Iron up-modulates the expression of transferrin receptors during monocyte-macrophage maturation

Abstract We have investigated the effect of iron on the expression of transferrin receptors (TrfRs) and ferritin chains in cultures of human peripheral blood monocytes maturing to macrophages. Monocyte-macrophage maturation is associated with a gradual rise of Trf-binding capacity in the absence of cell proliferation. At all culture times, treatment with ferric ammonium citrate induces a dose-dependent rise of the Trf-binding level as compared with nontreated cells. Scatchard analysis revealed that this phenomenon is due to an increase in receptor number rather than an alteration in ligand-receptor affinity. Biosynthesis experiments indicated that the rise in number of TrfRs is due to an increase of receptor synthesis, which is associated with a sustained elevation of the TrfR RNA level. The up-regulation of TrfR synthesis is specific in that expression of other macrophage membrane proteins is not affected by iron addition. Conversely, addition of an iron chelator induced a slight decrease of TrfR synthesis. The expression of heavy and light ferritin chains at RNA and protein levels was markedly more elevated in cultured macrophages than in fresh monocytes, thus suggesting modulation of ferritin genes at transcriptional or post-transcriptional levels. Addition of iron salts to monocyte-macrophage cultures sharply stimulated ferritin synthesis but only slightly enhanced the level of ferritin RNA, thus indicating a modulation at the translational level. These results suggests that in cultured human monocytes-macrophages, iron up-regulates TrfR expression, thus in sharp contrast to the negative feedback reported in a variety of other cell types. These observations may shed light on the mechanism(s) of iron storage in tissue macrophages under normal conditions and possibly on the pathogenesis of diseases characterized by abnormal iron storage

Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson\xe2\x80\x99s disease

The involvement of DNA damage and repair in aging processes is well established. Aging is an unequivocal risk factor for chronic neurodegenerative diseases, underscoring the relevance of investigations into the role that DNA alterations may have in the pathogenesis of these diseases. Consistently, even moderate impairment of DNA repair systems facilitates the onset of pathological features typical of PD that include derangement of the dopaminergic system, mitochondrial dysfunction, and alpha-synuclein stress. The latter establishes a connection between reduced DNA repair capacity and a cardinal feature of PD, alpha-synuclein pathology. It remains to be determined, however, whether alpha-synuclein stress activates in vivo the canonical signaling cascade associated with DNA damage, which is centered on the kinase ATM and substrates such as \xce\xb3H2Ax and 53BP1. Addressing these issues would shed light on age-related mechanisms impinging upon PD pathogenesis and neurodegeneration in particular. We analyzed two different synucleinopathy PD mouse models based either on intranigral delivery of AAV-expressing human alpha-synuclein, or intrastriatal injection of human alpha-synuclein pre-formed fibrils. In both cases, we detected a significant increase in \xce\xb3H2AX and 53BP1 foci, and in phospho-ATM immunoreactivity in dopaminergic neurons, which collectively indicate DNA damage and activation of the DNA damage response. Mechanistic experiments in cell cultures indicate that activation of the DNA damage response is caused, at least in part, by pro-oxidant species because it is prevented by exogenous or endogenous antioxidants, which also rescue mitochondrial anomalies caused by proteotoxic alpha-synuclein. These in vivo and in vitro findings reveal that the cellular stress mediated by alpha-synuclein\xe2\x80\x94a pathological hallmark in PD\xe2\x80\x94elicits DNA damage and activates the DNA damage response. The toxic cascade leading to DNA damage involves oxidant stress and mitochondrial dysfunction The data underscore the importance of DNA quality control for preservation of neuronal integrity and protection against neurodegenerative processes

An Innovative Approach to Treat Incisors Hypomineralization (MIH) : A Combined Use of Casein Phosphopeptide-Amorphous Calcium Phosphate and Hydrogen Peroxide—A Case Report

Molar Incisor Hypomineralization (MIH) is characterized by a developmentally derived deficiency in mineral enamel. Affected teeth present demarcated enamel opacities, ranging from white to brown; also hypoplasia can be associated. Patient frequently claims aesthetic discomfort if anterior teeth are involved. This problem leads patients to request a bleaching treatment to improve aestheticconditions.Nevertheless, hydrogen peroxide can produce serious side-effects, resulting from further mineral loss. Microabrasion and/or a composite restoration are the treatments of choice in teeth with mild/moderate MIH, but they also need enamel loss. Recently, a new remineralizing agent based on Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) has been proposed to be effective in hypomineralized enamel, improving also aesthetic conditions. The present paper presents a case report of a young man with white opacities on incisors treated with a combined use of CPP-ACP mousse and hydrogen peroxide gel to correct the aesthetic defect. The patient was instructed to use CPP-ACP for two hours per day for three months in order to obtain enamel remineralization followed by a combined use of CPP-ACP and bleaching agent for further two months. At the end of this five-month treatment, a noticeable aesthetic improvement of the opacities was observed

Multijet production in neutral current deep inelastic scattering at HERA and determination of α_{s}

Multijet production rates in neutral current deep inelastic scattering have been measured in the range of exchanged boson virtualities 10 5 GeV and –1 < η_{LAB}^{jet} < 2.5. Next-to-leading-order QCD calculations describe the data well. The value of the strong coupling constant α_{s} (M_{z}), determined from the ratio of the trijet to dijet cross sections, is α_{s} (M_{z}) = 0.1179 ± 0.0013 (stat.)_{-0.0046}^{+0.0028}(exp.)_{-0.0046}^{+0.0028}(th.)

