gebhart/patrepeval huggingface dataset:
Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier (2005)

The central nervous system (CNS) effects of many therapeutic drugs are blunted because of restricted entry into the brain. The basis for this poor permeability is the brain capillary endothelium, which comprises the blood-brain barrier. This tissue exhibits very low paracellular (tight-junctional) permeability and expresses potent, multispecific, drug export pumps. Together, these combine to limit use of pharmacotherapy to treat CNS disorders such as brain cancer and bacterial or viral infections. Of all the xenobiotic efflux pumps highly expressed in brain capillary endothelial cells, p-glycoprotein handles the largest fraction of commonly prescribed drugs and thus is an obvious target for manipulation. Here we review recent studies focused on understanding the mechanisms by which p-glycoprotein activity in the blood-brain barrier can be modulated. These include (i) direct inhibition by specific competitors, (ii) functional modulation, and (iii) transcriptional modulation. Each has the potential to specifically reduce p-glycoprotein function and thus selectively increase brain permeability of p-glycoprotein substrates.
Lambda/plasmid vector construction by in vivo cre/lox-mediated recombination. (1994)

Lambda/plasmid hybrid vectors have been previously constructed in which the plasmid sequences are separated from flanking lambda arms by lox sites. The lox sequence is the substrate of Cre-mediated site-specific recombination, allowing easy excision of plasmid sequences (automatic subcloning). We have developed a simple procedure to construct other such lambda hybrid vectors using in vivo cre/lox-mediated recombination to exchange new plasmids for plasmids previously incorporated into lambda/plasmid hybrids. Because hybrid vectors both with and without lacZ alpha plasmid sequences are available, producing either blue or clear plaques, respectively, the new lambda hybrid vectors can be distinguished from the parental hybrids by blue/clear plaque screening. This procedure has been successfully used to construct ten hybrid vectors. It generates new lambda/plasmid hybrid vectors, without ligation or lambda packaging, which retain the property of automatic subcloning.
Heterogeneity in polyadenylation cleavage sites in mammalian mRNA sequences: implications for SAGE analysis (2001)

The analysis of a human thyroid serial analysis of gene expression (SAGE) library shows the presence of an abundant SAGE tag corresponding to the mRNA of thyroglobulin (TG). Additional, less abundant tags are present that can not be linked to any other known gene, but show considerable homology to the wild-type TG tag. To determine whether these tags represent TG mRNA molecules with alternative cleavage, 3'-RACE clones were sequenced. The results show that the three putative TG SAGE tags can be attributed to TG transcripts and reflect the use of alternative polyadenylation cleavage sites downstream of a single polyadenylation signal in vivo. By screening more than 300 000 sequences corresponding to human, mouse and rat transcripts for this phenomenon we show that a considerable percentage of mRNA transcripts (44% human, 22% mouse and 22% rat) show cleavage site heterogeneity. When analyzing SAGE-generated expression data, this phenomenon should be considered, since, according to our calculations, 2.8% of human transcripts show two or more different SAGE tags corresponding to a single gene because of alternative cleavage site selection. Both experimental and in silico data show that the selection of the specific cleavage site for poly(A) addition using a given polyadenylation signal is more variable than was previously thought.
Grafting of Gelatin on Electrospun Poly(caprolactone) Nanofibers to Improve Endothelial Cell Spreading and Proliferation and to Control Cell Orientation (2005)

