gebhart/patrepeval huggingface dataset:
The moving parts of voltage-gated ion channels (1998)

Ion channels, like many other proteins, have moving parts that perform useful functions. The channel proteins contain an aqueous, ion-selective pore that crosses the plasma membrane, and they use a number of distinct ‘gating’ mechanisms to open and close this pore in response to biological stimuli such as the binding of a ligand or a change in the transmembrane voltage. This review is written at a watershed in our understanding of ion channels. 1. INTRODUCTION 240 1.1 Basic structure of voltage-activated channels 241 1.2 What are the physical motions of the channel protein during gating? 243 1.3 Gating involves several distinct mechanisms of activation and inactivation 246 2. ACTIVATION GATING 246 2.1 Early evidence for an activation gate at the intracellular mouth 247 2.1.1 Open channel blockade 247 2.1.2 The ‘ foot-in-the-door’ effect 249 2.1.3 Trapping of blockers behind closed activation gates 249 2.2 Site-directed mutagenesis and the difficulty of inferring structural roles from functional effects 250 2.3 State-dependent cysteine modification as a reporter of position and motion 251 2.4 Localization of activation gating 254 2.4.1 The trapping cavity 254 2.4.2 The activation gate 255 2.4.3 Is there more than one site of activation gating? 258 3. INACTIVATION GATING 259 3.1 Ball-and-chain ( N-type ) inactivation 261 3.1.1 Nature of the ‘ball’ – a tethered blocking particle 262 3.1.2 The ball receptor 263 3.1.3 The chain 264 3.1.4 Variations on the N-type inactivation theme: multiple balls, foreign balls, anti-balls 265 3.2 C-type inactivation 266 3.2.1 C-type inactivation and the outer mouth of the K + channel 266 3.2.2 The selectivity filter participates in C-type inactivation 267 3.2.3 A consistent structural picture of C-type inactivation 269 3.3 By what mechanism do other voltage-gated channels inactivate? 272 4. THE VOLTAGE SENSOR 273 4.1 Quantitative principles of voltage-dependent gating 276 4.2 S 4 ( and its neighbours ) as the principal voltage sensor 277 4.2.1 Mutational effects on voltage-dependence and charge movement 277 4.2.2 Evidence for the translocation of S 4 279 4.2.3 Real-time monitoring of S 4 motion by fluorescence 282 4.3 Coupling between the voltage sensor and gating 283 5. CONCLUSION 284 6. ACKNOWLEDGEMENTS 287 7. REFERENCES 287
The Reporter System for GPCR Assay with the Fission YeastSchizosaccharomyces pombe (2012)

G protein-coupled receptors (GPCRs) are associated with a great variety of biological activities. Yeasts are often utilized as a host for heterologous GPCR assay. We engineered the intense reporter plasmids for fission yeast to produce green fluorescent protein (GFP) through its endogenous GPCR pathway. As a control region of GFP expression on the reporter plasmid, we focused on seven endogenous genes specifically activated through the pathway. When upstream regions of these genes were used as an inducible promoter in combination with LPI terminator, the mam2 upstream region produced GFP most rapidly and intensely despite the high background. Subsequently, LPI terminator was replaced with the corresponding downstream regions. The SPBC4.01 downstream region enhanced the response with the low background. Furthermore, combining SPBC4.01 downstream region with the sxa2 upstream region, the signal to noise ratio was obviously better than those of other regions. We also evaluated the time- and dose-dependent GFP productions of the strains transformed with the reporter plasmids. Finally, we exhibited a model of simplified GPCR assay with the reporter plasmid by expressing endogenous GPCR under the control of the foreign promoter.
A Comparison of Platelet Size, Platelet Count, and Platelet 35S Incorporation as Assays for Thrombopoietin (1976)

