gebhart/patrepeval huggingface dataset:
Structural composition and functional characterization of soluble CD59: heterogeneity of the oligosaccharide and glycophosphoinositol (GPI) anchor revealed by laser-desorption mass spectrometric analysis (1996)

CD59 (protectin) is a glycophosphoinositol (GPI)-anchored inhibitor of the membrane attack complex of complement found on blood cells, endothelia and epithelial cells. In addition to the lipid-tailed CD59, soluble lipid-free forms of CD59 are present in human body fluids. We have investigated the detailed structural composition of the naturally occurring soluble urinary CD59 (CD59u) using peptide mapping, anion-exchange chromatography, sequential exoglycosidase digestion and matrix-assisted laser-desorption mass spectrometry (MALDI-MS). CD59u exhibited an average M(r) of 12444 in MALDI-MS. Mass analysis of the isolated C-terminal peptide (T9) indicated that a GPI-anchor (at Asn-77) without an inositol-associated phospholipid was present in soluble CD59u. By using residue-specific exoglycosidases, chemical modification and MALDI-MS structures of seven different GPI-anchor variants were determined. Variant forms of the anchor had deletions and/or extensions of one or more monosaccharide units. Sialic acid linked to an N-acetylhexosamine-galactose arm was found in two GPI-anchor variants. The N-linked carbohydrate side chain of CD59u (at Asn-18) also displayed considerable heterogeneity. The predominant oligosaccharide chains were fucosylated biantennary and triantennary complexes with variable sialylation. Mono Q anion-exchange chromatography resolved urinary CD59 into nine different fractions that bound equally well to the terminal complement SC5b-8 complexes. Despite binding to C5b-8, soluble CD59u inhibited complement lysis at an approx. 200-fold lower efficiency than erythrocyte CD59. These results document the structural heterogeneity of both the GPI anchor and N-linked oligosaccharide of CD59 and demonstrate that the phospholipid tail is needed for the full functional activity of CD59. The site of cleavage between the diradylglycerol phosphate and inositol suggests that a mammalian phospholipase D could be involved in the solubilization of GPI-anchored proteins.
A hyaluronan synthase suppressor, 4‐methylumbelliferone, inhibits liver metastasis of melanoma cells (2005)

4-Methylumbelliferone (MU) inhibits the cell surface hyaluronan (HA) formation, and that such inhibition results in suppression of adhesion and locomotion of cultured melanoma cells. Here, we examine the effect of MU on melanoma cell metastasis in vivo. MU-treated melanoma cells showed both decreased cell surface HA formation and suppression of liver metastasis after injection into the mice. Oral administration of MU to mice decreased tissue HA content. These HA knock-down mice displayed suppressed liver metastasis. Thus, both cell surface HA of melanoma cells and recipient liver HA can promote liver metastasis, indicating that MU has potential as an anti-metastatic agent.
Synthesis of Hexahydrocyclopenta[c]furans by an Intramolecular Iron‐Catalyzed Ring Expansion Reaction (2007)

Abstract The intramolecular iron‐catalyzed ring expansion reaction of epoxyalkenes was investigated with a preformed iron(salen) [Fe(Salen)] complex. The formal insertion of the alkene into the epoxide generated hexahydrocyclopenta[ c ]furan derivatives in moderate to good yields and diastereoselectivities depending on other functional groups present in the starting materials. In addition, oxygen‐tethered epoxyalkenes were used for the synthesis of lignan isomers. The scope and limitations of the Fe(Salen)‐catalyzed process of the reaction are discussed.
Metastability of Au−Ge Liquid Nanocatalysts: Ge Vapor–Liquid–Solid Nanowire Growth Far below the Bulk Eutectic Temperature (2007)

The vapor-liquid-solid mechanism of nanowire (NW) growth requires the presence of a liquid at one end of the wire; however, Au-catalyzed Ge nanowire growth by chemical vapor deposition can occur at approximately 100 degrees C below the bulk Au-Ge eutectic. In this paper, we investigate deep sub-eutectic stability of liquid Au-Ge catalysts on Ge NWs quantitatively, both theoretically and experimentally. We construct a binary Au-Ge phase diagram that is valid at the nanoscale and show that equilibrium arguments, based on capillarity, are inconsistent with stabilization of Au-Ge liquid at deep sub-eutectic temperatures, similar to those used in Ge NW growth. Hot-stage electron microscopy and X-ray diffraction are used to test the predictions of nanoscale phase equilibria. In addition to Ge supersaturation of the Au-Ge liquid droplet, which has recently been invoked as an explanation for deep sub-eutectic Ge NW growth, we find evidence of a substantial kinetic barrier to Au solidification during cooling below the nanoscale Au-Ge eutectic temperature.
Nonlinear techniques for forecasting solar activity directly from its time series (1992)

