gebhart/patrepeval huggingface dataset:
The discovery of finger loop inhibitors of the hepatitis C virus NS5B polymerase: status and prospects for novel HCV therapeutics. (2006)

Millions of people worldwide are infected with the hepatitis C virus (HCV), for which the main current therapy is associated with severe side effects, limited efficacy, is contraindicated in many patients, and has issues of compliance. As a result, new HCV therapies that are more effective and better tolerated are required. This review describes the discovery of a new class of allosteric, non-nucleoside HCV polymerase inhibitors that demonstrate potential for the development of novel anti-HCV therapeutics.
Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing (2003)

As dominant regulators of osteoclastogenesis and bone resorption, receptor activator of NFkappaB (RANK), receptor activator of NFkappaB ligand, and OPG have been identified as ideal drug targets for the treatment of metabolic bone disease. One concern regarding the therapeutic use of RANK signaling inhibitors is their effect on fracture healing. Therefore we tested if uncoupling and osteoclast depletion via RANK blockade affects callus formation, maturation and matrix remodeling, as well as union rates in a mouse tibia fracture model. Low dose (1 mg/kg i.p.) RANK:Fc therapy had no effect on callus formation, matrix maturation and remodeling, and resulted in 100% bony union by day 28. High dose RANK:Fc treatment (10 mg/kg i.p.) effectively eliminated osteoclasts at the fracture site on day 14, with no significant effects on fracture healing. When therapy was discontinued, normal numbers of osteoclasts were observed at the fracture site by day 28. However, continuous therapy resulted in a large osteopetrotic callus consisting of both mineralized and unmineralized matrix that was void of osteoclasts, but bony union was unaffected at day 28. We also evaluated this process in the complete absence of RANK signaling using RANK -/- mice. These animals exhibited significant radiographic and histologic evidence of callus formation, indicating that RANK signaling is not required for fracture callus formation. However, only 33% of RANK -/- animals formed bony unions compared to 100% of the osteopetrotic control mice. This defect was most likely a result of decreased blood flow, as evidenced by fewer blood vessels in the RANK -/- animals. Together, these data imply that osteoclast depletion via inhibition of RANK signaling is a viable option for the treatment of pathological bone loss since no adverse effects on fracture healing are observed when therapy is discontinued.
Nonviral Vectors in the New Millennium: Delivery Barriers in Gene Transfer (2001)

Development of an efficient method for introducing a therapeutic gene into target cells in vivo is the key issue in treating genetic and acquired diseases by gene therapy. To this end, various nonviral vectors have been designed and developed, and some of them are in clinical trials. The simplest approach is naked DNA injection into local tissues or systemic circulation. Physical (gene gun, electroporation) and chemical (cationic lipid or polymer) approaches have also been utilized to improve the efficiency and target cell specificity of gene transfer by plasmid DNA. After administration, however, nonviral vectors encounter many hurdles that result in diminished gene transfer in target cells. Cationic vectors sometimes attract serum proteins and blood cells when entering into blood circulation, which results in dynamic changes in their physicochemical properties. To reach target cells, nonviral vectors should pass through the capillaries, avoid recognition by mononuclear phagocytes, emerge from the blood vessels to the interstitium, and bind to the surface of the target cells. They then need to be internalized, escape from endosomes, and then find a way to the nucleus, avoiding cytoplasmic degradation. Successful clinical applications of nonviral vectors will rely on a better understanding of barriers in gene transfer and development of vectors that can overcome these barriers.
5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. (1999)

It has previously been reported that exercise causes an increase in glucose uptake in skeletal muscle and also an increase in 5' AMP-activated protein kinase (AMPK) activity. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICA-riboside), an analog of adenosine, is taken up into cells and phosphorylated to form AICA-riboside monophosphate (ZMP), which can also activate AMPK. This study was designed to determine whether the increase in glucose uptake observed with AMPK activation by AICA-riboside is due to GLUT4 translocation from an intracellular location to the plasma membranes, similar to that seen in response to contraction. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine erythrocytes, 8 mmol/l glucose, and +/-2 mmol/AICA-riboside or +/-60 nmol/l insulin. Perfusion medium containing AICA-riboside was found to significantly increase AMPK activity, glucose uptake, and GLUT4 translocation in skeletal muscle above basal levels. Insulin-perfused muscles showed significant increases in glucose uptake and GLUT4 translocation, but AMPK activation was not significantly changed from basal levels. These results provide evidence that the increased glucose uptake observed with AMPK activation by AICA-riboside in perfused rat hindlimb muscles is due to an increase in the translocation of GLUT4 to surface membranes.
A study of retrospective and on-line event detection (1998)

