gebhart/patrepeval huggingface dataset:
HCV infection: pathogenesis, clinical manifestations and therapy. (2008)

Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2-3%. It is believed that about 170 million people are currently infected (about 3% of the world's population), and a further 3-4 million are infected each year. HCV is the main reason for liver transplantation in the developed world, and the main cause of liver-related morbidity and mortality in a number of countries, including Italy. It is not only a frequent cause of chronic liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma, but is also involved in the pathogenesis of various autoimmune and rheumatic disorders (arthritis, vasculitis, sicca syndrome, porphyria cutanea tarda, lichen planus, nephropathies, thyroid diseases, and lung fibrosis), as well as in the development of B-cell lymphoproliferative diseases. Furthermore, patients suffering from C hepatitis tend to produce rheumatoid factor, cryoglobulins and a large series of autoantibodies (ANA, anti-SSA/SSB, SAM, ATG, aCL). The use of glucocorticoids or immuno-suppressant agents in HCV infected individuals, which are needed to treat autoimmune and rheumatic disorders, leads to a risk of worsening the clinical outcome of HCV. Under these conditions, the viral infection often needs to be treated with antiviral agents, mainly pegylated interferon combined with ribavirin. However, cyclosporine A seems to be safe and effective in patients with autoimmune disease (AD) and concomitant chronic HCV infection as is documented by the reduction in viremia and transaminases, particularly in patients with high baseline levels. Finally, HCV is the main trigger of mixed cryoglobulinemia. An attempt at viral eradication is therefore indicated in most patients, and is particularly effective in the case of mild or moderate manifestations. In severe cases, rituximab is an apparently safe and effective alternative to conventional immunosuppression and, specifically, it controls B-cell proliferation.
Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by Heparin-binding Epidermal Growth Factor (EGF)-like Growth Factor/EGF Receptor Signaling (2014)

Heparan sulfate (HS) is a component of cell surface and extracellular matrix proteoglycans that regulates numerous signaling pathways by binding and activating multiple growth factors and chemokines. The amount and pattern of HS sulfation are key determinants for the assembly of the trimolecular, HS-growth factor-receptor, signaling complex. Here we demonstrate that HS 6-O-sulfotransferases 1 and 2 (HS6ST-1 and HS6ST-2), which perform sulfation at 6-O position in glucosamine in HS, impact ovarian cancer angiogenesis through the HS-dependent HB-EGF/EGFR axis that subsequently modulates the expression of multiple angiogenic cytokines. Down-regulation of HS6ST-1 or HS6ST-2 in human ovarian cancer cell lines results in 30-50% reduction in glucosamine 6-O-sulfate levels in HS, impairing HB-EGF-dependent EGFR signaling and diminishing FGF2, IL-6, and IL-8 mRNA and protein levels in cancer cells. These cancer cell-related changes reduce endothelial cell signaling and tubule formation in vitro. In vivo, the development of subcutaneous tumor nodules with reduced 6-O-sulfation is significantly delayed at the initial stages of tumor establishment with further reduction in angiogenesis occurring throughout tumor growth. Our results show that in addition to the critical role that 6-O-sulfate moieties play in angiogenic cytokine activation, HS 6-O-sulfation level, determined by the expression of HS6ST isoforms in ovarian cancer cells, is a major regulator of angiogenic program in ovarian cancer cells impacting HB-EGF signaling and subsequent expression of angiogenic cytokines by cancer cells.
Recombinant Multiepitope Protein for Early Detection of Dengue Infections (2006)

