gebhart/patrepeval huggingface dataset:
CD4+ blood dendritic cells are potent producers of IFN-alpha in response to in vitro HIV-1 infection. (1994)

We determined the relative abilities of cell subpopulations from all major PBMC lineages of normal donors to produce IFN-alpha in response to in vitro stimulation with lymphocytotropic HIV-1 (IIIb and RF), monocytotropic HIV-1 (BaL), Sendai virus, and HSV-1. Active and inactive cell-free preparations of HIV-1 IIIb and cell-associated HIV-1 IIIb, and active cell-free preparations of the other viruses, induced comparable, maximal levels of acid-stable IFN-alpha in PBMC by 18 to 24 h. Negative selection and enrichment experiments indicated that HLA-DR+ "null" cells produced the majority of the IFN-alpha. A positive selection protocol using flow cytometric sorting enriched these HLA-DR+ CD3- CD19- CD16- CD56- CD14- cells to > 95% purity. These were identified as dendritic cells by their phenotype, large size, and veiled and ruffled morphology. The purified dendritic cells produced as much as 60-fold more IFN-alpha compared with purified, HLA-DR+ CD14+ monocytes in response to the viruses. IFN-alpha was not produced by CD3+ T cells or CD56+ NK cells. Purified CD19+ B cells produced a minimal amount of IFN-alpha in response to Sendai virus, and no IFN-alpha in response to the other viruses. Of significance, the dendritic cells expressed CD4 at a density similar to monocytes, and induction of IFN-alpha by HIV-1 could be blocked by HIV-1 gp120 anti-serum or anti-CD4 mAb. We conclude that the production of IFN-alpha constitutes a previously unrecognized major function of blood dendritic cells. This may be a mechanism of innate immunity mediated by dendritic cells against HIV-1 and other viral infections.
Effects of Alterations to the CX3C Motif and Secreted Form of Human Respiratory Syncytial Virus (RSV) G Protein on Immune Responses to a Parainfluenza Virus Vector Expressing the RSV G Protein (2019)

Human respiratory syncytial virus (RSV) is a major pediatric respiratory pathogen. The attachment (G) and fusion (F) glycoproteins are major neutralization and protective antigens. RSV G is expressed as membrane-anchored (mG) and -secreted (sG) forms, both containing a central fractalkine-like CX3C motif. The CX3C motif and sG are thought to interfere with host immune responses and have been suggested to be omitted from a vaccine. We used a chimeric bovine/human parainfluenza virus type 3 (rB/HPIV3) vector to express RSV wild-type (wt) G and modified forms, including sG alone, mG alone, mutants with ablated CX3C, and G with enhanced packaging into vector virions. In hamsters, these viruses replicated to similar titers. When assayed with a complement-enhanced neutralization assay in Vero cells, sG did not reduce the serum RSV- or PIV3-neutralizing antibody (NAb) responses, whereas ablating CX3C drastically reduced the RSV NAb response. Protective efficacy against RSV challenge was not reduced by sG but was strongly dependent on the CX3C motif. In ciliated human airway epithelial (HAE) cells, NAbs induced by wt G, but not by wt F, completely blocked RSV infection in the absence of added complement. This activity was dependent on the integrity of the CX3C motif. In hamsters, the rB/HPIV3 expressing wt G conferred better protection against RSV challenge than that expressing wt F. Codon optimization of the wt G further increased its immunogenicity and protective efficacy. This study showed that ablation of the CX3C motif or sG in an RSV vaccine, as has been suggested previously, would be ill advised.<b>IMPORTANCE</b> Human RSV is the leading viral cause of severe pediatric respiratory illness. An RSV vaccine is not yet available. The RSV attachment protein G is an important protective and neutralization antigen. G contains a conserved fractalkine-like CX3C motif and is expressed in mG and sG forms. sG and the CX3C motif are thought to interfere with host immune responses, but this remains poorly characterized. Here, we used an attenuated chimeric bovine/human parainfluenza virus type 3 (rB/HPIV3) vector to express various modified forms of RSV G. We demonstrated that strong antibody and protective responses could be induced by G alone, and that this was highly dependent on the integrity of the CX3C motif. There was no evidence that sG or the CX3C motif impaired immune responses against RSV G or the rB/HPIV3 vector. rB/HPIV3 expressing wt RSV G provides a bivalent vaccine against RSV and HPIV3.
Systematic Review of the Chronic Care Model in Chronic Obstructive Pulmonary Disease Prevention and Management (2007)

