gebhart/patrepeval huggingface dataset:
Methyl Effects on Protein–Ligand Binding (2012)

The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.
The Biochemistry and Cell Biology of Antigen Processing and Presentation (1993)

T lymphocytes with alpha beta receptors recognize antigen in association with the polymorphic products of the class I and class II loci of the major histocompatibility complex (MHC). This presentation of antigen results from the intracellular generation of protein fragments, and the binding and transport to the cell surface of these peptides in stable association with the MHC class I and class II molecules. Each class of MHC molecule appears specialized for capture of peptides present in a particular intracellular compartment. We describe here the structural basis of peptide-MHC molecule interaction, the differences in biochemical behavior that focus the two classes of MHC molecules on peptides of distinct size and location, and the cell biology of MHC molecule transport, peptide generation, and intracellular movement. The importance of conformational changes accompanying peptide binding that affect subunit stability of MHC molecules, and the relationship between these changes and the handling of proteins by intracellular chaperones, are emphasized as key features in the operation of the class I and class II presentation pathways.
Changes in the specificity of antibodies against steroid antigens by introduction of mutations into complementarity-determining regions of the V(H) domain (1998)

An attempt was made to change the specificity of antibodies (Abs) by introduction of mutations. A monoclonal Ab specific for 17alpha-hydroxyprogesterone (17-OHP) was used as the starting Ab. On the basis of a model that was generated by a computer-driven model-building system, we constructed a phage-display library of Abs in which 16 residues were mutated in three complementarity-determining regions of the heavy chain that appeared to form the steroid-binding pocket. We screened the library with 17-OHP and cortisol that had been conjugated with bovine serum albumin, and we isolated many clones that had retained 17-OHP-binding ability as well as clones with the newly developed ability to bind cortisol in addition to 17-OHP. We compared the amino acid sequences between 17-OHP-specific and cortisol-binding Abs, and then constructed several additional Abs. Our results indicated that a change in specificity could be achieved by changing only a single, critical amino acid residue. Models of the 17-OHP-and cortisol-binding pockets formed by the mutated Abs could explain these observations.
Oncolytic Efficacy and Enhanced Safety of Measles Virus Activated by Tumor-Secreted Matrix Metalloproteinases (2006)

Cancer cells secrete matrix metalloproteinases (MMP) that degrade the extracellular matrix and are responsible for some hallmarks of malignant cancer. Many viruses, including a few currently used in oncolytic virotherapy clinical trials, depend on intracellular proteases to process their proteins and activate their particles. We show here for measles virus (MV) that particle activation can be made dependent of proteases secreted by cancer cells. The MV depends on the intracellular protease furin to process and activate its envelope fusion (F) protein. To make F protein activation cancer cell specific, we introduced hexameric sequences recognized by an MMP and identified the mutant proteins most effective in fusing MMP-expressing human fibrosarcoma cells (HT1080). We showed that an MMP inhibitor interferes with syncytia formation elicited by mutant F proteins and confirmed MMP-dependent cleavage by Edman degradation sequence analysis. We generated recombinant MVs expressing the modified F proteins in place of furin-activated F. These viruses spread only in cells secreting MMP. In nude mice, an MMP-activated MV retarded HT1080 xenograft growth as efficiently as the furin-activated MV vaccine strain. In MV-susceptible mice, the furin-activated virus caused lethal encephalitis upon intracerebral inoculation, whereas the MMP-activated did not. Thus, MV particle activation can be made dependent of proteases secreted by cancer cells, enhancing safety. This study opens the perspective of combining targeting at the particle activation, receptor recognition, and selective replication levels to improve the therapeutic index of MV and other viruses in ongoing clinical trials of oncolysis.
Antigonadal Action of Prolactin: Further Studies on the Mechanism of Inhibition of Follicle-Stimulating Hormone-Induced Aromatase Activity in Rat Granulosa Cell Cultures* (1982)

