gebhart/patrepeval huggingface dataset:
Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model (2011)

Neurotrophins, activating the PI3K/Akt signaling pathway, control neuronal survival and plasticity. Alterations in NGF, BDNF, IGF-1, or insulin signaling are implicated in the pathogenesis of Alzheimer disease. We have previously characterized a bigenic PS1×APP transgenic mouse displaying early hippocampal Aβ deposition (3 to 4 months) but late (17 to 18 months) neurodegeneration of pyramidal cells, paralleled to the accumulation of soluble Aβ oligomers. We hypothesized that PI3K/Akt/GSK-3β signaling pathway could be involved in this apparent age-dependent neuroprotective/neurodegenerative status. In fact, our data demonstrated that, as compared with age-matched nontransgenic controls, the Ser-9 phosphorylation of GSK-3β was increased in the 6-month PS1×APP hippocampus, whereas in aged PS1×APP animals (18 months), GSK-3β phosphorylation levels displayed a marked decrease. Using N2a and primary neuronal cell cultures, we demonstrated that soluble amyloid precursor protein-α (sAPPα), the predominant APP-derived fragment in young PS1×APP mice, acting through IGF-1 and/or insulin receptors, activated the PI3K/Akt pathway, phosphorylated the GSK-3β activity, and in consequence, exerted a neuroprotective action. On the contrary, several oligomeric Aβ forms, present in the soluble fractions of aged PS1×APP mice, inhibited the induced phosphorylation of Akt/GSK-3β and decreased the neuronal survival. Furthermore, synthetic Aβ oligomers blocked the effect mediated by different neurotrophins (NGF, BDNF, insulin, and IGF-1) and sAPPα, displaying high selectivity for NGF. In conclusion, the age-dependent appearance of APP-derived soluble factors modulated the PI3K/Akt/GSK-3β signaling pathway through the major neurotrophin receptors. sAPPα stimulated and Aβ oligomers blocked the prosurvival signaling. Our data might provide insights into the selective vulnerability of specific neuronal groups in Alzheimer disease.
Scrapie and Creutzfeldt-Jakob disease prion proteins share physical properties and antigenic determinants. (1985)

Scrapie of sheep and goats as well as Creutzfeldt-Jakob disease (CJD) of humans are neurologic disorders caused by slow infectious pathogens. The novel molecular properties of the pathogen causing scrapie have prompted introduction of the term "prion" to denote a small proteinaceous infectious particle that resists inactivation by nucleic acid-modifying procedures. Antiserum to the major hamster scrapie prion protein (PrP 27-30) was found to cross-react with murine CJD proteins. The CJD proteins had molecular weights similar to those observed for scrapie prion proteins as determined by NaDodSO4 gel electrophoresis. In addition, the CJD proteins were resistant to digestion by proteinase K and appear to polymerize into rod-shaped particles. The purification procedure developed for scrapie prions was found to be useful in purifying the CJD agent. Purification of the two infectious pathogens by virtually identical procedures provided further evidence for similarities in their molecular structures. We conclude that the molecular and biologic properties of the CJD agent are sufficiently similar to those of the scrapie prion protein that CJD should be classified as a prion disease.
Generation of Insulin-Producing Islet-Like Clusters from Human Embryonic Stem Cells (2007)

Recent success in pancreatic islet transplantation has energized the field to discover an alternative source of stem cells with differentiation potential to beta cells. Generation of glucose-responsive, insulin-producing beta cells from self-renewing, pluripotent human ESCs (hESCs) has immense potential for diabetes treatment. We report here the development of a novel serum-free protocol to generate insulin-producing islet-like clusters (ILCs) from hESCs grown under feeder-free conditions. In this 36-day protocol, hESCs were treated with sodium butyrate and activin A to generate definitive endoderm coexpressing CXCR4 and Sox17, and CXCR4 and Foxa2. The endoderm population was then converted into cellular aggregates and further differentiated to Pdx1-expressing pancreatic endoderm in the presence of epidermal growth factor, basic fibroblast growth factor, and noggin. Soon thereafter, expression of Ptf1a and Ngn3 was detected, indicative of further pancreatic differentiation. The aggregates were finally matured in the presence of insulin-like growth factor II and nicotinamide. The temporal pattern of pancreas-specific gene expression in the hESC-derived ILCs showed considerable similarity to in vivo pancreas development, and the final population contained representatives of the ductal, exocrine, and endocrine pancreas. The hESC-derived ILCs contained 2%-8% human C-peptide-positive cells, as well as glucagon- and somatostatin-positive cells. Insulin content as high as 70 ng of insulin/mug of DNA was measured in the ILCs, representing levels higher than that of human fetal islets. In addition, the hESC-derived ILCs contained numerous secretory granules, as determined by electron microscopy, and secreted human C-peptide in a glucose-dependent manner. Disclosure of potential conflicts of interest is found at the end of this article.
Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function (2006)