Numerical techniques for constructing nonlinear predictive models to forecast solar flux directly from its time series are presented. This approach makes it possible to extract dynamical invariants of our system without reference to any underlying solar physics. We consider the dynamical evolution of solar activity in a reconstructed phase space that captures the attractor (strange), given a procedure for constructing a predictor of future solar activity, and discuss extraction of dynamical invariants such as Lyapunov exponents and attractor dimension.
Diabetes and atherosclerosis: An epidemiologic view (1987)

Diabetes is associated with changes in plasma lipids and lipoproteins into atherogenic direction. In IDDM these changes are small or absent if good metabolic control can be maintained. Diabetic nephropathy is, however, associated with the appearance of dyslipoproteinemia. In NIDDM plasma total and VLDL triglyceride levels are elevated, and HDL-cholesterol level is decreased, and this pattern of dyslipoproteinemia does not always respond to improved control of hyperglycemia. Abnormalities of lipoprotein metabolism, not reflected in conventional plasma lipid and lipoprotein level measurements, and glucosylation of lipoproteins and resulting alterations in lipoprotein catabolism may be of importance in the enhanced atherogenesis in diabetes. Both IDDM and NIDDM are associated with an increased frequency of hypertension, but the underlying mechanisms appear to be different. In IDDM hypertension is usually associated with the development of diabetic nephropathy and thus with a long duration of the disease. In NIDDM hypertension is often present already at the time of diagnosis, and also in IGT, the precursor stage of NIDDM, the prevalence of hypertension is already increased. Obesity explains only in part the high prevalence of hypertension in patients with NIDDM. Diabetes is known to be associated with multiple abnormalities in hemostatic factors and, although these abnormalities may contribute importantly to the increased risk of ASVD in diabetic patients, information about their real role is scanty and conflicting. The impact of general major risk factors for ASVD, elevated plasma cholesterol, elevated blood pressure, and smoking, on the risk of ASVD appears to be similar in diabetics and nondiabetics. Only a relatively small proportion of the excessive occurrence of ASVD in diabetics can, however, be explained by the effects of diabetes on the levels of general risk factors for ASVD. This proportion mediated through the effects of diabetes on risk factors is larger in female diabetics than in male diabetics. The major proportion of the excess of ASVD in diabetics remains, however, unexplained and must be due to effects of diabetes itself through mechanisms that are incompletely understood.
Functional and ontogenetic analysis of murine CD45Rhi and CD45Rlo CD4+ T cells. (1990)

CD4+ murine T cell clones, TH1 and TH2, can be distinguished by both functional responses and by their patterns of lymphokine secretion. Recently, a mAb, 23G2, which reacts with a subset of CD45 molecules (CD45R), has been reported to bind differentially to clones of TH1 and TH2 cells. In the present study, normal splenic T cells were analyzed for differences in 23G2-reactivity and were separated into two populations based on their density of CD45R (CD45Rhi and CD45Rlo). The CD45Rhi cells secrete more IL-2 than IL-4 after stimulation in vitro; the reverse is true for the CD45Rlo cells. Because neither population secretes only IL-2 or IL-4, we were unable to classify cells as TH1 or TH2. In vivo and in vitro analyses of the CD45Rhi and CD45Rlo cells suggest a lineage relationship between the two subsets that correlates with the degree of Ag exposure and the state of maturation of the mice. In newborn mice and mice raised under sterile conditions, splenic CD4+ T cells are predominantly CD45Rhi. Under conditions of increased antigenic exposure and maturation of the mice, CD45Rlo cells develop; after long term priming in vivo, the majority of specific Ag-reactive cells are CD45Rlo. Adoptive transfer studies using BALB/c nu/nu recipients demonstrate that CD45Rhi cells become CD45Rlo cells and that the recall response (IgG) to specific Ag is mediated by CD45Rlo cells. Taken together, these data indicate that the level of expression of CD45R on CD4+ T cells distinguishes virgin (CD45Rhi) from primed/memory (CD45Rlo) T cells in normal mice.
Appropriate and effective rheumatoid arthritis control: role of TNF antagonists. (2003)

