gebhart/patrepeval huggingface dataset:
Structural Basis for RNA Processing by Dicer (2006)

Dicer enzymes, found in nearly all eukaryotic cell types, cleave double‐stranded RNA substrates into the ~23 base‐pair products that are the effectors of gene silencing by RNA interference (RNAi). We describe the 3 Å crystal structure of the intact Dicer from Giardia intestinalis , revealing the structural basis for RNA recognition, measuring and cleavage by this class of enzymes. The hatchet‐shaped protein contains an RNA‐binding PAZ domain at one end and two RNase III domains at the other, connected by an N‐terminal domain and a long alpha‐helix. The connector helix sets the 60 Å distance between the PAZ and RNase III domains that corresponds the length of the double‐stranded RNA products of Dicer, implicating this structural element as the “ruler” that defines interfering RNA size. Other details of the structure and biochemical activity of Dicer, as well as implications for its catalytic mechanism and interactions with ligands, will be discussed.
Increasing the usage of open hypermedia systems (2003)

This paper argues that the existence of a developer support framework is a critical issue to the usage of Open Hypermedia Systems (OHSs). For this reason, the OHS Community would benefit by the adoption of both a service discovery mechanism and a set of standards and tools to approach the development of hypermedia clients in a transparent and methodological manner.
Modulation of chondrocyte cytokines synthesis by endogeneously produced nitric oxide (1997)

peer reviewed
Mechanical Properties of Linear Low‐density Polyethylene (LLDPE)/clay Nanocomposites: Estimation of Aspect Ratio and İnterfacial Strength by Composite Models (2008)

Ali Durmusa*, Ahmet Kaşgöza & Christopher W. Macoskob a Faculty of Engineering, Department of Chemical Engineering , Istanbul University , Avcilar, Istanbul, Turkey b Department of Chemical Engineering and Materials Science , University of Minnesota , Minneapolis, MN, USA
Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy (1999)

Cardiotrophin-1 (CT-1), an IL-6-related cytokine, causes hypertrophy of cardiac myocytes and has pleiotropic effects on various other cell types, including motoneurons. Here, we analyzed systemic CT-1 effects in progressive motor neuronopathy (pmn) mice that suffer from progressive motoneuronal degeneration, muscle paralysis, and premature death. Administration of an adenoviral CT-1 vector to newborn pmn mice leads to sustained CT-1 expression in the injected muscles and bloodstream, prolonged survival of animals, and improved motor functions. CT-1-treated pmn mice showed a significantly reduced degeneration of facial motoneuron cytons and phrenic nerve myelinated axons. The terminal innervation of skeletal muscle, grossly disturbed in untreated pmn mice, was almost completely preserved in CT-1-treated pmn mice. The remarkable neuroprotection conferred by CT-1 might become clinically relevant if CT-1 side effects, including cardiotoxicity, could be circumvented by a more targeted delivery of this cytokine to the nervous system.
Abstract 2515: Preclinical Development of ARRY-162, A Potent and Selective MEK 1/2 Inhibitor (2010)

