gebhart/patrepeval huggingface dataset:
Biological Rationale for New Drugs in the Bleeding Disorders Pipeline (2011)

Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.
Bromfenac ophthalmic solution for the treatment of postoperative ocular pain and inflammation: safety, efficacy, and patient adherence (2014)

Ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used by clinicians to manage ocular inflammation and pain following cataract surgery. Over the past decade, the US Food and Drug Administration has approved multiple topical NSAIDs for these purposes, including several reformulated products. One of these medications, bromfenac ophthalmic solution, has a long and extensive history, with proven efficacy and safety in patients following cataract surgery. The evolution of bromfenac ophthalmic solution over the years has involved either lowering the concentration of the active ingredient or extending the dosing interval to improve patient adherence/compliance. This review will focus on the history and progression of bromfenac ophthalmic solution and report the available patient preference and adherence data regarding this ocular NSAID throughout its evolution.
Conformational Analysis of Regular Enantiomeric Sequences (1974)

Cylindrical coordinates and symmetries of regular enantiomeric sequences were derived on the basis of eigenvalue-eigenvectors solns. to the Eyring-transformation matrix, and were used to show that the general structure of conformationally equiv. enantiomers was a ring. Helical structures could be formed in the case of quasi-conformational equivalence between the monomeric units. For regular L,D copolypeptides, these helical structures were stabilized by both van der Waals and H bond interactions, and were more stable than the α-helix in the absence of configurational disorder.
Chemiluminescence from a phenoxide-substituted 1,2-dioxetane: a model for firefly bioluminescence (1982)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChemiluminescence from a phenoxide-substituted 1,2-dioxetane: a model for firefly bioluminescenceA. Paul Schaap and Steven D. GagnonCite this: J. Am. Chem. Soc. 1982, 104, 12, 3504–3506Publication Date (Print):June 1, 1982Publication History Published online1 May 2002Published inissue 1 June 1982https://pubs.acs.org/doi/10.1021/ja00376a044https://doi.org/10.1021/ja00376a044research-articleACS PublicationsRequest reuse permissionsArticle Views861Altmetric-Citations109LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Microfluidic Assay for Continuous Bacteria Detection Using Antimicrobial Peptides and Isotachophoresis (2014)

We present a novel microfluidic assay for continuous and quantitative detection of bacteria in water. We leverage isotachophoresis (ITP), an electrophoretic focusing technique, to create a stationary high concentration zone of fluorescently labeled antimicrobial peptides (AMPs) in a microfluidic channel. The tested water sample flows continuously through this high concentration AMPs reaction zone; any bacteria present in the sample is simultaneously labeled by, and separated from, the high concentration AMPs. The labeled bacteria continue into the downstream pure-buffer zone where the fluorescence signal is monitored, providing a direct quantitative measurement of the original bacterial concentration in the sample. We present the principles of the technique, demonstrate its applicability for quantitative detection of E. coli as well as its stability over a 1 h monitoring time, and provide a simple model for predicting its performance at different operating conditions. The method could be potentially expanded for use with other types of probes and provide continuous analysis and monitoring of water samples at the point of need.
Rapid Electron Tunneling Through Oligophenylenevinylene Bridges (2001)

We measured rate constants of thermal, interfacial electron transfer through oligophenylenevinylene bridges between a gold electrode and a tethered redox species in contact with an aqueous electrolyte using the indirect laser-induced temperature jump technique. Analysis of the distance dependence indicates that, unlike other bridges studied to date, the rate constants are not limited by electronic coupling for bridges up to 28 angstroms long. The energy levels of the bridges relative to those of the redox species rule out hopping through the bridge. We conclude that, out to 28 angstroms, the transfer is limited by structural reorganization and that electron tunneling occurs in less than 20 picoseconds, suggesting that oligophenylenevinylene bridges could be useful for wiring molecular electronic elements.
Besprechungen - Comptes rendus - Die Sprachbezeichnungen Latinus und Romanus im Lateinischen und Romanischen (2001)

1. Intracellular recordings were obtained from the arterial smooth muscle cells of rat basilar artery during perivascular nerve stimulation and during the application of adrenoceptor agonists and antagonists. 2. Perivascular nerve stimulation evoked excitatory junction potentials. Increased stimulation resulted in action potentials which were associated with arterial constriction. 3. Bath-applied noradrenaline did not cause constriction but at high concentrations caused membrane depolarization. The depolarization caused by a given dose of noradrenaline was larger in the presence of cocaine. 4. Neither the depolarizations obtained by nerve stimulation nor those obtained by bath-applied noradrenaline were blocked by adrenoceptor blocking agents. 5. Unlike alpha-receptors, the receptors on the rat basilar artery were activated equally well by dopamine, adrenaline, and both optical isomers of noradrenaline. 6. Excitatory junction potentials could be obtained in the presence of high bath concentrations of noradrenaline.
Immune response to a Murray Valley encephalitis virus epitope expressed in the flagellin of an attenuated strain of Salmonella (1997)

