gebhart/patrepeval huggingface dataset:
ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation (2011)

ZAP-70 in chronic lymphocytic leukemia (CLL) has been associated with enhanced B-cell receptor (BCR) signaling, survival, and migration. We investigated whether ZAP-70 can directly govern migration and the underlying mechanisms. In the ZAP-70 stably transfected Ramos cell line, IgM stimulation, but no IgD, enhanced phosphorylation of ERK1/2, Akt and Syk, and delayed IgM and CD79b internalization. In contrast, in the Raji cell line, where ZAP-70 was constitutively phosphorylated, ERK1/2, but not Akt, was phosphorylated, suggesting that MAPK pathway mediates ZAP-70 effects. BCR stimulation modulated the expression of CCR7, CXCR4, CXCR5, CD44, CD49d, and CD62L, which were up-regulated in ZAP-70-positive CLL primary subclones. The most dramatic change after BCR engagement in ZAP-70-transfected cells was CCR7 up-regulation, this being impaired by ERK1/2 inhibition and translating into both increased signaling and migration toward CCL21. Primary CLL subclones with high ZAP-70 expression showed increased migration toward CCL21. In conclusion, ZAP-70 ectopic expression led to enhanced BCR signaling after IgM stimulation and increased the expression of CCR7 predominantly via ERK1/2, increasing the response and migration toward CCL21. In primary CLL samples, cellular subsets with high ZAP-70 expression had increased expression of adhesion molecules and chemokine receptors in addition to an enhanced ability to migrate toward CCL21.
Iron mobilization from hepatocyte monolayer cultures by chelators: the importance of membrane permeability and the iron-binding constant (1988)

A series of bidentate hydroxypyridinone iron chelators that have therapeutic potential as oral iron chelators, have been studied systematically to determine which properties are the most critical for the mobilization of hepatocyte iron. The relationship between lipid solubility of the free and complexed forms of each chelator and hepatocyte iron release has been investigated as well as the contribution of the binding constant for iron (III). Hydroxypyridin-4-ones that were approximately equally soluble in lipid and aqueous phases were the most active compounds, the partition coefficient of the free chelator appearing to be more critical in determining iron release than that of the iron-complexed form. Highly hydrophilic chelators did not mobilize intracellular iron pools, whereas highly lipophilic compounds were toxic to hepatocytes. The contribution of the binding constant for iron (III) to cellular iron release was assessed by comparing hydroxypyridin-4-ones (log beta 3 = 36) and hydroxypyridin-2-ones (log beta 3 = 32), which possess similar partition coefficients. The results show that the binding for iron (III) is particularly important at low concentrations of chelator (less than 100 mumol/L) and that at higher concentrations (greater than 500 mumol/L) iron mobilization is limited by the available chelatable pool. Measurement of iron release with other chelators confirms the importance of both the lipid solubilities and iron (III)-binding constants to iron mobilization. The most active hydroxypyridin-4-ones released more hepatocyte iron than did deferoxamine when compared at equimolar concentrations. The results suggest that the ability of an iron chelator to enter the cell is crucial for effective iron mobilization and that once within the cell the binding constant of the chelator for iron (III) becomes a dominant factor.
Headache Induced by Chronic Substance Use: Analysis of Medication Overused and Minimum Dose Required to Induce Headache (2004)

The minimum dose of medication required to induce chronic headache should be revised because a high proportion of patients are not classifiable using either the International Headache Society diagnostic criteria or the revised criteria recently proposed. A more comprehensive definition for the required minimum dose might be used. Triptan abuse can cause chronic headache and should be included in the International Headache Society classification.
SMP System Interconnect Instrumentation for Performance Analysis (2002)

The system interconnect is often the performance bottleneck in SMP computers. Although modern SMPs include event counters on processors and interconnects, these provide limited information about the interaction of processors vying for shared resources. Additionally, transaction sources and addresses are not readily available, making analysis of access patterns and data locality difficult. Enhanced system interconnect instrumentation is required to extract this information. This paper describes instrumentation implemented for monitoring the system interconnect on Sun Fire™ servers. The instrumentation supports sophisticated programmable filtering of event counters, allowing us to construct histograms of system interconnect activity, and a FIFO to capture trace sequences. Our implementation results in a very small hardware footprint, making it appropriate for inclusion in commodity hardware. We also describe a sampling of software tools and results based on this infrastructure. Applications have included performance profiling, architectural studies, and hardware bringup and debugging.
Intervention by PCT and Problems Awaiting Solution at Anjo Kosei Hospital: Usefulness of Rounds of Patients Receiving Opioids (2012)