Dengue fever is a mosquito-borne viral disease prevalent mainly in tropical countries. As the clinical manifestations of dengue are not very unique, laboratory diagnosis is crucial in identifying cases of dengue infection. Detection of dengue infection based on the identification of antidengue antibodies has emerged as a practical and reliable means of diagnosing dengue fever. We recently developed a customized recombinant dengue multiepitope protein (r-DME-G) that can specifically detect the immunoglobulin G (IgG) class of antidengue antibodies in patient sera. Using this strategy, we have now created another dengue multiepitope protein, r-DME-M, with specificity for the IgM class of antidengue antibodies. A synthetic gene encoding the r-DME-M protein was expressed as a maltose-binding protein fusion in Escherichia coli. The recombinant protein was purified in a single affinity chromatographic step to obtain yields of approximately 15 mg purified protein/liter of culture. The purified protein was used to develop an in-house IgM enzyme-linked immunosorbent assay (ELISA) and tested using a panel of 172 patient sera characterized using the commercially available Dengue Duo rapid strip test from PanBio, Australia. The IgM ELISA results showed that the r-DME-M protein not only recognized all IgM(+) samples identified by the PanBio test but also identified samples missed by the latter test. We also successfully adapted the r-DME-M protein to a rapid strip test format. This approach of creating customized antigens coupled to overexpression in E. coli and simple purification offers a promising alternative option to dengue diagnosis with the potential to circumvent the drawbacks of the whole virus antigen-based commercial kits.
T cell receptor alpha-chain influences reactivity to Mls-1 in V beta 8.1 transgenic mice (1992)

Most, but not all, V beta 8.1+ T cells respond to M1s-1 and are clonally deleted in the thymus of M1s-1-expressing animals. To formally examine the role of the TCR alpha-chain in reactivity and tolerance to M1s-1, we have analyzed M1s-1 reactivity in a large panel of CD4+ hybridomas generated from TCR V beta 8.1 transgenic mice, that express an identical, potentially M1s-1-reactive beta-chain. The data show that the alpha-chain strongly influences the M1s-1 reactivity of the hybridomas and that the differences in reactivity had relevance for tolerance. Thus, V alpha 11+ hybridiomas were biased toward M1s-1 reactivity and V alpha 11+ T cells were correspondingly absent from the peripheral repertoire of M1s-1-expressing transgenic mice. V alpha 2+ hybridomas, on the other hand, were biased against M1s-1 reactivity, and V alpha 2+ T cells were correspondingly amplified in the M1s-1-expressing transgenic mice. Structural analysis of the alpha-chains revealed that the M1s-1 reactivity of the V alpha 11+ hybridomas segregated precisely with family member, such that V alpha 11.1+ hybridomas were M1s-1-reactive and V alpha 11.3+ hybridomas were not M1s-1-reactive. On the other hand, there was not a clear correlation between family member and M1s-1 reactivity in the V alpha 2+ hybridomas. The hybridomas also showed striking variation in their reactivity to staphylococcal enterotoxin B (SEB), and the SEB reactivity of the V alpha 11+ hybridomas correlated precisely with family member and with M1s-1 reactivity. In contrast, there was not a clear correlation with V alpha 2+ alpha-chain structure and SEB reactivity. Also, there was no correlation between M1s-1 reactivity and SEB reactivity in individual V alpha 2+ hybridomas, suggesting that the recognition of the two superantigens by the same TCR is not equivalent. Taken together, these data define a role for the TCR alpha-chain in superantigen reactivity and T cell tolerance, and provide a structural explanation for the different fates of M1s-1-reactive T cells in normal and transgenic mice.
Therapeutic Relevance of Osteoprotegerin Gene Therapy in Osteosarcoma: Blockade of the Vicious Cycle between Tumor Cell Proliferation and Bone Resorption (2007)

Osteosarcoma is the most frequent primary bone tumor that develops mainly in the young, the median age of diagnosis being 18 years. Despite improvement in osteosarcoma treatment, survival rate is only 30% at 5 years for patients with pulmonary metastases at diagnosis. This warrants exploration of new therapeutic options, and among them, osteoprotegerin (OPG), a naturally occurring protein that inhibits bone resorption, is very promising in blocking the vicious cycle between bone resorption and tumor proliferation that takes place during tumor development in bone site. As OPG binds and inhibits the activity of tumor necrosis factor-related apoptosis-inducing ligand, the truncated form of murine OPG 1-194 was used. The cDNA encoding OPG was administered by gene transfer using replication-defective adenoviral vector or was associated with an amphiphilic polymer in two models of rodent osteosarcoma. In both models, OPG gene transfer was effective in preventing the formation of osteolytic lesions associated with osteosarcoma development, in reducing the tumor incidence and the local tumor growth, leading to a 4-fold augmentation of mice survival 28 days postimplantation. On the contrary, OPG did not prevent the development of pulmonary metastasis alone, suggesting that bone environment is necessary for OPG therapeutic efficacy. Because OPG has no direct activity on osteosarcoma cells in vitro (cell binding, cell proliferation, apoptosis, or cell cycle distribution), we show that OPG exerts indirect inhibitory effect on tumor progression through the inhibition of RANKL whose production is enhanced in bone tumor environment, leading to osteolysis inhibition as reflected by osteoclast number decrease.
Kinetic Dependence to HIV-1 Entry Inhibition (2006)