Jet production in charged current deep inelastic e⁺p scatteringat HERA

The production rates and substructure of jets have been studied in charged current deep inelastic e⁺p scattering for Q² > 200 GeV² with the ZEUS detector at HERA using an integrated luminosity of 110.5 pb⁻¹. Inclusive jet cross sections are presented for jets with transverse energies E_{T}^{jet} > 5 GeV. Measurements of the mean subjet multiplicity, 〈n_{sbj}〉, of the inclusive jet sample are presented. Predictions based on parton-shower Monte Carlo models and next-to-leading-order QCD calculations are compared to the measurements. The value of α_{s} (M_{z}), determined from 〈n_{sbj}〉 at y_{cut} = 10⁻² for jets with 25 < E_{T}^{jet} < 119 GeV, is α_{s} (M_{z}) = 0.1202 ± 0.0052 (stat.)_{-0.0019}^{+0.0060} (syst.)_{-0.0053}^{+0.0065} (th.). The mean subjet multiplicity as a function of Q² is found to be consistent with that measured in NC DIS

Combined QCD and electroweak analysis of HERA data

A simultaneous fit of parton distribution functions (PDFs) and electroweak parameters to HERA data on deep inelastic scattering is presented. The input data are the neutral current and charged current inclusive cross sections which were previously used in the QCD analysis leading to the HERAPDF2.0 PDFs. In addition, the polarisation of the electron beam was taken into account for the ZEUS data recorded between 2004 and 2007. Results on the vector and axial-vector couplings of the Z boson to u- and d-type quarks, on the value of the electroweak mixing angle and the mass of the W boson are presented. The values obtained for the electroweak parameters are in agreement with Standard Model predictions.Comment: 32 pages, 10 figures, accepted by Phys. Rev. D. Small corrections from proofing process and small change to Fig. 12 and Table

Limits on the effective quark radius from inclusive epep scattering at HERA

The high-precision HERA data allows searches up to TeV scales for Beyond the Standard Model contributions to electron-quark scattering. Combined measurements of the inclusive deep inelastic cross sections in neutral and charged current $ep$ scattering corresponding to a luminosity of around 1 fb$^{-1}$ have been used in this analysis. A new approach to the beyond the Standard Model analysis of the inclusive $ep$ data is presented; simultaneous fits of parton distribution functions together with contributions of "new physics" processes were performed. Results are presented considering a finite radius of quarks within the quark form-factor model. The resulting 95% C.L. upper limit on the effective quark radius is $0.43\cdot 10^{-16}$ cm.Comment: 10 pages, 4 figures, accepted by Phys. Lett.

Search for a narrow baryonic state decaying to pKS0{pK^0_S} and pˉKS0{\bar{p}K^0_S} in deep inelastic scattering at HERA

A search for a narrow baryonic state in the $pK^0_S$ and $\bar{p}K^0_S$ system has been performed in $ep$ collisions at HERA with the ZEUS detector using an integrated luminosity of 358 pb$^{-1}$ taken in 2003-2007. The search was performed with deep inelastic scattering events at an $ep$ centre-of-mass energy of 318 GeV for exchanged photon virtuality, $Q^2$, between 20 and 100 $\rm{} GeV^{2}$. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb$^{-1}$ taken in 1996-2000, no resonance peak was found in the $p(\bar{p})K^0_S$ invariant-mass distribution in the range 1.45-1.7 GeV. Upper limits on the production cross section are set.Comment: 16 pages, 4 figures, accepted by Phys. Lett. B. Minor changes from journal reviewing process, including a small correction to figure

Single-Cell Redox Imaging Demonstrates a Distinctive Response of Dopaminergic Neurons to Oxidative Insults

Producción CientíficaAims: The study of the intracellular oxido-reductive (redox) state is of extreme relevance to the dopamine (DA) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, and they selectively degenerate in Parkinson's disease under oxidative stress conditions. To test the hypothesis that these cells display a unique redox response to mild, physiologically relevant oxidative insults when compared with other neuronal populations, we sought to develop a novel method for quantitatively assessing mild variations in intracellular redox state. Results: We have developed a new imaging strategy to study redox variations in single cells, which is sensitive enough to detect changes within the physiological range. We studied DA neurons' physiological redox response in biological systems of increasing complexity--from primary cultures to zebrafish larvae, to mammalian brains-and identified a redox response that is distinctive for substantia nigra pars compacta DA neurons. We studied simultaneously, and in the same cells, redox state and signaling activation and found that these phenomena are synchronized. Innovation: The redox histochemistry method we have developed allows for sensitive quantification of intracellular redox state in situ. As this method is compatible with traditional immunohistochemical techniques, it can be applied to diverse settings to investigate, in theory, any cell type of interest. Conclusion: Although the technique we have developed is of general interest, these findings provide insights into the biology of DA neurons in health and disease and may have implications for therapeutic intervention