Trafficking of dendritic cells (DCs) to peripheral tissues and to secondary lymphoid organs depends on chemokines and lipid mediators. Here, we show that bone marrow-derived DCs (BM-DCs) express functional leukotriene B4 (LTB4) receptors as observed in dose-dependent chemotaxis and calcium mobilization responses. LTB4, at low concentrations, promoted the migration of immature and mature DCs to CCL19 and CCL21, which was associated with a rapid (30-minute) increase of CCR7 expression at the membrane level. At longer incubation times (6 hours), gene array analysis revealed a promoting role of LTB4, showing a significant increase of CCR7 and CCL19 mRNA levels. BM-DCs cultured from BLT1-/- or BLT1/2-/- mice showed a normal phenotype, but in vivo BLT1/2-/-DCs showed dramatic decrease in migration to the draining lymph nodes relative to wild-type (WT) DCs. Consistent with these observations, BLT1/2-/- mice showed a reduced response in a model of 2,4-dinitro-fluorobenzene (DNFB)-induced contact hypersensitivity. Adoptive transfer of 2,4-dinitrobenzene sulfonic acid (DNBS)-pulsed DCs directly implicated the defect in DC migration to lymph node with the defect in contact hypersensitivity. These results provide strong evidence for a role of LTB4 in regulating DC migration and the induction of adaptive immune responses.
In vivo Administration of Artificial Antigen-Presenting Cells Activates Low-Avidity T Cells for Treatment of Cancer (2009)

The development of effective antitumor immune responses is normally constrained by low-avidity, tumor-specific CTLs that are unable to eradicate the tumor. Strategies to rescue antitumor activity of low-avidity melanoma-specific CTLs in vivo may improve immunotherapy efficacy. To boost the in vivo effectiveness of low-avidity CTLs, we immunized mice bearing lung melanoma metastases with artificial antigen-presenting cells (aAPC), made by covalently coupling (pep)MHC-Ig dimers and B7.1-Ig molecules to magnetic beads. aAPC treatment induced significant tumor reduction in a mouse telomerase antigen system, and complete tumor eradication in a mouse TRP-2 antigen system, when low-avidity CTLs specific for these antigens were adoptively transferred. In addition, in an in vivo treatment model of subcutaneous melanoma, aAPC injection also augmented the activity of adoptively transferred CTLs and significantly delayed tumor growth. In vivo tumor clearance due to aAPC administration correlated with in situ proliferation of the transferred CTL. In vitro studies showed that aAPC effectively stimulated cytokine release, enhanced CTL-mediated lysis, and TCR downregulation in low-avidity CTLs. Therefore, in vivo aAPC administration represents a potentially novel approach to improve cancer immunotherapy.
Regulation of cell motility, morphology, and growth by sulfated glycosaminoglycans (1986)

