639 research outputs found
Visual stimulation activates ERK in synaptic and somatic compartments of rat cortical neurons with parallel kinetics.
BACKGROUND: Extracellular signal-regulated kinase (ERK) signalling pathway plays a crucial role in regulating diverse neuronal processes, such as cell proliferation and differentiation, and long-term synaptic plasticity. However, a detailed understanding of the action of ERK in neurons is made difficult by the lack of knowledge about its subcellular localization in response to physiological stimuli. To address this issue, we have studied the effect of visual stimulation in vivo of dark-reared rats on the spatial-temporal dynamics of ERK activation in pyramidal neurons of the visual cortex. METHODOLOGY/PRINCIPAL FINDINGS: Using immunogold electron microscopy, we show that phosphorylated ERK (pERK) is present in dendritic spines, both at synaptic and non-synaptic plasma membrane domains. Moreover, pERK is also detected in presynaptic axonal boutons forming connections with dendritic spines. Visual stimulation after dark rearing during the critical period causes a rapid increase in the number of pERK-labelled synapses in cortical layers I-II/III. This visually-induced activation of ERK at synaptic sites occurs in pre- and post-synaptic compartments and its temporal profile is identical to that of ERK activation in neuronal cell bodies. CONCLUSIONS/SIGNIFICANCE: Visual stimulation in vivo increases pERK expression at pre- and post-synaptic sites of axo-spinous junctions, suggesting that ERK plays an important role in the local modulation of synaptic function. The data presented here support a model in which pERK can have early and late actions both centrally in the cell nucleus and peripherally at synaptic contacts
A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation
Lymphocyte apoptosis is mainly induced by either death receptor-dependent activation of caspase-8 or mitochondria-dependent activation of caspase-9. Mutations in caspase-8 lead to autoimmunity/lymphoproliferation and immunodeficiency. This work describes a heterozygous H237P mutation in caspase-9 that can lead to similar disorders. H237P mutation was detected in two patients: Pt1 with autoimmunity/lymphoproliferation, severe hypogammaglobulinemia and Pt2 with mild hypogammaglobulinemia and Burkitt lymphoma. Their lymphocytes displayed defective caspase-9 activity and decreased apoptotic and activation responses. Transfection experiments showed that mutant caspase-9 display defective enzyme and proapoptotic activities and a dominant-negative effect on wild-type caspase-9. Ex vivo analysis of the patients' lymphocytes and in vitro transfection experiments showed that the expression of mutant caspase-9 correlated with a downregulation of BAFFR (B-cell-activating factor belonging to the TNF family (BAFF) receptor) in B cells and ICOS (inducible T-cell costimulator) in T cells. Both patients carried a second inherited heterozygous mutation missing in the relatives carrying H237P: Pt1 in the transmembrane activator and CAML interactor (TACI) gene (S144X) and Pt2 in the perforin (PRF1) gene (N252S). Both mutations have been previously associated with immunodeficiencies in homozygosis or compound heterozygosis. Taken together, these data suggest that caspase-9 mutations may predispose to immunodeficiency by cooperating with other genetic factors, possibly by downregulating the expression of BAFFR and ICO
Insertion of the DNA for the 163-171 peptide of IL1beta enables a DNA vaccine encoding p185(neu) to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice.
Insertion of the DNA for the 163–171 peptide of IL1β enables a DNA vaccine encoding p185 neu to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mic
Ultra-flat wideband single-pump Raman-enhanced parametric amplification
We experimentally optimize a single pump fiber optical parametric amplifier in terms of gain spectral bandwidth and gain variation (GV). We find that optimal performance is achieved with the pump tuned to the zero-dispersion wavelength of dispersion stable highly nonlinear fiber (HNLF). We demonstrate further improvement of parametric gain bandwidth and GV by decreasing the HNLF length. We discover that Raman and parametric gain spectra produced by the same pump may be merged together to enhance overall gain bandwidth, while keeping GV low. Consequently, we report an ultra-flat gain of 9.6±0.5 dB over a range of 111 nm (12.8 THz) on one side of the pump. Additionally, we demonstrate amplification of a 60 Gbit/s QPSK signal tuned over a portion of the available bandwidth with OSNR penalty less than 1 dB for Q2 below 14 dB
Efficient wavelength conversion and net parametric gain via four wave mixing in a high index doped silica waveguide
We demonstrate sub-picosecond wavelength conversion in the C-band via four wave mixing in a 45cm long high index doped silica spiral waveguide. We achieve an on/off conversion efficiency (signal to idler) of + 16.5dB as well as a parametric gain of + 15dB for a peak pump power of 38W over a wavelength range of 100nm. Furthermore, we demonstrated a minimum gain of + 5dB over a wavelength range as large as 200nm
Sr-containing mesoporous bioactive glasses bio-functionalized with recombinant ICOS-Fc: An in vitro study
