular techniques, two point mutations were detected in the coding sequence of the FX Vorarlberg gene: a G----A at base pair 160 in exon II resulting in a change of Gla14 (GAA) to Lys (AAA); a G----A at base pair 424 in exon V resulting in a change from Glu102 (GAG) to Lys (AAG). The mutations abolished a TaqI restriction site in exon II and an MnlI site in exon V. To determine whether these mutations are present on one or on both alleles, restriction analyses of amplified exon II and exon V fragments were performed. Analysis of the pedigree showed that the genotype for the mutation on exon II (homozygous versus heterozygous) correlates with the severity of the phenotypic coagulation defect. We therefore conclude that the mutation in exon II is responsible for the functional defect in FX Vorarlberg. We have also purified the mutant FX protein from patient plasma. Purified FX Vorarlberg is indistinguishable from normal FX on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its activity is 15% of normal FX upon activation with factor VIIa/tissue factor, 75% upon activation with factor IXa/factor VIIIa, and 100% upon activation with RVV. Activation at varying Ca2+ concentrations shows that the affinity of FX Vorarlberg for Ca2+ is decreased. Factor Xa Vorarlberg is able to convert prothrombin at a normal rate but also shows decreased affinity for Ca2+ in this interaction. Upon addition of Ca2+, FX Vorarlberg does not undergo the same conformational change as normal FX. Our data show that FX Vorarlberg has a decreased affinity for Ca2+ which impedes a normal conformational change. This leads to a decreased rate of activation by factor VIIa/tissue factor and by factor IXa. The decrease is much more marked for the extrinsic than for the intrinsic pathway.
Polymer Supported Reagents: An Efficient Method for the Synthesis of Diaryloxymethanes (1990)

Abstract Diaryloxymethanes were synthesized in high yield and in high purity by the treatment of polymer supported phenoxide ions with dichloromethane.
Capillary rise of surfactant solutions (2000)

The capillary flow of surfactant solutions in hydrophobic and hydrophilic capillaries has been studied. The results obtained are discussed in the light of surface tension relaxation and adsorption phenomena. Modes of surfactant transport and effects of surfactant adsorption, aggregation, and monomer–micelle interconversion on the capillary rise dynamics are further analyzed in the framework of a theoretical model. This provides a self-consistent and quantitatively correct picture of the experimental results. In the case of hydrophobic capillaries, two limiting types of dynamic behavior are adsorption-controlled rise and diffusion-controlled rise. In some cases, slow relaxation of adsorbed layers at the liquid/solid interface can cause a drift of the rise height over a long time under quasi-equilibrium conditions. A slow relaxation, as compared to the capillary rise rate, of the liquid/vapor interface may also produce a maximum in the rise s. time curve. This behavior was, for instance, seen for a surfactant solution penetrating into a hydrophilic capillary.
ChemInform Abstract: Thermotropic Liquid Crystalline Glycolipids (2008)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Molecular predictors of therapeutic response to specific anti-cancer agents (2023)

Herein is described the use of a collection of 50 breast cancer cell lines to match responses to 77 conventional and experimental therapeutic agents with transcriptional, proteomic and genomic subtypes found in primary tumors. Almost all compounds produced strong differential responses across the cell lines produced responses that were associated with transcriptional and proteomic subtypes and produced responses that were associated with recurrent genome copy number abnormalities. These associations can now be incorporated into clinical trials that test subtype markers and clinical responses simultaneously.
Application of Proper Orthogonal Decomposition to High Speed Imaging for the Study of Combustion Oscillations (2017)

The flame structure and characteristics generated by an industrial low emission, lean premixed, fuel swirl nozzle were analyzed for understanding combustion oscillations. The experimental facility is located at the Advanced Propulsion and Power Laboratory (APPL) at Virginia Tech. The experiments were carried out in a model optical can combustor operating at atmospheric pressures. Low-frequency oscillations (&lt;100 Hz) were observed during the reaction as opposed to no reaction, cold flow test cases. The objective of this paper is to understand the frequency and magnitude of oscillations due to combustion using high-speed imaging and associate them with corresponding structure or feature of the flame. Flame images were obtained using a Photron Fastcam SA4 high-speed camera at 500 frames per second. The experiments were conducted at equivalence ratios of 0.65, 0.75; different Reynolds numbers of 50K, 75K; and three pilot fuel to main fuel ratios of 0%, 3%, 6%. In this study, Reynolds number was based on the throat diameter of the fuel nozzle. Since the time averaged flame images are not adequate representation of the flame structures, proper orthogonal decomposition (POD) was applied to the flame images to extract the dominant features. The spatiotemporal dynamics of the images can be decomposed into their constituent modes of maximum spatial variance using POD so that the dominant features of the flame can be observed. The frequency of the dominant flame structures, as captured by the POD modes of the flame acquisitions, were consistent with pressure measurements taken at the exit of the combustor. Thus, the oscillations due to combustion can be visualized using POD. POD was further applied to high-speed images taken during instabilities. Specifically, the instabilities discussed in this paper are those encountered when the equivalence ratio is reduced to the levels approaching lean blowout (LBO). As the equivalence ratio is reduced to near blowout regime, it triggers low-frequency high amplitude instabilities. These low-frequency instabilities are visible as the flapping of the flame. The frequencies of the dominant POD modes are consistent with pressure measurements recorded during these studies.
SRI'S 2004 BROADCAST NEWS SPEECH TO TEXT SYSTEM (2004)

