gebhart/patrepeval huggingface dataset:
Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease (2020)

Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the <i>gem</i>-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the <i>gem</i>-dimethyl group.
Improved Extraction Procedure and RIA for Determination of Arginine8-Vasopressin in Plasma: Role of Premeasurement Sample Treatment and Reference Values in Children (1999)

Abstract We optimized an RIA for measurement of arginine8-vasopressin (AVP) in plasma by use of 100-mg Isolute C18 columns for extraction, addition of a preincubation step, and use of maximal dilution of a commercially available antiserum. The detection limit was 0.06 ng/L when 0.5 mL of acidified plasma was extracted. The within- and between-run CVs (n = 16) at physiological concentrations were 5.8–10.2% and 6.5–11.7%, respectively. Prolonged storage of blood at 25 °C, but not at 4 °C, led to a significant increase in measured plasma AVP concentrations. When plasma samples were prepared at several centrifugation speeds, plasma AVP was significantly correlated with the platelet count (r = 0.899; P &amp;lt;0.001). This emphasizes the need for careful sample preparation to avoid contamination of plasma with platelet-bound AVP. Basal plasma AVP in 203 children and adolescents (105 males and 98 females; ages, 1 day to 18 years) averaged 1.1 ± 0.6 ng/L. There was no significant difference between males and females and no correlation with age. In 16 healthy adult controls, plasma AVP averaged 1.0 ± 0.5 ng/L.
HNE interacts directly with JNK isoforms in human hepatic stellate cells. (1998)

4-Hydroxy-2,3-nonenal (HNE) is an aldehydic end product of lipid peroxidation which has been detected in vivo in clinical and experimental conditions of chronic liver damage. HNE has been shown to stimulate procollagen type I gene expression and synthesis in human hepatic stellate cells (hHSC) which are known to play a key role in liver fibrosis. In this study we investigated the molecular mechanisms underlying HNE actions in cultured hHSC. HNE, at doses compatible with those detected in vivo, lead to an early generation of nuclear HNE-protein adducts of 46, 54, and 66 kD, respectively, as revealed by using a monoclonal antibody specific for HNE-histidine adducts. This observation is related to the lack of crucial HNE-metabolizing enzymatic activities in hHSC. Kinetics of appearance of these nuclear adducts suggested translocation of cytosolic proteins. The p46 and p54 isoforms of c-Jun amino-terminal kinase (JNKs) were identified as HNE targets and were activated by this aldehyde. A biphasic increase in AP-1 DNA binding activity, associated with increased mRNA levels of c-jun, was also observed in response to HNE. HNE did not affect the Ras/ERK pathway, c-fos expression, DNA synthesis, or NF-kappaB binding. This study identifies a novel mechanism linking oxidative stress to nuclear signaling in hHSC. This mechanism is not based on redox sensors and is stimulated by concentrations of HNE compatible with those detected in vivo, and thus may be relevant during chronic liver diseases.
Multivalent Fvs: characterization of single-chain Fv oligomers and preparation of a bispecific Fv (1994)

Single-chain Fv proteins are known to aggregate and form multimeric species. We report here that these molecules represent a new class of molecular assembly, which we have termed multivalent Fvs. Each binding site in a multivalent Fv comprises the variable light-chain (VL) domain from a single-chain Fv, and the variable heavy-chain (VH) domain from a second single-chain Fv. Each single-chain Fv in a multivalent Fv is part of two binding sites. We have characterized the multivalent forms of the 4-4-20, CC49 and B6.2 sFvs. The degree of multivalent Fv formation is linker-dependent. Multivalent Fvs cannot form in the absence of an intact linker. Multivalent Fvs can be stabilized by their antigen. The conversion between different forms of the multivalent Fvs can be catalyzed by disassociating agents such as 0.5 M guanidine hydrochloride with 20% ethanol. Multivalent Fvs have significantly different stabilities depending on the specific variable domains from which they are constructed. Two models have been proposed for the structure of a multivalent Fv. We have tested each model by attempting to produce a heterodimer from the anti-fluorescein 4-4-20 and anti-tumor CC49 variable regions. We successfully produced a 4-4-20/CC49 heterodimer that comprises two mixed sFvs. The first mixed sFv is composed of the 4-4-20 VL domain, a 12 residue linker and the CC49 Vh domain. The second mixed sFv is composed of a CC49 VL domain, a 12 residue linker and the 4-4-20 VH domain. The 4-4-20/CC49 heterodimer bound both fluorescein and the tumor-associated glycoprotein-72 antigen. These results support a VH/VL 'rearrangement' model in which each variable domain of a multivalent Fv binding site comes from a different polypeptide chain.
ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures (2005)