There are several unmet needs for the appropriate and effective control of rheumatoid arthritis (RA), namely rapid onset of action; effectiveness in disease-modifying antirheumatic drug (DMARD)-resistant disease, including improvements in signs and symptoms, disability, quality of life and radiographic progression; sustainability of response; and a good risk/benefit ratio. Tumor necrosis factor (TNF) antagonists appear to address these needs and consequently have set a new therapeutic standard for the treatment of RA and have made it possible for rheumatologists to target remission as a primary therapeutic goal.
Abstract 4636: Novel immunoRNases comprising multiple copies of ranpirnase display potent cytotoxicity in human breast cancer cell lines expressing Trop-2 (2012)

Abstract Ranpirnase (Rap) is an amphibian ribonuclease originally isolated from the oocytes of Rana pipiens. Rap shows anti-tumor activity, which can be enhanced by linking Rap to a tumor-targeting antibody, as reported previously in CD22-, CD74-, and Trop-2-expressing human cancer cell lines and xenografts. To further improve the potency of Rap-based ImmunoRNases, we have used the Dock-and-Lock (DNL) method to tether the full IgG of hRS7 (humanized anti-Trop-2) with four copies of Rap and evaluated the resulting conjugate, termed E1-Rap, as a potential therapeutic for breast cancer. The modular nature of DNL also allowed us to substitute hRS7 with other humanized antibodies in-house, such as hLL2 (anti-CD22, epratuzumab), hLL1 (anti-CD74, milatuzumab), hA20 (anti-CD20, veltuzumab), hL243 (anti-HLA-DR), and hR1 (anti-IGF-1R), resulting in 22-Rap, 74-Rap, 20-Rap, C2-Rap, and 1R-Rap, respectively. In the present study, 22-Rap was evaluated along with E1-Rap in a panel of human breast cancer lines, including the basal-like, triple-negative subtype (MDA-MB-468, MDA-MB-231, BT20, HCC1806, and HCC1395), the luminal B, HER2-negative subtype (MCF-7), and the HER2-positive subtype (SKBR3), all except HCC1395 expressing high to moderate levels of Trop-2, but none expressing CD22. As demonstrated by flow cytometry, E1-Rap and hRS7 bound equivalently to MDA-MB-468, indicating the affinity of E1-Rap for Trop-2 is not compromised. Intriguingly, 22-Rap, but not epratuzumab, also bound substantially to MDA-MB-468, albeit to a lesser extent than E1-Rap. Additional experiments revealed 22-Rap was capable of binding to a variety of CD22-negative cell lines, which could be attributed to the enhanced association between the multiple copies of Rap in the DNL conjugate and heparan sulfate proteoglycans on the cell surface. Whereas the individual DNL component (IgG or Rap) alone or in combination showed negligible in vitro cytotoxicity in all the seven breast cancer cell lines examined, E1-Rap exhibited EC50 values of 1 nM or lower in MDA-MB-468 (0.03 nM), MCF-7 (0.1 nM), BT20 (0.18 nM), HCC1806 (0.19 nM), and SKBR3 (1.29 nM). In comparison, the potency of 22-Rap was at least 10-fold lower than E1-Rap in MDA-MB-468, BT20 and HCC1806, with EC50 about 2 nM. Neither E1-Rap nor 22-Rap was very effective in inhibiting the proliferation of the more aggressive MDA-MB231 (EC50 above 50 nM) or the Trop-2-negative HCC1395 (EC50 ∼100 nM). The results of immunofluorescence microscopy showed E1-Rap was effectively internalized in MDA-MB-468 and localized in the cytosol. Thus, these ImmunoRNases, as exemplified by E1-Rap, are potentially new cancer therapeutics for Trop-2-expressing breast and other solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4636. doi:1538-7445.AM2012-4636
Directed, efficient, and versatile modifications of the Drosophila genome by genomic engineering (2009)