We describe the system that we used to automatically transcribeBroadcastNewsSpeechin the2004NIST evaluationssponsored by the DARPA EARS program. We also describe some of our efforts leading up to the NIST evaluation, in particular, concerning data selection and model training. Since one of the hallmarksofthe 2004evaluationwasthe availabilityof relatively large amounts of quickly transcribed data, we describe our techniques, and those of others in adapting this data for model training, and experiments attempting to evaluate the suitability of this data for training purposes. We concludeby presenting results and also discussing whether or not increases in amounts of training data proportionately benefit the research community.
Resistive Switching of Individual, Chemically Synthesized TiO2Nanoparticles (2015)

Resistively switching devices are considered promising for next-generation nonvolatile random-access memories. Today, such memories are fabricated by means of "top-down approaches" applying thin films sandwiched between nanoscaled electrodes. In contrast, this work presents a "bottom-up approach" disclosing for the first time the resistive switching (RS) of individual TiO2 nanoparticles (NPs). The NPs, which have sizes of 80 and 350 nm, respectively, are obtained by wet chemical synthesis and thermally treated under oxidizing or vacuum conditions for crystallization, respectively. These NPs are deposited on a Pt/Ir bottom electrode and individual NPs are electrically characterized by means of a nanomanipulator system in situ, in a scanning electron microscope. While amorphous NPs and calcined NPs reveal no switching hysteresis, a very interesting behavior is found for the vacuum-annealed, crystalline TiO(2-x) NPs. These NPs reveal forming-free RS behavior, dominantly complementary switching (CS) and, to a small degree, bipolar switching (BS) characteristics. In contrast, similarly vacuum-annealed TiO2 thin films grown by atomic layer deposition show standard BS behavior under the same conditions. The interesting CS behavior of the TiO(2-x) NPs is attributed to the formation of a core-shell-like structure by re-oxidation of the reduced NPs as a unique feature.
Characterization of Microbridges Generated on Negative Resist Patterns (1999)

We analyze the mechanism of microbridge formation on chemically amplified negative resist patterns through direct observation of progressive development in alkali-developers. The microbridge formation was attributed to contact occurring between adjacent resist patterns due to swelling of the resist. These swollen resist patterns contracted upon immersion in deionized water; however, bridge structures remained as microbridges between these patterns. The swelling of the resist films occurred more easily at defocus positions than at a focus center, and the microbridges localized near the top of the pattern at defocus positions and delocalized at a focus center. An optical simulation suggested that both the crosslinking density and its distribution determine the number and position of the microbridges. A scaling law governing microbridge formation is observed as a function of focus position and exposure dose.
Repeatability and Reproducibility of the RTgill-W1 Cell Line Assay for Predicting Fish Acute Toxicity (2019)

Predicting fish acute toxicity of chemicals in vitro is an attractive alternative method to the conventional approach using juvenile and adult fish. The rainbow trout (Oncorhynchus mykiss) cell line assay with RTgill-W1 cells has been designed for this purpose. It quantifies cell viability using fluorescent measurements for metabolic activity, cell- and lysosomal-membrane integrity on the same set of cells. Results from over 70 organic chemicals attest to the high predictive capacity of this test. We here report on the repeatability (intralaboratory variability) and reproducibility (interlaboratory variability) of the RTgill-W1 cell line assay in a round-robin study focusing on 6 test chemicals involving 6 laboratories from the industrial and academic sector. All participating laboratories were able to establish the assay according to preset quality criteria even though, apart from the lead laboratory, none had previously worked with the RTgill-W1 cell line. Concentration-response modeling, based on either nominal or geometric mean-derived measured concentrations, yielded effect concentrations (EC50) that spanned approximately 4 orders of magnitude over the chemical range, covering all fish acute toxicity categories. Coefficients of variation for intralaboratory and interlaboratory variability for the average of the 3 fluorescent cell viability measurements were 15.5% and 30.8%, respectively, which is comparable to other fish-derived, small-scale bioassays. This study therefore underlines the robustness of the RTgill-W1 cell line assay and its accurate performance when carried out by operators in different laboratory settings.
Figure S1 from Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth <i>In Vitro</i> and <i>In Vivo</i> (2023)

&lt;p&gt;Supplementary figure S1&lt;/p&gt;
Fabrication of three-dimensional photonic crystals using lithographic processes (2004)

