gebhart/patrepeval huggingface dataset:
Lack of Site-Specific Integration of the Recombinant Adeno-Associated Virus 2 Genomes in Human Cells (1997)

The adeno-associated virus 2 (AAV)-based vector system has been suggested for its potential use in human gene therapy because the wild-type (wt) AAV genome appears to integrate into the human chromosomal DNA in a site-specific manner. We systematically investigated the integration patterns of the recombinant AAV genomes lacking one or both the viral coding sequences. Four recombinant AAV genomes were constructed containing the genes for resistance to tetracycline (TcR) and the herpesvirus thymidine kinase (TK) promoter-driven gene for resistance to neomycin (neoR; vTc.Neo), the genes for resistance to ampicillin (ApR) and TK-neoR (vAp.Neo), the genes for AAV replication (rep) genes and TK-neoR (vRep.Neo), and the AAV capsid (cap) genes and TK-neoR (vCap.Neo). The integration pattern of each of the recombinant AAV genomes in individual clonal isolates of the human nasopharyngeal carcinoma cell line (KB) analyzed on Southern blots using a neo-specific DNA probe was distinctly different. In addition, in none of the clones examined was the proviral genome covalently linked to the previously described AAV right-junction (Rt.Jn.) human chromosomal DNA fragment, the putative specific-site of integration for the wt AAV genome. Furthermore, whereas a 276-bp DNA fragment could be readily amplified from each of these clones, using a neo-specific primer-pair by polymerase chain reaction (PCR), no amplified DNA product was obtained using the neo- and the Rt.Jn. primer-pair under identical conditions. Fluorescence in situ hybridization (FISH) analyses further revealed the lack of integration of the recombinant AAV into human chromosome 19, even in the presence of a functional rep gene as determined by rescue of the recombinant AAV genome in the presence of adenovirus. These data suggest that the recombinant AAV genomes integrate at sites that are different from that characterized for the wt AAV genome. These studies may have implications in the development of the AAV-based vector system for its potential use in human gene therapy.
Structural basis for the inhibition of translation through eIF2α phosphorylation (2018)

Abstract One of the responses to stress by eukaryotic cells is the down-regulation of protein synthesis by phosphorylation of translation initiation factor eIF2. Phosphorylation results in low availability of the eIF2 ternary complex (eIF2-GTP-tRNA i ) by affecting its interaction with its GTP-GDP exchange factor eIF2B. We have determined the cryo-EM structure of eIF2B in complex with phosphorylated eIF2 at an overall resolution of 4.15 Å. Two eIF2 molecules bind opposite sides of an eIF2B hetero-decamer through eIF2α-D1, which contains the phosphorylated Ser51. eIF2α-D1 is mainly inserted between the N-terminal helix bundle domains of δ and α subunits of eIF2B. Phosphorylation of Ser51 enhances binding to eIF2B through direct interactions of phosphate groups with residues in eIF2Bα and indirectly by inducing contacts of eIF2α helix 58-63 with eIF2Bδ leading to a competition with Met-tRNA i .
Prolonged response to antisense cyclin D1 in a human squamous cancer xenograft model. (2000)

