gebhart/patrepeval huggingface dataset:
Discovery of an RNA virus 3′→5′ exoribonuclease that is critically involved in coronavirus RNA synthesis (2006)

Replication of the giant RNA genome of severe acute respiratory syndrome (SARS) coronavirus (CoV) and synthesis of as many as eight subgenomic (sg) mRNAs are mediated by a viral replicase-transcriptase of outstanding complexity that includes an essential endoribonuclease activity. Here, we show that the CoV replicative machinery, unlike that of other RNA viruses, also uses an exoribonuclease (ExoN) activity, which is associated with nonstructural protein (nsp) 14. Bacterially expressed forms of SARS-CoV nsp14 were shown to act on both ssRNAs and dsRNAs in a 3'-->5' direction. The activity depended on residues that are conserved in the DEDD exonuclease superfamily. The protein did not hydrolyze DNA or ribose-2'-O-methylated RNA substrates and required divalent metal ions for activity. A range of 5'-labeled ssRNA substrates were processed to final products of approximately 8-12 nucleotides. When part of dsRNA or in the presence of nonlabeled dsRNA, the 5'-labeled RNA substrates were processed to significantly smaller products, indicating that binding to dsRNA in cis or trans modulates the exonucleolytic activity of nsp14. Characterization of human CoV 229E ExoN active-site mutants revealed severe defects in viral RNA synthesis, and no viable virus could be recovered. Besides strongly reduced genome replication, specific defects in sg RNA synthesis, such as aberrant sizes of specific sg RNAs and changes in the molar ratios between individual sg RNA species, were observed. Taken together, the study identifies an RNA virus ExoN activity that is involved in the synthesis of multiple RNAs from the exceptionally large genomic RNA templates of CoVs.
Modulation of Retinoic Acid Receptor-related Orphan Receptor α and γ Activity by 7-Oxygenated Sterol Ligands (2009)

The retinoic acid receptor-related orphan receptors alpha and gamma (RORalpha (NR1F1) and RORgamma (NR1F3)) are orphan nuclear receptors and perform critical roles in regulation of development, metabolism, and immune function. Cholesterol and cholesterol sulfate have been suggested to be RORalpha ligands, but the physiological significance is unclear. To date, no endogenous RORgamma ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. One of the 7-oxygenated sterols, 7alpha-hydroxycholesterol (7alpha-OHC), serves as a key intermediate in bile acid metabolism, and we show that 7alpha-OHC modulates the expression of ROR target genes, including Glc-6-Pase and phosphoenolpyruvate carboxykinase, in an ROR-dependent manner. Furthermore, glucose output from hepatocytes is suppressed by 7alpha-OHC functioning as an RORalpha/gamma ligand. Thus, RORalpha and RORgamma are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols.
Discovery and development of new antimicrobial agents (1990)

The unprecedented growth in the number of new antibiotics over the past two decades has been the result of extensive research efforts that have exploited the growing body of knowledge describing the interactions of antibiotics with their targets in bacterial cells. Information gained from one class of antimicrobial agents has often been used to advance the development of other classes. In the case of beta-lactams, information on structure-activity relationships gleaned from penicillins and cephalosporins was rapidly applied to the cephamycins, monobactams, penems, and carbapenems in order to discover broad-spectrum agents with markedly improved potency. These efforts have led to the introduction of many new antibiotics that demonstrate outstanding clinical efficacy and improved pharmacokinetics in humans. The current review discusses those factors that have influenced the rapid proliferation of new antimicrobial agents, including the discovery of new lead structures from natural products and the impact of bacterial resistance development in the clinical setting. The development process for a new antibiotic is discussed in detail, from the stage of early safety testing in animals through phase I, II, and III clinical trials.
ENDOTHELIAL-DEPENDENT MECHANISMS IN CHRONIC INFLAMMATORY LEUKOCYTE RECRUITMENT (1996)

