gebhart/patrepeval huggingface dataset:
Beyond theT1Limit: Singlet Nuclear Spin States in Low Magnetic Fields (2004)

Low-field nuclear spin singlet states may be used to store nuclear spin order in a room temperature liquid for a time much longer than the spin-lattice relaxation time constant T1. The low-field nuclear spin singlets are unaffected by intramolecular dipole-dipole relaxation, which is generally the predominant relaxation mechanism. We demonstrate storage of nuclear spin order for more than 10 times longer than the measured value of T1. This phenomenon may facilitate the development of nuclear spin hyperpolarization methods and may allow the study of motional processes which occur too slowly for existing NMR techniques. This is the first time that the memory of nuclear spins has been extended well beyond the T1 limit in a system lacking intrinsic magnetic equivalence.
G-protein-coupled receptors and their regulation: activation of the MAP kinase signaling pathway by G-protein-coupled receptors. (1997)

G-protein-coupled receptors that mediate cellular responses to a variety of humoral, endothelial-, or platelet-derived substances are able to stimulate MAP kinase activity. In transfected model systems, G-protein-coupled receptors that couple to pertussis toxin-insensitive G proteins of the Gq/11 family mediate this activation predominantly via a PKC-dependent mechanism. In contrast, activation of MAP kinase by receptors that couple to pertussis toxin-sensitive Gi proteins is PKC-independent and requires downstream activation of the low-molecular-weight G protein, Ras. This pathway can be inhibited by coexpression of peptides that sequester Gbetagamma subunits, and is mimicked by overexpression of Gbetagamma subunits. This Ras-dependent MAP kinase activation requires tyrosine phosphorylation of "docking proteins," including the shc adapter protein, and depends upon recruitment of Grb2/Sos1 complexes to the plasma membrane, thus resembling the pathway of MAP kinase activation employed by the receptor tyrosine kinases. Other molecules, including PI-3-kinases and phosphotyrosine phosphatases, probably also contribute to Gbetagamma-subunit-mediated assembly of a mitogenic signaling complex. Identification of the G-protein-coupled, receptor-regulated tyrosine kinase(s), and the means by which the mitogenic signaling complex is assembled at the plasma membrane, remain subjects of further study.
Encapsulation of the topoisomerase I inhibitor GL147211C in pegylated (STEALTH) liposomes: pharmacokinetics and antitumor activity in HT29 colon tumor xenografts. (1998)

The topoisomerase I inhibitor GL147211C [7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-campto thecin trifluoroacetate], a camptothecin analogue, has significant activity in tumor cell cytotoxicity assays in vitro and antitumor activity in both animal tumor models and human patients. Its toxicity is significant, however, effectively limiting the amount of drug that can be administered and its clinical utility. To determine whether the therapeutic index of GL147211C could be improved, the drug was encapsulated in long-circulating, pegylated (STEALTH) liposomes (SPI-355). The pharmacokinetics and antitumor activity of SPI-355 were compared to those of nonliposomal GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typical of those of other pegylated liposomal formulations, with significantly increased blood circulation time; the dose-corrected area under the curve and Cmax of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg). The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon carcinoma xenografts. SPI-355 was 20-fold more effective than GL147211C in inhibiting tumor growth (1 mg/kg SPI-355 and 20 mg/kg GL147211C) and produced durable complete remissions of tumors at well-tolerated dose levels that were >5-fold lower than the maximally tolerated dose of GL147211C, which induced no durable complete responses. Signs of toxicity were similar between the two drugs, but liposome encapsulation increased the toxicity of drug approximately 4-fold, with increased weight loss and several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased approximately 5-fold over that of nonliposomal GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.
Altered establishment/clearance mechanisms during experimental micrometastasis with live and/or disabled bacterial lacZ-tagged tumor cells. (1992)