The specificity and mechanism of the action by which PRL inhibits FSH-induced aromatase activity have been studied in rat granulosa cells in culture. Granulosa cells isolated from 25-day-old diethylstilbestrol-primed rats and cultured under defined conditions for 48 or 72 h with NIH-FSH-S13 (300 ng/ml) had elevated levels of aromatase activity, as assessed by the release of 3H2O from [1β-3H]testosterone. PRL (1 μg ovine NIH-P-S7–ml) alone had no effect on aromatase activity, but when added together with FSH, it effectively suppressed the effect of FSH. The effect of PRL was not due to cell death, since the rate of incorporation of [3H]leucine into trichloroacetic acidinsoluble material was unchanged by prior treatment with FSH alone or with FSH and PRL. The effect of PRL on the release of 3H2O from [1β-3H]testosterone was dose dependent; the doses that caused 50% inhibition of the FSH-induced responses after 48 and 72 h of treatment were 45 and 47 ng/ml, respectively, which are within the physiological range found in human follicular fluid. Homologous rat PRL also effectively inhibited the FSH induction of aromatase activity. The specificity of PRL action was examined by comparison with the effects of GH. Both ovine and rat GHs were without significant effect at 1 μg/ml, but at higher concentrations (5 and 10 μg/ml), they inhibited the FSH response to an extent consistent with an effect of the contaminating PRL. Furthermore, the effects of PRL and GH were additive at lower concentrations, whereas GH did not influence the maximal PRL effect. In addition to inhibiting the FSH-induced response by the addition of hormone at the time of plating, PRL also facilitated a decrease in the aromatase activity subsequent to the initiation by FSH of the induction process. The inhibitory action of PRL on FSH-induced aromatase activity was reversible, and this was apparent 33 h after removal of the PRL from the culture medium. PRL pretreatment of granulosa cells effectively reduced the amount of active aromatase induced by FSH in cell sonicates incubated under optimal conditions. PRL added directly to the cell sonicates did not influence the enzymatic activity. PRL also interfered with dibutyryl cAMP plus 3-isobutyl-1-methylxanthine-stimulated aromatase activity, suggesting that one site of action of PRL may be distal to FSH-induced cAMP production. The studies reported here suggest that one contraceptive action of PRL may reside in its ability to interfere with FSH effects on estrogen biosynthesis.
A Critical Review of Gastric Retentive Controlled Drug Delivery (2007)

The promise of gastric retentive drug delivery systems has propagated numerous investigations and the formation of a number of companies. Three technologies have involved a substantial number of human clinical trials: mucoadhesion, density modification, and expansion. Standard, nondisintegrating controlled-release tablets can display significant gastric retention times, with that retention time being proportional to the calorie intake. When these data for standard tablets are factored in, gastric retention technologies do not appear to offer significant additional retention times. Although the goal remains valuable, the promise of gastric retentive drug delivery systems remains unfulfilled at this time.
Online Monitoring of Copolymerization Involving Comonomers of Similar Spectral Characteristics (2006)

Automatic continuous online monitoring of polymerization reactions (ACOMP) was applied to free radical copolymerization of acrylic comonomers, whose spectral characteristics are very similar. Determination of the instantaneous concentration of each comonomer during the reaction was made possible by incorporating a full spectrum UV spectrophotometer into the detector train. The working assumption was that a UV spectrum at any instant during conversion is a linear combination of the normalized basis spectra of the comonomers and the copolymer, and that the unknown comonomer concentrations can be found by minimizing the error between measured and computed spectra over many wavelengths, even when spectral differences are small at any given wavelength. Here, the copolymerization of butyl acrylate (BA) and methyl methacrylate (MMA) was monitored under different starting composition ratios. Continuous conversion kinetics, composition drift, and average composition distribution are all found from the data, in addition to the evolution of weight-average intrinsic viscosity and molar mass Mw. Reactivity ratios, rmma = 0.40 ± 0.05 and rba = 2.58 ±0.1, are close to the averages found from a literature survey over a wide range of conditions. Comonomer conversion results were independently cross-checked by GPC. Increasing the content of BA in the copolymer was found to increase Mw, while also leading to a significant increase in chain stiffness. This work sets the stage for extension to copolymerization of three and more comonomers.
Preparation and Properties of a TherapeuticFactor IX Concentrate (1977)

