Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.

IntroductionAcid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS).MethodsExperiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay.ResultsAcidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS.ConclusionsDecreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage

High-resolution NMR structure of the antimicrobial peptide protegrin-2 in the presence of DPC micelles

© 2014 Springer Science+Business Media Dordrecht. PG-1 adopts a dimeric structure in dodecylphosphocholine (DPC) micelles, and a channel is formed by the association of several dimers but the molecular mechanisms of the membrane damage by non-α-helical peptides are still unknown. The formation of the PG-1 dimer is important for pore formation in the lipid bilayer, since the dimer can be regarded as the primary unit for assembly into the ordered aggregates. It was supposed that only 12 residues (RGGRL-CYCRR-RFCVC-V) are needed to endow protegrin molecules with strong antibacterial activity and that at least four additional residues are needed to add potent antifungal properties. Thus, the 16-residue protegrin (PG-2) represents the minimal structure needed for broad-spectrum antimicrobial activity encompassing bacteria and fungi. As the peptide conformation and peptide-to-membrane binding properties are very sensitive to single amino acid substitutions, the solution structure of PG-2 in solution and in a membrane mimicking environment are crucial. In order to find evidence if the oligomerization state of PG-1 in a lipid environment will be the same or not for another protegrins, we investigate in the present work the PG-2 NMR solution structure in the presence of perdeuterated DPC micelles. The NMR study reported in the present work indicates that PG-2 form a well-defined structure (PDB: 2MUH) composed of a two-stranded antiparallel β-sheet when it binds to DPC micelles

Particle flows in a dc discharge in laboratory and microgravity conditions

We describe a series of experiments on dust particles flows in a positive column of a horizontal dc discharge operating in laboratory and microgravity conditions. The main observation is that the particle flow velocities in laboratory experiments are systematically higher than in microgravity experiments, for otherwise identical discharge conditions. The paper provides an explanation for this interesting and unexpected observation. The explanation is based on a physical model, which properly takes into account main plasma-particle interaction mechanisms relevant to the described experimental study. Comparison of experimentally measured particle velocities and those calculated using the proposed model demonstrates reasonable agreement, both in laboratory and microgravity conditions, in the entire range of discharge parameters investigated.Comment: 9 pages, 7 figure

Spatial structure of heptapeptide Aβ16-22 (beta-amyloid Aβ1-40 active fragment) in solution and in complex with a biological membrane model

The spatial structure of an active fragment of beta-amyloid Aβ1-40 heptapeptide Aβ16-22 (Lys-Leu-Val-Phe- Phe-Ala-Glu) in aqueous buffer solution and in complex with sodium dodecyl sulfate micelles as a model membrane system was investigated by 1H NMR spectroscopy and two-dimensional NMR (TOCSY, HSQC-HECADE (Heteronuclear Couplings from ASSCI-domain experiments with E.COSY-type crosspeaks), NOESY) spectroscopy. Complex formation was confirmed by the chemical shift changes of the heptapeptide's 1H NMR spectra, as well as by the signs and values of the NOE effects in different environments. We compared the spatial structure of the heptapeptide in borate buffer solution and in complex with a model of the cell surface membrane. Copyright © 2012 John Wiley & Sons, Ltd

Mechanism of Neuroprotective Mitochondrial Remodeling by PKA/AKAP1

The mitochondrial signaling complex PKA/AKAP1 protects neurons against mitochondrial fragmentation and cell death by phosphorylating and inactivating the mitochondrial fission enzyme Drp1

A pulsed source of continuous variable polarization entanglement

We have experimentally demonstrated polarization entanglement using continuous variables in an ultra-short pulsed laser system at telecommunication wavelengths. Exploiting the Kerr-nonlinearity of a glass fibre we generated a polarization squeezed pulse with S2 the only non-zero Stokes parameter thus S1 and S3 being the conjugate pair. Polarization entanglement was generated by interference of the polarization squeezed field with a vacuum on a 50:50 beam splitter. The two resultant beams exhibit strong quantum noise correlations in S1 and S3. The sum noise signal of S3 was at the respective shot noise level and the difference noise signal of S1 fell 2.9dB below this value

Psychopathological manifestations of multiple meningiomas in the right hemisphere

The paper gives the data available in the literature on meningiomas and their psychopathological manifestations that occupy a central position in the clinical picture in almost every 5 patients with these tumors. The authors provide a clinical and psychopathological analysis of a female patient with multiple meningiomas in the right hemisphere: a giant meningioma in the posterior third of the falx, a large meningioma in the temporal region, and three small meningiomas in the frontal and parietal regions. The disease started as headache; however, psychopathological symptoms remained missed by physicians, such as emotional lability; personality changes leading to family dissension; lower criticism; spatial orientation problems; hypomnesia; left-sided visual inattention,occurred in parallel. Surgical treatment was performed by stages: the two largest meningiomas were removed at an 11-day interval, which presented a means of observing psychopathological changes after each operation. It is concluded that greater attention should be given to the psychopathological manifestations of the disease, which is important to make a primary diagnosis and to define further treatment policy

Application of the Fibrous Autograft in Posttraumatic Bone Regeneration of the Lower Jaw

The search for new types of bone substitutes is one of the topical problems of biology and medicine. The paper considered the role of fibrous autograft in reparative bone regeneration in the rat’s lower jaw model. Thirty Wistar rats were taken in the experiment: 15 in the experimental and 15 in the control group. Fibrous autograft was formed on the cellophane basis under the skin on the back of rats. Injury in the lower jaw with a diameter of 2 mm was formed and a fibrous graft was placed in injuries in the experimental group. Five animals from each groups were sacrificed at the first, third and fifth weeks of the experiment. The object of the further research was the samples of the lower jaws stained according to Van Gieson. Histological examination of the bone defect of the experimental group after 1 week showed absence of bone fragments and formation of fibrous callosity in the trauma zone. Further study of regenerate at the 3rd and the 5th weeks showed accelerated bone wound healing in the experimental group (compared to the control group). Thus, the autograft stimulates the process of bone tissue restoration in the area of the defect of the lower jaw model