gebhart/patrepeval huggingface dataset:
Efficient and Highly Selective Copper(II) Transport across a Bulk Liquid Chloroform Membrane Mediated by Lipophilic Dipeptides (1997)

Several structurally simple N-monoalkylated and -dialkylated dipeptides made of α-amino acids Gly, Phe, and Leu, 1−11, were synthesized and investigated as carriers for the transport of Cu(II), Zn(II), and Ni(II) from an aqueous pH = 5.6 buffer source to a 0.1 M HCl receiving phase across a bulk chloroform membrane. The proton-driven translocation was followed during the process by analyzing the metal ion concentrations in the three phases. The transport efficiency depends on the ease of formation of a neutral complex with Cu(II) (the peptide group and carboxylic acid being deprotonated) at the source−chloroform interface and on that of its disruption by protonation at the receiving phase: the carrier's lipophilicity favors the metal ion uptake and not the release. By modulating the length of the N-alkyl chains and the hydrophobicity of the dipeptide moiety, a quite remarkable transport efficiency was observed for Cu(II), in most cases superior to that of the industrial extractant Kelex 100. Moreover, using l,l- and l,d-N-octyl-PheLeu as carriers, remarkable diastereomeric effects were observed in the rate of uptake and release of Cu(II) ion although the differences mutually compensate in the overall transport rate. Under the conditions used the carriers are much less effective in the translocation of Zn(II) and Ni(II) and their transport efficiency drops dramatically in the presence of Cu(II), the latter being favored by factors of 1.2 × 103 and >104, respectively. Such very high selectivities depend on the fact that only Cu(II) among other transition metal ions can form neutral complexes at the pH value of the source phase.
In vivo recovery of human platelets in severe combined immunodeficient mice as a measure of platelet damage (2007)

The SCID mouse model can detect differences between damaged and control human PLTs and could be useful in evaluating novel PLT collection, processing, and storage technologies that may impact PLT quality.
Immunity to and Frequency of Reinfection with Respiratory Syncytial Virus (1991)

To better understand the duration of immunity against respiratory syncytial virus (RSV) and the role of serum antibodies to the surface glycoproteins, F and G, in susceptibility to reinfection, 15 adults with previous natural RSV infection were challenged with RSV of the same strain group (A) at 2, 4, 8, 14, 20, and 26 months after natural infection. By 2 months about one-half and by 8 months two-thirds of the subjects became reinfected. Each challenge resulted in infection in at least one-fourth of the subjects. Within 26 months 73% had two or more and 47% had three or more infections. The duration of immunity tended to increase after two closely spaced infections. Higher neutralizing, F and GA antibody levels before challenge correlated significantly with protection against infection. However, even in subjects with the highest antibody levels, the risk of reinfection was 25%. Specific nasal IgA antibody titers did not correlate significantly with protection. This suggests that humoral neutralizing, F, and G antibodies correlate with resistance to reinfection, but protection is far from complete and is of short duration.
Toward Environmentally Friendly Photolithographic Materials:  A New Class of Water-Soluble Photoresists (2003)

New water-soluble styrenic polymers bearing two functional groups, pendant ammonium salts of half-esters of malonic acids and acid-labile alkyl esters, were synthesized and evaluated for water-soluble positive-tone photoresist application. These polymers feature two solubility switches: insolubilization of the entire film by baking and selective solubilization upon exposure to UV light. Time-resolved FT-IR measurement of the baked films showed sequential evaporation of ammonia from the films and the decarboxylation of the malonate half-esters. The rates of decarboxylation depend on the structure of substituents at the 2-position of the malonates. The choice of acid-labile esters, the structure of the half-esters, and the polymer compositions were carefully optimized, and high-resolution positive tone images were obtained that were fully processed in aqueous media.
A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vivo passage in rhesus monkeys (1996)

The utility of the simian immunodeficiency virus of macaques (SIVmac) model of AIDS has been limited by the genetic divergence of the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and the SIVs. To develop a better AIDS animal model, we have been exploring the infection of rhesus monkeys with chimeric simian/human immunodeficiency viruses (SHIVs) composed of SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rev. SHIV-89.6, constructed with the HIV-1 env of a cytopathic, macrophage-tropic clone of a patient isolate of HIV-1 (89.6), was previously shown to replicate to a high degree in monkeys during primary infection. However, pathogenic consequences of chronic infection were not evident. We now show that after two serial in vivo passages by intravenous blood inoculation of naive rhesus monkeys, this SHIV (SHIV-89.6P) induced CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. Genetic and serologic evaluation indicated that the reisolated SHIV-89.6P expressed envelope glycoproteins that resembled those of HIV-1. When inoculated into naive rhesus monkeys, SHIV-89.6P caused persistent infection and CD4 lymphopenia. This chimeric virus expressing patient isolate HIV-1 envelope glycoproteins will be valuable as a challenge virus for evaluating HIV-1 envelope-based vaccines and for exploring the genetic determinants of HIV-1 pathogenicity.
Organizer-Specific Homeobox Genes in Xenopus laevis Embryos (1991)