Average platelet size, platelet count, and 35S-incorporation into platelets were compared as methods for the measurement of thrombopoietin-stimulated thrombopoiesis. In mice injected with rabbit anti-mouse platelet serum (RAMPS) average platelet size was shown to be increased as mice were recovering from thrombocytopenia. Also, 35S-measurements on platelets of these mice showed significant increases in cpm/average platelet 2-4 days after RAMPS treatment. Significant increases in 35S-incorporation into the total circulating mass of platelets were found on days 3-4. In normal mice or mice in rebound-thrombocytosis injected with thrombopoietin, platelet size remained unchanged, whereas the platelet cound and 35S-incorporation into platelets were shown to be significantly increased. Moreover, a dose-response experiment in mice pretreated with RAMPS showed a slight increase in platelet count as the dose of TSF was increased, but platelet sizes were unaltered. The % 35S-incorporation into platelets showed a significant linear dose-response, i.e. as the dose of thrombopoietin was increased, as increase in % 35S-incorporation into platelets was observed. These data indicated that of the three indirect measurements of thrombopoietin, the % 35S-incorporation into mouse platelets was the most sensitive, followed by platelet counting; the least sensitive measurement of thrombopoiesis was change in platelet size.
Stimulation of human gamma interferon production by diterpene esters (1981)

The diterpene ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and several structurally related compounds were tested for their ability to stimulate interferon (IFN) production in primary cultures of human leukocytes. In cultures of Ficoll-Hypaque-purified mononuclear cells, TPA treatment alone induced only low levels of IFN, but TPA pretreatment of cells caused significant enhancement of IFN yields produced with phytohemagglutinin or several other T cell mitogens. In cultures of unprocessed cells derived from plateletpheresis residues or buffy coats, TPA treatment alone induced high levels of IFN and costimulation with TPA and phytohemagglutinin produced some further enhancement of IFN production. Phorbol 12,13-dibutyrate was comparable to TPA in its ability to enhance phytohemagglutinin-induced IFN production. Several other phorbol ester analogs were also active, but maximal stimulation occurred only at higher drug concentrations. Mezerein, a structurally related diterpene ester, was at least as active as TPA in stimulating IFN production in either Ficoll-Hypaque-purified or unprocessed cells. IFN produced after stimulation with TPA or mezerein, singly or in combination with phytohemagglutinin, had several properties characteristic of IFN-gamma, e.g., it was largely inactivated by dialysis at pH 2, or after exposure to sodium dodecyl sulfate, whereas it was not neutralized by antibody to IFN-alpha and IFN-beta. The stimulatory effect of diterpene esters has proved helpful in producing IFN-gamma for physicochemical analysis and other studies.
395. The synthesis of 5- and 7-methoxytryptophan, and of some derivatives (1951)

R. H. Marchant and D. G. Harvey, J. Chem. Soc., 1951, 1808 DOI: 10.1039/JR9510001808
Water-Soluble Ag Nanoclusters Exhibit Strong Two-Photon-Induced Fluorescence (2008)

Water-soluble ssDNA-encapsulated Ag clusters exhibit large two-photon cross sections reaching 50 000 GM, with high quantum yields in the red and near-IR. Three distinct, spectrally pure, several atom clusters emitting at 660, 680, or 710 nm have been created with two-photon cross sections rivaling those of much larger water-soluble semiconductor quantum dots. Their stability, biocompatibility, and small size offer the promise of nontoxic, sensitive high-resolution biological imaging.
Cytolysis of leukemic B-cells by T-cells activated via two bispecific antibodies. (1993)

Bispecific monoclonal antibodies can be used in the activation of effector cells to lyse autologous tumor cells. We analyzed the activation of human T-cells in vitro with bispecific monoclonal antibodies, which were generated by hybridoma-hybridoma fusion. Preactivated allogeneic and autologous T-cells could be triggered to lyse tumoral B-cells in the presence of CD3 x CD19 bispecific antibodies. In addition, the combined use of two CD3 x CD19 plus CD28 x CD22 bispecific antibodies induced optimal interleukin 2 secretion by Jurkat T-cell acute lymphocytic leukemia cells in the presence of target B-cells. The same antibody combination was able to generate cytolytic effector cells without prior activation, when resting T-cells were cocultured with freshly isolated autologous leukemic B-cells in the presence of the bispecific antibodies. The results suggest that signals required to activate cytolytic T-cell precursors can be provided by the two bispecific antibodies. Although activation of resting T-cells can be achieved by CD3 x CD19 bispecific antibodies in association with monospecific bivalent CD28 antibodies, the second bispecific antibody, CD28 x CD22, further increases the specificity of the target cell dependent activation of T-cells. When used for immunotherapy of B-cell malignancies, the CD3 x CD19 and CD28 x CD22 bispecific antibody combination may avoid the need for ex vivo activated effector cells, because the antibodies may induce T-cell activation directly at the tumor site.
Capturing genes encoding membrane and secreted proteins important for mouse development. (1995)

