gebhart/patrepeval huggingface dataset:
A new protein antidenaturant agent, bindarit, reduces secondary phase of adjuvant arthritis in rats. (1992)

Bindarit (or 2-[(1-benzyl-indazol-3-yl)methoxy]-2-methyl propionic acid) reduces heat induced denaturation of bovine and rat serum albumin in vitro (EC50 = 8.5 and 65 micrograms/ml, respectively) and inhibits heat induced serum albumin denaturation after in vivo (12.5-25-50 mg/kg po) administration in rats. To assess the relationship between protein denaturation and the development of chronic inflammatory diseases, the drug (0.5 or 0.12% medicated diet) was studied in comparison with indomethacin (1 mg/kg po daily) in rats injected with complete Freund's adjuvant. Bindarit appeared different from aspirin-like drugs, antiinflammatory steroids and immunosuppressants because it does not reduce primary inflammation of arthritic rats and was shown to be completely inactive on cyclo and lipooxygenase activity in vitro and on immune reactions of mice in vivo. Nevertheless, the drug strongly reduced the development of the secondary phase of adjuvant induced arthritis. The most significant effect of bindarit in this phase was a strong inhibition of serum albumin denaturation in arthritic rats. Assessment of both electrophoretic and quantitative changes suggests that the reduction of albumin during inflammation is due, at least in part, to a denaturation of native albumin, which loses its electrophoretic mobility. The involvement of protein denaturation in the production of new antigenic determinants, their pathogenic relevance in the development of adjuvant arthritis and the possibility that protein stabilization by bindarit could be the mechanism of action of the drug are discussed.
Histological and Clinical Evaluation of Facial Resurfacing Using a Carbon Dioxide Laser With the Computer Pattern Generator (1997)

The carbon dioxide laser with the CPG is an effective modality for cutaneous exfoliation. With the proper treatment parameters, extreme accuracy and uniformity of tissue ablation can be achieved. The tissue is ablated with micrometer accuracy and minimal thermal effect to the underlying dermis. Postoperative healing is comparable to that of the traditional modalities of dermabrasion and chemical peel. Postresurfacing erythema is transient and resolved in all patients.
Transendothelial Migration of Megakaryocytes in Response to Stromal Cell-derived Factor 1 (SDF-1) Enhances Platelet Formation (1998)

Although thrombopoietin has been shown to promote megakaryocyte (MK) proliferation and maturation, the exact mechanism and site of platelet formation are not well defined. Studies have shown that MKs may transmigrate through bone marrow endothelial cells (BMEC), and release platelets within the sinusoidal space or lung capillaries. In search for chemotactic factor(s) that may mediate transmigration of MKs, we have discovered that mature polyploid MKs express the G protein-coupled chemokine receptor CXCR4 (Fusin, LESTR). Therefore, we explored the possibility that stromal cell-derived factor 1 (SDF-1), the ligand for CXCR4, may also induce transendothelial migration of mature MKs. SDF-1, but not other CXC or CC chemokines, was able to mediate MK migration (ED50 = 125 pmol/liter). The MK chemotaxis induced by SDF-1 was inhibited by the CXCR4-specific mAb (12G5) and by pertussis toxin, demonstrating that signaling via the G protein-coupled receptor CXCR4 was necessary for migration. SDF-1 also induced MKs to migrate through confluent monolayers of BMEC by increasing the affinity of MKs for BMEC. Activation of BMEC with interleukin 1beta resulted in a threefold increase in the migration of MKs in response to SDF-1. Neutralizing mAb to the endothelial-specific adhesion molecule E-selectin blocked the migration of MKs by 50%, suggesting that cellular interaction of MKs with BMEC is critical for the migration of MKs. Light microscopy and ploidy determination of transmigrated MKs demonstrated predominance of polyploid MKs. Virtually all platelets generated in the lower chamber also expressed CXCR4. Platelets formed in the lower chamber were functional and expressed P-selectin (CD62P) in response to thrombin stimulation. Electron microscopy of the cells that transmigrated through the BMEC monolayers in response to SDF-1 demonstrated the presence of intact polyploid MKs as well as MKs in the process of platelet formation. These results suggest that SDF-1 is a potent chemotactic factor for mature MKs. Expression of CXCR4 may be the critical cellular signal for transmigration of MKs and platelet formation.
Analysis of 25 underivatized amino acids in human plasma using ion‐pairing reversed‐phase liquid chromatography/time‐of‐flight mass spectrometry (2007)