To study micrometastasis at its earliest stages, the bacterial lacZ marker gene was introduced into human EJ Ha-ras-transformed BALB/c 3T3 cells (LZEJ), followed by their intravenous injection into nude mice. Lung micrometastases were easily identified by blue staining of lacZ-tagged cells minutes/hours after injection, permitting effective evaluation of establishment/clearance mechanisms of LZEJ cells. Different treatments were used to disable LZEJ cells (fixation, irradiation, or mitomycin C) to determine modulation of these processes--although unable to divide, these cells stain for lacZ expression for days after treatment. Fixation-killed cells generated large microfoci (> 13-15 cells/focus) with well-rounded morphologies while live, irradiated, or mitomycin-treated cells generated smaller, irregularly shaped foci (3-7 cells/focus). Fixed-cell foci were cleared more slowly from lungs than the other three classes, even when prefiltered to remove large aggregates. All foci of disabled cells were eventually cleared while a basal level of live-cell foci persisted. Co-injection of fixed and live cells (or preinjection of fixed cells, followed by live cells) resulted in complete clearance of live-cell microfoci; in contrast, preinjection of live cells (then injection of fixed cells) led to survival of live-cell micrometastases. Therefore, altered deformability and/or cell surface interactions of tumor cells modulate the effectiveness of host-clearing mechanisms in the lung and in some situations these altered cells facilitate clearance of live tumor cells that are normally tumor-progressing.
Categorical Reparameterization with Gumbel-Softmax (2016)

Categorical variables are a natural choice for representing discrete structure in the world. However, stochastic neural networks rarely use categorical latent variables due to the inability to backpropagate through samples. In this work, we present an efficient gradient estimator that replaces the non-differentiable sample from a categorical distribution with a differentiable sample from a novel Gumbel-Softmax distribution. This distribution has the essential property that it can be smoothly annealed into a categorical distribution. We show that our Gumbel-Softmax estimator outperforms state-of-the-art gradient estimators on structured output prediction and unsupervised generative modeling tasks with categorical latent variables, and enables large speedups on semi-supervised classification.
The Structure of Human Cytochrome P450 2C9 Complexed with Flurbiprofen at 2.0-Å Resolution (2004)

The structure of human P450 2C9 complexed with flurbiprofen was determined to 2.0 A by x-ray crystallography. In contrast to other structurally characterized P450 2C enzymes, 2C5, 2C8, and a 2C9 chimera, the native catalytic domain of P450 2C9 differs significantly in the conformation of the helix F to helix G region and exhibits an extra turn at the N terminus of helix A. In addition, a distinct conformation of the helix B to helix C region allows Arg-108 to hydrogen bond with Asp-293 and Asn-289 on helix I and to interact directly with the carboxylate of flurbiprofen. These interactions position the substrate for regioselective oxidation in a relatively large active site cavity and are likely to account for the high catalytic efficiency exhibited by P450 2C9 for the regioselective oxidation of several anionic non-steroidal anti-inflammatory drugs. The structure provides a basis for interpretation of a number of observations regarding the substrate selectivity of P450 2C9 and the observed effects of mutations on catalysis.
Immunogenicity of Vibrio cholerae O1 toxin-coregulated pili in experimental and clinical cholera (1991)

A functional tcpA gene, encoding the major subunit of toxin-coregulated pili (TCP), is necessary for Vibrio cholerae O1 Ogawa strain 395 to colonize the human intestine and confer protective immunity to virulent challenge. The immunogenicity of TCP and other antigens in experimental and naturally acquired cholera was determined. Seroconversion to cholera toxin (CT), whole cell preparations, and to Ogawa lipopolysaccharide but not to purified native TCP or to a TcpA mimiotope was found in volunteers. Local intestinal secretory immunoglobulin A from volunteers showed conversions to cholera toxin and lipopolysaccharide but not to TCP. Cholera patients in Indonesia showed a seroconversion rate to TCP of 3 of 6 and a seroconversion to a TcpA mimiotope of 1 of 6. Volunteer and patient sera showed similar vibriocidal seroconversions when assayed against either TCP-positive and TCP-negative V. cholerae O1 strains, suggesting that TCP do not contribute demonstrably to the vibriocidal antigen. We conclude that although seroconversion to TCP can occur in naturally acquired cholera, solid long-term protection can be engendered in the absence of a detectable anti-TCP immune response.
Conformation of a β-Adrenoceptor-Derived Signal Transducing Peptide As Inferred by Circular Dichroism and 1H NMR Spectroscopy (1996)

