gebhart/patrepeval huggingface dataset:
Bureaucracy, politics, and decision making in post-Mao China (1992)

Using a model of fragmented authoritarianism, this volume sharpens our view of the inner workings of the Chinese bureaucracy. The contributors' interviews with politically well-placed bureaucrats and scholars, along with documentary and field research, illuminate the bargaining and maneuvering among officials on the national, provincial, and local levels.
Trimming of two major type 1 diabetes driving antigens, GAD65 and IA-2, allows for successful expression in Lactococcus lactis (2015)

Type 1 diabetes (T1D) is a chronic autoimmune disease characterised by excessive immune reactions against auto-antigens of pancreatic β-cells. Restoring auto-antigen tolerance remains the superior therapeutic strategy. Oral auto-antigen administration uses the tolerogenic nature of the gut-associated immune system to induce antigen-specific tolerance. However, due to gastric degradation, proper mucosal product delivery often imposes a challenge. Recombinant Lactococcus lactis have proven to be effective and safe carriers for gastrointestinal delivery of therapeutic products: L. lactis secreting diabetes-associated auto-antigens in combination with interleukin (IL)-10 have demonstrated therapeutic efficacy in a well-defined mouse model for T1D. Here, we describe the construction of recombinant L. lactis secreting the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and tyrosine phosphatase-like protein ICA512 (IA-2), two major T1D-related auto-antigens. Attempts to secrete full size human GAD65 and IA-2 protein by L. lactis were unsuccessful. Trimming of GAD65 and IA-2 was investigated to optimise antigen secretion while maintaining sufficient bacterial growth. GAD65370-575 and IA-2635-979 showed to be efficiently secreted by recombinant L. lactis. Antigen secretion was verified by immunoblotting. Plasmid-derived GAD65 and IA-2 expression was combined in single strains with human IL-10 expression, a desired combination to allow tolerance induction. This study reports the generation of recombinant L. lactis secreting two major diabetes-related auto-antigens: human GAD65 and IA-2, by themselves or combined with the anti-inflammatory cytokine human IL-10. Prohibitive sequence obstacles hampering antigen secretion were resolved by trimming the full size proteins.
The role of social networks in information diffusion (2012)

Online social networking technologies enable individuals to simultaneously share information with any number of peers. Quantifying the causal effect of these mediums on the dissemination of information requires not only identification of who influences whom, but also of whether individuals would still propagate information in the absence of social signals about that information. We examine the role of social networks in online information diffusion with a large-scale field experiment that randomizes exposure to signals about friends' information sharing among 253 million subjects in situ. Those who are exposed are significantly more likely to spread information, and do so sooner than those who are not exposed. We further examine the relative role of strong and weak ties in information propagation. We show that, although stronger ties are individually more influential, it is the more abundant weak ties who are responsible for the propagation of novel information. This suggests that weak ties may play a more dominant role in the dissemination of information online than currently believed.
Replacement by site-directed mutagenesis indicates a role for histidine 170 in the glutamine amide transfer function of anthranilate synthase. (1985)

Anthranilate synthase is a glutamine amidotransferase that catalyzes the first reaction in tryptophan biosynthesis. Conserved amino acid residues likely to be essential for glutamine-dependent activity were identified by alignment of the glutamine amide transfer domains in four different enzymes: anthranilate synthase component II (AS II), p-aminobenzoate synthase component II, GMP synthetase, and carbamoyl-P synthetase. Conserved amino acids were mainly localized in three clusters. A single conserved histidine, AS II His-170, was replaced by tyrosine using site-directed mutagenesis. Glutamine-dependent enzyme activity was undetectable in the Tyr-170 mutant, whereas the NH3-dependent activity was unchanged. Affinity labeling of AS II active site Cys-84 by 6-diazo-5-oxonorleucine was used to distinguish whether His-170 has a role in formation or in breakdown of the covalent glutaminyl-Cys-84 intermediate. The data favor the interpretation that His-170 functions as a general base to promote glutaminylation of Cys-84. Reversion analysis was consistent with a proposed role of His-170 in catalysis as opposed to a structural function. These experiments demonstrate the application of combining sequence analyses to identify conserved, possibly functional amino acids, site-directed mutagenesis to replace candidate amino acids, and protein chemistry for analysis of mutationally altered proteins, a regimen that can provide new insights into enzyme function.
Sarcoma Immunotherapy (2011)

Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.
Ultrasound Enhances Reporter Gene Expression After Transfection of Vascular Cells In Vitro (1999)

Adjunctive USE was associated with enhanced transgene expression in VSMCs and ECs and reduced VSMC but not EC proliferation in vitro, which suggests that ultrasound-assisted local gene therapy has potential as an antirestenotic therapy.
Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine. (1994)

Leflunomide is a compound recently shown to reduce T and B cell-mediated responses in a number of experimental rat, mouse, and human systems. To explore its potential as an immunosuppressant, we studied leflunomide in 128 Brown-Norway/Lewis cardiac transplants and in 48 unoperated Lewis rats. At doses ranging from 0.63 mg/kg to 10 mg/kg given for 7 days, leflunomide significantly prolonged graft survival compared with controls. When cyclosporine or leflunomide was given for 21 days at a dose of 5 mg/kg, indefinite graft survival occurred in 3/6 animals receiving leflunomide but in none of the 21-day cyclosporine-treated animals. When acute rejection was allowed to develop for four days in untreated rats, leflunomide but not cyclosporine reversed the rejection, returning histology to a normal appearance by seven days. Alloantibody responses measured in microcytoxicity assays as well as total allospecific IgG and IgM in the rejecting animals also were returned to baseline levels by leflunomide but not cyclosporine. When both drugs were used together, a synergistic effect was observed at low doses of both drugs. Pharmacokinetics studies showed that their combined use for up to 28 days did not affect the trough levels of cyclosporine or cyclosporine elimination, suggesting that the synergistic effect was not caused by reduced elimination. The toxicity of each drug was negligible in a group of 32 rats receiving the drugs alone or in combination as measured by serial observation of general appearance, testing of serum ALT, AST, bilirubin, creatinine, white blood cell counts, hemoglobin, and gross necropsy appearance. Weight gain was slightly reduced by both drugs but combined drug use did not alter the pattern. The results of these experiments show leflunomide to be a potent, well-tolerated immunosuppressant, synergistic in its activity with cyclosporine, and would seem to encourage a closer look at this drug for potential use in man.
Inhibition of nitric oxide synthase expression by PPM-18, a novel anti-inflammatory agent, in vitro and in vivo (1997)

We studied the effect of PPM-18, a chemically synthesized naphthoquinone derivative and also an anti-inflammatory agent, on the lipopolysaccharide (LPS)-activated inducible NO synthase (iNOS) expression in rat alveolar macrophages. Pretreatment of macrophages with PPM-18 (0.1-10 microM) significantly inhibited nitrite production, iNOS protein expression and iNOS mRNA accumulation. PPM-18 did not directly affect the enzymic activities of iNOS and other constitutive NOS forms. The LPS-induced increase in nuclear transcription factor kappaB (NF-kappaB) p65 and p50 in nucleus was suppressed by PPM-18 (10 microM). Moreover electrophoretic mobility-shift assays demonstrated that PPM-18 inhibited DNA binding to NF-kappaB induced by LPS in whole cells but not when added in the nuclear extract, suggesting that PPM-18 did not interfere directly with the binding of NF-kappaB to DNA and that some events had to be processed before NF-kappaB could bind DNA. Examination of NF-kappaB showed that PPM-18 stabilized the NF-kappaB inhibitor, IkappaBalpha, by preventing its degradation from NF-kappaB. Therefore the stabilization of IkappaBalpha might have contributed to the inhibition of NF-kappaB activation. These results also indicate strongly that NF-kappaB is involved in the production of NO on stimulation by LPS. PPM-18 significantly decreased the production of tumour necrosis factor alpha in response to LPS. PPM-18 protects mice against LPS-induced lethal toxicity. These results also indicate that PPM-18 is a potent inhibitor of iNOS expression by blocking the binding of NF-kappaB to promoter and exerts a beneficial effect in the mouse model of sepsis.
Cyclic polyhydroxy ketones. II. xylo-trihydroxycyclohexenediolic acid and keto-inositols (1964)