A method for the large-scale preparation of a coagulation factor IX concentrate from human plasma is described. The method includes absorption of the coagulation factors from cryosupernatant plasma onto DEAE-Sephadex, extensive washing of the gel and elution of the coagulation factors with 0.5 M phosphate buffer at 6.85, followed by desalting of the eluate in a column of Sephadex G-25, then by lyophilization, dissolving and sterile filtration, and finally by freeze-drying of the final product. Experiments performed with HBsAg-positive plasma demonstrated a decrease in the HBsAg content by a factor of 10^-5 during the process. The product is inactive in Na-PTT assay. The process yields an about 100-fold purified factor IX concentrate containing also factors II,VII, and X, but in relatively smaller amounts. The average yield relative to factor IX is 60%. The batch size has been from 16 to 150 litres of plasma and about 300 batches of the concentrate have been prepared. About 5,100 bottles (about 4.0 x 10^6 U of factor IX) of the concentrate have been used in the treatment of patients with haemophilia B. The clinical effect has always been good and the in vivo response to factor IX was 1.15±0.30%/U/kg body weight. Two cases of HBsAg-negative hepatitis that may have been caused by the concentrate, were detected. No thrombotic complications were found.
Molecular Cloning and Characterization of a Novel Chloride Intracellular Channel-related Protein, Parchorin, Expressed in Water-secreting Cells (2000)

We previously reported a 120-kDa phosphoprotein that translocated from cytosol to the apical membrane of gastric parietal cells in association with stimulation of HCl secretion. To determine the molecular identity of the protein, we performed molecular cloning and expression of the protein. Immunoblot analysis showed that this protein was highly enriched in tissues that secrete water, such as parietal cell, choroid plexus, salivary duct, lacrimal gland, kidney, airway epithelia, and chorioretinal epithelia. We named this protein "parchorin" based on its highest enrichment in parietal cells and choroid plexus. We obtained cDNA for parchorin from rabbit choroid plexus coding a protein consisting of 637 amino acids with a predicted molecular mass of 65 kDa. The discrepancy in size on 6% SDS-polyacrylamide gel electrophoresis is considered to be due to its highly acidic nature (pI = 4.18), because COS-7 cells transfected with parchorin cDNA produced a protein with apparent molecular mass of 120 kDa on 6% SDS-polyacrylamide gel electrophoresis. Parchorin is a novel protein that has significant homology to the family of chloride intracellular channels (CLIC), especially the chloride channel from bovine kidney, p64, in the C-terminal 235 amino acids. When expressed as a fusion protein with green fluorescent protein (GFP) in the LLC-PK1 kidney cell line, GFP-parchorin, unlike other CLIC family members, existed mainly in the cytosol. Furthermore, when Cl(-) efflux from the cell was elicited, GFP-parchorin translocated to the plasma membrane. These results suggest that parchorin generally plays a critical role in water-secreting cells, possibly through the regulation of chloride ion transport.
A Common Mechanism of Chromosomal Translocation in T- and B-Cell Neoplasia (1986)

The chromosomal breakpoint involved in the t(8;14)(q24;q11) chromosome translocation in the SKW-3 cell line, which directly involves the 3' flanking region of the c-myc gene, was cloned and sequenced. The breakpoint on chromosome 8 mapped to a position 3 kb 3' of c-myc while the chromosome 14 breakpoint occurred 36 kb 5' of the gene for the constant region of the alpha chain of the T-cell receptor (TCR). The translocation resulted in a precise rearrangement of sequences on chromosome 8 and what appears to be a functional J alpha segment on chromosome 14. Signal sequences for V-J joining occurred at the breakpoint positions on both chromosomes 14 and 8, suggesting that the translocation occurs during TCR gene rearrangement and that it is catalyzed by the enzymatic systems involved in V-J joining reactions. The involvement of c-myc in the translocation and the association of joining signals at the breakpoints provides a parallel to the situation observed in the translocations involving c-myc and the immunoglobulin loci in B-cell neoplasms and suggests that common mechanisms of translocation and oncogene deregulation are involved in B- and T-cell malignancies.
A General Model for the Surface Glycoproteins of HIV and Other Retroviruses (1995)