The dorsal blastopore lip of the early Xenopus laevis gastrula can organize a complete secondary body axis when transplanted to another embryo. A search for potential gene regulatory components specifically expressed in the organizer was undertaken that resulted in the identification of four types of complementary DNAs from homeobox-containing genes that fulfill this criterion. The most abundant of these encodes a DNA-binding specificity similar to that of the Drosophila melanogaster anterior morphogen bicoid. The other three are also homologous to developmentally significant Drosophila genes. These four genes may participate in the regulation of the developmental potential of the organizer.
Adenosine: A potential mediator of seizure arrest and postictal refractoriness (1992)

Abstract Adenosine is a potent inhibitory neuromodulator and has been proposed as an endogenous anticonvulsant. Depth electrodes modified to include a microdialysis probe were implanted for 10 to 16 days in the hippocampi of 4 patients with intractable complex partial epilepsy to test the hypothesis that during seizures extracellular adenosine reaches levels that may depress epileptiform activity. Samples were collected bilaterally at 3‐minute intervals before, during, and after a single, spontaneous‐onset seizure in each patient. All seizures commenced in one hippocampus and propagated to the contralateral hippocampus. Extracellular adenosine levels increased by 6‐ to 31‐fold with the increase significantly greater in the epileptogenic hippocampus. During seizures, levels of adenosine in the dialysate reached concentrations as high as 2.5 μM, reflecting extracellular concentrations of approximately 65 μM. Adenosine at concentrations of 40 to 50 μM depresses epileptiform activity in vitro, so the levels we report may suppress seizure activity in vivo. Moreover, adenosine levels remain elevated above basal values for the entire 18‐minute postical period. These data support the role of adenosine in mediating seizure arrest and postictal refractoriness and suggest that treatments which facilitate adenosine may be effective in preventing seizures.
Neutralizing Epitopes of Type O Foot-and-Mouth Disease Virus. II. Mapping Three Conformational Sites with Synthetic Peptide Reagents (1989)

Four neutralizing monoclonal antibodies (MAbs), recognizing three functionally independent, conformational sites on type O foot-and-mouth disease virus (FMDV) failed to react with immobilized structural proteins or synthetic peptides but bound to the isolated capsid protein VP1 and peptides in solution. Inhibition ELISA techniques were, therefore, applied using peptide antigens and anti-peptide sera to block MAb binding to virus particles, permitting the identification of those portions of the VP1 protein contributing to the epitopes. The binding site of one MAb, which neutralized a range of type O FMDV isolates, was shown to have components within regions 146 to 150 and 200 to 213 of VP1 with a critical involvement of the amino acids at positions 146 and 206 or 207. The determinants recognized by two other MAbs which were directed at similar, but not identical, epitopes from a second site included components from the 200 to 213 and 143 to 146 regions with amino acids 143 and 144, respectively, appearing critical for the inhibition of the virus binding of the two antibodies. These results demonstrate that the two previously identified immunogenic tracts of VP1 are brought into proximity in the quaternary structure of the virion to form an antigenic domain containing several conformational epitopes, some of which are functionally independent. A fourth, strain-specific MAb was effectively blocked from reacting with virus by peptides corresponding to residues 161 to 180 and 200 to 213.
Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis (2004)

MicroRNAs (miRNAs) are approximately 21-nt-long RNAs involved in regulating development, differentiation, and other processes in eukaryotes. In metazoa, nearly all miRNAs control gene expression by imperfectly base-pairing with the 3'-untranslated region (3'-UTR) of target mRNAs and repressing protein synthesis by an unknown mechanism. It is also unknown whether miRNA-mRNA duplexes containing mismatches and bulges provide specific features that are recognized by factors mediating the repression. miRNAs form part of ribonucleoprotein complexes, miRNPs, that contain Argonaute (Ago) and other proteins. Here we demonstrate that effects of miRNAs on translation can be mimicked in human HeLa cells by the miRNA-independent tethering of Ago proteins to the 3'-UTR of a reporter mRNA. Inhibition of protein synthesis occurred without a change in the reporter mRNA level and was dependent on the number, but not the position, of the hairpins tethering hAgo2 to the 3'-UTR. These findings indicate that a primary function of miRNAs is to guide their associated proteins to the mRNA.
Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: implications for cellular survival and tumor promotion. (1996)