In this paper we present lithographic-based fabrication methods for the realization of three-dimensional photonic crystals (PhCs). These methods are based on novel implementations of single and multi-step UV lithography. To this end, we begin by presenting a technique based on a multi-step process that allows for the stacking of planar photonic lattice layers that when repeated in the vertical direction serves to construct a three-dimensional PhC lattice. This process offers the unique ability to implement arbitrary defects, which thereby enables resonant cavities and embedded PhC waveguides. In addition, we also present a process based on three-dimensional interference lithography, which enables the realization of 3D photonic crystal lattices in a single lithographic step. Details of these processes and preliminary experimental results are presented.
High-power, high-reliability 1.48-μm strained-layer multiple-quantum-well laser and its application to a high-performance erbium-doped-fiber amplifer (1993)

High-power semiconductor laser diodes (LD’s) emitting at a 1.48-μm wavelength have become increasingly important as pumping light sources for erbium-doped-fiber amplifiers (EDFA’s).1,2 Recently, introducing strained-layer multiple quantum wells (SL-MQW’s) as active layers in the LD’s has been a most promising approach for enhancing the output power of long-wavelength LD’s.3,4 Elsewhere we have reported fabrication of what is, to our knowledge, the most powerful yet 1.48-μm SL-MQW LD with a compressive strain of 1%.4 In this paper we report the reliability test of the 1.48-μm SL-MQW LD’s at an output power of 160 mW. We also describe the fabrication and the characterization of the pumping-LD module and EDFA with a single pumping LD in application of high-output-power 1.48-μm SL-MQW LD.
Security Bootstrapping Solution for Resource-Constrained Devices (2012)

We present a solution to initially configure the network of resource
constrained nodes securely, a.k.a., security bootstrapping. The
solution is based on EAP-TLS authentication with the use of raw public
keys as certificates.
Let Them Fall Where They May: Capture Regions of Curved Objects and Polyhedra (1997)

When a three-dimensional object is placed in contact with a supporting plane, gravitational forces move it to one of a finite set of stable poses. For each stable pose, there is a region in the part's configuration space called a capture region; for any initial configuration within the region, the object is guaranteed to converge to that pose. The problem of computing maximal capture regions from an object model is analyzed assuming only that the dynamics are dissipative; the precise equations governing the system are unnecessary. An algorithm, based on Morse theory, is first developed for objects with smooth, convex hulls. The formulation is then extended to objects with piecewise-smooth hulls using a catalog of critical points de rived from stratified Morse theory. Algorithms have been fully implemented for objects with smooth and polyhedral convex hulls. As examples from the implementation demonstrate, calcu lating these regions from a geometric model is computationally practical.
Critical Undercooling in DNA-Mediated Nanoparticle Crystallization* (2020)

The nucleation of DNA-functionalized nanoparticle superlattices is observed to exhibit a temperature hysteresis between melting (superlattice dissociation) and freezing (particle association) transitions that allows for the study of nucleation thermodynamics. Through detailed study of the assembly of these particles, which can be considered programmable atom equivalents (PAEs), we identify this hysteresis as critical undercooling—a phase transition phenomenon related to a thermodynamic barrier to nucleation. The separable nature of the DNA bonding elements and nanoparticle 960core enables the PAE platform to pose unique questions about the microscopic dependencies of critical undercooling and, ultimately, to control the nucleation pathway. Specifically, we find that the undercooling required to initiate nucleation increases as the nanoparticle coordination number increases (number of particles to which a can
A Responsive Mesoporous Silica Nanoparticle Platform for Magnetic Resonance Imaging-Guided High-Intensity Focused Ultrasound-Stimulated Cargo Delivery with Controllable Location, Time, and Dose (2019)

Magnetic resonance imaging (MRI) is an essential modality for clinical diagnosis, and MRI-guided high-intensity focused ultrasound (MRgHIFU) is a powerful technology for targeted therapy. Clinical applications of MRgHIFU primarily utilize hyperthermia and ablation to treat cancerous tissue, but for drug delivery applications thermal damage is undesirable. A biofriendly MRgHIFU-responsive mesoporous silica nanoparticle (MSN) platform that is stimulated within a physiological safe temperature range has been developed, reducing the possibility of thermal damage to the surrounding healthy tissues. Biocompatible polyethylene glycol (PEG) was employed to cap the pores of MSNs, and the release of cargo molecules by HIFU occurs without substantial temperature increase (∼4 °C). To visualize by MRI and measure the stimulated delivery in situ, a U.S. Food and Drug Administration (FDA)-approved gadolinium-based contrast agent, gadopentetate dimeglumine (Gd(DTPA)<sup>2-</sup>), was used as the imageable cargo. Taking advantage of the three-dimensional (3-D) imaging and targeting capabilities of MRgHIFU, the release of Gd(DTPA)<sup>2-</sup> stimulated by HIFU was pinpointed at the HIFU focal point in 3-D space in a tissue-mimicking gel phantom. The amount of Gd(DTPA)<sup>2-</sup> released was controlled by HIFU stimulation times and power levels. A positive correlation between the amount of Gd(DTPA)<sup>2-</sup> released and <i>T</i><sub>1</sub> was found. The MRgHIFU-stimulated cargo release was further imaged in a sample of ex vivo animal tissue. With this technology, the biodistribution of the nanocarriers can be tracked and the MRgHIFU-stimulated cargo release can be pinpointed, opening up an opportunity for future image-guided theranostic applications.