Peripheral blood leukocytes interact with the vascular endothelium in a wide range of physiologic and pathophysiologic situations. A current working concept is that activation of vascular endothelium is an important event during the inflammatory response, conferring spatial and temporal localization and leukocyte-type selectivity to the recruitment process. This chapter highlights recent advances in our understanding of the endothelial-dependent molecular mechanisms that mediate recruitment of mononuclear leukocytes (lymphocytes and monocytes) and discusses these advances in the context of chronic inflammatory diseases and their potential therapeutic interventions.
Early proto-oncogene expression in rat aortic smooth muscle cells following endothelial removal. (1990)

To study the mechanism(s) of vascular smooth muscle cell proliferation in vivo, mRNA levels of c-fos, c-jun, and c-myc were determined by Northern blot analysis following vascular balloon de-endothelialization (BDE). Medial smooth muscle cells (SMC) were separated and studied by enzymatic digestion of the vessel wall. mRNA levels of c-fos and c-jun from aortic smooth muscle cells (SMC) were simultaneously induced within 30 minutes of BDE and declined to baseline by 1.5 hours, c-myc mRNA did not begin to increase until 1 hour after vascular injury. Levels of c-myc peaked at 2 hours and were sustained for an additional 4 hours before gradually declining. Smooth muscle cells derived from enzyme-treated control aortae that did not undergo BDE expressed c-fos and c-jun, but showed no evidence of c-myc message. In contrast, nonenzymatically treated, non-BDE whole aortae (containing both media and adventitia) demonstrated a prominent c-myc signal, but failed to express c-fos and c-jun. Corresponding examination of adventitia derived from enzyme-treated aortae showed this tissue to be a source of all three proto-oncogenes. The results of this study demonstrate the earliest in vivo molecular markers of vascular injury reported to date and implicate SMC proto-oncogene expression in the initiation of SMC proliferation. Furthermore these findings suggest two avenues for proto-oncogene induction, that are due to (1) vessel wall manipulation and (2) humoral stimulation.
Migraine Diagnosis and Treatment in the UCD Inadequate (2002)

To determine the adequacy of diagnosis and treatment of headache in the urgent care department (UCD), these researchers reviewed visits by patients with headache to one UCD. Patients were seen in the UCD by internal-medicine or family-practice physicians between 7 AM and 10 PM daily. Patients who made 3 or more visits within 6 months were excluded.

Of 174 patients with a documented migraine diagnosis in the UCD during a 6-month period, the need for prophylaxis was assessed …
Multiagent system for joke generation: Humor and emotions combined in human-agent conversation (2010)

In this paper we present an innovative work on a multiagent joking conversational system. In our research so far we have shown that implementing humor into a chatterbot can visibly improve its performance. The results presented in this paper are the
Intake and transformation to a glycoside of ( Z )-3-hexenol from infested neighbors reveals a mode of plant odor reception and defense (2014)

Plants receive volatile compounds emitted by neighboring plants that are infested by herbivores, and consequently the receiver plants begin to defend against forthcoming herbivory. However, to date, how plants receive volatiles and, consequently, how they fortify their defenses, is largely unknown. In this study, we found that undamaged tomato plants exposed to volatiles emitted by conspecifics infested with common cutworms (exposed plants) became more defensive against the larvae than those exposed to volatiles from uninfested conspecifics (control plants) in a constant airflow system under laboratory conditions. Comprehensive metabolite analyses showed that only the amount of (Z)-3-hexenylvicianoside (HexVic) was higher in exposed than control plants. This compound negatively affected the performance of common cutworms when added to an artificial diet. The aglycon of HexVic, (Z)-3-hexenol, was obtained from neighboring infested plants via the air. The amount of jasmonates (JAs) was not higher in exposed plants, and HexVic biosynthesis was independent of JA signaling. The use of (Z)-3-hexenol from neighboring damaged conspecifics for HexVic biosynthesis in exposed plants was also observed in an experimental field, indicating that (Z)-3-hexenol intake occurred even under fluctuating environmental conditions. Specific use of airborne (Z)-3-hexenol to form HexVic in undamaged tomato plants reveals a previously unidentified mechanism of plant defense.
Effect of E. coli Nissle 1917 on post‐inflammatory visceral sensory function in a rat model (2005)

