gebhart/patrepeval huggingface dataset:
Safinamide (Newron Pharmaceuticals). (2001)

Safinamide (formerly PNU-151774E), a sodium and calcium channel modulator that also inhibits monoamine oxidase B (MAOB), is under development by Newron Pharmaceuticals for the potential treatment of epilepsy, Parkinson's disease (PD), pain and stroke [345222], [348351]. Phase I trials for epilepsy and PD have been completed, and dose-finding studies for both indications had commenced in March 2001 [401685]. The compound was previously developed by Pharmacia & Upjohn (P&U) for the potential treatment of epilepsy, an indication for which it initially reached phase I trials [294891], [345007]. Newron acquired the rights to safinamide from P&U at the end of 1998. Results from two phase I trials of the compound (single ascending dose and steady state at three doses), completed in March 2000, demonstrated that the drug is well tolerated with good bioavailability and linear pharmacokinetics [359652].
Continuous Oral Administration of l-Dihydroxyphenylalanine (l-DOPA) Solution to Patients with Advanced Parkinsonʼs Disease (1989)

In six patients with advanced Parkinson's disease (PD), we have characterized the clinical responses and serum levels of DOPA and 3-O-methyldopa in response to continuous i.v., nasogastroduodenal (NGD), and oral (p.o.) administration of L-DOPA solution with concomitant suppression of peripheral decarboxylase activity by carbidopa. When compared to therapy with L-DOPA/carbidopa tablets, all patients experienced increased "on" and decreased "off" time with continuous L-DOPA intake. This improvement in mobility was accompanied by increases in duration and severity of dyskinesias. Serum levels of DOPA and 3-O-methyldopa were linearly related in ultrafiltered serum water compared to perchloric acid-treated serum samples, suggesting little protein binding. DOPA serum levels at which patients first turned "on" and those after several hours of continuous i.v. infusion clustered over a narrow range and were not predictable based on i.v. infusion rates, in spite of concomitant carbidopa intake. Continuous p.o. intake of L-DOPA solution produced serum levels of both DOPA and 3-O-methyldopa that were generally steady over the day and predictable based on L-DOPA intake rate. We conclude that "continuous" intake of L-DOPA solution orally, while cumbersome to and demanding of patients, can produce stable DOPA serum levels and approximate the improvement seen with continuous i.v. infusion. In our study, the apparent volume of distribution of L-DOPA was predictable with p.o. intake but not with i.v. administration of L-DOPA solution.
Nanomesh‐Structured Ultrathin Membranes Harnessing the Unidirectional Alignment of Viruses on a Graphene‐Oxide Film (2014)

Ultrathin membranes of M13 viruses are demonstrated. Genetically engineered viruses are first selectively bound on the edges of graphene-oxide nanosheets. Further applying a shear flow on the assembled viruses results in their unidirectional alignment with a constant interspacing. These unit viral layers are stacked such that each layer is perpendicular to the preceding layer, forming a nanomesh structure, which is utilized for the separation of nanoparticles.
Serum promotes asbestos-induced injury to human pulmonary epithelial cells. (1990)

Asbestos exposure causes chronic interstitial pulmonary fibrosis. Injury to human pulmonary epithelial cells (HPEC) is speculated to precede the fibrotic response. We investigated whether asbestos, either alone or in conjunction with serum, injured cultured HPEC as assessed in a standard chromium 51 release assay. Amosite asbestos in serum-free media induced modest HPEC injury (9.4% +/- 3.3% Cr release), which was significantly enhanced (2.7-fold) in the presence of serum (25.5% +/- 4% Cr release). HPEC cytotoxicity was both asbestos and serum dose-dependent. Additionally, we demonstrated that, compared with HPEC injury induced by asbestos plus serum, (1) heat-decomplemented serum or serum fractions of a wide range of molecular weights were equipotent to fresh serum, (2) catalase, superoxide dismutase, or dimethylthiourea was not protective, (3) 3-aminobenzamide, which prevents oxidant-induced adenosine triphosphate depletion by inhibiting poly-adenosine diphosphate-ribose polymerase, afforded significant protection (32% decrease in HPEC injury), and (4) deferoxamine-treated asbestos was significantly less toxic to HPEC compared with untreated asbestos, causing a 57% decrease in HPEC cytotoxicity. Electron microscopic studies revealed that, compared with buffer, serum increased the amount of amosite asbestos along the surface and inside HPEC. Thus, amosite asbestos is cytotoxic to cultured HPEC and serum promotes this injurious effect by augmenting the interaction of asbestos with HPEC. These data suggest that this effect may occur by increasing intracellular oxidant stress mediated in part by the iron in asbestos.
Nitric oxide reaction with red blood cells and hemoglobin under heterogeneous conditions (2002)