The mitogen-activated protein kinase (MAPK) cascade plays an important role in carcinogenic development. Herein, we show that the skin tumor promoter butylated hydroxytoluene hydroperoxide (BHTOOH) stimulates a rapid and potent (14- to 20-fold) activation of extracellular signal-regulated kinase (ERK) in vivo and in cultured mouse keratinocytes. BHTOOH also moderately (5-fold) activated c-jun-N-terminal kinase, and 38-kDa MAPK-related protein in these same cells. N-acetylcysteine and o-phenanthroline abolished ERK activation by BHTOOH, consistent with a requirement for metal-dependent formation of reactive intermediates. Indeed, 4-CD3-BHTOOH, an analogue that generates less of the metabolite BHT-quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) and fewer tumors in vivo, accordingly exhibited diminished potency for activating ERK. ERK activation by BHTOOH was inhibited by suramin, and by expression of dominant-negative Ras-N-17 in PC12 cells, suggesting overlap between the pathways for BHTOOH and growth factor signaling. Induction of MAPK-dependent genes c-fos and MAPK phosphatase-1 by BHTOOH was also blocked by Ras-N-17 expression. Moreover, expression of Ras-N-17 or kinase-defective MAPK kinase (MEK) diminished cell survival following BHTOOH exposure. Similarly, pretreatment with suramin or the MEK inhibitor PD098059 also potentiated the toxicity of BHTOOH. On the other hand, expression of constitutively active MEK enhanced cell survival. Thus, we demonstrate that the MAPK cascade is critical to the cellular response to BHTOOH. This study suggests a functional role for MAPK activation in tumor promotion stimulated by oxidants and other agents.
Solution Thermodynamics and Kinetics of Metal Complexation with a Hydroxypyridinone Chelator Designed for Thorium-227 Targeted Alpha Therapy (2018)

The solution chemistry of a chelator developed for <sup>227</sup>Th targeted alpha therapy was probed. The compound of interest is an octadentate ligand comprising four N-methyl-3-hydroxy-pyridine-2-one metal-binding units, two tertiary amine groups, and one carboxylate arm appended for bioconjugation. The seven p K<sub>a</sub> values of the ligand and the stability constants of complexes formed with Th(IV), Hf(IV), Zr(IV), Gd(III), Eu(III), Al(III), and Fe(III) were determined. The ligand exhibits extreme thermodynamic selectivity toward tetravalent metal ions with a ca. 20 orders of magnitude difference between the formation constant of the Th(IV) species formed at physiological pH, namely [ThL]<sup>-</sup>, and that of its Eu(III) analogue. Likewise, log β<sub>110</sub> values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25 °C) were measured for [ThL]<sup>-</sup> and [Fe<sup>III</sup>L]<sup>2-</sup>, respectively, highlighting the high affinity and selectivity of the ligand for Th ions over potentially competing endogenous metals. Single crystal X-ray analysis of the Fe(III) complex revealed a dinuclear 2:2 metal:chelator complex crystallizing in the space group P1̅. The formation of this dimeric species is likely favored by several intramolecular hydrogen bonds and the protonation state of the chelator in acidic media. L<sub>III</sub> edge EXAFS data on the Th(IV) complexes of both the ligand and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Finally, kinetic experiments demonstrated that labeling the bioconjugated ligand with Th(IV) could be achieved and completed after 1 h at room temperature, reinforcing the high suitability of this chelator for <sup>227</sup>Th targeted alpha therapy.
Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism (2007)

Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARalpha is the molecular target for the fibrate class of drugs. Activation of PPARalpha in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPARalpha activation in humans. PPARgamma is the molecular target for the thiazolidinedione class of drugs. Activation of PPARgamma in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARalpha, activation of PPARbeta/delta leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.
Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients. (1983)

The results of this study demonstrate that spleen cells taken from mice at the height of the primary immune response to intravenous infection with Mycobacterium tuberculosis possess the capacity to transfer adoptive protection to M. tuberculosis-infected recipients, but only if these recipients are first rendered T cell-deficient, either by thymectomy and gamma irradiation, or by sublethal irradiation. A similar requirement was necessary to demonstrate the adoptive protection of the lungs after exposure to an acute aerosol-delivered M. tuberculosis infection. In both infectious models successful adoptive immunotherapy was shown to be mediated by T lymphocytes, which were acquired in the donor animals in response to the immunizing infection. It is proposed that the results of this study may serve as a basic model for the subsequent analysis of the nature of the T cell-mediated immune response to both systemic and aerogenic infections with M. tuberculosis.
An OCO3–Trianionic Pincer Tungsten(VI) Alkylidyne: Rational Design of a Highly Active Alkyne Polymerization Catalyst (2012)

