gebhart/patrepeval huggingface dataset:
The Vesicular Stomatitis Virus Matrix Protein Inhibits Glycoprotein 130-Dependent STAT Activation (2001)

Infection of cells by vesicular stomatitis virus (VSV) results in the inhibition of host transcription. We show in this study that infection of HeLa cells with VSV leads to a strongly diminished activation of STAT3 and STAT1 by the inflammatory cytokine IL-6. This effect was mimicked by forced expression of a single viral protein, the matrix (M)-protein of VSV, which blocked STAT activation via chimeric receptors containing the cytoplasmic domain of the IL-6 signal transducer gp130. Western blot analysis revealed that VSV M-protein did not inhibit the nuclear translocation of activated STAT3 but did inhibit its tyrosine phosphorylation. Inhibition of STAT activation was not dependent on tyrosine 759 of the IL-6 signal transducer gp130, suggesting that the inhibitory action of VSV M-protein is not mediated by the induction of the suppressor of cytokine signaling 3. VSV M-protein inhibited gene transcription from cotransfected alpha(2)-macroglobulin or antichymotrypsin promoter/luciferase reporter constructs which contain STAT3-binding sites. However, transcription from a STAT5-dependent construct was not negatively affected. In conclusion, our data suggest that infection by VSV and specifically overexpression of the viral M-protein interferes with an important signaling pathway necessary for triggering antiviral and inflammatory responses.
Nonviral Methods for siRNA Delivery (2008)

RNA interference (RNAi) as a mechanism to selectively degrade mRNA (mRNA) expression has emerged as a potential novel approach for drug target validation and the study of functional genomics. Small interfering RNAs (siRNA) therapeutics has developed rapidly and already there are clinical trials ongoing or planned. Although other challenges remain, delivery strategies for siRNA become the main hurdle that must be resolved prior to the full-scale clinical development of siRNA therapeutics. This review provides an overview of the current delivery strategies for synthetic siRNA, focusing on the targeted, self-assembled nanoparticles which show potential to become a useful and efficient tool in cancer therapy.
Development of a Companion Diagnostic PD-L1 Immunohistochemistry Assay for Pembrolizumab Therapy in Non–Small-cell Lung Cancer (2016)

A companion diagnostic assay was codeveloped by Dako for pembrolizumab non-small-cell lung cancer clinical trials to detect PD-L1 expression by immunohistochemistry (IHC). This automated IHC assay has been analytically verified and validated using Dako's autostainer Link 48 and 22C3 mouse anti-PD-L1 monoclonal antibody to detect the PD-L1 expression in formalin-fixed paraffin-embedded human tumor tissue specimens. The PD-L1 22C3 IHC assay was optimized for high sensitivity and specificity. Repeatability and reproducibility studies were conducted at Dako and at 3 Clinical Laboratory Improvement Amendments certified laboratories during assay development. The studies included: intersite and intrasite, interobserver and intraobserver, interinstrument, interoperator, interday, and interlot, and intraday and intrarun. All precision studies performed at Dako and external laboratories achieved >85% point-estimate agreements for all 3 agreement types (negative, positive, and overall). A clinical cutoff (tumor proportion score ≥50%) of PD-L1 expression was determined and evaluated through a phase 1 clinical trial (KEYNOTE-001) for advanced non-small-cell lung cancer patients treated with pembrolizumab. The treatment effect of pembrolizumab in the 61 subjects who had a tumor PD-L1 of tumor proportion score ≥50% was substantial, with an overall response rate of 41% (95% confidence interval, 28.6-54.3) as compared with 20.6% (95% confidence interval, 15.5-26.5) observed in the 223 subjects irrespective of PD-L1 status. PD-L1 IHC 22C3 pharmDx is a sensitive, precise, and robust companion diagnostic assay, which will facilitate safe and effective use for pembrolizumab in cancer patients.
Muscle Perfusion after Intramedullary Nailing of the Canine Tibia (1998)

The results of this study demonstrate that in the presence of an intact soft-tissue envelope, intramedullary reaming of the canine tibia has a major effect on increasing the circulation to the surrounding muscles. The increased extraosseous circulation may have implications for fracture healing.
Boxer: a reconstructible computational medium (1986)

Programming is most often viewed as a way for experts to get computers to perform complex tasks efficiently and reliably. Boxer presents an alternative image—programming as a way for nonexperts to control a reconstructible medium, much like written language, but with dramatically extended interactive capabilities.
Bi-i: a standalone ultra high speed cellular vision system (2005)