Recent developments in vaccine construction include the use of attenuated, avirulent strains of Salmonella as carriers of foreign antigens. These recombinant strains can elicit a heterologous immune response when injected into animals, demonstrating potential for their use in the construction of many vaccines. In the present study, a B-cell epitope of Murray Valley encephalitis virus (MVE) was identified and expressed in a Salmonella strain to evaluate its potential to induce a specific immune response to MVE. A synthetic oligonucleotide encoding the B-cell epitope (residues E201-224) of the envelope protein of MVE was inserted into the cloned flagellin gene of the Salmonella strain. The construct was sequenced to ensure correct orientation of the epitope. Expression of the epitope was demonstrated by Western blot analysis and immunogold electron microscopy with monoclonal antibody specific to the epitope. Electron microscopy analysis revealed multiple copies of the epitope along the flagella. The recombinant Salmonella carrying the hybrid flagellin gene elicited an immune response to the MVE epitope in a mouse model. The MVE-specific antibodies partially neutralised the virus in vitro. The significance of this system for engineering vaccines for other medically important flaviviruses is discussed.
Gene Cloning, Transcriptional Analysis, Purification, and Characterization of Phenolic Acid Decarboxylase from Bacillus subtilis (1998)

Bacillus subtilis displays a substrate-inducible decarboxylating activity with the following three phenolic acids: ferulic, p-coumaric, and caffeic acids. Based on DNA sequence homologies between the Bacillus pumilus ferulate decarboxylase gene (fdc) (A. Zago, G. Degrassi, and C. V. Bruschi, Appl. Environ. Microbiol. 61:4484-4486, 1995) and the Lactobacillus plantarum p-coumarate decarboxylase gene (pdc) (J.-F. Cavin, L. Barthelmebs, and C. Diviès, Appl. Environ. Microbiol. 63:1939-1944, 1997), a DNA probe of about 300 nucleotides for the L. plantarum pdc gene was used to screen a B. subtilis genomic library in order to clone the corresponding gene in this bacterium. One clone was detected with this heterologous probe, and this clone exhibited phenolic acid decarboxylase (PAD) activity. The corresponding 5-kb insertion was partially sequenced and was found to contain a 528-bp open reading frame coding for a 161-amino-acid protein exhibiting 71 and 84% identity with the pdc- and fdc-encoded enzymes, respectively. The PAD gene (pad) is transcriptionally regulated by p-coumaric, ferulic, or caffeic acid; these three acids are the three substrates of PAD. The pad gene was overexpressed constitutively in Escherichia coli, and the stable purified enzyme was characterized. The difference in substrate specificity between this PAD and other PADs seems to be related to a few differences in the amino acid sequence. Therefore, this novel enzyme should facilitate identification of regions involved in catalysis and substrate specificity.
Crystal Structure of the Platelet Glycoprotein Ibα N-terminal Domain Reveals an Unmasking Mechanism for Receptor Activation (2002)

Glycoprotein Ib (GPIb) is a platelet receptor with a critical role in mediating the arrest of platelets at sites of vascular damage. GPIb binds to the A1 domain of von Willebrand factor (vWF-A1) at high blood shear, initiating platelet adhesion and contributing to the formation of a thrombus. To investigate the molecular basis of GPIb regulation and ligand binding, we have determined the structure of the N-terminal domain of the GPIb(alpha) chain (residues 1-279). This structure is the first determined from the cell adhesion/signaling class of leucine-rich repeat (LRR) proteins and reveals the topology of the characteristic disulfide-bonded flanking regions. The fold consists of an N-terminal beta-hairpin, eight leucine-rich repeats, a disulfide-bonded loop, and a C-terminal anionic region. The structure also demonstrates a novel LRR motif in the form of an M-shaped arrangement of three tandem beta-turns. Negatively charged binding surfaces on the LRR concave face and anionic region indicate two-step binding kinetics to vWF-A1, which can be regulated by an unmasking mechanism involving conformational change of a key loop. Using molecular docking of the GPIb and vWF-A1 crystal structures, we were also able to model the GPIb.vWF-A1 complex.
nippon kagaku kaishi (1979)

