gebhart/patrepeval huggingface dataset:
Voltage-Gated Sodium Channel Blockers as Immunomodulators (2006)

Several Voltage-Gated Sodium Channels (VGSC) are widely expressed on lymphocytes and macrophages but their role in immune function is still debated. Nevertheless, Na(+) influx through VGSC is required for lymphocytes activation and proliferation, since these responses are blocked by Na(+)-free medium or by VGSC blockers. These effects may be mediated by the reduced intracellular Na(+) levels, which in turn may impair the activity of Na(+)/Ca(++) exchanger resulting in reduced intracellular Ca(++) levels during lymphocyte activation. Furthermore, in Jurkat cell line VGSC appear to be involved in cell volume regulation, migration in artificial matrix and cell death by apoptosis. VGSC play a role in macrophage function as well, and VGSC blockers impair both phagocytosis and inflammatory responses. Several VGSC blockers have shown immunomodulatory properties in mice models, skewing the immune response toward a Th2-mediated response, while suppressing Th1-mediated responses, and VGSC already used in clinical practice are known to modulate immunoglobulin (Ig) levels both in mice and in humans. These effects suggest that VGSC blockers may find clinical application in the treatment of autoimmune and inflammatory disease. However, many of these drugs induce a number of severe side effects. The relevance of VGSC function in immune regulation suggest that the testing of newly patented VGSC blockers for their effect on immunity may be worthwhile.
Possible Roles of Proinflammatory and Chemoattractive Cytokines Produced by Human Fetal Membrane Cells in the Pathology of Adverse Pregnancy Outcomes Associated with Influenza Virus Infection (2012)

Pregnant women are at an increased risk of influenza-associated adverse outcomes, such as premature delivery, based on data from the latest pandemic with a novel influenza A (H1N1) virus in 2009-2010. It has been suggested that the transplacental transmission of influenza viruses is rarely detected in humans. A series of our study has demonstrated that influenza virus infection induced apoptosis in primary cultured human fetal membrane chorion cells, from which a factor with monocyte differentiation-inducing (MDI) activity was secreted. Proinflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-β, were identified as a member of the MDI factor. Influenza virus infection induced the mRNA expression of not only the proinflammatory cytokines but also chemoattractive cytokines, such as monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1β, IL-8, growth-regulated oncogene (GRO)-α, GRO-β, epithelial cell-derived neutrophil-activating protein (ENA)-78, and interferon inducible protein (IP)-10 in cultured chorion cells. These cytokines are postulated to associate with human parturition. This paper, therefore, reviews (1) lessons from pandemic H1N1 2009 in pregnancy, (2) production of proinflammatory and chemoattractive cytokines by human fetal membranes and their functions in gestational tissues, and (3) possible roles of cytokines produced by human fetal membranes in the pathology of adverse pregnancy outcomes associated with influenza virus infection.
DNA vaccine for hepatitis B: evidence for immunogenicity in chimpanzees and comparison with other vaccines. (1996)

Vaccination of two chimpanzees against hepatitis B virus (HBV) by intramuscular injection of plasmid DNA encoding the major and middle HBV envelope proteins induced group-, subtype- and preS2-specific antibodies. These were initially of IgM isotype, and then they were of IgG (predominantly IgGl) isotype. The chimpanzee injected with 2 mg of DNA attained >100 milli-international units/ml of anti-HBs antibody after one injection and 14,000 milli-international units/ml after four injections. A smaller dose (400 microg) induced lower and transient titers, but a strong anamnestic response occurred 1 year later. Comparison with responses in 23 chimpanzees receiving various antigen-based HBV vaccines suggests that the DNA approach is promising for prophylactic immunization against HBV.
Expression of Fibronectin Isoforms in Human Breast Tissue: Production of Extra Domain A+/Extra Domain B+ by Cancer Cells and Extra Domain A+ by Stromal Cells (1999)

The expression of fibronectin (FN) isoforms including extra domain A (EDA) and extra domain B (EDB) segments, was investigated in 36 invasive ductal carcinomas and 13 benign tumors of human breast tissues by in situ hybridization using probes specific to alternative splicing sites. Signals for the constant region of FN mRNA in cancer cells were found in 53% of the invasive ductal carcinomas. The EDA+ and EDB+ mRNA signals were found in 47% and 33%, respectively. Stromal cells expressing FN, EDA+ and EDB+ mRNA signals were present in 100%, 69% and 14% of cases, respectively. Expression of FN mRNAs by cancer cells was most frequent in intraductal lesions or large cancer nests, and that by stromal cells was associated with desmoplastic areas. In representative cases, proportions of FN mRNA-positive cancer cells expressing EDA and EDB segments were 45% and 39%, respectively, signals for both being frequently found in the same cells. EDA+ and EDB+ mRNA were labeled in 25% and 6% of the FN mRNA-positive stromal cells, a large proportion thus being EDA-/EDB- FN. In conclusion, the splicing pattern of FN pre-mRNA is dependent on the cell type and histology of breast cancer tissues. The observed lack of expression in fibroadenomas and other benign conditions suggests a link with tumor progression.
Therapy of X-linked adrenoleukodystrophy (2008)