Understanding the interaction of nitric oxide (NO) with red blood cells (RBCs) is vital to elucidating the metabolic fate of NO in the vasculature. Because hemoglobin (Hb) is the most abundant intraerythrocytic protein and reacts rapidly with NO, the interaction of NO with Hb has been studied extensively. We and others have shown the NO reaction with RBCs is nearly 1,000-fold slower than the reaction with cell-free Hb. Because the reaction rate of NO with cell-free Hb and RBCs is quite different, we hypothesize that different reaction products evolve under locally high NO concentrations, which can be generated by bolus NO addition or NO inhalation. Here we use electron paramagnetic resonance to show that bolus NO addition to cell-free Hb solutions results in nitrosylhemoglobin [HbFe(II)NO] formation as a minor product through a MetHb-dependent pathway. Further, the RBC is shown to be more prone to form HbFe(II)NO under this heterogeneous condition compared with an equivalent free-Hb solution. In both cases, trapping MetHb with cyanide blocked the formation of HbFe(II)NO. We conclude that the formation of HbFe(II)NO is a heterogeneous phenomenon involving three successive reactions of NO with the same heme molecule. These results were supported further by mathematically modeling NO-Hb reactions and diffusion.
The Workforce Wellness Index (2013)

Employers that address employees' health risk factors may be able to reduce their medical spending and achieve an improvement in their WWI scores.
Distinct immunohistochemical localization of two isoforms of Ca2+/calmodulin‐dependent protein kinase kinases in the adult rat brain (2000)

Ca2+/calmodulin-dependent protein kinase IV (CaM-KIV) is thought to be involved in regulating gene expression by phosphorylating various transcriptional factors. CaM-KIV as well as CaM-KI are activated upon phosphorylation by two distinct isoforms of Ca2+/calmodulin-dependent protein kinase kinases, CaM-KKs alpha and beta. In this study, we raised isoform-specific monoclonal antibodies against CaM-KKs and examined the immunohistochemical localization of CaM-KKs in the rat brain, compared with that of CaM-KIV. CaM-KK alpha-immunoreactivity was rather widely distributed in neurons throughout the brain, except cerebellar cortex. The highest levels of CaM-KK alpha-immunoreactivity were observed in the cerebral cortex, facial nucleus and motor neurons of the spinal cord. Moderate CaM-KK alpha-immunoreactivity was observed in the hippocampal formation, pontine nuclei and various brain stem nuclei including trigeminal, vestibular, cochlear and hypoglossal nuclei. In contrast, CaM-KK beta-immunoreactivity was relatively restricted in some neuronal populations. The highest levels of CaM-KK beta-immunoreactivity were observed in the cerebellar granule cell layer, and moderate immunoreactivity was observed in the cerebral cortex, hippocampal formation, caudate putamen, pontine nuclei, cochlear nucleus and molecular layer of the cerebellum. In contrast to the prominent nuclear localization of CaM-KIV, both isoforms of CaM-KKs were localized in the perikaryal cytoplasm, dendrites and nerve terminals, but not in the cell nuclei. The distinct localization of two isoforms of CaM-KKs suggests that the complicated mechanisms for activation of CaM-KIV by CaM-KKs may be exerted in region-specific manners as well as intracellularly.
Widely tunable bottom-emitting vertical-cavity SOAs (2005)

We present bottom-emitting tunable vertical-cavity semiconductor optical amplifiers (VCSOAs) with an effective wavelength tuning range of >20 nm. These devices utilize a high reflectivity micromechanically tunable Bragg mirror as the back reflector. Compared with our first generation tunable VCSOAs, the bottom-emitting devices exhibit a two-fold increase in the effective tuning range as well as a five-fold reduction in the required tuning voltage.
A Miniaturized Microbial Fuel Cell (2002)