We modified the surface of electrospun poly(caprolactone) (PCL) nanofibers to improve their compatibility with endothelial cells (ECs) and to show the potential application of PCL nanofibers as a blood vessel tissue-engineering scaffold. Nonwoven PCL nanofibers (PCL NF) and aligned PCL nanofibers (APCL NF) were fabricated by electrospinning technology. To graft gelatin on the nanofiber surface, PCL nanofibers were first treated with air plasma to introduce -COOH groups on the surface, followed by covalent grafting of gelatin molecules, using water-soluble carbodiimide as the coupling agent. The chemical change in the material surface during surface modification was confirmed by X-ray photoelectron spectroscopy and quantified by colorimetric methods. ECs were cultured to evaluate the cytocompatibility of surface-modified PCL NF and APCL NF. Gelatin grafting can obviously enhance EC spreading and proliferation compared with the original material. Moreover, gelatin-grafted APCL NF readily orients ECs along the fibers whereas unmodified APCL NF does not. Immunostaining micrographs showed that ECs cultured on gelatin-grafted PCL NF were able to maintain the expression of three characteristic markers: platelet-endothelial cell adhesion molecule 1 (PECAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). The surface-modified PCL nanofibrous material is a potential candidate material in blood vessel tissue engineering.
Multiple tumor marker analyses (PSA, hK2, PSCA, trp-p8) in primary prostate cancers using quantitative RT-PCR (2003)

The identification of new diagnostic markers and potential treatment targets for prostate carcinoma (PCa) necessitates the evaluation of expression patterns in both malignant and non-malignant tissue specimens. In this study, we compared the mRNA expression of recently identified prostate-associated genes, prostate stem cell antigen (PSCA) and transient receptor potential p8 (trp-p8), to the mRNA expression of the most commonly used markers for PCa, prostate-specific antigen (PSA) and human kallikrein 2 (hK2). For these four candidates we performed highly specific quantitative real-time LightCycler RT-PCR assays with cDNA originating from matched tissue specimens of 40 patients with primary PCa. The highest transcript amounts were found for PSA in malignant as well as in non-malignant tissue specimens followed by hK2, trp-p8 and PSCA with an mRNA expression remarkably lower. The relative transcript levels of PSA, hK2 and trp-p8 were elevated in malignant in comparison to non-malignant tissues, but only for trp-p8 this increased expression was statistically significant. Focussing on organ confined tumors, we found a significant difference of the mRNA expression of PSA and trp-p8 between malignant and non-malignant tissue specimens. The marker trp-p8 is also suited to differentiate between the tumor stages when quantifying its transcript levels within tumor tissue specimens. The evaluation of the mRNA expression patterns of these markers by quantitative real-time RT-PCR could provide new tools for differential diagnosis and molecular staging. According to our data, the novel marker trp-p8 seems to represent a highly prostate-specific and PCa-associated gene qualifying it as a potential target for specific therapies.
Structure and Gene Silencing Activities of Monovalent and Pentavalent Cationic Lipid Vectors Complexed with siRNA (2007)

Small interfering RNAs (siRNAs) of 19-25 bp mediate the cleavage of complementary mRNA, leading to post-transcriptional gene silencing. We examined cationic lipid (CL)-mediated delivery of siRNA into mammalian cells and made comparisons to CL-based DNA delivery. The effect of lipid composition and headgroup charge on the biophysical and biological properties of CL-siRNA vectors was determined. X-ray diffraction revealed that CL-siRNA complexes exhibited lamellar and inverted hexagonal phases, qualitatively similar to CL-DNA complexes, but also formed other nonlamellar structures. Surprisingly, optimally formulated inverted hexagonal 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) CL-siRNA complexes exhibited high toxicity and much lower target-specific gene silencing than lamellar CL-siRNA complexes even though optimally formulated, inverted hexagonal CL-DNA complexes show high transfection efficiency in cell culture. We further found that efficient silencing required cationic lipid/nucleic acid molar charge ratios (rhochg) nearly an order of magnitude larger than those yielding efficiently transfecting CL-DNA complexes. This second unexpected finding has implications for cell toxicity. Multivalent lipids (MVLs) require a smaller number of cationic lipids at a given rhochg of the complex. Consistent with this observation, the pentavalent lipid MVL5 exhibited lower toxicity and superior silencing efficiency over a large range in both the lipid composition and rhochg when compared to monovalent DOTAP. Most importantly, MVL5 achieved much higher total knockdown of the target gene in CL-siRNA complex regimes where toxicity was low. This property of CL-siRNA complexes contrasts to CL-DNA complexes, where the optimized transfection efficiencies of multivalent and monovalent lipids are comparable.
Amyotrophic lateral sclerosis: update for family physicians. (2006)