Local recurrence of squamous cell cancer (SCC) causes high morbidity and is often readily accessible, making such patients potential candidates for gene therapy. Cyclin D1 (CD1), critical in the G1-S transition in the cell cycle, is amplified in 20-50% and overexpressed in up to 80% of head and neck SCC. Our earlier studies indicated that CD1 expression increased with progression from low grade to high grade dysplasia, and that treatment of established tumors with antisense cyclin D1 (AS-cyclin D1) led to tumor regression during a one week evaluation period. We hypothesized that: 1) CD1 expression increases with disease progression to advanced SCC, and 2) AS-cyclin D1 therapy would lead to prolonged tumor regression in a xenograft model of human SCC. CD1 expression, evaluated by immunostain in 30 stage III/IV head and neck SCC, increased in the basal layer from normal-dysplasia (P = 0.06) and from dysplasia-carcinoma (P = 0.004). In the germinative layer CD1 expression increased from dysplasia-carcinoma (P = 0.002) but not from normal-dysplasia. Western blotting of eight SCC and two transformed keratinocyte cell lines demonstrated CD1 overexpression in 8/10 (80%) lines. An 11th cell line (A431) had previously been shown to overexpress cyclin D1. 8/9 (89%) cell lines overexpressing CD1 formed tumors in immunodeficient mice, whereas 0/2 cell lines without CD1 overexpression formed a tumor. Three established SCCs, one fast growing, one with moderate growth rate (with CD1 overexpression) and one slow growing (without increased CD1), shrank significantly for 2-4 weeks after AS-cyclin D1 treatment, while tumors transduced with control vector grew. Cyclin D1 expression increases in frequency with disease progression, and antisense cyclin D1 was effective in a xenograft model of human cancer, independent of tumor growth rate.
Nerve growth factor receptors on chick embryo sympathetic ganglion cells: binding characteristics and development (1986)

NGF is essential for the development and maintenance of sympathetic and certain sensory neurons. The NGF receptors on the surface of sympathetic ganglion cells from chick embryos were characterized; they consist of high-affinity receptors with a dissociation constant of about 10(-11) M, and low-affinity receptors with a dissociation constant of about 10(-9) M. There are more than 10 times as many low-affinity as high-affinity receptors per cell. The heterogeneity of NGF binding is not due to negatively cooperative interactions among the receptors. The high- and low-affinity components of NGF binding defined at steady state correspond to slowly and rapidly dissociating components of bound NGF seen in kinetic experiments. In addition, a very slowly dissociating component of bound NGF was observed; this component was a small fraction of binding at low concentrations of NGF but increased to 20-60% of bound NGF at the highest NGF concentrations examined. This very slowly dissociating component of bound NGF accounts for several peculiarities in the binding data not accounted for by steady-state binding of NGF to its high- and low-affinity receptors. Developmental studies showed that both high- and low-affinity NGF receptors were present on chick embryo sympathetic ganglion cells from 6.5 to 20 d in ovo. No significant differences in the numbers or affinities of the receptors were seen with cells from ganglia at 9, 11, or 15 d of development. Cultured non-neuronal cells from sympathetic ganglia had only low-affinity NGF receptors.
Ontology-based design information extraction and retrieval (2007)

Because of the increasing complexity of products and the design process, as well as the popularity of computer-aided documentation tools, the number of electronic and textual design documents being generated has exploded. The availability of such extensive document resources has created new challenges and opportunities for research. These include improving design information retrieval to achieve a more coherent environment for design exploration, learning, and reuse. One critical issue is related to the construction of a structured representation for indexing design documents that record engineers' ideas and reasoning processes for a specific design. This representation should explicitly and accurately capture the important design concepts as well as the relationships between these concepts so that engineers can locate their documents of interest with less effort. For design information retrieval, we propose to use shallow natural language processing and domain-specific design ontology to automatically construct a structured and semantics-based representation from unstructured design documents. The design concepts and relationships of the representation are recognized from the document based on the identified linguistic patterns. The recognized concepts and relationships are joined to form a concept graph. The integration of these concept graphs builds an application-specific design ontology, which can be seen as the structured representation of the content of the corporate document repository, as well as an automatically populated knowledge base from previous designs. To improve the performance of design information retrieval, we have developed ontology-based query processing, where users' requests are interpreted based on their domain-specific meanings. Our approach contrasts with the traditionally used keyword-based search. An experiment to test the retrieval performance is conducted by using the design documents from a product design scenario. The results demonstrate that our method outperforms the keyword-based search techniques. This research contributes to the development and use of engineering ontology for design information retrieval.
Rationale, design and methods of the ESPRIT study: Energy, Sexual desire and body PropoRtions wIth AndroGel®, Testosterone 1% gel therapy, in hypogonadal men (2008)

