gebhart/patrepeval huggingface dataset:
Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan (2015)

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ETA and ETB receptor antagonist with high affinity and sustained receptor binding is the first ET receptor antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug-drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
Non-invasive techniques for analysing hormonal indicators of stress. (2004)

The growing concern over animal welfare has led to an increased awareness of the need to monitor and reduce stress in laboratory, zoo, and farm animals. To do so, valid and reliable methods are necessary. In the present work, we discuss non-invasive techniques for analysing hormonal indicators of stress, particularly glucocorticoids. Specifically, we describe methods for analysing samples of saliva, urine, and faeces, the collection of which, unlike blood sampling, does not represent a source of stress and thus a potential source of bias. We also address species-specific responses to stress and inter-individual variability, the reliability of specific hormonal assays, and the use of indirect measures of circulating stress hormones.
Stabilization of liquid crystal photoaligning layers by reactive mesogens (2009)

Via passivation of liquid crystal (LC) photoaligning layers by thin layers of reactive mesogens, strong enhancement in LC alignment stability is achieved. Simultaneously, the passivation layers improve alignment uniformity and chemical stability of photoaligning layers and widely change pretilt angle of liquid crystal.
TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. (2000)

Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. The hypothesis that aberrant methylation plays a direct causal role in carcinogenesis hinges on the question of whether aberrant methylation is sufficient to drive gene silencing. To identify downstream targets of methylation-induced gene silencing, we used a human cell model in which aberrant CpG island methylation is induced by ectopic expression of DNA methyltransferase. Here we report the isolation and characterization of TMS1 (target of methylation-induced silencing), a novel CpG island-associated gene that becomes hypermethylated and silenced in cells overexpressing DNA cytosine-5-methyltransferase-1. We also show that TMS1 is aberrantly methylated and silenced in human breast cancer cells. Forty percent (11 of 27) of primary breast tumors exhibited aberrant methylation of TMS1. TMS1 is localized to chromosome 16p11.2-12.1 and encodes a 22-kDa predicted protein containing a COOH-terminal caspase recruitment domain, a recently described protein interaction motif found in apoptotic signaling molecules. Ectopic expression of TMS1 induced apoptosis in 293 cells and inhibited the survival of human breast cancer cells. The data suggest that methylation-mediated silencing of TMS1 confers a survival advantage by allowing cells to escape from apoptosis, supporting a new role for aberrant methylation in breast tumorigenesis.
Network tomography on general topologies (2002)

In this paper we consider the problem of inferring link-level loss rates from end-to-end multicast measurements taken from a collection of trees. We give conditions under which loss rates are identifiable on a specified set of links. Two algorithms are presented to perform the link-level inferences for those links on which losses can be identified. One, the minimum variance weighted average (MVWA) algorithm treats the trees separately and then averages the results. The second, based on expectation-maximization (EM) merges all of the measurements into one computation. Simulations show that EM is slightly more accurate than MVWA, most likely due to its more efficient use of the measurements. We also describe extensions to the inference of link-level delay, inference from end-to-end unicast measurements, and inference when some measurements are missing.
Class IIA HDACs in the regulation of neurodegeneration (2007)

Neurodegenerative diseases affect millions of patients annually and are a significant burden on the health care systems around the world. While there are symptomatic remedies for patients suffering from various neurodegenerative diseases, there are no cures as of today. Cell death by apoptosis is a common hallmark of neurodegeneration. Therefore, deciphering the molecular pathways regulating this process is of significant value to scientists' endeavor to understand neurodegenerative disorders. Efforts along these lines have uncovered a number of molecular pathways that regulate neuronal apoptosis. Recently, a family of proteins known as histone deacetylases (HDACs) has been linked to regulation of cell survival as well as death. The focus of this review is to summarize our current understanding of the role of HDACs and in particular a subgroup of proteins in this family classified as class IIa HDACs in the regulation of neuronal cell death. It is apparent based on the information presented in this review that although very similar in their primary sequence, members of this family of proteins often have distinct roles in orchestrating apoptotic cell death in the brain.
Expression Patterns of Plasma Proteins in Spontaneously Diabetic Rats after Oral Administration of a Kampo Medicine, Hachimi-jio-gan, Using SELDI ProteinChip Platform (2005)

