gebhart/patrepeval huggingface dataset:
Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor. (1998)

A recombinant soluble form of the mouse membrane complement inhibitor Crry (complement receptor-related gene y) fused to IgG1 hinge, CH2, and CH3 domains has been created and designated Crry-Ig. Crry has been used because, similar to human soluble CR1, it demonstrates decay-accelerating activity for both the classical and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. The mouse IgG1 isotype was incorporated because it is a noncomplement-activating isotype and, when fused to Crry, results in a complement inhibitor that should not be recognized as foreign when used chronically in murine models. Crry-Ig demonstrated complement-inhibitory activity in both the fluid phase and on target surfaces. Following in vivo injection, Crry-Ig manifested a two-phase serum elimination profile, a rapid initial loss most likely reflecting tissue redistribution and a second more prolonged decline with a t1/2 of 40 h. Inhibition of complement activation in mice following injection of Crry-Ig was demonstrated by a marked decrease in the ability of serum from treated mice to be activated by zymosan particles in vitro. Finally, in vivo efficacy of Crry-Ig was demonstrated by its ability to substantially diminish renal injury induced by complement-fixing nephrotoxic Ab. The use of Crry-Ig in vivo in murine models of chronic inflammatory and autoimmune disease should allow further insight into the potential therapeutic effects and possible untoward complications of continuous blockade of complement using inhibitors that act on activation products of C4 and C3.
Gene therapy of the brain (2001)

Gene therapy is a paradigm shift in the development of pharmaceuticals, and much more so than any changes brought about by the introduction of biotechnology to classical pharmaceutics. As discussed in the Preface, present-day pharmaceutics is a chemistry-driven science that originated early in the twentieth century (Drews, 2000), and is based almost singularly on drug discovery of small molecules. The introduction of recombinant DNA technology and biotechnology represent only changes in the methodology of drug discovery. The large pharmaceutical industry uses biotechnology to clone receptors and establish high-throughput screening (HTS) programs to identify classical organic small molecules. The singular focus on organic small molecules, and the belief that these molecules are able to diffuse freely across biological membranes, underlies the persistent inattention to drugtargeting science on the part of the pharmaceutical industry. The reason that gene therapy is such a paradigm shift is that gene therapy requires a primary emphasis in drug development on biology, not chemistry. The development of genes as drugs also brings into focus the need for new technologies that enable the targeting of genes, or drugs, through the biological membrane barriers of the body.
The RNA component of the Bacillus subtilis RNase P. Sequence, activity, and partial secondary structure. (1986)

The gene defining the catalytic RNA component of RNase P in Bacillus subtilis 168 was cloned into bacteriophage lambda and plasmid vectors. The nucleotide sequence of the gene and its surroundings was determined from the cloned DNA and by directly sequencing or reverse transcribing the RNase P RNA. The B. subtilis RNase P RNA sequence (400-401 nucleotides) is remarkably different from that of Escherichia coli (377 nucleotides) (Reed, R. E., Baer, M. F., Guerrier-Takada, C., Donis-Keller, H., and Altman, S. (1982) Cell 30, 627-636; Sakamoto, H., Kimura, N., Nagawa, F., and Shimura, Y. (1983) Nucleic Acids Res. 11, 8237-8251). At best the two are less than 50% similar in sequence. To verify that the RNase P RNA gene was analyzed, a modified, putative gene was cloned adjacent to a bacteriophage T7 promoter and various transcripts were tested for RNase P activity. The intact gene transcript, but not fragments, showed full activity. Full catalytic activity was restored upon mixing the fragments. The extensive differences between the B. subtilis and E. coli RNase P RNAs precluded full covariance analysis of secondary structure, but phylogenetically consistent foldings for portions of both molecules could be derived.
Cyclo (Leu-Gly) attenuates the striatal dopaminergic supersensitivity induced by chronic morphine. (1987)