Amino acids in biological fluids have previously been shown to be detectable using liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) with perfluorinated acids as ion-pairing agents. To date, these studies have used precursor mass, retention time and tandem mass spectrometry (MS/MS) to identify and quantify amino acids. While this is a potentially powerful technique, we sought to adapt the method to time-of-flight (TOF)MS. A new application of a recently described liquid chromatographic separation method was coupled with TOFMS to employ accurate mass for qualitative identification; resulting in additional qualitative data not available with standard single quadrupole data. In the current study, we evaluated 25 physiological amino acids and one dipeptide that are routinely quantified in human plasma. Accuracy and precision of the method was evaluated by spiking human plasma with a mix of the 25 amino acids; in addition, the inclusion of a cation-exchange cleanup step was evaluated. The calibration curves were linear over a range from 1.56 to 400 microM. The dynamic range was found to be within physiological levels for all amino acids analyzed. Accuracy and precision for most of the amino acids was between 80-120% spike recovery and <10% relative standard deviation (RSD). The LC/MS technique described in this study relies on mass accuracy and is suitable for the quantitation of free amino acids in plasma.
Swine Influenza H1N1 Virus Induces Acute Inflammatory Immune Responses in Pig Lungs: a Potential Animal Model for Human H1N1 Influenza Virus (2010)

Pigs are capable of generating reassortant influenza viruses of pandemic potential, as both the avian and mammalian influenza viruses can infect pig epithelial cells in the respiratory tract. The source of the current influenza pandemic is H1N1 influenza A virus, possibly of swine origin. This study was conducted to understand better the pathogenesis of H1N1 influenza virus and associated host mucosal immune responses during acute infection in humans. Therefore, we chose a H1N1 swine influenza virus, Sw/OH/24366/07 (SwIV), which has a history of transmission to humans. Clinically, inoculated pigs had nasal discharge and fever and shed virus through nasal secretions. Like pandemic H1N1, SwIV also replicated extensively in both the upper and lower respiratory tracts, and lung lesions were typical of H1N1 infection. We detected innate, proinflammatory, Th1, Th2, and Th3 cytokines, as well as SwIV-specific IgA antibody in lungs of the virus-inoculated pigs. Production of IFN-γ by lymphocytes of the tracheobronchial lymph nodes was also detected. Higher frequencies of cytotoxic T lymphocytes, γδ T cells, dendritic cells, activated T cells, and CD4+ and CD8+ T cells were detected in SwIV-infected pig lungs. Concomitantly, higher frequencies of the immunosuppressive T regulatory cells were also detected in the virus-infected pig lungs. The findings of this study have relevance to pathogenesis of the pandemic H1N1 influenza virus in humans; thus, pigs may serve as a useful animal model to design and test effective mucosal vaccines and therapeutics against influenza virus.
A novel monoclonal antibody against murine IL-2 receptor beta-chain. Characterization of receptor expression in normal lymphoid cells and EL-4 cells (1991)

A mAb specific for the murine IL-2R beta-chain (IL-2R beta) was produced by immunizing a rat with a rat transfectant cell line expressing a large number of cDNA-encoded murine IL-2R beta. The mAb, designated TM-beta 1, is specifically reactive with the murine IL-2R beta cDNA-transfectant but not with the recipient cell, and immunoprecipitates murine IL-2R beta of Mr 75 to 85 kDa. TM-beta 1 mAb completely abolished the high affinity IL-2 binding by inhibiting the ligand binding to IL-2R beta. Murine IL-2R beta was found to be constitutively expressed on a subpopulation of CD8+ T cells and almost all NK1.1+ NK cells in the spleen, whereas TM-beta 1 mAb inhibited the proliferation of spleen cells induced by 1 nM of IL-2. Interestingly, EL-4 cells that express murine IL-2R beta as detected by TM-beta 1 mAb can bind neither human nor murine IL-2 under the intermediate affinity conditions, although cDNA-directed human IL-2R beta expressed in the same EL-4 cells has been previously shown to manifest the intermediate affinity IL-2 binding. These results may imply that functional expression of IL-2R beta is differentially regulated between humans and mice. Finally, our neutralizing anti-IL-2R beta mAb TM-beta 1 will be useful not only for various in vitro studies but also for in vivo studies to directly investigate the possible involvement of the IL-2/IL-2R pathway in the generation and differentiation of T lymphocytes and NK cells.
Portable sulphotransferase domain determines sequence specificity of heparan sulphate 3-O-sulphotransferases (2001)

