Effect of Co substitution on the structural,dielectric and optical properties of KBiFe2O5

Cobalt (Co)-modified brownmillerite KBiFe2O5 (KBFO; [KBiFe2(1?x)Co2xO5 (x = 0, 0.05)]) polycrystalline is synthesized following the solid-state reaction route. Rietveld refinement of X-ray diffraction data confirmed the phase purity of KBFO and KBiFe1.9Co0.1O5 (KBFCO). The optical bandgap energy (Eg) of KBFO decreased from 1.59 to 1.51 eV because of Co substitution. The decrease in bandgap can be attributed to the tilting of the Fe–O tetrahedral structure of KBFCO. The observed room-temperature Raman peaks of KBFCO shifted by 3 cm?1 toward a lower wavenumber than that of KBFO. The shift in Raman active modes can be attributed to the change in the bond angles and bond lengths of the Fe–O tetrahedral structure and modification in response to oxygen deficiency in KBFO because of Co doping. Compared with that of KBFO, the frequency-dependent dielectric constant and dielectric loss of KBFCO decrease at room temperature, which is a con-sequence of the reduction in oxygen migration and modification in response to vibrational modes present in the sample.     

Dielectric relaxation and conduction mechanism in Aurivillius ceramic Bi5Ti3FeO15

For this study, we synthesized Aurivillius Bi5Ti3FeO15 ceramic using the generic solid-state reaction route and then performed room-temperature X-ray diffraction to confirm that the compound had a single phase with no impurities. The surface morphology of the prepared sample was observed to contain microstructural grains approximately 0.2–2 μm in size. The dielectric properties of the sample were determ-ined as a function of frequency in a range of approximately 100 Hz to 1 MHz at various temperatures (303 K ≤ T ≤ 773 K). Nyquist plots of the impedance data were found to exhibit a semi-circular arc in the high-temperature region, which is explained by the equivalent electrical circuit (R1C1)(R2QC2), where R1 and R2 represent the resistances associated with the grains and grain boundaries, respectively, C1 and C2 are the re-spective capacitances, and Q is the constant phase element (CPE), which accounts for non-Debye type of behavior. Our results indicate that both the resistance and capacitance of the grain boundaries are more prominent than those of the grains. The alternating current (ac) conductiv-ity data were analyzed based on the Jonscher universal power law, which indicated that the conduction process is dominated by the hopping mechanism. The calculated activation energies of the relaxation and conduction processes were very similar (0.32 to 0.53 eV), from which we conclude that the same type of charge carriers are involved in both processes.     

Molecular function of the novel α7β2 nicotinic receptor

The α7 nicotinic receptor is a promising drug target for neurological and inflammatory disorders. Although it is the homomeric member of the family, a novel α7β2 heteromeric receptor has been discovered. To decipher the functional contribution of the β2 subunit, we generated heteromeric receptors with fixed stoichiometry by two different approaches comprising concatenated and unlinked subunits. Receptors containing up to three β2 subunits are functional. As the number of β2 subunits increases in the pentameric arrangement, the durations of channel openings and activation episodes increase progressively probably due to decreased desensitization. The prolonged activation episodes conform the kinetic signature of α7β2 and may have an impact on neuronal excitability. For activation of α7β2 receptors, an α7/α7 binding-site interface is required, thus indicating that the three β2 subunits are located consecutively in the pentameric arrangement. α7-positive allosteric modulators (PAMs) are emerging as novel therapeutic drugs. The presence of β2 in the pentamer affects neither type II PAM potentiation nor activation by an allosteric agonist whereas it impairs type I PAM potentiation. This first single-channel study provides fundamental basis required to decipher the role and function of the novel α7β2 receptor and opens doors to develop selective therapeutic drugs.     

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Introduction

Islets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets.

Materials and methods

GPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay.

Results

We have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion.

Discussion

The detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.

     

Mechanisms regulating immune surveillance of cellular stress in cancer

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57–70, 67; Cell 144:646–674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823–837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.     

Prion protein cleavage fragments regulate adult neural stem cell quiescence through redox modulation of mitochondrial fission and SOD2 expression

Neurogenesis continues in the post-developmental brain throughout life. The ability to stimulate the production of new neurones requires both quiescent and actively proliferating pools of neural stem cells (NSCs). Actively proliferating NSCs ensure that neurogenic demand can be met, whilst the quiescent pool makes certain NSC reserves do not become depleted. The processes preserving the NSC quiescent pool are only just beginning to be defined. Herein, we identify a switch between NSC proliferation and quiescence through changing intracellular redox signalling. We show that N-terminal post-translational cleavage products of the prion protein (PrP) induce a quiescent state, halting NSC cellular growth, migration, and neurite outgrowth. Quiescence is initiated by the PrP cleavage products through reducing intracellular levels of reactive oxygen species. First, inhibition of redox signalling results in increased mitochondrial fission, which rapidly signals quiescence. Thereafter, quiescence is maintained through downstream increases in the expression and activity of superoxide dismutase-2 that reduces mitochondrial superoxide. We further observe that PrP is predominantly cleaved in quiescent NSCs indicating a homeostatic role for this cascade. Our findings provide new insight into the regulation of NSC quiescence, which potentially could influence brain health throughout adult life.     

Inhibition of protein misfolding and aggregation by natural phenolic compounds

Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer’s and Parkinson’s diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.