Limited published data exist evaluating the efficacy of CCM components in chronic obstructive pulmonary disease management. However, pooled data demonstrated that patients with chronic obstructive pulmonary disease who received interventions with 2 or more CCM components had lower rates of hospitalizations and emergency/unscheduled visits and a shorter length of stay compared with control groups. The results of this review highlight the need for well-designed trials in this population.
A human serotonin 1D receptor variant (5HT1D beta) encoded by an intronless gene on chromosome 6. (1992)

An intronless gene encoding a serotonin receptor (5HT1D beta) has been cloned and functionally expressed in mammalian fibroblast cultures. Based on the deduced amino acid sequence, the gene encodes a 390-amino acid protein displaying considerable homology, within putative transmembrane domains (approximately 75% identity) to the canine and human 5HT1D receptors. Membranes prepared from CHO cells stably expressing the receptor bound [3H]serotonin with high affinity (Kd 4 nM) and displayed a pharmacological profile consistent, but not identical, with that of the characterized serotonin 5HT1D receptor. Most notably, metergoline and serotonergic piperazine derivatives, as a group, display 3- to 8-fold lower affinity for the 5HT1D beta receptor than for the 5HT1D receptor, whereas both receptors display similar affinities for tryptamine derivatives, including the antimigraine drug sumatriptan. Northern blot analysis revealed an mRNA of approximately 5.5 kilobases expressed in human and monkey frontal cortex, medulla, striatum, hippocampus and amygdala but not in cerebellum, olfactory tubercle, and pituitary. The 5HT1D beta gene maps to human chromosome 6. The existence of multiple neuronal 5HT1D-like receptors may help account for some of the complexities associated with [3H]serotonin binding patterns in native membranes.
In vitro activation of human chondrocytes and synoviocytes by a human interleukin‐1‐like factor (1984)

Monocytes have been shown to secrete factors which stimulate the destruction of cartilage. Since one of the monocyte products, interleukin-1 (IL-1), has been shown to stimulate the release of collagenase and prostaglandin E from synoviocytes, we have investigated whether IL-1 is also responsible for chondrocyte activation. Purified preparations of IL-1 derived from human blood monocytes stimulated the production of prostaglandin E and plasminogen activator by human articular chondrocytes. After Sephadex G-75 chromatography, the lymphocyte-activating and the chondrocyte-activating activities of IL-1 eluted together in the regions corresponding to the void volume and to Kav = 0.2-0.3 (Mr 30,000-45,000) and Kav = 0.5-0.65 (Mr 12,000-17,000). The major peak of stimulating activity was the 12,000-17,000 dalton peak. Upon further analysis of the 12,000-17,000 dalton peak by isoelectric focusing, the major peak of lymphocyte-activating factor activity was recovered at a pI of 6.3 with a minor peak at 4.6-5.3. Similar patterns of activity were observed when the fractions were assayed for the stimulation of the production of prostaglandin E and plasminogen activator by human chondrocytes and of prostaglandin E by human synoviocytes. Treatment of the partially purified lymphocyte activating factor with phenylglyoxal reduced the thymocyte-stimulating activity 99% and the chondrocyte-stimulating activity 100%. These results suggest that IL-1 may stimulate the degradation of connective tissues during inflammation.
In vivo induced antigenic determinants of Actinobacillus actinomycetemcomitans (2004)

Actinobacillus actinomycetemcomitans is a Gram-negative capnophilic rod and the etiological agent of localized aggressive periodontitis. The genome-wide survey of A. actinomycetemcomitans using in vivo induced antigen technology (IVIAT) has previously resulted in the discovery of antigenic determinants expressed specifically in diseased patients. The present study evaluated the potential of these antigens as putative disease markers, and investigating their contribution to the pathogenesis of the microorganism. Sera from patients had a significantly greater antibody titer than sera from healthy controls against six antigens, which supports the in vivo expression of these antigens, and suggests their usefulness as disease markers. A. actinomycetemcomitans invasion of epithelium-derived HeLa cells resulted in the induction of all three genes tested, as evidenced by real-time PCR. Isogenic mutants of these three genes were constructed and the adhesion and intracellular survival of the mutants was assayed in a competition assay with the wild-type strain. A significant defect in the intracellular survival of two of these mutant strains (orf1402 and orf859) was found. This defect could not be attributed to an adhesion defect. In contrast, a mutation in vapA, a homologue of a novel putative transcriptional regulator, out-competed the wild-type strain in the same assay. The virulent phenotype was restored for a mutant strain in orf859 upon complementation. This data provided new insight into the pathogenic personality of A. actinomycetemcomitans in vivo and supported the use of HeLa cells as a valid in vitro host-pathogen interactions model for that microorganism. IVIAT is applicable to most pathogens and will undoubtedly lead to the discovery of novel therapies, antibiotics and diagnostic tools.
Tetracycline repressor-regulated gene repression in recombinant human cytomegalovirus (1995)

