gebhart/patrepeval huggingface dataset:
Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF) (1990)

Interleukin 1 (IL 1), IL 6, and tumor necrosis factor (TNF) are typical examples of multifunctional cytokines involved in the regulation of the immune response, hematopoiesis, and inflammation. Their functions are widely overlapping but each shows its own characteristic properties. IL 6 was originally identified as a B cell differentiation factor, and thus one of the major functions of IL 6 is antibody induction. Transgenic mice have provided much needed information on the pathophysiological role of cytokines. With IL 6 transgenic mice, deregulation of the IL 6 expression was suggested to be involved in the generation of plasmacytoma/myeloma and mesangium proliferative glomerulonephritis. The cis-regulatory elements and trans-acting nuclear factor (or factors) for the IL 6 expression (NF-IL 6) have been identified. NF-IL 6 was shown to be a member of a C/EBP family, and the possible involvement of NF-IL 6 not only in the IL 6 regulation but also in the induction of various acute phase proteins was also observed. The findings suggest the presence of a positive regulatory loop in acute-phase reaction. IL 1 receptor belongs to an Ig superfamily, but the IL 6 receptor is a member of a newly identified cytokine receptor family. The IL 6 receptor system was shown to be composed of a ligand binding chain and a signal-transducing molecule. IL 6 was found to trigger the association of these two polypeptide chains. This unique mechanism may be applied to other cytokine receptor systems.
Physiological insulin replacement in type 1 diabetes mellitus (2001)

The DCCT and UKPDS studies have definitely established that in type 1 as well as in type 2 diabetes mellitus, long-term near-normoglycaemia strongly protects against onset and/or progression of microangiopathic complications. Therefore, implementation of insulin strategies to maintain long-term near-normoglycaemia is of key importance in the management of diabetes mellitus. To successfully reach the goal of near-normoglycaemia, insulin therapy has to be physiological, i.e. it has to mimic nature by providing a bolus of insulin at meal ingestion, and by replacing the need for basal insulin between meals and during the night. The meal-time insulin needs can be best met by s.c. injection of a short-acting insulin analogue (lispro, aspart). Short-acting insulin analogues should be preferred to human regular insulin for three main reasons. First, convenience (meal-time injection, better adaptation of insulin dose to carbohydrate content of the meal); second, lower blood glucose 2-hour after meals; third, less risk for late post-prandial hypoglycaemia. However, the benefits of meal-time treatment with short-acting insulin analogues become apparent only by the extent to which replacement of basal insulin is optimised as well. The interprandial (especially nocturnal) need for basal insulin can be best met by the continuous s.c. insulin infusion by an external minipump, the gold standard of basal insulin replacement. Continuous s.c. insulin infusion in the basal state is so good because it uses a short-acting insulin analogue (low variability in s.c. absorption, flat and peak-less action profile), not insulin preparations with retarded action (high variability of s.c. absorption, peak of action) likewise the model of multiple daily insulin injections. A second choice option is s.c. injection of an insulin preparation with retarded action. At present, the long-acting insulin analogue glargine is the retarded insulin preparation of choice because its action profile is flat, peakless and long-lasting (approximately 24 hours). This is in contrast with the peak action profile of NPH insulin which exhibits a short duration of action (10-15 h). Thus, the modern insulin strategies for intensive therapy always include use of a short-acting insulin analogue at meal-time, and use of either continuous s.c. insulin infusion, or a s.c. injection of insulin glargine to replace basal insulin. Insulin glargine reproduces closely the pharmacokinetics and pharmacodynamics of continuous s.c. insulin infusion, and should always be preferred to NPH in all insulin-requiring diabetic patients, both type 1 and type 2.
Expression profiling of cardiovascular disease (2004)