We investigated the changes (increase or decrease in peak intensity) in the expression of plasma proteins in spontaneously diabetic WBN/Kob rats that were with complicated diabetic nephropathy, to determine multiple biomarkers in the plasma of diabetic rats. The present study using surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) demonstrated that six peaks at mass/charge ratios (m/z) of 4678, 4732, 4808, 9058, 9323, and 9465, among approximately 80 peaks per spectrum in the 2000—10000 Da mass range, had increased peak intensities with the development or progression of diabetic nephropathy in plasma of spontaneously diabetic WBN/Kob rats as compared with those of normal Wistar rats. Administration of the Kampo medicine Hachimi-jio-gan was effective at reducing the expression of diabetic nephropathy but not at reducing blood glucose levels. It also improved the increased levels of these plasma proteins. Other biomarker peaks at m/z 5067, 5279, 7598, and 7917 were not affected by Hachimi-jio-gan administration. Further study will be needed to identify these positive biomarkers and to evaluate the relationship between the efficacy and expression patterns of the plasma proteins in greater detail. The expression patterns of proteins and molecular-related ions revealed that several proteins in plasma may be involved in the development and/or progression of diabetic nephropathy in WBN/Kob rats and the efficacy of Hachimi-jio-gan. This study using ProteinChip technology may provide a useful basis in the search for multiple biomarkers in plasma for the diagnosis of disease and therapeutic evaluation of Kampo medicines.
Contents, Vol. 18, 1979 (1979)

In tern ation al Jo u rn a l o f E xp erim en tal and C lin ic a l P h a rm a c o lo g y
A unified 7.5nm dash-type confined cell for high performance PRAM device (2008)

We present a new-type confine structure within 7.5 nm width dash-contact for sub 20 nm generation PRAMs. Phase change material (PCM) by chemical vapor deposition (CVD) was perfectly filled in a 7.5 nm width dash-contact without void along with 30 nm depth. By adopting confined CVD-PCM, we were able to reduce the reset current below ~160 muA and to obtain high reliability. In addition, the programming time of dash-confined cell was much improved to 50 ns due to volume confinement of PCM cell. Consequently, we firstly demonstrate the high performance of the 7.5 nm width confined cell, which is the smallest size close to physical limit.
Converting IL-15 to a superagonist by binding to soluble IL-15Rα (2006)

IL-15 is normally presented in vivo as a cell-associated cytokine bound to IL-15Ralpha. We show here that the biological activity of soluble IL-15 is much improved after interaction with recombinant soluble IL-15Ralpha; after injection, soluble IL-15/IL-15Ralpha complexes rapidly induce strong and selective expansion of memory-phenotype CD8(+) cells and natural killer cells. These findings imply that binding of IL-15Ralpha to IL-15 may create a conformational change that potentiates IL-15 recognition by the betagamma(c) receptor on T cells. The enhancing effect of IL-15Ralpha binding may explain why IL-15 normally functions as a cell-associated cytokine. Significantly, the results with IL-2, a soluble cytokine, are quite different; thus, IL-2 function is markedly inhibited by binding to soluble IL-2Ralpha.
Multiple-Electrode Radiofrequency Ablation of Symptomatic Hepatic Cavernous Hemangioma (2007)

Multiple-Electrode Radiofrequency Ablation of Symptomatic Hepatic Cavernous HemangiomaJ. Louis Hinshaw1, Paul J. Laeseke1, Sharon M. Weber2 and Fred T. Lee, Jr.1Audio Available | Share
Discovery of Allosteric Potentiators for the Metabotropic Glutamate 2 Receptor:  Synthesis and Subtype Selectivity of N-(4-(2-Methoxyphenoxy)phenyl)-N-(2,2,2− trifluoroethylsulfonyl)pyrid-3-ylmethylamine (2003)

This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g., 3) potentiate glutamate, shifting agonist potency by 2-fold. This effect was specific for mGlu2 (vs mGlu1,3-8 receptors). Also, 3 failed to potentiate a chimeric mGlu2/1 receptor, demonstrating the mGlu2 transmembrane region's critical involvement. In a fear-potentiated startle model, 3 showed anxiolytic activity that was prevented by mGlu2/3 antagonist pretreatment. Thus, these pyridylmethylsulfonamides represent the first mGlu2 receptor potentiators discovered.
Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target (2009)

Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from about 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses.
High-efficiency incorporation of functional influenza virus glycoproteins into recombinant vesicular stomatitis viruses (1997)