The EcN administration caused a significant reduction of VH. Whether EcN might play a role in the treatment of post-infectious functional bowel disorders remains to be investigated in further studies.
Genes encoding three new members of the leukocyte antigen 6 superfamily and a novel member of Ig superfamily, together with genes encoding the regulatory nuclear chloride ion channel protein (hRNCC) and an N omega-N omega-dimethylarginine dimethylaminohydrolase homologue, are found in a 30-kb segment of the MHC class III region. (1999)

Many of the genes in the class III region of the human MHC encode proteins involved in the immune and inflammatory responses. We have sequenced a 30-kb segment of the MHC class III region lying between the heat shock protein 70 and TNF genes as part of a program aimed at identifying genes that could be involved in autoimmune disease susceptibility. The sequence analysis has revealed the localization of seven genes, whose precise position and order is cen-G7-G6-G6A-G6B-G6C-G6D-G6E-tel, five of which are fully encoded in the sequence, allowing their genomic structures to be defined. Three of them (G6C, G6D, and G6E) encode putative proteins that belong to the Ly-6 superfamily, known to be GPI-anchored proteins attached to the cell surface. Members of the family are specifically expressed and are important in leukocyte maturation. A fourth gene, G6B, encodes a novel member of the Ig superfamily containing a single Ig V-like domain and a cytoplasmic tail with several signal transduction features. The G6 gene encodes a regulatory nuclear chloride ion channel protein, while the G6A gene encodes a putative homologue of the enzyme N omega,N omega-dimethylarginine dimethylaminohydrolase, which is thought to be involved in regulating nitric oxide synthesis. In addition, three microsatellite markers, 9N-1, 82-2, and D6S273 are contained within the sequence, the last two of which have been reported to be strongly associated with the autoimmune disease ankylosing spondylitis.
Contact of nominally flat surfaces (1966)

Abstract It is usually assumed that the real area of contact between two nominally flat metal surfaces is determined by the plastic deformation of their highest asperities. This leads at once to the result that the real area of contact is directly proportional to the load and independent of the apparent area—a result with many applications in the theories of electric contacts and friction. Archard pointed out that plastic deformation could not be the universal rule, and introduced a model which showed that, contrary to earlier ideas, the area of contact could be proportional to the load even with purely elastic contact. This paper describes a new theory of elastic contact, which is more closely related to real surfaces than earlier theories. We show how the contact deformation depends on the topography of the surface, and establish the criterion for distinguishing surfaces which touch elastically from those which touch plastically. The theory also indicates the existence of an ‘elastic contact hardness’, a composite quantity depending on the elastic properties and the topography, which plays the same role in elastic contact as the conventional hardness does in plastic contact. A new instrument for measuring surface topography has been built; with it the various parameters shown by the theory to govern surface contact can be measured experimentally. The typical radii of surface asperities have been measured. They were found, surprisingly, to be orders of magnitude larger than the heights of the asperities. More generally we have been able to study the distributions of asperity heights and of other surface features for a variety of surfaces prepared by standard techniques. Using these data we find that contact between surfaces is frequently plastic, as usually assumed, but that surfaces which touch elastically are by no means uncommon in engineering practice.
Cutaneous Injection of Human Subjects with Macrophage Inflammatory Protein-1α Induces Significant Recruitment of Neutrophils and Monocytes (2000)

