gebhart/patrepeval huggingface dataset:
A phase I study of 17-AAG in relapsed/refractory pediatric patients with solid tumors: A Children’s Oncology Groups study (2006)

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m 2 /dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m 2 /dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m 2 /day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.
A Tumbling Magnetic Microrobot System for Biomedical Applications (2020)

Abstract A microrobot system comprised of an untethered tumbling magnetic microrobot, a two degree of freedom rotating permanent magnet, and an ultrasound imaging system has been developed for in vitro and in vivo biomedical applications. The microrobot tumbles end-over-end in a net forward motion due to applied magnetic torque from the rotating magnet. By turning the rotational axis of the magnet, two-dimensional directional control is possible and the microrobot was steered along various trajectories, including a circular path and P-shaped path. The microrobot is capable of moving over the unstructured terrain within a murine colon in in vitro , in situ , and in vivo conditions, as well as a porcine colon in ex vivo conditions. High frequency ultrasound imaging allows for real-time determination of the microrobot’s position while it is optically occluded by animal tissue. When coated with a fluorescein payload, the microrobot was shown to release the majority of the payload over a one hour time period in phosphate-buffered saline. Cytotoxicity tests demonstrated that the microrobot’s constituent materials, SU-8 and polydimethylsiloxane (PDMS), did not show a statistically significant difference in toxicity to murine fibroblasts from the negative control, even when the materials were doped with magnetic neodymium microparticles. The microrobot system’s capabilities make it promising for targeted drug delivery and other in vivo biomedical applications.
Preliminary design of the internal geometry in a minimally invasive left ventricular assist device under pulsatile-flow conditions (2018)

We found that it is possible to shape the pump performance curve for specifically targeted gradients over the operating region through geometric variations inside the pump.
Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure (2015)

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders.
Efficient joint bandwidth and cache leasing in Information Centric Networks (2013)

Information Centric Networking (ICN) is a novel paradigm that aims at improving the performance of today's Internet by supporting universal caching and multicast content delivery features on every network device.
Cover Feature: 1,3‐Dioxolane: A Strategy to Improve Electrode Interfaces in Lithium Ion and Lithium‐Sulfur Batteries (ChemElectroChem 9/2018) (2018)

The Cover Feature illustrates the in situ electropolymerization of 1,3-dioxolane at voltages higher than 4 V. This electropolymerization produces a polyether-based layer on the electrode surface. This turns out to be a promising strategy to improve the electrode/electrolyte interface of high-voltage cathodes and to stabilize Li/S cell performance upon long-term cycling. More information be found in the Article by A. La Monaca et al. on page 1272 in Issue 9, 2018 (DOI: 10.1002/celc.201701348).
Review of safety improvement on sodium-cooled fast reactors after Fukushima accident (2012)

Several countries are developing and deploying SFRs even after the accident at Tokyo Electric Power Company’s Fukushima Dai-Ichi Nuclear Power Station. However, the Fukushima accident prompted all countries to redefine the fast reactor programs. The drastic safety enhancement is the most important issue to be established. In light of this situation, key essence of the safety improvement is reviewed in this paper by referring the achievements of the recent International Workshop on Prevention and Mitigation of Severe Accidents in SFRs which was held by Japan Atomic Energy Agency (JAEA) in cooperation with the International Atomic Energy Agency (IAEA) in June, 2012 and the findings published in the past journals including those of the International Conference on Fast Reactor and Related Fuel Cycles (FR09) held by IAEA in December, 2009.
O‐glycan initiation directs distinct biological pathways and controls epithelial differentiation (2020)