がん患者に対しその症状の早期から介入するため，安城更生病院の緩和ケアチーム (以下，PCT) は，オピオイド使用患者を対象に，病棟ラウンド (以下，スクリーニング回診) を実施している。本研究の目的は，スクリーニング回診を実施する当院PCTの活動状況並びに現状の問題点を解析し，その問題点の解決法を見出すことである。 我々は，PCTの介入状況および介入患者に対して行なった薬物療法に関する提案228件について，PCTが介入した196例をレトロスペクティブに調査した。 103例に対しては，医師からの依頼により介入を行なった (以下，依頼群)。また，93例には，PCTによるスクリーニング回診による介入が行なわれた (以下，スクリーニング群)。 スクリーニング回診によって，PCTの介入症例は増加した。スクリーニング回診を実施する以前には，PCTへ介入依頼のなかった医師からの介入依頼症例数も増加した。 他方，PCTの介入に関する問題点も明らかとなった。PCTが積極的に介入したスクリーニング群において，処方薬の提案に対してレスポンスがないケースが33%存在した。この問題は，PCTと各病棟スタッフとの間の情報交換が主に電子カルテを介したもので，PCTと各病棟スタッフ間の十分な信頼関係を築けなかったことに一部由来するかもしれない。今後は，より良いPCT介入を行なうために，カンファレンスなどの直接的な情報交換を介し，各病棟スタッフとの連携体制 (協力的な体制) を構築する必要がある。
Two Coordinately Regulated Homologs of FLOWERING LOCUS T Are Involved in the Control of Photoperiodic Flowering in Soybean (2010)

FLOWERING LOCUS T (FT) is a key flowering integrator in Arabidopsis (Arabidopsis thaliana), with homologs that encode florigens in many plant species regardless of the type of photoperiodic response. We identified 10 FT homologs, which were arranged as five pairs of linked genes in different homoeologous chromosomal regions, in soybean (Glycine max), a paleopolyploid species. Two of the FT homologs, GmFT2a and GmFT5a, were highly up-regulated under short-day (SD) conditions (inductive for flowering in soybean) and had diurnal expression patterns with the highest expression 4 h after dawn. Under long-day (LD) conditions, expression of GmFT2a and GmFT5a was down-regulated and did not follow a diurnal pattern. Flowering took much longer to initiate under LD than under SD, and only the GmFT5a transcript accumulated late in development under LD. Ectopic expression analysis in Arabidopsis confirmed that both GmFT2a and GmFT5a had the same function as Arabidopsis FT, but the effect of GmFT5a was more prominent. A double-mutant soybean line for two PHYTOCHROME A (PHYA) genes expressed high levels of GmFT2a and GmFT5a under LD, and it flowered slightly earlier under LD than the wild type grown under SD. The expression levels of GmFT2a and GmFT5a were regulated by the PHYA-mediated photoperiodic regulation system, and the GmFT5a expression was also regulated by a photoperiod-independent system in LD. Taken together, our results suggest that GmFT2a and GmFT5a coordinately control flowering and enable the adaptation of soybean to a wide range of photoperiodic environments.
Self-renewal and Proliferation of Murine Embryonic Stem Cells: A Study of Glycosaminoglycans Effect on Feeder-Free Cultures (2007)

The self-renewal and proliferation of murine embryonic stem (ES) cells can be preserved indefinitely in the presence of the mouse embryonic fibroblast (MEF) feeder layer. Since the feeder layer has several drawbacks, including viral contamination and large-scale production, gelatin solutions are the most prominent alternative to replacing it. In this investigation, self-renewal and proliferation of ES cells was carried out by supplementing the gelatin solution with glycosaminoglycan components, such as chondroitin sulfate and heparin. The methylcellulose-based embryoid body (EB) assay was used to evaluate the self-renewal ability of the ES cells. Chondroitin sulfate and heparin were mixed with 0.1% gelatin solution in 0:100, 50:50 and 100:0 (heparin/chondroitin sulfate) ratios and compared with 0.1% gelatin (positive control) and MEF (negative control) in three independent parallel experiments. Chondroitin sulfate addition to 0.1% gelatin enhanced the cell population and the number of EBs by 57 and 32%, respectively.
Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history (2001)