Macrophage inflammatory protein (MIP-1 alpha), a member of the CC chemokine subfamily, has been shown to attract T cells and monocytes in vitro and to be expressed at sites of inflammation. Although the in vitro activities of MIP-1 alpha have been well documented, the in vivo biological activities of MIP-1 alpha in humans have not been studied. To address this, we challenged human subjects by intradermal injection with up to 1000 pmol of MIP-1 alpha and performed biopsies 2, 10, and 24 h later. Although no acute cutaneous or systemic reactions were noted, endothelial cell activation, as indicated by the expression of E-selectin, was observed. In agreement with its in vitro activity, monocyte, lymphocyte, and, to a lesser degree, eosinophil infiltration was observed, peaking at 10-24 h. Surprisingly, in contrast to its reported lack of in vitro neutrophil-stimulating activity, a rapid infiltration of neutrophils was observed in vivo. This neutrophil infiltration occurred as early as 2 h, preceding the appearance of other cells, and peaked at 10 h. Interestingly, we found that neutrophils in whole blood, but not after isolation, expressed CCR1 on their cell surface. This CCR1 was thought to be functional as assessed by neutrophil CD11b up-regulation following whole-blood MIP-1 alpha stimulation. These studies substantiate the biological effects of MIP-1 alpha on monocytes and lymphocytes and uncover the previously unrecognized activity of MIP-1 alpha to induce neutrophil infiltration and endothelial cell activation, underscoring the need to evaluate chemokines in vivo in humans.
Molecular cloning of the mouse dopamine transporter and pharmacological comparison with the human homologue (1999)

Drug abuse is a serious problem in the United States and in the world. Cocaine and amphetamines, widely used drugs of abuse, bind to dopamine (DA), serotonin, and norepinephrine transporters with high affinity and block their functions. It is believed that the dopamine transporter plays a key role in the mechanism of cocaine addiction. Because a good portion of our knowledge about drug addiction is derived from studying mouse as an animal model, it is essential to compare the properties of dopamine transporter from human and mouse. We report here the cloning of the mouse dopamine transporter (mDAT) cDNA and its expression and comparison with the human DAT. The 3.4 kilobase (kb) cDNA encodes a polypeptide that is 93.5% identical to the hDAT, with 619 amino acid residues and a calculated molecular weight of 68.8kDa. Dopamine transporters from mouse and human were stably expressed in the same parental MDCK cells and their properties were compared. The Michaelis-Menten constant Km values are 2.0 microM for mDAT and 2.4 microM for hDAT. Mouse and human DAT were also compared for drug inhibition profiles. Dopamine transporters from the two species have the same sensitivity to amphetamine (Kd: 0.75 microM) and bupropion (Kd: 1.5 microM). However, hDAT is more sensitive than mDAT to cocaine (Kd: 0.14 microM and 0. 29 microM respectively) and to ritalin (Kd: 0.038 microM and 0. 12 microM respectively). The cloning of mDAT cDNA provides an important tool for further study of the mechanism of drug addiction using mouse as an animal model.
tPA in acute ischemic stroke (1998)

The approval of tissue plasminogen activator (tPA) for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of an acute stroke. Despite this approval and the lack of an alternative therapy, the use of tPA in stroke has been quite low. Several explanations for this underutilization have been identified, including lack of patient awareness, potential complications, infrastructure deficiencies, and physician concerns. This article explores these issues and suggests strategies for improving the use of tPA as an acute therapy in stroke.
Application of a Local Drug Delivery System to Periodontal Therapy: (1989)

For the purpose of applying a local drug delivery system to periodontal therapy, atelocollagen preparations with immobilized tetracycline (TC) were prepared by modifying the form of the collagen, the concentration of the immobilized TC, and the time of the cross-link process with glutaraldehyde. The course of the TC release from the collagen preparations into an aqueous solution was determined in relation to time. The preparations were also inserted into periodontal pockets, and the amount of TC remaining in the pocket was determined daily. The results obtained were as follows: 1) The degree of drug release could be controlled to some extent by adjusting the TC concentration and the time of the cross-link process; and 2) an amount of TC exceeding the effective dose in the gingival crevicular fluid was present in the periodontal pocket even 10 days after the insertion of TC fixed in the cross-linked processed collagen film in the periodontal pockets.
Diagnostic Role of Procalcitonin in Patients with Suspected Appendicitis (2012)

The study does not support the hypothesis that the PCT test may be useful for screening ED patients for appendicitis. However, determination of the PCT level may be useful for risk assessment of ED patients with suspected complicated appendicitis.
Core cross-linked star (CCS) polymers with tunable polarity: synthesis by RAFT dispersion polymerization, self-assembly and emulsification (2013)