Because ALS is a complex disease, care of ALS patients is best provided at multidisciplinary clinics that specialize in managing patients with this disorder.
Mimicking live flavivirus immunization with a noninfectious RNA vaccine (2004)

Flaviviruses are human pathogens of world-wide medical importance. They have recently received much additional attention because of their spread to new regions (such as West Nile virus to North America), highlighting their potential as newly emerging disease agents. Using tick-borne encephalitis virus, we have developed and evaluated in mice a new genetic vaccine based on self-replicating but noninfectious RNA. This RNA contains all of the necessary genetic information for establishing its replication machinery in the host cell, thus mimicking a natural infection. However, genetic modifications in the region encoding the capsid protein simultaneously prevent the assembly of infectious virus particles and promote the secretion of noninfectious subviral particles that elicit neutralizing antibodies. These characteristics demonstrate that a new generation of flavivirus vaccines can be designed that stimulate the same spectrum of innate and specific immune responses as a live vaccine but have the safety features of an inactivated vaccine.
Arguments Against Legalization of Illicit Drugs (1991)

No abstract available for this article.
Li-Based Thermal Neutron Scintillator Research; ${\hbox {Rb}}_{2}{\hbox {LiYBr}}_{6}:{\hbox {Ce}}^{3+}$ and Other Elpasolites (2008)

We investigated gamma- and neutron-scintillation properties of A <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> LiLnX <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sub> :Ce <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3+</sup> (A=Cs, Rb, K, Na, Li; Ln=La, Y, Lu, Sc; X=Br, I) with the aim to develop new scintillators with high neutron detection efficiencies. Among the investigated thermal neutron scintillators, Rb <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> LiYBr <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sub> :Ce <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3+</sup> shows an excellent neutron peak resolution of 3.6%. This is the best neutron peak resolution ever reported. Together with the large alpha/beta ratio of 0.74, Rb <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> LiYBr <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sub> :Ce <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3+</sup> offers the possibility of excellent neutron/gamma discrimination. The highest thermal neutron scintillation light yield of 83,000 photons/neutron is also reported for Rb <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> LiYBr <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sub> :Ce <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3+</sup> .
Analysis of Alcohol and Alkylphenol Polyethers via Packed Column Supercritical Fluid Chromatography (2004)

Alkylphenol ethoxylates (APEOs), alcohol ethoxylates (AEOs), and alcohol propoxylates (APOs) are non-ionic surfactants used in daily care products and detergents. They are formed as an oligomeric series with a varying distribution, which determines their commercial application. The goal of the research performed was the development of sample characterization methods for non-ionic surfactants utilizing supercritical fluid chromatography (SFC) under mild instrument operating conditions. The aryl group present in APEOs allowed ultraviolet (UV) detection, with an equal molar response for oligomers, allowing average molar oligomer values to be calculated. APEOs were separated by ethoxylate unit via SFC-UV as well as normal phase HPLC-UV employing packed columns. Stationary phase and column length were varied in the SFC setup to produce the most favorable separation conditions. Fractions from SFC runs of APEOs were collected and analyzed by flow injection analysis electrospray ionization mass spectrometry (FIA-ESI-MS) to identify fraction composition. SFC provided shorter retention times with similar resolution as HPLC for separation of APEOs and consumed a smaller amount of organic solvent. \nAEOs and APOs lack functionality capable of absorbing UV light outside the UV cut-off of normal organic solvents. SFC was able to separate AEOs and APOs derivatized as trimethylsilyl ethers (TMS) with pure CO2 with detection at 195 nm. The instrumental conditions, however, needed for separation necessitated high temperature and high CO2 pressure. Derivatization of alcohol polyether samples with an UV absorbing agent was achieved with phenylated disilazane-chlorosilane mixtures forming phenylsilylethers detected at 215 nm. Use of an organic solvent-modified CO2 mobile phase afforded lower pressure and temperature conditions for oligomer separation. \n The use of polar embedded alkyl phases combined with use of organic modified CO2 produced good resolution between oligomers. Better peak shape and shorter retention times were realized with methanol-modified CO2 than acetonitrile-modified CO2. \nPeak assignments were made via SFC coupled with ESI-MS detection in the positive ion mode. SFC-UV and SFC-ESI-MS data were jointly used for calculation of average molar oligomer values. Proton nuclear magnetic resonance (1H-NMR) analysis of non-derivatized samples was performed to determine average molar oligomer values and was used for comparison with values calculated from SFC-UV data.
Transformation properties of type 5 adenovirus mutants that differentially express the E1A gene products. (1984)