A strategy based on the gene trap was developed to prescreen mouse embryonic stem cells for insertional mutations in genes encoding secreted and membrane-spanning proteins. The "secretory trap" relies on capturing the N-terminal signal sequence of an endogenous gene to generate an active beta-galactosidase fusion protein. Insertions were found in a cadherin gene, an unc6-related laminin (netrin) gene, the sek receptor tyrosine kinase gene, and genes encoding two receptor-linked protein-tyrosine phosphatases, LAR and PTP kappa. Analysis of homozygous mice carrying insertions in LAR and PTP kappa showed that both genes were effectively disrupted, but neither was essential for normal embryonic development.
Caveolar Localization Dictates Physiologic Signaling of β2-Adrenoceptors in Neonatal Cardiac Myocytes (2002)

There is a growing body of evidence that G protein-coupled receptors function in the context of plasma membrane signaling compartments. These compartments may facilitate interaction between receptors and specific downstream signaling components while restricting access to other signaling molecules. We recently reported that beta(1)- and beta(2)-adrenergic receptors (AR) regulate the intrinsic contraction rate in neonatal mouse myocytes through distinct signaling pathways. By studying neonatal myocytes isolated from beta(1)AR and beta(2)AR knockout mice, we found that stimulation of the beta(1)AR leads to a protein kinase A-dependent increase in the contraction rate. In contrast, stimulation of the beta(2)AR has a biphasic effect on the contraction rate. The biphasic effect includes an initial protein kinase A-independent increase in the contraction rate followed by a sustained decrease in the contraction rate that can be blocked by pertussis toxin. Here we present evidence that caveolar localization is required for physiologic signaling by the beta(2)AR but not the beta(1)AR in neonatal cardiac myocytes. Evidence for beta(2)AR localization to caveolae includes co-localization by confocal imaging, co-immunoprecipitation of the beta(2)AR and caveolin 3, and co-migration of the beta(2)AR with a caveolin-3-enriched membrane fraction. The beta(2)AR-stimulated increase in the myocyte contraction rate is increased by approximately 2-fold and markedly prolonged by filipin, an agent that disrupts lipid rafts such as caveolae and significantly reduces co-immunoprecipitation of beta(2)AR and caveolin 3 and co-migration of beta(2)AR and caveolin-3 enriched membranes. In contrast, filipin has no effect on beta(1)AR signaling. These observations suggest that beta(2)ARs are normally restricted to caveolae in myocyte membranes and that this localization is essential for physiologic signaling of this receptor subtype.
ChemInform Abstract: A NOVEL METHOD FOR THE SYNTHESIS OF COPPER(II) COMPLEXES OF MIXED‐ALDEHYDE AND β‐DIKETONE SYSTEMS (1979)

Abstract Die gemischten Aldehydato‐ und Ketonato‐Cu(II)‐Komplexe (II) werden durch die Umsetzung der Methoxy‐Derivate (I), in denen die Bindung der koordinierten Methoxygruppe labil ist, mit den entsprechenden zweizähnigen Aldehyden und Ketonen dargestellt und elementaranalytisch charakterisiert.
Posttranslational modification of the glycosylation inhibiting factor (GIF) gene product generates bioactive GIF (2000)

Glycosylation inhibiting factor (GIF) and macrophage migration inhibitory factor (MIF) share an identical structure gene. Here we unravel two steps of posttranslational modifications in GIF/MIF molecules in human suppressor T (Ts) cell hybridomas. Peptide mapping and MS analysis of the affinity-purified GIF from the Ts cells revealed that one modification is cysteinylation at Cys-60, and the other is phosphorylation at Ser-91. Cysteinylated GIF, but not the wild-type GIF/MIF, possessed immunosuppressive effects on the in vitro IgE antibody response and had high affinity for GIF receptors on the T helper hybridoma cells. In vitro treatment of wild-type recombinant human GIF/MIF with cystine resulted in preferential cysteinylation of Cys-60 in the molecules. The cysteinylated recombinant human GIF and the Ts hybridoma-derived cysteinylated GIF were comparable both in the affinity for the receptors and in the immunosuppressive activity. Polyclonal antibodies specific for a stretch of the amino acid sequence in alpha2-helix of GIF bound bioactive cysteinylated GIF but failed to bind wild-type GIF/MIF. These results strongly suggest that cysteinylation of Cys-60 and consequent conformational changes in the GIF/MIF molecules are responsible for the generation of GIF bioactivity.
The response to unfolded protein is involved in osmotolerance of Pichia pastoris (2010)