Infection by human immunodeficiency virus type 1 (HIV-1) involves the fusion of viral and cellular membranes mediated by formation of the gp41 trimer-of-hairpins. A designed protein, 5-Helix, targets the C-terminal region of the gp41 ectodomain, disrupting trimer-of-hairpins formation and blocking viral entry. Here we show that the nanomolar inhibitory potency of 5-Helix (IC50 approximately 6 nm) is 4 orders of magnitude larger than its subpicomolar binding affinity (K(D) approximately 0.6 pm). This discrepancy results from the transient exposure of the 5-Helix binding site on gp41. As a consequence, inhibitory potency is determined by the association rate, not by binding affinity. For a series of 5-Helix variants with mutations in their gp41 binding sites, the IC50 and K(D) values poorly correlate. By contrast, an inverse relationship between IC50 values and association rate constants (k(on)) extends for over 2 orders of magnitude. The kinetic dependence to inhibition places temporal restrictions on an intermediate state of HIV-1 membrane fusion and suggests that access to the C-terminal region of the gp41 ectodomain is largely free from steric hindrance. Our results support the importance of association kinetics in the development of improved HIV-1 fusion inhibitors.
[Expression of Survivin and its significance in tongue squamous cell carcinoma]. (2007)

The positive staining of Survivin increased in different grades of TSCC, and Survivin is relative to carcinogenesis, progression and prognosis of TSCC. It may be a new clinical therapeutic target for TSCC.
MicroRNA-21 Limits In Vivo Immune Response-Mediated Activation of the IL-12/IFN-γ Pathway, Th1 Polarization, and the Severity of Delayed-Type Hypersensitivity (2011)

An altered balance between Th1 and Th2 cytokines is responsible for a variety of immunoinflammatory disorders such as asthma, yet the role of posttranscriptional mechanisms, such as those mediated by microRNAs (miRs), in adjusting the relative magnitude and balance of Th cytokine expression have been largely unexplored. In this study, we show that miR-21 has a central role in setting a balance between Th1 and Th2 responses to Ags. Targeted ablation of miR-21 in mice led to reduced lung eosinophilia after allergen challenge, with a broadly reprogrammed immunoactivation transcriptome and significantly increased levels of the Th1 cytokine IFN-γ. Biological network-based transcriptome analysis of OVA-challenged miR-21(-/-) mice identified an unexpected prominent dysregulation of IL-12/IFN-γ pathways as the most significantly affected in the lungs, with a key role for miR-21 in IFN-γ signaling and T cell polarization, consistent with a functional miR-21 binding site in IL-12p35. In support of these hypotheses, miR-21 deficiency led dendritic cells to produce more IL-12 after LPS stimulation and OVA-challenged CD4(+) T lymphocytes to produce increased IFN-γ and decreased IL-4. Further, loss of miR-21 significantly enhanced the Th1-associated delayed-type hypersensitivity cutaneous responses. Thus, our results define miR-21 as a major regulator of Th1 versus Th2 responses, defining a new mechanism for regulating polarized immunoinflammatory responses.
Functional Analysis of the RING-Type Ubiquitin Ligase Family of Arabidopsis (2005)