Synthesis, characterization, and catalytic alkyne polymerization results for the first trianionic pincer alkylidyne complex, [(t)BuOCO]W≡CC(CH(3))(3)(THF)(2) (6), are described. Complex 6 is a highly active catalyst for the polymerization of acetylenes and exhibits a high turnover number (4371), activity (1.05 × 10(6) g(PPA) mol(cat)(-1) h(-1)),and yield (87%) for the polymerization of 1-ethynyl-4-fluorobenzene.
Dexamethasone acts locally to inhibit longitudinal bone growth in rabbits (1992)

Excess glucocorticoid is a potent inhibitor of epiphysial growth. Several mechanisms have been suggested to explain this growth inhibition, including both direct local effects of glucocorticoid on the epiphysial growth plate and indirect systemic effects. Previous studies do not distinguish which of these proposed mechanisms is actually responsible for the growth suppression in vivo. To resolve this controversy, we developed a method for delivering glucocorticoid directly into the rabbit epiphysial growth plate and for accurately measuring the resulting epiphysial growth rate. Five-week-old male rabbits received a local infusion of dexamethasone phosphate (80 ng/microliters, 1 microliters/h) into one proximal tibial growth plate and an infusion of vehicle into the contralateral growth plate. Growth rate was determined by inserting metal pins into the bone immediately adjacent to the growth plate and measuring the change in distance between pins on serial radiographs. This method permitted growth rates to be measured over intervals as short as 3 days, with an error of approximately 5%. Local dexamethasone administration decreased proximal tibial growth rate by 77% compared with the contralateral vehicle-treated tibia (P less than 0.0001). We conclude that excess glucocorticoid causes a rapid potent inhibition of growth by a direct local action on the growth plate.
Production Kinetics and Stability of a Transfectoma Cell Line Secreting Murine/Human Chimeric Antibody (1993)

We have developed a transfectoma cell line H69K that secrets secreting chimeric antibody with specificity for the pre-S2 surface antigen by the introduction of the chimeric heavy and light chain genes into murine SP2/0 hybridoma cells. In order to apply the production kinetics to the large-scale production of chimeric antibody, the cell growth, productivity and stability of the cell line have been characterized. The results showed that the specific growth rate of the cells was almost the same in both the 5% serum medium and the serum free medium, but the specific productivity was higher in the serum free medium. The productivity also increased during the stationary phase of the culture, suggesting that the kinetics of the chimeric antibody-production by the transfectoma cell line is associated with growth phase. The transfectoma cell line was stable for three months even without selection and thereafter slightly lost the productivity. Ribonuclease protection assay of the heavy and light chain mRNA from the long-term cultures revealed that decrease in the productivity may be due to the loss of the Ig genes in some cells. The informations obtained from this study will be useful in the large- scale production of the chimeric antibody by this transfectoma cell line.
Design and Synthesis of an Orally Bioavailable and Selective Peptide Epoxyketone Proteasome Inhibitor (PR-047) (2009)

Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and non-Hodgkin's lymphoma. Carfilzomib, an epoxyketone currently undergoing clinical trials in malignant diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib, which would have potential for improved dosing flexibility and patient convenience over intravenously administered agents. The lead compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome (beta5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral administration at doses resulting in >80% proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.
Competition (2007)

Humans, like primates, expect their fellows to cooperate and react with outrage when others do not conform to the rules. Is the desire for justice not another human universal? Anthropologists recognize an amazing diversity in laws and customs around the world, but they have good reason to think that an individual sense of justice emerges in early childhood, rooted in the same reciprocity that underpins daily collaboration.1 Notions of right and wrong are rooted in our emotions. Virtually universal are rules forbidding killing members of one's group, stealing objects in others' possession, raping virgins, or seeking adulterous relations with married women. Universal, too, is the notion that individuals are responsible for many of their actions. We know that people everywhere deliberately lie, dissimulate, and otherwise cheat their superiors, their peers and their subordinates.2 Cheating and deception come naturally, and everybody practices them to some degree. These tricks are held in check only by virtue of a universal vigilance against them, and by the implicit threat of vengeance. Not only do we resent the people who cheat us, we can also empathize with victims of violence or duplicity and feel delight in teaching the perpetrators a lesson.3 This sense of rules and the order that results from it certainly predates the elaboration of law, which is principally a codification of the informal rules humans and primates live by.4 KeywordsHuman NatureCriminal ProcedureCivil LitigationAttempted MurderCapital SentenceThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.