gebhart/patrepeval huggingface dataset:
Retinoblastoma protein family in cell cycle and cancer: A review (1996)

Two genes, p107 and Rb2/p130, are strictly related to RB, the most investigated tumor suppressor gene, responsible for susceptibility to retinoblastoma. The products of these three genes, namely pRb, p107, and pRb2/p130 are characterized by a peculiar steric conformation, called "pocket," responsible for most of the functional interactions characterizing the activity of these proteins in the homeostasis of the cell cycle. The interest in these genes and proteins springs from their ability to regulate cell cycle processes negatively, being able, for example, to dramatically slow down neoplastic growth. So far, among these genes, only RB is firmly established to act as a tumor suppressor, because its lack-of-function is clearly involved in tumor onset and progression. It has been found deleted or mutated in most retinoblastomas and sarcomas, but its inactivation is likely to play a crucial role in other types of human cancers. The two other members of the family have been discovered more recently and are currently under extensive investigation. We review analogies and differences among the pocket protein family members, in an attempt to understand their functions in normal and cancer cells.
Oxo/Imido Heterometathesis Reactions Catalyzed by a Silica-Supported Tantalum Imido Complex (2013)

Grafting Ta(═NtBu)(CH2CMe2Ph)3 onto the surface of silica partially dehydroxylated at 300 °C leads to the formation of the surface imido complex (≡SiO)2Ta(═NtBu)(CH2CMe2Ph) as a major species, which was characterized with EXAFS, 13C CP/MAS NMR, diffuse reflectance FTIR, elemental analyses, and chemical reactivity. The obtained material acts as an efficient heterogeneous catalyst for various oxo/imido heterometathesis transformations: imidation of ketones and DMF with N-sulfinylamines and condensation of N-sulfinylamines into sulfurdiimines and phenyl isocyanate into diphenylcarbodiimide.
Multilayer microwave integrated quantum circuits for scalable quantum computing (2016)

Abstract As experimental quantum information processing (QIP) rapidly advances, an emerging challenge is to design a scalable architecture that combines various quantum elements into a complex device without compromising their performance. In particular, superconducting quantum circuits have successfully demonstrated many of the requirements for quantum computing, including coherence levels that approach the thresholds for scaling. However, it remains challenging to couple a large number of circuit components through controllable channels while suppressing any other interactions. We propose a hardware platform intended to address these challenges, which combines the advantages of integrated circuit fabrication and the long coherence times achievable in three-dimensional circuit quantum electrodynamics. This multilayer microwave integrated quantum circuit platform provides a path towards the realisation of increasingly complex superconducting devices in pursuit of a scalable quantum computer.
Drug Detection and Its Role in Law Enforcement (2001)

This paper details drug testing procedures and their usefulness in law enforcement. Currently, testing for illicit drugs is primarily through urinalysis, but the paper also outlines the advantages and disadvantages of using other biological specimens, including saliva and hair. The testing of drugs themselves for identification purposes is also described. Drug testing provides useful corroborative evidence to courts and to law enforcement officers in their line of duty, but further technological developments are needed, which will require appropriate levels of investment in research.
Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery (1992)