Due to the recent observation that heparin binds to several growth factors and cell adhesion molecules, the effect of heparin on biological processes governed by growth factors and cell adhesion molecules was investigated. Pharmacological doses of heparin were found to alter cell growth rate, cellular morphology, and cell motility. Concentrations (microgram/ml) of heparin or dextran sulfate decreased cell growth rate, but not the final cell density attained in plateau phase. The effect of heparin on cell growth rate was most pronounced when cells were cultured in low concentrations of serum. A heparin-induced decrease in cell growth rate could be reversed by addition of platelet-derived growth factor (PDGF), a heparin-binding growth factor. Heparin altered the morphology of all cell lines studied to various degrees. The effect of heparin on cell morphology was quantitated by measuring the heparin-induced change in cell surface area. HT-1080 and HeLa cells nearly doubled in surface area upon exposure to 10 micrograms/ml heparin. Since several heparin-binding cell adhesion proteins mediate both cell spreading and cell migration, the influence of heparin on cell migration was investigated with an improved version of the phagokinetic track technique. Low concentrations of heparin and dextran sulfate were found to increase the rate of cell migration in a dose-dependent fashion. Since the quantitative effect of heparin on cell growth rate, morphology, and migration depends on the cell line studied, it is suggested that three separate phenomena may be involved. The results presented indicate a central role for sulfated glycosaminoglycans in the control of both cell growth and cell-cell interactions.
Spinal cord edema and changes in tissue content of Na+, K+, and Mg2+ after impact trauma in rats. (1990)

Changes in the tissue content of water, Na+, K+, and Mg2+ were measured in spinal cord samples from anesthetized rats subjected to impact trauma (T9 spinal segment) of varying severity: 25 g-cm (low injury), 100 g-cm (high injury). Laminectomized animals served as controls. Rats with high injury were killed at 15 min, 60 min, 4 hr, 24 hr, 3 days, or 7 days after trauma. Those with low injury were killed at 24-hr postinjury. In all groups, spinal cord tissue was rapidly removed (less than 30 sec), frozen in liquid nitrogen, and dissected into the injured segment and adjacent two caudal and rostral segments. Water content was determined as wet weight/dry weight ratios, and cations were measured by atomic absorption spectrophotometry. High injury resulted in statistically significant increases in water content as early as 15 min after trauma. There were concomitant increases in Na+ and decreases in K+ that were apparent at 15 min and were statistically significant by 60-min posttrauma. The increases in water content and Na+ were present to a similar degree in the 4-hr, 24-hr, 3-day, and 7-day groups. In contrast, tissue Mg2+ was reduced and significantly decreased at 4 hr and 24 hr; Mg2+ levels had recovered partially by 3 days and completely by 7 days. Whereas changes in the tissue content of water, Na+, and K+ occurred at 24 hr regardless of the injury severity, changes in total Mg2+ were correlated with the degree of injury. These data are consistent with the conclusion that edema formation (and associated Na+ and K+ changes) after spinal cord trauma may be an epiphenomenon and does not significantly contribute to injury progression. In contrast, reductions in Mg2+ content may represent an important factor in the development of irreversible tissue damage.
A vaccine that prevents pregnancy in women. (1994)

We report here results of clinical trials on a birth control vaccine, consisting of a heterospecies dimer of the beta subunit of human chorionic gonadotropin (hCG) associated noncovalently with the alpha subunit of ovine luteinizing hormone and conjugated to tetanus and diphtheria toxoids as carriers, that induces antibodies of high avidity (K(a) approximately 10(10) M-1) against hCG. Fertile women exposed to conception over 1224 cycles recorded only one pregnancy at antibody titers of > 50 ng/ml (hCG bioneutralization capacity). The antibody response declines with time; fertility was regained when titers fell to < 35 ng/ml. This study presents evidence of the feasibility of a vaccine for control of human fertility.
Metformin and reduced risk of cancer in diabetic patients (2005)

Voluntary surveillance systems are subject to under-reporting. Figures may underestimate true numbers. Miscategorisation of probable country of infection by presuming the country with the highest prevalence as the likely country of infection will underestimate the number of infections acquired in the United Kingdom, particularly among people originating from countries with high prevalence. New HIV diagnoses do not represent new HIV infections, as diagnosis can occur at any point between infection and death, which in the natural course of infection is typically 10-12 years. Furthermore, surveillance reports do not distinguish between partners infected in high prevalence countries while visiting and partners infected before migrating from those countries.
Thick Plate-Shaped Al<sub>2</sub>O<sub>3</sub>/ZrO<sub>2</sub> Composites with Continuous Gradient Processed by Electrophoretic Deposition (2003)

