1,478 research outputs found
Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways
Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall.Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen activated protein kinase (MAPK) activation, though the molecular mechanisms of this process are poorly understood.
Here we report that tribbles-1, a recently described modulator of MAPK activation controls vascular smooth muscle cell proliferation and chemotaxis via the Jun Kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The
activity of this kinase is dependent on tribbles-1 levels, whilst the activation and the expression of MKK4/SEK1 is not. In addition, tribbles-1 expression is elevated in
human atherosclerotic arteries compared to non-atherosclerotic controls, suggesting that this protein may pay a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology
Next generation organofluorine containing blockbuster drugs
Funding: the National Natural Science Foundation of China (No. 21761132021), the Hungarian Research Foundation (NKFIH No. K 119282), and Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT. The Qinlan Project of Jiangsu Province, and IKERBASQUE, the Basque Foundation for Science are also acknowledged.The role of organo-fluorine compounds in modern health, food and energy related industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasing being used in the development of new bioactivities. Around 25% of the current blockbuster drugs contain fluorine and this number is increasing to well above 30% for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action.PostprintPeer reviewe
Identification of 34 Novel Proinflammatory Proteins in a Genome-Wide Macrophage Functional Screen
Signal transduction pathways activated by Toll-like Receptors and the IL-1 family of cytokines are fundamental to mounting an innate immune response and thus to clearing pathogens and promoting wound healing. Whilst mechanistic understanding of the regulation of innate signalling pathways has advanced considerably in recent years, there are still a number of critical controllers to be discovered. In order to characterise novel regulators of macrophage inflammation, we have carried out an extensive, cDNA-based forward genetic screen and identified 34 novel activators, based on their ability to induce the expression of cxcl2. Many are physiologically expressed in macrophages, although the majority of genes uncovered in our screen have not previously been linked to innate immunity. We show that expression of particular activators has profound but distinct impacts on LPS-induced inflammatory gene expression, including switch-type, amplifier and sensitiser behaviours. Furthermore, the novel genes identified here interact with the canonical inflammatory signalling network via specific mechanisms, as demonstrated by the use of dominant negative forms of IL1/TLR signalling mediators
Ecto-nucleoside triphosphate diphosphohydrolase 3 in the ventral and lateral hypothalamic area of female rats: morphological characterization and functional implications
<p>Abstract</p> <p>Background</p> <p>Based on its distribution in the brain, ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3) may play a role in the hypothalamic regulation of homeostatic systems, including feeding, sleep-wake behavior and reproduction. To further characterize the morphological attributes of NTPDase3-immunoreactive (IR) hypothalamic structures in the rat brain, here we investigated: 1.) The cellular and subcellular localization of NTPDase3; 2.) The effects of 17ÎČ-estradiol on the expression level of hypothalamic NTPDase3; and 3.) The effects of NTPDase inhibition in hypothalamic synaptosomal preparations.</p> <p>Methods</p> <p>Combined light- and electron microscopic analyses were carried out to characterize the cellular and subcellular localization of NTPDase3-immunoreactivity. The effects of estrogen on hypothalamic NTPDase3 expression was studied by western blot technique. Finally, the effects of NTPDase inhibition on mitochondrial respiration were investigated using a Clark-type oxygen electrode.