gebhart/patrepeval huggingface dataset:
Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation (1993)

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2–4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had &lt; or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and &lt; or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2–4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.
Polyhydroxyalkanoate (PHA)/Inorganic Phase Composites for Tissue Engineering Applications (2006)

Polyhydroxyalkanoates are emerging as a class of biodegradable polymers for applications in tissue engineering. Members of the polyhydroxyalkanoates family encompass a wide variety of materials, from hard and brittle materials to soft and elastomeric. Over the years, efforts have been made to extend the group of polyhydroxyalkanoates and to investigate their use in numerous biomedical applications, such as sutures, cardiovascular patches, wound dressings, guided tissue repair/regeneration devices, and tissue engineering scaffolds. Along with the development of polyhydroxyalkanoates, researchers have looked into the possibility of designing composites in combination with inorganic phases to further improve the mechanical properties, rate of degradation, and also impart bioactivity. Poly(3-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) are some of the polymers which have been studied extensively to fabricate composites in combination with hydroxyapatite, bioactive glass, and glass-ceramic fillers or coatings. This paper reviews international research carried out toward development of polyhydroxyalkanoates/inorganic phase composites in terms of systems investigated, microstructures, properties achieved, and applications, with special focus on tissue engineering scaffolds. A comparison between different composite systems developed in the past few years is presented. The paper also addresses the prospect of potential further development of polyhydroxyalkanoates/inorganic phase composites with optimized microstructure and properties for improved tissue engineering scaffolds.
Molecular approaches in the diagnosis of primary immunodeficiency diseases (2006)

Over 120 inherited primary immunodeficiency diseases (PIDs) are known to exist. The genes responsible for many of these diseases have also been identified. Recent advances in diagnostic procedures have enabled these to be identified earlier and appropriately treated. While a number of approaches are available to identify mutations, direct sequencing remains the gold standard. This approach identifies the exact genetic change with substantial precision. We suggest that a sensitive and economical approach to mutation detection could be the direct sequencing of cDNA followed by the confirmatory sequencing of the corresponding exon. While screening techniques such as single-stranded conformation polymorphism (SSCP), heteroduplex analysis (HA), denaturing gradient gel electrophoresis (DGGE), and denaturing high-performance liquid chromatography (dHPLC) have proven useful, each has inherent advantages and disadvantages. We discuss these advantages and disadvantages and also discuss the potential of future sequencing technologies such as pyrosequencing, combinatorial sequencing-by-hybridization, multiplex polymerase colony (polony), and resequencing arrays as tools for future mutation detection. In addition we briefly discuss several high-throughput SNP detection technologies.
Pharmacokinetics and Pharmacodynamics of Propofol in a New Solvent (1997)

Pain on injection is the most commonly reported adverse event after propofol injection.In a randomized, cross-over study in two groups of 12 healthy male volunteers (24-42 yr), we compared the pharmacokinetics and pharmacodynamics of two new propofol formulations (1% and 2% concentrations) in a fat emulsion consisting of medium- and long-chain triglycerides with the standard propofol formulation. After a single intravenous bolus injection of 2 mg/kg, propofol blood levels were measured for 24 h and evaluated according to an open three-compartment model. The derived pharmacokinetic variables were not different among formulations. Additionally, electroencephalographic recordings of the onset and duration of hypnotic action were comparable with all formulations. After propofol 1% in the new formulation, fewer volunteers reported severe or moderate pain on injection (9%) than after the standard formulation (59%) (P < 0.05). We attribute this result to a lower concentration of free propofol in the aqueous phase of the new formulation. Implications: Changing the composition of the carrier fat emulsion for propofol does not have an impact on the pharmacokinetics and efficacy of propofol, but it promises to provide better patient acceptance by lowering the incidence of moderate and severe pain on injection. (Anesth Analg 1997;85:1399-403)
Rapid induction by wounding and bacterial infection of an S gene family receptor-like kinase gene in Brassica oleracea. (1997)

A receptor-like kinase, SRK, has been implicated in the autoincompatible response that leads to the rejection of self-pollen in Brassica plants. SRK is encoded by one member of a multigene family, which includes several receptor-like kinase genes with patterns of expression very different from that of SRK but of unknown function. Here, we report the characterization of a novel member of the Brassica S gene family, SFR2. RNA gel blot analysis demonstrated that SFR2 mRNA accumulated rapidly in response both to wounding and to infiltration with either of two bacteria: Xanthomonas campestris, a pathogen, and Escherichia coli, a saprophyte. SFR2 mRNA also accumulated rapidly after treatment with salicylic acid, a molecule that has been implicated in plant defense response signaling pathways. A SFR2 promoter and reporter gene fusion was introduced into tobacco and was shown to be induced by bacteria of another genus, Ralstonia (Pseudomonas) solanacearum. The accumulation of SFR2 mRNA in response to wounding and pathogen invasion is typical of a gene involved in the defense responses of the plant. The rapidity of SFR2 mRNA accumulation is consistent with SFR2 playing a role in the signal transduction pathway that leads to induction of plant defense proteins, such as pathogenesis-related proteins or enzymes of phenylpropanoid metabolism.
Long‐term culture of disaggregated rat osteoclasts: Inhibition of bone resorption and reduction of osteoclast‐like cell number by calcitonin and PTHrP[107‐139] (1993)