3-O-Sulphates are the rarest substituent of heparan sulphate and are therefore ideally suited to the selective regulation of biological activities. Individual isoforms of heparan sulphate d-glucosaminyl 3-O-sulphotransferase (3-OST) exhibit sequence-specific action, which creates heparan sulphate structures with distinct biological functions. For example, 3-OST-1 preferentially generates binding sites for anti-thrombin, whereas 3-OST-3 isoforms create binding sites for the gD envelope protein of herpes simplex virus 1 (HSV-1), which enables viral entry. 3-OST enzymes comprise a presumptive sulphotransferase domain and a divergent N-terminal region. To localize determinants of sequence specificity, we conducted domain swaps between cDNA species. The N-terminal region of 3-OST-1 was fused with the sulphotransferase domain of 3-OST-3A to generate N1-ST3A. Similarly, the N-terminal region of 3-OST-3A was fused to the sulphotransferase domain of 3-OST-1 to generate N3A-ST1. Wild-type and chimaeric enzymes were transiently expressed in COS-7 cells and extracts were analysed for selective generation of binding sites for anti-thrombin. 3-OST-1 was 270-fold more efficient at forming anti-thrombin-binding sites than 3-OST-3A, indicating its significantly greater selectivity for substrates that can be 3-O-sulphated to yield such sites. N3A-ST1 was as active as 3-OST-1, whereas the activity of N1-ST3A was as low as that of 3-OST-3A. Analysis of Chinese hamster ovary cell transfectants revealed that only 3-OST-3A and N1-ST3A generated gD-binding sites and conveyed susceptibility to infection by HSV-1. Thus sequence-specific properties of 3-OSTs are defined by a self-contained sulphotransferase domain and are not directly influenced by the divergent N-terminal region.
Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. (1996)

While there is an extensive literature on cytokine regulation in vivo using human cell lines or peripheral blood monocytes, very little is known about cytokine regulation within the multicellular environment of inflammatory sites in vivo. We have previously shown that in rheumatoid synovial membrane cultures, a complex, but pathophysiologically relevant mixture of cells, the addition of a neutralizing anti TNF-alpha antibody inhibits the production of IL-1 and GM-CSF, indicating the presence of a cytokine 'cascade' in this inflammatory tissue. In this paper we demonstrate that the interactivities between cytokines in rheumatoid arthritis also extends to other cytokines, such as IL-6 and IL-8, and that within the IL-1 family it is IL-1 beta in particular which is downregulated by neutralizing TNF-alpha activity. The cytokine interactions are unidirectional, in that neutralization of TNF-alpha reduced IL-1 beta, IL-6 and IL-8 production, whereas treatment of the rheumatoid synovial membrane cells with a neutralizing concentration of the IL-1 receptor antagonist (IL-1ra) reduced IL-6 and IL-8 production but not TNF-alpha production. These results suggest a rationale for the profound anti-inflammatory effects and consequent clinical benefit noted in RA patients treated recently in clinical trials with a chimeric anti-TNF-alpha antibody in vivo.
Sequence-specific cleavage of Huntingtin mRNA by catalytic DNA (1999)

The selective loss of neurons in Huntington's disease (HD) is caused by the abnormal expansion of the CAG triplet (>36 repeats) of the HD gene. Although the molecular events that lead to neuronal death are not clear, it is most likely that mutant HD protein operates through a "gain-of-function" mechanism. One possible therapeutic approach that does not require definition of the toxic mechanism(s) involves reduction in the levels of mutant HD protein by decreasing the quantity of translatable HD mRNA. In this report, we demonstrate the first effective destruction of the HD mRNA, using a catalytic DNA--an oligodeoxynucleotide with RNA-cleaving enzymatic activity. We show that the cleavage of HD mRNA by the catalytic DNA occurs in a sequence-specific manner, and leads to significant reduction of HD protein expression in mammalian cells. The catalytic DNAs we have developed are a valuable research tool for studying HD, and may have the therapeutic potential of reducing cellular toxicity caused by mutant HD protein.
Trophoblast migration during human placental implantation (1996)