Stem cell proliferation induced by potent cytokines usually leads to a loss of primitive potential through differentiation. In this study, the ability of cytokines and murine MS5 stromal cells to independently regulate the proliferation and long-term culture-initiating cell (LTC-IC) activity of primitive CD34(+)CD38(low/neg) human bone marrow cells was evaluated. To compare populations with identical proliferation histories, cells were labeled with carboxy fluorescein diacetate succinimidyl ester, and LTC-IC activity was assessed 4 days later in cells that had accomplished the same number of divisions with or without MS5 cells. MS5 cells counteracted dramatically the loss of LTC-IC activity observed in the presence of cytokines alone. Thus, in the presence of MS5 cells, means of 1233 (n = 5) and 355 (n = 9) LTC-IC-derived colony-forming cells (CFCs) were generated by 1000 cells that performed 3 and 4 divisions respectively, whereas 311 (n = 5) and 64 (n = 5) CFCs were generated by 1000 cells cultured without MS5 cells. Interestingly, MS5 cells had no detectable effect on the LTC-IC activity of cells that divided only twice in 4 days-1606 CFCs (n = 6) and 1993 (n = 6) CFCs, respectively, without and with MS5 cells-and a 48 additional hours of coculture were necessary to unmask changes in the LTC-IC activity mediated by stromal cells. These results indicate that cytokines and stroma-derived signals can regulate independently the proliferation and differentiation of primitive cells and that these stroma-derived extracellular factors act directly on their target cells.
Lysine acetylation in obesity, diabetes and metabolic disease (2011)

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) mediate acetylation and deacetylation of histone proteins and transcription factors. There is abundant evidence that these enzymes regulate the acetylation state of many cytoplasmic proteins, including lysine residues in important metabolic enzymes. Lysine acetylation regulates major cellular functions as a common post-transcriptional modification of proteins, conserved from prokaryotes to humans. In this article, we refer to HATs and HDACs broadly as lysine acetyltransferases (KATs) and deacetylases (KDACs). Lysine acetylation is vitally important in both immunological and metabolic pathways and may regulate the balance between energy storage and expenditure. Obesity, type II diabetes and cardiovascular disease (metabolic syndrome) are widely recognised as features of a chronic low-grade inflammatory state, involving significant alterations in primary immunometabolism. Identifying effective therapeutic and preventive options to treat this multi-factorial syndrome has proven to be very challenging, with an emerging focus on developing anti-inflammatory agents that can combat adiposity and metabolic disease. Here, we summarise current evidence and understanding of innate immune and metabolic pathways relevant to adiposity and metabolic disease regulated by lysine acetylation. Developing this understanding in greater detail may facilitate strategic development of novel and enzyme-specific lysine deacetylase modulators that regulate both metabolic and immune systems.
alpha-2 Macroglobulin receptor/Ldl receptor-related protein(Lrp)-dependent internalization of the urokinase receptor. (1995)

The GPI-anchored urokinase plasminogen activator receptor (uPAR) does not internalize free urokinase (uPA). On the contrary, uPAR-bound complexes of uPA with its serpin inhibitors PAI-1 (plasminogen activator inhibitor type-1) or PN-1 (protease nexin-1) are readily internalized in several cell types. Here we address the question whether uPAR is internalized as well upon binding of uPA-serpin complexes. Both LB6 clone 19 cells, a mouse cell line transfected with the human uPAR cDNA, and the human U937 monocytic cell line, express in addition to uPAR also the endocytic alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP/alpha 2-MR) which is required to internalize uPAR-bound uPA-PAI-1 and uPA-PN-1 complexes. Downregulation of cell surface uPAR molecules in U937 cells was detected by cytofluorimetric analysis after uPA-PAI-1 and uPA-PN-1 incubation for 30 min at 37 degrees C; this effect was blocked by preincubation with the ligand of LRP/alpha 2-MR, RAP (LRP/alpha 2-MR-associated protein), known to block the binding of the uPA complexes to LRP/alpha 2-. MR. Downregulation correlated in time with the intracellular appearance of uPAR as assessed by confocal microscopy and immuno-electron microscopy. After 30 min incubation with uPA-PAI-1 or uPA-PN-1 (but not with free uPA), confocal microscopy showed that uPAR staining in permeabilized LB6 clone 19 cells moved from a mostly surface associated to a largely perinuclear position. This effect was inhibited by the LRP/alpha 2-MR RAP. Perinuclear uPAR did not represent newly synthesized nor a preexisting intracellular pool of uPAR, since this fluorescence pattern was not modified by treatment with the protein synthesis inhibitor cycloheximide, and since in LB6 clone 19 cells all of uPAR was expressed on the cell surface. Immuno-electron microscopy confirmed the plasma membrane to intracellular translocation of uPAR, and its dependence on LRP/alpha 2-MR in LB6 clone 19 cells only after binding to the uPA-PAI-1 complex. After 30 min incubation at 37 degrees C with uPA-PAI-1, 93% of the specific immunogold particles were present in cytoplasmic vacuoles vs 17.6% in the case of DFP-uPA. We conclude therefore that in the process of uPA-serpin internalization, uPAR itself is internalized, and that internalization requires the LRP/alpha 2-MR.
β-2 Adrenergic Receptor Variants Affect Resting Blood Pressure and Agonist-Induced Vasodilation in Young Adult Caucasians (1999)