We derived recombinant vesicular stomatitis virus (VSV) expressing either influenza virus hemagglutinin (HA) or neuraminidase (NA) glycoproteins from extra genes inserted in the viral genome. The HA protein was expressed from a site downstream of the VSV glycoprotein (G) gene, while NA protein was expressed from a site upstream of the VSV G gene. The HA protein was expressed at lower levels than the VSV G protein, while the NA protein was expressed at higher levels, as expected from the gradient of VSV transcription that follows the gene order. The HA and NA proteins were transported to the cell surface and were functional as demonstrated by hemadsorption, hemolysis, and NA assays. Biochemical analysis showed that both HA and NA proteins were incorporated into VSV particles at high levels, although there was a preference for incorporation of the VSV G protein over either of the influenza virus proteins. Immunoelectron microscopy of the recombinants showed that the particles derived from the recombinants were mosaics carrying both the VSV G protein and the influenza virus membrane glycoproteins. These results extend earlier studies showing incorporation of the cellular glycoprotein CD4 and two other viral glycoproteins into VSV particles. Our results indicate that there is significant space in the VSV membrane that can accommodate foreign membrane proteins and that the foreign protein can represent as much as 35% of the total protein in the viral envelope. Incorporation of foreign proteins into VSV virions can, in many cases, occur passively in the absence of specific incorporation signals.
Diverse Gene Junctions of Respiratory Syncytial Virus Modulate the Efficiency of Transcription Termination and Respond Differently to M2-Mediated Antitermination (1999)

The ability of the diverse gene junctions of respiratory syncytial (RS) virus to signal the termination of transcription was analyzed. Nine dicistronic subgenomic replicons of RS virus were constructed; each contained one of the RS virus gene junctions in its natural upstream and downstream sequence context. The RNA synthesis activities of these subgenomic replicons were analyzed in the absence and presence of the M2 protein, which we showed previously to function as a transcription antiterminator. Our data showed that the efficiency with which the polymerase terminated transcription was affected by the gene junction that it encountered. The M2 protein significantly decreased the efficiency of the termination of transcription, resulting in increased levels of readthrough transcription at all the gene junctions. The diverse gene junctions fell into three broad groups with respect to their ability to signal transcription termination. One group of gene junctions (NS1/NS2, NS2/N, M2/L, and L/trailer) showed inefficient termination in the absence or the presence of the M2 protein. A second group of gene junctions (N/P, P/M, M/SH, SH/G, and G/F) terminated transcription efficiently. The SH/G gene junction terminated transcription with the greatest efficiency and produced low levels of readthrough transcripts in the absence or the presence of the M2 protein, correlating with the absence of SH/G polycistronic transcripts in RS virus-infected cells. The F/M2 gene junction was particularly sensitive to the M2 protein: it efficiently signaled termination in the absence of the M2 protein but produced high levels of readthrough transcripts in the presence of the M2 protein. This result suggests that the M2 protein may regulate its own production by negative feedback. The data presented here show that the different gene junctions of RS virus do modulate RS virus transcription termination. The M2 protein reduced termination at all gene junctions. The magnitude of antitermination due to the M2 protein, however, varied at the different gene junctions. The data presented here indicate that the mechanism for the regulation of RS virus gene expression is more complex than was previously appreciated.
Securing elastic applications on mobile devices for cloud computing (2009)

Cloud computing provides elastic computing infrastructure and resources which enable resource-on-demand and pay-as-you-go utility computing models. We believe that new applications can leverage these models to achieve new features that are not available for legacy applications. In our project we aim to build elastic applications which augment resource-constrained platforms, such as mobile phones, with elastic computing resources from clouds. An elastic application consists of one or more weblets, each of which can be launched on a device or cloud, and can be migrated between them according to dynamic changes of the computing environment or user preferences on the device. This paper overviews the general concept of this new application model, analyzes its unique security requirements, and presents our design considerations to build secure elastic applications. As first steps we propose a solution for authentication and secure session management between weblets running device side and those on the cloud. We then propose secure migration and how to authorize cloud weblets to access sensitive user data such as via external web services. We believe some principles in our solution can be applied in other cloud computing scenarios such as application integration between private and public clouds in an enterprise environment.
Consistency control of replicated data in federated databases (2002)

The effective use of distributed databases requires a proper balance between autonomy and coordination. A critical decision influencing the autonomy of local sites concerns the method for update propagation to replicated data. An identity connection model is designed to specify replication, permissible delay in the consistency of copies, and data derivation rules. This model allows the nature of the coupling between autonomous sites in a distributed database to be declared. A transaction processing mechanism is under development for consistency control of replicated data based on the identity connection model. The mechanism unifies existing approaches to update propagation, and it supports the filtering of update transactions that cannot meet consistency requirements as well as the alerting of query transactions that cannot see consistent data.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Molecular Cloning and Expression of a Third Type of Rabbit GDP-L-Fucose:β-D-Galactoside 2-α-L-Fucosyltransferase (1996)