During the process of implantation in humans, fetal trophoblast cells invade and migrate into the maternal decidua. During this migration, trophoblast cells destroy the wall of the maternal spiral arteries, converting them from muscular vessels into flaccid sinusoidal sacs. This vascular transformation is important to ensure an adequate blood supply to the feto-placental unit. Both cell-cell and cell-matrix interactions are important for trophoblast invasion of the decidual stroma and decidual spiral arteries. Cell-matrix adhesions are mediated by specific receptors, mostly belonging to the family of integrins. Signals transduced to the cells from the matrix via integrins could play a pivotal role in the control of cellular behaviour and gene expression, such as metalloproteinases that facilitate matrix degradation and tissue remodelling. This review focuses on the role of integrins and extracellular matrix in trophoblast cell migration, trophoblast invasion of the decidual spiral arteries and matrix degradation by trophoblast during implantation.
Cyclin A2 maintains colon homeostasis and is a prognostic factor in colorectal cancer (2020)

To clarify the function of cyclin A2 in colon homeostasis and colorectal cancer (CRC), we generated mice deficient for cyclin A2 in colonic epithelial cells (CECs). Colons of these mice displayed architectural changes in the mucosa and signs of inflammation, as well as increased proliferation of CECs associated with the appearance of low- and high-grade dysplasias. The main initial events triggering those alterations in cyclin A2-deficient CECs appeared to be abnormal mitoses and DNA damage. Cyclin A2 deletion in CECs promoted the development of dysplasia and adenocarcinomas in a murine colitis-associated cancer model. We next explored the status of cyclin A2 expression in clinical CRC samples at the mRNA and protein levels and found higher expression in tumors of patients with stage 1 or 2 CRC compared with those of patients with stage 3 or 4 CRC. A meta-analysis of 11 transcriptome data sets comprising 2239 primary CRC tumors revealed different expression levels of CCNA2 (the mRNA coding for cyclin A2) among the CRC tumor subtypes, with the highest expression detected in consensus molecular subtype 1 (CMS1) and the lowest in CMS4 tumors. Moreover, we found high expression of CCNA2 to be a new, independent prognosis factor for CRC tumors.
Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis (2000)

Patients with severe RA who do not respond to MTX treatment have a poor prognosis, with >4-fold increased mortality compared with the general population, while RA patients who respond to MTX treatment have only a moderately increased mortality rate.
Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells (2014)

Despite therapeutic advancement, pulmonary disease still remains a major cause of morbidity and mortality around the world. Opportunities to study human lung disease either in vivo or in vitro are currently limited. Using induced pluripotent stem cells (iPSCs), we generated mature multiciliated cells in a functional airway epithelium. Robust multiciliogenesis occurred when notch signaling was inhibited and was confirmed by (i) the assembly of multiple pericentrin-stained centrioles at the apical surface, (ii) expression of transcription factor forkhead box protein J1, and (iii) presence of multiple acetylated tubulin-labeled cilia projections in individual cells. Clara, goblet, and basal cells were all present, confirming the generation of a complete polarized epithelial-cell layer. Additionally, cAMP-activated and cystic fibrosis transmembrane regulator inhibitor 172-sensitive cystic fibrosis transmembrane regulator currents were recorded in isolated epithelial cells. Our report demonstrating the generation of mature multiciliated cells in respiratory epithelium from iPSCs is a significant advance toward modeling a number of human respiratory diseases in vitro.
Ig DH Gene Segment Transcription and Rearrangement Before Surface Expression of the Pan-B–Cell Marker CD19 in Normal Human Bone Marrow (1997)

The onset of IgH transcription and rearrangement is a defining characteristic of the progenitor population in which B-lineage commitment occurs. These features were used to better define the earliest stage of B-cell commitment in humans and to determine if these stages differ as a function of human ontogeny. Fetal and adult bone marrow mononuclear cells were sorted into B-lineage subpopulations on the basis of surface expression of the stem cell marker CD34, the pan-B–cell marker CD19, and IgM and analyzed for transcription and rearrangement of the IgH locus. The locus was found to be transcriptionally active before surface expression of CD19, as indicated by the presence of germline Iμ, Cμ, and DHQ52 transcripts in the CD34+ CD19− subpopulation. Transcripts from IgH alleles that had undergone DJCμ rearrangements were also detected in the CD34+ CD19− subpopulation. Within this subpopulation, low levels of DXP-containing DJCμ transcripts were detected in both fetal and adult cells. Although DHQ52 DJCμ transcripts were abundant in fetal CD34+ CD19− cells, they were not detected in cells of the same phenotype derived from adult bone marrow. In both fetus and adult, VH3-and VH6-containing VDJCμ transcripts were detected only in the CD19+ subpopulations. These data indicate that transcription of DHQ52-JH and DXP-JH rearrangements differs during fetal and adult B lymphopoiesis. Moreover, in both fetus and adult, transcription of unrearranged components of the IgH locus and DJ rearrangements can proceed before the surface expression of CD19.
Technology evolution for mobile and personal communications (2002)

