gebhart/patrepeval huggingface dataset:
Comparative Effects of Two Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibodies in the RSV Murine Model: Time versus Potency (2005)

Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at -24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.
Cost-effectiveness analysis of ferric carboxymaltose in iron-deficient patients with chronic heart failure in Sweden (2015)

Treatment of iron deficiency in CHF with FCM compared with placebo is estimated to be cost-effective. The ICER in the base case scenario is twice as high as previously thought, but noticeably below SEK 500,000 (€54,300) per QALY, an informal average reference value used by the Swedish Dental and Pharmaceutical Benefits Agency. Increased HRQoL and fewer hospitalizations are the key drivers of this result.
Combinatorial Biomimetic Chemistry: Parallel Synthesis of a Small Library ofβ-Hairpin Mimetics Based on Loop III from Human Platelet-Derived Growth Factor B (2000)

Combinatorial diversity in hypervariable β-hairpin loops is exploited by the immune system to select binding sites on antibodies for a wide variety of different protein antigens. In a first step towards mimicking this strategy in vitro, for the selection of novel protein ligands, an approach is described here for the parallel synthesis of small libraries of conformationally defined β-hairpin protein epitope mimetics. Starting from a protruding hairpin loop in platelet-derived growth factor B (PDGF-B), 8 and 12 residues were first transplanted from the protein to a D-Pro-L-Pro template, to afford the cyclic peptide-loop mimetics 1 and 2, respectively. NMR and MD studies in aqueous solution show that both mimetics populate conformations which closely mimic the β-hairpin in the crystal structure of the native protein (Fig. 5). Based on 1 as a scaffold, a library of 24 mimetics was synthesized in which the four residues at the tip of the loop (VRKK) were held constant, and flanking residues at positions 1, 2, 7, and 8 in the hairpin were varied (Fig. 7). The library was prepared by parallel synthesis in a two-stage solid-phase assembly/solution-phase cyclization process. The products were analyzed by MS, NMR, and CD. 2D-NOESY revealed for most library members characteristic long-range NOEs that show that the hairpin conformation is stably maintained. The results suggest that this approach may be useful for the synthesis of much larger libraries of peptide and protein mimetics based on a β-hairpin scaffold.
Molecular determinants of amyloid deposition in Alzheimer's disease: conformational studies of synthetic .beta.-protein fragments (1990)

The amyloid beta-protein (1-42) is a major constituent of the abnormal extracellular amyloid plaque that characterizes the brains of victims of Alzheimer's disease. Two peptides, with sequences derived from the previously unexplored C-terminal region of the beta-protein, beta 26-33 (H2N-SNKGAIIG-CO2H) and beta 34-42 (H2N-LMVGGVVIA-CO2H), were synthesized and purified, and their solubility and conformational properties were analyzed. Peptide beta 26-33 was found to be freely soluble in water; however, peptide beta 34-42 was virtually insoluble in aqueous media, including 6 M guanidinium thiocyanate. The peptides formed assemblies having distinct fibrillar morphologies and different dimensions as observed by electron microscopy of negatively stained samples. X-ray diffraction revealed that the peptide conformation in the fibrils was cross-beta. A correlation between solubility and beta-structure formation was inferred from FTIR studies: beta 26-33, when dissolved in water, existed as a random coil, whereas the water-insoluble peptide beta 34-42 possessed antiparallel beta-sheet structure in the solid state. Solubilization of beta 34-42 in organic media resulted in the disappearance of beta-structure. These data suggest that the sequence 34-42, by virtue of its ability to form unusually stable beta-structure, is a major contributor to the insolubility of the beta-protein and may nucleate the formation of the fibrils that constitute amyloid plaque.
R-1-Acetamido-2-phenylethaneboronic acid. A specific transition-state analog for chymotrypsin (1981)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTR-1-Acetamido-2-phenylethaneboronic acid. A specific transition-state analog for chymotrypsinDonald S. Matteson, Kizhakethil M. Sadhu, and Gustav E. LienhardCite this: J. Am. Chem. Soc. 1981, 103, 17, 5241–5242Publication Date (Print):August 1, 1981Publication History Published online1 May 2002Published inissue 1 August 1981https://pubs.acs.org/doi/10.1021/ja00407a051https://doi.org/10.1021/ja00407a051research-articleACS PublicationsRequest reuse permissionsArticle Views1717Altmetric-Citations130LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Antiviral Treatment: From Concept to Reality (1997)