This paper concerns the processing of free standing objects with a gradient composition. The possibility to shape 5 mm thick ZrO2-Al2O3 FGM discs by means of electrophoretic deposition (EPD) from suitable stable suspensions was explored. The EPD processing parameters and sintering schedules are described, and the densified FGM composites are evaluated. A mathematical model was established for the EPD process, allowing to calculate the composition gradient in plate-shaped FGM materials from the starting composition of the suspensions, the EPD operating parameters and the powder specific EPD characteristics. The model was essential to engineer the gradient profiles in the green deposits. Defect free Al2O3/ZrO2 FGM discs with a diameter of 55 mm, and a thickness of 5 mm could be successfully processed.
Synthesis, Luminescence Quantum Yields, and Lifetimes of Trischelated Ruthenium(II) Mixed-ligand Complexes Including 3,3′-Dimethyl-2,2′-bipyridyl (1982)

Abstract New five complexes of the type of [RuL3−x(dmby)x]X2(x=1,2,3, L=2,2′-bipyridyl or 1,10-phenanthroline, dmby=3,3′-dimethyl-2,2′-bipyridyl, X=halide ion) have been synthesized in order to investigate the effects of two methyl groups of dmby on the absorption and emission spectra, luminescence quantum yields, and lifetimes. Values of the radiative and nonradiative rate constants have been calculated from these data at 77 K. Although the absorption and emission maxima and the lifetimes are not much affected by the dmby ligand substitution, the molar extinction coefficients and emission quantum yields are decreased compared with trischelated complexes of the parent bipyridyl or phenanthroline ligands. At 25 °C the emission yields of the complexes containing dmby decrease by 3–4 orders of magnitude than at 77 K. Possible causes of the decrease in the quantum yields are discussed.
An immunoblotting diagnostic assay for heartwater based on the immunodominant 32-kilodalton protein of Cowdria ruminantium detects false positives in field sera (1993)

Heartwater, a major constraint to improved livestock production in Zimbabwe, threatens to invade areas which have been previously unaffected. To monitor its spread in Zimbabwe, an immunoblotting diagnostic assay based on the responses of animals to the immunodominant, conserved 32-kDa protein of Cowdria ruminantium was evaluated. In this assay, no false reactions were detected with sera known to be positive and negative, but sera from some cattle, sheep, and goats from heartwater-free areas of Zimbabwe reacted strongly with the 32-kDa protein, suggesting that either these animals had previous exposure to heartwater or they were false positives. To investigate the possibility of previous exposure to heartwater, 11 immunoblot-positive and 6 immunoblot-negative sheep from heartwater-free areas of Zimbabwe were compared regarding their susceptibilities to challenge with C. ruminantium. Prior to challenge, C. ruminantium could not be detected in any sheep by transmission to Amblyomma hebraeum ticks or by the polymerase chain reaction (PCR) conducted with plasma samples. All sheep were equally susceptible to the challenge, and infection was confirmed by brain biopsy, necropsy, PCR, and transmission of C. ruminantium to ticks. Our data suggest that the immunoblot-positive reactions of sera from heartwater-free areas were due not to previous C. ruminantium infection but rather to antigenic cross-reactivity between C. ruminantium and another agent(s) such as Ehrlichia species. In conclusion, the immunodominant 32-kDa protein is not antigenically specific to C. ruminantium and its use in serological diagnosis of heartwater requires reevaluation.
Comment on "Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment" (2007)

Jacobs et al. (Reports, 23 March 2007, p. 1723) reported that plasticity in the mammalian visual system permitted the emergence of "a new dimension of sensory experience" in mice genetically engineered to express a human long-wavelength-sensitive cone photopigment. However, neither neural plasticity nor a new dimension of sensory experience is required to explain their results.
Alteraciones cognitivas en la epilepsiaa (2018)

La epilepsia es una enfermedad neurologica asociada con frecuencia a alteraciones cognitivas, las 
cuales alteran significativamente la calidad de vida de los pacientes. Por lo que, el objetivo de este 
articulo es brindar un panorama general sobre los multiples factores implicados en dicha asociacion, 
como son el estres, la ansiedad, la depresion, los medicamentos y el dano generado por la propia 
enfermedad. Tambien se mencionan los principales predictores conocidos para desarrollar un 
deterioro cognitivo durante la epilepsia, como son la edad, la duracion y la localizacion de las crisis. 
Finalmente se comentan los beneficios de algunos tratamientos anticonvulsivantes sobre la 
cognicion
Telomerase activity in normal human endothelial cells. (1997)