The peptide T345-359 representing the fourth intracellular loop of the avian beta-adrenoceptor has been shown to strongly inhibit receptor-mediated adenylate cyclase activity [Münch, G., Dees, C., Hekman, M., & Palm, D. (1991) Eur. J. Biochem. 198, 357-364]. Circular dichroism and two-dimensional 1H NMR techniques were used to investigate the three-dimensional structure of the peptide in trifluoroethanol, phospholipid micelles, and small unilamellar phospholipid vesicles. The prepared vesicles were tested for size distribution and stability by using electron microscopy, photon correlation spectroscopy, and 31P NMR spectroscopy. The peptide T345-359 adopted a predominantly alpha-helical conformation in either trifluoroethanol or phospholipid micelles and vesicles. No structural differences were found for the conformation of the peptide in the presence of phospholipid micelles or vesicles, respectively, using 2D 1H NMR techniques, suggesting a unique conformation of T345-359 when associated with model membranes. A computer-aided model of the micelle-associated peptide was derived. The relevance of the 3D structure of the intracellular loops of receptors to communicate with the G protein in the signal transduction cascade is discussed.
Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin. (1991)

Lysyl oxidase was partially purified from serum by a diethylaminoethyl batch procedure in the presence of 6 mol/L urea and dialyzed against 3 mol/L KSCN. Using this method, we determined serum lysyl oxidase activity in 52 patients with liver disease and in 14 healthy controls, and we examined usefulness of serum lysyl oxidase in assessing liver fibrogenesis. For this purpose, serum lysyl oxidase activity in chronic liver disease was compared with serum levels of prolyl hydroxylase and laminin P1. As compared with controls, serum lysyl oxidase activity increased 1.6-fold in chronic persistent hepatitis, 4.4-fold in chronic active hepatitis and 11.8-fold in cirrhosis, indicating an increase in concert with the development of liver fibrosis. In hepatocellular carcinoma, the serum activity, although significantly increased, was lower than that in cirrhosis. Serum prolyl hydroxylase was significantly increased in chronic active hepatitis, in liver cirrhosis and in hepatocellular carcinoma. Serum laminin P1 was significantly increased in chronic active hepatitis, in cirrhosis and in hepatocellular carcinoma. Serum lysyl oxidase activity did not correlate significantly with serum levels of prolyl hydroxylase and laminin P1 in any subject or in any subgroup. The magnitude of the increase and the abnormal percentage of serum lysyl oxidase activity were larger than those for serum prolyl hydroxylase and laminin P1. These results suggest that serum lysyl oxidase activity is a more sensitive indicator of liver fibrosis than serum prolyl hydroxylase and laminin P1.
Protein Corona of Nanoparticles: Distinct Proteins Regulate the Cellular Uptake (2015)

Understanding nanoparticle-protein interactions is a crucial issue in the development of targeted nanomaterial delivery. Besides unraveling the composition of the nanoparticle's protein coronas, distinct proteins thereof could control nanoparticle uptake into specific cell types. Here we differentially analyzed the protein corona composition on four polymeric differently functionalized nanoparticles by label-free quantitative mass spectrometry. Next, we correlated the relative abundance of identified proteins in the corona with enhanced or decreased cellular uptake of nanoparticles into human cancer and bone marrow stem cells to identify key candidates. Finally, we verified these candidate proteins by artificially decorating nanoparticles with individual proteins showing that nanoparticles precoated with the apolipoproteins ApoA4 or ApoC3 significantly decreased the cellular uptake, whereas precoating with ApoH increased the cellular uptake.
Process-strained Si (PSS) CMOS technology featuring 3D strain engineering (2004)