Cardiovascular disease is the most important cause of morbidity and mortality in developed countries, causing twice as many deaths as cancer in the USA. The major cardiovascular diseases, including coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF) and common congenital heart disease (CHD), are caused by multiple genetic and environmental factors, as well as the interactions between them. The underlying molecular pathogenic mechanisms for these disorders are still largely unknown, but gene expression may play a central role in the development and progression of cardiovascular disease. Microarrays are high-throughput genomic tools that allow the comparison of global expression changes in thousands of genes between normal and diseased cells/tissues. Microarrays have recently been applied to CAD/MI, CHF and CHD to profile changes in gene expression patterns in diseased and non-diseased patients. This same technology has also been used to characterise endothelial cells, vascular smooth muscle cells and inflammatory cells, with or without various treatments that mimic disease processes involved in CAD/MI. These studies have led to the identification of unique subsets of genes associated with specific diseases and disease processes. Ongoing microarray studies in the field will provide insights into the molecular mechanism of cardiovascular disease and may generate new diagnostic and therapeutic markers.
Evaluation of MR-Induced Hot Spots for Different Temporal SAR Modes Using a Time-Dependent Finite Difference Method With Explicit Temperature Gradient Treatment (2007)

An investigation of magnetic resonance (MR)-induced hot spots in a high-resolution human model is performed, motivated by safety aspects for the use of MR tomographs. The human model is placed in an MR whole body resonator that is driven in a quadrature excitation mode. The MR-induced hot spots are studied by varying the following: (1) the temporal specific absorption rate (SAR) mode ("steady imaging", "intermittent imaging"), (2) the simulation procedure (related to given power levels or to limiting temperatures), and (3) different thermal tissue properties including temperature-independent and temperature-dependent perfusion models. Both electromagnetic and thermodynamic simulations have been performed. For the electromagnetic modeling, a commercial finite-integration theory (FIT) code is applied. For the thermodynamic modeling, a time-domain finite-difference (FD) scheme is formulated that uses an explicit treatment of temperature gradient components. This allows a flux-vector-based implementation of heat transfer boundary conditions on cubical faces. It is shown that this FD scheme significantly reduces the staircase errors at thermal boundaries that are locally sloped or curved with respect to the cubical grid elements.
Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis (2012)

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4(+) T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing.
Assessment of key plasma metabolites in combat casualties (2016)

Prognostic study, level III.
Systemic Administration of Abeta mAb Reduces Retinal Deposition of Abeta and Activated Complement C3 in Age-Related Macular Degeneration Mouse Model (2013)

Age-related macular degeneration (AMD) is a leading cause of legal blindness in the Western world. There are effective treatments for the vascular complications of neo-vascular AMD, but no effective therapies are available for the dry/atrophic form of the disease. A previously described transgenic CFH-gene deficient mouse model, (cfh-/-), shows hallmarks of early AMD. The ocular phenotype has been further analysed to demonstrate amyloid beta (Aβ) rich basement membrane deposits associated with activated complement C3. Cfh-/- mice were treated systemically in both prophylactic and therapeutic regimes with an anti-Aβ monoclonal antibody (mAb), 6F6, to determine the effect on the cfh-/- retinal phenotype. Prophylactic treatment with 6F6 demonstrated a dose dependent reduction in the accumulation of both Aβ and activated C3 deposition. A similar reduction in the retinal endpoints could be seen after therapeutic treatment. Serum Aβ levels after systemic administration of 6F6 show accumulation of Aβ in the periphery suggestive of a peripheral sink mechanism. In summary, anti-Aβ mAb treatment can partially prevent or reverse ocular phenotypes of the cfh-/- mouse. The data support this therapeutic approach in humans potentially modulating two key elements in the pathogenesis of AMD - Aβ and activated, complement C3.
Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on Myocardial Perfusion (2000)

Although not designed to demonstrate rhVEGF efficacy, these phase 1 data support the concept that rhVEGF improves myocardial perfusion at rest and provide evidence of a dose-dependent effect.
Neutral proteinases and inhibitors secreted by human rectal adenocarcinoma cell line (RCM-1). (1989)