Abstract Activation of the Ras/Raf/MEK/MAP kinase pathway is implicated in uncontrolled cell proliferation and tumor growth. Inappropriate activation of the RAS pathway can occur through several distinct mechanisms, including activating mutations in Ras and B-raf, or activated growth factor-signaling, cytokines and stress responses. Mutated, oncogenic forms of Ras are found in 50% of colon, 90% of pancreatic, and 30% of lung cancers. Also, B-Raf mutations have been identified in more than 60% of malignant melanomas and from 40-70% of papillary thyroid cancers. MEK, a dual specific kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. These data suggest that targeting MEK can inhibit cancer cell signaling mediated by a wide variety of signals, making MEK an attractive target for the treatment of cancer. We have discovered ARRY-162, a novel ATP-uncompetitive inhibitor of MEK 1/2, which is un-competitive with respect to ATP. ARRY-162 has nanomolar activity against purified MEK enzyme (IC50 = 12 nM) and is highly selective. It has been evaluated against 220 serine/threonine and tyrosine kinases with no inhibitory activity observed up to 20 μM. ARRY-162 inhibits both basal and induced levels of ERK phosphorylation in numerous cancer cell lines with IC50s as low as 5 nM. ARRY-162 is especially potent at inhibiting the cell proliferation of mutant B-Raf and Ras cell lines such as HT29, Malme-3M, SK-MEL-2, COLO 205, SK-MEL-28 and A375 (IC50s from 30-250 nM). In vivo, ARRY-162 has demonstrated efficacy in several xenograft tumor models in mice, including HT29, BxPC3, MIA PaCa2, A549, LoVo, Calu6, DU145 and COLO 205. In the HT29 and in the COLO 205 colon carcinoma models, dose-dependent inhibition of tumor growth (up to 75% TGI) was observed at doses ranging from 3 to 30 mg/kg, QD, PO for 21 days. In the Colo-205 colon carcinoma model, significant tumor regressions were observed with 50% partial responses and 13% complete responses at 30 mg/kg, PO, QD. In the BxPC3 pancreatic carcinoma model (which does not harbor either Ras or Raf mutations), tumor growth inhibition (∼70% TGI) and 13% partial responses were seen at doses of 30 mg/kg, QD, PO for 21 days. Consistent with ARRY-162's mechanism of action, tumor growth inhibition correlates with decreased phospho-ERK levels in tumor xenografts. In addition to its potency against MEK, this compound demonstrates other desirable attributes for development including good physical chemical characteristics, low clearance, medium-to-high Caco-2 permeability and minimal predicted drug-drug interactions. With preclinical efficacy and safety studies on ARRY-162 completed, this compound has entered clinical development for treatment of cancer. 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 2515.
Trial Watch (2013)

Radiotherapy has extensively been employed as a curative or palliative intervention against cancer throughout the last century, with a varying degree of success. For a long time, the antineoplastic activity of X- and γ-rays was entirely ascribed to their capacity of damaging macromolecules, in particular DNA, and hence triggering the (apoptotic) demise of malignant cells. However, accumulating evidence indicates that (at least part of) the clinical potential of radiotherapy stems from cancer cell-extrinsic mechanisms, including the normalization of tumor vasculature as well as short- and long-range bystander effects. Local bystander effects involve either the direct transmission of lethal signals between cells connected by gap junctions or the production of diffusible cytotoxic mediators, including reactive oxygen species, nitric oxide and cytokines. Conversely, long-range bystander effects, also known as out-of-field or abscopal effects, presumably reflect the elicitation of tumor-specific adaptive immune responses. Ionizing rays have indeed been shown to promote the immunogenic demise of malignant cells, a process that relies on the spatiotemporally defined emanation of specific damage-associated molecular patterns (DAMPs). Thus, irradiation reportedly improves the clinical efficacy of other treatment modalities such as surgery (both in neo-adjuvant and adjuvant settings) or chemotherapy. Moreover, at least under some circumstances, radiotherapy may potentiate anticancer immune responses as elicited by various immunotherapeutic agents, including (but presumably not limited to) immunomodulatory monoclonal antibodies, cancer-specific vaccines, dendritic cell-based interventions and Toll-like receptor agonists. Here, we review the rationale of using radiotherapy, alone or combined with immunomodulatory agents, as a means to elicit or boost anticancer immune responses, and present recent clinical trials investigating the therapeutic potential of this approach in cancer patients.
Supplementary Figure S3 from Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04) (2023)

&lt;p&gt;IC50 values for devimistat in biliary cancer cell lines&lt;/p&gt;
Characterization Of A Space Charge Limited Non Relativistic Electron Beam Diode Operating At 300 KV/cm (2005)