A new crystalline compound, dl-<i>xylo</i>-trihydroxycyclohexenediolic acid (dl-<i>xylo</i>-pentahydroxy-2-cyelohexen-1-one) (I), has been isolated from the products of oxidation of <i>myo</i>-inositol with nitric acid, and its structure has been established. Compound (I) reduces Tillmans reagent, reacts with iodine in neutral or slightly acidic solution, produces a blue color with ferric chloride solution, and exhibits other properties characteristic of an enediolic acid. On catalytic reduction, it gives both <i>scyllo</i>-inositol and <i>myo</i>-inositol. On oxidation, it yields a new triketo-inositol, <i>xylo</i>-4,5,6-trihydroxycyclohexane-l,2,3-trione (II). Under acidic conditions, catalytic acetylation of I gives two pentaacetates, the infrared spectra of which are similar but not identical. One of these acetates exists in two forms, both of which, on deacetylation, yield the parent acid I. The product formed by deacetylation of the other pentaacetate has not been identified. Benzoylation of I gives a crystalline pentabenzoate. Under basic conditions, acetylation of I proceeds with simultaneous aromatization, resulting in the formation of pentaacetoxybenzene, from which pentahydroxybenzene is obtained by hydrolysis. <i>xylo</i>-4,5,6-Trihydroxycyclohexane-l,2,3-trione (II) gives a crystalline bis(phenylhydrazone). By acetylation under basic conditions, it yields hexaacetoxybenzene. Mechanisms are presented for the aromatization of keto-inositols by enolization and <i>beta</i> elimination-reactions, and certain observations reported in the literature are rationalized. Infrared and ultraviolet absorption spectra are reported for the new compounds.
MEMS-based force sensor: Design and applications (2005)

Micromachined force detectors are extremely sensitive instruments capable of measuring forces as small as 10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">−15</sup> N. We describe one such instrument that combines a novel micromachined torsional oscillator with an interferometric position-sensing mechanism that allows fine control of vertical scans. The design, fabrication, and operation of MEMS-based force sensors are described. The sensitivity and unique features of micromachined torsional oscillators allow us to undertake experiments that set new constraints on corrections to Newtonian gravitational forces at separations below 1 μm. Moreover, the measurements provide the most precise characterization of quantum vacuum fluctuation forces to date.
Vagotomy Dissociates Short- and Long-Term Controls of Circulating Ghrelin (2003)

Plasma ghrelin levels are responsive to short- and long-term nutrient fluctuation, rapidly decreasing with food consumption and increasing with food deprivation or weight loss. We hypothesized a vagal contribution to both responses. Nutrient-related ghrelin suppression may be mediated by gastrointestinal load-related vagal afferent activity, or depend upon vagal efferent input to the foregut, where most ghrelin is produced. Similarly, the deprivation-induced ghrelin rise could require state-related vagal afferent or efferent activity. Here, we examined the role of the vagus nerve in the regulation of plasma ghrelin by sampling blood from rats with subdiaphragmatic vagotomy and from sham-operated controls over 48 h of food deprivation, and before and after gastric gavage of liquid diet. Vagotomy affected neither baseline ghrelin levels nor the suppression of ghrelin by a nutrient load. The food deprivation-induced elevation of plasma ghrelin levels ( approximately 160% of baseline), however, was completely prevented by subdiaphragmatic vagotomy. In a separate experiment, the deprivation-related rise in plasma ghrelin was substantially reduced by atropine methyl nitrate treatment, indicating that the response to fasting is driven by increased vagal efferent tone. The dissociation between nutrient load- and deprivation-related ghrelin responses indicates that the regulation of circulating ghrelin levels involves separate mechanisms operating through anatomically distinct pathways.
Optically active co-ordination compounds. Part XX. Reactions of 1,10-phenanthroline co-ordinated to cobalt(III) (1970)