Telomerase, a ribonucleoprotein complex, adds hexameric repeats of 5' T T A G G G 3' to the ends of chromosomes called telomeres. Telomerase activity is present in germ cells but not in most somatic cells. An overwhelming majority of cancer cells show elevated levels of telomerase activity. Once thought to be cancer-cell specific, it is becoming apparent that many proliferating normal cells express telomerase activity. In this study, we demonstrate that normal human endothelial cells express telomerase activity: the activity is growth related. In quiescent, confluent cultures, the telomerase activity is repressed. Furthermore, the activity is lost upon subculturing of the endothelial cells in vitro. Finally, G2/M arrest induced by nocodazole treatment of endothelial cells abolished telomerase activity. Primary cultures of endothelial cells offer a powerful model to study the role, if any, of telomerase in normal cells.
Role of neutrophils in ischemia-reperfusion-induced microvascular injury (1987)

Recent studies indicate that polymorphonuclear neutrophils (PMNs) infiltrate the intestinal mucosa during ischemia and after reperfusion. To determine whether PMNs mediate the increased microvascular permeability produced by ischemia-reperfusion (I/R) we treated cats with either saline, antineutrophil serum (ANS), or a monoclonal antibody specific for the beta-chain of the CD18 complex (MoAb 60.3) that prevents neutrophil adherence and extravasation. Intestinal microvascular permeability to plasma proteins was measured in control preparations (0.08 +/- 0.007), in preparations subjected to 1 h of ischemia then reperfusion (I/R, 0.32 +/- 0.02), I/R preparations treated with ANS (0.13 +/- 0.01), and I/R preparations treated with MoAb (0.12 +/- 0.003). Our results indicate that both PMN depletion (to less than 10% control) and prevention of PMN adherence significantly attenuate the increased microvascular permeability induced by I/R. These findings, coupled to previous results obtained from this model, support the hypothesis that neutrophils, which accumulate in the mucosa in response to xanthine oxidase activation, mediate the oxyradical-dependent injury produced by reperfusion of the ischemic bowel.
Fast Dissolving Tablet: An Overview (2009)

Fast dissolving Tablets are disintegrating and/or d issolve rapidly in the saliva without the need for water. Some tablets are designed to dissolve in saliva remarkably fast, within a few seconds, and are true fast-dissolving tablets. Others contai n agents to enhance the rate of tablet disintegration in the oral cavity, and are more app ropriately termed fast-disintegrating tablets, as they may take up to a minute to completely disinteg rate. Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest, most convenient and most economical method of drug delivery having the highest patient compliance. This tablet format is designed to allow administration of an or al solid dose form in the absence of water or fluid intake. Such tablets readily dissolve or disi ntegrate in the saliva generally within <60 seconds. Fast- or mouth dissolving tablets have bee n formulated for pediatric, geriatric, and bedridden patients and for active patients who are busy and traveling and may not have access to water. Such formulations provide an opportunity for product line extension in the Many elderly persons will have difficulties in taking convention al oral dosage forms (viz., solutions, suspensions, tablets, and capsules) because of hand tremors and dysphagia. Swallowing problems also are common in young individuals because of their underdeveloped muscular and nervous systems. Other groups that may experience problems using conventional oral dosage forms include the mentally ill, the developmentally disabled, and patients who are uncooperative, on reduced liquid-intake plans, or are nauseated. I n some cases such as motion sickness, sudden episodes of allergic attack or coughing, and an una vailability of water, swallowing conventional tablets may be difficult.
Click chemistry reactions in medicinal chemistry: Applications of the 1,3‐dipolar cycloaddition between azides and alkynes (2007)

In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chemistry to keep pace with the multitude of information derived from modern biological screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddition ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purification of the resulting products have opened new opportunities in generating vast arrays of compounds with biological potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chemistry applications in which click-chemistry might be relevant in the future.