Cyclo(Leu-Gly) (CLG), a diketopiperazine analog of Pro-Leu-Gly-NH2 (MIF), has direct effects on dopamine (DA) mediated behaviors as well as on D-2 DA receptors. Endogenous opioids, as well as morphine have also been implicated as neuromodulators of dopaminergic function. We studied these interactions in an animal model in which chronic morphine administration induces a dopaminergic supersensitivity that can be detected during the 48 hour (h) period following withdrawal of morphine. At 24 h following morphine withdrawal, there was a 3.5-fold increase in stereotypic behavior in rats following a challenge dose of apomorphine (APO) (0.5 mg/kg). By 48 h this effect had disappeared. Co-administration of CLG (8 mg/kg s.c.) with morphine attenuated the development of the behavioral supersensitivity to APO. D-2 DA receptor binding analysis indicated that parallel molecular changes occurred. There was a morphine-induced increase in the affinity (+167 percent) in antagonist (i.e. 3H-spiroperidol displaced by butaclamol) binding at 24 h after withdrawal. Co-administration of CLG with morphine attenuated these DA receptor changes at 24 hours which is consistent with the peptide's effect on stereotyped behavior. However, antagonist binding parameters did not parallel changes in behavior at 48 h. Agonist binding was then studied by examining DA displaceable 3H-spiroperidol (75 pM) binding to the D-2 DA receptor. Two receptor subpopulations D-2-HI and D-2-LO were revealed. Morphine caused an increase in the affinity for agonist binding to the D-2-HI site (83-fold increase). Affinity changes at the D-2-HI site correlated positively and strongly with the behavioral changes in all groups at both 24 and 48 h. We conclude that changes in agonist binding to D-2 DA receptors rather than antagonist binding is more consistent with the behaviors induced by morphine and CLG.
Site-Directed Mutagenesis of UDP-Galactopyranose Mutase Reveals a Critical Role for the Active-Site, Conserved Arginine Residues (2007)

The flavoenzyme UDP-galactopyranose mutase (UGM) is a mediator of cell wall biosynthesis in many pathogenic microorganisms. UGM catalyzes a unique ring contraction reaction that results in the conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UDP-Galf is an essential precursor to the galactofuranose residues found in many different cell wall glycoconjugates. Due to the important consequences of UGM catalysis, structural and biochemical studies are needed to elucidate the mechanism and identify the key residues involved. Here, we report the results of site-directed mutagenesis studies on the absolutely conserved residues in the putative active site cleft. By generating variants of the UGM from Klebsiella pneumoniae, we have identified two arginine residues that play critical catalytic roles (alanine substitution abolishes detectable activity). These residues also have a profound effect on the binding of a fluorescent UDP derivative that inhibits UGM, suggesting that the Arg variants are defective in their ability to bind substrate. One of the residues, Arg280, is located in the putative active site, but, surprisingly, the structural studies conducted to date suggest that Arg174 is not. Molecular dynamics simulations indicate that closed UGM conformations can be accessed in which this residue contacts the pyrophosphoryl group of the UDP-Gal substrates. These results provide strong evidence that the mobile loop, noted in all the reported crystal structures, must move in order for UGM to bind its UDP-galactose substrate.
Stevia rebaudiana (Bert.) Bertoni ─ A Review (2010)

The Sweet Herb of Paraguay, Stevia rebaudiana (Bert.) Bertoni is fast becoming a major source of high potency sweetener which produces sweet taste but has no calorific value. Many research activities on its chemical and biological properties have been done in recent past. Several countries including India have started its commercial cultivation. The published literature on this crop is quite scattered. Therefore an effort to compile the literature and review the current status of research and development including cultivation practices has been done in this paper.
Beta-alanine synthesis in Escherichia coli (1980)

The enzyme, aspartate 1-decarboxylase (L-aspartate 1-carboxy-lyase; EC 4.1.1.15), that catalyzes the reaction aspartate leads to beta-alanine + CO2 was found in extracts of Escherichia coli. panD mutants of E. coli are defective in beta-alanine biosynthesis and lack aspartate 1-decarboxylase. Therefore, the enzyme functions in the biosynthesis of the beta-alanine moiety of pantothenate. The genetic lesion in these mutants is closely linked to the other pantothenate (pan) loci of E. coli K-12.
Effects of the Mammalian Target of Rapamycin Inhibitor CCI-779 Used Alone or with Chemotherapy on Human Prostate Cancer Cells and Xenografts (2005)