This paper presents a miniaturized microbial fuel cell as an energy source for MEMS. A microorganism, Saccharomyces cerevisiae, is used to catalyse glucose and electricity is produced by the overall redox reaction. The fabricated miniaturized microbial fuel cell has an electrode area of 0.07 cm 2 . The bio-electrical responses of the miniaturized microbial fuel cell are characterized. The open-circuit potential is measured as 300 mV and lasts for 2 hours. The current density is measured as 286 nA/cm 2 and lasts for 30 minutes under a 100 ohm load.
Protein adsorption and human osteoblast‐like cell attachment and growth on alkylthiol on gold self‐assembled monolayers (2001)

Protein adsorption and growth of primary human osteoblasts on self-assembled monolayers of alkylthiols on gold (SAMs) with carboxylic acid and hydroxyl and methyl termini were investigated. Single-component SAMs and SAMs patterned by photolithographic techniques were used. Cell growth on patterned SAMs demonstrated preferences for one pattern region in all combinations of alkylthiols, with the hierarchical preference COOH > OH > CH(3). Patterned SAMs and immunochemistry were used to investigate adsorption of fibronectin and albumin with respect to different alkylthiol termini. Fibronectin adsorption from both pure solution and serum containing cell culture medium (SDMEM) followed the sequence COOH > OH > CH(3). Albumin adsorption from pure solution followed the sequence OH > COOH > CH(3); from SDMEM the sequence was CH(3) > OH > COOH. Cell attachment to SAMs with the above termini, after preadsorption with fibronectin, albumin, or mixtures of fibronectin and albumin, was measured. Attachment was maximal on COOH-terminated SAMs precoated with fibronectin. Attachment to COOH was significantly reduced only when fibronectin was omitted from the protein preadsorption solution. On OH and CH(3) SAMs increasing the proportion of albumin in the solution was sufficient to significantly reduce cell attachment. The distribution vinculin and the integrins alpha(5)beta(1) and alpha(v)beta(3) indicated that focal contact formation by cells varied with alkylthiol termini in the following sequence: COOH > OH > CH(3).
Adobe Premiere Pro 2.0 Studio Techniques (2004)

Tight deadlines and tighter budgets define digital video production today--a fact Adobe has acknowledged and responded to with its completely revamped Windows XP-only Premiere Pro video editing software. By focusing on a single (non-Mac) version of Premiere, Adobe has been able to deliver a product that raises the bar for desktop digital video editing; this approachable, complete volume gets readers beyond the basics. Offering in-depth explanations guaranteed to make the knowledge stick (and in an easygoing style that makes the book fun to read), filmmaker and Premiere whiz Jacob Rosenberg focuses on the concepts, features, and techniques that are key to mastering Adobe Premiere Pro. If you're a novice user, you'll get the grounding you need to begin capturing, editing, and outputting digital video. And if you're a Premiere veteran, you can go straight to the comprehensive coverage of all that's new: three-point color correction, multiple timelines, a new audio mixer, enhanced media management, and more. The accompanying DVD includes project files, sample footage, Third Party Plug-ins and an hour of video tutorials that help articulate concepts and features that are better suited for video explanations than on a page.Jacob's skills and enthusiasm as an editor have been an invaluable resource to the product team throughout the development lifecycle of Premiere Pro. It is no understatement to say that he has been instrumental in charting the course of this application. His knowledge is seemingly without limit, as can be attested to by anyone who has watched him present his master classes at various tradeshows across the globe. I can think of no one better as a guide through the intricacies and depths of Premiere Pro 1.5--the best version of Premiere to date.--Richard Townhill, Group Product Manager, Adobe Video Products
Humoral and CD4+ T helper (Th) cell responses to the hepatitis C virus non-structural 3 (NS3) protein: NS3 primes Th1-like responses more effectively as a DNA-based immunogen than as a recombinant protein (2001)

