F. Bartolomé

Magnetic nanoparticles with bulklike properties (invited)

The magnetic behavior of Fe3� xO4 nanoparticles synthesized by either high-temperature decomposition of an organic iron precursor or low-temperature coprecipitation in aqueous conditions is compared. Transmission electron microscopy, x-ray absorption spectroscopy, x-ray magnetic circular dichroism, and magnetization measurements show that nanoparticles synthesized by thermal decomposition display high crystal quality and bulklike magnetic and electronic properties, while nanoparticles synthesized by coprecipitation show much poorer crystallinity and particlelike phenomenology, including reduced magnetization, high closure fields, and shifted hysteresis loops. The key role of the crystal quality is thus suggested, because particlelike behavior for particles larger than about 5 nm is observed only when the particles are structurally defective. These conclusions are supported by Monte Carlo simulations. It is also shown that thermal decomposition is capable of producing nanoparticles that, after further stabilization in physiological conditions, are suitable for biomedical applications such as magnetic resonance imaging or biodistribution studies. V C 2011 American Institute of Physics. [doi:10.1063/1.3559504]

Enhanced proteasome-dependent degradation of the CDK inhibitor p27kip1 in immortalized lymphocytes from Alzheimer´s dementia patients

Cyclin-dependent kinase inhibitor p27(kip1) (p27), a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals. We have recently reported the existence of a molecular link between decreased p27 levels and enhanced phosphorylation of pRb protein and proliferation of immortalized lymphocytes from Alzheimers disease (AD) patients. These cell cycle disturbances might be considered systemic manifestations, which mirror changes thought to occur in the brain, where post-mitotic neurons have been shown to display various cell cycle markers prior to degeneration. This work was undertaken to delineate the molecular mechanisms underlying the p27 down-regulation associated with AD. To this end, we evaluated the p27 protein stability in control and AD lymphoblasts. Half-life of p27 protein was markedly reduced in lymphoblasts from AD patients compared with that in control cells. The increased phosphorylation of p27 at Thr187, rather than changes in the 26S proteasome activity, is likely responsible for the enhanced degradation of p27 in AD cells. The serum-induced enhanced proliferation of AD lymphoblasts and decreased levels of p27 were abrogated by calmodulin (CaM) antagonists. The findings presented here suggest that Ca(2+)/CaM-dependent overactivation of PI3K/Akt signaling cascade in AD cells, plays an important role in regulating p27 abundance by increasing its degradation in the ubiquitin-proteasome pathway.

Extrinsic origin of ferromagnetism in doped ZnO

Different synthetic routes have been tested to prepare bulk doped ZnO. The doping elements were Mn, Fe and Co. We were able to prepare single-phase compounds at high temperature by using ceramic procedures and at very low temperature using a sol–gel method. No ferromagnetism has been observed for these samples. In contrast, spontaneous magnetization is observed in samples obtained from non-optimal conditions and exhibiting secondary phases. Magnetic impurities have been easily identified for Fe- and Co-doped samples. However, the nature of the room temperature magnetic impurity for the Mn-based compound is not so clear and different possibilities are discussed. We have also checked the effect of the grain size on the magnetic properties by synthesizing nano-materials using a sol–gel route. The single-phase nano-compounds are also not ferromagnets showing similar properties to the well-sintered polycrystalline materials.

HMG-CoA Reductase Inhibitor Simvastatin Inhibits Cell Cycle Progression at the G1/S Checkpoint in Immortalized Lymphocytes from Alzheimer's Disease Patients Independently of Cholesterol-Lowering Effects

Recent work has suggested that statins may exert beneficial effects on patients suffering from Alzheimers disease (AD). The pharmacological effects of statins extend beyond their cholesterol-lowering properties. Based on the antineoplastic and apoptotic effects of statins in several cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle. A growing body of evidence indicates that neurodegeneration involves the activation of cell cycle machinery in postmitotic neurons. We and others have presented direct evidence to support the hypothesis that the failure of cell cycle control is not restricted to neurons in AD patients, but that it occurs in peripheral cells as well. For these reasons, we found it worthy to study the role of simvastatin on cell proliferation in immortalized lymphocytes from AD patients. We report here that simvastatin (SIM) inhibits the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G1/S transition. SIM induces a partial blockade of retinoblastoma protein phosphorylation and inhibition of cyclin E/cyclin-dependent kinase (CDK)2 activity associated with increased levels of the CDK inhibitors p21Cip1 and p27kip1. These effects of SIM on AD lymphoblasts are dependent on inhibition of the proteasome-mediated degradation of p21 and p27 proteins. The antiproliferative effect of this natural statin may provide a therapeutic approach for AD disease.