Article Free Access Share on A study of retrospective and on-line event detection Authors: Yiming Yang School of Computer Science, Carnegie Mellon University, Pittsburgh, PA School of Computer Science, Carnegie Mellon University, Pittsburgh, PAView Profile , Tom Pierce School of Computer Science, Carnegie Mellon University, Pittsburgh, PA School of Computer Science, Carnegie Mellon University, Pittsburgh, PAView Profile , Jaime Carbonell School of Computer Science, Carnegie Mellon University, Pittsburgh, PA School of Computer Science, Carnegie Mellon University, Pittsburgh, PAView Profile Authors Info & Claims SIGIR '98: Proceedings of the 21st annual international ACM SIGIR conference on Research and development in information retrievalAugust 1998 Pages 28–36https://doi.org/10.1145/290941.290953Published:01 August 1998Publication History 488citation3,380DownloadsMetricsTotal Citations488Total Downloads3,380Last 12 Months171Last 6 weeks18 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteeReaderPDF
Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. (1966)

Understanding the biological basis of social anxiety disorder (SAD), one of the most disabling of the anxiety disorders, will allow for novel treatment strategies to be developed. Here, we show that gut microbiota may be such a target. Mice ...Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut ...
Tyrosine hydroxylase Val-81-Met polymorphism associated with early-onset alcoholism (2005)

The present study examined the association of the Tyrosine hydroxylase Val-81-Met polymorphism with alcohol dependence. One hundred and fifty-nine patients in a psychiatric unit with alcohol dependence were genotyped as well as 92 healthy volunteers. The Val allele was more frequent in patients with alcohol dependence (69.5%) than in controls (62.5%). This effect was largely due to the association with early-onset alcoholism (77.8%), whereas no difference was noted between late-onset patients and controls. Our results suggest a role for tyrosine hydroxylase in early-onset alcoholism.
Activity of human 11-cis-retinol dehydrogenase (Rdh5) with steroids and retinoids and expression of its mRNA in extra-ocular human tissue (1999)

This report describes the activity of recombinant human Rdh5 (11-cis-retinol dehydrogenase) with steroids and retinoids and expression of the Rdh5 mRNA in extra-ocular human tissue. The data show that Rdh5 catalyses 9-cis-retinol metabolism equally efficiently as 11-cis-retinol metabolism and recognizes 5α-androstan-3α,17β-diol and androsterone as substrates (3α-hydroxysteroid dehydrogenase activity), but not testosterone, dihydrotestosterone, oestradiol and corticosterone (lack of 17β-hydroxysteroid and 11β-hydroxysteroid dehydrogenase activities). Rdh5 mRNA expression was widespread in extra-ocular tissues with human liver (100% relative expression in extra-ocular tissues only) and mammary gland (97% relative to liver) showing the most intense signals. Other noteworthy relatively intense expression sites included colon (45%), thymus (43%), small intestine (39%), kidney (37%), bladder (29%), pancreas and spleen (28% each), heart (26%), uterus and ovary (25% each), testis (22%) and spinal cord (24%). Human fetal tissues also expressed Rdh5 with fetal liver showing the most intense expression among the fetal tissues (20%). Considered along with the identical nucleotide sequences in the untranslated regions of human Rdh5 and human 9-cis-retinol dehydrogenase cDNAs and the nearly identical nucleotide sequences overall (99% identity), the current results suggest that the two cDNAs represent a single gene product.
Two‐Color Two‐Photon Excitation of Fluorescence (1996)

We report the observation of two-photon excitation of an organic fluorophore with two different wavelengths, a phenomenon we refer to as two-color two-photon (2C2P) excitation. Ultraviolet emission of p-terphenyl at 340 nm was observed when the sample was illuminated with both 375 and 750 nm pulses from a picosecond dye laser. The emission of p-terphenyl was about 100-fold and more than 1000-fold less for illumination at only 375 or 750 nm, respectively. Observation of the 2C2P signal required temporal and spatial overlap of the 375 and 750 nm pulses. The amplitude of the signal depended on the polarization of each beam. 2C2P excitation can have applications in fluorescence microscopy and elsewhere when spatially localized excitation is desirable.
Sensor fusion for mobile robot dead-reckoning with a precision-calibrated fiber optic gyroscope (2002)

Fiber optic gyros with very low drift rates have become available and affordable. Because of their low drift rate attention is warranted to sources of errors that were previously considered as of secondary importance. In the KVH E-Core RD2100 gyros, we found that the temperature dependency and the non-linearity of the scale-factor caused significant errors. A precision calibration procedure, described in the paper, reduces the resulting errors by one order of magnitude. In addition to the calibration procedure, we integrated the gyro with the odometry system of a four-wheel drive, skid-steer Pioneer AT mobile robot by means of an indirect feedback Kalman filter that fuses the sensor data from both sensor modalities. Based on our experimental results the paper compares the relative effectiveness of both enhancements (precision gyro calibration and Kalman filter).
Direkte Synthese von Trifluormethylketonen aus Carbonsäureestern: Trifluormethylierung mit Trimethyl(trifluormethyl)silan (1998)

