gebhart/patrepeval huggingface dataset:
Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis (2004)

Neurodegenerative processes determine the clinical disease course of multiple sclerosis, an inflammatory autoimmune CNS disease that frequently manifests with acute optic neuritis. None of the established multiple sclerosis therapies has been shown to clearly reduce neurodegeneration. In a rat model of experimental autoimmune encephalomyelitis, we recently demonstrated increased neuronal apoptosis under methylprednisolone therapy, although CNS inflammation was effectively controlled. In the present study, we combined steroid treatment with application of erythropoietin to target inflammatory as well as neurodegenerative aspects. After immunization with myelin oligodendrocyte glycoprotein (MOG), animals were randomly assigned to six treatment groups receiving different combinations of erythropoietin and methylprednisolone, or respective monotherapies. After MOG-induced experimental autoimmune encephalomyelitis became clinically manifest, optic neuritis was monitored by recording visual evoked potentials. The function of retinal ganglion cells, the neurons that form the axons of the optic nerve, was measured by electroretinograms. Functional and histo pathological data of retinal ganglion cells and optic nerves revealed that neuron and axon protection was most effective when erythropoietin treatment that was started at immunization was combined with high-dose methylprednisolone therapy given from days 1 to 3 of MOG-induced experimental autoimmune encephalomyelitis. In contrast, isolated neuronal or axonal protection without clinical benefit was achieved under monotherapy with erythropoietin or methylprednisolone, respectively.
Inhibitory and excitatory perigenital-to-bladder spinal reflexes in the cat (2007)

This study revealed that in awake chronic spinal cord-injured (SCI) cats reflexes from perigenital skin area to the bladder can be either inhibitory or excitatory. Electrical perigenital stimulation at frequencies between 5 and 7 Hz significantly inhibited large-amplitude rhythmic reflex bladder activity, whereas frequencies between 20 and 40 Hz induced large-amplitude bladder contractions even at low bladder volumes when reflex bladder activity was absent. Both inhibitory and excitatory effects were enhanced as the stimulation intensity increased (5-30 V, 0.2-ms pulse width). During cystometrograms, the inhibitory stimulation (7 Hz) significantly increased the micturition volume threshold 35 +/- 13% above the control volume, while the excitatory stimulation (30 Hz) significantly reduced the threshold 21 +/- 3%. Mechanical perigenital stimulation applied by repeated light stroking of the perigenital skin with a cotton swab only induced an excitatory effect on the bladder. Both electrical and mechanical perigenital stimuli induced large-amplitude (>30 cm H(2)O) bladder contractions that were relatively consistent over a range of bladder volumes (10-90% of the capacity). However, the excitatory electrical stimulation only induced bladder contractions lasting on average 42.2 +/- 3.9 s, but the mechanical stimulation induced bladder contractions that lasted as long as the stimulation continued (2-3 min). Excitatory electrical or mechanical perigenital stimulation also induced poststimulus voiding. The ability to either inhibit or excite the bladder by noninvasive methods could significantly transform the current clinical management of bladder function after SCI.
The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts (2002)

The metalloprotease ADAM 10 is an important APP alpha-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPs alpha generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative alpha-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity.
Mobile cellular telecommunications systems (1989)

Baca tentang semua perkembangan terakhir di bidang teknologi seluler yang berubah dengan cepat di edisi baru referensi klasik ini. Ditulis oleh otoritas terkenal di dunia, buku ini memberi Anda deskripsi teknis lengkap mengenai desain, analisis, dan pemeliharaan sistem seluler yang tidak ada duanya.
Synthesis, Characterization, and Ion Exchange Behavior of a Framework Potassium Titanium Trisilicate K2TiSi3O9·H2O and Its Protonated Phases (2000)

A framework potassium titanium silicate K2TiSi3O9·H2O, compound I, was synthesized by the reaction of a titanium−hydrogen peroxide complex and SiO2 in alkaline media under mild hydrothermal conditions (180 °C). This compound was converted to the corresponding sodium phase, Na2TiSi3O9·H2O (IV) and two proton-containing phases, K1.26H0.74TiSi3O9·1.8H2O (II) and K0.3H1.7TiSi3O9·2.4H2O (III) by ion exchange. These products were characterized by elemental analysis, TGA, FT-IR, MAS 29Si NMR, and X-ray diffraction. The ion exchange behavior of K2TiSi3O9·H2O and K0.3H1.7TiSi3O9·2H2O toward alkali, alkaline earth, and some transition metal ions solutions was studied. A high affinity of the protonic form of titanium trisilicate exchanger for cesium and potassium makes it promising for radionuclide-contaminated groundwater treatment and certain analytical separations. The crystal structure of K2TiSi3O9·H2O was found to be isomorphous with that of the zirconium analogue and contains a framework enclosing two types of tunnels. The exchange properties were interpreted on the basis of this structure and selectivity of the Zr and Ti phases rationalized on the basis of the tunnel sizes. The structure of II was solved on the basis of a monoclinic cell, whereas the K2TiSi3O9·H2O phase is orthorhombic. The relationship of structure II, monoclinic, to the parent orthorhombic structure is described. Phase III yielded a complex X-ray pattern with evidence of disorder and a highly complex 29Si NMR spectrum. On reexchanging with K+, the original crystal lattice was restored.
Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off‐Target Effects from Chemical Structure (2007)