Hypogonadism is associated with a range of disease states that have significant effects on morbidity and mortality, and also affect quality of life. The ESPRIT study (Energy, Sexual desire and body PropoRtions wIth AndroGel, Testosterone 1% gel therapy) is a 6-month, multinational, open label, observational study in hypogonadal men being treated with transdermal AndroGel in usual daily clinical practice; 1,700-2,400 patients will be enrolled in Canada, Germany, Central and Eastern Europe, Russia and the Middle East. The main objective will be to evaluate the effect of AndroGel on symptoms of hypogonadism and quality of life as assessed by the Aging Males' Symptoms scale. Further objectives include evaluating the effect and time to onset of improvement in erectile dysfunction and libido/sexual desire (International Index of Erectile Function), fatigue (Multi-dimensional Fatigue Index) and body composition (waist circumference, body mass index). Subgroup analyses will be performed: <50 years versus > or = 50 years; absence versus presence of metabolic syndrome. The safety of AndroGel will also be assessed. The study population will consist of newly diagnosed hypogonadal men (age > or = 18 years), in whom testosterone deficiency has been confirmed by clinical features and biochemical tests according to international guidelines, who are currently being prescribed AndroGel (testosterone 1% gel, starting dose 50 mg testosterone per day).
Synthesis of Water-Dispersible Fluorescent, Radio-Opaque, and Paramagnetic CdS:Mn/ZnS Quantum Dots:  A Multifunctional Probe for Bioimaging (2005)

Ultra-small (3.1 nm) multifunctional CdS:Mn/ZnS core-shell semiconductor quantum dots (Qdots), which possess fluorescent, radio-opacity, and paramagnetic properties, have been shown here. To demonstrate in vivo bioimaging capability, a rat was administered endovascularly with Qdots conjugated with a TAT peptide. The labeling efficacy of these Qdots was demonstrated on the basis of the histological analysis of the microtome sliced brain tissue, clearly showing that TAT-conjugated Qdots stained brain blood vessels.
Characterization of epidermal cytokine profiles in sensitization and elicitation phases of allergic contact dermatitis as well as irritant contact dermatitis in mouse skin. (1994)

Epidermal cytokines are known to participate in the initiation of immune and inflammatory processes in the skin. In the present study, we examined epidermal cytokine mRNA levels to elucidate the initial molecular events in the sensitization and elicitation phases of allergic contact dermatitis (ACD) as well as in irritant contact dermatitis (ICD). BALB/c mice were sensitized on the dorsal skin with 0.5% dinitrofluorobenzene (DNFB) and challenged with 0.2% DNFB on the ears 6 days later to elicit allergic contact hypersensitivity (ACDe), the elicitation phase. To examine cytokine profiles during the sensitization phase from the same anatomic area, other animals were sensitized on ear instead of dorsal skin. The sensitization phase of ACD (ACDs) was induced by painting the ears of naive mice with 0.5% DNFB. Sodium lauryl sulfate (SLS), utilized as an irritant control, was also applied to the ears of another group of mice to induce ICD. Total RNA was extracted from the epidermis of the treated ears at various time points after each treatment, reverse transcribed to cDNA, and amplified by PCR using radiolabeled cytokine-specific primers. Amplified products were sized by electrophoresis and autoradiography and semiquantitated by densitometry. Autoradiographs were normalized relative to beta-actin signals. ACDs and ACDe showed similar patterns of cytokine mRNA levels; that is, at 6 h after hapten application, interleukin (IL)-1 beta, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA levels were upregulated, and this upregulation was observed until 24 h after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Robust and Efficient Foreground Analysis for Real-Time Video Surveillance (2005)

We present a new method to robustly and efficiently analyze foreground when we detect background for a fixed camera view by using mixture of Gaussians models and multiple cues. The background is modeled by three Gaussian mixtures as in the work of Stauffer and Grimson (1999). Then the intensity and texture information are integrated to remove shadows and to enable the algorithm working for quick lighting changes. For foreground analysis, the same Gaussian mixture model is employed to detect the static foreground regions without using any tracking or motion information. Then the whole static regions are pushed back to the background model to avoid a common problem in background subtraction /spl times/ fragmentation (one object becomes multiple parts). The method was tested on our real time video surveillance system. It is robust and run about 130 fpsfor color images and 150 fps for grayscale images at size 160/spl times/120 on a 2GB Pentium IV machine with MMX optimization.
Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. (1997)