Key amino acid positions that are important for maintaining the 3D structure of a protein and/or its function(s), e.g. catalytic activity, binding to ligand, DNA or other proteins, are often under strong evolutionary constraints. Thus, the biological importance of a residue often correlates with its level of evolutionary conservation within the protein family. ConSurf (http://consurf.tau.ac.il/) is a web-based tool that automatically calculates evolutionary conservation scores and maps them on protein structures via a user-friendly interface. Structurally and functionally important regions in the protein typically appear as patches of evolutionarily conserved residues that are spatially close to each other. We present here version 3.0 of ConSurf. This new version includes an empirical Bayesian method for scoring conservation, which is more accurate than the maximum-likelihood method that was used in the earlier release. Various additional steps in the calculation can now be controlled by a number of advanced options, thus further improving the accuracy of the calculation. Moreover, ConSurf version 3.0 also includes a measure of confidence for the inferred amino acid conservation scores.
Highly Active Ruthenium Metathesis Catalysts Exhibiting Unprecedented Activity and Z-Selectivity (2013)

A novel chelated ruthenium-based metathesis catalyst bearing an N-2,6-diisopropylphenyl group is reported and displays near-perfect selectivity for the Z-olefin (>95%), as well as unparalleled TONs of up to 7400, in a variety of homodimerization and industrially relevant metathesis reactions. This derivative and other new catalytically active species were synthesized using an improved method employing sodium carboxylates to induce the salt metathesis and C-H activation of these chelated complexes. All of these new ruthenium-based catalysts are highly Z-selective in the homodimerization of terminal olefins.
Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy (2008)

Decreased p27(Kip1) levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCF(Skp2) E3 ligase function, resulting in enhanced p27 ubiquitination and proteasome-mediated degradation. While proteasome inhibitors stabilize p27(Kip1), agents inhibiting SCF(Skp2) may represent more directly targeted drugs with the promise of enhanced efficacy and reduced toxicity. Using high-throughput screening, we identified Compound A (CpdA), which interfered with SCF(Skp2) ligase function in vitro, and induced specific accumulation of p21 and other SCF(Skp2) substrates in cells without activating a heat-shock protein response. CpdA prevented incorporation of Skp2 into the SCF(Skp2) ligase, and induced G(1)/S cell-cycle arrest as well as SCF(Skp2)- and p27-dependent cell killing. This programmed cell death was caspase-independent, and instead occurred through activation of autophagy. In models of multiple myeloma, CpdA overcame resistance to dexamethasone, doxorubicin, and melphalan, as well as to bortezomib, and also acted synergistically with this proteasome inhibitor. Importantly, CpdA was active against patient-derived plasma cells and both myeloid and lymphoblastoid leukemia blasts, and showed preferential activity against neoplastic cells while relatively sparing other marrow components. These findings provide a rational framework for further development of SCF(Skp2) inhibitors as a novel class of antitumor agents.
Conversion of furfuryl alcohol into 2-methylfuran at room temperature using Pd/TiO2 catalyst (2014)

The selective hydrogenation of furfuryl alcohol into 2-methylfuran was investigated at room temperature using palladium supported catalysts.
Temporal noise control for sketchy animation (2011)