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred from findings in clinical trials, animal experiments, and molecular studies going back more than forty years. In this work we explore PSP chemical space and its relevance for the prediction of adverse drug reactions. Firstly, in silico (computational) Bayesian models for 70 PSP-related targets were built, which are able to detect 93% of the ligands binding at IC(50) < or = 10 microM at an overall correct classification rate of about 94%. Secondly, employing the World Drug Index (WDI), a model for adverse drug reactions was built directly based on normalized side-effect annotations in the WDI, which does not require any underlying functional knowledge. This is, to our knowledge, the first attempt to predict adverse drug reactions across hundreds of categories from chemical structure alone. On average 90% of the adverse drug reactions observed with known, clinically used compounds were detected, an overall correct classification rate of 92%. Drugs withdrawn from the market (Rapacuronium, Suprofen) were tested in the model and their predicted ADRs align well with known ADRs. The analysis was repeated for acetylsalicylic acid and Benperidol which are still on the market. Importantly, features of the models are interpretable and back-projectable to chemical structure, raising the possibility of rationally engineering out adverse effects. By combining PSP and ADR models new hypotheses linking targets and adverse effects can be proposed and examples for the opioid mu and the muscarinic M2 receptors, as well as for cyclooxygenase-1 are presented. It is hoped that the generation of predictive models for adverse drug reactions is able to help support early SAR to accelerate drug discovery and decrease late stage attrition in drug discovery projects. In addition, models such as the ones presented here can be used for compound profiling in all development stages.
Focus-2D: a new approach to the design of targeted combinatorial chemical libraries. (1998)

A strategy for rational design of targeted combinatorial libraries is described. The aim of this approach is to select a subset of available building blocks for the library synthesis that are most likely to be present in the active compounds. Building blocks that are used in the underlying combinatorial chemical reaction are randomly assembled to produce virtual combinatorial library compounds, which are represented by various chemical descriptors. Stochastic algorithms (simulated annealing, genetic algorithms, neural net methods) are used to search the potentially large structural space of virtual chemical libraries in order to identify compounds similar to lead compound(-s). The selection of a virtual molecule as a candidate for the targeted library is based either on its chemical similarity to a biologically active probe or on its biological activity predicted from a pre-constructed QSAR equation. Frequency analysis of building block composition of the selected virtual compounds identifies building blocks that can be used in combinatorial synthesis of chemical libraries with high similarity to the lead compound(-s). This method is applied to rational design of the library with bradykinin potentiating activity. Twenty eight bradykinin potentiating pentapeptides were used as a training set for the development of a QSAR equation, and, alternatively, two active pentapeptides, VEWAK and VKWAP, were used as probe molecules. In each case, the frequency distribution of amino acids in the top 100 peptides suggested by the method resembles the frequency distribution of amino acids found in the active peptides. The results obtained after GA optimization also compared favorably with those obtained by the exhaustive analysis of all possible 3.2 millions pentapeptides.
Effect of nafamostat mesilate on bradykinin generation during low-density lipoprotein apheresis using a dextran sulfate cellulose column. (1992)

The dextran sulfate (DS) cellulose column usually used for low-density lipoprotein (LDL) apheresis, is an activator of the contact phase of intrinsic coagulation pathway. Hageman factor (factor XII), high-molecular-weight kininogen (HMWK) and prekallikrein (PK) form a complex on the surface of this activator, and bradykinin is released from HMWK by the action of kallikrein converted from PK. Heparin, a frequently used anticoagulant, has no effect on this process, whereas a protease inhibitor, nafamostat mesilate (FUT-175) is thought to inhibit the process. Five patients with severe hypercholesterolemia were treated with LDL apheresis using heparin or FUT-175, each on a different day. During treatment with heparin, factor XII, HMWK, and PK were markedly decreased by passing through the DS column. A distinct generation of bradykinin was observed by passing through the DS column, which led to an increase of blood bradykinin levels from 12.5 +/- 5.3(Mean +/- SEM) pg/ml to 127.3 +/- 67.1 pg/ml after 1000 ml plasma treatment. FUT-175 almost completely suppressed this bradykinin generation. Because bradykinin generated during LDL apheresis seems to have some vasodilative effect, FUT-175 might be preferred in cases with unstable hemodynamics, although this presumption remains to be demonstrated.
Update on the Principles and Novel Local and Systemic Therapies for the Treatment of Non-Infectious Uveitis (2013)