The isolated osteoclast bone resorption assay has proved to be a useful means of examining the response of mammalian and avian osteoclasts to a variety of stimuli. The assay has traditionally been performed over a period of 24 hours. By extending the duration of the osteoclast bone resorption assay, we have been able to assess the long-term effects of carboxyl-terminal parathyroid hormone-related protein (hPTHrP[107-139]), salmon calcitonin (sCT) and hPTH[1-34] on bone resorption and TRACP-positive osteoclast-like cell number. We found that, in control cultures over a period of up to 144 hours, the osteoclast-like cells not only remained viable but their numbers also increased. The number of mononucleated and multinucleated osteoclast-like cells doubled in the first 48 hours before stabilizing over the remainder of the incubation period. Osteoblasts also proliferated, resulting in a resorption response to hPTH[1-34] being evident from 48 hours onward. hPTHrP]107-139] persistently inhibited basal and PTH-stimulated bone resorption for at least 96-144 hours, whereas "escape" from the inhibitory effect of sCT was seen after 48-72 hours. Decreased numbers of both mononucleated and multinucleated TRACP-positive osteoclast-like cells were seen by 48 hours in cultures treated with sCT. In contrast, hPTHrP[107-139] reduced the number of mononuclear TRACP-positive cells with only a late effect on multinucleated cells. Furthermore, the increased number of osteoclast-like cells seen in response to hPTH[1-34] was inhibited by carboxyl-terminal PTHrP. In summary, this study indicates that the extended bone resorption assay system is a complex one where both osteoclastic resorption and osteoclast maturation are evident. Using this system, we have shown that hPTHrP[107-139] acts as a potent long-term inhibitor of osteoclastic bone resorption, without evidence of escape from its effect. Its action to reduce the number of mononucleated osteoclast-like cells suggests that it affects several aspects of osteoclast activity.
Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication (2016)

We demonstrate that a poly(lactide-co-glycolide) (PLG) cancer vaccine can be used in combination with immune checkpoint antibodies, anti-CTLA-4 or anti-PD-1, to enhance cytotoxic T-cell (CTL) activity and induce the regression of solid B16 tumors in mice. Combination therapy obviated the need for vaccine boosting and significantly skewed intratumoral reactions toward CTL activity, resulting in the regression of B16 tumors up to 50 mm(2) in size and 75% survival rates. These data suggest that combining material-based cancer vaccines with checkpoint antibodies has the potential to mediate tumor regression in humans.
Molecular and Cellular Mechanisms RegulatingTand B Cell Apoptosis through Fas/FasL Interaction (1999)

Fas (CD95) and Fas ligand (FasL) are a receptor/ligand pair critically involved in lymphocyte homeostasis and peripheral tolerance such that genetic defect in either Fas or FasL results in an autoimmune lymphoproliferative syndrome. Fas is a type I transmembrane protein and a member of the tumor necrosis factor receptor (TNFR) family whereas FasL is a type II transmembrane protein and a member of TNF family. Binding of Fas by FasL induces apoptosis of the Fas-expressing cells. In the past few years, Fas/FasL interaction has been connected to a series of important phenomena previously viewed as independent immune processes. The activation-induced T cell death (AICD) and the FasL-mediated cytotoxicity by activated T cells are two critical mechanisms that can account for most of these phenomena. It is in the context of the two mechanisms that we discuss in this review the molecular and cellular events that occur during T/T and T/B interactions that account for the down-regulation of the immune response. We have also discussed recent advances in the areas of FasL gene regulation, lymphokine regulation of AICD, and regulation of B cell susceptibility to FasL. Investigation in these areas should help elucidate the role of Fas/FasL in the complex network of regulatory mechanisms that control immune response and autoimmunity.
In Vitro and In Vivo Potency of Insulin Analogues Designed for Clinical Use (1991)