Post-translational modifications (PTMs) greatly expand the function and potential for regulation of protein activity, and O-glycosylation is among the most abundant and diverse PTMs. Initiation of O-GalNAc glycosylation is regulated by 20 distinct GalNAc-transferases (GalNAc-Ts), and deficiencies in individual GalNAc-Ts are associated with human disease, causing subtle but distinct phenotypes in model organisms. Here, we generate a set of isogenic keratinocyte cell lines lacking either of the three dominant and differentially expressed GalNAc-Ts. Through the ability of keratinocytes to form epithelia, we investigate the phenotypic consequences of the loss of individual GalNAc-Ts. Moreover, we probe the cellular responses through global transcriptomic, differential glycoproteomic, and differential phosphoproteomic analyses. We demonstrate that loss of individual GalNAc-T isoforms causes distinct epithelial phenotypes through their effect on specific biological pathways; GalNAc-T1 targets are associated with components of the endomembrane system, GalNAc-T2 targets with cell-ECM adhesion, and GalNAc-T3 targets with epithelial differentiation. Thus, GalNAc-T isoforms serve specific roles during human epithelial tissue formation.
ChemInform Abstract: Efficient Synthesis of Purine Analogues: An FeCl3—SiO2‐Promoted Cyclization Reaction of 4,5‐Diaminopyrimidines with Aldehydes Leading to 6,8,9‐Trisubstituted Purines. (2000)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.
A Mild and Efficient Synthesis of Oxindoles: Progress Towards the Synthesis of Welwitindolinone A Isonitrile (2004)

The complete carbon skeleton of welwitindolinone A isonitrile has been prepared by using a [2+2] cycloaddition to establish the bicyclo[4.2.0]octane core and a SmI2-mediated intramolecular reductive cyclization between an enone and an aryl isocyanate to stereoselectively install the spiro-oxindole (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene).
Aging causes changes in transcriptional noise across a diverse set of cell types (2022)

Aging and its associated diseases result from complex changes in cell state which can be examined with single-cell transcriptomic approaches. We analyzed gene expression noise, a measure of cellular heterogeneity, across age and many cell types and tissues using the single cell atlas Tabula Muris Senis , and characterized the noise properties of most coding genes. We developed a quantitative, well-calibrated statistical model of single-cell RNAseq measurement from which we sensitively detected changes in gene expression noise. We found thousands of genes with significantly changing gene expression noise with age. Not all genes had increasing noise with age—many showed a robust decreases of noise. There were clear biological correlation between subsets of genes, with a systemic decrease of noise in oxidative phosphorylation pathways while immune pathways involved in antigen presentation saw an increase. These effects were seen robustly across cell types and tissues, impacting many organs of healthy, aging mice.
Augmenting and sharing memory with eyeBlog (2004)

eyeBlog is an automatic personal video recording and publishing system. It consists of ECSGlasses [1], which are a pair of glasses augmented with a wireless eye contact and glyph sensing camera, and a web application that visualizes the video from the ECSGlasses camera as chronologically delineated blog entries. The blog format allows for easy annotation, grading, cataloging and searching of video segments by the wearer or anyone else with internet access. eyeBlog reduces the editing effort of video bloggers by recording video only when something of interest is registered by the camera. Interest is determined by a combination of independent methods. For example, recording can automatically be triggered upon detection of eye contact towards the wearer of the glasses, allowing all face-to-face interactions to be recorded. Recording can also be triggered by the detection of image patterns such as glyphs in the frame of the camera. This allows the wearer to record their interactions with any object that has an associated unique marker. Finally, by pressing a button the user can manually initiate recording.
ChemInform Abstract: CHLOROACETAMIDE PHOTOCYCLIZATION OF INDOLE DERIVATIVES. SYNTHESIS, STEREOCHEMISTRY, AND CRYSTAL STRUCTURE OF 3,7‐METHANO‐3‐AZACYCLOUNDECINO(5,4‐B)INDOLE (DEETHYLQUEBRACHAMINE) DERIVATIVES (1979)

Abstract Aus den Indolyl‐2‐carbonestern (I) erhält man mit LDA und 3‐Methylpyridin (II) die Ketone (III), die zu (IV) hydriert und in die Chloracetylderivate (V) übergeführt werden.
A short radiosynthesis of 6-[C3H3]-dorzolamide at very high specific activity and optical purity (1996)

6-[C3H3]-Dorzolamide was prepared starting from N, N′-bis-Boc-6-desmethyl-dorzolamide. An efficient radiosynthesis was developed involving a regioselective and stereo-controlled 3H-methylation of the α-sulfone carbanion in the presence of the monoprotected sulfonamide anion. The methylation led to a mixture (ca. 7 : 1 for 4S,6R : 4S,6S) of the diastereomeric, tritiated products. Removal of the Boc protecting groups followed by HPLC purification of the resulting diastereomers afforded 6-[C3H3]-dorzolamide with > 99% radiochemical purity, > 98.4% enantiomeric excess, and a specific activity of > 74 Ci/mmol.
Closed-loop control of direct ink writing via reinforcement learning (2022)