High current density (>100 A/cm/sup 2/) electron beam diodes operating beyond 250 kV/cm in a 1-cm gap configuration are described. The principal features of the electron source are the high current density and high field gradient without the onset of vacuum arcs or arc collapse prior to gap closure. The electron beam diode was controlled by a variable pulse-width output Marx generator. Fields of up to 600 kV/cm were applied for 25 to 30 nsec, and up to 300 kV/cm during space--charge limited current conduction at pulse lengths of 100 to 120 nsec. Evidence of the transition to space-charge limited unipolar flow and transition to bipolar space--charge limited flow was obtained. Estimation of plasma closure velocity were made from several gap closure events and perveance plotting. Traces of the typical behavior and the different transitions shown. Beam uniformity was measured by using a set of Faraday cups. The Faraday cup set-up was then used to demonstrate suppression of electron emission from surfaces coated with a dielectric film.
Genetics of Greenbug (Homoptera: Aphididae) Virulence to Resistance in Sorghum (1995)

Greenbug, Schizaphis graminum (Rondani), biotypes C, E, and F were inbred, crossbred, and backcrossed with recessive testers under laboratory conditions to determine the inheritance of virulence to resistance in sorghum (Sorghum bicolor [L.] Moench). Each progeny was reared to adult and cloned during its parthenogenesis reproductive phase. Clones were. evaluated on three sorghum entries with greenbug resistance acquired from different germplasm sources. Greenbug virulence to biotype F-resistant 'Piper' was dominantly inherited and governed by a duplicate-dominant gene that was influenced by a third modifier gene. The modifier gene was epistatic to one of the duplicate genes when dominant. Virulence to biotype C- and E-resistant 'Pioneer 8493' with resistance from PI 264453 was also controlled by a duplicate dominant gene-modifier gene, but green bug virulence was recessive. The modifier gene Was also epistatic to one of the duplicate genes when dominant. In contrast, greenbug virulence to biotype C-resistant 'Pioneer 8515' with resistance from SA 7536-1 was recessive and simply inherited. No linkage occurred between the genes governing virulence to these resistant sorghum entries, regardless of biotype. The genes influencing virulence to a particular resistant sorghum, were found to be allelic among the biotypes. Specific greenbug virulence-sorghum resistance interactions followed a gene-for-gene relationship similar to those first reported in plant-pathogen interactions. Our results provide further evidence that genetic recombination during the green bug's sexual cycle can produce the biotypic variation inherent to this aphid.
Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways (2023)

Glucagon has emerged as a key regulator of extracellular amino acid (AA) homeostasis. Insufficient glucagon signaling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Aside from mammalian target of rapamycin complex 1 (mTORC1), the role of other AA sensors in α cell proliferation has not been described. Here, using both genders of mouse islets and glucagon receptor (gcgr)-deficient zebrafish (Danio rerio), we show α cell proliferation requires activation of the extracellular signal-regulated protein kinase (ERK1/2) by the AA-sensitive calcium sensing receptor (CaSR). Inactivation of CaSR dampened α cell proliferation, which was rescued by re-expression of CaSR or activation of Gq, but not Gi, signaling in α cells. CaSR was also unexpectedly necessary for mTORC1 activation in α cells. Furthermore, coactivation of Gq and mTORC1 induced α cell proliferation independent of hyperaminoacidemia. These results reveal another AA-sensitive mediator and identify pathways necessary and sufficient for hyperaminoacidemia-induced α cell proliferation.
Abstract 15429: A Comparison of Left Atrial Appendage Closure to Warfarin and NOACs in Routine Clinical Practice (2017)

Introduction: In clinical trials, left atrial appendage closure (LAAC) demonstrated a lower risk of hemorrhagic stroke and cardiovascular death, but a trend toward higher risk of ischemic stroke or...
Two-photon and fMRI measurements of activity dependent single vessel dynamics in mouse (2017)

I will discuss recent two-photon optical and high-field functional MRI measurements that link brain activity with changes in cortical arteriole and venule diameter. The data support a “Bagpipe” model (Drew et al PNAS 2011) in which arterioles dilate upon heightened intrinsic or stimulus-driven neuronal activity and form a reservoir of blood to perfuse cortex. Implications and extensions of this result will be discussed.
Evaluation of Visual Quality in Patients With Fuchs Endothelial Corneal Dystrophy (2016)