Type 5 adenovirus mutants that differentially express E1A 13S, 12S, or 9S mRNAs were constructed to study the role of their gene products in transformation. H5dl520 expresses the 243-amino-acid (AA) protein encoded in the 12S mRNA but not the 13S mRNA-encoded 289-AA protein. This mutant transformed both cloned rat embryo fibroblast (CREF) cells and baby rat kidney (BRK) cells at a frequency 40-100 times greater than did wild-type viruses. In addition, all of the foci produced were fibroblastic and grew very slowly at 32 degrees C. In contrast, H5dl21, which was mutated so that only the 54-AA protein encoded by the 9S mRNA was synthesized, did not transform either cell type. DNA transfection studies with plasmids from which these mutants were constructed demonstrated that the differences in transformation frequencies were not as marked. The plasmid pD1/D2, which directs the synthesis of the 54-AA protein only, was found to transform baby rat kidney cells at low frequency, provided the gene was linked to a fragment from the simian virus 40 genome containing the transcriptional enhancer element.
Isoform-specific Binding of Selenoprotein P to the β-Propeller Domain of Apolipoprotein E Receptor 2 Mediates Selenium Supply (2014)

Sepp1 supplies selenium to tissues via receptor-mediated endocytosis. Mice, rats, and humans have 10 selenocysteines in Sepp1, which are incorporated via recoding of the stop codon, UGA. Four isoforms of rat Sepp1 have been identified, including full-length Sepp1 and three others, which terminate at the second, third, and seventh UGA codons. Previous studies have shown that the longer Sepp1 isoforms bind to the low density lipoprotein receptor apoER2, but the mechanism remains unclear. To identify the essential residues for apoER2 binding, an in vitro Sepp1 binding assay was developed using different Sec to Cys substituted variants of Sepp1 produced in HEK293T cells. ApoER2 was found to bind the two longest isoforms. These results suggest that Sepp1 isoforms with six or more selenocysteines are taken up by apoER2. Furthermore, the C-terminal domain of Sepp1 alone can bind to apoER2. These results indicate that apoER2 binds to the Sepp1 C-terminal domain and does not require the heparin-binding site, which is located in the N-terminal domain. Site-directed mutagenesis identified three residues of Sepp1 that are necessary for apoER2 binding. Sequential deletion of extracellular domains of apoER2 surprisingly identified the YWTD β-propeller domain as the Sepp1 binding site. Finally, we show that apoER2 missing the ligand-binding repeat region, which can result from cleavage at a furin cleavage site present in some apoER2 isoforms, can act as a receptor for Sepp1. Thus, longer isoforms of Sepp1 with high selenium content interact with a binding site distinct from the ligand-binding domain of apoER2 for selenium delivery.
Additions, Losses, and Rearrangements on the Evolutionary Route from a Reconstructed Ancestor to the Modern Saccharomyces cerevisiae Genome (2009)