Experimental autoimmune encephalomyelitis (EAE) serves as an important animal model for understanding the events that lead to immune-mediated inflammation and tissue destruction within the central nervous system. We have utilized a murine adoptive transfer model of EAE and semiquantitative reverse transcriptase-polymerase chain reaction analysis to examine cytokine mRNA expression within the central nervous system in relation to the onset and resolution of paralysis associated with EAE. Spinal cord samples, obtained from mice as they progressed through discrete clinical stages of EAE, were examined for the expression of six cytokine genes (IL-1 alpha, IL-2, IL-4, IL-6, IL-10, and IFN-gamma). Distinct patterns of cytokine gene expression were observed during the acute, recovery, and chronic phases of EAE. The acute phase of disease was characterized by rapid increases in the levels of mRNA for IL-2, IL-4, IL-6, IFN-gamma, and IL-1 alpha. In fact, peak expression of several cytokine mRNA (e.g., IL-2, IL-4, IL-6, and IFN-gamma) occurred before the peak in clinical severity. In contrast, IL-1 alpha mRNA levels were elevated throughout the initial disease course. IL-10 mRNA demonstrated only modest increases during the acute phase of EAE. Stabilization of the clinical symptoms was characterized by rapid declines in the mRNA levels of IL-2, IL-4, IL-6, and IFN-gamma. The decreases in these four cytokine mRNA levels occurred concomitant with a dramatic rise in IL-10 mRNA. Finally, of the six cytokine mRNA examined, only IL-1 alpha, IFN-gamma, and IL-10 mRNA remained elevated during the early chronic stage. These results suggest that local cytokine production varies significantly during the course of EAE and that increases in discrete sets of cytokines are associated with the acute response and the recovery/chronic phase of disease.
Augmentation of human natural cell-mediated cytotoxicity by recombinant human interleukin 2. (1984)

Human peripheral blood mononuclear cells (PBMC) demonstrated increased natural cell-mediated cytotoxicity (NCMC) activity after only 5 min of exposure to purified recombinant human IL 2 or interferon (IFN)-gamma. The mechanism of NCMC augmentation by treatment with IL 2 is not entirely dependent on IFN-gamma production because: a) IL 2 was found to augment NCMC activity at levels which did not induce detectable IFN-gamma; b) IL 2 required only 5 min of exposure to PBMC to augment NCMC activity, whereas 3 hr of contact were required to demonstrate detectable IFN-gamma levels; c) the levels of NCMC enhancement by treatment with IL 2 exceeded the amount of NCMC enhancement that could be due to IFN alone; d) anti-recombinant IFN-gamma, which totally eliminated the augmentation of NCMC enhancement by IFN-gamma, only partially reduced the augmentation of NCMC activity by IL 2; and e) combination treatment of PBMC with IL 2 and IFN-gamma resulted in a synergistic enhancement of NCMC. The results strongly support the conclusion that augmentation of NCMC by IL 2 and IFN-gamma involve overlapping mechanisms.
Site-Directed Mutagenesis of Recombinant Equine Chorionic Gonadotropin/Luteinizing Hormone: Differential Role of Oligosaccharides in Luteinizing Hormone- and Follicle-Stimulating Hormone-Like Activities. (1996)

Equine chorionic gonadotropin (eCG) consists of highly glycosylated alpha- and beta-subunits and belongs to the glycoprotein hormone family that includes LH and FSH. eCG is a unique member of the gonadotropin family because it elicits response characteristics of both FSH and LH in other species than the horse. To determine the biological role of the N-linked oligosaccharide at Asn 56 of the alpha-subunit and O-linked oligosaccharides at the carboxyl-terminal peptide (CTP) of the beta-subunit, two mutant eCGs, in which Asn 56 of the alpha-subunit was replaced with Gln (eCG alpha 56/beta) or CTP was deleted (eCG alpha/ beta-CTP), were produced by site-directed mutagenesis and transfecting chinese hamster ovary (CHO-K1) cells. LH- and FSH-like activities were assayed in terms of testosterone production and aromatase activity in primary cultured rat Leydig cells and granulosa cells, respectively. The wild type eCG showed similar LH- and FSH-like activities to native eCG in the in vitro bioassays. The LH-like activity of eCG alpha 56/beta was greatly reduced, whereas that of eCG alpha/beta-CTP was unaffected, demonstrating that the oligosaccharide at Asn 56 of the alpha-subunit of eCG plays an indispensable role in LH-like activity. Interestingly, the FSH-like activity of eCG alpha 56/beta was increased markedly in comparison with the wild type, and that of eCG alpha/beta-CTP was also considerably increased. These data indicate that the dual activities of eCG, LH- and FSH-like activities, could be separated by removal of the N-linked oligosaccharide on the alpha-subunit Asn 56 or CTP-associated O-linked oligosaccharides.
Skin toxicity caused by EGFR antagonists—An autoinflammatory condition triggered by deregulated IL‐1 signaling? (2008)