</p> <p>Results</p> <p>Combined light- and electron microscopic analysis of immunostained hypothalamic slices revealed that NTPDase3-IR is linked to ribosomes and mitochondria, is predominantly present in excitatory axon terminals and in distinct segments of the perikaryal plasma membrane. Immunohistochemical labeling of NTPDase3 and glutamic acid decarboxylase (GAD) indicated that Îł-amino-butyric-acid- (GABA) ergic hypothalamic neurons do not express NTPDase3, further suggesting that in the hypothalamus, NTPDase3 is predominantly present in excitatory neurons. We also investigated whether estrogen influences the expression level of NTPDase3 in the ventrobasal and lateral hypothalamus. A single subcutaneous injection of estrogen differentially increased NTPDase3 expression in the medial and lateral parts of the hypothalamus, indicating that this enzyme likely plays region-specific roles in estrogen-dependent hypothalamic regulatory mechanisms. Determination of mitochondrial respiration rates with and without the inhibition of NTPDases confirmed the presence of NTPDases, including NTPDase3 in neuronal mitochondria and showed that blockade of mitochondrial NTPDase functions decreases state 3 mitochondrial respiration rate and total mitochondrial respiratory capacity.</p> <p>Conclusion</p> <p>Altogether, these results suggest the possibility that NTPDases, among them NTPDase3, may play an estrogen-dependent modulatory role in the regulation of intracellular availability of ATP needed for excitatory neuronal functions including neurotransmission.</p
The Period Changes of the Cepheid RT Aurigae
Observations of the light curve for the 3.7-day Cepheid RT Aur both before
and since 1980 indicate that the variable is undergoing an overall period
increase, amounting to +0.082 +-0.012 s/yr, rather than a period decrease, as
implied by all observations prior to 1980. Superposed on the star's O-C
variations is a sinusoidal trend that cannot be attributed to random
fluctuations in pulsation period. Rather, it appears to arise from light travel
time effects in a binary system. The derived orbital period for the system is P
= 26,429 +-89 days (72.36 +-0.24 years). The inferred orbital parameters from
the O-C residuals differ from those indicated by existing radial velocity data.
The latter imply the most reasonable results, namely a1 sin i = 9.09 (+-1.81) x
10^8 km and a minimum secondary mass of M2 = 1.15 +-0.25 Msun. Continued
monitoring of the brightness and radial velocity changes in the Cepheid are
necessary to confirm the long-term trend and to provide data for a proper
spectroscopic solution to the orbit.Comment: Accepted for publication in PASP (November 2007
Moment Closure - A Brief Review
Moment closure methods appear in myriad scientific disciplines in the
modelling of complex systems. The goal is to achieve a closed form of a large,
usually even infinite, set of coupled differential (or difference) equations.
Each equation describes the evolution of one "moment", a suitable
coarse-grained quantity computable from the full state space. If the system is
too large for analytical and/or numerical methods, then one aims to reduce it
by finding a moment closure relation expressing "higher-order moments" in terms
of "lower-order moments". In this brief review, we focus on highlighting how
moment closure methods occur in different contexts. We also conjecture via a
geometric explanation why it has been difficult to rigorously justify many
moment closure approximations although they work very well in practice.Comment: short survey paper (max 20 pages) for a broad audience in
mathematics, physics, chemistry and quantitative biolog
L\'evy-stable two-pion Bose-Einstein correlations in GeV AuAu collisions
We present a detailed measurement of charged two-pion correlation functions
in 0%-30% centrality GeV AuAu collisions by the
PHENIX experiment at the Relativistic Heavy Ion Collider. The data are well
described by Bose-Einstein correlation functions stemming from L\'evy-stable
source distributions. Using a fine transverse momentum binning, we extract the
correlation strength parameter , the L\'evy index of stability
and the L\'evy length scale parameter as a function of average
transverse mass of the pair . We find that the positively and the
negatively charged pion pairs yield consistent results, and their correlation
functions are represented, within uncertainties, by the same L\'evy-stable
source functions. The measurements indicate a decrease of the
strength of the correlations at low . The L\'evy length scale parameter
decreases with increasing , following a hydrodynamically
predicted type of scaling behavior. The values of the L\'evy index of stability
are found to be significantly lower than the Gaussian case of
, but also significantly larger than the conjectured value that may
characterize the critical point of a second-order quark-hadron phase
transition.Comment: 448 authors, 25 pages, 11 figures, 4 tables, 2010 data. v2 is version
accepted for publication in Phys. Rev. C. Plain text data tables for the
points plotted in figures for this and previous PHENIX publications are (or
will be) publicly available at http://www.phenix.bnl.gov/papers.htm
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