Approximately 5% of the Arabidopsis (Arabidopsis thaliana) proteome is predicted to be involved in the ubiquitination/26S proteasome pathway. The majority of these predicted proteins have identity to conserved domains found in E3 ligases, of which there are multiple types. The RING-type E3 is characterized by the presence of a cysteine-rich domain that coordinates two zinc atoms. Database searches followed by extensive manual curation identified 469 predicted Arabidopsis RING domain-containing proteins. In addition to the two canonical RING types (C3H2C3 or C3HC4), additional types of modified RING domains, named RING-v, RING-D, RING-S/T, RING-G, and RING-C2, were identified. The modified RINGs differ in either the spacing between metal ligands or have substitutions at one or more of the metal ligand positions. The majority of the canonical and modified RING domain-containing proteins analyzed were active in in vitro ubiquitination assays, catalyzing polyubiquitination with the E2 AtUBC8. To help identity regions of the proteins that may interact with substrates, domain analyses of the amino acids outside the RING domain classified RING proteins into 30 different groups. Several characterized protein-protein interaction domains were identified, as well as additional conserved domains not described previously. The two largest classes of RING proteins contain either no identifiable domain or a transmembrane domain. The presence of such a large and diverse number of RING domain-containing proteins that function as ubiquitin E3 ligases suggests that target-specific proteolysis by these E3 ligases is a complex and important part of cellular regulation in Arabidopsis.
Investigation of Astrocyte – Oligodendrocyte Interactions in Human Cultures (2011)

Multiple sclerosis (MS) is characterized by CNS demyelination and oligodendrocyte depletion, axonal loss, and reactive astrogliosis. Myelin loss causes conduction block, while remyelination is associated with recovery of conduction and return of function. Reactive astrocytes are a prominent feature of MS plaques, and have been implicated as producing factors regulating oligodendrocyte progenitor differentiation and myelin formation. Understanding their impact on these events may lead to new approaches for oligodendrocyte protection and/or remyelination in MS. Here, we outline protocols for the establishment and analysis of primary monocultures and cocultures of human astrocytes and oligodendrocytes. These approaches are designed to facilitate analysis of mechanisms underlying astrocytic regulation of progenitor survival and myelin repair.
Bacterial Endosymbionts of Free‐living Amoebae1 (2004)

The occurrence of bacterial endosymbionts in free-living amoebae has been known for decades, but their obligate intracellular lifestyle hampered their identification. Application of the full cycle rRNA approach, including 16S rRNA gene sequencing and fluorescence in-situ hybridization with 16S rRNA-targeted oligonucleotide probes, assigned the symbionts of Acanthamoeba spp. and Hartmannella sp. to five different evolutionary lineages within the Proteobacteria, the Bacteroidetes, and the Chlamydiae, respectively. Some of these bacterial symbionts are most closely related to bacterial pathogens of humans, and it has been suggested that they should be considered potential emerging pathogens. Complete genome sequence analysis of a chlamydia-related symbiont of Acanthamoeba sp. showed that this endosymbiont uses similar mechanisms for interaction with its eukaryotic host cell as do the well-known bacterial pathogens of humans. Furthermore, phylogenetic analysis suggested that these mechanisms have been evolved by the ancestor of these amoeba symbionts in interplay with ancient unicellular eukaryotes.
High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis (2003)

Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.
Multiple forms of prostate-specific antigen in serum: differences in immunorecognition by monoclonal and polyclonal assays (1993)

Abstract Prostate-specific antigen (PSA) in serum is primarily complexed with alpha 1-antichymotrypsin (alpha 1-ACT). However, 12-15% of prostate cancer (PCa) patients present with the predominant form being uncomplexed (free) PSA (Lilja et al., Clin Chem 1991;37:1618-24). We report that commercial immunoassays demonstrate variations in reactivity, especially to the uncomplexed form. We fractionated and analyzed commercial controls, PSA complexes prepared in vitro, and sera from patients with PCa or benign prostatic hyperplasia, using molecular sieve chromatography and Hybritech Tandem-R, Abbott IMx, and Ciba Corning ACS PSA assays. Peak integration of PCa samples demonstrated ACS:Tandem-R ratios of 1-1.3 for PSA/alpha 1-ACT complex. In contrast, ratios of uncomplexed peaks ranged from 2 to 4, suggesting a greater reactivity of the uncomplexed form in the ACS PSA assay. Discrepancies between assays, when PSA was measured in unfractionated sera, correlated directly with the percentage of the uncomplexed form. In controls, fractionation revealed the presence of uncomplexed PSA only, with ratios of ACS:Tandem-R and IMx:Tandem-R of 3:1 and 1.8:1, respectively. Immunoblots of PCa sera detected uncomplexed PSA (approximately 30 kDa) and PSA complexes of approximately 95 kDa (PSA/alpha 1-ACT) and &amp;gt; 200 kDa, indicative of alpha 2-macroglobulin. Maximal recognition of all forms of PSA may be important for early detection of disease progression.
Use of Carbodiimides as Stabilizing Agents to Deliver Water—Labile Active Ingredients in Liquid Systems Including Aqueous Medium—Amitraz as a Case Study (2005)