Mice lacking mdr1-type P-glycoproteins (mdr1a/1b [-/-] mice) display large changes in the pharmacokinetics of digoxin and other drugs. Using the kinetics of digoxin in mdr1a/1b (-/-) mice as a model representing a complete block of P-glycoprotein activity, we investigated the activity and specificity of the reversal agent SDZ PSC833 in inhibiting mdr1-type P-glycoproteins in vivo. Oral PSC833 was coadministered with intravenous [3H]digoxin to wild-type and mdr1a/1b (-/-) mice. The direct excretion of [3H]digoxin mediated by P-glycoprotein in the intestinal mucosa of wild-type mice was abolished by administration of PSC833. Hepatobiliary excretion of [3H]digoxin was markedly decreased in both wild-type and mdr1a/1b (-/-) mice by PSC833, the latter effect indicating that in vivo, PSC833 inhibits not only mdr1-type P-glycoproteins, but also other drug transporters. Upon coadministration of PSC833, brain levels of [3H]digoxin in wild-type mice showed a large increase, approaching (but not equaling) the levels found in brains of PSC833-treated mdr1a/1b (-/-) mice. Thus, orally administered PSC833 can inhibit blood-brain barrier P-glycoprotein extensively, and intestinal P-glycoprotein completely. These profound pharmacokinetic effects of PSC833 treatment imply potential risks, but also promising pharmacological applications of the use of effective reversal agents.
Evidence for the Systemic Delivery of a Transgene Product from Salivary Glands (1996)

The aim of this study was to assess the feasibility of using gene transfer to salivary glands to direct the systemic delivery of therapeutic proteins in vivo. We used a replication-deficient recombinant adenovirus vector (Ad alpha 1AT) that encodes human alpha 1-antitrypsin (h alpha 1-AT), which we used as a marker protein. Ad alpha 1AT (5 x 10(9) pfu) was administered by retrograde ductal instillation to the submandibular glands of male rats. The amount of h alpha 1-AT found in the salivary glands, saliva, serum, and other tissues was analyzed by a sensitive enzyme-linked immunosorbent assay (ELISA). Maximal levels of the marker protein were detected at 24-48 hr post-virus administration for glands (274 ng/mg protein), saliva (approximately 313 ng/ml), and serum (approximately 5 ng/ml). Serum levels remained elevated for 96 hr, whereas the measured half-life for the marker protein was approximately 2 hr. Generally little to no h alpha 1-AT was detectable in most other organs. However, we were able to measure low levels of marker protein in tissues immediately surrounding infected glands. In all animals studied, levels of h alpha 1-AT were higher in the glandular venous effluent than in arterial blood. Similar results were found with parotid glands. The aggregate data demonstrate that salivary glands may be a target for the nonsurgical, systemic delivery of transgene-encoded therapeutic proteins for diseases that require relatively low circulating protein levels.
Synthesis of the metabolites and degradation products of 2-amino-7-isopropyl-5-oxo-5H-(1)benzopyrano(2,3-b)pyridine-3-carboxylic acid (Amoxanox). (1985)

The metabolites and degradation products of 2-amino-7-isopropyl-5-oxo-5H-[1] benzopyrano-[2, 3-b] pyridine-3-carboxylic acid (Amoxanox, AA-673, 1), a promising drug for the treatment of bronchial asthma, were synthesized to confirm the proposed structures and to determine their activity in the rat passive cutaneous anaphylaxis test.
New Therapies for the Treatment of Chronic Hepatitis C (2002)