Recent evidence suggests that the prodownregulatory Gly16 allele of the beta-2 adrenergic receptor (beta-2 AR) is associated with essential hypertension in African Caribbeans. To further investigate the effect of the glycine (Gly)16 and arginine (Arg)16 beta-2 AR variants on hemodynamics, we investigated the agonist-mediated in vivo vasodilation in normotensive Austrian Caucasians and analyzed the results with respect to the Gly16/Arg16 polymorphism. Fifty-seven normotensive men, 20 to 32 years of age with body mass index of 18.7 to 29.9 kg/m2, were genotyped for the Arg16/Gly16 beta-2 AR alleles. All 15 Gly16/Gly16 subjects, all 12 Arg16/Arg/16 subjects, and 27 of 30 heterozygous subjects underwent hemodynamic measurements while supine after an overnight fast. The observers were unaware of the subjects' genotypes. The subjects received a graded infusion of the selective beta-2 AR agonist salbutamol (0.07, 0.14, and 0.21 microgram/kg per minute, respectively), each dose over 8 minutes. Stroke volume and blood pressure were determined continuously by means of impedance cardiography and oscillometry, respectively. The last 4 minutes of each infusion were evaluated statistically. Basal mean blood pressure was higher in the Gly16/Gly16 subjects compared with Arg16/Arg16 subjects (mean+/-SD: 81.6+/-6.14 versus 75.2+/-4.93 mm Hg, P<0.01). Homozygous Gly16 subjects showed a significantly decreased vasodilation during the first dose of salbutamol infusion compared with Arg16/Arg16 subjects (Deltatotal peripheral resistance index -17.9+/-14.4 versus -30. 6+/-8.3%, P<0.01) despite increased sympathetic counterregulation in the Arg16/Arg16 group (Deltaheart rate +16.9+/-7.0% versus +8.6+/-7. 0%, P<0.01; Deltacardiac index +39.5+/-18.5% versus 21.4+/-18.8%, P<0.05). Our results provide additional evidence that the Gly16/Arg16 alleles of the beta-2 AR are intimately related to blood pressure regulation and deserve further studies in the pathogenesis of essential hypertension.
A comparative design and tuning for conventional fuzzy control (1997)

A new methodology is introduced for designing and tuning the scaling gains of the conventional fuzzy logic controller (FLC) based on its well-tuned linear counterpart. The conventional FLC with a linear rule base is very similar to its linear counterpart. The linear three-term controller has proportional, integral and/or derivative gains. Similarly, the conventional fuzzy three-term controller also has fuzzy proportional, integral and/or derivative gains. The new concept "fuzzy transfer function" is invented to connect these fuzzy gains with the corresponding scaling gains. The comparative gain design is presented by using the gains of the well-tuned linear counterpart as the initial fuzzy gains of the conventional FLC. Furthermore, the relationship between the scaling gains and the performance can be deduced to produce the comparative tuning algorithm, which can tune the scaling gains to their optimum by less trial and error. The performance comparison in the simulation demonstrates the viability of the new methodology.
Efficient incorporation of transfected blastodermal cells into chimeric chicken embryos (1993)