We report the demonstration of a process-strained Si (PSS) CMOS technology using the concept of three-dimensional (3D) strain engineering. Methods of producing PSS include stress engineering of trench isolation, silicide, and cap layer, to improve NMOS and PMOS performance simultaneously. Each of these approaches results in a 5-10% enhancement in the ring oscillator (RO) speed. By taking advantage of preferential 3D strain engineering via one or combining more PSS techniques, CMOS performance can be further improved. PSS is a cost effective technology for meeting CMOS power-performance requirements.
Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines. (2002)

There is increasing evidence that leptin affects immune responses and that in the absence of leptin, immunity is suboptimal. Most data so far indicate that leptin increases proinflammatory immune responses by an effect on T cells and macrophages. Here we show that, under certain circumstances, leptin can inhibit T cell proliferative responses. Separation of the responding T cells into different subpopulations revealed an interesting heterogeneity of cellular behavior in that naïve and memory T cells were differentially affected by leptin. The anti-CD3-driven proliferation of memory T cells was inhibited by leptin, whereas that of naïve T cells was markedly enhanced. Despite the inhibition of proliferation of the memory T cells, their production of interferon-gamma was substantially increased. These data show that leptin can inhibit certain immune responses in vitro. However, despite this inhibition of proliferation, the production of proinflammatory cytokines is significantly enhanced by leptin. The findings demonstrated here show further complexity in the actions of leptin on the immune system.
Behavioral profile of adults with Prader-Willi syndrome: correlations with individual and environmental variables (2013)

Significant rates of behavioral disorders were highlighted and their typology described in a large cohort of adults with PWS. The deletion genotype was related to a lower severity of symptoms. Some major behavioral problems, such as hyperphagia, may be well controlled if living circumstances are adapted to the specific requirements of individuals with PWS.
Atrial Structure and Plasma ANF Levels in Rats With Chronic Diabetes Mellitus (1990)

The effect of streptozocin-induced diabetes (STZ-D) on right atrial structure was investigated in male Wistar rats. STZ (55 mg/kg) or saline (1 ml/kg) was administered by intravenous injection 12 wk before the experimental studies. Tissue was sampled from four regions of the atrium, processed, and embedded in plastic. Quantitative stereological analysis indicated that in STZ-D rats, there was a significant diminution in size of the musculi pectinati (muscular ridges), which form a network making up the wall of the atrium. In addition, within the muscular ridges, there was a significant reduction in the relative proportion of cardiocytes within the cardiac tissue. The rest of the cardiac tissue consisted of interstitial regions, connective tissue, and blood vessels, which correspondingly increased. This suggests there was some form of cardiomyopathy. When atrial granularity was determined relative to cardiocyte volume density, a significant decrease (54%) was found in tissue from STZ-D rats. The blood pressure of conscious STZ-D rats was significantly lower than control rats, whereas right atrial pressure was not different. The level of resting plasma immunoreactive atrial natriuretic factor (ANF) in conscious STZ-D rats (98 +/- 5 pg/ml) was significantly higher than in control rats (52 +/- 7 pg/ml). The decreased atrial granularity could be related to the higher resting plasma ANF levels, suggesting a more rapid turnover or increased synthesis bypassing storage in the granular form.
Regulation of IgH Gene Assembly: Role of the Intronic Enhancer and 5′DQ52 Region in Targeting DHJH Recombination (2006)