Fuchs endothelial corneal dystrophy (FECD) is a bilateral corneal endothelial dystrophy characterized by the deposition of extracellular matrix (guttae), thickening of Descemet membrane, and progressive loss of corneal endothelial cells. Progressive endothelial cellular loss leads to corneal edema and impairs visual function. In eyes with FECD, corneal edema begins in the central cornea and expands into the periphery. FECD is the most common dystrophic reason for corneal transplantation in many countries. Some patients with FECD report visual discomfort despite the absence of corneal edema. Intraocular forward light scatter impairs patients' quality of vision (QOV), and corneal guttae associated with FECD may cause intraocular light scatter and glare, which can be extremely debilitating despite the absence of edema. We recently investigated the effect of the severity of corneal guttae on QOV in patients with mild FECD. It was shown that corneal guttae increased forward light scatter that negatively affected QOV in eyes with mild FECD without severe corneal edema. Therefore, quantification of corneal guttae would be useful to determine surgical indications for eyes with mild FECD. This review discusses QOV in patients with FECD.
Manipulation of Photons by 2D and 3D Photonic Crystals (2008)

The author gives a slide presentation on light photon manipulation by 2D and 3D photonic crystals.
MYC Phosphorylation, Activation, and Tumorigenic Potential in Hepatocellular Carcinoma Are Regulated by HMG-CoA Reductase (2011)

MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors.
Cytotoxic 1,2-Dialkynylimidazole-Based Aza-Enediynes: Aza-Bergman Rearrangement Rates Do Not Predict Cytotoxicity (2011)

A new class of potential antitumor agents inspired by the enediyne antitumor antibiotics has been synthesized: the 1,2-dialkynylimidazoles. The aza-Bergman rearrangement of these 1,2-dialkynylimidazoles has been investigated theoretically at the B3LYP/6-31G(d,p) level and experimentally by measuring the kinetics of rearrangement in 1,4-cyclohexadiene. There is a good correlation between the theoretical and experimental results; subtle substituent effects on the initial aza-Bergman cyclization barrier predicted by theory are confirmed by experiment. Yet, despite the ability of these 1,2-dialkynylimidazoles to undergo Bergman rearrangement to diradical/carbene intermediates under relatively mild conditions, there is no correlation between the rate of Bergman cyclization and cytotoxicity to A459 cells. In addition, cytotoxic 1,2-dialkynylimidazoles do not cause nicking of supercoiled plasmid DNA or cleavage of bovine serum albumin. An alternative mechanism for cytotoxicity involving the unexpected selective thiol addition to the N-ethynyl group of certain 1,2-dialkynylimidazoles is proposed.
Benefits of Thermal Spray Coatings in Internal Combustion Engines, with Specific View on Friction Reduction and Thermal Management (2013)

&lt;div class="section abstract"&gt;&lt;div class="htmlview paragraph"&gt;The design of internal combustion engines is more and more oriented toward sustainability, especially fuel economy. To reach this aim, several technologies have been developed, however, most significantly increase engine complexity and cost. An attractive way to achieve better fuel economy is the reduction of the engine's mechanical losses, which directly has positive influence on fuel economy.&lt;/div&gt;&lt;div class="htmlview paragraph"&gt;The strongest contributor to these losses is still the friction of the piston assembly. During the past decades, considerable progress in the reduction of piston and piston ring friction has been achieved. Beside the material and design of pistons and piston rings, the optimization of the liner's surface structure was always of interest, and a major role in this development was - and still is - played by surface coating technologies. The subject of this paper is the investigation of a Thermal Spray Coating, the &lt;b&gt;P&lt;/b&gt;lasma &lt;b&gt;T&lt;/b&gt;ransferred &lt;b&gt;W&lt;/b&gt;ire &lt;b&gt;A&lt;/b&gt;rc (PTWA), which offers an interesting combination of several positive effects, including friction reduction and thermal benefits. This is based on the nature of the PTWA-coating, which consists of a thin layer of porous metal. The properties of this layer can be adapted by several parameters, to suit the specific requirements of the engine's application.&lt;/div&gt;&lt;/div&gt;
Discovery and Development of AMG 333: A TRPM8 Antagonist for Migraine (2019)