The formation of transgenic chimeric chickens for use in developmental studies and as intermediates in the production of transgenic chickens requires the incorporation of stably transfected blastodermal cells into a chimera. To obtain blastodermal cells, area pellucidae of stage X (Eyal-Giladi and Kochav, Dev. Biol. 49:321-337, 1976:E.-G.&K.) embryos were collected from unincubated, freshly oviposited Barred Plymouth Rock eggs and dissociated in 0.25% trypsin/0.04% EDTA (w/v) and 2% (v/v) chicken serum in phosphate-buffered saline (Ca2+ and Mg2+ free) at 4 degrees C for 10 min. The blastodermal cells were suspended in Dulbecco's Modified Eagle's Medium (DMEM) and transfected by lipofection with superhelical pmiwZ, a plasmid containing a hybrid lacZ gene encoding bacterial beta-galactosidase (beta-gal) under the control of a chicken beta-actin/Rous sarcoma virus promoter. A mixture of 2.5 micrograms Lipofectin and 1.56 micrograms pmiwZ in 250 microliters DMEM was incubated for 30 min at 37 degrees C and added to 500 microliters of 20-40,000 cells in suspension. Cells incubated with the transfection reagents in the presence or absence of pmiwZ were either plated and cultured for 48 h at 37 degrees C in 5% CO2/95% air, or injected through a shell window into the subgerminal cavity of White Leghorn stage X (E.-G.&K.) embryos previously exposed to 500-600 rads from a 60Co source, after which the window was sealed and the egg incubated at 38 +/- 1 degrees C for 72 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Emergence of targeted immune therapies for systemic lupus (2005)

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterised by flares of rampant inflammation that can threaten, in an unpredictable manner, almost any organ in the body. Current standard of care is largely empiric, involving the use of corticosteroids and toxic immune suppressive agents that are widely acknowledged to have unacceptable side effects for long-term use. Recently, there have been significant advances in understanding the nature of some fundamental immune imbalances underlying the complicated clinical manifestations of SLE. Nevertheless attempts to develop and test more targeted, and potentially safer immune-modulating drugs for lupus have encountered significant obstacles, due to the lack of validated biological markers for disease flare and remission, and difficulties in the clinical assessment of the heterogeneous patients. In support of renewed interest in drug development for lupus, large collaborative groups have formed, and efforts are underway to develop objective biomarkers for SLE as well as to improve the standardisation and reproducibility of clinical outcome measures in multi-centre trials.
Antibody-cytokine fusion proteins: production, functionality and application prospects in oncology (2013)

УДК 616–006–097:576.8.097.3 Поступила 27.06.2013 г.Е.Н. Кособокова, к.б.н., старший научный сотрудник лаборатории трансгенных препаратов;В.С. Косоруков, к.б.н., зав. лабораторией трансгенных препаратов;А.Ю. Барышников, д.м.н., профессор, директор НИИ экспериментальной диагностики и терапии опухолейРоссийский онкологический научный центр им. Н.Н. Блохина РАМН, Москва, 115478, Каширское шоссе, 24В медицине цитокины играют важную роль, являясь модуляторами иммунного ответа. Однако применение высоких доз биоло-гически активных препаратов в онкологии сопровождается рядом нежелательных побочных эффектов, приводящих к прекращению лечения. Биологически направленная (таргетная) терапия позволяет увеличить эффективность использования цитокинов, а следова-тельно, снизить дозы препарата. Достижения в генной инженерии и биотехнологии привели к росту числа новых — слитных — белков, полученных на основе ан-тител. Такие гибриды могут сохранять свойства всех компонентов и приобретают преимущества по сравнению с отдельными белками. Например, моноклональные антитела, специфичные к определенному опухолевому антигену, связанные с цитокинами (МАт–Ц), обес-печивают накопление последних в микроокружении злокачественного образования, увеличение противоопухолевого эффекта антител и усиление иммунного ответа против опухоли. За последние двадцать лет созданы МАт–Ц с разной специфической направленностью к ряду опухолей. В экспериментах на животных было показано, что такие слитные белки, аккумулируясь в районе новообразования, способны вызывать значительный противоопухолевый ответ, который в ряде случаев приводит к полной элиминации опухоли. В об-зоре суммируются данные по существующим моделям слитных белков на основе антител, технологиям их создания и перспективам применения в онкологии.Ключевые слова: цитокины; антитела; слитные белки; противоопухолевые препараты.Для контактов: Кособокова Екатерина Николаевна, тел. раб. 8(495)324-14-59, тел. моб. +7 903-590-05-91; e-mail: ekkos@mail.ru
A loosely-coupled parallel graphics architecture based on a conflict-free multiport frame buffer (2003)

This paper describes a parallel computer architecture for real-time image synthesis. The architecture is based on a loosely-coupled array of general purpose processors equipped with a novel frame buffer subsystem called a conflict-free multiport frame buffer (CFMFB) which enables every processor to write any region of the screen without access conflicts. An efficient polygon rendering method using the CFMFB is also described. The method assigns a subset of the polygons to each processor, which independently calculates the images of the assigned polygons with the Z-buffer algorithm. The performance of the system is estimated through simulation experiments with sample scenes.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer (2015)

UMIN UMIN000007527.