Selective inhibition of repopulation of surviving tumor cells between courses of chemotherapy might improve the outcome of treatment. A potential target for inhibiting repopulation is the mammalian target of rapamycin pathway; PTEN-negative tumor cells are particularly sensitive to inhibition of this pathway. Here we study the rapamycin analogue CCI-779, alone or with chemotherapy, as an inhibitor of proliferation of the human prostate cancer cell lines PC-3 and DU145. The PTEN and phospho-Akt/PKB status and the effect of CCI-779 on phosphorylation of ribosomal protein S6 were evaluated by immunostaining and/or Western blotting. Expression of phospho-Akt/PKB in PTEN mutant PC-3 cells and xenografts was higher than in PTEN wild-type DU145 cells. Phosphorylation of S6 was inhibited by CCI-779 in both cell lines. Cultured cells were treated weekly with mitoxantrone or docetaxel for two cycles, and CCI-779 or vehicle was given between courses. Growth and clonogenic survival of both cell lines were inhibited in a dose-dependent manner by CCI-779, but there were minimal effects when CCI-779 was given between courses of chemotherapy. CCI-779 inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. CCI-779 caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. Our results suggest that repopulation of PTEN-negative cancer cells between courses of chemotherapy might be inhibited by CCI-779.
In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells (2015)

A definitive understanding of survival and differentiation potential in humans of T cell subpopulations is of paramount importance for the development of effective T cell therapies. In particular, uncovering the dynamics in vivo in humans of the recently described T memory stem cells (TSCM) would be crucial for therapeutic approaches that aim at taking advantage of a stable cellular vehicle with precursor potential. We exploited data derived from two gene therapy clinical trials for an inherited immunodeficiency, using either retrovirally engineered hematopoietic stem cells or mature lymphocytes to trace individual T cell clones directly in vivo in humans. We compared healthy donors and bone marrow-transplanted patients, studied long-term in vivo T cell composition under different clinical conditions, and specifically examined TSCM contribution according to age, conditioning regimen, disease background, cell source, long-term reconstitution, and ex vivo gene correction processing. High-throughput sequencing of retroviral vector integration sites (ISs) allowed tracing the fate of more than 1700 individual T cell clones in gene therapy patients after infusion of gene-corrected hematopoietic stem cells or mature lymphocytes. We shed light on long-term in vivo clonal relationships among different T cell subtypes, and we unveiled that TSCM are able to persist and to preserve their precursor potential in humans for up to 12 years after infusion of gene-corrected lymphocytes. Overall, this work provides high-resolution tracking of T cell fate and activity and validates, in humans, the safe and functional decade-long survival of engineered TSCM, paving the way for their future application in clinical settings.
ADVANTAGE OF COLD STORAGE OVER MACHINE PERFUSION FOR PRESERVATION OF CADAVER KIDNEYS (1982)

Evidence is provided that, with cold ischemia up to 48 hr and warm ischemia up to 60 min, simple storage preservation results in equally good or better transplant success rates than pulsatile machine perfusion. In the critical 24- to 43-hr preservation period, 1-year survival rates were 53 +/- 3% for 282 kidneys preserved in Collins solution, as compared with 40 +/- 2% for 565 kidneys on the Belzer machine (P less than 0.0001) and 48 +/- 1% for 1441 kidneys perfused on the Waters machine (P = not significant). Warm ischemia of 40 to 60 min also yielded better results with simple cold storage than with machine preservation (P less than 0.05). Although it has been maintained that one of the functions of preservation machines is to select out kidneys of poor quality, we found that this preselection actually has resulted in lower transplant survival rates. Because storage in Collins solution is simpler, safer, and much less expensive, we conclude that there is no longer any reason to preserve kidneys by pulsatile perfusion on machines.
Natural Products with Anti-HIV Activity from Marine Organisms (2003)