Abstract Several active ingredients such as sulfonylureas and diimidines (Amitraz) are unstable in water. They undergo hydrolysis producing metabolites that are no longer biologically active. The rate of hydrolysis is a function of several factors, such as the solvent system, access to water, pH, temperature, ionic strength, and the types of emulsifiers used in the liquid matrices. Some of the active ingredients undergo rapid hydrolysis even with the residual water present in the emulsifier system in an organic emulsifiable concentrate formulation. It is therefore difficult to formulate such active ingredients in liquid delivery systems. Use of carbodiimides like Stabaxol I® (bis-2,6-diisopropylphenylcarbodiimide) as a water scavenger to stabilize oil-based formulations for Amitraz is well documented and is commercially practiced. We have found that unique combinations of carbodiimides with specific solvent-emulsifier-polymer blends in a buffered system can produce stable microemulsions of Amitraz in water. Such aqueous formulations with 200–500 ppm Amitraz in &amp;gt;99 % water, were stable with 95 % retention on accelerated storage at 50°C for two weeks. This data translates to greater than two years stability at room temperature. Such formulations may be extended to deliver sulfonylureas. We also observed that the concentrate and the matrix containing Stabaxol I® and emulsifiers can produce gels on storage, adversely affecting physical stability. We have identified several additives and alternatives to prevent gel formation enabling long-term storage stability of the matrix and the concentrate. Examples with supporting data will be provided. A rationale and proposed mechanism for the enhanced stability and potential biological activity will be discussed.
Iterative Decoding of Bit-Interleaved Coded Modulation (2007)

This thesis addresses techniques for wireless communication systems to transmit high data rates with high reliability.The investigations are focused on the bit-interleaved coded modulation (BICM) system that is the serial concatenation of a channel encoder, an interleaver and a symbol mapper for high order modulation.The performance of BICM can be greatly improved through iterative information exchange between the demapper and the decoder at the receiver.This system is usually referred to as BICM with iterative decoding (BICM-ID).The major contributions of this work are the study of the iterative BICM receiver and the investigation of modulation techniques to improve the adaptability and performance of the system: First, properties of decoder and demapper EXIT functions are derived to gain additional insights on the convergence of the iterative BICM receiver.Then, the focus is on mapping techniques, i.e. on the assignment of bit sequences to signal points of a high order signal constellation.Methods to characterize and optimize mappings for a variety of applications are investigated.In particular, mappings optimized for iterative receivers are proposed.Along the same line of thought, the combination of different signal constellations and mappings within one code word, nonunique mappings and superimposed mappings are investigated to improve the adaptability and performance of the system using modulation techniques. ZusammenfassungIn der vorliegenden Dissertation werden Methoden fr drahtlose Kommunikationssysteme untersucht, die es ermglichen Information sowohl mit hohen Datenraten als auch mit einer hohen Zuverlssigkeit zu bertragen.Es wird insbesondere das Bit-Interleaved Coded Modulation (BICM)-System betrachtet, das aus einer seriellen Verkettung eines Kanalencoders, eines Interleavers sowie einer Abbildung der Bits auf Symbole einer hherstufigen Signalraumkonstellation (sog.Mapping) besteht.Die Leistungsfhigkeit von BICM kann durch iterativen Informationsaustausch zwischen dem Demapper und dem Decoder stark verbessert werden.Dieses System wird blicherweise als BICM mit iterativer Decodierung bezeichnet (BICM-ID).Die Hauptbeitrge dieser Arbeit sind die Untersuchung des iterativen BICM Empfngers und die Entwicklung von Modulationstechniken, um die Anpassungs-und Leistungsfhigkeit des Systems zu verbessern: Zuerst werden Eigenschaften der Decoder-und Demapper EXIT-Funktionen abgeleitet, wodurch zustzliche Einblicke in das Konvergenzverhalten des iterativen BICM Empfngers erlangt werden.Anschlieend liegt der Schwerpunkt auf