gebhart/patrepeval huggingface dataset:
Recent Progress in the Synthesis and Characterization of Group II Metabotropic Glutamate Receptor Allosteric Modulators (2011)

Group II metabotropic glutamate (mGlu) receptors consist of the metabotropic glutamate 2 (mGlu(2)) and metabotropic glutamate 3 (mGlu(3)) receptor subtypes which modulate glutamate transmission by second messenger activation to negatively regulate the activity of adenylyl cyclase. Excessive accumulation of glutamate in the perisynaptic extracellular region triggers mGlu(2) and mGlu(3) receptors to inhibit further release of glutamate. There is growing evidence that the modulation of glutamatergic neurotransmission by small molecule modulators of Group II mGlu receptors has significant potential for the treatment of several neuropsychiatric and neurodegenerative diseases. This review provides an overview of recent progress on the synthesis and pharmacological characterization of positive and negative allosteric modulators of the Group II mGlu receptors.
Critical Reevaluation of Endothelial Progenitor Cell Phenotypes for Therapeutic and Diagnostic Use (2012)

Diverse subsets of endothelial progenitor cells (EPCs) are used for the treatment of ischemic diseases in clinical trials, and circulating EPCs levels are considered as biomarkers for coronary and peripheral artery disease. However, despite significant steps forward in defining their potential for both therapeutic and diagnostic purposes, further progress has been mired by unresolved questions around the definition and the mechanism of action of EPCs. Diverse culturing methods and detection of various combinations of different surface antigens were used to enrich and identify EPCs. These attempts were particularly challenged by the close relationship and overlapping markers of the endothelial and hematopoietic lineages. This article will critically review the most commonly used protocols to define EPCs by culture assays or by fluorescence-activated cell sorter in the context of their therapeutic or diagnostic use. We also delineate new research avenues to move forward our knowledge on EPC biology.
Mutations in Severe, Type III von Willebrand’s Disease in the Dutch Population: Candidate Missense and Nonsense Mutations Associated with Reduced Levels of von Willebrand Factor Messenger RNA (1992)

The von Willebrand factor (vWF) genes of nine unrelated, severe, type III von Willebrand's disease (vWD) patients (six of Dutch origin) and four unrelated Dutch type I vWD patients were screened for mutations in exons that contain CGA codons (Arg), which are liable to mutation to TGA stop codons. The nine exons of the vWF gene (3, 8, 9, 10, 28, 31, 32, 43 and 45) that contain all the CGA codons (11 in total) of the vWF cDNA were amplified by the polymerase chain reaction and screened for mutations by single-strand conformation polymorphism analysis, restriction enzyme - and/or nucleotide sequence analysis. Three of the severe vWD patients were found to be heterozygous for a nonsense mutation: CGA Arg 2535-->TGA Stop. Three other severe vWD patients were homozygous for a single nucleotide substitution, AAC Asn 2546-->TAC Tyr. The transcription of these mutated alleles was tested by cDNA dependent amplification of platelet RNA. The level of transcription product was strongly reduced for either mutant allele.
Glycolysis and sperm motility: does a spoonful of sugar help the flagellum go round? (2006)

It is doubtful that diffusion can deliver sufficient ATP from the mitochondria to sustain activity at the distal end of the sperm flagellum. Glycolytic enzymes bound to the fibrous sheath could provide energy along the flagellum at the point it is required. An obligatory role for glycolysis is supported by the lack of progressive motility in sperm from mice where the gene for sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHs) had been 'knocked out'. Here, I review some evidence against this idea. First, pure diffusion from the mitochondrion is likely to be adequate in species with smaller sperm, and it is possible that rapid ATP delivery required in larger sperm could be achieved by an adenylate kinase shuttle. Second, experience with alpha-chlorohydrin demonstrates that sperm can remain motile with normal ATP concentrations despite inhibition of GAPDHs; adverse effects only occur if glucose is added and high levels of glycolytic intermediates accumulate. These observations undermine the GAPDHs knockout mouse as evidence for an essential role of local glycolysis. Third, sperm from many species can remain motile for long periods in sugar-free media and excepting dog sperm, evidence that gluconeogenesis is a possible explanation, is weak. In most species, it is unlikely that local glycolysis is the only way that ATP can be supplied to the distal flagellum.
Synthesis and Characterization of Insulin-like Growth Factor-binding Protein (IGFBP)-7 (1996)