Ocular inflammatory disorders constitute a sight-threatening group of diseases that might be managed according to their severity. Their treatment guidelines experience constant changes with new agents that improve the results obtained with former drugs. Nowadays we can make use of a five step protocol in which topical, periocular and systemic corticosteroids remain as the main therapy for non-infectious uveitis. In addition, immunosuppresive drugs can be added in order to enhance the anti-inflammatory effects and to play the role of corticosteroid-sparing agents. These can be organized in four other steps: cyclosporine and methotrexate in a second one; azathioprine, mycophenolate and tacrolimus in a third step; biological anti-TNF drugs in fourth position; and a last one with cyclophosphamide and chlorambucil. In the present review we go through the main characteristics and complications of all these treatments and make a rational of this five-step treatment protocol for non-infectious posterior uveitis.
Integrated Affinity and Electrophoresis Systems for Multiplexed Biomarker Analysis (2012)

The integration of affinity columns in microfluidic devices generates a micro-total analysis system which has high value in applications such as analyte extraction and preconcentration. In this chapter we describe the preparation of affinity columns in situ by photopolymerization of acrylate monomers. The epoxy groups on the columns are further functionalized with antibodies to form affinity columns. We describe in detail the use of our affinity columns in extracting cancer biomarkers from model mixtures and blood serum. The purified biomarkers are then eluted from the column, separated by microchip capillary electrophoresis, and detected by laser-induced fluorescence. Our procedures allow efficient sample pretreatment and preconcentration, as well as simultaneous and rapid quantification of multiple biomarkers.
Relative Dominance of Gag p24-Specific Cytotoxic T Lymphocytes Is Associated with Human Immunodeficiency Virus Control (2006)

Conflicting data on the role of total virus- and protein-specific cytotoxic-T-lymphocyte (CTL) responses in the control of human immunodeficiency virus (HIV) disease progression exist. We present data generated from a Peruvian cohort of untreated, clade B-infected subjects, demonstrating that the proportion of Gag-specific, and in particular p24-reactive, CTL responses among the total virus-specific CTL activity is associated with individuals' CD4 counts and viral loads. Analyses in a second cohort in the United States confirm these findings and point towards a dominant role of Gag-specific immunity in effective control of HIV infection, providing important guidance for HIV vaccine development.
Structural basis of β‐adrenergic receptor function (1989)

Receptors that mediate their actions by stimulating guanine nucleotide binding regulatory proteins (G proteins) share structural as well as functional similarities. The structural motif characteristic of receptors of this class includes seven hydrophobic putative transmembrane domains linked by hydrophilic loops. Genetic analysis of the beta-adrenergic receptor (beta AR) revealed that the ligand binding domain of this receptor, like that of rhodopsin, involves residues within the hydrophobic core of the protein. On the basis of these studies, a model for ligand binding to the receptor has been developed in which the amino group of an agonist or antagonist is anchored to the receptor through the carboxylate side chain of Asp113 in the third transmembrane helix. Other interactions between specific residues of the receptor and functional groups on the ligand have also been proposed. The interaction between the beta AR and the G protein Gs has been shown to involve an intracellular region that is postulated to form an amphiphilic alpha helix. This region of the beta AR is also critical for sequestration, which accompanies agonist-mediated desensitization, to occur. Structural similarities among G protein-linked receptors suggest that the information gained from the genetic analysis of the beta AR should help define functionally important regions of other receptors of this class.
Microfiber formation: Immiscible polymer blends involving thermoplastic poly(vinyl alcohol) as an extractable matrix (1994)