Recent molecular investigation revealed that two closely related structural genes encode distinct GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferases (alpha1,2-fucosyltransferases). Some human cancer cells or tissues may express an aberrant alpha1, 2-fucosyltransferase other than H- and Secretor-type alpha1, 2-fucosyltransferase. However, definite evidence of the existence of a third type of alpha1,2-fucosyltransferase has not been demonstrated. Here we report the molecular cloning of a third type of rabbit alpha1,2-fucosyltransferase (RFT-III) from a rabbit genomic DNA library. The DNA sequence included an open reading frame coding for 347 amino acids, and the deduced amino acid sequence of RFT-III showed 59 and 80% identity with those of the previously reported two types of rabbit alpha1,2-fucosyltransferase, RFT-I and RFT-II, respectively. COS-7 cells transfected with the RFT-III gene exhibited alpha1,2-fucosyltransferase activity toward phenyl-beta-Gal as a substrate. Neuro2a (a murine neuroblastoma cell line) cells transfected with the RFT-III gene expressed fucosyl GM1 (type 3 H) but not Ulex europaeus agglutinin-1 lectin reactive antigens (type 2 H). Kinetic studies revealed that RFT-III exhibits higher affinity to types 1 (Galbeta1, 3GlcNAc) and 3 (Galbeta1, 3GalNAc) than to type 2 (Galbeta1, 4GlcNAc) oligosaccharides, which suggests that RFT-III as well as RFT-II is a Secretor-type alpha1, 2-fucosyltransferase. RFT-III was expressed in the adult gastrointestinal tract. The RFT-I, -II, and -III genes were assigned within 90 kilobases on pulsed field gel electrophoresis analysis. These results constitute direct evidence that, at least in one mammalian species, three active alpha1,2-fucosyltransferases exist.
Clinical Evaluation of a Biodegradable Collagen Membrane in Guided Tissue Regeneration (1990)

A bio-resorbable type I collagen membrane was investigated as a barrier for guided tissue regeneration. Ten human subjects with at least one pair of contralateral periodontal lesions with probing pocket depths of greater than or equal to 5 mm and radiographic evidence of greater than or equal to 40% bone loss were included. Each patient underwent contralateral surgical flap procedures. A collagen barrier was adapted to the tooth in the experimental defect and the flap replaced and sutured. The controls consisted of the same procedure without the placement of the barrier. Standardized measurements of change in probing attachment levels and fill of intrabony defects were obtained at the time of surgery and 1 year later at the time of surgical re-entry. The differences in change of probing attachment levels and amount of bone fill between individual test and control sites were compared utilizing the student's t-test for paired samples. The mean probing attachment gain in the test sites was 0.56 +/- 0.57 mm, and there was a mean probing attachment loss of 0.71 +/- 0.91 mm in the control sites (P less than 0.01). The gain of bone in test lesions was 1.16 +/- 0.95 mm, while no gain was observed in the control lesions (P less than 0.01). The results of this study demonstrated that sites treated with a collagen barrier comprised of cross-linked bovine Type I collagen exhibited significantly better healing as compared to control sites over the 1-year period of the study.
High-quality draft assemblies of mammalian genomes from massively parallel sequence data (2010)

Massively parallel DNA sequencing technologies are revolutionizing genomics by making it possible to generate billions of relatively short (~100-base) sequence reads at very low cost. Whereas such data can be readily used for a wide range of biomedical applications, it has proven difficult to use them to generate high-quality de novo genome assemblies of large, repeat-rich vertebrate genomes. To date, the genome assemblies generated from such data have fallen far short of those obtained with the older (but much more expensive) capillary-based sequencing approach. Here, we report the development of an algorithm for genome assembly, ALLPATHS-LG, and its application to massively parallel DNA sequence data from the human and mouse genomes, generated on the Illumina platform. The resulting draft genome assemblies have good accuracy, short-range contiguity, long-range connectivity, and coverage of the genome. In particular, the base accuracy is high (≥99.95%) and the scaffold sizes (N50 size = 11.5 Mb for human and 7.2 Mb for mouse) approach those obtained with capillary-based sequencing. The combination of improved sequencing technology and improved computational methods should now make it possible to increase dramatically the de novo sequencing of large genomes. The ALLPATHS-LG program is available at http://www.broadinstitute.org/science/programs/genome-biology/crd.
Synergistic enhancement of selective nanophotothermolysis with gold nanoclusters: Potential for cancer therapy (2005)

The described approach uses relatively small and simple gold nanoparticles offering more effective delivery to target. In addition, the further self-assembling of these nanoparticles into nanoclusters on live cells provides significant enhancement of laser-induced cell damage. These nanoclusters (gold "nanobombs") can be activated in cancer cells only by confining near-IR laser pulse energy within the critical mass of the nanoparticles in the nanoclusters.