We propose a technique to control the temporal noise present in sketchy animations. Given an input animation drawn digitally, our approach works by combining motion extraction and inbetweening techniques to generate a reduced-noise sketchy animation registered to the input animation. The amount of noise is then controlled by a continuous parameter value. Our method can be applied to effectively reduce the temporal noise present in sequences of sketches to a desired rate, while preserving the geometric richness of the sketchy style in each frame. This provides the manipulation of temporal noise as an additional artistic parameter, e.g. to emphasize character emotions and scene atmosphere, and enables the display of sketchy content to broader audiences by producing animations with comfortable noise levels. We demonstrate the effectiveness of our approach on a series of rough hand-drawn animations.
Abstract 3048: OMP-59R5 (Anti-Notch2/3) inhibits tumor growth and reduces cancer stem cell frequency in patient derived SCLC xenografts (2014)

Abstract Small cell lung cancer (SCLC) is a devastating disease with very poor prognosis and few treatment options. We have established patient derived xenografts from SCLC tumors and determined that Notch pathway target genes are up-regulated in this disease relative to normal lung tissues and relative to other tumor types. We examined the in vivo efficacy of OMP-59R5, an antibody that was initially identified by binding to Notch2 and was subsequently shown to block signaling of both human and mouse Notch2 and Notch3. We performed in vivo growth inhibition and tumorigenicity studies with this Notch2/3 antibody alone or in combination with chemotherapeutic agents in a panel of six patient-derived SCLC xenograft models. We found that OMP-59R5 treatment significantly reduced tumor recurrence in combination with chemotherapy in five of the six models. Through a serial transplantation study from a sensitive tumor, we found that OMP-59R5 in combination with chemotherapy (cisplatin plus irinotecan) profoundly reduced the cancer stem cell (CSC) frequency. In contrast, treatment with chemotherapeutic agents alone had the opposite effect and increased CSC frequency. In minimal residual disease models, we analyzed the ability of OMP-59R5 to delay tumor recurrence following chemotherapy-induced tumor regression. While chemotherapeutic agent-treated tumors re-grew rapidly following treatment termination, the growth of recurrent tumors was delayed by OMP-59R5. We also evaluated changes in gene expression post treatment and found that OMP-59R5 modulated the expression of Notch pathway, epithelial-to-mesenchymal transition, stromal and vasculature genes. Furthermore, we observed an increase in expression of neuroendocrine differentiation markers after OMP-59R5 treatment in sensitive tumors. Following up on these preclinical findings, OMP-59R5 is currently being evaluated for safety and efficacy in combination with cisplatin and etoposide for treatment of SCLC in an ongoing Phase 1b/2 clinical trial (PINNACLE). Citation Format: Marcus M. Fischer, Jalpa Shah, Jennifer Cain, Belinda Cancilla, James W. Evans, Christopher L. Murriel, Tracy Tang, Jie Wei, Wan-Ching Yen, Chun Zhang, Austin Gurney, John Lewicki, Ann M. Kapoun, Timothy Hoey. OMP-59R5 (Anti-Notch2/3) inhibits tumor growth and reduces cancer stem cell frequency in patient derived SCLC xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3048. doi:10.1158/1538-7445.AM2014-3048
Transformation and Regeneration of Two Cultivars of Pea (Pisum sativum L.) (1993)

A reproducible transformation system was developed for pea (Pisum sativum L.) using as explants sections from the embryonic axis of immature seeds. A construct containing two chimeric genes, nopaline synthase-phosphinothricin acetyl transferase (bar) and cauliflower mosaic virus 35S-neomycin phosphotransferase (nptII), was introduced into two pea cultivars using Agrobacterium tumefaciens-mediated transformation procedures. Regeneration was via organogenesis, and transformed plants were selected on medium containing 15 mg/L of phosphinothricin. Transgenic peas were raised in the glasshouse to produce flowers and viable seeds. The bar and nptII genes were expressed in both the primary transgenic pea plants and in the next generation progeny, in which they showed a typical 3:1 Mendelian inheritance pattern. Transformation of regenerated plants was confirmed by assays for neomycin phosphotransferase and phosphinothricin acetyl transferase activity and by northern blot analyses. Transformed plants were resistant to the herbicide Basta when sprayed at rates used in field practice.
Chelate radiochemistry: Cleavable linkers lead to altered levels of radioactivity in the liver (1988)