These data point out that the physiological response to increased osmolarity is different to S. cerevisiae. Increased osmolarity resulted in an unfolded protein response (UPR) like response in P. pastoris and lead to pre-conditioning of the recombinant Fab producing strain of P. pastoris to growth at high osmolarity. The current data demonstrate a strong similarity of environmental stress response mechanisms and recombinant protein related stresses. Therefore, these results might be used in future strain and bioprocess engineering of this biotechnologically relevant yeast.
Use of the automated tail suspension test for the primary screening of psychotropic agents. (1987)

Mice, when suspended by the tail, will alternate between active attempts to escape and immobility. A specially developed computerized device (ITEMATIC-TST) automatically measures the duration of immobility of 6 mice at one time and at the same time provides a measure of the energy expended by each animal, the power of the movements. Use of these 2 parameters enables activity profiles to be generated which can distinguish different classes of psychotropic activity. Immobility is decreased by antidepressants and psychostimulants, but increased by neuroleptics and minor tranquillizers. Minor tranquillizers can be distinguished from neuroleptics in that they decrease the power of the movements, whereas neuroleptics are without effect on this parameter. The present experiments were undertaken to see whether the activity profiles generated in this procedure could indeed be useful for primary psychotropic screening. Eighteen compounds, including antidepressants, neuroleptics, minor tranquillizers, sedative/hypnotics, dopaminergic stimulants and 3 dummy compounds were first submitted to a shortened primary observation procedure for dose finding and were then investigated at 2 doses in the automated tail suspension test. All experiments were conducted blind. The results obtained largely confirm the activity profiles already reported in this test and show that the combined use of primary observation and the automated tail suspension test permit the unambiguous identification of the pharmacological activity of 15 of the compounds tested with tentative identification of the 3 remaining compounds.
The ultrastructure of Candida albicans infections (1981)

Scrapings of Candida albicans plaques from the tongue and buccal mucosa of patients with oral candidiasis were examined by electron microscopy. In addition, urine sediment from patients with infection of their catheterized urinary tracts was similarly examined. Three types of C. albicans-oral epithelial cell interactions were noted: a loose adherence apparently mediated by a ruthenium red positive matrix, a "tight" adherence where no space could be seen between the host and yeast cell. and invasion of host cells by yeast hyphal elements. Adhesion of Candida blastospores to hyphal elements and adhesion of bacteria to Candida cells was also frequently observed. Urine sediments from patients with mixed bacteria-yeast infections demonstrated adhesion of the bacteria to the yeast cells. This phenomenon was also demonstrated in in vitro experiments and fibrous ruthenium red material invariably occupied the zone of adhesion. Phagocytosis of yeast by polymorphonuclear leukocytes was found in urinary, but not in oral. candidiasis. Our in vivo and in vitro observations indicate that a ruthenium red positive matrix covers the surfaces involved in the yeast to yeast, yeast to host, and yeast to bacteria adhesion.
Serpent: A Proposal for the Advanced Encryption Standard (1998)

. We propose a new block cipher as a candidate for the Advanced Encryption Standard. Its design is highly conservative, yet still allows a very e#cient implementation. It uses S-boxes similar to those of DES in a new structure that simultaneously allows a more rapid avalanche, a more e#cient bitslice implementation, and an easy analysis that enables us to demonstrate its security against all known types of attack. With a 128-bit block size and a 256-bit key, it is as fast as DES on the market leading Intel Pentium/MMX platforms (and at least as fast on many others); yet we believe it to be more secure than three-key triple-DES. 1 Introduction For many applications, the Data Encryption Standard algorithm is nearing the end of its useful life. Its 56-bit key is too small, as shown by a recent distributed key search exercise [28]. Although triple-DES can solve the key length problem, the DES algorithm was also designed primarily for hardware encryption, yet the great majority o...
Metabonomic Characterization of Genetic Variations in Toxicological and Metabolic Responses Using Probabilistic Neural Networks (2001)