With the completion of genome sequences of major model organisms, increasingly sophisticated genetic tools are necessary for investigating the complex and coordinated functions of genes. Here we describe a genetic manipulation system termed "genomic engineering" in Drosophila. Genomic engineering is a 2-step process that combines the ends-out (replacement) gene targeting with phage integrase phiC31-mediated DNA integration. First, through an improved and modified gene targeting method, a founder knock-out line is generated by deleting the target gene and replacing it with an integration site of phiC31. Second, DNA integration by phiC31 is used to reintroduce modified target-gene DNA into the native locus in the founder knock-out line. Genomic engineering permits directed and highly efficient modifications of a chosen genomic locus into virtually any desired mutant allele. We have successfully applied the genomic engineering scheme on 6 different genes and have generated at their loci more than 70 unique alleles.
Enantio- and Diastereoselective Intermolecular Stetter Reaction of Glyoxamide and Alkylidene Ketoamides (2009)

A triazolinylidene carbene catalyzed intermolecular Stetter reaction of glyoxamide and alkylidene ketoamides has been developed. 1,4-Dicarbonyl products are afforded in good to excellent yields, enantioselectivities, and diastereoselectivities. Further derivatization of the products affords useful intermediates for organic synthesis.
A Critical Review of the Evidence Supporting a Relationship Between Impaired Fibrinolytic Activity and Venous Thromboembolism (1991)

We critically evaluated the evidence for an association between venous thromboembolism and impaired fibrinolytic activity, as determined by global tests of fibrinolytic activity or specific tests for tissue plasminogen activator and plasminogen activator inhibitor. A computer-assisted and manual search was performed to retrieve all articles that reported on fibrinolytic activity and venous thromboembolism. The strength of the evidence for an association was assessed by analysis of the design of individual studies with special attention directed to choice of controls and methods of diagnosis of venous thromboembolism. It is concluded that for patients with symptomatic thrombosis the published evidence does not prove an association between impaired fibrinolytic activity and increased risk of thrombosis. In contrast, for postoperative thrombosis there is good evidence for an association between impaired fibrinolytic activity measured either preoperatively or postoperatively and increased risk of postoperative thrombosis. Whether this association is causal or coincidental is unclear, since randomized clinical trials that used interventions to enhance fibrinolytic activity produced inconsistent results.
Neuronal Plasticity: Increasing the Gain in Pain (2000)

We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
Intrathoracic Impedance Monitoring in Patients With Heart Failure (2005)

Intrathoracic impedance is inversely correlated with pulmonary capillary wedge pressure and fluid balance and decreased before the onset of patient symptoms and before hospital admission for fluid overload. Regular monitoring of impedance may provide early warning of impending decompensation and diagnostic information for titration of medication.
A DNA aptamer which binds to and inhibits thrombin exhibits a new structural motif for DNA (1993)

The investigation of the three-dimensional structure of the DNA aptamer d(G1G2T3-T4G5G6T7G8T9G10G11T12T13G14G15) which binds to and inhibits thrombin has been carried out by NMR methods. This DNA exhibits a number of long-range NOEs between residues which are not adjacent in sequence, which allowed the determination of the novel tertiary structure adopted. This DNA adopts a highly compact, highly symmetrical structure which consists of two tetrads of guanosine base pairs and three loops. The residues of the tetrads alternate anti-syn-anti-syn. This novel structural motif for DNA may also be relevant to the structure of telomere DNA.
Myosin A tail domain interacting protein (MTIP) localizes to the inner membrane complex ofPlasmodiumsporozoites (2002)

Apicomplexan host cell invasion and gliding motility depend on the parasite's actomyosin system located beneath the plasma membrane of invasive stages. Myosin A (MyoA), a class XIV unconventional myosin, is the motor protein. A model has been proposed to explain how the actomyosin motor operates but little is known about the components, topology and connectivity of the motor complex. Using the MyoA neck and tail domain as bait in a yeast two-hybrid screen we identified MTIP, a novel 24 kDa protein that interacts with MyoA. Deletion analysis shows that the 15 amino-acid C-terminal tail domain of MyoA, rather than the neck domain, specifically interacts with MTIP. In Plasmodium sporozoites MTIP localizes to the inner membrane complex (IMC), where it is found clustered with MyoA. The data support a model for apicomplexan motility and invasion in which the MyoA motor protein is associated via its tail domain with MTIP, immobilizing it at the outer IMC membrane. The head domain of the immobilized MyoA moves actin filaments that, directly or via a bridging protein, connect to the cytoplasmic domain of a transmembrane protein of the TRAP family. The actin/TRAP complex is then redistributed by the stationary MyoA from the anterior to the posterior end of the zoite, leading to its forward movement on a substrate or to penetration of a host cell.
Rapid HATU-Mediated Solution Phase siRNA Conjugation (2011)