In order to combat the human immunodeficiency virus (HIV), diverse strategies have been developed to research on compounds which can be developed as therapeutic agents. Screening of natural products derived from numerous species has afforded metabolites with significant antiviral activity against the HIV. The marine environment representing approximately half of the global biodiversity offers an enormous resource for novel compounds. Currently more than 150 natural products with promising levels of anti-HIV activity have been isolated following bioassay guided protocols from aqueous or organic extracts of marine organisms. Some of the most characteristic marinemetabolites that have exhibited significant anti-HIV activity on different biochemical assays designed for chemotherapeutic strategies are: Cyanovirin-N, a protein from a blue green alga; various sulfated polysaccharides extracted from seaweeds (i.e. Nothogenia fastigiata, Aghardhiella tenera); the peptides tachyplesin and polyphemusin, which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus; sponge metabolites such as avarol, avarone, ilimaquinone and several phloroglucinols; and a number of metabolites from marine fungi such as equisetin, phomasetin and integric acid. Considering that number of unique metabolites that have been isolated from a small extent of the ocean's biological and chemical diversity, the oceans represent a virtually untapped resource for the discovery of novel bioactive compounds.
Contribution of Coagulases towards Staphylococcus aureus Disease and Protective Immunity (2010)

The bacterial pathogen Staphylococcus aureus seeds abscesses in host tissues to replicate at the center of these lesions, protected from host immune cells via a pseudocapsule. Using histochemical staining, we identified prothrombin and fibrin within abscesses and pseudocapsules. S. aureus secretes two clotting factors, coagulase (Coa) and von Willebrand factor binding protein (vWbp). We report here that Coa and vWbp together are required for the formation of abscesses. Coa and vWbp promote the non-proteolytic activation of prothrombin and cleavage of fibrinogen, reactions that are inhibited with specific antibody against each of these molecules. Coa and vWbp specific antibodies confer protection against abscess formation and S. aureus lethal bacteremia, suggesting that coagulases function as protective antigens for a staphylococcal vaccine.
Demonstration of inverse scattering in optical coherence tomography (2006)

An object structure can be better resolved in optical coherence tomography by using inverse scattering theory, which takes into account the finite beam width and focusing. Specifically, we show experiments where scatterers are resolved outside of the confocal region such that resolution is uniform to the focused region. Numerical simulations demonstrate the effectiveness of this technique. When the algorithm is applied to experimentally-acquired OCT data, the transverse resolution outside of the confocal parameter is improved, extending the apparent confocal parameter range. The experimental results validate improvement for capabilities of OCT to perform high-resolution cross-sectional imaging.
Which way does the citric acid cycle turn during hypoxia? The critical role of α‐ketoglutarate dehydrogenase complex (2013)

The citric acid cycle forms a major metabolic hub and as such it is involved in many disease states involving energetic imbalance. In spite of the fact that it is being branded as a "cycle", during hypoxia, when the electron transport chain does not oxidize reducing equivalents, segments of this metabolic pathway remain operational but exhibit opposing directionalities. This serves the purpose of harnessing high-energy phosphates through matrix substrate-level phosphorylation in the absence of oxidative phosphorylation. In this Mini-Review, these segments are appraised, pointing to the critical importance of the α-ketoglutarate dehydrogenase complex dictating their directionalities.
Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease (2012)

Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscure. Here, we investigated the contribution of tumor Gal1 to tumor growth, metastasis, and immunosuppression in breast cancer. We found that the frequency of Gal1(+) cells in human breast cancer biopsies correlated positively with tumor grade, while specimens from patients with benign hyperplasia showed negative or limited Gal1 staining. To examine the pathophysiologic relevance of Gal1 in breast cancer, we used the metastatic mouse mammary tumor 4T1, which expresses and secretes substantial amounts of Gal1. Silencing Gal1 expression in this model induced a marked reduction in both tumor growth and the number of lung metastases. This effect was abrogated when mice were inoculated with wild-type 4T1 tumor cells in their contralateral flank, suggesting involvement of a systemic modulation of the immune response. Gal1 attenuation in 4T1 cells also reduced the frequency of CD4(+)CD25(+) Foxp3(+) regulatory T (T(reg)) cells within the tumor, draining lymph nodes, spleen, and lung metastases. Further, it abrogated the immunosuppressive function of T(reg) cells and selectively lowered the expression of the T-cell regulatory molecule LAT (linker for activation of T cells) on these cells, disarming their suppressive activity. Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease.
Overexpression of EB1 in human esophageal squamous cell carcinoma (ESCC) may promote cellular growth by activating β-catenin/TCF pathway (2005)

Esophageal squamous cell carcinoma (ESCC) has a multifactorial etiology involving environmental and/or genetic factors. End-binding protein 1 (EB1), which was cloned as an interacting partner of the adenomatous polyposis coli (APC) tumor suppressor protein, was previously found overexpressed in ESCC. However, the precise role of EB1 in the development of this malignancy has not yet been elucidated. In this study, we analysed freshly resected ESCC specimens and demonstrated that EB1 was overexpressed in approximately 63% of tumor samples compared to matched normal tissue. We report that overexpression of EB1 in the ESCC line EC9706 significantly promotes cell growth, whereas suppression of EB1 protein level by RNA interference significantly inhibited growth of esophageal tumor cells. In addition, EB1 overexpression induced nuclear accumulation of beta-catenin and promoted the transcriptional activity of beta-catenin/T-cell factor (TCF). These effects were partially or completely abolished by coexpression of APC or DeltaN TCF4, respectively. Also, we found that EB1 affected the interaction between beta-catenin and APC. Furthermore, EB1 overexpression was correlated with cytoplasmic/nuclear accumulation of beta-catenin in primary human ESCC. Taken together, these results support the novel hypothesis that EB1 overexpression may play a role in the development of ESCC by affecting APC function and activating the beta-catenin/TCF pathway.
Post‐oligomerization of α‐olefin oligomers: A route to single‐component and multicomponent synthetic lubricating oils (2008)

Abstract This article describes a synthetic route to single‐component and multicomponent base stocks for synthetic lubricated oils. The synthesis was carried out in two stages. First, oligomers of α‐olefins (1‐hexene, 4‐methyl‐1‐pentene, and 1‐decene) were prepared via reactions catalyzed by metallocene catalysts. The distribution of the oligomers with respect to their oligomerization number could be controlled by the reaction temperature. The oligomer mixtures were then fractionated, and the lightest components, dimers and trimers, were separated. Finally, the latter materials, branched α‐olefins containing vinylidene double bonds, were further oligomerized with cationic catalysts. One such material prepared in the two‐stage process, the dimer of the 1‐decene dimer (C 40 product), has a kinematic viscosity of 6.4 cs at 100°C and a viscosity index of 147. It represents the first example of a single‐component base stock for synthetic lubricating oils. The post‐oligomerization procedure was performed on unfractionated oligomer mixtures as well, leading to an improved distribution of the final materials with respect to the carbon atom number. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Mimicry of CD40 Signals by Epstein-Barr Virus LMP1 in B Lymphocyte Responses (1999)

The effect of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) on the activation and differentiation of normal B cells was investigated. B cells of transgenic mice expressing LMP1 under the control of immunoglobulin promoter/enhancer displayed enhanced expression of activation antigens and spontaneously proliferated and produced antibody. Humoral immune responses of LMP1 transgenic mice in CD40-deficient or normal backgrounds revealed that LMP1 mimics CD40 signals to induce extrafollicular B cell differentiation but, unlike CD40, blocks germinal center formation. Thus, these specific properties of LMP1 may determine the site of primary B cell infection and the state of infection in the natural course of EBV infection, whereas subsequent loss of LMP1 expression may affect the site of persistent latent infection.