The Bi-i standalone cellular vision system is introduced and discussed. In the first part, the underlying sensor and system level architectures are presented and various implementations are overviewed. This computing platform consists of state-of-the-art sensing, cellular sensing-processing, digital signal processing and communication devices that make it possible to use the system as an ideal computing platform for combined topographic and non-topographic calculations in sensing-processing-actuation scenarios. In the second part of the paper, ultra-high frame rate laboratory experiments are shown and discussed to highlight the most peculiar features of the system and its applicability in various industrial quality control areas. The overview underlines the potentials of the Bi-i vision system for unmanned intelligent vehicle applications in visual exploration, identification, tracking and navigation.
Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery (2018)

Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to ‘backpack’ large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface–conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.
Local Delivery of Basic Fibroblast Growth Factor (bFGF) Using Adsorbed Silyl-heparin, Benzyl-bis(dimethylsilylmethyl)oxycarbamoyl-heparin (2002)

A growth factor delivery system was developed that is based on the use of silyl-heparin, a chemically modified analogue of heparin. The silyl-heparin was adsorbed onto surfaces by hydrophobic interaction via the prosthetic unit and can then be used as a solid-phase adsorbent for bFGF. All the coating steps were performed by adsorption, a process that allowed preparation of surfaces by immersion or "dip-coating". In this study a series of silyl-heparins were synthesized and each of the analogues found to function similar to unmodified heparin relative to their binding of antithrombin III and also the binding of bFGF. The silyl-heparins were found to be adsorbed onto a wide variety of substrates including polystyrene and lactide:glycolide copolymer. Enzyme-linked immumosorbant assay (ELISA) was used to establish that bFGF was readily bound to surface adsorbed silyl-heparin, and that the amount bound was directly related to amount offered for binding. Once adsorbed the silyl-heparin/FGF was able to induce capillary tube formation of endothelial cells and to increase the growth of endothelial cells. When coated onto suture material and implanted in muscle, the FGF/silyl-heparin coating caused an increased density of mesenchymal cells in the area of the implant. This coating method could prove to be useful in a number of tissue engineering applications for the local delivery of FGF and other growth factors.
T-Cell Responses to CD1-Presented Lipid Antigens in Humans with Mycobacterium tuberculosis Infection (2003)

CD1-restricted presentation of lipid or glycolipid antigens derived from Mycobacterium tuberculosis has been demonstrated by in vitro experiments using cultured T-cell lines. In the present work, the frequency of T-cell responses to natural mycobacterial lipids was analyzed in ex vivo studies of peripheral blood lymphocytes from human patients with pulmonary tuberculosis, from asymptomatic individuals with known contact with M. tuberculosis documented by conversion of their tuberculin skin tests, and from healthy tuberculin skin test-negative individuals or individuals vaccinated with Mycobacterium bovis BCG. Proliferation and gamma interferon enzyme-linked immunospot assays using peripheral blood lymphocytes and autologous CD1(+) immature dendritic cells revealed that T cells from asymptomatic M. tuberculosis-infected donors responded with significantly greater magnitude and frequency to mycobacterial lipid antigen preparations than lymphocytes from uninfected healthy donors. By use of these methods, lipid-antigen-specific proliferative responses were minimally detectable or absent in blood samples from patients with active tuberculosis prior to chemotherapy but became detectable in blood samples drawn 2 weeks after the start of treatment. Lipid antigen-reactive T cells were detected predominantly in the CD4-enriched T-cell fractions of circulating lymphocytes, and anti-CD1 antibody blocking experiments confirmed the CD1 restriction of these T-cell responses. Our results provide further support for the hypothesis that lipid antigens serve as targets of the recall response to M. tuberculosis, and they indicate that CD1-restricted T cells responding to these antigens comprise a significant portion of the circulating pool of M. tuberculosis-reactive T cells in healthy individuals with previous exposure to M. tuberculosis.
Cyclooxygenase-2 Inhibitors. Synthesis and Pharmacological Activities of 5-Methanesulfonamido-1-indanone Derivatives (1995)

The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.
Vertical MOS transistors with 70 nm channel length (1996)

Vertical nMOS transistors with channel lengths down to 70 nm and thin gate oxides have been fabricated using LPCVD epitaxy for the definition of the channel region instead of fine line lithography. The devices show drain current and transconductance values comparable to very advanced planar transistors. For the shortest channel length a very strong increase of saturation current is observed and is attributed to V/sub t/ shift and floating substrate effects. Moreover, transconductance may indicate ballistic overshoot. Besides high saturation currents due to very short channel lengths higher integration density seems to be very attractive for special applications.
Bacterial RNA Chaperones Confer Abiotic Stress Tolerance in Plants and Improved Grain Yield in Maize under Water-Limited Conditions (2008)

Limited available water is the single most important factor that reduces global crop yields, with far reaching socioeconomic implications. In North America alone, it is estimated that 40% of yearly maize ( Zea mays ) crop losses are due to suboptimal water availability ([Boyer, 1982][1]).
Multi-level ray tracing algorithm (2005)