AMG 333 is a potent inhibitor of the transient receptor potential melastatin 8 ion channel and was pursued as a potential therapeutic for migraine pain. This chapter first summarizes the medicinal chemistry leading to the discovery of this compound, with a focus on imparting druglike properties to initial lead compounds and early synthetic chemistry work done by medicinal chemistry. Next, we discuss the process chemistry route optimization from the preliminary synthesis used during the discovery phase and additional development work leading to the multikilogram synthesis of active pharmaceutical ingredient.
Zero-Loss Virtual Machine Migration with IPv6 Segment Routing (2018)

International audience
Kallistatin Inhibits Vascular Inflammation by Antagonizing Tumor Necrosis Factor-α–Induced Nuclear Factor κB Activation (2010)

Kallistatin is a plasma protein with anti-inflammatory properties. In this study, we investigated the role and mechanisms of kallistatin in inhibiting endothelial inflammation through its heparin-binding domain. We showed that recombinant wild-type kallistatin dose-dependently competed with tumor necrosis factor (TNF)-alpha binding to TNF-alpha receptor in endothelial cells, whereas kallistatin mutant at the heparin-binding domain had no effect. Kallistatin, but not kallistatin mutant at the heparin-binding domain, abrogated TNF-alpha-induced endothelial cell activation, as evidenced by inhibition of TNF receptor 1-associated death domain protein activation, inhibitor of nuclear factor kappaB-alpha degradation, nuclear factor kappaB translocation, and p38 mitogen-activated protein kinase phosphorylation, as well as cell adhesion molecule and cytokine expression. Moreover, kallistatin, but not kallistatin mutant at the heparin-binding domain, inhibited TNF-alpha-induced human monocytic THP-1 cell adhesion to endothelial cells and prevented vascular endothelial growth factor-induced endothelial permeability. In mice, kallistatin gene delivery prevented vascular leakage provoked by complement factor C5a, whereas delivery of kallistatin heparin mutant gene had no effect. Similarly, gene transfer of kallistatin, but not the kallistatin heparin mutant, inhibited collagen/adjuvant-induced arthritis in rats. These results indicate that kallistatin's heparin-binding site plays an essential role in preventing TNF-alpha-mediated endothelial activation and reducing vascular endothelial growth factor-induced vascular permeability, resulting in attenuation of vascular inflammation in cultured endothelial cells and animal models. This study identifies a protective role of kallistatin in vascular injury, thereby implicating the therapeutic potential of kallistatin for vascular and inflammatory diseases.
Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW 264.7 Macrophages through Activating the Nuclear Factor Erythroid 2-Related Factor-2/Heme Oxygenase-1 Pathway (2019)

Reactive oxygen species (ROS), products of oxidative stress, contribute to the initiation and progression of the pathogenesis of various diseases. Glutathione is a major antioxidant that can help prevent the process through the removal of ROS. The aim of this study was to evaluate the protective effect of glutathione on ROS-mediated DNA damage and apoptosis caused by hydrogen peroxide, H₂O₂, in RAW 264.7 macrophages and to investigate the role of the nuclear factor erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. The results showed that the decrease in the survival rate of RAW 264.7 cells treated with H₂O₂ was due to the induction of DNA damage and apoptosis accompanied by the increased production of ROS. However, H₂O₂-induced cytotoxicity and ROS generation were significantly reversed by glutathione. In addition, the H₂O₂-induced loss of mitochondrial membrane potential was related to a decrease in adenosine triphosphate (ATP) levels, and these changes were also significantly attenuated in the presence of glutathione. These protective actions were accompanied by a increase in the expression rate of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) and poly(ADP-ribose) polymerase cleavage by the inactivation of caspase-3. Moreover, glutathione-mediated cytoprotective properties were associated with an increased activation of Nrf2 and expression of HO-1; however, the inhibition of the HO-1 function using an HO-1 specific inhibitor, zinc protoporphyrin IX, significantly weakened the cytoprotective effects of glutathione. Collectively, the results demonstrate that the exogenous administration of glutathione is able to protect RAW 264.7 cells against oxidative stress-induced mitochondria-mediated apoptosis along with the activity of the Nrf2/HO-1 signaling pathway.