The initial development of antiviral compounds was slow, with the first clinical antiviral agent not available until the 1960s. Early development was hindered by the lack of understanding of virus life-cycles and the absence of an assay system for antiviral activity. The appearance of the first assay system, the fertilized egg yolk sac, led to the identification of methisazone. This was the first antiviral agent to be used clinically. The improvement in antiviral assay systems, and the start of directed research programmes led to the development of the first antiherpes agents idoxuridine, trifluorothymidine (TFT) and vidarabine. However, all of these agents were associated with significant adverse effects. Antiherpes therapy took a major step forward with the development of the acyclic nucleoside analogue, aciclovir. Aciclovir is much more potent than previous antiherpesvirus agents. Its mode of action results in selectivity for herpesvirus-infected cells, thus significantly reducing the side-effects seen with earlier agents. Because of this, it became the standard therapy for herpes simplex virus type 1 (HSV-1), HSV-2 and varicella zoster virus infections. However, the bioavailability of oral aciclovir is poor, requiring high and frequent doses. This led to the search for better absorbed agents and to the development of two prodrugs, famciclovir and valaciclovir. Both famciclovir and valaciclovir offer much improved bioavailability of the nucleosides penciclovir and aciclovir, compared with aciclovir. Once in the body the conversion of valaciclovir to aciclovir means that the two agents have similar pharmacokinetic properties. Similarly, famciclovir is converted to penciclovir in the body. Penciclovir, when phosphorylated in virus-infected cells, persists within the cell for a much longer period than aciclovir triphosphate. Over the last 10 years we have seen an acceleration in the development of antiviral agents and some major advances in antiviral therapy. Many challenges, however, still lie ahead.
Controlling Nonspecific Protein Interactions in Silicon Biomicrosystems with Nanostructured Poly(ethylene glycol) Films (2002)

Protein interaction with surfaces is one of the most important criteria for the selection of implantable biomaterials as it can mediate further cellular interaction and therefore influence biocompatibility of the surfaces. An ideal biomaterial would adsorb no protein, which is practically impossible to achieve. Here we have demonstrated that control of protein adsorption can be achieved by modifying silicon surfaces with a biocompatible polymer like poly(ethylene glycol) (PEG). Two different methods to modify the silicon surface were used. Two model proteins, namely, fibrinogen and bovine serum albumin, were used to study the adsorption on PEG-modified surfaces. The adsorbed protein was characterized using fluorescence microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy.
Rat Parathyroid Hormone 1 − 34 Signals through the MEK/ERK Pathway to Induce Cardiac Hypertrophy (2008)

This study aimed to characterize the role of the mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in cardiac hypertrophy induced by parathyroid hormone (PTH). Various concentrations of rat PTH1-34 were used to induce hypertrophy in neonatal rat ventricular cardiomyocytes, and the effects were compared with control cells and those treated with PD98059, a selective inhibitor of MEK1. Hypertrophy was assessed in terms of cell diameter, atrial natriuretic peptide (ANP) mRNA expression and protein synthesis; the MEK/ERK pathway was assessed by measuring levels of phosphorylated ERK1/2. Treatment with PTH1-34 at 100 nM for 24 h effectively induced cardiac hypertrophy (increased cell diameter, protein synthesis and ANP mRNA expression) and also increased levels of phosphorylated ERK1/2 compared with normal control cells. Treatment with PTH1-34 plus PD98059 significantly attenuated these changes. These results demonstrate that inhibition of the MEK/ERK pathway blocks PTH1-34-induced cardiac hypertrophy, suggesting that PTH1-34 might signal through the MAPK pathway to induce hypertrophy in cardiomyocytes.
Characterization of the cytotoxic effect of extracellular ATP in J774 mouse macrophages (1992)

Extracellular ATP (ATPo) is known to be cytotoxic to many cell types through a mechanism which is largely unknown. Very recently this nucleotide has been shown to cause cell death by apoptosis, probably by interacting with specific cell-surface receptors. In the present study we have investigated the mechanism of ATPo-dependent cytotoxicity in the macrophage-like mouse cell line J774. It has been previously reported that in this cell type ATPo activates trans-membrane Ca2+ and Na+ fluxes and a drastic increase in the plasma-membrane permeability to hydrophilic solutes smaller than 900 Da. These changes are followed by cell swelling and lysis. We show in the present study that, although this nucleotide triggers a rise in the cytoplasmic Ca2+ concentration, neither cell swelling nor lysis is Ca(2+)-dependent. Furthermore, cell lysis is not dependent on Na+ influx, as it is not prevented by iso-osmotic replacement of extracellular Na+ with choline or N-methylglucamine. On the contrary, ATPo-dependent cytotoxicity, but not the ATPo-dependent increase in plasma-membrane permeability, is completely abrogated in sucrose medium. Under our experimental conditions ATPo does not cause DNA fragmentation in J774 cells. We conclude from these findings that ATPo does not cause apoptosis of J774 macrophages and promotes a Ca(2+)- and Na(+)-independent colloido-osmotic lysis.
Cerebral ischemia detected with diffusion-weighted MR imaging after stent implantation in the carotid artery. (2002)