Impaired apoptosis in lymphoblasts from Alzheimer’s disease patients: Cross-talk of Ca2+/calmodulin and ERK1/2 signaling pathways

Abstract.We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer’s disease (AD) patients to escape from serum deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca2+/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2 pathway setting by Ca2+/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic factor withdrawal.

Nanostructural origin of the spin and orbital contribution to the magnetic moment in Fe3−xO4 magnetite nanoparticles

5 nm Fe3−xO4 nanoparticles were synthesized either by high-temperature decomposition in organic phase or in low-temperature aqueous conditions. In the first case oleic acid was covalently bonded to the nanoparticles; in the second case polyvinyl alcohol (PVA) yielded a protective coating without chemical bond. Magnetization measurements and x-ray magnetic circular dichroism showed a saturation magnetization close to bulk magnetite and an orbital moment effectively quenched in covalently bonded nanoparticles. PVA-coated nanoparticles showed a reduced value of the magnetization and ∼3 fold increase in the orbital moment. High resolution electron microscopy suggested that this was related to the nanostructure of the samples.

Altered cell cycle‐related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer’s disease [amyloid precursor protein/presenilin 1 (PS1)]

Cumulative evidence indicates that aberrant re‐expression of many cell cycle‐related proteins and inappropriate neuronal cell cycle control are critical events in Alzheimer’s disease (AD) pathogenesis. Evidence of cell cycle activation in post‐mitotic neurons has also been observed in murine models of AD, despite the fact that most of these mice do not show massive loss of neuronal bodies. Dysfunction of the cell cycle appears to affect cells other than neurons, as peripheral cells, such as lymphocytes and fibroblasts from patients with AD, show an altered response to mitogenic stimulation. We sought to determine whether cell cycle disturbances are present simultaneously in both brain and peripheral cells from the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD, in order to validate the use of peripheral cells from patients not only to study cell cycle abnormalities as a pathogenic feature of AD, but also as a means to test novel therapeutic approaches. By using cell cycle pathway‐specific RT2Profiler™ PCR Arrays, we detected changes in a number of cell cycle‐related genes in brain as well as in lymphocytes from APP/PS1 mice. Moreover, we found enhanced 5′‐bromo‐2′‐deoxyuridine incorporation into DNA in lymphocytes from APP/PS1 mice, and increased expression of the cell proliferation marker proliferating cell nuclear antigen (PCNA), and the cyclin‐dependent kinase (CDK) inhibitor Cdkn2a, as detected by immunohistochemistry in cortical neurons of the APP/PS1 mice. Taken together, the cell cycle‐related changes in brain and blood cells reported here support the mitosis failure hypothesis in AD and validate the use of peripheral cells as surrogate tissue to study the molecular basis of AD pathogenesis.

Alteration in cell cycle-related proteins in lymphoblasts from carriers of the c.709-1G>A PGRN mutation associated with FTLD-TDP dementia.

Frontotemporal lobar degeneration with neuronal inclusions containing TAR DNA binding protein 43 (TDP-43) is associated in most cases with null-mutations in the progranulin gene (PGRN). While the mechanisms by which PGRN haploinsufficiency leads to neurodegeneration remained speculative, increasing evidence support the hypothesis that cell cycle reentry of postmitotic neurons precedes many instances of neuronal death. Based in the mitogenic and neurotrophic activities of PGRN, we hypothesized that PGRN deficit may induce cell cycle disturbances and alterations in neuronal vulnerability. Because cell cycle dysfunction is not restricted to neurons, we studied the influence of PGRN haploinsufficiency, on cell cycle control in peripheral cells from patients suffering from frontotemporal dementia, bearing the PGRN mutation c.709-1G>A. Here we show that progranulin deficit increased cell cycle activity in immortalized lymphocytes. This effect was associated with increased levels of cyclin-dependent kinase 6 (CDK6) and phosphorylation of retinoblastoma protein (pRb), resulting in a G(1)/S regulatory failure. A loss of function of TDP-43 repressing CDK6 expression may result from altered subcellular TDP-43 distribution. The distinct functional features of lymphoblastoid cells from c.709-1 G>A carriers offer an invaluable, noninvasive tool to investigate the etiopathogenesis of frontotemporal lobar degeneration.

Magnetic ground state of CeNi1-xCux : A calorimetric investigation

We present a detailed specific heat study of the CeNi

Element-specific magnetometry on negatively magnetized NdMnO3+δ

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