Bifunctional chelating agents based on benzyl-EDTA bind 111In stably under physiological conditions. Available evidence indicates that the indium is cleared from the body in its original chelated form. Initial studies of a series of antibody-chelate conjugates joined by different molecular linkers show that the 111In biodistribution is strongly dependent on the nature of the linker. Linkers containing thiourea, thioether, peptide, ester, and disulfide groups were compared in healthy BALB/c mice. The disulfide linker led to particularly rapid clearance of 111In from the liver, and from the whole body. Results did not appear to be as favorable as those currently obtainable with reversible radiolabelling techniques, in which the 111In chelate is bound non-covalently to the antibody and a competing hapten is used to displace it when desired. However, the concept of a metabolically cleavable linker is sound. Further exploration is needed to produce a conjugate with the desired properties.
Miniature 10 kHz thermo-optic delay line in silicon (2010)

The scanning delay line is a key component of time-domain optical coherence tomography systems. It has evolved since its inception toward higher scan rates and simpler implementation. However, existing approaches still suffer from drawbacks in terms of size, cost, and complexity, and they are not suitable for implementation using integrated optics. In this Letter, we report a rapid scanning delay line based on the thermo-optic effect of silicon at λ = 1.3 μm manufactured around a generic planar lightwave circuit technology. The reported device attained line scan rates of 10 kHz and demonstrated a scan range of 0.95 mm without suffering any observable loss of resolution (15 µm FWHM) owing to depth-dependent chromatic dispersion.
A voice activity detection algorithm for communication systems with dynamically varying background acoustic noise (2002)

Speech can be modeled as short bursts of vocal energy separated by silence gaps. During typical conversation talk-spurts comprise only 31.5% of each party's speech and the remaining 68.5% is silence. Communication systems can achieve significant gains in spectral efficiency and energy efficiency by disconnecting the users from the spectral resource during the silence periods. This paper develops a simple, efficient, and robust voice activity detection (VAD) algorithm to work in a mobile or portable environment exhibiting dynamically varying background noise. The VAD uses probabilistic distances based on the energy content, the periodicity, the stationarity and the spectral distribution within the low frequency band to decide if the presented speech frame is speech or silence.
Review: Monoclonal Antibodies to the Vascular Endothelial Growth Factor Receptor-2 in Cancer Therapy (2007)

Angiogenesis is a fundamental mechanism of cancer growth and invasion. Current translational approaches are using both small-molecule inhibitors and antibodies that modulate various steps of these processes, and several such compounds have already received regulatory approval for the therapy of specific indications in cancer. Among the many molecular targets involved in the control of angiogenesis, the vascular endothelial growth factor receptor-2 (VEGFR-2; or kinase insert domain-containing receptor) is attractive as shown in part by the efficacy of small-molecule inhibitors directed to this receptor. Two small-molecule inhibitors that target VEGFR-2 have recently been granted approval for the treatment of renal cell cancer and gastrointestinal stromal tumors. The development of antibodies that can selectively block VEGFR-2 could potentially result in improved potency or tolerability. Here, we discuss the role of VEGFR-2 in cancer and ongoing efforts to develop highly specific monoclonal antibodies for cancer therapy.
Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19 (2020)

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor <i>in vitro</i> of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent <i>in vitro</i> antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, <i>in vitro</i> , and <i>in vivo</i> antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.
Receptor-mediated transport of heme by hemopexin regulates gene expression in mammalian cells (1989)