Enabling additive manufacturing to employ a wide range of novel, functional materials can be a major boost to this technology. However, making such materials printable requires painstaking trial-and-error by an expert operator, as they typically tend to exhibit peculiar rheological or hysteresis properties. Even in the case of successfully finding the process parameters, there is no guarantee of print-to-print consistency due to material differences between batches. These challenges make closed-loop feedback an attractive option where the process parameters are adjusted on-the-fly. There are several challenges for designing an efficient controller: the deposition parameters are complex and highly coupled, artifacts occur after long time horizons, simulating the deposition is computationally costly, and learning on hardware is intractable. In this work, we demonstrate the feasibility of learning a closed-loop control policy for additive manufacturing using reinforcement learning. We show that approximate, but efficient, numerical simulation is sufficient as long as it allows learning the behavioral patterns of deposition that translate to real-world experiences. In combination with reinforcement learning, our model can be used to discover control policies that outperform baseline controllers. Furthermore, the recovered policies have a minimal sim-to-real gap. We showcase this by applying our control policy in-vivo on a single-layer printer using low and high viscosity materials.
Advanced Television and Signal Processing Program (1991)

Contains an introduction and reports on fifteen research projects.
Insights into the Structural Determinants Required for High-Affinity Binding of Chiral Cyclopropane-Containing Ligands to α4β2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally Active Nicotinic Ligands (2012)

Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human α4β2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies.
Supplementary Figure Legends from EPHA2 Is a Mediator of Vemurafenib Resistance and a Novel Therapeutic Target in Melanoma (2023)

&lt;p&gt;Supplementary Figure Legends&lt;/p&gt;
Antigen modifications improve nucleoside-modified mRNA-based influenza virus vaccines in mice (2021)

Nucleoside-modified, lipid nanoparticle-encapsulated mRNAs have recently emerged as suitable vaccines for influenza viruses and other pathogens in part because the platform allows delivery of multiple antigens in a single immunization. mRNA vaccines allow for easy antigen modification, enabling rapid iterative design. We studied protein modifications such as mutating functional sites, changing secretion potential, and altering protein conformation, which could improve the safety and/or potency of mRNA-based influenza virus vaccines. Mice were vaccinated intradermally with wild-type or mutant constructs of influenza virus hemagglutinin (HA), neuraminidase (NA), matrix protein 2 (M2), nucleoprotein (NP), or matrix protein 1 (M1). Membrane-bound HA constructs elicited more potent and protective antibody responses than secreted forms. Altering the catalytic site of NA to reduce enzymatic activity decreased reactogenicity while protective immunity was maintained. Disruption of M2 ion channel activity improved immunogenicity and protective efficacy. A comparison of internal proteins NP and M1 revealed the superiority of NP in conferring protection from influenza virus challenge. These findings support the use of the nucleoside-modified mRNA platform for guided antigen design for influenza virus with extension to other pathogens.
ChemInform Abstract: Nucleic Acid Related Compounds. Part 53. Synthesis and Biological Evaluation of 2′‐Deoxy‐β‐threo‐pentofuranosyl Nucleosides. “Reversion to Starting Alcohol” in Barton‐Type Reductions of Thionocarbonates. (1988)

Abstract The title nucleosides (V) and (VIII) are prepared via a Barton‐type reduction of thionocarbonates of type (III).
Supplementary figure S2 from <i>BIRC6</i> Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer (2023)

&lt;p&gt;MTS proliferation assay of MR42D ENZ-resistant CRPC cells treated with ASO-6w2&lt;/p&gt;
Primary cilia in fibroblast-like type B synoviocytes lie within a cilium pit: a site of endocytosis. (2010)

