180 research outputs found
Mini Review: Specificity in cytokine signal transduction: lessons learned from the IL-3:IL-5:GM-CSF receptor family
Cytokines mediate the transduction of proliferative, differentiation and survival signals in the hematopoietic system. Although
the cytokine family is large and diverse, many different cytokines display broadly overlapping functions. This can be explained by the fact that cytokine receptors often share multiple subunits. Specificity in signal transduction can however be achieved through several mechanisms. This review focuses on how signal specificity can be achieved within the IL-3, IL-5 and GM-CSF receptor family. This is discussed in terms of receptor expression, recent advances in our understanding of intracellular signalling components, and analysis of null mutant knock-out mice
Cytokine-mediated cPLA2 phosphorylation is regulated by multiple MAPK family members
Cytosolic phospholipase A2 (cPLA2) plays a critical
role in various neutrophil functions including the generation of
leukotrienes and platelet-activating factor release. Enzyme
activity is regulated both by translocation to the membrane in
a Ca^(2+) -dependent manner and serine phosphorylation by
members of the mitogen-activated protein kinase (MAPK)
family. In this report, we have investigated the role of
granulocyte/macrophage colony-stimulating factor (GM-CSF)-
mediated signalling pathways in the regulation of cPLA2. GM-
CSF-induced cPLA2 phosphorylation was not affected by
pharmacological inhibition of p38 MAPK, phosphatidylinositol
3-kinase or Src. However, inhibition of extracellular signal-
regulated kinase (ERK) MAPK activation resulted in a partial
inhibition of cPLA2 phosphorylation, revealed in a slower onset
of phosphorylation. A cell line stably transfected with the GM-
CSF receptor was used to further analyze GM-CSF-mediated
cPLA2 phosphorylation. Mutation of tyrosine residues 577 and
612 resulted in a delayed cPLA2 phosphorylation similar to the
pharmacological ERK inhibition. Furthermore, inhibition of p38
MAPK in cells bearing the double mutant ßc577/612 completely
abrogated GM-CSF-induced cPLA2 phosphorylation. We con-
clude that GM-CSF can mediate cPLA2 phosphorylation
through the redundant activation of both p38 and ERK MAP
kinases
Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function
Although it is known that many stimuli can activate mitogen-
activated protein kinases (MAPKs) and phosphatidylinositol 3-
kinases (PI3K) in human neutrophils, little is known concerning
either the mechanisms or function of this activation. We have
utilized a selective inhibitor of MAPKkinase (MEK), PD098059,
and two inhibitors of PI3K, wortmannin and LY294002, to
investigate the roles of these kinases in the regulation of
neutrophil effector functions. Granulocyte/macrophage colony-
stimulating factor, platelet-activating factor (PAF) and N-for-
mylmethionyl-leucyl-phenylalanine are capable of activating
both p44^(ERK1) and p42^(ERK2) MAPKs and phosphotyrosine-asso-
ciated PI3K in human neutrophils. The activation of extracellular
signal-related protein kinases (ERKs) is correlated with the
activation of p21^(ras) by both tyrosine kinase and G-protein-
coupled receptors as measured by a novel assay for GTP loading.
Wortmannin and LY294002 inhibit, to various degrees, super-
oxide generation, neutrophil migration and PAF release. In-
cubation with PD098059, however, inhibits only the PAF release
stimulated by serum-treated zymosan. This demonstrates that,
while neither MEK nor ERK kinases are involved in the acti-
vation of respiratory burst or neutrophil migration, inhibition
of PAF release suggests a potential role in the activation of
cytosolic phospholipase A2 . PI3K isoforms, however, seem to
have a much wider role in regulating neutrophil functioning
Повернення в Ніжин (корпус документів з епістолярію І.Г. Спаського)
Підготовка до друку та переднє слово Наталії ДМИТРЕНКО (Ніжин), коментарі Сергія ЗОЗУЛІ (Київ–Ніжин):
Уперше вводиться до наукового обігу корпус джерел з епістолярію українського та російського радянського історика-нумізмата, музейника І.Г. Спаського. Корпус джерел який містить кореспонденцію, отриману відомим науковцем від кореспондентів-ніжинців, і де, здебільшого, відображена “ніжинська тематика” – проблеми збереження культурної спадщини Ніжина, післявоєнного розвитку міста тощо.Подготовка к печати и предисловие Наталии ДМИТРЕНКО (Нежин), комментарии Сергея ЗОЗУЛИ (Киев–Нежин):
Впервые вводится в научный оборот корпус источников из эпистолярия украинского и российского советского историка-нумизмата, музейщика И.Г. Спасского. Корпус источников содержит корреспонденцию, полученную известным ученым от корреспондентов-нежинцев, и в котором преимущественно отображена “нежинская тематика” – проблемы сохранения культурного наследия Нежина, послевоенного развития города и т.п.Preparation to the print and preface of Nataliya DMYTRENKO (Nizhyn), comments of Serhiy ZOZULYA (Kyiv–Nizhyn):