Hemopexin (HPX) transports heme to liver parenchymal cells, undergoes receptor-mediated endocytosis, and recycles intact. Incubation of mouse hepatoma (Hepa) cells with heme-HPX causes a rapid dose- and time-dependent increase in the steady-state level of heme oxygenase (HO) mRNA. A maximum induction of 20-25-fold is achieved within 3 h after incubation with 10 microM heme-HPX. This accumulation of HO mRNA results primarily from increased transcription of the HO gene as judged by in vitro nuclear run-on assays. In addition, receptor-mediated transport of heme into Hepa cells significantly decreases the steady-state level of transferrin receptor (TfR) mRNA. While a 25-30-fold decrease in the amount of TfR mRNA is observed within 3 h of incubation of Hepa cells with 10 microM heme-HPX, no significant change in the rate of TfR gene transcription was detected. These regulatory effects of heme-HPX are not restricted to hepatic cells but are also observed in human promyelocytic HL-60 cells. This is the first direct demonstration of receptor-mediated transport of heme by hemopexin regulating gene expression in mammalian cells.
Bleomycin-Induced Alveolitis Detected by FDG Positron Emission Tomography (2002)

From The Clinical PET Centre, Guy’s and St. Thomas’ Hospital, Guy’s, King’s and St. Thomas’ School of Medicine, London, United Kingdom Received for publication October 10, 2001. Revision accepted December 24, 2001. Correspondence: Sharon F. Hain, The Clinical PET Centre, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail: [email protected]
Different functional sites on rIFN-alpha 2 and their relation to the cellular receptor binding site. (1987)

Functional domains on the recombinant interferon-alpha 2 (rIFN-alpha 2) molecule, which are involved in antiviral and NK enhancing activities, have been defined by immunochemical mapping with MAb, and their relationship with the IFN cellular receptor binding site has been studied. With 20 different anti-IFN-alpha 2 MAb selected by their binding to 125I-labeled IFN and by immunoprecipitation of the 20 Kd IFN molecule, we have defined three spatially separated epitopes (designated as sites A, B, and C) and two partially overlapping antigenic determinants on the IFN-alpha 2 molecule. Functional relation of IFN-alpha 2 A, B, and C epitopes have been determined by assaying the effect of various anti-IFN MAb on IFN-mediated biologic activities. MAb directed to sites A and B neutralized the antiviral activity of IFN. Furthermore, the MAb specific for site B displayed a neutralizing potency threefold higher than MAb directed to site A. Site B was also involved in the enhancing activity of IFN on NK-mediated cell cytotoxicity, whereas site A was not. MAb directed to site C partially affected the IFN-boosted NK activity but did not neutralize the IFN antiviral activity. Inhibition studies of 125I-IFN binding to human U-937 myelomonocytic cells by anti-IFN MAb demonstrated that MAb directed to site B blocked different IFN biologic functions by preventing its binding to the cellular receptor, whereas MAb directed to sites A and C caused no inhibition and partial inhibition of this binding, respectively.
THE ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN OCULAR HEALTH AND DISEASE (2005)

The leading causes of blindness are retinal and choroidal diseases manifesting abnormal vessel permeability and growth. Scientists have sought to understand the mechanisms underlying these pathologic conditions with the hope of developing directed and effective pharmacologic therapies. Research has yielded important new mechanistic data, making possible the development of new drugs. One of the most important targets to have emerged is a secreted protein named vascular endothelial growth factor. This review will summarize the current state of our knowledge regarding this growth factor and outline some important questions that remain to be answered.
Short-Term Clinical Outcome of Patients With Acute Pulmonary Embolism, Normal Blood Pressure, and Echocardiographic Right Ventricular Dysfunction (2000)

A significant proportion (31%) of normotensive patients with acute PE presents with RV dysfunction; these patients with latent hemodynamic impairment have a 10% rate of PE-related shock and 5% in-hospital mortality and may require aggressive therapeutic strategies. Conversely, normotensive patients without echocardiographic RV dysfunction have a benign short-term prognosis. Thus, early detection of echocardiographic RV dysfunction is of major importance in the risk stratification of normotensive patients with acute PE.