In 29% of the procedures, stent implantation in the carotid artery was associated with new areas of cerebral ischemia, as detected by using diffusion-weighted MR images; these findings indicated the occurrence of cerebral microemboli during such procedures. In all patients except one, the new lesions were clinically silent.
Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). (1987)

Vesicles are released during the in vitro culture of sheep reticulocytes which can be harvested by centrifugation at 100,000 X g for 90 min. These vesicles contain a number of activities, characteristic of the reticulocyte plasma membrane, which are known to diminish or disappear upon reticulocyte maturation. The activities include acetylcholinesterase, cytochalasin B binding (glucose transporter) nucleoside binding (i.e. nucleoside transporter), Na+-independent amino acid transport, and the transferrin receptor. Enzymes of cytosolic origin are not detectable or are present at low activity in the vesicles. Cultures of whole blood, mature red cells, or white cells do not yield comparable levels of these activities, supporting the conclusion that the activities arise from the reticulocytes. In addition, the lipid composition of the vesicles shows the high sphingomyelin content characteristic of sheep red cell plasma membranes, but not white cell or platelet membranes, also consistent with the conclusion that the vesicles are of reticulocyte origin. It is suggested that vesicle externalization may be a mechanism for shedding of specific membrane functions which are known to diminish during maturation of reticulocytes to erythrocytes.
Phytoalexin synthesis by the sorghum mesocotyl in response to infection by pathogenic and nonpathogenic fungi (1987)

Infection of the sorghum mesocotyl by Helminthosporium maydis (a nonpathogen) and Colletotrichum graminicola (a pathogen) resulted in the rapid accumulation of a pigment complex by two sorghum cultivars. The components of the complex were fungitoxic. The principal compounds have been identified as the 3-deoxyanthocyanidins apigeninidin and luteolinidin. Apigeninidin accumulated in both sorghum cultivars in response to infection and was the predominant pigment. Luteolinidin accumulated in only one of the cultivars. Because of the speed of synthesis, occurrence only in response to inoculation, and fungitoxicity of the individual components, we propose that synthesis of the pigment complex constitutes a defense response and that the compounds apigeninidin and luteolinidin should be considered as phytoalexins.
Time‐course of sodium transport along the nephron in nephrotic syndrome: The role of potassium (2019)

The mechanism of sodium retention and its location in kidney tubules may vary with time in nephrotic syndrome (NS). We studied the mechanisms of sodium retention in transgenic POD-ATTAC mice, which display an inducible podocyte-specific apoptosis. At day 2 after the induction of NS, the increased abundance of NHE3 and phosphorylated NCC in nephrotic mice compared with controls suggest that early sodium retention occurs mainly in the proximal and distal tubules. At day 3, the abundance of NHE3 normalized, phosphorylated NCC levels decreased, and cleavage and apical localization of γ-ENaC increased in nephrotic mice. These findings indicate that sodium retention shifted from the proximal and distal tubules to the collecting system. Increased cleavage and apical localization of γ-ENaC persisted at day 5 in nephrotic mice when hypovolemia resolved and steady-state was reached. Sodium retention and γ-ENaC cleavage were independent of the increased plasma levels of aldosterone. Nephrotic mice displayed decreased glomerular filtration rate and urinary potassium excretion associated with hyperkaliemia at day 3. Feeding nephrotic mice with a low potassium diet prevented hyperkaliemia, γ-ENaC cleavage, and led to persistent increased phosphorylation of NCC. These results suggest that potassium homeostasis is a major determinant of the tubular site of sodium retention in nephrotic mice.
Atomic Structure of FKBP-FK506, an Immunophilin-Immunosuppressant Complex (1991)