The non-structural 3 (NS3) protein is one of the most conserved proteins of hepatitis C virus, and T helper 1 (Th1)-like responses to NS3 in humans correlate with clearance of infection. Several studies have proposed that DNA-based immunizations are highly immunogenic and prime Th1-like responses, although few head-to-head comparisons with exogenous protein immunizations have been described. A full-length NS3/NS4A gene was cloned in eukaryotic vectors with expression directed to different subcellular compartments. Inbred mice were immunized twice in regenerating tibialis anterior (TA) muscles with either plasmid DNA or recombinant NS3 (rNS3). After two 100 micrograms DNA immunizations, specific antibody titres of up to 12960 were detected at week 5, dominated by IgG2a and IgG2b. NS3-specific CD4(+) T cell responses in DNA-immunized mice peaked at day 13, as measured by proliferation and IL-2 and IFN-gamma production. Mice immunized with 1-10 micrograms rNS3 without adjuvant developed antibody titres comparable to those of the DNA-immunized mice, but dominated instead by IgG1. CD4(+) T cell responses in these mice showed peaks of IL-2 response at day 3 and IL-6 and IFN-gamma responses at day 6. With adjuvant, rNS3 was around 10-fold more immunogenic with respect to speed and magnitude of the immune responses. Thus, immunization with rNS3 in adjuvant is superior to DNA immunization with respect to kinetics and quantity in priming specific antibodies and CD4(+) T cells. However, as a DNA immunogen, NS3 elicits stronger Th1-like immune responses, whereas rNS3 primes a mixed Th1/Th2-like response regardless of the route, dose or adjuvant.
Chapter 8: Estrogen Receptor-Mediated Processes in Normal and Cancer Cells (2000)

The role of estrogens in breast and other cancers has been extensively investigated for many years, and historically most of these studies have focused on the hormonal regulation of cell proliferation. The most recent work in this area has focused on the expression of genes likely to mediate proliferation (e.g., growth factors, proto-oncogenes, etc.) and their regulation by the classic nuclear estrogen receptor, ER-alpha. In this chapter, we present a synopsis of several new developments in this area of ER-regulated gene expression. These developments include the following: 1) the selective activation of ER domains by partial estrogen antagonists, such as tamoxifen and other ligands; 2) the effects of ER-alpha overexpression and gene knockout on the development of breast and uterine cancers in experimental animal models; 3) mechanisms by which steroid hormones regulate programmed cell death, cell cycle progression, cell-substratum interactions, and genomic instability in cancer cells; 4) identification of nuclear proteins that interact with the ER in the presence of agonists and antagonists, the effect of ligand binding on the receptor structure, and the interactions of liganded and nonliganded receptors with coactivators, corepressors, and other regulatory proteins; and 5) the biochemical properties, cellular distribution, and potential biologic roles for the newly discovered ER-beta. Although there is an increasing interest in understanding the role of estrogens as endogenous carcinogens, it remains clear that ER-mediated regulation of gene expression plays many significant roles in normal and cancer cells, and increased knowledge of the mechanisms involved will improve our overall understanding of hormonal carcinogenesis.
How the protease thrombin talks to cells (1999)

How does a protease act like a hormone to regulate cellular functions? The coagulation protease thrombin (EC 3.4.21.5) activates platelets and regulates the behavior of other cells by means of G protein-coupled protease-activated receptors (PARs). PAR1 is activated when thrombin binds to and cleaves its amino-terminal exodomain to unmask a new receptor amino terminus. This new amino terminus then serves as a tethered peptide ligand, binding intramolecularly to the body of the receptor to effect transmembrane signaling. The irreversibility of PAR1's proteolytic activation mechanism stands in contrast to the reversible ligand binding that activates classical G protein-coupled receptors and compels special mechanisms for desensitization and resensitization. In endothelial cells and fibroblasts, activated PAR1 rapidly internalizes and then sorts to lysosomes rather than recycling to the plasma membrane as do classical G protein-coupled receptors. This trafficking behavior is critical for termination of thrombin signaling. An intracellular pool of thrombin receptors refreshes the cell surface with naïve receptors, thereby maintaining thrombin responsiveness. Thus cells have evolved a trafficking solution to the signaling problem presented by PARs. Four PARs have now been identified. PAR1, PAR3, and PAR4 can all be activated by thrombin. PAR2 is activated by trypsin and by trypsin-like proteases but not by thrombin. Recent studies with knockout mice, receptor-activating peptides, and blocking antibodies are beginning to define the role of these receptors in vivo.
Methotrexate analogs. 22. Synthesis, dihydrofolate reductase affinity, cytotoxicity, and in vivo antitumor activity of some putative degradation products of methotrexate-poly(L-lysine) conjugates (1984)