Acneiform skin eruptions associated with sterile inflammation frequently accompany pharmacological inhibition of signaling through the epidermal growth factor receptor (EGFR) in cancer patients. Here we discuss possible pathogenic mechanisms for this phenomenon linked to control of inflammatory mediators by EGFR blockade in keratinocytes of the outer root sheath of the hair follicle. This discussion is focused on the putative role of EGFR activation in restraining interleukin (IL)-1-dependent inflammatory networks at the hair follicle.
Thrombogenesis, atherogenesis and angiogenesis in vascular disease: a new ‘vascular triad’ (2004)

Amongst the components of the pathophysiology of atherosclerosis are the tendency to thrombus formation (i.e., thrombogenesis) and the loss of endothelial cell integrity. The endothelium is also implicated in atherogenesis, as vasa vasorum are present in the adventitia and media at a higher density in atherosclerotic tissue, and that neovascularisation leading to collateral growth bypassing obstruction and/or stenoses provides important alternative routes to feeding distal tissues. The development of these new blood vessels is the process of angiogenesis. The present 'viewpoint' article will explore the relationships between the three processes. There is considerable evidence that atherogenesis and thrombogenesis are intimately linked, but angiogenesis in cardiovascular disease is a recently developed concept. We propose a new 'vascular triad' of these abnormal pathophysiological processes, leading to an alternative view of the pathogenesis of vascular disease. Indeed, we suggest that angiogenesis is an important aspect of the pathophysiology of cardiovascular disease, impacting with both thrombogenesis and atherogenesis, in a new vascular triad (the 'Birmingham vascular triad').
High-level hepatitis B virus replication in transgenic mice (1995)

Hepatitis B virus (HBV) transgenic mice whose hepatocytes replicate the virus at levels comparable to that in the infected livers of patients with chronic hepatitis have been produced, without any evidence of cytopathology. High-level viral gene expression was obtained in the liver and kidney tissues in three independent lineages. These animals were produced with a terminally redundant viral DNA construct (HBV 1.3) that starts just upstream of HBV enhancer I, extends completely around the circular viral genome, and ends just downstream of the unique polyadenylation site in HBV. In these animals, the viral mRNA is more abundant in centrilobular hepatocytes than elsewhere in the hepatic lobule. High-level viral DNA replication occurs inside viral nucleocapsid particles that preferentially form in the cytoplasm of these centrilobular hepatocytes, suggesting that an expression threshold must be reached for nucleocapsid assembly and viral replication to occur. Despite the restricted distribution of the viral replication machinery in centrilobular cytoplasmic nucleocapsids, nucleocapsid particles are detectable in the vast majority of hepatocyte nuclei throughout the hepatic lobule. The intranuclear nucleocapsid particles are empty, however, suggesting that viral nucleocapsid particle assembly occurs independently in the nucleus and the cytoplasm of the hepatocyte and implying that cytoplasmic nucleocapsid particles do not transport the viral genome across the nuclear membrane into the nucleus during the viral life cycle. This model creates the opportunity to examine the influence of viral and host factors on HBV pathogenesis and replication and to assess the antiviral potential of pharmacological agents and physiological processes, including the immune response.
Air oxidation of d‐limonene (the citrus solvent) creates potent allergens (1992)

Products containing as much as 95% of d-limonene are used for, e.g., degreasing metal before industrial painting and for cleaning assemblies. Experimental studies on the sensitizing potential of limonene show diverging results. In a previous study, we found that the sensitizing potential of d-limonene increased with prolonged air exposure. The aim of this study was to make further chemical analyses, to identify compounds formed by air exposure of d-limonene and to study their allergenic potential. d-limonene was found to be a sensitizer after prolonged exposure to air according to 2 Freund's complete adjuvant test (FCAT) experiments and 1 guinea pig maximization test (GPMT) study. No significant response was obtained to d-limonene not air exposed, even if the animals were sensitized to oxidized d-limonene. 5 main oxidation products of d-limonene were identified. (R)-(-)-carvone and a mixture of cis and trans isomers of (+)-limonene oxide were found to be potent sensitizers, while no significant reactions were obtained in the animals induced with a mixture of cis and trans isomers of (-)-carveol. It can be concluded that air oxidation of d-limonene is essential for its sensitizing potential, and that potent allergens are created.
Dominant-negative inhibitors of EBNA-1 of Epstein-Barr virus (1997)