We propose new approaches to ray tracing that greatly reduce the required number of operations while strictly preserving the geometrical correctness of the solution. A hierarchical "beam" structure serves as a proxy for a collection of rays. It is tested against a kd-tree representing the overall scene in order to discard from consideration the sub-set of the kd-tree (and hence the scene) that is guaranteed not to intersect with any possible ray inside the beam. This allows for all the rays inside the beam to start traversing the tree from some node deep inside thus eliminating unnecessary operations. The original beam can be further sub-divided, and we can either continue looking for new optimal entry points for the sub-beams, or we can decompose the beam into individual rays. This is a hierarchical process that can be adapted to the geometrical complexity of a particular view direction allowing for efficient geometric anti-aliasing. By amortizing the cost of partially traversing the tree for all the rays in a beam, up to an order of magnitude performance improvement can be achieved enabling interactivity for complex scenes on ordinary desktop machines.
Molecular cloning and characterization of genes required for ribose transport and utilization in Escherichia coli K-12 (1984)

We isolated spontaneous and transposon insertion mutants of Escherichia coli K-12 that were specifically defective in utilization or in high-affinity transport of D-ribose (or in both). Cotransduction studies located all of the mutations near ilv, at the same position as previously identified mutations causing defects in ribokinase ( rbsK ) or ribose transport ( rbsP ). Plasmids that complemented the rbs mutations were isolated from the collection of ColE1 hybrid plasmids constructed by Clarke and Carbon. Analysis of those plasmids as well as of fragments cloned into pBR322 and pACYC184 allowed definition of the rbs region. Products of rbs genes were identified by examination of the proteins produced in minicells containing various rbs plasmids. We identified four rbs genes: rbsB , which codes for the 29-kilodalton ribose-binding protein; rbsK , which codes for the 34-kilodalton ribokinase ; rbsA , which codes for a 50-kilodalton protein required for high-affinity transport; and rbsC , which codes for a 27-kilodalton protein likely to be a transport system component. Our studies showed that these genes are transcribed from a common promoter in the order rbsA rbsC rbsB rbsK . It appears that the high-affinity transport system for ribose consists of the three components, ribose-binding protein, the 50-kilodalton RbsA protein, and the 27-kilodalton RbsC protein, although a fourth, unidentified component could exist. Mutants defective in this transport system, but normal for ribokinase , are able to grow normally on high concentrations of the sugar, indicating that there is at least a second, low-affinity transport system for ribose in E. coli K-12.
Functional analysis of an individual IFT protein: IFT46 is required for transport of outer dynein arms into flagella (2007)

Intraflagellar transport (IFT), which is the bidirectional movement of particles within flagella, is required for flagellar assembly. IFT particles are composed of approximately 16 proteins, which are organized into complexes A and B. We have cloned Chlamydomonas reinhardtii and mouse IFT46, and show that IFT46 is a highly conserved complex B protein in both organisms. A C. reinhardtii insertional mutant null for IFT46 has short, paralyzed flagella lacking dynein arms and with central pair defects. The mutant has greatly reduced levels of most complex B proteins, indicating that IFT46 is necessary for complex B stability. A partial suppressor mutation restores flagellar length to the ift46 mutant. IFT46 is still absent, but levels of the other IFT particle proteins are largely restored, indicating that complex B is stabilized in the suppressed strain. Axonemal ultrastructure is restored, except that the outer arms are still missing, although outer arm subunits are present in the cytoplasm. Thus, IFT46 is specifically required for transporting outer arms into the flagellum.
New-generation projection optics for ArF lithography (2002)

We have developed an ArF scanner with 0.7NA, the FPA- 5000AS2, to meet the requirements of the semiconductor industry. The biggest improvement of this system from the previous model is its projection optics. The new projection lens design allows residual aberrations to be extremely small in order to satisfy the requirements of increasingly severe device production. Furthermore, the aberrations derived from the manufacturing process are minimized in the same manner as conventional i-line and KrF lenses by precisely measuring them with a phase measuring interferometer (PMI). To reduce manufacturing-induced aberrations, we calculate various components of imaging performance at each lens manufacturing process and feed them back to the tuning process. Focusing only on aberration in the expression of root mean square (RMS) can never be sufficient for optimal aberration reduction. Lens performance can be optimally improved by gaining a balance among Zernike terms, which represent aberrations, for critical dimensions of various device patterns. It helps us supply users with a projection lens having performance that meets their requirements. This paper reports on the imaging performance of the new lens for both static and dynamic exposure as well as simulation results using PMI data. It also presents the mechanical barrel system that holds the high performance projection lens, intrinsic birefringence (IBR) of CaF<SUB>2</SUB>, and leading-edge ArF lens technologies such as chemical clean technology. And imaging performance of the newest 0.75 NAArF projection lens is demonstrated.
Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children, 1965. II. (1966)