Analogues of human insulin designed to have improved absorption properties after subcutaneous injection have been prepared by recombinant DNA technology. Five rapidly absorbed analogues, being predominantly in mono- or di-meric states in the pharmaceutical preparation, and a hexameric analogue with very low solubility at neutral pH and slow absorption, were studied. Receptor binding assays with HEP-G2 cells showed overall agreement with mouse free adipocyte assays. Two analogues, B28Asp and A21Gly + B27Arg + B30Thr-NH2, had nearly the same molar in vitro potency as human insulin. Another two showed increased adipocyte potency and receptor binding, B10Asp 194% and 333% and A8His + B4His + B10Glu + B27His 575% and 511%, while B9Asp + B27Glu showed 29% and 18% and the B25Asp analogue only 0.12% and 0.05% potency. Bioassays in mice or rabbits of the analogues except B25Asp showed that they had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation had the same in vivo potency as human insulin 1.00 IU = 6.00 nmol. Thus the variation in in vivo potency reflects the differences in receptor binding affinity. Relative to human insulin a low concentration is sufficient for a high affinity analogue to produce a given receptor complex formation and metabolic response. In conclusion, human insulin and analogues with markedly different in vitro potencies were equipotent in terms of hypoglycaemic effect. This is in agreement with the concept that elimination of insulin from blood and its subsequent degradation is mediated by insulin receptors.
Nitriles in heterocyclic synthesis: A novel synthesis of some thieno[2,3‐d]pyrimidine and thieno[2,3‐b]pyridine derivatives (1996)

A simple route to the synthesis of the pharmaceutically important thieno[2,3-d]pyrimidine derivatives and of thieno[2,3-b]pyridine derivatives via the use of 5-amino-3-phenylthiophene-2,4-dicarbonitrile (2) as a starting material is described. © 1996 John Wiley & Sons, Inc.
Flavivirus premembrane protein cleavage and spike heterodimer secretion require the function of the viral proteinase NS3. (1993)

Flavivirus protein biosynthesis involves the proteolytic processing of a single polyprotein precursor by host- and virus-encoded proteinases. In this study, the requirement for the proteolytic function of the viral proteinase NS3 for correct processing of a polyprotein segment encompassing the Murray Valley encephalitis virus structural proteins is shown. The NS3-mediated cleavage in the structural polyprotein region presumably releases the capsid protein from its membrane anchor and triggers the appearance of the premembrane (prM) protein. This suggests that cleavage of prM by signal peptidase in the lumen of the endoplasmic reticulum is under control of a cytoplasmic cleavage catalyzed by a viral proteinase. The function of the viral proteinase is also essential for secretion of flaviviral spike proteins when expressed from cDNA via vaccinia virus recombinants or in COS cell transfections. This has important implications for the design of flavivirus subunit vaccines.
High-Q measurements of fused-silica microspheres in the near infrared (1998)

Measurements of the quality factor Q approximately 8x10(9) are reported for the whispering-gallery modes (WGM's) of quartz microspheres for the wavelengths 670, 780, and 850 nm; these results correspond to finesse f approximately 2.2x10(6) . The observed independence of Q from wavelength indicates that losses for the WGM's are dominated by a mechanism other than bulk absorption in fused silica in the near infrared. Data obtained by atomic force microscopy combined with a simple model for surface scattering suggest that Q can be limited by residual surface inhomogeneities. Absorption by absorbed water can also explain why the material limit is not reached at longer wavelengths in the near infrared.
The Metalloprotease Disintegrin ADAM8 (2002)

ADAMs (a disintegrin and metalloprotease domains) are metalloprotease and disintegrin domain-containing transmembrane glycoproteins with proteolytic, cell adhesion, cell fusion, and cell signaling properties. ADAM8 was originally cloned from monocytic cells, and its distinct expression pattern indicates possible roles in both immunology and neuropathology. Here we describe our analysis of its biochemical properties. In transfected COS-7 cells, ADAM8 is localized to the plasma membrane and processed into two forms derived either by prodomain removal or as remnant protein comprising the extracellular region with the disintegrin domain at the N terminus. Proteolytic removal of the ADAM8 propeptide was completely blocked in mutant ADAM8 with a Glu(330) to Gln exchange (EQ-A8) in the Zn(2+) binding motif (HE(330)LGHNLGMSHD), arguing for autocatalytic prodomain removal. In co-transfection experiments, the ectodomain but not the entire MP domain of ADAM8 was able to remove the prodomain from EQ-ADAM8. With cells expressing ADAM8, cell adhesion to a substrate-bound recombinant ADAM8 disintegrin/Cys-rich domain was observed in the absence of serum, blocked by an antibody directed against the ADAM8 disintegrin domain. Soluble ADAM8 protease, consisting of either the metalloprotease domain or the complete ectodomain, cleaved myelin basic protein and a fluorogenic peptide substrate, and was inhibited by batimastat (BB-94, IC(50) approximately 50 nm) but not by recombinant tissue inhibitor of matrix metalloproteinases 1, 2, 3, and 4. Our findings demonstrate that ADAM8 processing by autocatalysis leads to a potential sheddase and to a form of ADAM8 with a function in cell adhesion.
Nociception and TRP Channels (2004)