The mac25 cDNA was originally cloned from leptomeningial cells and subsequently reisolated through differential display as a sequence preferentially expressed in senescent human mammary epithelial cells. The deduced amino acid sequence of the human mac25 propeptide shares a 20-25% identity to human insulin-like growth factor-binding proteins (IGFBPs), suggesting that mac25 could be another member of the IGFBP family. In the present study, we have generated recombinant human mac25 (rh-mac25) in a baculovirus expression system and assessed its affinity for IGFs and have evaluated the pattern of expression of the mac25 gene in human tissues. Binding of 125I-IGF-I and 125I-IGF-II to rh-mac25 was demonstrated by Western ligand blotting after nondenaturing polyacrylamide gel electrophoresis and by affinity cross-linking with as little as 2 nM rh-mac25. Specificity of rh-mac25 binding to 125I-IGFs was demonstrated by competition for rh-mac25 binding with unlabeled IGFs, but not with [QAYLL]IGF-II analog, which has 100-fold less affinity for IGFBPs. In comparison with IGFBP-3, rh-mac25 has at least a 5-6-fold lower affinity for IGF-I and 20-25-fold lower affinity for IGF-II. mac25 mRNA was detectable in a wide range of normal human tissues, with decreased expression in breast, prostate, colon, and lung cancer cell lines. In conclusion, mac25 specifically binds IGFs and constitutes a new member of the IGFBP family, IGFBP-7. Its wider distribution in normal tissue and lower expression in several cancer cells indicate that IGFBP-7 may function as a growth-suppressing factor, as well as an IGF-binding protein.
Visually Coupled Systems Hardware and the Human Interface (1995)

A visually coupled system (VCS) has been defined as “ . . . a special ‘subsystem’ which integrates the natural visual and motor skills of an operator into the system he is controlling” (Birt and Task, 1973). A basic VCS consists of three major components: (1) a head- or helmet-mounted (or head-directed) visual display, (2) a means of tracking head and/or eye pointing direction, and (3) a source of visual information which is dependent on eye/head viewing direction. The concept of a VCS is relatively simple: an operator looks in a particular direction, the head or eye tracker determines what that direction is, and the visual information source produces appropriate imagery to be viewed on the display by the operator. In this manner the operator is visually coupled to the system represented by the visual information source. The visual information source could be a physical imaging sensor such as a television camera or it could be a synthetic source such as computer-generated imagery (the basis for a virtual reality (VR) or virtual environment system). Thus, a VR system is really a subset of a VCS which can present both real-world and virtual information to an operator, often on a see-through display. The display is usually a helmet/head-mounted display (HMD) but it could also be the interior of a dome capable of displaying a projected image or it could be a mechanically mounted display that is not supported by the head but is attached to the head which in recent times has been referred to as a binocular omni-oriented monitor (BOOM) display. Both eye-tracking and head-tracking devices have been developed but by far the least expensive and most widely used is head tracking (this is based on the reasonable assumption that the eyes will be looking in the general direction that the head is pointing). Figures 6-1 through 6-4 are photographs of some early helmet-mounted and BOOM displays. In this chapter we will concentrate primarily on helmet/head-mounted displays and helmet/head trackers. This section describes each of the three main components of a visually coupled system and defines characteristics that are used in the specification of these components.
Flow cytometric detection and quantitation of the epidermal growth factor receptor in comparison to Scatchard analysis in human bladder carcinoma cell lines (1994)