The tetracycline repressor (TetR)-regulated gene expression system from Escherichia coli was used to control gene expression in recombinant human cytomegalovirus (HCMV). To adapt the TetR system in HCMV, derivatives of the viral US11 (early) gene promoter, which controls the beta-glucuronidase reporter gene, were constructed by systematic insertion of the tetracycline operator (tetO) sequences. Gene expression from constructs containing two or three appropriately placed tetO sequences adjacent to the TATA box were efficiently repressed by a TetR-VP16 fusion protein (tTA) in a transient expression system. Efficient repression (50- to 120-fold) also occurred in tTA-expressing stably transfected human cells which were infected with recombinant HCMV containing a US11 promoter surrounded by three tetO sequences. The tTA-mediated gene repression was relieved in the presence of 1 microgram of tetracycline per ml. The results of this study are significant in three respects. (i) This is the first demonstration that a TetR-derived protein can be used to efficiently repress gene expression in a mammalian system. (ii) Efficient repression was dependent on the presence of the transcriptional activation domain from the herpes simplex virus type 1 VP16 protein. (iii) The ability to regulate gene expression in a controlled fashion in order to elucidate viral gene function is an important development in the HCMV field. The tTA-mediated gene repression system may be extremely useful for creating host-range mutants in essential genes in order to study their role in the HCMV replicative cycle, a system that is otherwise exceedingly difficult to genetically dissect.
Someone Will Make Money on Your Funds - Why Not You?: A Better Way to Pick Mutual and Exchange-Traded Funds (2005)

Acknowledgments. Introduction. Chapter 1: A Framework for Saving and Investing. Chapter 2: Assets, Liabilities, and Financial Planning. Chapter 3: Tax-Efficient Financial Planning and Investing. Chapter 4: Controlling Investment Costs: Money Market and Brokerage Account Economics, Separate Investments versus Funds. Chapter 5: How to Cut Your Fund Costs. Chapter 6: Reducing Costs with Index Funds. Chapter 7: Fund Advisory Services-or Do-It-Yourself? Chapter 8: Some Winning Funds-and Why They Win. Chapter 9: Active Investment Management: Can You Find a Manager Who Can Beat the Market? Chapter 10: Reinventing the Mutual Fund: Actively Managed Exchange-Traded Funds. Chapter 11: Improving the Efficiency of Custom Investment Management: Some ETF Applications. Appendix A: Sources of Additional Information on the Internet. Appendix B: Conventional Mutual Funds versus Exchange-Traded Funds: Making Choices. Glossary. Notes. References. Index. About the Author.
Naturally arising CD25+ CD4+ regulatory T cells in auto-immunity and tumor immunity (2003)

There is accumulating evidence that naturally arising CD4+ regulatory T cells (T-reg), the majority of which constitutively express CD25, actively contribute to the maintenance of natural immunologic self-tolerance. Removal of CD25+ CD4+ T-reg from the periphery of normal mice, for example, leads to spontaneous development of various autoimmune diseases. CD25+ CD4+ T-reg also constitutively express CTLA-4 and GITR (glucocorticoid-induced TNF receptor-related gene); and blockade of CTLA-4 or ligation of GITR on the T-reg by specific monoclonal antibodies (mAbs) can attenuate their suppressive activity, leading to the development of autoimmune disease. As the other side of the coin, naturally present CD25+ CD4+ T-reg may impede development of tumor immunity by hampering the generation and activation of tumor-effector T cells recognizing autologous tumor cells. Indeed, reduction of CD25+ CD4+ T-reg by administration of anti-CD25 mAb for a limited period provoked effective tumor-specific immunity against syngeneic tumor cells. Furthermore, administration of anti-CTLA-4 or anti-GITR mAb resulted in enhanced tumor immunity partly due to attenuation of the suppressive activity of natural CD25+ CD4+ T-reg and consequent activation of tumor effector cells. Tumor effector cells can also be generated in vitro by simply eliminating CD25+ CD4+ T cells from splenic cell suspensions prepared even from tumor-nonsensitized mice. In this in vitro induction of tumor immunity, CD25- CD4+ T cells responding to self-peptides/class II MHC molecules expressed on syngeneic APCs spontaneously proliferated upon removal of CD25+ CD4+ regulatory T cells. A large amount of IL-2 produced by such CD4+ self-reactive T cells generated NK-like tumor effector cells as lymphokine-activated killer (LAK) cells capable of promiscuously killing various tumor cells. Thus, removal or functional alteration of CD25+ CD4+ T-reg can abrogate immunological unresponsiveness to syngeneic tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones. This novel way of evoking tumor immunity would help to devise effective immunotherapy for cancer in humans. This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.
Throwing new light on lung cancer pathogenesis: Updates on three recent topics (2005)

Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. It has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.
The production of PCR products with 5′ single-stranded tails using primers that incorporate novel phosphoramidite intermediates (1993)

We have prepared several novel phosphoramidites and have synthesised oligonucleotides incorporating them internally. The presence of these residues in an oligonucleotide template presents an impossible barrier to primed synthesis by Taq DNA polymerase. When extended as polymerase chain reaction products, these oligonucleotides no longer serve as templates for the polymerase beyond the insertion sites of the modified intermediates, thereby producing single-stranded tails on amplification products. These tails can then be used for solid phase capture and colorimetric detection of PCR products.
Predictor-directed stream buffers (2000)

An effective method for reducing the effect of load latency in modern processors is data prefetching. One form of data prefetching, stream buffers, has been shown to be particularly effective due to its' ability to detect data streams and run ahead of them, prefetching as it goes. Unfortunately, in the past, the applicability of streaming was limited to stride intensive code.
Electrically-Assisted Nucleic Acids Delivery to Tissues In Vivo: Where Do We Stand? (2006)

Electropulsation (electroporation) is a physical method for delivery of various molecules into the cells in vitro and in vivo. It is an expanding field due to its applicability in cancer therapy, where combined application of electric pulses and chemotherapeutic drugs is used for treatment of cutaneous and subcutaneous nodules of different malignancies. Another application of electropulsation in vivo is electrogene therapy, where after injection of naked plasmid DNA and delivery of electric pulses directly to the tissue the expression of gene of interest can be obtained. However, the transfection efficiency of this methodology in vivo is still lower than with viral vectors. Nevertheless, due to the lack of immunogenicity of the method, easiness of the preparation of large quantities of endotoxin free plasmid DNA, control and reproducibility of the method and the development of electropulsators approved for the clinical use, electrically-assisted nucleic-acid delivery holds a great potential for the clinical application. This aim of this minireview is to critically discuss the main limitations and obstacles associated with electrogene therapy and the failures and problems as well as the successes. Topics on electric field distribution in the tissue, electrode geometries, construction of plasmid, modulation of extracellular space, tissue damage, pro-inflammatory and immune response as well as blood flow modification associated with application of electric pulses and injection of naked DNA are presented with possible directions how to overcome these limitations. Furthermore, for successful electrogene therapy in clinical setting it is of utmost importance to elucidate the mechanisms of DNA transfer into the cells of tissues in vivo. This will enable appropriate selection of electric pulse parameters and plasmid DNA constructs for each particular intended use. In the long run, this review should encourage other scientists to consider electrically assisted gene delivery for gene therapy as it matures.
A high-density association screen of 155 ion transport genes for involvement with common migraine (2008)

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.
[Oncolytic adenovirus for the treatment of cerebral tumors: past, present and future]. (2001)

The transfer of genetic material as a therapy (gene therapy) is one of the experimental treatments being considered in patients with brain tumors resistant to any conventional treatment. Several clinical trials have proved that the intratumoral administration of genes is fairly safe for patients, however the anti-tumor effect of these strategies remains suboptimal. One of the main problems in cancer gene therapy is the failure of current vectors to achieve enough tumor transduction in a suficient number of cells. This is even true for vectors derived from viruses with high infectivity ability such as adenovirus. For that reason, current strategies explore the use of adenoviruses able to replicate and spread throughout the tumor. The local, intratumoral injection of adenovirus is an especially suitable strategy for gliomas because these tumors, although infiltrative, rarely metastasize. Two approaches have been used to generate tumor-selective replicative adenoviruses: use of tumor-specific promoters to regulate the expression of viral genes, and the deletion of the viral functions required for the activation of the cell cycle. Since normal cells surrounding giomas are quiescent, the second strategy is particularly attractive to develop new treatments for brain tumors.
Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumours: immunohistochemical case review (2003)

Specimens of normal human brain, contused brain, brain with bacterial meningitis, and brain tumours were immunolabelled for aquaporin 4 (AQP4) and Kir4.1. In normal brain tissue, AQP4 and Kir4.1 were detected around the microvessels. In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain. Changes in alpha syntrophin expression paralleled those of AQP4 and Kir4.1. The following hypothesis is proposed: in astrocytes, under normal conditions, AQP4 couples water transport with Kir4.1 mediated K+ siphoning, but in pathological states, AQP4 facilitates the flow of brain oedema fluid, and Kir4.1 buffers increased extracellular K+.