The assembly of Ag receptor genes by V(D)J recombination is regulated by transcriptional promoters and enhancers which control chromatin accessibility at Ig and TCR gene segments to the RAG-1/RAG-2 recombinase complex. Paradoxically, germline deletions of the IgH enhancer (Emu) only modestly reduce D(H)-->J(H) rearrangements when assessed in peripheral B cells. However, deletion of Emu severely impairs recombination of V(H) gene segments, which are located over 100 kb away. We now test two alternative explanations for the minimal effect of Emu deletions on primary D(H)-->J(H) rearrangement: 1) Accessibility at the D(H)J(H) cluster is controlled by a redundant cis-element in the absence of Emu. One candidate for this element lies 5' to D(Q52) (PD(Q52)) and exhibits promoter/enhancer activity in pre-B cells. 2) In contrast to endpoint B cells, D(H)-->J(H) recombination may be significantly impaired in pro-B cells from enhancer-deficient mice. To elucidate the roles of PD(Q52) and Emu in the regulation of IgH locus accessibility, we generated mice with targeted deletions of these elements. We report that the defined PD(Q52) promoter is dispensable for germline transcription and recombination of the D(H)J(H) cluster. In contrast, we demonstrate that Emu directly regulates accessibility of the D(H)J(H) region. These findings reveal a significant role for Emu in the control mechanisms that activate IgH gene assembly and suggest that impaired V(H)-->D(H)J(H) rearrangement in enhancer-deficient cells may be a downstream consequence of the primary block in D(H)-->J(H) recombination.
The novel receptors that mediate the entry of herpes simplex viruses and animal alphaherpesviruses into cells (2000)

An extended array of cell surface molecules serve as receptors for HSV entry into cells. In addition to the heparan sulphate glycosaminoglycans, which mediate the attachment of virion to cells, HSV requires an entry receptor. The repertoire of entry receptors into human cells includes molecules from three structurally unrelated molecular families. They are (i) HveA (herpesvirus entry mediator A), (ii) members of the nectin family, (iii) 3-O-sulphated heparan sulphate. The molecules have different attributes and play potentially different roles in HSV infection and spread to human tissues. All the human entry receptors interact physically with the virion envelope glycoprotein D (gD). (i) HveA is a member of the TNF-receptor family. It mediates entry of a restricted range of HSV strains. Its expression is restricted to few lineages (e.g. T-lymphocytes). (ii) The human nectin1alpha (HIgR), nectin1delta (PRR1-HveC), and the nectin2alpha (PRR2alpha-HveB) and nectin2delta (PRR2delta) belong to the immunoglobulin superfamily. They are homologues of the poliovirus receptor (CD155), with which they share the overall structure of the ectodomain. The human nectin1alpha-delta are broadly expressed in cell lines of different lineages, are expressed in human tissue targets of HSV infection, serve as receptors for all HSV-1 and HSV-2 strains tested and mediate entry not only of free virions, but also cell-to-cell spread of virus. (iii) The 3-O-sulphated heparan sulphate is expressed in some selected human cell lines (e.g. endothelial and mast cells) and human tissues, and mediates entry of HSV-1, but not HSV-2. The human nectin2alpha and nectin2delta serve as receptors for a narrow range of viruses. A characteristic of the human nectin1alpha-delta is the promiscuous species non-specific receptor activity towards the animal alphaherpesviruses, pseudorabies virus (PrV) and bovine herpesvirus 1 (BHV-1). By contrast with the human nectin1delta, its murine homologue (mNectin1delta) does not bind gD at detectable level, yet it mediates entry of HSV, as well as of PrV and BHV-1. This provides the first example of a mediator of HSV entry independent of a detectable interaction with gD.
Propagation of the virus of porcine epidemic diarrhea in cell culture (1988)

Porcine epidemic diarrhea virus (PEDV) was adapted to serial propagation in Vero cell cultures by adding trypsin to the medium. PEDV-infected cells showed a distinct cytoplasmic fluorescence when examined by a fluorescent-antibody-staining technique. Cytopathic effects, such as vacuolation, formation of syncytia, and fusion of cells, were detected even at passage 1 of the PEDV in Vero cells. Once adapted, the virus induced numerous syncytia containing over 100 nuclei. From virus passage 5 on, all cells forming the monolayer were fused and totally destroyed within 24 h after inoculation. Cell culture-grown PEDV had typical coronavirus morphology when viewed by electron microscopy. Attempts to propagate PEDV in several primary and secondary fetal porcine cell cultures in the presence or absence of trypsin were unsuccessful.