The epidermal growth factor receptor (EGFR) is considered a tumor-related marker with potential diagnostic and prognostic value. In order to assess the sensitivity of flow cytometry to detect EGFR and to quantify receptors objectively, two human bladder carcinoma cell lines with different urothelial differentiation, RT4 and J82, were grown in vitro, and their membrane EGFR content was measured by flow cytometry. Exponential monolayers showed decrease of EGFR content after 20 min pulses with 10 ng/ml EGF in medium, as detected with the antibody EGFR1 in a double staining technique with propidium iodide for DNA evaluation. Further decrease of green fluorescence intensity was seen in cells constantly exposed to EGF. Absolute receptor numbers were determined by Scatchard analysis with radioactive EGF and resulted in relatively low receptor numbers for both cell lines (approximately 3-4 x 10(4) EGFR/cell), as well as one affinity class. These findings could be matched by absolute receptor quantification by flow cytometry, adding beads with defined antigenic sites (Quantum Simply Cellular, Microbead Corporation) to the cell suspension for staining. Our data suggest that flow cytometric EGFR detection and quantitation may be supplied to in vivo tumor samples and that measurements by multiparameter analysis may define subpopulations valuable for tumor diagnosis and judgment on tumor progression.
Involvement of the Matrix Protein in Attachment of Porcine Reproductive and Respiratory Syndrome Virus to a Heparinlike Receptor on Porcine Alveolar Macrophages (2002)

The porcine reproductive and respiratory syndrome virus (PRRSV) has a very restricted tropism for well-differentiated cells of the monocyte-macrophage lineage, which is probably determined by specific receptors on these cells. In this study, the importance of heparinlike molecules on porcine alveolar macrophages (PAM) for PRRSV infection was determined. Heparin interacted with the virus and reduced infection of PAM up to 92 or 88% for the American and European types of PRRSV, respectively. Other glycosaminoglycans, similar to heparin, had no significant effect on infection while heparinase treatment of PAM resulted in a significant reduction of the infection. Analysis of infection kinetics showed that PRRSV attachment to heparan sulfate occurs early in infection. A heparin-sensitive binding step was observed which converted completely into a heparin-resistant binding after 120 min at 4 degrees C. Using heparin-affinity chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), it was observed that the structural matrix (M) and nucleocapsid (N) proteins attached to heparin. Nonreducing SDS-PAGE revealed that M bound to heparin mainly as a complex with glycoprotein GP(5) and that the N protein bound to heparin as a homodimer. GP(3), which was identified as a minor structural protein of European types of PRRSV, did not bind to heparin. Since the N protein is not exposed on the virion surface, it was concluded that the structural M protein and the M-GP(5) complex contribute to PRRSV attachment on a heparinlike receptor on PAM. This is the first report that identifies a PRRSV ligand for a cell surface heparinlike receptor on PAM.
Soluble aggregates of the amyloid‐β protein selectively stimulate permeability in human brain microvascular endothelial monolayers (2008)

Cerebral amyloid angiopathy associated with Alzheimer's disease is characterized by cerebrovascular deposition of the amyloid-beta protein (Abeta). Abeta elicits a number of morphological and biochemical alterations in the cerebral microvasculature, which culminate in hemorrhagic stroke. Among these changes, compromise of the blood-brain barrier has been described in Alzheimer's disease brain, transgenic animal models of Alzheimer's disease, and cell culture experiments. In the current study, presented data illustrates that isolated soluble Abeta(1-40) aggregates, but not unaggregated monomer or mature fibril, enhance permeability in human brain microvascular endothelial monolayers. Abeta(1-40)-induced changes in permeability are paralleled by both a decrease in transendothelial electrical resistance and a re-localization of the tight junction-associated protein zonula occludin-1 away from cell borders and into the cytoplasm. Small soluble Abeta(1-40) aggregates are confirmed to be the most potent stimulators of endothelial monolayer permeability by establishing an inverse relationship between average aggregate size and stimulated changes in diffusional permeability coefficients. These results support previous findings demonstrating that small soluble Abeta(1-40) aggregates are also primarily responsible for endothelial activation, suggesting that these same species may elicit other changes in the cerebrovasculature associated with cerebral amyloid angiopathy and Alzheimer's disease.
Selective palladium-catalyzed carbonylative synthesis of aurones with formic acid as the CO source (2016)

A general and practical strategy has been developed to prepare aurone derivatives.
Induction of tissue transglutaminase in the trabecular meshwork by TGF-beta1 and TGF-beta2. (2000)