A human rectal adenocarcinoma cell line, RCM-1, secreted some neutral proteinases: metallo-, serine and cysteine proteinases; and trypsin inhibitors into the serum-free conditioned medium (SFCM) in vitro. They were separated by anion-exchange and gel filtration high-performance liquid chromatography. SFCM from the cells of early passage numbers (20-24) contained native activities of serine proteinase and collagenolytic metalloproteinase. However, after several passages the native activities of them were diminished and latent form of metalloproteinase increased. In contrast to the native proteolytic activities, trypsin inhibitory activity was elevated in SFCM from the cells of passages 38-42. It inhibited the serine proteinase secreted by the same cells of early passage numbers. Furthermore, the serine proteinase was able to activate the latent form of metalloproteinase. Cooperative roles of these tumor-secreted proteinases and inhibitors may be important in tumor invasion.
Control of the structure and properties of aluminum oxide coatings deposited by pulsed magnetron sputtering (1999)

Alumina coatings offer the potential to protect metallic components operating in hostile corrosive, or oxidative environments. Until recently, though, the high rate deposition of fully dense, defect-free oxide coatings has proved extremely difficult. Oxide coatings can be produced by the reactive direct current (dc) sputtering of a metallic target in an oxygen atmosphere, or by radio frequency sputtering of an oxide target. The latter process results in very low deposition rates and is difficult to scale up for commercial applications. Reactive dc sputtering of highly insulating materials, such as alumina, is also problematic. The build up of an insulating layer on the surface of the target causes arcing. Arc events affect the stability of the deposition process and can adversely effect the structure and properties of the growing film. However, a new technique, pulsed magnetron sputtering, has been developed which significantly increases the viability of producing this type of material. It has been shown that pulsing the magnetron discharge in the 10–200 kHz range prevents the formation of arcs at the target. The process is stable and high deposition rates can be achieved. This technique has, therefore, been used to deposit coatings with compositions ranging from pure aluminum to stoichiometric Al2O3. The coatings were characterized by scanning and transmission electron microscopy, x-ray diffraction, four-point probe, and nano-indentation techniques. The observed variations in structure and properties are considered in terms of the composition of the coatings and expressed schematically in the form of a novel structure zone model.
Fibroblasts of patients affected by Down's syndrome oversecrete amyloid precursor protein and are hyporesponsive to protein kinase C stimulation (1996)

The present study investigates the ability of the pharmacologic activation of protein kinase C (PKC) to modulate amyloid precursor protein (APP) secretion in human skin fibroblasts from patients affected by Down's syndrome (DS). We assessed DS subjects at the Hospital Institute of Sospiro, Cremona, and at the Alzheimer's Disease Unit of the Sacred Heart Hospital in Brescia, and we subdivided them into nondemented (NDS) and demented (DDS) patients. All DS patients were trisomy 21 karyotype. DS fibroblasts had an increased content of APP immunoreactive material as revealed by immunocytochemistry analysis. The basal secretion of soluble APP was higher (+94.6%) in Down's cells with respect to controls. The observation on the fibroblasts prepared from DS is consistent with these patients' possessing an extra copy of the APP gene (mapped on chromosome 21) leading to increased APP expression. Phorbol-12,13-dibutyrate (PdBu, 9 to 150 nM) treatment promoted a dose-dependent increase of secreted APP in the conditioned medium of control fibroblasts. The peak response (+102.2%) was attained using 150 nM PdBu. In Down's fibroblasts, PdBu stimulated APP secretion already maximally at low concentrations (9 nM), but the peak response, due to the higher basal release, was lower on a percentage basis (+16.4%) than in control fibroblasts. The results indicate that in Down's fibroblasts the mechanisms controlling APP release are at least quantitatively altered. In addition, these results suggest caution when using information obtained from Down's patients to model Alzheimer's disease biochemical defects.
Identification of Bacterial Protein O-Oligosaccharyltransferases and Their Glycoprotein Substrates (2013)