Abstract The utilization of polymer‐blend technology to prepare microfibers via extraction of one of the components is known technology. Achieving fibrillation (microfiber formation) is not an a priori consequence of polymer blends exposed to a shear or elongational flow field. The viscosity ratio, concentration ratio, interfacial tension, and second normal stress function have all been noted to be important factors in achieving fibrillation in polymer blends. It has been found that thermoplastic poly(vinyl alcohol) is particularly effective in this technology, yielding fibrillated systems that can be easily extracted to yield microfibers (0.1–5 μ diameter). Thermoplastic poly(vinyl alcohol) (PVOH) offers cold‐water solubility, biodegradability, and fibrillation characteristics with many commodity polymers (polyolefins, polystyrene, scrap mixtures), thus offering advantages over previously investigated extractable polymers. In addition, the resultant microfibers via this process can be pulped and handled in paper‐making processes. The process for microfiber formation, the process variables, the polymers applicable to the formation of microfibers using PVOH as an extractable matrix, and the properties of the resultant microfibers are discussed with emphasis on the characterization of the microfibers as a fibrous thixotrope additive. Potential utility of the microfibers via this process include polymeric paper and admixtures with cellulosic‐based pulp, oil‐ or water‐adsorbent mats, fibrous thixotrope additives, filters, filler rentention and pitch control in paper applications, and ultralow denier fibers. © 1994 John Wiley &amp; Sons, Inc.
Poly(ADP-ribose) Polymerase 1 Is Inhibited by a Histone H2A Variant, MacroH2A, and Contributes to Silencing of the Inactive X Chromosome (2007)

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in modulating chromatin structure, regulation of gene expression, and sensing DNA damage. Here, we report that PARP-1 enzymatic activity is inhibited by macroH2A, a vertebrate histone H2A variant that is enriched on facultative heterochromatin. MacroH2A family members have a large C-terminal non-histone domain (NHD) and H2A-like histone domain. MacroH2A1.2 and PARP-1 interact in vivo and in vitro via the NHD. The NHD of each macroH2A family member was sufficient to inhibit PARP-1 enzymatic activity in vitro. The NHD of macroH2A1.2 was a mixed inhibitor of PARP-1 catalytic activity, with affects on both catalytic activity and the substrate binding affinity of PARP-1. Depletion of PARP-1 by RNA interference caused reactivation of a reporter gene on the inactive X chromosome, demonstrating that PARP-1 participates in the maintenance of silencing. These results suggest that one function of macroH2A in gene silencing is to inhibit PARP-1 enzymatic activity, and this may affect PARP-1 association with chromatin.
Arrays of multilayered nanowires (invited) (1996)

Multilayered Co/Cu wires with a diameter of 80 nm and a length of 6 μm were produced by electrodeposition in nanoporous polycarbonate membranes. Their magnetoresistance has been measured in a geometry where the current was perpendicular to the layer plane. The anisotropic part of the magnetoresistance was limited to 1.5%. The study, for layer thicknesses ranging from 3 to 100 nm interpreted in terms of the Valet and Fert model, gave estimates of the spin dependent bulk and interface resistivities and their change with temperature. The large Co bulk resistivity value, caused by a large amount of Cu impurities, limited the magnetoresistance in our samples to 20% at room temperature and 30% at 20 K. The Cu spin flip mean free path was found to be temperature independent and determined by scattering at Co impurities in the Cu layer. It was measured for two sets of samples with different amounts of Co impurities.
The Impact of Cytokines and Chemokines on Non-Alcoholic Fatty Liver Disease (NAFLD) (2014)

 Abstract— There is a slight or no production of cytokines in the liver, under physiological conditions. However, pathological stimuli, such as lipid gathering, trigger the production of inflammatory molecules by hepatic cells. The active role that cytokines might play lies in the evolution of NAFLD by stimulating hepatic inflammation, cell necrosis and apoptosis, as well as by inducing fibrosis. In this review proof of the pathophysiological impact of cytokines in NAFLD is noted and examined.
Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions (2003)

To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period. Before treatment, active-SLE patients had circulating CD38bright Ig-secreting cells that were not found in normal individuals. Disappearance of this plasma cell subset during treatment was associated with decreases in anti–double-stranded DNA (anti-dsDNA) Ab levels, proteinuria, and SLE disease activity index. Consistent with this finding, peripheral B cells cultured in vitro spontaneously proliferated and secreted Ig in a manner that was inhibited by anti-CD154 mAb. Finally, the CD38+/++IgD+, CD38+++, and CD38+IgD– B cell subsets present in the peripheral blood also disappeared following treatment with humanized anti-CD154. Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies.
Conductivity of carbon nanotube polymer composites (2006)

Dissipative Particle Dynamics (DPD) simulations were used to investigate methods of controlling the assembly of percolating networks of carbon nanotubes (CNTs) in thin films of block copolymer melts. For suitably chosen polymers the CNTs were found to spontaneously self-assemble into topologically interesting patterns. The mesoscale morphology was projected onto a finite-element grid and the electrical conductivity of the films computed. The conductivity displayed non-monotonic behavior as a function of relative polymer fractions in the melt. Results are compared and contrasted with CNT dispersion in small-molecule fluids and mixtures.