The enzyme tTgase is expressed in the HTM and is inducible by TGF-beta1 or -beta2 in cultured HTM cells. Extracellular tTgase is able to polymerize fibronectin. Increased levels of TGF-beta2 in the aqueous humor may lead to an increase of tTgase expression and activity in the HTM, causing an increase of irreversibly cross-linked ECM proteins. This mechanism might play a role for the increased outflow resistance seen in glaucomatous eyes.
社会主义—市场—计划 (1991)

今天,人们常常怀着不安的心情提出以下问题:为什么顺利开始的改革将国家推向了令人沮丧的境地?应该怎样做?出路何在?从我们收集到的国内外情报资料中可以看到不少对这一迫切问题的尝试性答案,提出了许多摆脱危机状况的意见和方法。对此,有必要作些评述和总结。经过数月的争论,到1990年年中,意见趋于明朗:向市场经济过渡已成定局,认为这是摆脱困境、使经济高速发展的唯一途径。然而,市场机制并不可能马上解决国民经济的稳定问题、克服日益恶化的食品危机,而且,到目前为止,这一点并非所有人
Mesenchymal Stromal Cells in Animal Bleomycin Pulmonary Fibrosis Models: A Systematic Review (2015)

There has been increased interest in mesenchymal stromal cell therapy for lung diseases. A few small clinical trials are under way in idiopathic pulmonary fibrosis. Preclinical evidence was assessed in a systematic review, as is often done for clinical studies. The existing studies offer better support for efficacy in the initial inflammatory phase rather than the fibrotic phase that human trials are targeting.
A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube (2005)

During development, many signaling factors behave as morphogens, long-range signals eliciting different cellular responses according to their concentration. In ventral regions of the spinal cord, Sonic Hedgehog (Shh) is such a signal and controls the emergence, in precise spatial order, of distinct neuronal subtypes. The Gli family of transcription factors plays a central role in this process. Here we demonstrate that a gradient of Gli activity is sufficient to mediate, cell-autonomously, the full range of Shh responses in the neural tube. The incremental two- to threefold changes in Shh concentration, which determine alternative neuronal subtypes, are mimicked by similar small changes in the level of Gli activity, indicating that a gradient of Gli activity represents the intracellular correlate of graded Shh signaling. Moreover, our analysis suggests that cells integrate the level of signaling over time, consistent with the idea that signal duration, in addition to signal strength, is an important parameter controlling dorsal-ventral patterning. Together, these data indicate that Shh signaling is transduced, without amplification, into a gradient of Gli activity that orchestrates patterning of the ventral neural tube.
High-Dose Glucocorticoid Treatment of Resistant Myeloma (1986)

Intermittent, high-dose dexamethasone treatment was given to 49 consecutive patients with refractory multiple myeloma. In patients who were unresponsive to previous treatment, the response rate of 27% was similar to that achieved with the VAD regimen, which combines the same schedule of dexamethasone with vincristine and doxorubicin given by continuous infusion. Among patients with relapses, VAD chemotherapy induced remissions in 11 of 17 patients (65%), whereas dexamethasone alone induced remissions in 4 of 19 (21%). The median survival of all patients responding to either treatment, 22 months, was longer than that from any previous program for treatment of resistant myeloma. These findings indicate the value of frequent dexamethasone administration in patients unresponsive to standard therapy and show the major role of vincristine and doxorubicin given by continuous infusion in patients with relapses. They also suggest different mechanisms for primary and secondary resistance to chemotherapy.
High-dose vasopressin is not superior to norepinephrine in septic shock* (2003)

Vasopressin, in doses sufficient to replace the vasopressor norepinephrine, had mixed effects in septic shock patients. Hepatosplanchnic blood flow was preserved during substantial reduction in cardiac output. An increased gastric PCO2 gap suggests that the gut blood flow could have been redistributed to the disadvantage of the mucosa. Based on these limited data, it does not appear beneficial to directly replace norepinephrine with vasopressin in septic shock.
A Binary Rewriting Defense Against Stack based Buffer Overflow Attacks. (2003)