A hypothetical model of the surface (SU) glycoproteins of human immunodeficiency virus (HIV) and other retroviruses is proposed. The model is based on repetition of a limited number of sequence motifs conserved within the virus family; similarities in biological, immunological, or genetic properties; as well as the tendency for regions of dissimilar sequence to share protein structures predicted by computer algorithms. It is proposed that the protein consists of three structural and functional domains interspersed by relatively conserved interdomain regions. For each retrovirus, these amino-terminal, central, and carboxy-terminal domains may play different roles in binding, postbinding events, and the immune response to viral infection.
Empirical formula for propagation loss in land mobile radio services (1980)

An empirical formula for propagation loss is derived from Okumura's report in order to put his propagation prediction method to computational use. The propagation loss in an urban area is presented in a simple form: A + B log <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">10</inf> R, where A and B are frequency and antenna height functions and R is the distance. The introduced formula is applicable to system designs for UHF and VHF land mobile radio services, with a small formulation error, under the following conditions: frequency range 100-1500 MHz, distance 1-20 km, base station antenna height 30-200 m, and vehicular antenna height 1-10 m.
Behavior of the ATP grasp domain of biotin carboxylase monomers and dimers studied using molecular dynamics simulations (2010)

The enzyme biotin carboxylase (BC) uses adenosine triphosphate (ATP) to carboxylate biotin and is involved in fatty acid synthesis. Structural evidence suggests that the B domain of BC undergoes a large hinge motion of ∼45° when binding and releasing substrates. Escherichia coli BC can function as a natural homodimer and as a mutant monomer. Using molecular dynamics simulations, we evaluate the free energy profile along a closure angle of the B domain of E. coli BC for three cases: a monomer without bound Mg(2)ATP, a monomer with bound Mg(2)ATP, and a homodimer with bound Mg(2)ATP in one subunit. The simulation results show that a closed state is the most probable for the monomer with or without bound Mg(2)ATP. For the dimer with Mg(2)ATP in one of its subunits, communication between the two subunits was observed. Specifically, in the dimer, the opening of the subunit without Mg(2)ATP caused the other subunit to open, and hysteresis was observed upon reclosing it. The most stable state of the dimer is one in which the B domain of both subunits is closed; however, the open state for the B domain without Mg(2)ATP is only approximately 2k(B)T higher in free energy than the closed state. A simple diffusion model indicates that the mean times for opening and closing of the B domain in the monomer with and without Mg(2)ATP are much smaller than the overall reaction time, which is on the order of seconds.
Co-expression of 9-O-acetylated sialoglycoproteins and their binding proteins on lymphoblasts of childhood acute lymphoblastic leukemia: an anti-apoptotic role (2009)

Enhanced levels of 9-O-acetylated sialoglycoproteins (Neu5,9Ac(2)GPs) as disease-associated molecules was reported to act as signaling molecules for promoting survival of lymphoblasts in childhood acute lymphoblastic leukemia (ALL). Here, we searched for potential physiological ligands for Neu5,9Ac(2)GPs that could be involved in modulating the survival of lymphoblasts. Accordingly, we examined the presence of binding proteins for Neu5,9Ac(2)GPs on cell lines and primary cells of patients with B- and T-ALL, at presentation of the disease. Peripheral blood mononuclear cells from normal healthy donors and cells from myeloid leukemia patients were used for comparison. Neu5,9Ac(2)GPs-binding proteins (BPs) were specifically detected on the surface of both T- and B-ALL-lymphoblasts and ALL-cell lines along with the consistent presence of Neu5,9Ac(2)GPs. The Neu5,9Ac(2)GPs and BPs also co-localized on the cell surface and interacted specifically in vitro. Apoptosis of lymphoblasts, induced by serum starvation, was reversed in the presence of purified Neu5,9Ac(2)GPs due to possible engagement of BPs, and the anti-apoptotic role of this interaction was established. This is the first report of the presence of potential physiological ligands for disease-associated molecules like Neu5,9Ac(2)GPs, the interaction of which is able to trigger an anti-apoptotic signal conferring a survival advantage to leukemic cells in childhood ALL.
REVIEWS (1993)

