IGF-1 stimulated upregulation of cyclin D1 is mediated via STAT5 signaling pathway in neuronal cells

Signal Transducer and Activator of Transcription (STATs) regulate various target genes such as cyclin D1, MYC, and BCL2 in nonneuronal cells which contribute towards progression as well as prevention of apoptosis and are involved in differentiation and cell survival. However, in neuronal cells, the role of STATs in the activation and regulation of these target genes and their signaling pathways are still not well established. In this study, a robust cyclin D1 expression was observed following IGF-1 stimulation in SY5Y cells as well as neurospheres. JAK/STAT pathway was shown to be involved in this upregulation. A detailed promoter analysis revealed that the specific STAT involved was STAT5, which acted as a positive regulatory element for cyclin D1 expression. Overexpression studies confirmed increase in cyclin D1 expression in response to STAT5a and STAT5b constructs when compared to dominant-negative STAT5. siRNA targeting STAT5, diminished the cyclin D1 expression, further confirming that STAT5 specifically regulated cyclin D1 in neuronal cells. Together, these findings shed new light on the mechanism of IGF-1 mediated upregulation of cyclin D1 expression in neural cell lines as well as in neural stem cells via the JAK/STAT5 signaling cascade.

Mammalian neuronal sodium channel Blocker mu-conotoxin BuIIIB has a structured N-terminus that influences potency

Among the mu-conotoxins that block vertebrate voltage-gated sodium channels (VGSCs), some have been shown to be potent analgesics following systemic administration in mice. We have determined the solution structure of a new representative of this family, mu-BuIIIB, and established its disulfide connectivities by direct mass spectrometric collision induced dissociation fragmentation of the peptide with disulfides intact The major oxidative folding product adopts a 1-4/2-5/3-6 pattern with the following disulfide bridges: Cys5-Cys17, Cys6-Cys23, and Cys13-Cys24. The solution structure reveals that the unique N-terminal extension in mu-BuIIIB, which is also present in mu-BuIIIA and mu-BuIIIC but absent in other mu-conotoxins, forms part of a short a-helix encompassing Glu3 to Asn8. This helix is packed against the rest of the toxin and stabilized by the Cys5-Cys17 and Cys6-Cys23 disulfide bonds. As such, the side chain of Val1 is located close to the aromatic rings of Trp16 and His20, which are located on the canonical helix that displays several residues found to be essential for VGSC blockade in related mu-conotoxins. Mutations of residues 2 and 3 in the N-terminal extension enhanced the potency of mu-BuIIIB for Na(v)1.3. One analogue, D-Ala2]BuIIIB, showed a 40-fold increase, making it the most potent peptide blocker of this channel characterized to date and thus a useful new tool with which to characterize this channel. On the basis of previous results for related mu-conotoxins, the dramatic effects of mutations at the N-terminus were unanticipated and suggest that further gains in potency might be achieved by additional modifications of this region.

The effect of cell size and channel density on neuronal information encoding and energy efficiency

Identifying the determinants of neuronal energy consumption and their relationship to information coding is critical to understanding neuronal function and evolution. Three of the main determinants are cell size, ion channel density, and stimulus statistics. Here we investigate their impact on neuronal energy consumption and information coding by comparing single-compartment spiking neuron models of different sizes with different densities of stochastic voltage-gated Na+ and K+ channels and different statistics of synaptic inputs. The largest compartments have the highest information rates but the lowest energy efficiency for a given voltage-gated ion channel density, and the highest signaling efficiency (bits spike(-1)) for a given firing rate. For a given cell size, our models revealed that the ion channel density that maximizes energy efficiency is lower than that maximizing information rate. Low rates of small synaptic inputs improve energy efficiency but the highest information rates occur with higher rates and larger inputs. These relationships produce a Law of Diminishing Returns that penalizes costly excess information coding capacity, promoting the reduction of cell size, channel density, and input stimuli to the minimum possible, suggesting that the trade-off between energy and information has influenced all aspects of neuronal anatomy and physiology.

Morphology and electrostatics play active role in neuronal differentiation processes on flexible conducting substrates

This commentary discusses and summarizes the key highlights of our recently reported work entitled ``Neuronal Differentiation of Embryonic Stem Cell Derived Neuronal Progenitors Can Be Regulated by Stretchable Conducting Polymers.'' The prospect of controlling the mechanical-rigidity and the surface conductance properties offers a unique combination for tailoring the growth and differentiation of neuronal cells. We emphasize the utility of transparent elastomeric substrates with coatings of electrically conducting polymer to realize the desired substrate-characteristics for cellular development processes. Our study showed that neuronal differentiation from ES cells is highly influenced by the specific substrates on which they are growing. Thus, our results provide a better strategy for regulated neuronal differentiation by using such functional conducting surfaces.