X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies.
The RING Finger of c-Cbl Mediates Desensitization of the Epidermal Growth Factor Receptor (1999)

Ligand-induced activation of surface receptors, including the epidermal growth factor receptor (EGFR), is followed by a desensitization process involving endocytosis and receptor degradation. c-Cbl, a tyrosine phosphorylation substrate shared by several signaling pathways, accelerates desensitization by recruiting EGFR and increasing receptor polyubiquitination. Here we demonstrate that the RING type zinc finger of c-Cbl is essential for ubiquitination and subsequent desensitization of EGFR. Mutagenesis of a single cysteine residue impaired the ability of c-Cbl to enhance both down-regulation and ubiquitination of EGFR in living cells, although the mutant retained binding to the activated receptor. Consequently, the mutant form of c-Cbl acquired a dominant inhibitory function and lost the ability to inhibit signaling downstream to EGFR. In vitro reconstitution of EGFR ubiquitination implies that the RING finger plays an essential direct role in ubiquitin ligation. Our results attribute to the RING finger of c-Cbl a causative role in endocytic sorting of EGFR and desensitization of signal transduction.
Evolutionary genomics of inversions in Drosophila pseudoobscura : Evidence for epistasis (2003)

Drosophila pseudoobscura harbors a rich polymorphism for paracentric inversions on the third chromosome, and the clines in the inversion frequencies across the southwestern United States indicate that strong natural selection operates on them. Isogenic inversion strains were made from isofemale lines collected from four localities, and eight molecular markers were mapped on the third chromosome. Nucleotide diversity was measured for these loci and formed the basis of an evolutionary genomic analysis. The loci were differentiated among inversions. The inversions did not show significant differences among populations, however, likely the result of extensive gene flow among populations. Some loci had significant reductions in nucleotide diversity within inversions compared with interspecies divergence, suggesting that these loci are near inversion breakpoints or are near targets of directional selection. Linkage disequilibrium (LD) levels tended to decrease with distance between loci, indicating that some genetic exchange occurs among gene arrangements despite the presence of inversions. In some cases, however, adjacent genes had low levels of interlocus LD and loosely linked genes had high levels of interlocus LD, suggesting strong epistatic selection. Our results support the hypothesis that the inversions of D. pseudoobscura have emerged as suppressors of recombination to maintain positive epistatic relationships among loci within gene arrangements that developed as the species adapted to a heterogeneous environment.
Micro-diaphragm pressure sensor (1986)

A micro-diaphragm pressure sensor with silicon nitride diaphragm of 80 µm × 80 µm was fabricated by applying micromachining technique. The main feature is that it is a complete planar type pressure sensor formed by single-side processing solely on the top surface of
Locked Nucleic Acid In situ Hybridization Analysis of miR-21 Expression during Colorectal Cancer Development (2009)

Using the LNA-ISH system for miRNA detection, miR-21 was detectable in precancerous adenomas. The frequency and extent of miR-21 expression increased during the transition from precancerous colorectal adenoma to advanced carcinoma. Expression patterns of miR-21 RNA and its target, tumor suppressor protein PDCD4, were mutually exclusive. This pattern may have clinical application as a biomarker for colorectal cancer development and might be emphasized by self-reinforcing regulatory systems integrated with the miR-21 gene, which has been previously shown in cell culture.
Primate Gammaretroviruses Require an Ancillary Factor Not Required for Murine Gammaretroviruses To Infect BHK Cells (2011)

ABSTRACT BHK cells remain resistant to xenotropic murine retrovirus-related virus (XMRV) or gibbon ape leukemia virus (GALV) infection, even when their respective receptors, Xpr1 or PiT1, are expressed. We set out to determine the stage at which viral infection is blocked and whether this block is mediated by a dominant-negative factor or the absence of a requisite ancillary factor. BHK cells bind neither XMRV nor GALV envelope proteins. BHK cells expressing the appropriate receptors bind XMRV or GALV envelope proteins. BHK cells can be infected by NZB-XMV(New Zealand Black mouse xenotropic murine v irus)-enveloped vectors, expressing an envelope derived from a xenotropic retrovirus that, like XMRV, employs Xpr1 as a receptor, and also by vectors bearing the envelope of 10A1 murine leukemia virus (MLV), a murine retrovirus that can use PiT1 as a receptor. The retroviral vectors used in these analyses differ solely in their viral envelope proteins, suggesting that the block to XMRV and GALV infection is mediated at the level of envelope-receptor interactions. N-linked glycosylation of the receptors was not found to mediate resistance of receptor-expressing BHK cells to GALV or XMRV, as shown by tunicamycin treatment and mutation of the specific glycosylation site of the PiT1 receptor. Hybrid cells produced by fusing BHKXpr1 or BHKPiT1 to XMRV- or GALV-resistant cells, respectively, can mediate efficient XMRV or GALV infection. These findings indicate that BHK cells lack a factor that is required for infection by primate xenotropic viruses. This factor is not required for viruses that use the same receptors but were directly isolated from mice.
Telomerase as a Potential Molecular Target to Study G-Quartet Phosphorothioates (1996)

