gebhart/patrepeval huggingface dataset:
Characteristics and Significance of the Amorphous State in Pharmaceutical Systems (1997)

The amorphous state is critical in determining the solid-state physical and chemical properties of many pharmaceutical dosage forms. This review describes the characteristics of the amorphous state and some of the most common methods that can be used to measure them. Examples of pharmaceutical situations where the presence of the amorphous state plays an important role are presented. The application of our current knowledge to pharmaceutical formulation problems is illustrated, and some strategies for working with amorphous character in pharmaceutical systems are provided.
The ABC of APC (2001)

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by the presence of adenomatous polyps in the colon and rectum, with inevitable development of colorectal cancer if left untreated. FAP is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Somatic mutations in the APC gene are an early event in colorectal tumorigenesis, and can be detected in the majority of colorectal tumours. The APC gene encodes a large protein with multiple cellular functions and interactions, including roles in signal transduction in the wnt-signalling pathway, mediation of intercellular adhesion, stabilization of the cytoskeleton and possibly regulation of the cell cycle and apoptosis. The fact that APC is an integral part of so many different pathways makes it an ideal target for mutation in carcinogenesis. This review deals with our understanding to date of how mutations in the APC gene translate into changes at the protein level, which in turn contribute to the role of APC in tumorigenesis.
GT-094, a NO-NSAID, Inhibits Colon Cancer Cell Growth by Activation of a Reactive Oxygen Species-MicroRNA-27a: ZBTB10-Specificity Protein Pathway (2010)

Ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094) is a novel nitric oxide (NO) chimera containing an nonsteroidal anti-inflammatory drug (NSAID) and NO moieties and also a disulfide pharmacophore that in itself exhibits cancer chemopreventive activity. In this study, the effects and mechanism of action of GT-094 were investigated in RKO and SW480 colon cancer cells. GT-094 inhibited cell proliferation and induced apoptosis in both cell lines and this was accompanied by decreased mitochondrial membrane potential (MMP) and induction of reactive oxygen species (ROS), and these responses were reversed after cotreatment with the antioxidant glutathione. GT-094 also downregulated genes associated with cell growth [cyclin D1, hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR)], survival (bcl-2, survivin), and angiogenesis [VEGF and its receptors (VEGFR1 and VEGFR2)]. Results of previous RNA interference studies in this laboratory has shown that these genes are regulated, in part, by specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 that are overexpressed in colon and other cancer cell lines and not surprisingly, GT-094 also decreased Sp1, Sp3, and Sp4 in colon cancer cells. GT-094-mediated repression of Sp and Sp-regulated gene products was due to downregulation of microRNA-27a (miR-27a) and induction of ZBTB10, an Sp repressor that is regulated by miR-27a in colon cancer cells. Moreover, the effects of GT-094 on Sp1, Sp3, Sp4, miR-27a, and ZBTB10 were also inhibited by glutathione suggesting that the anticancer activity of GT-094 in colon cancer cells is due, in part, to activation of an ROS-miR-27a:ZBTB10-Sp transcription factor pathway.
Role of the Adenovirus DNA-Binding Protein in In Vitro Adeno-Associated Virus DNA Replication (1998)

A basic question in adeno-associated virus (AAV) biology has been whether adenovirus (Ad) infection provided any function which directly promoted replication of AAV DNA. Previously in vitro assays for AAV DNA replication, using linear duplex AAV DNA as the template, uninfected or Ad-infected HeLa cell extracts, and exogenous AAV Rep protein, demonstrated that Ad infection provides a direct helper effect for AAV DNA replication. It was shown that the nature of this helper effect was to increase the processivity of AAV DNA replication. Left unanswered was the question of whether this effect was the result of cellular factors whose activity was enhanced by Ad infection or was the result of direct participation of Ad proteins in AAV DNA replication. In this report, we show that in the in vitro assay, enhancement of processivity occurs with the addition of either the Ad DNA-binding protein (Ad-DBP) or the human single-stranded DNA-binding protein (replication protein A [RPA]). Clearly Ad-DBP is present after Ad infection but not before, whereas the cellular level of RPA is not apparently affected by Ad infection. However, we have not measured possible modifications of RPA which might occur after Ad infection and affect AAV DNA replication. When the substrate for replication was an AAV genome inserted into a plasmid vector, RPA was not an effective substitute for Ad-DBP. Extracts supplemented with Ad-DBP preferentially replicated AAV sequences rather than adjacent vector sequences; in contrast, extracts supplemented with RPA preferentially replicated vector sequences.
Lossy encoding of motion vectors using entropy-constrained vector quantization (2002)