Homoarm and heteroarm core cross-linked star (CCS) polymers based on poly(N,N-dimethylacrylamide) (PDMA) as the high-polarity arm and poly(2-methoxyethylacrylate) (PMEA) as the low-polarity arm were efficiently prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization in a dispersion polymerization system. PDMA and PMEA arm polymers exhibited similar conversion rates, such that their composition in the heteroarm CCS polymers was easily controlled by the feed ratio in the synthesis. The ability to control the arm composition allowed facile tuning of the polarity of the CCS polymers. Heteroarm CCS polymers self-assembled in water to form aggregates and their size was related to the composition and polarity of the CCS polymers. The composition and polarity of the CCS polymers significantly affected the emulsifying behaviour of the CCS polymers as emulsifiers. Oil-in-water (o/w) emulsions were favoured for CCS polymers with relatively high polarity and lowering the polarity of CCS polymers to a certain degree enhanced the stability of the emulsions. Multiple emulsions, both o/w and water-in-oil (w/o), were gradually produced when the polarity of CCS polymers was gradually lowered and the oil fraction in the emulsion samples was gradually increased, and at the same time the emulsions also became increasingly less stable.
Percutaneous MRI-guided laser thermal therapy in canine prostate (2005)

Prostate cancer is the most common cancer in American men excluding skin cancer, and approximately 230,000 cases of prostate cancer will be diagnosed in the U.S. in 2004. In the non-surgical treatment of localized prostate cancer, fiberoptically delivered interstitial laser thermal therapy may be ideal for treating discrete tumors with minimal invasiveness. Real-time magnetic resonance imaging can be used to compute temperature changes based on the proton resonance frequency (PRF) shift, and two-dimensional maps of temperature rise and chronic thermal damage can be constructed in order to control laser therapy. In this work, we describe an MRI-compatible percutaneous grid template and localization and planning software for precise placement of minimally invasive laser catheters to effect a target ablation zone. We evaluated the accuracy of the catheter placement, and we present our preliminary experience with percutaneous MRI-guided feedback controlled laser ablation in a canine prostate model. Histological analysis is used to assess the effectiveness and accuracy of treatment visualization.
CS-21 * EphA2 PROMOTES INFILTRATIVE INVASION OF GLIOMA STEM CELLS IN VIVO THROUGH CROSSTALK WITH Akt AND REGULATES STEM PROPERTIES (2014)

Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma (GBM), but the underlying mechanisms remain incompletely understood. Using human glioblastoma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrin-As in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild type littermates. Mechanistically EphA2 knockdown suppressed stem properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem properties in a kinase-independent manner and increased Sox2 expression. In addition to suppressing invasion, disrupting Akt-EphA2 crosstalk attenuated stem marker expression and neurosphere formation while having minimal effects on tumorigenesis, suggesting that the Akt-EphA2 signaling axis contributes to the stem properties. Taken together, the results show that EphA2 endows invasiveness of GSCs in vivo in cooperation with Akt and contributes to the maintenance of stem properties.
Effects of composition on the formation temperatures and electrical resistivities of C54 titanium germanosilicide in Ti–Si1−xGex systems (1999)

The effects of alloy composition on the formation temperature and electrical resistivities of C54 titanium germanosilicide formed during the Ti/Si1−xGex (x=0, 0.3, 0.4, 0.7, 1) solid state reaction have been investigated. Ti5(Si1−yGey)3, C49– and C54–Ti(Si1−zGez)2 were observed to form in the Ti/Si1−xGex (x⩾0.4) systems. On the other hand, Ti6(Si1−yGey)5 and C54–Ti(Si1−zGez)2 were found in the Ti/Si1−xGex (x≧0.7) systems. For both cases, the relationship of x&amp;gt;y&amp;gt;z was found. The appearance and agglomeration temperature of low-resistivity C54–Ti(Si1−zGez)2 were both found to decrease with the Ge concentration. The resistivities of C54–Ti(Si1−zGez)2 were measured to be 15–20 μΩ/cm. The segregation of Si1−wGew (w&amp;gt;x) was found in all samples annealed above 800 °C. The effects of thermodynamic driving force, kinetic factor, and composition of the micro-area are discussed.