Treatment of chronic hepatitis C (HCV) was based on Interferon alpha IFNalpha administration three times a week (tiw), but the efficacy of this schedule (evaluated as virological sustained response) was limited to less than 20% of patients. The combination of Ribavirin and IFN is known to be significantly more effective than IFN monotherapy in naive and relapser patients but it induces a sustained response only in 41% of patients and in less than 30% of patients infected with genotype 1. Several studies on IFN and viral kinetics suggested that daily administration of IFN may increase the sustained response rate. The development of pegylated IFNs, characterized by a long half life and weekly administrability, seems to induce a significant improvement in the treatment of chronic hepatitis particularly in combination with Ribavirin. In order to further improve the efficacy of treatment in chronic hepatitis C (HCV) many controlled clinical trials evaluating Amantadine, Micophenolate, alpha1 Thymosin, Maxamine (in combination with IFN or pegylated IFN), Protease, Helicase, Polymerase inhibitors, Ribozymes and anti-sense olygonucleotides, and Interleukin 10 are in progress. Finally anti-HCV vaccine development seems to be very promising.
Multiple Organ Dysfunction Syndrome in Humans and Animals (2014)

Multiple organ dysfunction syndrome (MODS), defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, is a cause of high morbidity and mortality in humans and animals. Many advances have been made in understanding the pathophysiology and treatment of this syndrome in human medicine, but much still is unknown. This comparative review will provide information regarding the history and pathophysiology of MODS in humans and discuss how MODS affects each major organ system in animals.
Silicon piezoresistive stress sensors and their application in electronic packaging (2001)

Structural reliability of integrated circuit (IC) chips in electronic packages continues to be a major concern due to ever-increasing die size, circuit densities, power dissipation, operating temperatures, and the use of a wide range of low-cost packaging materials. A powerful method for experimental eval- uation of silicon die stress distributions is the use of test chips incorporating integral piezoresistive sensors. In this paper, a review is made of the state-of-the-art in the area of silicon piezore- sistive stress sensor test chips. Developments in sensor theory, calibration methods, and packaging applications are presented. In the absence of die failure, packaging-induced stresses result in changes in the parametric performance of circuitry on the die, and the theory discussed here can be used to predict such changes. Index Terms—Electronic packaging, piezoresistive, stress sensor, test chip.
One role for DNA methylation in vertebrate cells is strand discrimination in mismatch repair. (1985)

Although the occurrence of 5-methylcytosine (m5C) in DNA is widespread, the function of this modified base remains unclear. At some specific sites it apparently has an effect in controlling gene expression, but many sites do not appear to be involved in this regulation. Balanced against its regulatory usefulness at some sites is the mutational risk it imposes upon the cell. Deamination of m5C can lead to its replacement by thymine (T). One possible role for excess methylation is strand discrimination in the repair of mismatches. We constructed the complementary hemimethylated single-base-pair mismatches, G T and A C, at a CG site in simian virus 40 DNA, transfected these into the host African green monkey kidney cells (CV-1), and examined DNA of the progeny for repair at this site. Hemimethylation at two Hha I sites (Gm5CGC) bracketing the mismatch directed repair to occur only on the unmethylated strand. Methylation at the multiple Cm5CATGG and Gm6ATC sites, a pattern normally seen in bacteria, also instructed repair to proceed on the unmethylated strand, although less efficiently. Hemimethylation at only one site, adjacent to the mispaired bases (Hpa II, Cm5CGG) produced repaired molecules in a ratio that may represent random repair of the A C mismatch and strand-directed repair in the complementary G T mismatch. The -mCG- -GT- mismatch could result from deamination of m5C in the most commonly methylated dinucleotide in vertebrates, CpG. Methylation may be able to compensate for the errors it causes by serving as a mechanism for strand discrimination in correcting those errors. In addition, single-strand nicks were also shown to direct repair.
Inhaled Nitric Oxide in Premature Infants with the Respiratory Distress Syndrome (2003)

The use of inhaled nitric oxide in premature infants with the respiratory distress syndrome decreases the incidence of chronic lung disease and death.