Photocytotoxic ternary copper(II) complexes of histamine Schiff base and pyridyl ligands

Ternary copper(Il) complexes of salicylaldehyde-histamine Schiff base (HL) and pyridyl ligands, viz. Cu(bpy)(L)](ClO4) (1) and Cu(dppz)(L)](C104) (2), where bpy is 2,2'-bipyridine (in 1) and dppz is dipyrido3,2-a:2',3'-c]phenazine (in 2), were synthesized, characterized and their DNA binding, photo-activated DNA cleavage activity and photocytotoxicity studied. The 1:1 electrolytic one-electron paramagnetic complexes showed a d-d band near 670 nm in aqueous DMF (1:1 v/v). The crystal structure of complex 1 showed the metal in CuN4O distorted square-pyramidal geometry. Complex 2 intercalatively binds to calf-thymus (ct) DNA with a binding constant (K-b) of similar to 10(5) M-1. It exhibited moderate chemical nuclease activity but excellent DNA photocleavage activity in red light of 647 nm forming (OH)-O-center dot radicals. It showed remarkable photocytotoxicity in human cervical cancer cells (HeLa) giving IC50 of 1.6 mu M in visible light (400-700 nm) with low dark toxicity. The photo-induced cell death is via generation of oxidative stress by reactive oxygen species.

Conformation-activity correlations for chemotactic tripeptide analogs incorporating dialkyl residues with linear and cyclic alkyl sidechains at position 2

Five stereochemically constrained analogs of the chemotactic tripeptide incorporating 1-aminocycloalkane-1-carboxylic acid (Ac(n)c) and alpha,alpha-dialkylglycines (Deg, diethylglycine; Dpg, n,n-dipropylglycine and Dbg, n,n-dibutylglycine) at position 2 have been synthesized. NMR studies of peptides For-Met-Xxx-Phe-OMe (Xxx = Ac(7)c, I; Ac(8)c, II; Deg, III; Dpg, IV and Dbg, V; For, formyl) establish that peptides with cycloalkyl residues, I and II, adopt folded beta-turn conformations in CDCl3 and (CD3)(2)SO. In contrast, analogs with linear alkyl sidechains, III-V, favour fully extended (C-5) conformations in solution. Peptides I-V exhibit high activity in inducing beta-glucosaminidase release from rabbit neutrophils, with ED(50) values ranging from 1.4-8.0 x 10(-11)M. In human neutrophils the Dxg peptides III-V have ED(50) values ranging from 2.3 x 10(-8) to 5.9 x 10(-10) M, with the activity order being V > IV > III. While peptides I-IV are less active than the parent. For-Met-Leu-Phe-OH, in stimulating histamine release from human basophils, the Dbg peptide V is appreciably more potent, suggesting its potential utility as a probe for formyl peptide receptors.

Resolution and sensitivity of the eyes of the Asian honeybees Apis florea, Apis cerana and Apis dorsata

Bees of the genus Apis are important foragers of nectar and pollen resources. Although the European honeybee, Apis mellifera, has been well studied with respect to its sensory abilities, learning behaviour and role as pollinators, much less is known about the other Apis species. We studied the anatomical spatial resolution and absolute sensitivity of the eyes of three sympatric species of Asian honeybees, Apis cerana, Apis florea and Apis dorsata and compared them with the eyes of A. mellifera. Of these four species, the giant honeybee A. dorsata (which forages during moonlit nights) has the lowest spatial resolution and the most sensitive eyes, followed by A. mellifera, A. cerana and the dwarf honeybee, A. florea (which has the smallest acceptance angles and the least sensitive eyes). Moreover, unlike the strictly diurnal A. cerana and A. florea, A. dorsata possess large ocelli, a feature that it shares with all dim-light bees. However, the eyes of the facultatively nocturnal A. dorsata are much less sensitive than those of known obligately nocturnal bees such as Megalopta genalis in Panama and Xylocopa tranquebarica in India. The differences in sensitivity between the eyes of A. dorsata and other strictly diurnal Apis species cannot alone explain why the former is able to fly, orient and forage at half-moon light levels. We assume that additional neuronal adaptations, as has been proposed for A. mellifera, M. genalis and X. tranquebarica, might exist in A. dorsata.