The reactivity towards nitration and oxidation of the known ions D(+)-[Co(en)2(phen)]3+ and D(+)-[Co(phen)3]3+ has been studied. (+)[Co(en)2(phen)] reacts rapidly at room temperature under normal nitrating conditions to give exclusively the 5-nitro-1, 10-phenanthroline derivative which is then slowly oxidised to the 1,10-phenanthroline-5,6-quinone (quinone hereafter) derivative. Both of these reactions occur with no racemisation at the cobalt.The reactivity of D(+)-[Co(phen)3]3+ towards nitration is much less; but D(+)-[Co(quinone)3]3+ has been prepared without loss of optical activity, by oxidation with nitric acid–sulphuric acid in the presence of bromide ion. Several chemical correlations of optical configurations emerge from the various reactions and the circular dichroism spectra are discussed in relation to the configurations thereby revealed. The tris-bipyridyl cobalt(III) ion has been obtained optically active, and its properties are described.A new synthesis of the free ligand 1,10-phenanthroline-5,6-quinone from the 5-nitro-derivative is described, together with a method for isolating the same compound from its cobalt complex.
New therapeutic options for urge incontinence. (2001)

A critical evaluation of the literature published over the past year reveals several therapeutic options for urge incontinence. Basic science advances in understanding the pathophysiology of bladder instability are paramount in the development of new therapeutic options, chief of which is sacral neuromodulation. Epidemiologic studies from around the world impact the therapies and diagnosis. Therapies include hormone delivery systems, pharmaceutical, combined behavioral and drug, botulinum, surgery, magnetic stimulation, and sacral neuromodulation.
A Model of a Magnetically Sprung Vibration Generator for Power Harvesting Applications (2007)

This paper presents a new topology for a magnetically sprung electromagnetic velocity damped resonant generator for applications in harvesting energy from mechanical vibrations. It is demonstrated that the use of a magnetic suspension can achieve a low compliant spring rate required for optimal operation of a small resonant generator at low excitation frequencies. Similar characteristics can be difficult to achieve using a conventional mechanical spring. A model of the vibration generator is described and is based on an electrical equivalent network. Analytical expressions are used to determine the network components as functions of the generator geometry and material properties. These are validated through experimental measurements taken from a prototype generator. The model is to be used in the design optimization of such generators.
Endocytic Trafficking Routes of Wild Type and ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (2004)

Intracellular trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) is a focus of attention because it is defective in most patients with cystic fibrosis. DeltaF508 CFTR, which does not mature conformationally, normally does not exit the endoplasmic reticulum, but if induced to do so at reduced temperature is short-lived at the surface. We used external epitope-tagged constructs to elucidate the itinerary and kinetics of wild type and DeltaF508 CFTR in the endocytic pathway and visualized movement of CFTR from the surface to intracellular compartments. Modulation of different endocytic steps with low temperature (16 degrees C) block, protease inhibitors, and overexpression of wild type and mutant Rab GTPases revealed that surface CFTR enters several different routes, including a Rab5-dependent initial step to early endosomes, then either Rab11-dependent recycling back to the surface or Rab7-regulated movement to late endosomes or alternatively Rab9-mediated transit to the trans-Golgi network. Without any of these modulations DeltaF508 CFTR rapidly disappears from and does not return to the cell surface, confirming that its altered structure is detected in the distal as well as proximal secretory pathway. Importantly, however, the mutant protein can be rescued at the plasma membrane by Rab11 overexpression, proteasome inhibitors, or inhibition of Rab5-dependent endocytosis.
New Reagents on the Horizon for Immune Tolerance (2006)

Recent advances in immunology and a growing arsenal of new drugs are bringing the focus of tolerance research from animal models into the clinical setting. The conceptual framework for therapeutic tolerance induction has shifted from a "sledgehammer" approach that relies solely on cellular depletion and cytokine targeting, to a strategy directed toward restoring a functional balance across the immune system, namely the different populations of naive cells, effector and memory cells, and regulatory cells. Unlocking the key to tolerance induction in the future will likely depend on our ability to harness the functions of T regulatory cells. Also, dendritic cells are strategically positioned at the interface between innate and adaptive immunity and may be subject to deliberate medical intervention in a way that can control a chronic inflammatory response. Many reagents with tolerance-inducing potential are currently undergoing clinical testing in transplantation, autoimmune diseases, and allergic diseases, and even more that are on the horizon promise to offer enormous benefits to human health.
Transforming the TGFbeta pathway: convergence of distinct lead generation strategies on a novel kinase pharmacophore for TbetaRI (ALK5). (2004)

The pathological activation of the transforming growth factor beta (TGFbeta) pathway plays a critical role in the progression of fibrotic diseases and also enhances tumor invasiveness and metastasis. Due to its central role in TGFbeta signaling, the TGFbeta type I receptor (TbetaRI) is emerging as an exciting target for blockade of the TGFbeta pathway. In this review we will discuss how three independent drug discovery strategies, ie, target-hopping, high-throughput screening and virtual screening, have converged in the identification of inhibitors of TalphaRI kinase. Structural studies have provided insight into the potency and selectivity of these inhibitors and form the basis for structure-based design optimization strategies. These efforts have enabled the production of potent, selective inhibitors for dissecting the TGFalpha pathway and assessing the usefulness of TalphaRI blockade in the treatment of fibrotic diseases and cancer.
Envelope and long terminal repeat sequences of a cloned infectious NZB xenotropic murine leukemia virus (1985)

An infectious NZB xenotropic murine leukemia virus (MuLV) provirus (NZB was molecularly cloned from the Hirt supernatant of NZB-IU-6-infected mink cells, and the nucleotide sequence of its env gene and long terminal repeat (LTR) was determined. The partial nucleotide sequence previously reported for the env gene of NFS-Th-1 xenotropic proviral DNA (Repaske, et al., J. Virol. 46:204-211, 1983) is identical to that of the infectious NZB xenotropic MuLV DNA reported here. Alignment of nucleotide or deduced amino acid sequences, or both, of xenotropic, mink cell focus-forming, and ecotropic MuLV proviral DNAs in the env region identified sequence differences among the three host range classes of C-type MuLVs. Major differences were confined to the 5' half of env; a high degree of homology was found among the three classes of MuLVs in the 3' half of env. Alignment of the nucleotide sequence of the LTR of NZB xenotropic MuLV with those of the LTRs of NFS-Th-1 xenotropic, mink cell focus-forming, and ecotropic MuLVs revealed extensive homology between the LTRs of xenotropic and MCF247 MuLVs. An inserted 6-base-pair repeat 5' to the TATA box was a unique feature of both NZB and NFS-Th-1 xenotropic LTRs.
Advanced RF-driven H<sup>-</sup> ion sources at the SNS (2007)

The US spallation neutron source* (SNS), will require substantially higher average and pulse H" beam current than can be produced from conventional H <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-</sup> ion sources such as the baseline LBNL-SNS source. H <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-</sup> currents of 70-100 mA with an RMS emittance of 0.20-0.35 π mm mrad and a ˜7% duty-factor will be needed for the SNS power upgrade project in 2010. We are therefore investigating several advanced ion source concepts based on RF plasma excitation. First, a generalized discussion of our source development strategy is presented as well as the performance characteristics of a large-plasma-volume, external antenna source based on an AI <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> O <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> plasma chamber. The design and results of computational modeling of a high-power version of this source featuring an AlN plasma chamber is subsequently discussed as well as a high-efficiency extraction system necessary for high- current operation.