Inhibition of gene expression by phosphorothioate oligomers is complex and involves specific and nonspecific mechanisms. Oligomers that contain a G-quartet elicit distinct effects in vitro and in vivo that are dependent on the context of the G-quartet's occurrence within a sequence. The enzyme telomerase, a ribonucleoprotein, has a stretch of C residues in the RNA template, which are used to add terminal dG-rich telomeric repeats to the ends of chromosomes. Some but not all phosphorothioates containing a G-quartet, depending on the context of occurrence, inhibited telomerase activity in vitro. Non-G-quartet phosphorothioates did not inhibit this activity. Activities of control enzymes, such as reverse transcriptase or taq polymerase, were not affected by the G-quartet oligomers. Neither phosphodiester nor chimeric oligomers of a G-quartet-containing oligomer were as potent inhibition of telomerase activity as phosphorothioate oligomers. These results may provide a molecular target to study the effects of G-quartet-containing oligomers.
Immunohistochemical evidence for apoptosis in Alzheimerʼs disease (1994)

Recently, in vitro studies conducted in our laboratory and others have suggested that apoptosis may have a role in the neuronal cell death associated with Alzheimer's disease (AD). To evaluate this hypothesis, the hippocampi and entorhinal cortices of AD, aged control, and surgical biopsy tissue were examined using the ApopTag system for the detection of DNA fragmentation and DNA strains to reveal nuclear morphology. Numerous neuronal nuclei displaying distinct morphological characteristics of apoptosis were present within tangle-bearing neurons as well as non-tangle-bearing neurons in AD brain, whereas few or no such nuclei were detected in control brain. Our in vivo results support the hypothesis that apoptosis may be one mechanism leading neuronal cell death in AD.
Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda -7/IL-24–mediated toxicity (2011)

Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1), is required for mda-7/IL-24-mediated apoptosis of prostate carcinomas. Here we demonstrate that pharmacological inhibition of Mcl-1 expression with the unique Apogossypol derivative BI-97C1, also called Sabutoclax, is sufficient to sensitize prostate tumors to mda-7/IL-24-induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not sensitize mda-7/IL-24-mediated cytotoxicity. A combination regimen of tropism-modified adenovirus delivered mda-7/IL-24 (Ad.5/3-mda-7) and BI-97C1 enhances cytotoxicity in human PC cells, including those resistant to mda-7/IL-24 or BI-97C1 alone. The combination regimen causes autophagy that facilitates NOXA- and Bim-induced and Bak/Bax-mediated mitochondrial apoptosis. Treatment with Ad.5/3-mda-7 and BI-97C1 significantly inhibits the growth of human PC xenografts in nude mice and spontaneously induced PC in Hi-myc transgenic mice. Tumor growth inhibition correlated with increased TUNEL staining and decreased Ki-67 expression in both PC xenografts and prostates of Hi-myc mice. These findings demonstrate that pharmacological inhibition of Mcl-1 with the Apogossypol derivative, BI-97C1, sensitizes human PCs to mda-7/IL-24-mediated cytotoxicity, thus potentially augmenting the therapeutic benefit of this combinatorial approach toward PC.
Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera) (2012)

Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation.
Two Novel Adenovirus Vector Systems Permitting Regulated Protein Expression in Gene Transfer Experiments (1998)

Two new adenovirus vector systems based on the tetracycline-regulated Tet-ON- (Gossen, M., et al., Science 268:1766-1769, 1995) and the RU 486-regulated progesterone antagonist (Wang, Y., et al., Proc. Natl. Acad. Sci. USA 91:8180-8184, 1994)-induced gene expression systems are described. We show that both systems permit a tight control of chloramphenicol acetyltransferase reporter gene expression in a variety of cell types, with induction levels of approximately 1,800-fold (Tet-ON system) and 600-fold (RU 486-regulated system), respectively. A significant advantage of our vector systems is that reporter protein expression can be adjusted over a wide range by varying the amount of inducer. The Tet-ON system is also shown to permit an efficient control of reporter gene expression in mice.
Non‐Destructive Wafer Recycling for Low‐Cost Thin‐Film Flexible Optoelectronics (2014)