The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography. The conformation of the protein changes little upon complexation, but the conformation of FK506 is markedly different in the bound and unbound forms. The drug's association with the protein involves five hydrogen bonds, a hydrophobic binding pocket lined with conserved aromatic residues, and an unusual carbonyl binding pocket. The nature of this complex has implications for the mechanism of rotamase catalysis and for the biological actions of FK506 and rapamycin.
Inhibition of protein farnesyltransferase: a possible mechanism of tumor prevention by dehydroepiandrosterone sulfate (1994)

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant adrenal steroid with apparent anticarcinogenic properties. Given our recent observation of the dehydro-epiandrosterone-mediated inhibition of protein isoprenylation and the fact that 99% of the circulating dehydro-epiandrosterone is sulfated, with less than 1% representing the free steroid, we investigated the effects of DHEAS on post-translational isoprenylation of proteins. We here report that exposure of HT-29 SF human colonic adenocarcinoma cells to DHEAS inhibited the incorporation of [3H]mevalonate into cellular proteins in a dose-dependent manner when endogenous mevalonate synthesis was blocked by lovastatin. Interestingly, significant inhibition was observed at concentrations of DHEAS which are comparable to peak serum levels of this steroid occurring in the second decade of life. Immunoprecipitation revealed that isoprenylation of p21ras was also suppressed in DHEAS-treated HT-29 SF cells. In a cell-free system, DHEAS inhibited the farnesylation of a biotinylated decapeptide corresponding to the C-terminus of K-ras by 50% at a concentration of 100 microM. This suggests that DHEAS inhibits isoprenylation of cellular proteins, including p21ras, at a point in the mevalonate pathway distal to 3-hydroxy-3-methylglutaryl-CoA reductase and that the DHEAS-mediated suppression of protein farnesylation may largely be due to inhibition at the level of protein farnesyltransferase. Thus, these findings may provide a plausible explanation for the antitumor activity of DHEAS.
The regulator of MAT2 (ROM2) protein binds to early maturation promoters and represses PvALF-activated transcription. (1996)

The regulation of maturation (MAT)- and late embryogenesis (LEA)-specific gene expression in dicots involves factors related to ABI3, a seed-specific component of the abscisic acid signal transduction pathways from Arabidopsis. In French bean (Phaseolus vulgaris), the ABI3-like factor, PvALF, activates transcription from MAT promoters of phytohemagglutinin (DLEC2) and beta-phaseolin (PHS beta) genes. We describe the regulator of MAT2 (ROM2) as a basic leucine zipper (bZIP) DNA binding protein that recognizes motifs with symmetric (ACGT) and asymmetric (ACCT) core elements present in both MAT promoters. ROM2 antagonizes trans-activation of the DLEC2 promoter by PvALF in transient expression assays. Repression was abolished by mutations that prevented binding of ROM2 to the DLEC2 seed enhancer region. Moreover, a hybrid protein composed of a PvALF activation domain and the DNA binding and dimerization domain of ROM2 activated gene expression, indicating that ROM2 recognizes the DLEC2 enhancer in vivo; consequently, ROM2 functions as a DNA binding site-dependent repressor. Supershift analysis of nuclear proteins, using a ROM2-specific antibody, revealed an increase in ROM2 DNA binding activity during seed desiccation. A corresponding increase in ROM2 mRNA coincided with the period when DLEC2 mRNA levels declined in embryos. These results demonstrate developmental regulation of the ROM2 repressor and point to a role for this factor in silencing DLEC2 transcription during late embryogenesis.
Type 1/Type 2 Immunity in Infectious Diseases (2001)

T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.
Ability of SPI2 mutant of S. typhi to effectively induce antibody responses to the mucosal antigen enterotoxigenic E. coli heat labile toxin B subunit after oral delivery to humans (2007)

We have evaluated an oral vaccine based on an Salmonella enteric serovar typhi (S. typhi) Ty2 derivative TSB7 harboring deletion mutations in ssaV (SPI-2) and aroC together with a chromosomally integrated copy of eltB encoding the B subunit of enterotoxigenic Escherichia coli heat labile toxin (LT-B) in volunteers. Two oral doses of 10(8) or 10(9)CFU were administered to two groups of volunteers and both doses were well tolerated, with no vaccinemia, and only transient stool shedding. Immune responses to LT-B and S. typhi lipopolysaccharide were demonstrated in 67 and 97% of subjects, respectively, without evidence of anti-carrier immunity preventing boosting of LT-B responses in many cases. Further development of this salmonella-based (spi-VEC) system for oral delivery of heterologous antigens appears warranted.