Bisher schwer zugängliche aliphatische und alicyclische Trifluormethylketone, die als potentielle Enzyminhibitoren pharmakologisch interessant sind, z. B. 1 bzw. 2, können jetzt einfach und effizient synthetisiert werden. Ausgehend von Carbonsäureestern und Trimethyl(trifluormethyl)silan wird die einstufige Reaktion in unpolaren, aprotischen Lösungsmitteln durch Tetrabutylammoniumfluorid induziert und verläuft ohne Bildung von Doppeladditionsprodukten.
Two-dimensional Scanning Tactile Display using Ultrasound Radiation Pressure (2006)

In this paper, we propose a new tactile display which produces spatio-temporal stress patterns on a 2-D plane. The first prototype of the display consists of an octagonal arrangement of ultrasound linear arrays. Each array has 40 pieces of PZT(lead zirconate titanate) transducer. The 320 channel driving circuit was designed to produce 1000 frames of 2-D stress patterns per second. The 2-D stress patterns can cover 1cm by 1cm area. Simulation studies were carried out to examine the adequacy of the proposed design. It showed that the octagonal arrangement can produce a well-focused force spot to be scanned in the display area. The results were satisfactory compared to other polygonal arrangement. Several initial results on the 2-D prototype are also discussed.
Development of a18F‐Labeled Tetrazine with Favorable Pharmacokinetics for Bioorthogonal PET Imaging (2014)

A low-molecular-weight (18) F-labeled tetrazine derivative was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of (18) F through additional steps were evaded by direct (18) F-fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddition with trans-cyclooctenes were investigated by applying quantum chemical calculations and stopped-flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile-tagged (bio)molecules. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the (18) F-labeled tetrazine that also passes the blood-brain barrier. An in vivo click experiment confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chemical and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research.
Mouse Models of Insulin Resistance (2004)

Insulin resistance plays a key role in the pathogenesis of several human diseases, including diabetes, obesity, hypertension, and cardiovascular diseases. The predisposition to insulin resistance results from genetic and environmental factors. The search for gene variants that predispose to insulin resistance has been thwarted by its genetically heterogeneous pathogenesis. However, using techniques of targeted mutagenesis and transgenesis in rodents, investigators have developed mouse models to test critical hypotheses on the pathogenesis of insulin resistance. Moreover, experimental crosses among mutant mice have shed light onto the polygenic nature of the interactions underlying this complex metabolic condition.
A link between double-strand break-related repair and V(D)J recombination: the scid mutation. (1991)

We show here that mammalian site-specific recombination and DNA-repair pathways share a common factor. The effects of DNA-damaging agents on cell lines derived from mice homozygous for the scid (severe combined immune deficiency) mutation were studied. Surprisingly, all scid cell lines exhibited a profound hypersensitivity to DNA-damaging agents that caused double-strand breaks (x-irradiation and bleomycin) but not to other chemicals that caused single-strand breaks or cross-links. Neutral filter elution assays demonstrated that the x-irradiation hypersensitivity could be correlated with a deficiency in repairing double-strand breaks. These data suggest that the scid gene product is involved in two pathways: DNA repair of random double-strand breaks and the site-specific and lymphoid-restricted variable-(diversity)-joining [V(D)J] DNA rearrangement process. We propose that the scid gene product performs a similar function in both pathways and may be a ubiquitous protein.
Insulin-Like Growth Factor Binding Protein-1 Is Elevated in Patients With Polycythemia Vera and Stimulates Erythroid Burst Formation In Vitro (1997)