m-キシレンの水蒸気脱アルキル反応における水の活性化機構を明らかにするため,Rh/MWO4(M=Mg,CaそしてSr)触媒とRh/Al2O3触媒を用いて,m-キシレン,COあるいは水を反応物とするパルス反応を行なった。Rh/Al2O3触媒では,水がAl2O3表面にヒドロキシル基の形で吸着して活性化される。一方,Rh/MWO,触媒では,Rh/Al2O3触媒の場合と異なり,水は気相水素と表面酸素に解離して活性化されることが明らかとなった。Rh/MgWO4触媒上のこの表面酸素は,m-キシレンに対し高い反応性を示し,Rh/MgWO4触媒が高い脱アルキル活性を有する点をよく説明した。Rh/MWO4触媒上での水の活性化は,次式により進行するものと推定した1/dx MWO4+ R → 1/dx MO + 1/dx W O3-dx RO (a)1/dx MO + 1/dx WO3-dx + H2O → 1/dx MWO4 + H2 (b)R:ロジウム上の脱メチル中間体
Reduced NO-dependent arteriolar dilation during the development of cardiomyopathy (2000)

Our previous studies have suggested that there is reduced nitric oxide (NO) production in canine coronary blood vessels after the development of pacing-induced heart failure. The goal of these studies was to determine whether flow-induced NO-mediated dilation is altered in coronary arterioles during the development of heart failure. Subepicardial coronary arterioles (basal diameter 80 microm) were isolated from normal canine hearts, from hearts with dysfunction but no heart failure, and from hearts with severe cardiac decompensation. Arterioles were perfused at increasing flow or administered agonists with no flow in vitro. In arterioles from normal hearts, flow increased arteriolar diameter, with one-half of the response being NO dependent and one-half prostaglandin dependent. Shear stress-induced dilation was eliminated by removing the endothelium. Arterioles from normal hearts and hearts with dysfunction but no failure responded to increasing shear stress with dilation that reached a maximum at a shear stress of 20 dyn/cm(2). In contrast, arterioles from failing hearts showed a reduced dilation, reaching only 55% of the dilation seen in vessels of normal hearts at a shear stress of 100 dyn/cm(2). This remaining dilation was eliminated by indomethacin, suggesting that the NO-dependent component was absent in coronary microvessels after the development of heart failure. Similarly, agonist-induced NO-dependent coronary arteriolar dilation was markedly attenuated after the development of heart failure. After the development of severe dilated cardiomyopathy and heart failure, the NO-dependent component of both shear stress- and agonist-induced arteriolar dilation is reduced or entirely absent.
Interaction of Soluble Form of Recombinant Extracellular TLR4 Domain with MD-2 Enables Lipopolysaccharide Binding and Attenuates TLR4-Mediated Signaling (2004)

TLRs have been implicated in recognition of pathogen-associated molecular patterns. TLR4 is a signaling receptor for LPS, but requires MD-2 to respond efficiently to LPS. The purposes of this study were to examine the interactions of the extracellular TLR4 domain with MD-2 and LPS. We generated soluble forms of rTLR4 (sTLR4) and TLR2 (sTLR2) lacking the putative intracellular and transmembrane domains. sTLR4 consisted of Glu(24)-Lys(631). MD-2 bound to sTLR4, but not to sTLR2 or soluble CD14. BIAcore analysis demonstrated the direct binding of sTLR4 to MD-2 with a dissociation constant of K(D) = 6.29 x 10(-8) M. LPS-conjugated beads precipitated MD-2, but not sTLR4. However, LPS beads coprecipitated sTLR4 and MD-2 when both proteins were coincubated. The addition of sTLR4 to the medium containing the MD-2 protein significantly attenuated LPS-induced NF-kappaB activation and IL-8 secretion in wild-type TLR4-expressing cells. These results indicate that the extracellular TLR4 domain-MD-2 complex is capable of binding LPS, and that the extracellular TLR4 domain consisting of Glu(24)-Lys(631) enables MD-2 binding and LPS recognition to TLR4. In addition, the use of sTLR4 may lead to a new therapeutic strategy for dampening endotoxin-induced inflammation.
Simultaneous Detection and Segmentation of Pedestrians using Top-down and Bottom-up Processing (2007)

We present a method for the simultaneous detection and segmentation of people from static images. The proposed technique requires no manual segmentation during training, and exploits top-down and bottom-up processing within a single framework for both object localization and 2D shape estimation. First, the coarse shape of the object is learned from a simple training phase utilizing low-level edge features. Motivated by the observation that most object categories have regular shapes and closed boundaries, relations between these features are then exploited to derive mid-level cues, such as continuity and closure. A novel Markov random field defined on the edge features is presented that integrates the coarse shape information with our expectation that objects are likely to have boundaries that are regular and closed. The algorithm is evaluated on pedestrian datasets of varying difficulty, including a wide range of camera viewpoints, and person orientations. Quantitative results are presented for person detection and segmentation, demonstrating the effectiveness of the proposed technique to simultaneously address both these tasks.
CD4 Receptor Localized to Non-raft Membrane Microdomains Supports HIV-1 Entry (2003)