Conditions for facile solution-phase amide conjugation of amine-modified siRNA with a diverse set of carboxylic acid partners using the coupling reagent HATU are described. These conditions eliminate the need for isolated activated esters and allow for rapid access to conjugates with a wide range of lipophilicity and functionality in good yield.
The folding of bovine pancreatic trypsin inhibitor in the Escherichia coli periplasm. (1994)

PreOmpA-bovine pancreatic trypsin inhibitor (BPTI) (Goldenberg, D. P. (1988) Biochemistry 27, 2481-2489) was expressed in Escherichia coli, and the folding pathway of the mature protein in the periplasmic space was analyzed by pulse-chase experiments. Folding intermediates were trapped with iodoacetamide, immunoprecipitated with antisera specific for either the reduced or the native protein, and resolved by electrophoresis. In vivo, native BPTI formed with a half-life of 7 min which is 3-fold faster than the optimal in vitro folding rate in growth media supplemented with low molecular weight disulfides. The measured in vivo half-life includes the time required for translocation and processing by leader peptidase and therefore represents the lower limit for the actual folding rate in the cell. In addition to the native species, two-disulfide intermediates accumulated in the cell at appreciable levels and did not chase to the native species for at least 20 min. We found that the folding of BPTI in E. coli was absolutely dependent on DsbA, a protein which accelerates the formation of disulfide bonds in the periplasm. In a dsbA mutant strain, trace amounts of oxidized BPTI could be detected only in cultures grown under strongly oxidizing conditions. In wild-type cells, the addition of different concentrations of GSH/GSSG or oxidized dithiothreitol did not affect the kinetics of BPTI oxidation by DsbA. Finally, even though the folding of BPTI in vitro decreases by almost 10-fold/unit pH decrease, folding in cells grown at pH 6.0 was only marginally slower than folding in cells grown at neutral pH, despite the fact that the pH of the periplasmic space varies in response to the extracellular fluid.
GAS-GENERATING SYSTEMS IN ACUTE RENAL ALLOGRAFT REJECTION IN THE RAT (1996)

Gases are now viewed as biologic messengers, and in this regard, carbon monoxide and nitric oxide are incriminated in signaling processes in neural tissue. Carbon monoxide is generated by heme oxygenase (HO), an enzyme inducible by heme, cytokines, and oxidative stress and considered an antioxidant response; nitric oxide is generated by nitric oxide synthase, an enzyme also inducible by cytokines. Since mononuclear cells infiltrate the acutely rejecting kidney, and foster within the kidney oxidative stress and a cytokine-enriched milieu, we examined the expression of these enzymes in acute renal allograft rejection (AR) (Brown Norway kidney to a Lewis rat; n = 17) and in control isografts (Lewis kidney to a Lewis rat; n = 17). No immunosuppressives were used. We found marked induction of HO mRNA and protein in renal allografts at day 5 after transplantation. Prominent expression of HO protein, as detected by immunofluorescence, was observed in the mononuclear cells infiltrating the renal allograft. More than 80% of these cells were macrophages, as identified by positive staining with ED1 antibody. ED1+ cells were rare in isografts and did not stain for HO. We also found co-expression of mRNA and protein for the inducible isoform of nitric oxide synthase (iNOS) in AR at day 5 after transplantation. Induction of HO and iNOS may reflect the cellular effect of diverse cytokines elaborated in the rejecting kidney. HO may enable the macrophage to degrade heme-containing proteins released from erythrocytes and other damaged cells; alternatively, induction of HO may defend the macrophage against oxidant injury. Increased nitric oxide, as a result of iNOS activity, may antagonize the vasoconstrictive effects of a number of mediators (i.e., thromboxane and endothelin) present in acute rejection; conversely, nitric oxide may prove cytotoxic through a number of recognized effects. Our studies provide the first demonstration of the induction of HO in the rejecting renal allograft as well as the first demonstration in vivo for the induction of HO in macrophages at the site of an inflammatory response. Such expression, linked as it is to the expression of iNOS, indicates that the macrophage mimics the behavior of neural cells by generating these gaseous messengers; thus, neural cells are not alone in deploying these mediators. Through a number of effects, these products of HO and iNOS may influence the nature and severity of tissue injury in AR.