O-glycosylation of proteins in Neisseria meningitidis is catalyzed by PglL, which belongs to a protein family including WaaL O-antigen ligases. We developed two hidden Markov models that identify 31 novel candidate PglL homologs in diverse bacterial species, and describe several conserved sequence and structural features. Most of these genes are adjacent to possible novel target proteins for glycosylation. We show that in the general glycosylation system of N. meningitidis, efficient glycosylation of additional protein substrates requires local structural similarity to the pilin acceptor site. For some Neisserial PglL substrates identified by sensitive analytical approaches, only a small fraction of the total protein pool is modified in the native organism, whereas others are completely glycosylated. Our results show that bacterial protein O-glycosylation is common, and that substrate selection in the general Neisserial system is dominated by recognition of structural homology.
Graying the black box: Understanding DQNs (2016)

In recent years there is a growing interest in using deep representations for reinforcement learning. In this paper, we present a methodology and tools to analyze Deep Q-networks (DQNs) in a non-blind matter. Moreover, we propose a new model, the Semi Aggregated Markov Decision Process (SAMDP), and an algorithm that learns it automatically. The SAMDP model allows us to identify spatio-temporal abstractions directly from features and may be used as a sub-goal detector in future work. Using our tools we reveal that the features learned by DQNs aggregate the state space in a hierarchical fashion, explaining its success. Moreover, we are able to understand and describe the policies learned by DQNs for three different Atari2600 games and suggest ways to interpret, debug and optimize deep neural networks in reinforcement learning.
What if there were desktop access to the computer science literature? (1993)

What if there were an electronic computer science library? Consider the possibilities of having your favorite publications available within finger's reach. Consider Project Envision, an ongoing effort to build a user-centered database from the computer science literature. This paper describes the project's first year progress, stressing the underlying motivation, user-centered development, and the overall design.
Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. (2003)

Active FLT3 receptor mutants have transforming potential in hematopoietic cells and induce a strong activation of STAT5 in primary AML cells. The FLT3-STAT5 pathway contributes to the malignant phenotype and represents a promising molecular therapeutic target structure in AML.
Neutralization of IFNγ defeats haemophagocytosis in LCMV‐infected perforin‐ and Rab27a‐deficient mice (2009)

Hereditary haemophagocytic lymphohistiocytosis (HLH) is a fatal inflammatory disease and treatments currently may lead to serious side effects. There is a pressing need for effective, less toxic treatments for this disease. Previous reports have suggested that interferon gamma (IFNgamma) has a role in the pathogenesis of HLH. Here, we report that blocking IFNgamma had a therapeutic effect in two different murine models of human hereditary HLH (perforin-deficient and Rab27a-deficient mice, both infected with lymphocytic choriomeningitis virus). Therapeutic administration of an anti-IFNgamma antibody induced recovery from haemophagocytosis in both genetic models, as evidenced by increased survival in perforin-deficient mice and correction of blood cytopenia, moderation of body temperature changes, decreased cytokinaemia, restoration of splenic architecture and reduced haemophagocytosis in the liver of both murine models. Involvement of the central nervous system in Rab27a-deficient mice was prevented by anti-IFNgamma therapy. Hepatic T-cell infiltrates and virus persisted, with no detectable harm during the time course of these studies. These data strongly suggest that neutralization of IFNgamma could be used in humans to safely alleviate the clinical manifestations of haemophagocytosis.
Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes (1988)