The synovium is a thin connective tissue that lines the joint space of free moving articulations. In this report, the expression, structure, and composition of non-motile (primary) cilia in fibroblast-like synoviocytes (FLS) that populate the synovium have been studied. Primary cilia are non-motile, microtubule-based organelles that have been found in a variety of vertebrate cell types. We document that primary cilia are expressed in normal human synovium FLS, cultured human FLS, and FLS cells present in human synovial fluid, and that the cellular region occupied by the primary cilium shows a similar and highly defined architecture within these FLS. This architecture includes the presence of a unique structure that surrounds the lower portion of the cilium shaft. This structure, given the term cilium-pit, includes a space, the pit reservoir. Actin filament bundles surround the cilium-pit, and when these bundles are removed experimentally the volume of the cilium-pit and its continuity with the extracellular environment changes. Finally, this study documents that the cilium-pit is a site of endocytosis and is also the site for the localization of receptors (TNF receptors TNFR1 and TNFR2) associated with synoviocyte function. Taken together, the results of the present study suggest that the FLS cilium-pit functions to regulate the exposure of the primary cilium, both spatially and temporally to extracellular molecules and to couple primary cilium based signaling pathways with those linked to endocytosis.
Introduction (1997)

Abstract This introductory chapter explains the coverage of this book, which is about the political, economic, cultural, and international factors that influenced Chinese Communist Party (CCP) chairman Mao Zedong to launch the Cultural Revolution. This book chronicles how Mao came to focus upon the nation's spiritual metamorphosis after having failed in the material transformation of China. It attempts to explain why Mao decided to tear down and rebuild a regime that he had done so much to create. It discusses the failure of the Great Leap Forward (GLF) and Mao's conflict with Soviet Union Communist Party First Secretary Nikita Khrushchev.
Securing the Internet of Things: New Perspectives and Research Challenges. (2018)

The Internet of Things (IoT) realizes a vision where billions of interconnected devices are deployed just about everywhere, from inside our bodies to the most remote areas of the globe. As the IoT will soon pervade every aspect of our lives and will be accessible from anywhere, addressing critical IoT security threats is now more important than ever. Traditional approaches where security is applied as an afterthought and as a patch against known attacks are insufficient. IoT challenges require a new secure-by-design vision, where threats are addressed proactively and IoT devices learn to dynamically adapt to different threats. In this paper, we first provide a taxonomy and survey the state of the art in IoT security research, and offer a roadmap of concrete research challenges to address existing and next-generation IoT security threats.
A Protease-Independent Function for SPPL3 in NFAT Activation (2014)

The signal peptide peptidase (SPP)-related intramembrane aspartyl proteases are a homologous group of polytopic membrane proteins, some of which function in innate or adaptive immunity by cleaving proteins involved in antigen presentation or intracellular signaling. Signal peptide peptidase-like 3 (SPPL3) is a poorly characterized endoplasmic reticulum (ER)-localized member of this family, with no validated cellular substrates. We report here the isolation of SPPL3 in a screen for activators of NFAT, a transcription factor that controls lymphocyte development and function. We find that SPPL3 is required downstream of T cell receptor engagement for maximal Ca(2+) influx and NFAT activation. Surprisingly, the proteolytic activity of SPPL3 is not required for its role in this pathway. SPPL3 enhances the signal-induced association of stromal interaction molecule 1 (STIM1) and Orai1 and is even required for the full activity of constitutively active STIM1 variants that bind Orai1 independently of ER Ca(2+) release. SPPL3 associates with STIM1 through at least two independent domains, the transmembrane region and the CRAC activation domain (CAD), and can promote the association of the STIM1 CAD with Orai1. Our results assign a function in lymphocyte signaling to SPPL3 and highlight the emerging importance of nonproteolytic functions for members of the intramembrane aspartyl protease family.
S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling (2023)

KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.
ChemInform Abstract: USE OF POLYMERS AS PROTECTING GROUPS IN ORGANIC SYNTHESIS. APPLICATION OF POLYSTYRYLBORONIC ACID TO THE ONE‐POT SYNTHESIS OF ACYLATED CARBOHYDRATE DERIVATIVES (1979)

Abstract Das nach einem einfachen 4‐Stufen‐Verfahren dargestellte Polystyrolboronsäure‐Harz (II) wird bei der Acylierung der α‐L‐Rhamncpyranoside (IV) verwendet.
Supplementary Figures 1-7 from VS-5584, a Novel and Highly Selective PI3K/mTOR Kinase Inhibitor for the Treatment of Cancer (2023)

&lt;p&gt;PDF file - 663K, Ambit kinome tree, Cell proliferation data, Pharmacokinetics, Body weight changes in PC3 efficacy study, Active vessel stain in COLO-205 efficacy study, MV4-11 efficacy model, Drug sensitivity profiling and correlation to mutation status&lt;/p&gt;