Comparative genomics can be used to infer the history of genomic rearrangements that occurred during the evolution of a species. We used the principle of parsimony, applied to aligned synteny blocks from 11 yeast species, to infer the gene content and gene order that existed in the genome of an extinct ancestral yeast about 100 Mya, immediately before it underwent whole-genome duplication (WGD). The reconstructed ancestral genome contains 4,703 ordered loci on eight chromosomes. The reconstruction is complete except for the subtelomeric regions. We then inferred the series of rearrangement steps that led from this ancestor to the current Saccharomyces cerevisiae genome; relative to the ancestral genome we observe 73 inversions, 66 reciprocal translocations, and five translocations involving telomeres. Some fragile chromosomal sites were reused as evolutionary breakpoints multiple times. We identified 124 genes that have been gained by S. cerevisiae in the time since the WGD, including one that is derived from a hAT family transposon, and 88 ancestral loci at which S. cerevisiae did not retain either of the gene copies that were formed by WGD. Sites of gene gain and evolutionary breakpoints both tend to be associated with tRNA genes and, to a lesser extent, with origins of replication. Many of the gained genes in S. cerevisiae have functions associated with ethanol production, growth in hypoxic environments, or the uptake of alternative nutrient sources.
Multi-unit ribozyme-mediated cleavage of bcr-abl mRNA in myeloid leukemias (1995)

Chronic myelogenous leukemia is characterized by the Philadelphia chromosome, which at the molecular level results from the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity. In this study, we have synthesized a multi-unti ribozyme that targets bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cleavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into murine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozyme transfection was accomplished either by liposomes or using follic acid-polylysine as a carrier. Multi-unit ribozyme transfection reduced the level of bcr-abl mRNA 3 logs when transfected via folate receptor-mediated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia.
<title>Temperature compensation scheme for refractive index grating-based optical fiber devices</title> (1996)

A major problem currently affecting the implementation of grating-based optical fiber devices is the drift in wavelength modulation due to the change in the ambient temperature. For accurate and reliable long term operation of these devices, suitable temperature compensation techniques are a necessity. This paper presents a novel temperature compensation technique for in-fiber refractive index grating-based devices and components. The proposed technique is based on the temperature-dependent spectral characteristics of a dielectric multi-layer thin film interference filter fabricated on the endface of refractive-index grating impressed optical fiber. Temperature compensation is achieved by comparing the reflected intensities at the grating- reflected and the interference filter-reflected wavelengths. The proposed scheme also compensates for any light source fluctuations and lead-in fiber bending losses. Thus a self- calibrated optical fiber sensor configuration is obtained.
Life and Death Decisions: ced-9 and Programmed Cell Death in Caenorhabditis elegans (1995)

In his grand prize-winning essay for the Pharmacia Biotech &amp; Science Prize for Young Scientists, M. Hengartner discusses the phenomenon of programmed cell death and the gene ced-9 from C. elegans , a small nematode in which the pattern of cell death during development is completely known. The ced-9 gene seems to keep the cell death program off in cells that are scheduled to live.
Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation (2001)

The cytoplasm seems to provide an environment that favors conversion of the prion protein (PrP) to a form with the physical characteristics of the PrP(Sc) conformation, which is associated with transmissible spongiform encephalopathies. However, it is not clear whether PrP would ever exist in the cytoplasm under normal circumstances. We report that PrP accumulates in the cytoplasm when proteasome activity is compromised. The accumulated PrP seems to have been subjected to the normal proteolytic cleavage events associated with N- and C-terminal processing in the endoplasmic reticulum, suggesting that it arrives in the cytoplasm through retrograde transport. In the cytoplasm, PrP forms aggregates, often in association with Hsc70. With prolonged incubation, these aggregates accumulate in an "aggresome"-like state, surrounding the centrosome. A mutant (D177N), which is associated with a heritable and transmissible form of the spongiform encephalopathies, is less efficiently trafficked to the surface than wild-type PrP and accumulates in the cytoplasm even without proteasome inhibition. These results demonstrate that PrP can accumulate in the cytoplasm and is likely to enter this compartment through normal protein quality-control pathways. Its potential to accumulate in the cytoplasm has implications for pathogenesis.