Derivatives of methotrexate (MTX) in which the gamma-carboxyl group is joined to the epsilon-amino group of L-lysine, L-lysyl-L-lysine, or L-lysyl-L-lysyl-L-lysine, respectively, were prepared for evaluation of their dihydrofolate reductase (DHFR) affinity, their ability to retard cell growth in culture, and their antitumor activity in vivo. These small lysine derivatives of MTX are of interest as putative breakdown products of MTX-poly(L-lysine). Inhibition of DHFR in a cell-free assay was decreased only 3-fold relative to MTX, indicating that gamma-substitution by up to three lysines is well tolerated for binding. On the other hand, toxicity toward L1210 murine leukemia cells in culture decreased up to 120-fold relative to MTX as the lysines increased in number from one to three, suggesting that uptake across the cell membrane becomes difficult when positively charged lysines are at the gamma-position. Growth inhibition of H35 rat hepatoma cells was decreased 40- to 60-fold relative to MTX, but in H35R0.3 cells, which have normal DHFR content but are 180-fold MTX resistant by virtue of a transport defect, the lysine derivatives were only 3- to 7-fold less toxic than MTX. When the adducts were given to L1210 leukemic mice by twice-daily injection for 10 days, an increase in life span (ILS) of 80-100% was observed at 40 mg/kg (equivalent to 20-30 mg/kg of MTX). MTX itself, on the same schedule, gave a 100% ILS at 0.5 mg/kg. The low in vivo activity of the mono-, di-, and trilysine adducts suggests minimal systemic hydrolysis to free MTX.
Cytokine Gene Therapy of Cancer Using Gene Gun Technology: Superior Antitumor Activity of Interleukin-12 (1997)

We compared the antitumor effect of several transgene expression plasmids encoding specific cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-12, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF), following gene gun-mediated DNA delivery into the epidermis overlying an established intradermal murine tumor. IL-12 gene therapy was much more effective than treatment with any other tested cytokine gene for induction of tumor regression. Strong activation of antitumor immunity in response to IL-12 gene therapy was evidenced by an augmented CD8+ T cell-mediated cytolytic activity in the draining lymph nodes of tumor-bearing mice. Furthermore, following the IL-12 gene therapy protocol, test mice were able to eradicate not only the treated but also the untreated solid tumors at distant sites. This systemic antitumor effect of IL-12 gene therapy was not associated with visible signs of toxicity or significantly elevated systemic levels of IFN-gamma. These results show that gene gun-mediated in vivo delivery of IL-12 cDNA clearly distinguishes itself from the other cytokine gene therapy approaches tested in parallel, suggesting that this delivery system may be employed as an efficient model for comparative studies of in vivo cytokine gene therapy. The results also suggest that the current IL-12 gene therapy strategy may provide a safer alternative to IL-12 protein therapy for clinical treatment of cancers.
Mesothelin Is Not Required for Normal Mouse Development or Reproduction (2000)

Mesothelin is a glycosylphosphatidylinositol-linked glycoprotein highly expressed in mesothelial cells, mesotheliomas, and ovarian cancer, but the biological function(s) of the protein is not known. We have analyzed the expression of the mouse mesothelin gene in different developmental stages and in various adult tissues by Northern hybridization. The 2.5-kb mesothelin transcript was detected in the mRNA of E 7.0, E 15.0, and E 17.0 stages of mouse development. In adult tissues the mesothelin gene was expressed in lung, heart, spleen, liver, kidney, and testis. To directly assess the function of the mesothelin in vivo, we generated mutant mice in which the mesothelin gene was inactivated by replacing it with the neomycin resistance gene. In homozygous mutant mice neither mesothelin mRNA nor the protein product was detected. Null mutant mice were obtained in accordance with Mendelian laws, and both males and females produced offspring normally. No anatomical or histological abnormalities were detected in any tissues where mesothelin was reportedly expressed in wild-type mice. Our results demonstrate that mesothelin function is not essential for growth or reproduction in mice.
New expression vectors for the fission yeast Schizosaccharomyces pombe (1989)

A general expression vector (pMB332) for the fission yeast Schizosaccharomyces pombe was constructed. The heterologous gene expression is driven by the S. pombe alcohol dehydrogenase (adh) promoter. Transcription termination signals were isolated from the S. pombe actin gene. The vectors carry the Saccharomyces cerevisiae Ura3 gene, which complements the S. pombe ura4 mutation. The plasmid stability is conferred by the S. pombe ars and stb elements isolated from pFL120 [(1983) Cell 32, 371-377]. An 'ATG' vector (pMB340) was created, which allows the expression of protein fragments fused to a translational start codon downstream of the adh promoter. The function of this vector system is shown by the production of the human blood coagulation protein factor XIIIa.