Buffer overflow attack is the most common and arguably the most dangerous attack method used in Internet security breach incidents reported in the public literature. Various solutions have been developed to address the buffer overflow vulnerability problem in both research and commercial communities. Almost all the solutions that provide adequate protection against buffer overflow attacks are implemented as compiler extensions and hence require the source code of the programs being protected to be available so that they can be re-compiled. While this requirement is reasonable in many cases, there are scenarios in which it is not feasible, e.g., legacy applications that are purchased from an outside vendor. The work reported in this paper explores application of static binary translation to protect Internet software from buffer overflow attacks. Specifically, we use a binary rewriting approach to augment existing Win32/Intel Portable Executable (PE) binary programs with a return address defense (RAD) mechanism [1], which protects the integrity of the return address on the stack with a redundant copy. This paper presents the disassembly and instrumentation issues involved in static binary translation, how our tool achieves satisfactory disassembly precision in the presence of indirect branches, position-independent code sequences, hand crafted assembly code and arbitrary code/data mixing, and how it ensures safe binary instrumentation in most practical cases. The paper reports our experiences with this approach, based on results of applying the resulting prototype to rewriting several commercial grade Windows applications (Ftp server, Telnet Server, DNS server, DHCP server, Outlook Express, MS FrontPage, MS Publisher, Telnet, Ftp, Winhlp, Notepad, CL compiler, MS NetMeeting, MS PowerPoint, MS Access, etc.), as well as experimentation with published buffer overflow exploits.
Electrical cell-substrate impedance sensing as a non-invasive tool for cancer cell study (2010)

Cell-substrate interactions are investigated in a number of studies for drug targets including angiogenesis, arteriosclerosis, chronic inflammatory diseases and carcinogenesis. One characteristic of malignant cancerous cells is their ability to invade tissue. Cell adhesion and cytoskeletal activity have served as valuable indicators for understanding the cancer cell behaviours, such as proliferation, migration and invasion. This review focuses on bio-impedance based measurement for monitoring the behaviours in real time and without using labels. Electric cell-substrate impedance sensing (ECIS) provides rich information about cell-substrate interactions, cell-cell communication and cell adhesion. High sensitivity of the ECIS method allows for observing events down to single-cell level and achieving nanoscale resolution of cell-substrate distances. Recently, its miniaturization and integration with fluorescent detection techniques have been highlighted as a new tool to deliver a high-content platform for anticancer drug development.
The cell and molecular basis of leukocyte common antigen (CD45)- triggered, lymphocyte function-associated antigen-1-/intercellular adhesion molecule-1-dependent, leukocyte adhesion (1994)

We recently reported that cross-linking the leukocyte common antigen (CD45) can rapidly induce aggregation of human peripheral blood mononuclear cells via lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) interactions. Herein, we have examined both T-cell--monocyte cellular interactions and the molecular signaling that are involved in this phenomenon. Experiments using highly purified T lymphocytes showed that CD45-induced aggregation requires the presence of both T cells and monocytes. Cross- linking CD45 only on T lymphocytes, but not on monocytes, initiated cellular clustering after reconstituting to the respective untreated cell type. By several criteria, CD45-induced clustering of T cells to autologous monocytes was shown to be Fc-receptor--independent. When comparing intracellular signaling in leukocyte aggregation induced by CD45 cross-linking versus phorbol myristate-12–13-acetate (PMA) treatment, the former was found to be fivefold to 10-fold more sensitive to H-8, a reagent that effectively blocks cAMP- and cGMP- dependent protein kinases. On the other hand, reagents that increase intracellular cAMP levels (eg, dbcAMP, forskolin, and IBMX), protein kinase C (PKC) inhibitors (eg, staurosporine), and tyrosine kinase inhibitors (eg, herbimycin A and genistein) all readily inhibited PMA- induced, but not CD45 monoclonal antibody-induced, aggregation. We conclude that cross-linking the leukocyte common antigen on T cells induces LFA-1--/ICAM-1--dependent T-cell--monocyte aggregation through a unique signaling pathway independent of PKC, which involves instead cAMP-/cGMP-dependent protein kinases.