Standards: Chronological Age-based and Individual Type We now consider how to construct velocity standards, to answer our second question 'Has this child's rate of growth been within normal limits ?' We are again confronted with the alternatives of plotting against chronological or developmental age at adolescence and we have adopted the same solution as before. First we give, in the conven- tional manner, centiles plotted against chrono- logical age, over the whole age span. These are calculated simply from two measurements a year apart, without using further longitudinal data. They depend on a two-occasion longitudinal study, nothing further. At adolescence these standards are greatly scattered by the phase-difference effect. If we know nothing about a boy except that he is 12 years old and grew 3 cm. during the last year, we must plot 3 cm. at 11 * 5 years and interpret this according to the chronological age centiles. If, however, we know that he is mid- pubescent, or that his skeletal age is 14 * 0 years, then in theory we could make a more effective interpretation if we had the appropriate standards.
Review Article: New insights into the mechanisms of hepatic transport and bile secretion (1996)

The transport processes responsible for bile flow are reviewed. Canalicular bile acid-dependent flow is the result of active transport of bile acids by the hepatocyte into bile canaliculi. Bile acids are taken up by at least two transport systems whose mRNA have been expressed in Xenopus oocytes: (i) a Na(+)-dependent system, named NTCP, and (ii) a Na(+)- independent system, named OATP. Bile acids are then secreted into bile by two other transport systems, an ATP-dependent system and an 'electrogenic' voltage-dependent system. It is not known whether these two systems are mediated by the same protein or by two different proteins. Canalicular bile acid-independent flow is mainly the result of the secretion of glutathione into bile. The canalicular membrane also contains several proteins of the multi drug resistance (MDR) family. MDRI is responsible for biliary secretion of cationic drugs. MDR3 (mdr 2 in mice) plays a major role in the secretion of phospholipids. A third MDR-related protein has been shown recently to be the canalicular carrier of organic anions, such as bilirubin and dyes (the canalicular multiple organic anion transporter, or cMOAT). Biliary epithelial cells secrete a bicarbonate-rich solution, mostly in response to secretin. This secretion depends upon the presence, on the apical membrane of these cells of the CFTR, a chloride channel activated by cAMP and of a chloride/bicarbonate exchanger. Knowledge of these transport systems should allow a better understanding of the mechanisms involved in cholestasis.
A Unique Chemoenzymatic Synthesis of α-Galactosyl Epitope Derivatives Containing Free Amino Groups:  Efficient Separation and Further Manipulation (1999)

A novel chemoenzymatic approach for the synthesis of oligosacchrides containing free amino groups has been developed in which thermophilic glycosidases and a fusion enzyme containing catalytic domains of uridine-5‘-diphospho-galactose 4-epimerase and α(1→3) galactosyltransferase were used. This methodology, in conjunction with a convenient purification procedure employing ion exchange chromatography, facilitates the lengthy and high-cost process of carbohydrate synthesis. The prepared oligosaccharides range from disaccharide lactosamine (1a), trisaccharide α-Gal-(1→3)-β-Gal-(1→4)-GlcNH2 (2), tetrasaccharide β-Gal-(1→4)-β-GlcNH2-(1→3)-β-Gal-(1→4)-β-Glc-N3 (7), to pentasaccharide α-Gal-(1→3)-β-Gal-(1→4)-β-GlcNH2-(1→3)-β-Gal-(1→4)-β-Glc-N3 (15). Compounds 2 and 15 are derivatives of natural α-Gal epitopes. Both of them have shown comparable activities with their natural parent compounds toward human anti-Gal IgG. This method provides a practical approach for the preparation and purification of oligosaccharides containing free amino groups, which can be further derivatized for the enhancement of biological activities.
Caspase cleavage of members of the amyloid precursor family of proteins (2002)

The synapse loss and neuronal cell death characteristic of Alzheimer's disease (AD) are believed to result in large part from the neurotoxic effects of beta-amyloid peptide (Abeta), a 40-42 amino acid peptide(s) derived proteolytically from beta-amyloid precursor protein (APP). However, APP is also cleaved intracellularly to generate a second cytotoxic peptide, C31, and this cleavage event occurs in vivo as well as in vitro and preferentially in the brains of AD patients (Lu et al. 2000). Here we show that APPC31 is toxic to neurons in primary culture, and that like APP, the APP family members APLP1 and possibly APLP2 are cleaved by caspases at their C-termini. The carboxy-terminal peptide derived from caspase cleavage of APLP1 shows a degree of neurotoxicity comparable to APPC31. Our results suggest that even though APLP1 and APLP2 cannot generate Abeta, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31.