Despite the preferential localization of CD4 to lipid rafts, the significance and role of these microdomains in HIV-1 entry is still controversial. The possibility that CD4, when localized to non-raft domains, might be able to support virus entry cannot be excluded. Because disintegration of rafts by extraction of cellular cholesterol with methyl-beta-cyclodextrin suffers from various adverse effects, we investigated molecular determinants controlling raft localization of the CD4 receptor. Extensive mutagenesis of the receptor showed that a raft-localizing marker, consisting of a short sequence of positively charged amino acid residues, RHRRR, was present in the membrane-proximal cytoplasmic domain of CD4. Substitution of the RHRRR sequence with alanine residues abolished raft localization of the CD4 mutant, RA5, as determined biochemically using solubilization in nonionic detergents and by confocal microscopy. The possible inhibitory effect of the introduced mutations on the adjacent CVRC palmitoylation site was ruled out because wild type (wt) CD4 and RA5, but not a palmitoylation-deficient mutant, were efficiently palmitoylated. Nonetheless, the RA5 mutant supported productive virus entry to levels equivalent to that of wild type (wt) CD4. Sucrose gradient analysis of Triton X-100 virus lysates showed that Gag and envelope gp120 proteins accumulated in low buoyant, high-density fractions. This pattern was changed after virus incubation with cells. Whereas Gag proteins localized to lipid rafts in cells expressing wt CD4 and RA5, gp120 accumulated in rafts in cells expressing wt CD4 but not RA5. We propose that raft localization of CD4 is not required for virus entry, however, post-binding fusion/entry steps may require lipid raft assembly.
The Human Antimicrobial Peptide LL-37 Is a Multifunctional Modulator of Innate Immune Responses (2002)

The role of LL-37, a human cationic antimicrobial peptide, in the immune system is not yet clearly understood. It is a widely expressed peptide that can be up-regulated during an immune response. In this report, we demonstrate that LL-37 is a potent antisepsis agent with the ability to inhibit macrophage stimulation by bacterial components such as LPS, lipoteichoic acid, and noncapped lipoarabinomannan. We also demonstrate that LL-37 protects mice against lethal endotoxemia. In addition to preventing macrophage activation by bacterial components, we hypothesized the LL-37 may also have direct effects on macrophage function. We therefore used gene expression profiling to identify macrophage functions that might be modulated by LL-37. These studies revealed that LL-37 directly up-regulates 29 genes and down-regulated another 20 genes. Among the genes predicted to be up-regulated by LL-37 were those encoding chemokines and chemokine receptors. Consistent with this, LL-37 up-regulated the expression of chemokines in macrophages and the mouse lung (monocyte chemoattractant protein 1), human A549 epithelial cells (IL-8), and whole human blood (monocyte chemoattractant protein 1 and IL-8), without stimulating the proinflammatory cytokine, TNFalpha. LL-37 also up-regulated the chemokine receptors CXCR-4, CCR2, and IL-8RB. These findings indicate that LL-37 may contribute to the immune response by limiting the damage caused by bacterial products and by recruiting immune cells to the site of infection so that they can clear the infection.
Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model. (2001)

Modulation of thiol levels may alter both the efficacy and toxicity of chemotherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intracarotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcysteine (NAC) and sodium thiosulfate were administered into the descending aorta to limit brain delivery. BSO treatment reduced rat brain and intracerebral tumor glutathione levels by 50-65%, equivalent to the reduction in liver and s.c. tumor. BSO treatment significantly enhanced the toxicity of chemotherapy with carboplatin, melphalan, and etoposide phosphate against granulocytes, total white cells, and platelets. Intracarotid administration of NAC resulted in high delivery to the brain, whereas infusion via the descending aorta minimized brain delivery. When NAC, with or without sodium thiosulfate, was administered via aortic infusion prior to chemotherapy, the magnitude of the bone marrow toxicity nadir was minimized, even with BSO-enhanced myelosuppression. Thus, BSO depleted brain and brain tumor glutathione but thereby increased chemotherapy-induced myelosuppression. Surprisingly, although NAC was found to readily cross the blood-brain barrier when given into the carotid artery, aortic infusion of NAC resulted in minimal exposure to the central nervous system (CNS) vasculature because of rapid clearance. As a result, aortic infusion of NAC to perfuse bone marrow and minimize myelosuppression and toxicity to visceral organs could be performed without interfering with the CNS cytotoxicity of intracarotid alkylators, even after BSO depletion of CNS glutathione.