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) is required in trans to support replication of the EBV genome once per cell cycle via the latent origin of replication, oriP. EBNA-1 can also activate transcription on binding to the family of repeats of oriP to enhance some heterologous as well as native EBV promoters. We have made and screened derivatives of EBNA-1 for the ability to act as inhibitors of wild-type EBNA-1. These derivatives lack the linking or the retention functions of EBNA-1 and were analyzed for the residual ability to activate transcription and replication. We have identified derivatives of EBNA-1 that can inhibit up to 98% of wild-type EBNA-1's activities. We have also identified one derivative of EBNA-1 with only two of EBNA-1's three linking domains which can support transcription and replication inefficiently.
The Arrangement of Disulfide Loops in Human α2-HS Glycoprotein (1989)

The complete disulfide loop structure of human alpha 2-HS glycoprotein has been elucidated. alpha 2-HS glycoprotein isolated from human plasma was found to be a two-chain protein composed of a heavy and a light chain. The heavy chain comprises the A-chain of alpha 2-HS glycoprotein (Yoshioka, Y., Gejyo, F., Marti, T., Rickli, E. E., Bürgi, W., Offner, G. D., Troxler, R. F., and Schmid, K. (1986) J. Biol. Chem. 261, 1665-1676) and part of the connecting peptide which has been predicted from the corresponding cDNA sequence (Lee, C. C., Bowman, B. H., and Yang, F. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 4403-4407), whereas the light chain corresponds to the beta-chain of alpha 2-HS glycoprotein (Gejyo, F., Chang, J. L., Bürgi, W., Schmid, K., Offner, G. D., Troxler, R. F., Van Halbeek, H., Dorland, L., Gerwig, G. J., Vliegenthart, J. F. G. (1983) J. Biol. Chem. 258, 4966-4971). Twelve half-cystine residues are present in the alpha 2-HS glycoprotein molecule, and 11 of them are positioned in the heavy chain and a single one in the light chain of the molecule; they form six disulfide bridges. The first and the last half-cystine residues of the amino acid sequence of alpha 2-HS glycoprotein are engaged in the formation of a loop spanning the extreme NH2- and COOH-terminal portions of the molecule, thereby connecting the heavy and light chains. The other 10 half-cystines residues are linked consecutively in the heavy chain and form five loops which span 4-19 amino acid residues. Among them are two pairs of loops which are characterized by mutual sequence homology. The particular arrangement of disulfide loops in alpha 2-HS glycoprotein is similar to the patterns of linearly arranged and tandemly repeated disulfide loops of cysteine proteinase inhibitors, i.e. the cystatins and the kininogens. It is concluded that alpha 2-HS glycoprotein represents a structural prototype of a novel family among the cystatin superfamily, characterized by the presence of two cystatin-like building blocks. Extensive similarity among the NH2-terminal sequences of alpha 2-HS glycoprotein and human histidine-rich glycoprotein suggest that the latter protein is another candidate protein of this new family.
Design and CAD for 3D integrated circuits (2008)

High density Through Silicon Vias (TSV) can be used to build 3DICs that enable unique applications in computing, signal processing and memory intensive systems. This paper presents several case studies that are uniquely enhanced through 3D implementation, including a 3D CAM, an FFT processor, and a SAR processor. The CAD flow used to implement for these designs is described. 3DIC requires higher fidelity thermal modeling than 2DIC design. The rationale for this requirement is established and a possible solution is presented.
Immunogenicity of Attenuated Vesicular Stomatitis Virus Vectors Expressing HIV Type 1 Env and SIV Gag Proteins: Comparison of Intranasal and Intramuscular Vaccination Routes (2004)