Compound semiconductors are the basis for many of the highest performance optical and electronic devices in use today. Their widespread commercial application has, however, been limited due to the high cost of substrates. Device costs can be significantly reduced if the substrate is reused in a simple, totally non‐destructive and rapid process. Here, a method that allows the indefinite reuse and recycling of wafers is demonstrated, employing a combination of epitaxial “protection layers”, plasma cleaning techniques that return the wafers to their original, pristine, and epi‐ready condition following epitaxial layer removal, and adhesive‐free bonding to a secondary plastic substrate. The generality of this process is demonstrated by fabricating high performance GaAs‐based photovoltaic cells, light emitting diodes, and metal‐semiconductor field effect transistors that are transferred without loss of performance onto flexible and lightweight plastic substrates, and then the parent wafer is recycled for subsequent growth of additional device layers. This process potentially leads to a transformational change in device cost, arising from the inevitable consumption of the wafer that accompanies conventional epitaxial liftoff followed by chemo‐mechanical polishing.
Adenosine infusion during isoflurane‐nitrous oxide anaesthesia: indications of perioperative analgesic effect (1992)

Adenosine, an endogenous compound with a known antinociceptive effect when administered into the CNS, was applied in nine patients (21-65 years) by the peripheral intravenous route (70-130 micrograms.kg-1.min-1) as a replacement for peroperative opioids during inhalation anaesthesia for surgical procedures not requiring muscle relaxation. Lorazepam was given as premedication, thiopentone was used for induction, and succinylcholine facilitated intubation of the trachea. Anaesthesia was maintained with isoflurane [initial surgery endtidal concentration (ET) 0.88% (range 0.7-1%)] and nitrous oxide (60-70%) in oxygen. Adenosine infusion was initiated 5-10 min prior to surgery, and stopped close to or when isoflurane was terminated at the end of surgery. The duration of anaesthesia, adenosine infusion, and surgery were 120 min (range 80-165), 90 min (range 70-145), and 90 min (range 60-135), respectively. Spontaneous unassisted ventilation was maintained in all patients. Mean heart rate increased 10 beats.min-1 (range 0-35) upon induction of surgery, while systolic blood pressure was unaffected at 105 mmHg (range 85-120) (14 kPa (range 11.3-16.0)). Spo2 and ETCO2 were in the normal range. The isoflurane concentration was gradually reduced in most cases [mid-surgery ET 0.63% (range 0.5-0.8) and end-surgery ET 0.57% (range 0.3-0.8)]. Extubation and verbal communication were rapidly achieved after anaesthesia. The mean postoperative (24 h) opioid requirement was 4 mg (range 0-10 mg). These pilot cases suggest that systemic adenosine infusion may replace opioids during inhalation anaesthesia, and that adequate spontaneous ventilation can be achieved.
Engineering toward a bacterial “endoplasmic reticulum” for the rapid expression of immunoglobulin proteins (2014)

Antibodies are well-established as therapeutics, and the preclinical and clinical pipeline of these important biologics is growing rapidly. Consequently, there is considerable interest in technologies to engineer and manufacture them. Mammalian cell culture is commonly used for production because eukaryotic expression systems have evolved complex and efficient chaperone systems for the folding of antibodies. However, given the ease and manipulability of bacteria, antibody discovery efforts often employ bacterial expression systems despite their limitations in generating high titers of functional antibody. Open-Cell Free Synthesis (OCFS) is a coupled transcription-translation system that has the advantages of prokaryotic systems while achieving high titers of antibody expression. Due to the open nature of OCFS, it is easily modified by chemical or protein additives to improve the folding of select proteins. As such, we undertook a protein additive screen to identify chaperone proteins that improve the folding and assembly of trastuzumab in OCFS. From the screen, we identified the disulfide isomerase DsbC and the prolyl isomerase FkpA as important positive effectors of IgG folding. These periplasmic chaperones function synergistically for the folding and assembly of IgG, and, when present in sufficient quantities, gram per liter IgG titers can be produced. This technological advancement allows the rapid development and manufacturing of immunoglobulin proteins and pushes OCFS to the forefront of production technologies for biologics.
VIRON: an annotation-based video information retrieval system (2002)

To provide efficient search and retrieval of video data from large archives, we need to model video data appropriately. We propose a video data model and describe the design and implementation of the annotation-based video retrieval system VIRON (Video Information Retrieval On Notation) based on the proposed model. This model provides the mechanism of sharing and reusing annotations among users by introducing descriptor schema. In order to process a query efficiently, an annotated video unit is mapped into a unified video annotation stream. VIRON is composed of three tools: CVU manager, which is used to manage and visualize conceptual video units; annotator to annotate video data by offering an interactive video player; and a video query tool to pose and process video queries.