Previously, we found that, in the myeloproliferative disorder polycythemia vera (PV), circulating erythroid progenitor cells were hypersensitive to insulin-like growth factor I (IGF-I), an effect shown to occur through the IGF-I receptor. Also, in cells of PV patients, the IGF-I receptor was hyperphosphorylated on tyrosine residues under basal conditions, and its tyrosine phosphorylation in response to exogenous IGF-I was strongly augmented. Thus, because IGF-I appeared to play a role in the pathogenesis of PV, we wished to assess its level in the circulation of these patients. Normally, most of the circulating IGF-I is bound to specific high-affinity IGF binding proteins that can regulate its activity. We determined the circulating levels of IGF-I and two of its key binding proteins, IGFBP-1 and IGFBP-3. In two separate experiments, plasma samples from a total of 23 PV patients age- and sex-matched with 41 normal individuals were compared by radioimmunoassay. The levels of IGFBP-1 in patients with PV (37.80 +/- 4.33 microg/L) were more than fourfold higher than in normals (9.34 +/- 1.34 microg/L) or patients with secondary erythrocytosis (9.47 +/- 1.96 microg/L), whereas the plasma concentrations of IGFBP-3 and IGF-I in these patients were similar to those of normal subjects. Because circulating IGFBP-1 levels may be influenced by insulin, we measured the concentrations of insulin in the same samples. Our data showed that the elevation of circulating IGFBP-1 in PV could not be attributed to low levels of insulin in these patients. The substantial increase in concentration of IGFBP-1 was confirmed on ligand blots performed with (125)I-IGF-I. IGFBP-1 can be either inhibitory or stimulatory to the action of IGF-I under different conditions. We reasoned that if IGFBP-1 were stimulatory for erythropoiesis, an elevated IGFBP-1 level could help to explain the increased sensitivity to IGF-I observed in PV. If IGFBP-1 were inhibitory, it might suggest a compensatory mechanism in which a hyperphosphorylated IGF-I receptor in PV might induce a negative modulator of IGF-I action, in this case IGFBP-1. To distinguish between these two hypotheses, we titrated the effect of IGFBP-1 in the presence of IGF-I with respect to erythroid burst formation and found that IGFBP-1 was strikingly stimulatory. The elevated level of IGFBP-1 coupled with its ability to stimulate erythroid burst formation provide an attractive mechanism to account for the increased sensitivity of erythroid progenitor cells to IGF-I and the consequent overproduction of red blood cells characteristic of PV.
CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes (2015)

Since Río-Hortega's description of oligodendrocyte morphologies nearly a century ago, many studies have observed myelin sheath-length diversity between CNS regions. Myelin sheath length directly impacts axonal conduction velocity by influencing the spacing between nodes of Ranvier. Such differences likely affect neural signal coordination and synchronization. What accounts for regional differences in myelin sheath lengths is unknown; are myelin sheath lengths determined solely by axons or do intrinsic properties of different oligodendrocyte precursor cell populations affect length? The prevailing view is that axons provide molecular cues necessary for oligodendrocyte myelination and appropriate sheath lengths. This view is based upon the observation that axon diameters correlate with myelin sheath length, as well as reports that PNS axonal neuregulin-1 type III regulates the initiation and properties of Schwann cell myelin sheaths. However, in the CNS, no such instructive molecules have been shown to be required, and increasing in vitro evidence supports an oligodendrocyte-driven, neuron-independent ability to differentiate and form initial sheaths. We test this alternative signal-independent hypothesis--that variation in internode lengths reflects regional oligodendrocyte-intrinsic properties. Using microfibers, we find that oligodendrocytes have a remarkable ability to self-regulate the formation of compact, multilamellar myelin and generate sheaths of physiological length. Our results show that oligodendrocytes respond to fiber diameters and that spinal cord oligodendrocytes generate longer sheaths than cortical oligodendrocytes on fibers, co-cultures, and explants, revealing that oligodendrocytes have regional identity and generate different sheath lengths that mirror internodes in vivo.
Direct Air Capture of CO2 with an Amine Resin: A Molecular Modeling Study of the CO2 Capturing Process (2017)

Several reactions, known from other amine systems for CO<sub>2</sub> capture, have been proposed for Lewatit R VP OC 1065. The aim of this molecular modeling study is to elucidate the CO<sub>2</sub> capture process: the physisorption process prior to the CO<sub>2</sub>-capture and the reactions. Molecular modeling yields that the resin has a structure with benzyl amine groups on alternating positions in close vicinity of each other. Based on this structure, the preferred adsorption mode of CO<sub>2</sub> and H<sub>2</sub>O was established. Next, using standard Density Functional Theory two catalytic reactions responsible for the actual CO<sub>2</sub> capture were identified: direct amine and amine-H<sub>2</sub>O catalyzed formation of carbamic acid. The latter is a new type of catalysis. Other reactions are unlikely. Quantitative verification of the molecular modeling results with known experimental CO<sub>2</sub> adsorption isotherms, applying a dual site Langmuir adsorption isotherm model, further supports all results of this molecular modeling study.
Co-Stimulation through 4-1BB/CD137 Improves the Expansion and Function of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy (2013)

Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the "rapid expansion protocol" (REP) were not designed to enhance the generation of optimal effector-memory CD8(+) T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8(+) effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8(+) T cells, on the yield, phenotype, and functional activity of expanded CD8(+) T cells during the REP. We found that CD8(+) TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8(+) T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8(+) post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8(+) T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.