The corps of sources from the epistolary legacy of the Ukrainian and Russian soviet historiannumismatist and museum worker I.G. Spas’kiy is entered to the scientific appeal in the first time. This corps of sources contains correspondence got the known scientist from Nizhynians and contains mostly “Nizhyn themes” – problems of protect of Nizhyn’s cultural legacy, post-war development of this town etc
Optimizing eHealth tools for older patients: Collaborative redesign of a hospital website
Most hospital websites have not been developed in collaboration with patients and, therefore, rarely take into account the preferences and abilities of older patients. This study describes the systematic redesign of an existing hospital website in a co‐design process with patients and professional stakeholders (e.g. researchers, physicians, nurses, department heads, policymakers, website designers), with the aim to make it more user‐friendly for older patients with colorectal cancer (CRC). The redesign process consisted of three phases, where (I) both existing content and design were evaluated among CRC patients; (II) a prototype website was developed based on these insights; which (III) was evaluated again before making final adjustments. Mixed research methods were used for the redesign process. Specifically, insights from existing literature, outcomes from qualitative and quantitative empirical studies conducted by our team, and expert knowledge from relevant stakeholders, were collected and discussed in multidisciplinary consensus meetings, and served as input for the redesigned website. While the existing website was evaluated poorly, the qualitative evaluation of the prototype website in phase 3 showed that the newly redesigned website was usable for older CRC patients. A practical roadmap on how to collaboratively redesign and optimise existing eHealth tools to make them suitable for and operational in clinical settings is provided
Tailored Web-Based Information for Younger and Older Patients with Cancer: Randomized Controlled Trial of a Preparatory Educational Intervention on Patient Outcomes
Деформационное упрочнение начально-изотропных металлов при деформировании по траекториям малой кривизны
На примере стали мартенситного класса исследованы закономерности деформационного
упрочнения при нагружении по траекториям, имеющим вид двухзвенных ломаных, которым
соответствуют траектории деформирования малой кривизны. Показано, что поверхность
нагружения, разделяющая области упругого и упругопластического деформирования, смещается
в направлении вектора, который соединяет центр поверхности нагружения и изображающую
точку на траектории нагружения, при этом не изменяется форма ее фронтальной
части. Зависимость величины смещения центра поверхности нагружения от
интенсивности накопленных пластических деформаций описывается кривой, инвариантной
к виду траектории нагружения.На прикладі сталі мартенситного класу досліджено закономірності деформаційного
зміцнення при навантаженні по траєкторіях, що мають вигляд
дволанкових ламаних, яким відповідають траєкторії деформування малої
кривини. Показано, що поверхня навантаження, яка розділяє області пружного
та пружнопластичного деформування, зміщується у напрямку вектора,
який з ’єднує центр поверхні навантаження та відображуючу точку на траєкторії
навантаження, при цьому форма фронтальної частини не змінюється.
Залежність величини зміщення центра поверхні навантаження від інтенсивності
накопичених пластичних деформацій описується кривою, яка є інваріантною
відносно траєкторії навантаження.By the example of martensitic steel we study
regularities of strain hardening under loading
along two-section broken lines corresponding
to slightly curved strain paths. It is shown that
the loading surface separating domains of elastic
and elastoplastic strains (yield surface) is
displaced in the direction of a vector connecting
the surface center with the loading trajectory
image point, while the shape of its frontal
part remains unchanged. The yield surface center
displacement versus the intensity of accumulated
plastic strains is described by a curve
invariant to the loading trajectory
Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation
Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene
Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids
To replicate functional liver tissue in vitro for drug testing or transplantation, 3D tissue engineering requires representative cell models as well as scaffolds that not only promote tissue production but also are applicable in a clinical setting. Recently, adult liver-derived liver organoids are found to be of much interest due to their genetic stability, expansion potential, and ability to differentiate toward a hepatocyte-like fate. The current standard for culturing these organoids is a basement membrane hydrogel like Matrigel (MG), which is derived from murine tumor material and apart from its variability and high costs, possesses an undefined composition and is therefore not clinically applicable. Here, a cellulose nanofibril (CNF) hydrogel is investigated with regard to its potential to serve as an alternative clinical grade scaffold to differentiate liver organoids. The re
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