Many well-known video coding algorithms employ block motion estimation and compensation. But not much attention has been given to the problem of rate allocation for encoding the motion vectors and motion compensated difference frame. We propose entropy-constrained vector quantization of a dense motion vector field as a means of controlling the rate allocated to encoding of motion vectors. An algorithm is proposed for accomplishing this task and extension to motion vector encoding using prediction is discussed.
Tied mixture continuous parameter modeling for speech recognition (1990)

The acoustic-modeling problem in automatic speech recognition is examined with the goal of unifying discrete and continuous parameter approaches. To model a sequence of information-bearing acoustic feature vectors which has been extracted from the speech waveform via some appropriate front-end signal processing, a speech recognizer basically faces two alternatives: (1) assign a multivariate probability distribution directly to the stream of vectors, or (2) use a time-synchronous labeling acoustic processor to perform vector quantization on this stream, and assign a multinomial probability distribution to the output of the vector quantizer. With a few exceptions, these two methods have traditionally been given separate treatment. A class of very general hidden Markov models which can accommodate feature vector sequences lying either in a discrete or in a continuous space is considered; the new class allows one to represent the prototypes in an assumption-limited, yet convenient way, as tied mixtures of simple multivariate densities. Speech recognition experiments, reported for two (5000- and 20000-word vocabulary) office correspondence tasks, demonstrate some of the benefits associated with this technique.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Monoclonal antibodies against recombinant parts of the Ki‐67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave‐processed formalin‐fixed paraffin sections (1992)

The monoclonal antibody Ki-67 reacts with a human nuclear cell proliferation-associated antigen that is expressed in all active parts of the cell cycle. Recently we have raised monoclonal antibodies, MIB 1-3, against recombinant parts of the Ki-67 antigen. These antibodies are true Ki-67 equivalents, as demonstrated by immunostaining of fresh specimens, biochemistry, and molecular biological techniques. Formalin-fixed, paraffin-embedded sections routinely processed for immunohistochemistry failed to stain for Ki-67 and MIB 2. Antibodies MIB 1 and MIB 3 labelled mitotic figures, while non-mitotic proliferating cells were negative under these conditions. However, when dewaxed microwave oven-processed paraffin sections of formalin-fixed tissues were used, MIB 1 and MIB 3 gave strong nuclear staining of those cells presumed to proliferate under a variety of normal and neoplastic conditions. Moreover, routine decalcification or depigmentation techniques did not alter the immunoreactivity of MIB 1 and MIB 3 with microwave-processed paraffin sections. This method is highly reproducible, easy to perform at low cost, and no additional technical skill is needed because after microwave treatment just routine immunohistochemical methods are used. Since we have successfully applied this new method to sections obtained from paraffin blocks stored for a long time (in one case more than 60 years), the assessment of cell kinetics through the detection of Ki-67 antigen is now possible on archival material collected in histopathology departments all over the world.
Fast LMS/Newton Algorithms for Stereophonic Acoustic Echo Cancelation (2009)

This paper presents a new class of adaptive filtering algorithms to solve the stereophonic acoustic echo cancelation (AEC) problem in teleconferencing systems. While stereophonic AEC may be seen as a simple generalization of the well-known single-channel AEC, it is a fundamentally far more complex and challenging problem to solve. The main reason being the strong cross correlation that exists between the two input audio channels. In the past, nonlinearities have been introduced to reduce this correlation. However, nonlinearities bring with it additional harmonics that are undesirable. We propose an elegant linear technique to decorrelate the two-channel input signals and thus avoid the undesirable nonlinear distortions. We derive two low complexity adaptive algorithms based on the two-channel gradient lattice algorithm. The models assume the input sequences to the adaptive filters to be autoregressive (AR) processes whose orders are much lower than the lengths of the adaptive filters. This results in an algorithm, whose complexity is only slightly higher than the normalized least-mean-square (NLMS) algorithm; the simplest adaptive filtering method. Simulation results show that the proposed algorithms perform favorably when compared with the state-of-the-art algorithms.
Novel n-3 Fatty Acid Oxidation Products Activate Nrf2 by Destabilizing the Association between Keap1 and Cullin3 (2006)

Consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can mitigate the progression of diseases in which oxidative stress represents a common underlying biochemical process. Nrf2-regulated gene expression regulates detoxification of reactive oxygen species. EPA and DHA were subjected to an in vitro free radical oxidation process that models in vivo conditions. Oxidized n-3 fatty acids reacted directly with the negative regulator of Nrf2, Keap1, initiating Keap1 dissociation with Cullin3, thereby inducing Nrf2-directed gene expression. Liquid chromatography-tandem mass spectrometry analyses of oxidized EPA demonstrated the presence of novel cyclopentenone-containing molecules termed J3-isoprostanes in vitro and in vivo and were shown to induce Nrf2-directed gene expression. These experiments provide a biochemical basis for the hypothesis that formation of J-ring compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based cellular defense systems.
Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes (1990)

Monocytes activated by lipopolysaccharide (LPS) and interferon gamma (IFN gamma) rapidly secrete a number of monokines with different functional properties. Interleukin-4 (IL-4), a T-cell derived cytokine, has been shown to reduce the production of monokines with cytostatic activity for tumor cells, chemotactic activity for monocytes, and factors that stimulate thymocyte proliferation. This latter activity is mediated by a number of monokines like IL-1, tumor necrosis factor alpha (TNF alpha), and IL-6. To elucidate which cytokines produced by monocytes are controlled by IL-4, we tested the effect of IL-4 on the secretion of IL-1 alpha, IL-1 beta, TNF alpha, and IL-6 induced by LPS or IFN gamma. IL-4 was found to inhibit the secretion of IL-1 beta and TNF alpha by activated monocytes almost 100%. The secretion of IL-6 was found to be reduced 70% to 85% in the presence of IL-4, whereas there was no effect on the secretion of IL-1 alpha (IL-1 alpha is mainly cell-associated). Time-course experiments demonstrate that IL-4 reduces the secretion of monokines for a prolonged period of time (greater than 40 hours). The reduced secretion of IL-1 beta and TNF alpha was specifically induced by IL-4 because anti-IL-4 antiserum completely restored normal monokine production. These data suggest that IL-4 plays a role in the regulation of immune responses by reducing the production of functionally important monokines.
Factor VII activity state in coronary artery disease. (1988)

In a recent study, Dalaker et al. (Br J Haematol 1985; 61:315-22) reported that men at high risk for cardiovascular disease had an increased mean level of factor VII procoagulant activity that was apparently attributable to an increase of a phospholipase C-sensitive form of factor VII in their plasma. We chose to investigate this phenomenon further by observing patients at high risk of coronary artery disease with assays that reflect the activity state of factor VII. We measured factor VII levels in patients before coronary arteriography and in normal subjects by an amidolytic assay (FVIIam assay) and by a standard clotting assay (FVIIc-A assay), both of which reflect the total amount of factor VII and are insensitive to activated factor VII, and by the method of Seligson et al. (Blood 1978;52:978-88) (FVIIc-B assay), which is sensitive to the presence of activated factor VII. In the FVIIc-A and FVIIam assays, the patients had a significantly higher mean value than the normal subjects; in the FVIIc-B assay, the patients had a significantly lower mean value than did the normal subjects. Moreover, the ratio of FVIIc-B to FVIIam, which is an indicator of the factor VII activity state, was much lower for the patients (0.70) than for the normal subjects (0.99). Thus, patients at high risk for coronary artery disease have an increased mean level of total factor VII that is not associated with an increase in activated factor VII and therefore presumably reflects an increase in zymogen factor VII.
Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage (2011)

The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy-guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients.
Active lens control for high precision computer imaging (2002)

Lenses used in computer vision systems have many nonideal behaviors that can have a significant effect on vision tasks if not taken into account or compensated for. The authors show how two nonideal lens behaviors, chromatic aberration and focus magnification, can cause significant problems in color image analysis and focus ranging respectively. They show how precise active lens control can be used to reduce these effects significantly.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Systemic Delivery of scAAV9 Expressing SMN Prolongs Survival in a Model of Spinal Muscular Atrophy (2010)

Spinal muscular atrophy is one of the most common genetic causes of death in childhood, and there is currently no effective treatment. The disease is caused by mutations in the survival motor neuron gene. Gene therapy aimed at restoring the protein encoded by this gene is a rational therapeutic approach to ameliorate the disease phenotype. We previously reported that intramuscular delivery of a lentiviral vector expressing survival motor neuron increased the life expectancy of transgenic mice with spinal muscular atrophy. The marginal efficacy of this therapeutic approach, however, prompted us to explore different strategies for gene therapy delivery to motor neurons to achieve a more clinically relevant effect. Here, we report that a single injection of self-complementary adeno-associated virus serotype 9 expressing green fluorescent protein or of a codon-optimized version of the survival motor neuron protein into the facial vein 1 day after birth in mice carrying a defective survival motor neuron gene led to widespread gene transfer. Furthermore, this gene therapy resulted in a substantial extension of life span in these animals. These data demonstrate a significant increase in survival in a mouse model of spinal muscular atrophy and provide evidence for effective therapy.
Role of the Synthase Domain of Ags1p in Cell Wall α-Glucan Biosynthesis in Fission Yeast (2007)