Current emphasis on efficient screening of novel therapeutic agents in toxicological studies has resulted in the evaluation of novel analytical technologies, including genomic (transcriptomic) and proteomic approaches. We have shown that high-resolution 1H NMR spectroscopy of biofluids and tissues coupled with appropriate chemometric analysis can also provide complementary data for use in in vivo toxicological screening of drugs. Metabonomics concerns the quantitative analysis of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification [Nicholson, J. K., Lindon, J. C., and Holmes, E. (1999) Xenobiotica 11, 1181-1189]. In this study, we have used 1H NMR spectroscopy to characterize the time-related changes in the urinary metabolite profiles of laboratory rats treated with 13 model toxins and drugs which predominantly target liver or kidney. These 1H NMR spectra were data-reduced and subsequently analyzed using a probabilistic neural network (PNN) approach. The methods encompassed a database of 1310 samples, of which 583 comprised a training set for the neural network, with the remaining 727 (independent cases) employed as a test set for validation. Using these techniques, the 13 classes of toxicity, together with the variations associated with strain, were distinguishable to >90%. Analysis of the 1H NMR spectral data by multilayer perceptron networks and principal components analysis gave a similar but less accurate classification than PNN analysis. This study has highlighted the value of probabilistic neural networks in developing accurate NMR-based metabonomic models for the prediction of xenobiotic-induced toxicity in experimental animals and indicates possible future uses in accelerated drug discovery programs. Furthermore, the sensitivity of this tool to strain differences may prove to be useful in investigating the genetic variation of metabolic responses and for assessing the validity of specific animal models.
Location of polar substituents and fatty acyl chains on lipid A precursors from a 3-deoxy-D-manno-octulosonic acid-deficient mutant of Salmonella typhimurium. Studies by 1H, 13C, and 31P nuclear magnetic resonance. (1985)

Eight anionic disaccharide precursors of lipid A accumulate at 42 degrees C in 3-deoxy-D-manno-octulosonic acid-deficient temperature-sensitive mutants of Salmonella typhimurium. These compounds comprise a series of lipids based on the minimal structure, O-[2-amino-2-deoxy-N2,O3-bis(3-hydroxytetradecanoyl)-beta-D-glucopyranos yl] -(1----6)-2-amino-2-deoxy-N2, O3-bis(3-hydroxytetradecanoyl)-alpha-D-glucopyranose 1,4'- bisphosphate (designated lipid IVA) that differ from each other by the presence of an additional phosphoethanolamine moiety (IIIA), or an aminodeoxypentose moiety (IIA), or both (IA). A homologous set of metabolites is further derivatized with a palmitoyl function; these are designated IVB, IIIB, IIB, and IB (Raetz, C. R. H., Purcell, S., Meyer, M. V., Qureshi, N., and Takayama, K. (1985) J. Biol. Chem. 260, 16080-16088). The attachment of the palmitoyl moiety, known to be on the reducing terminal GlcN residue by mass spectrometry, was determined to be O-beta of the N2-linked beta-hydroxymyristoyl group of that residue of IVB by 13C NMR and two-dimensional 1H chemical shift correlation spectroscopy experiments. 31P NMR indicated the presence of diphosphodiester moieties in IIIA, IIIB, and IA and monophosphodiester moieties in IIA and IA. Selective 1H decoupling of the 31P spectrum of IIIA demonstrated that the O-diphosphoethanolamine moiety is attached to the O4' position in IIIA. On the basis of the observed 31P chemical shifts it was concluded that the aminodeoxypentose is located at position 1 in IIA and IA, while diphosphoethanolamine is most likely located at O-4' in IA and IIIB, as in IIIA.
An altered 11-kilobase transcript in leukemic cell lines with the t(4;11)(q21;q23) chromosome translocation. (1992)

The 11q23 chromosome band is frequently associated with chromosomal aberrations in human leukemias. We have previously cloned a DNA fragment derived from chromosome 11 which could be used as a probe to detect rearrangements in DNAs from the leukemic cells of patients with the t(4;11), t(9;11), and t(11;19) translocations. In this study we now show that the same probe detects DNA rearrangements in malignant cells from patients with the t(1;11), t(6;11), t(10;11), and del (11q23) chromosomal abnormalities. A second probe obtained from a region located centrometric to the breakpoint cluster detects major and minor transcripts of 12.5 and 11.5 kilobases, respectively, in all cell lines examined. The same probe identifies an altered 11-kilobase RNA in all three independent cell lines with the t(4;11)(q21;q23) chromosome translocation.