An experimental AIDS vaccine based on attenuated, recombinant vesicular stomatitis virus (rVSV), when administered by a combination of parenteral and mucosal routes, has proven effective at preventing AIDS in a rhesus macaque model (Rose NF, et al.: Cell 2001;106:539–549). In an effort to determine the optimal route of vaccine administration we evaluated the ability of rVSV-based vaccine vectors expressing HIV-1 Env and SIV Gag proteins, when given either intramuscularly (i.m.) or intranasally (i.n.), to elicit antigen-specific cellular and humoral immune responses, and to protect from a subsequent vaginal challenge with simian–human immunodeficiency virus (SHIV89.6P). Our results demonstrate that macaques vaccinated by the i.n. route developed significantly higher antigen-specific cellular immune responses as determined by MHC class I tetramer staining, IFN-γ ELISPOT, and cytotoxic T cell assays. However, systemic and mucosal humoral immune responses did not vary significantly with the route of vaccine administration. Given the importance of cell-mediated immune responses in slowing AIDS progression, intranasal delivery of a VSV-based AIDS vaccine may be an optimal as well as practical route for vaccination and should be considered in design of clinical trials.
In vivo Off-Resonance Saturation Magnetic Resonance Imaging of αvβ3-Targeted Superparamagnetic Nanoparticles (2009)

Magnetic resonance imaging is a powerful clinical imaging technique that allows for noninvasive tomographic visualization of anatomic structures with high spatial resolution and soft tissue contrast. However, its application in molecular imaging of cancer has been limited by the lack of sensitivity and detection accuracy in depicting the biochemical expression of these diseases. Here, we combine an ultrasensitive design of superparamagnetic polymeric micelles (SPPM) and an off-resonance saturation (ORS) method to enhance the imaging efficacy of tumor biomarkers in vivo. SPPM nanoparticles encoded with cyclic(RGDfK) were able to target the alpha(v)beta(3)-expressing microvasculature in A549 non-small cell lung tumor xenografts in mice. ORS greatly improved tumor detection accuracy over the conventional T(2)*-weighted method by its ability to turn "ON" the contrast of SPPM. This combination of ORS imaging with a tumor vasculature-targeted, ultrasensitive SPPM design offers new opportunities in molecular imaging of cancer.
DeepLanes: End-To-End Lane Position Estimation Using Deep Neural Networks (2016)

Camera-based lane detection algorithms are one of the key enablers for many semi-autonomous and fully-autonomous systems, ranging from lane keep assist to level-5 automated vehicles. Positioning a vehicle between lane boundaries is the core navigational aspect of a self-driving car. Even though this should be trivial, given the clarity of lane markings on most standard roadway systems, the process is typically mired with tedious pre-processing and computational effort. We present an approach to estimate lane positions directly using a deep neural network that operates on images from laterally-mounted down-facing cameras. To create a diverse training set, we present a method to generate semi-artificial images. Besides the ability to distinguish whether there is a lane-marker present or not, the network is able to estimate the position of a lane marker with sub-centimeter accuracy at an average of 100 frames/s on an embedded automotive platform, requiring no pre-or post-processing. This system can be used not only to estimate lane position for navigation, but also provide an efficient way to validate the robustness of driver-assist features which depend on lane information.
The c-Jun N-terminal kinase pathway and apoptotic signaling (review). (2000)

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) is activated in mammalian cells by environmental stress, pro-inflammatory cytokines, and mitogenic stimuli. Biochemical and genetic studies demonstrate that JNK regulates the activities of many transcription factors, and that the JNK pathway is required for the regulation of inflammatory responses, cell proliferation, and apoptosis. The involvement of JNK in apoptotic cell death is particularly intriguing, and has been actively studied in recent years. An improved understanding of JNK-mediated apoptotic signaling may provide novel strategies in prevention and treatment of cancers.
The Glucagon-Like Peptide-1 Receptor Agonist Oxyntomodulin Enhances β-Cell Function but Does Not Inhibit Gastric Emptying in Mice (2008)

The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine beta-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders.