gebhart/patrepeval huggingface dataset:
T cell recognition of hepatitis B and C viral antigens (1994)

The outcome of hepatitis B and C heavily depends on the appropriate virus specific T cell response. Both CD8+ and CD4+ T lymphocytes do not recognize native viral proteins but processed peptides bound to MHC class I and class II, respectively. For therapeutical intervention aimed at T lymphocytes in chronic carriers as well as for the development of new vaccines, a precise identification of immunodominant epitopes, which can be recognized by a majority of patients, is necessary. Biological features of certain viral antigens have been partly characterized in animal models, but with the availability of modern molecular technology it is possible to extend these findings to the human system. The identification of anchor residues and motifs in peptides, which are essential for binding to certain MHC class I and class II molecules, allows the prediction of MHC allele-specific epitopes within viral proteins. By the use of synthetic peptides and vaccinia expression vectors, several epitopes for cytotoxic and helper T lymphocytes have been identified in HBV and HCV antigens. In HBV infection cytotoxic T lymphocytes recognize epitopes within the polymerase protein, the envelope protein and the nucleocapsid. In HCV cytotoxic epitopes have so far been identified within the nucleocapsid, E1, E2 and NS2. Since virus specific CD8+ T lymphocytes lyse virus infected cells in vitro and seem to play an important role for viral elimination in vivo, activation of virus specific effector cells may be achieved by immunizing chronically infected patients with the MHC-allele-specific peptides. Epitopes for CD4+ T lymphocytes have been demonstrated in the majority of HBV- and HCV-proteins. Different subsets of CD4+ T lymphocytes influence the course of infection by the production of lymphokines which either support antibody production by B cells or cellular antiviral effector mechanisms. In acute and chronic HBV infection the HBcAg/HBeAg-specific T cell response is closely correlated to viral elimination and the occurrence of anti-HBe- and anti-HBs antibodies. In HCV infection the CD4+ T cell response appears to be more heterogenous, and better functional characterization of the CD4+ response to immunodominant peptide epitopes in association with certain disease stages is required. Since T cell activation, the resulting effector functions and binding of the peptide to the HLA-molecule mainly depend on the peptide structure, viral mutations leading to amino acid changes may contribute to T cell non-responsiveness or an inappropriate T cell response.(ABSTRACT TRUNCATED AT 400 WORDS)
CLONING, EXPRESSION AND CHARACTERIZATION OF THE P64k OUTER MEMBRANE PROTEIN FROM N. meningitidis (1995)

Gerardo Guillen^1, Ricardo Silva^1, Anabel Alvarez^1, Lidia I. Novoa^1, Sonia Gonzalez^1, Alexis Musacchio^1, Manuel Selman^1, Alejandro Martin^1, Vivian Morera^2, Julio Fernandez^1, Juan Morales^1, Gustavo Sierra^1, Vladimir Besada^2, Edelgis Coizeau^1, Evelyn Caballero^1, Consuelo Nazabal^1, Tania Carmenate^1, Olivia Niebla^1, Jesus del Valle^1, Beatriz Tamargo^1, Javier Gonzalez^2, Regla Estrada^2, Yanet Tambara^2, Gabriel Padron^2, and Luis Herrera^1.
Phosphoramidate Prodrugs of 2′-C-Methylcytidine for Therapy of Hepatitis C Virus Infection (2009)

The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.
Indigo ‐ A Natural Pigment for High Performance Ambipolar Organic Field Effect Transistors and Circuits (2011)

Millenniums-old natural dye indigo--a "new" ambipolar organic semiconductor. Indigo shows balanced electron and hole mobilities of 1 × 10(-2) cm(2) V(-1) s(-1) and good stability against degradation in air. Inverters with gains of 105 in the first and 110 in the third quadrant are demonstrated. Fabricated entirely from natural and biodegradable compounds, these devices show the large potential of such materials for green organic electronics.
Sodium phenylbutyrate prolongs survival and regulates expression of anti‐apoptotic genes in transgenic amyotrophic lateral sclerosis mice (2005)

Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor-kappaB (NF-kappaB) p50, the phosphorylated inhibitory subunit of NF-kappaB (pIkappaB) and beta cell lymphoma 2 (bcl-2), but reduced cytochrome c and caspase expression. Curcumin, an NF-kappaB inhibitor, and mutation of the NF-kappaB responsive element in the bcl-2 promoter, blocked butyrate-induced bcl-2 promoter activity. We provide evidence that the pharmacological induction of NF-kappaB-dependent transcription and bcl-2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IkappaB, translocating NF-kappaB p50 to the nucleus, or to directly acetylate NF-kappaB p50. NF-kappaB p50 transactivates bcl-2 gene expression. Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post-translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.
A reusable biosensor chip for SERS-fluorescence dual mode immunoassay (2015)

Research continues in an effort to develop a versatile platform for clinical diagnosis with easy operation and low cost. In the present study, a biosensor chip has been designed and fabricated for surface enhanced Raman scattering (SERS)- fluorescence dual mode immunoassay. Here, a dual channel microfluidic chip was employed for simultaneous SERS and fluorescence detection. Unlike previously reported microfluidic immunoassays using fluorescence or SERS method independently, the proposed dual mode biosensor combined the advantages of these two optical detection techniques. The fluorescence mode can be used for fast screening of biomolecules while the SERS mode can be employed for accurate and sensitive quantitative analysis. In addition, the chip-based microfluidic platform greatly reduced the reagents cost and complicated operation. The whole detection process from sample preparation to optical detection can be finished in 90 min. Moreover, the reversibly bonded biosensor chip could be reused after cleaning, which further reduced the cost for each assay. All these merits make it a potential powerful tool for practical clinical diagnosis.
Anti‐CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis (2016)

Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor α chain (IL-2Rα or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R.
Friction Factors for Pipe Flow (1944)

Abstract The object of this paper is to furnish the engineer with a simple means of estimating the friction factors to be used in computing the loss of head in clean new pipes and in closed conduits running full with steady flow. The modern developments in the application of theoretical hydrodynamics to the fluid-friction problem are impressive and scattered through an extensive literature. This paper is not intended as a critical survey of this wide field. For a concise review, Professor Bakhmeteff’s (1) small book on the mechanics of fluid flow is an excellent reference. Prandtl and Tietjens (2) and Rouse (3) have also made notable contributions to the subject. The author does not claim to offer anything particularly new or original, his aim merely being to embody the now accepted conclusions in convenient form for engineering use.
Specific Binding of T Lymphocytes to Macrophages. II. Role of Macrophage-Associated Antigen (1978)

Abstract In “Specific Binding of T Lymphocytes to Macrophages. II. Role of Macrophage-Associated Antigen” by Shlomo Z. Ben-Sasson, Mary F. Lipscomb, Thomas F. Tucker, and Jonathan W. Uhr in the October issue of The Journal of Immunology, Volume 119, Number 4, page 1495, column 1, paragraph 2, line 11, reads “A p &amp;gt; 9.25…. This should read “A p &amp;gt; 0.25….” In the same article on p. 1499, column 2, the sentence beginning on line 8 should read “Pronase a more powerful and less specific enzyme….”
Osteoprotegerin and osteoprotegerin ligand effects on osteoclast formation from human peripheral blood mononuclear cell precursors (1999)

Osteoprotegerin (OPG) and its ligand (OPGL) negatively and positively regulate osteoclastogenesis in the mouse. OPG inhibits osteoclastogenesis by sequestering its ligand, OPGL, the osteoclast differentiation and activation factor. This study demonstrates the effects of soluble muOPGL and huOPG on the developing human osteoclast phenotype, on bone slices, using peripheral blood mononuclear cells (PBMCs), cultured for 2 weeks, without stromal cells. OPGL (2-50 ng/ml), in combination with CSF-1, hydrocortisone (HC), and 1,25(OH)2D3, increases the size of osteoclast-like cells on bone, as defined by the acquisition of osteoclast markers: vitronectin receptor (VR), tartrate-resistant acid phosphatase (TRAP), multinuclearity, and bone resorption. By 14 days, with 20 ng/ml OPGL, the largest cells/10x field have achieved an average diameter of 163+/-38 microm, but only approximately 10-20 microm in its absence and the number of osteoclast-like cells/mm2 bone surface is about 128. By scanning electron microscopy, OPGL-treated (20-ng/ml) cultures contain small osteoclast-like cells on bone with ruffled "apical" surfaces by day 7; by day 15, large osteoclast-like cells are spread over resorption lacunae. At 15 ng/ml OPGL, about 37% of the bone slice area is covered by resorption lacunae. OPG (5-250 ng/ml) antagonizes the effects of OPGL on the morphology of the osteoclast-like cells that form, as well as bone erosion. For cells grown on plastic, Cathepsin K mRNA levels, which are barely detectable at plating, are elevated 7-fold, by 5 days, in the presence, not the absence, of OPGL (20 ng/ml) + CSF-1 (25 ng/ml). Similar findings are observed in experiments performed in the absence of HC and 1,25(OH)2D3, indicating that HC and 1,25(OH)2D3 are not needed for OPGL-induced osteoclast differentiation. In conclusion, this study confirms a pivotal role for OPGL and OPG in the modulation of human osteoclast differentiation and function, suggesting a use for OPG for treating osteoclast-mediated bone disease in humans.
Recent approaches to the development of antigen-specific immunotherapies for myasthenia gravis (2010)

Acquired autoimmune myasthenia gravis (MG) is the most common disease that affects the neuromuscular junction (NMJ). MG is associated with autoantibodies (auto-Abs) to components of the NMJ. About 85-90% of MG patients have auto-Abs against the muscle nicotinic acetylcholine receptor (AChR), while about half of the remaining patients have auto-Abs against muscle-specific kinase. Auto-Abs, in combination with local deposition of complement, reduce the number of available post-synaptic nicotinic AChRs and thereby impair neuromuscular transmission. Current medications for MG are non-specific and include acetylcholinesterase inhibitors, immunosuppressants, plasma exchange, intravenous Ig administration and thymectomy. Treatments that selectively target the anti-AChR auto-Abs may prove to be more effective and free of side-effects. We here review two approaches aimed at the development of antigen-specific therapies for MG. The first is specific apheresis of Abs from patients' sera using immobilised recombinant AChR domains as immunoadsorbents. Indeed, we have recently shown that the combined recombinant extracellular domains of all human AChR subunits are capable of specifically immunoadsorbing the majority of pathogenic auto-Abs from several MG sera. The second therapeutic approach is the development of non-pathogenic anti-AChR monoclonal Abs that could potentially be used as protective agents by blocking the binding of patients' auto-Abs to the AChR.
Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. (1982)

Conditioned medium from cultures of mouse peritoneal exudate cells incubated wih endotoxin contains a mediator that markedly suppresses (greater than 90%) lipoprotein lipase (triacylglycero-protein acylhydrolase, EC 3.1.1.34) activity in differentiating 3T3-L1 mouse preadipocytes. The effect is dependent upon the amount of mediator and is evident as early as 30 min after the addition of the mediator-containing medium to 3T3-L1 cell cultures. Neither endotoxin nor conditioned medium from cultures of exudate cells not exposed to endotoxin shows the presence of the mediator. Lysates of the exudate cells are also unable to suppress the lipase activity. Increasing the amount of insulin does not reverse this suppression, even at 1000 times the concentration used for standard experiments. The lipoprotein lipase suppression mediator present in the conditioned medium of endotoxin-treated exudate cells is heat labile and has an apparent molecular weight of at least 12,000. The mediator does not inhibit lipoprotein lipase activity directly nor does it affect the half-life of enzyme activity released in the medium. The present study demonstrates that endotoxin promotes the release of a mediator from exudate cells that suppresses the activity of lipoprotein lipase in 3T3-L1 preadipocytes.
miR-126 inhibits proliferation of small cell lung cancer cells by targeting SLC7A5 (2011)

Despite intensive efforts to improve therapies, small cell lung cancer (SCLC) still has a dismal median survival of 18 months. Since miR-126 is under-expressed in the majority of SCLC tumors, we investigated the effect of miR-126 overexpression on the proliferation and cell cycle distribution of H69 cells. Our results demonstrate that miR-126 inhibits proliferation of H69 cells, by delaying the cells in the G1 phase. Short interfering RNA (siRNA) mediated suppression of SLC7A5, a predicted target of mir-126, has the same effect on H69 cells. We also show for the first time that SLC7A5 is a direct target of miR-126.
Law and adaptivity in requirements engineering (2013)

The great impact that law has on the design of software systems has been widely recognized in past years. However, little attention has been paid to the challenge of coping with variability characterizing the legal domain (e.g., multiple ways to comply with a given law, frequent updates to regulations, different jurisdictions, etc.) on the design of software systems. This position paper advocates the use of adaptation mechanisms in order to support regulatory compliance for software systems. First we show an example of how Zanshin, a requirements-based adaptation framework, can be used to design a system that adapts to legal requirements to accommodate legal variability. Then we examine how legal texts can be analyzed as sources for parameters and indicators needed to support adaptation. As motivating running example we consider legal situations concerning the Google driverless car and its recent legalization in the highways of Nevada and soon also in California.
Advances in the osteoblast lineage (1998)

Osteoblasts are the skeletal cells responsible for synthesis, deposition and mineralization of the extracellular matrix of bone. By mechanisms that are only beginning to be understood, stem and primitive osteoprogenitors and related mesenchymal precursors arise in the embryo and at least some appear to persist in the adult organism, where they contribute to replacement of osteoblasts in bone turnover and in fracture healing. In this review, we describe the morphological, molecular, and biochemical criteria by which osteoblasts are defined and cell culture approaches that have helped to clarify transitional stages in osteoblast differentiation. Current understanding of differential expression of osteoblast-associated genes during osteoprogenitor proliferation and differentiation to mature matrix synthesizing osteoblasts is summarized. Evidence is provided to support the hypothesis that the mature osteoblast phenotype is heterogeneous with subpopulations of osteoblasts expressing only subsets of the known osteoblast markers. Throughout this paper, outstanding uncertainties and areas for future investigation are also identified.
In Vitro Refolding/Unfolding Pathways of Amphioxus Insulin-like Peptide (2004)

Amphioxus insulin-like peptide (AILP) belongs to the insulin superfamily and is proposed as the common ancestor of insulin and insulin-like growth factor 1. Herein, the studies on oxidative refolding and reductive unfolding of AILP are reported. During the refolding process, four major intermediates, P1, P2, P3, and P4, were captured, which were almost identical to those intermediates, U1, U2, U3, and U4, captured during the AILP unfolding process. P4 (U4) has the native disulfide A20-B19; P1 (U1), P2 (U2), and P3 (U3) have two disulfide bonds, which include A20-B19. Based on the analysis of the time course distribution and properties of the intermediates, we proposed that fully reduced AILP refolded through 1SS, 2SS, and 3SS intermediate stages to the native form; native AILP unfolded through 2SS and 1SS intermediate stages to the full reduced form. A schematic flow chart of major oxidative refolding and reductive unfolding pathways of AILP was proposed. Implication for the folding behavior of insulin family proteins was discussed. There may be seen three common folding features in the insulin superfamily: 1) A20-B19 disulfide is most important and formed during the initial stage of folding process; 2) the second disulfide is nonspecifically formed, which then rearranged to native disulfide; 3) in vitro refolding and unfolding pathways may share some common folding intermediates but flow in opposite directions. Furthermore, although swap AILP is a thermodynamically stable final product, a refolding study of swap AILP demonstrated that it is also a productive intermediate of native AILP during refolding.
Trials, Tribulations, and Trends in Tumor Modeling in Mice (2004)

Selection of mouse models of cancer is often based simply on availability of a mouse strain and a known compatible tumor. Frequently this results in use of tumor models long on history but short on homology and quality control. Other factors including genetics, sex, immunological status, method and site of tumor implantation, technical competence, biological activity of the tumor, protocol sequence and timing, and selection of endpoints interact to produce outcomes in tumor models. Common reliance on survival and tumor burden data in a single mouse model often skews expectations towards high remission and cure rates; a finding seldom duplicated in clinical trials. Inherent limitations of tumor models coupled with the advent of new therapeutic targets reinforce need for careful attention to design, conduct, and stringent selection of in vivo and ex vivo endpoints. Preclinical efficacy testing for anti-tumor therapies should progress through a series of models of increasing sophistication that includes incorporation of genetically engineered animals, and orthotopic and combination therapy models. Pharmacology and safety testing in tumor-bearing animals may also help to improve predictive value of these models for clinical efficacy. Trends in bioinformatics, genetic refinements, and specialized imaging techniques are helping to maintain mice as the most scientifically and economically powerful model of malignant neoplasms.
Animal models of drug‐resistant epilepsy* (2012)

Several animal models are discussed in order to outline features of difficult-to-treat or drug-resistant epilepsy. These models can be categorised as those which show a poor response to different antiepileptic drugs and those in which subgroups of drug-resistant animals are selected, based on interindividual differences. Non-responders to antiepileptic drugs have been described in the amygdala kindling model, as well as the chronic phase of post-status epilepticus models. Epileptic dogs which do not respond to standard antiepileptic drugs may serve as a translational model to provide a more clinical environment for drug testing. Drug resistance or a poor response to several antiepileptic drugs has been reported for the 6-Hz model, lamotrigine-pretreated kindled rats, pentylentetrazole-induced seizures in rats pre-exposed to pilocarpine, as well as following intrauterine exposure of rats to methylazoxymethanol. Using models to select non-responders is highly time-consuming and elaborate, limiting their use in routine drug-screening procedures. Current efforts to identify biomarkers of drug resistance may simplify the selection process, e.g. replacing several weeks of seizure monitoring by a single imaging scan. Moreover, further elucidation of mechanisms of resistance may help to design a series of ex vivo or in vitro screening procedures in order to evaluate whether a test compound is affected.