Noxious thermal, mechanical, or chemical stimuli evoke pain through excitation of the peripheral terminals called nociceptor, and many kinds of ionotropic and metabotropic receptors are involved in this process. Capsaicin receptor TRPV1 is a nociceptor-specific ion channel that serves as the molecular target of capsaicin. TRPV1 can be activated not only by capsaicin but also by noxious heat (with a thermal threshold >43 degrees C) or protons (acidification), all of which are known to cause pain in vivo. Studies using TRPV1-deficient mice have shown that TRPV1 is essential for selective modalities of pain sensation and for thermal hyperalgesia. One mechanism underlying inflammatory pain which is initiated by tissue damage/inflammation and characterized by hypersensitivity is sensitization of TRPV1. In addition to TRPV1, there are five thermosensitive ion channels in mammals, all of which belong to the TRP (transient receptor potential) super family. These include TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. These channels exhibit distinct thermal activation thresholds (> 52 degrees C for TRPV2, > approximately 34-38 degrees C for TRPV3, > approximately 27-35 degrees C for TRPV4, < approximately 25-28 degrees C for TRPM8 and < 17 degrees C for TRPA1) and are expressed in primary sensory neurons as well as other tissues. Some of the thermosensitive TRP channels are likely to be involved in thermal nociception, since their activation thresholds are within the noxious range of temperatures.
Identification and characterization of a nuclear localization sequence-binding protein in yeast. (1989)

Nuclear proteins contain specific regions that are required for entry into the nucleus. Using ligand blotting, we have shown that a 67-kDa yeast nuclear envelope protein (p67) recognizes synthetic peptides containing the yeast histone H2B or simian virus 40 large tumor antigen nuclear localization sequence. Both free peptide and peptide conjugated to human serum albumin are recognized. The interaction between p67 and the nuclear localization sequences is specific; neither a mutant peptide that is incompetent for nuclear transport in vivo nor HSA can interact with p67 on blots. Moreover, although the wild-type peptide competes for binding to p67, the mutant peptides do not. p67 appears to be located at the nuclear envelope and is not present in other subcellular fractions. The nuclear localization sequence-binding protein is not extracted from the nuclear envelope with nonionic detergents and only partially extracted with high-salt buffer or 8 M urea, suggestive of a tight association with the nuclear envelope. Together our results are consistent with a role for p67 in nuclear transport.
Catalytic Mechanism of Glycosyltransferases:  Hybrid Quantum Mechanical/Molecular Mechanical Study of the Inverting N-Acetylglucosaminyltransferase I (2006)

The Golgi glycosyltransferase, N-acetylglucosaminyltransferase I (GnT-I), catalyzes the transfer of a GlcNAc residue from the donor UDP-GlcNAc to the C2-hydroxyl group of a mannose residue in the trimannosyl core of the Man5GlcNAc2-Asn-X oligosaccharide. The catalytic mechanism of GnT-I was investigated using a hybrid quantum mechanical/molecular mechanical (QM/MM) method with a QM part containing 88 atoms treated with density functional theory (DFT) at the BP/TZP level. The remaining parts of a GnT-I complex, altogether 5633 atoms, were modeled using the AMBER molecular force field. A theoretical model of a Michaelis complex was built using the X-ray structure of GnT-I in complex with the donor having geometrical features consistent with kinetic studies. The QM(DFT)/MM model identified a concerted SN2-type of transition state with D291 as the catalytic base for the reaction in the enzyme active site. The TS model features nearly simultaneous nucleophilic addition and dissociation steps accompanied by the transfer of the nucleophile proton Hb2 to the catalytic base D291. The structure of the TS model is characterized by the Ob2-C1 and C1-O1 bond distances of 1.912 and 2.542 A, respectively. The activation energy for the proposed reaction mechanism was estimated to be approximately 19 kcal mol-1. The calculated alpha-deuterium kinetic isotope effect of 1.060 is consistent with the proposed reaction mechanism. Theoretical results also identified interactions between the Hb6 and beta-phosphate oxygen of the UDP and a low-barrier hydrogen bond between the nucleophile and the catalytic base D291. It is proposed that these interactions contribute to a stabilization of TS. This modeling study provided detailed insight into the mechanism of the GlcNAc transfer catalyzed by GnT-I, which is the first step in the conversion of high mannose oligosaccharides to complex and hybrid N-glycan structures.
Molecular cloning of murine FLT and FLT4. (1993)

A wide range of growth and differentiation processes are regulated by the signalling of receptor tyrosine kinases (RTKs). We have developed a nested polymerase chain reaction (PCR) procedure with degenerate primers, and used it to identify RTKs expressed in murine fetal thymus. A novel RTK, called FLT4, and the murine homologue of FLT were found, and their PCR fragment sequences were used to isolate larger cDNA clones spanning the complete coding regions of these receptors. FLT4 was found to contain an extracellular region similar to the corresponding sequences of FLT and Flk-1, containing seven immunoglobulin domains.