The cell wall is important for maintenance of the structural integrity and morphology of fungal cells. Besides beta-glucan and chitin, alpha-glucan is a major polysaccharide in the cell wall of many fungi. In the fission yeast Schizosaccharomyces pombe, cell wall alpha-glucan is an essential component, consisting mainly of (1,3)-alpha-glucan with approximately 10% (1,4)-linked alpha-glucose residues. The multidomain protein Ags1p is required for alpha-glucan biosynthesis and is conserved among cell wall alpha-glucan-containing fungi. One of its domains shares amino acid sequence motifs with (1,4)-alpha-glucan synthases such as bacterial glycogen synthases and plant starch synthases. Whether Ags1p is involved in the synthesis of the (1,4)-alpha-glucan constituent of cell wall alpha-glucan had remained unclear. Here, we show that overexpression of Ags1p in S. pombe cells results in accumulation of (1,4)-alpha-glucan. To determine whether the synthase domain of Ags1p is responsible for this activity, we overexpressed Ags1p-E1526A, which carries a mutation in a putative catalytic residue of the synthase domain, but observed no accumulation of (1,4)-alpha-glucan. Compared with wild-type Ags1p, this mutant Ags1p showed a markedly reduced ability to complement the cell lysis phenotype of the temperature-sensitive ags1-1 mutant. Therefore, we conclude that, in S. pombe, the production of (1,4)-alpha-glucan by the synthase domain of Ags1p is important for the biosynthesis of cell wall alpha-glucan.
The Use of Antiepileptic Drugs—Principles and Practice (2004)

Up to 70% of people developing epilepsy may expect to become seizure free with optimum antiepileptic drug (AED) therapy. The remaining 30% are the most difficult to treat. Most patients are controlled on a single AED, but a small proportion requires a combination of two agents. Add-on therapy with a second drug, rather than substitution, may be a viable and rational approach in some patients, particularly if the first drug is relatively well tolerated. Precise classification of the type of seizures, as well as the epilepsy syndrome, together with careful recording of both seizures and adverse effects, are essential if rational management decisions are to be made. The goal of therapy should be complete seizure freedom with a single drug taken once or twice a day and without adverse effects. If control is difficult to achieve, the maximum tolerated dose of each drug should be explored, but a balance needs to be struck between adverse effects and control of seizures. In patients in whom treatment appears to be ineffective, the diagnosis of epilepsy and adherence to therapy should be reviewed. Drugs used in combination must be carefully selected, as poor adherence, drug interactions, and toxicity are more likely if more than one drug is prescribed. Agents are usually chosen according to seizure type, patient characteristics, and often by clinician preference. Those that are better tolerated have a low potential for pharmacokinetic and pharmacodynamic interactions, and those that can be easily introduced without any complicated titration schedule have an advantage.
Factor Xa induces mitogenesis of coronary artery smooth muscle cell via activation of PAR‐2 (2002)

Factor Xa-induced stimulation of coronary artery smooth muscle cells (CASMC) was investigated by analyzing [(3)H]thymidine incorporation, cell proliferation, and ERK-1/2 activation. Exposure of the cells to factor Xa evoked a time-dependent activation of ERK-1/2 with increased [(3)H]thymidine incorporation and cell proliferation. The factor Xa-induced ERK-1/2 activation was not desensitized by preincubation of the cells with thrombin. However, ERK-1/2 activation was markedly attenuated by prior exposure of the cells to protease-activated receptor-2 (PAR-2) activating peptide, SLIGKV. The mitogenic effect of factor Xa was significantly reduced in the presence of anti-PAR-2 monoclonal antibody. Several lines of experimental evidence indicate that factor Xa-induced mitogenesis of CASMC is a cellular process mediated by PAR-2 activation.
Virulence of Agrobacterium tumefaciens Strain A281 on Legumes (1987)

This study addresses the basis of host range on legumes of Agrobacterium tumefaciens strain A281, an l,l-succinamopine strain. We tested virulence of T-DNA and vir region constructs from this tumor-inducing (Ti) plasmid with complementary Ti plasmid regions from heterologous nopaline and octopine strains.