Journal Article REVIEWS Get access THE IMPACT OF PACE. POLICING IN A NORTHERN FORCE. By KEITH BOTTOMLEY, CLIVE COLEMAN, DAVID DIXON, MARTIN GILL, and DAVID WALL. (Hull: University of Hull Centre for Criminology and Criminal Justice, 1991. 204 pp £10.95.) Carole Helen Adams Carole Helen Adams Department of Law, London School of Economics Search for other works by this author on: Oxford Academic Google Scholar The British Journal of Criminology, Volume 33, Issue 2, Spring 1993, Pages 306–307, https://doi.org/10.1093/oxfordjournals.bjc.a048321 Published: 01 March 1993
Collagen-presealed or Uncoated Aortic Bifurcation Dacron Prostheses: A 5-Year Clinical Follow-up Study (1991)

A total of 70 patients undergoing replacement of the aortic bifurcation between October 1983 and June 1985, were studied 5 years postoperatively for graft patency. In 35 cases a collagen-coated knitted Dacron prosthesis (group I) was implanted, while an identical, but uncoated, Dacron graft was used in a second group of 35 patients (group II). Distribution of vascular risk factors were similar in both patient groups. The underlying disease was aortoiliac occlusive disease in 24 patients of group I and in 33 of group II. Aortoiliac aneurysmal disease was present in 10 patients of group I and in 2 patients of group II. One patient of group I was suffering from Takayasu's disease of the descending type. At follow-up, all grafts were patent in group I, while in group II 8 distal limb occlusions occurred between 6 and 46 months postoperatively. This represents a 5-year limb patency rate of 100% for collagen-presealed grafts versus 88.6% for uncoated prostheses (p less than 0.01). A higher incidence of distal anastomotic aneurysms was found in group I (7/70 limbs) compared to group II (1/70 limbs) (p less than 0.05). It is concluded that long-term patency of knitted Dacron prostheses in aortic bifurcation replacement is not reduced by presealing with collagen. It appears that this type of coating may actually enhance long-term patency after reconstruction of the aortoiliac axis. The higher rate of distal anastomotic aneurysm formation in patients with presealed grafts, however, could not be correlated with a failure of the sealant material or with the underlying disease of the patients involved.
Influence of K-ras activation on the survival responses of Caco-2 cells to the chemopreventive agents sulindac and difluoromethylornithine. (2000)

The nonsteroidal anti-inflammatory drug sulindac and the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) are both potent inhibitors of colon carcinogenesis in experimental models of this disease. The combination of these two agents is undergoing evaluation as a strategy for colon cancer chemoprevention in humans with resected colon polyps. We evaluated the effects of the major sulfide and sulfone metabolites of sulindac and DFMO alone, or in combinations, on the growth and survival of Caco-2 colon cancer-derived cells and in clones of these cells transfected with an activated K-ras oncogene. Both the sulfide and sulfone metabolites of sulindac reduced cell viability, measured by colony-forming assays, primarily by inducing apoptosis. Expression of an activated K-ras oncogene caused cells treated with either sulindac sulfide or sulfone to undergo apoptosis earlier than nontransfected controls. However, clonogenic survival, measured 2 weeks after drug treatment, was the same in both Caco-2 and ras-transfected Caco-2 cells treated with sulindac metabolites. A 24-h treatment with DFMO caused a dose-dependent decrease in the colony-forming ability of cells expressing an activated K-ras but had no effect on the viability of the parental Caco-2 cells. The DFMO-dependent decrease in colony formation in K-ras-activated cells occurred in the absence of apoptosis. Assessment of cell survival by colony-forming assays indicated that these two agents acted in an additive manner when combined. These data indicate that K-ras can influence the kinetics of apoptosis induction by sulindac metabolites and cell survival in response to DFMO. However, cytotoxicity induced by these agents occurs via unique mechanisms. These studies suggest that the combination of DFMO and sulindac may be useful in human cancer prevention strategies.