Today we are witnessing a true revolution in wireless communications. The history and technology behind mobile communications is fascinating, and Bell Labs has had a major role in launching this multi-billion dollar industry. In this paper, we take a brief look at the history of mobile communications — including many Bell Labs milestones and contributions to wireless technology — and provide a glimpse into the future. We also summarize the development of the industry and the path leading to today's imminent launch of third-generation (3G) systems. Finally, we identify and present in detail several selected enabling technologies, along with breakthrough Bell Labs research in these areas.
Homologous recombination in the nuclear genome of Chlamydomonas reinhardtii. (1993)

Nuclear transformation of the unicellular green alga Chlamydomonas reinhardtii has thus far been characterized by integration of the introduced DNA into nonhomologous sites. In this study, the occurrence of homologous recombination events during transformation was investigated with the intent of developing strategies for gene targeting and gene disruption. Homologous recombination was monitored by using nonfunctional 5' and 3' deletion derivatives of the wild-type C. reinhardtii nit1 gene (encodes nitrate reductase) as selectable markers (p5' delta and p3' delta respectively) and the low reverting nit1-305 strain as the transformation recipient. After introduction of the DNA into the cell, intermolecular recombination between p5' delta and p3' delta occurs at a high frequency to restore a functional nit1 gene, indicating the presence of homologous recombination machinery in mitotic cells. Gene-targeting events at the nit1 locus were selected by restoring nit1-305 cells to prototrophy after transformation with only p5' delta and were confirmed by analysis of genomic DNA. By comparing the number of transformants obtained after transformation with p5' delta to the number obtained after transformation with a functional nit1 gene, the frequency of homologous-to-random integration events ranged between 1:1000 after glass bead-mediated transformation and 1:24 after bombardment with DNA-coated tungsten microprojectiles.
Role of Class-II Major Histocompatibility Complex (MHC)-Antigen–Positive Donor Leukocytes in Transfusion-Induced Alloimmunization to Donor Class-I MHC Antigens (1998)

It has been shown that peripheral-blood mononuclear leukocytes (MNL) are responsible for transfusion-induced alloimmunization to donor major histocompatability complex (MHC) antigens. However, it is not known which subset of MNL is responsible for this immune response. Because elimination of class-II MHC antigen-positive passenger leukocytes effectively prolongs the survival of allografts, it has been hypothesized that class-II positive MNL are responsible for immunizing transfusion recipients to donor MHC antigens. To test this hypothesis, two different approaches were used. First, we compared the alloantigenicity of BALB/c mice (H-2(d)) peripheral blood MNL before and after depletion of class-II positive cells. CBA mice (H-2(k)) were used as transfusion recipients. Antibody development to donor class-I H-2 antigens was determined by flow cytometry and enzyme-linked immunoassay. After four weekly transfusions of MNL depleted for class-II positive cells, only 25% of recipient mice developed antibodies to donor H-2(d) antigens. In contrast, all mice transfused with control MNL became immunized. Second, we studied the alloantigenicity of peripheral MNL from C57BL/6 mice (H-2(b)) with homozygous deficiency of class-II MHC molecules in H-2 disparate recipient mice. After transfusions with class-II MHC molecule-deficient MNL, 0% of BALB/c, 40% of C57BR, and 25% of CBA-recipient mice developed antibodies to donor H-2(b) antigen. All control recipient mice were immunized. The antibody activities of the controls were also higher than those in the treatment group who became immunized. Thus, our study shows that class-II MHC antigen-positive MNL play a significant role in transfusion-induced alloimmunization to donor class-I MHC antigens. The results also support the hypothesis that direct antigen presentation by donor class-II positive MNL to the immune system of transfusion recipients is critical for the initiation of humoral immune response to donor MHC antigens.