Osteoporotic bone fractures represent a critical clinical issue and require personalized and specific treatments in order to stimulate compromised bone tissue regeneration. In this clinical context, the development of smart nano-biomaterials able to synergistically combine chemical and biological cues to exert specific therapeutic effects (i.e., pro-osteogenic, anti-clastogenic) can allow the design of effective medical solutions. With this aim, in this work, strontium-containing mesoporous bioactive glasses (MBGs) were bio-functionalized with ICOS-Fc, a molecule able to reversibly inhibit osteoclast activity by binding the respective ligand (ICOS-L) and to induce a decrease of bone resorption activity. N2 adsorption analysis and FT-IR spectroscopy were used to assess the successful grafting of ICOS-Fc on the surface of Sr-containing MBGs, which were also proved to retain the peculiar ability to release osteogenic strontium ions and an excellent bioactivity after functionalization. An ELISA-like assay allowed to confirm that grafted ICOS-Fc molecules were able to bind ICOS-L (the ICOS binding ligand) and to investigate the stability of the amide binding to hydrolysis in aqueous environment up to 21 days. In analogy to the free form of the molecule, the inhibitory effect of grafted ICOS-Fc on cell migratory activity was demonstrated by using ICOSL positive cell lines and the ability to inhibit osteoclast differentiation and function was confirmed by monitoring the differentiation of monocyte-derived osteoclasts (MDOCs), which revealed a strong inhibitory effect, also proven by the downregulation of osteoclast differentiation genes. The obtained results showed that the combination of ICOS-Fc with the intrinsic properties of Sr-containing MBGs represents a very promising approach to design personalized solutions for patients affected by compromised bone remodeling (i.e., osteoporosis fractures)
Mid-infrared optical parametric amplifier using silicon nanophotonic waveguides
All-optical signal processing is envisioned as an approach to dramatically
decrease power consumption and speed up performance of next-generation optical
telecommunications networks. Nonlinear optical effects, such as four-wave
mixing (FWM) and parametric gain, have long been explored to realize
all-optical functions in glass fibers. An alternative approach is to employ
nanoscale engineering of silicon waveguides to enhance the optical
nonlinearities by up to five orders of magnitude, enabling integrated
chip-scale all-optical signal processing. Previously, strong two-photon
absorption (TPA) of the telecom-band pump has been a fundamental and
unavoidable obstacle, limiting parametric gain to values on the order of a few
dB. Here we demonstrate a silicon nanophotonic optical parametric amplifier
exhibiting gain as large as 25.4 dB, by operating the pump in the mid-IR near
one-half the band-gap energy (E~0.55eV, lambda~2200nm), at which parasitic
TPA-related absorption vanishes. This gain is high enough to compensate all
insertion losses, resulting in 13 dB net off-chip amplification. Furthermore,
dispersion engineering dramatically increases the gain bandwidth to more than
220 nm, all realized using an ultra-compact 4 mm silicon chip. Beyond its
significant relevance to all-optical signal processing, the broadband
parametric gain also facilitates the simultaneous generation of multiple
on-chip mid-IR sources through cascaded FWM, covering a 500 nm spectral range.
Together, these results provide a foundation for the construction of
silicon-based room-temperature mid-IR light sources including tunable
chip-scale parametric oscillators, optical frequency combs, and supercontinuum
generators
Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model.
Rett syndrome (RTT) is a neurodevelopmental disorder with no efficient treatment that is caused in the majority of cases by mutations in the gene methyl-CpG binding-protein 2 (MECP2). RTT becomes manifest after a period of apparently normal development and causes growth deceleration, severe psychomotor impairment and mental retardation. Effective animal models for RTT are available and show morphofunctional abnormalities of synaptic connectivity. However, the molecular consequences of MeCP2 disruption leading to neuronal and synaptic alterations are not known. Protein synthesis regulation via the mammalian target of the rapamycin (mTOR) pathway is crucial for synaptic organization, and its disruption is involved in a number of neurodevelopmental diseases. We investigated the phosphorylation of the ribosomal protein (rp) S6, whose activation is highly dependent from mTOR activity. Immunohistochemistry showed that rpS6 phosphorylation is severely affected in neurons across the cortical areas of Mecp2 mutants and that this alteration precedes the severe symptomatic phase of the disease. Moreover, we found a severe defect of the initiation of protein synthesis in the brain of presymptomatic Mecp2 mutant that was not restricted to a specific subset of transcripts. Finally, we provide evidence for a general dysfunction of the Akt/mTOR, but not extracellular-regulated kinase, signaling associated with the disease progression in mutant brains. Our results indicate that defects in the AKT/mTOR pathway are responsible for the altered translational control in Mecp2 mutant neurons and disclosed a novel putative biomarker of the pathological process. Importantly, this study provides a novel context of therapeutic interventions that can be designed to successfully restrain or ameliorate the development of RTT
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