The specific binding of 3H-labeled gamma-aminobutyric acid ([3H]GABA) to synaptic plasma membranes from rat brains was inhibited by various quinolonecarboxylic acid derivatives (quinolones), and these inhibitions were concentration dependent. The binding of [3H]muscimol to GABAA sites was also inhibited. These inhibitory potencies differed widely among the quinolones examined. The Dixon plots showed that a newly developed difluorinated quinolone, NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride], competitively inhibits the receptor bindings of [3H]GABA and [3H]muscimol. In conclusion, our findings suggest that the inhibition of GABA binding to receptors (including uptake sites) in the brain may be involved in the induction of epileptogenic neurotoxicities by quinolones.
Salmonella Pathogenicity Island 2 Mediates Protection of Intracellular Salmonella from Reactive Nitrogen Intermediates (2002)

Salmonella typhimurium causes an invasive disease in mice that has similarities to human typhoid. A type III protein secretion system encoded by Salmonella pathogenicity island 2 (SPI2) is essential for virulence in mice, as well as survival and multiplication within macrophages. Reactive nitrogen intermediates (RNI) synthesized by inducible nitric oxide synthase (iNOS) are involved in the control of intracellular pathogens, including S. typhimurium. We studied the effect of Salmonella infection on iNOS activity in macrophages. Immunofluorescence microscopy demonstrated efficient colocalization of iNOS with bacteria deficient in SPI2 but not wild-type Salmonella, and suggests that the SPI2 system interferes with the localization of iNOS and Salmonella. Furthermore, localization of nitrotyrosine residues in the proximity was observed for SPI2 mutant strains but not wild-type Salmonella, indicating that peroxynitrite, a potent antimicrobial compound, is excluded from Salmonella-containing vacuoles by action of SPI2. Altered colocalization of iNOS with intracellular Salmonella required the function of the SPI2-encoded type III secretion system, but not of an individual "Salmonella translocated effector." Inhibition of iNOS increased intracellular proliferation of SPI2 mutant bacteria and, to a lesser extent, of wild-type Salmonella. The defect in systemic infection of a SPI2 mutant strain was partially restored in iNOS(-/-) mice. In addition to various strategies to detoxify RNI or repair damage due to RNI, avoidance of colocalization with RNI is important in adaptation of a pathogen to an intracellular life style.
On the Einstein Podolsky Rosen paradox (1964)

Received 4 November 1964DOI:https://doi.org/10.1103/PhysicsPhysiqueFizika.1.195Copyright © 1964 Physics Publishing Co.
Induction of vitreolysis and vitreous detachment with hyaluronidase and perfluoropropane gas (1995)

To simulate the posterior vitreous detachment (PVD) in the rabbit, 1 IU hyaluronidase and/or 0.2 ml of perfluoropropane gas was intravitreally injected. Ophthalmoscopic, light microscopic examination prepared by cryotechnique, electron microscopic examination, and electroretinogram were done on the 3rd and 28th postoperative days. As a result, the eyes undergone simultaneous intravitreal injection of 1 IU hyaluronidase and 0.2 ml perfluoropropane gas showed membranous structure split from the internal limiting membrane of the superior retina in 3 days after injection. The eyes also demonstrated membranous structure separated from the superior retina after 28 days, simulating vitreous detachment. On the contrary, neither agent alone induced vitreous detachment. No toxic retinal changes associated with simultaneous intravitreal injection of 1 IU hyaluronidase and 0.2 ml perfluoropropane gas were observed. Therefore, with a future support by histologic examination other than cryotechnique and by immunohistochemical analysis, the simultaneous intravitreal injection of perfluoropropane gas and hyaluronidase would be a promising method to induce vitreous detachment in non-vitrectomized eye.
Computer Engineering: Hardware Design (1988)

PART I. 1. Binary Numbers and Codes. 2. Digital Circuits. 3. Combinational Systems. 4. Sequential Logic. PART II. 5. Registers and Counters. 6. Memory and Programmable Logic. 7. Register Transfer and Computer Operations. 8. Control Logic Design. PART III. 9. Computer Instructions and Addressing Modes. 10. Design of a Central Processing Unit (CPU). 11. Input-Output and Communication. 12. Memory Management. Index.