Comparative mparative Effects of Antiserum to Luteinizing Hormone on Pseudopregnancy and Pregnancy Induced in the Same Rat

The comparative role of luteinizing hormone (LH) in maintaining pregnancy and histamine-induced decidualization in the rat was studied with the help of a new system, wherein the above two states could be brought about simultaneously in the same animal, but in different uterine horns. Specific and well-characterized LH antiserum, administered daily, both during the pre-trauma (days 1-4) and post-trauma (days 5-8) periods, resulted in the termination of pregnancy and inhibition of decidualization. This antiserum effect could be reversed by suitable steroid therapy. Results suggest that the antiserum blockade of ovarian steroidogenesis continued even after cessation of its treatment. Early pregnancy and decidualization seem directly comparable in that both are dependent upon LH to stimulate the ovarian synthesis of much-needed progesterone and estrogen.

Evaluation of anti-inflammatory potential of Chloranthus erectus (Buch.-Ham.) Verd. leaf extract in rats

Aim of the study: Chloranthus erectus (Buch.-Ham.) Verdcourt (Chloranthaceae) is a shrub native to tropical and temperate zone of Eastern Himalaya of India and South-East Asia and have traditionally been used as a folklore medicine to treat localised swelling, joint pain, skin inflammation, fever and bodyache. In this study, an attempthas been made to demonstrate the anti-inflammatory activity of methanol extract obtained from Chloranthus erectus leaves (MECEL) in acute, sub-acute and chronic mouse models. Materials and methods: Inflammation in the hind paw of Wistar albino rat was induced by carrageenan, histamine and serotonin, and tissue granuloma pouch was induced by cotton pellet method. Antiinflammatory drug-phenylbutazone was used as standard drug for comparison. Results: In acute carrageenan-induced rat hind paw edema, oral administration of MECEL at 200 mg/kg produced significant inhibition of edema by 38.34 % (p<0.01) while the histamine- and serotonin-induced sub-acute model, the inhibition of paw edema reached 52.54 % (p < 0.001) and 25.5 % (p < 0.01), respectively. in a 7-day study, MECEL at 20 and 50 mg/kg produced significant suppression of cotton pellet-induced tissue granuloma formation in rats. Conclusions: This preliminary study revealed that the methanol extract of Chloranthus erectus exhibited significant anti-inflammatory activity in the tested models, and may provide the scientific rationale for its popular folk medicine as anti-inflammatory agent.

Distress call-induced gene expression in the brain of the Indian short-nosed fruit bat, Cynopterus sphinx

Individuals in distress emit audible vocalizations to either warn or inform conspecifics. The Indian short-nosed fruit bat, Cynopterus sphinx, emits distress calls soon after becoming entangled in mist nets, which appear to attract conspecifics. Phase I of these distress calls is longer and louder, and includes a secondary peak, compared to phase II. Activity-dependent expression of egr-1 was examined in free-ranging C. sphinx following the emissions and responses to a distress call. We found that the level of expression of egr-1 was higher in bats that emitted a distress call, in adults that responded, and in pups than in silent bats. Up-regulated cDNA was amplified to identify the target gene (TOE1) of the protein Egr-1. The observed expression pattern Toe1 was similar to that of egr-1. These findings suggest that the neuronal activity related to recognition of a distress call and an auditory feedback mechanism induces the expression of Egr-1. Co-expression of egr-1 with Toe1 may play a role in initial triggering of the genetic mechanism that could be involved in the consolidation or stabilization of distress call memories.

New evidences on Tau-DNA interactions and relevance to neurodegeneration

Tau is mainly distributed in cytoplasm and also found to be localized in the nucleus. There is limited data on DNA binding potential of Tau.We provide novel evidence on nicking of DNA by Tau. Tau nicks the supercoiled DNA leading to open circular and linear forms. The metal ion magnesium (a co-factor for endonuclease) enhanced the Tau DNA nicking ability, while an endonuclease specific inhibitor,aurinetricarboxylic acid (ATA) inhibited the Tau DNA nicking ability Further, we also evidenced that Tau induces B-C-A mixed conformational transition in DNA and also changes DNA stability. Tau-scDNA complex is more sensitive to DNAse I digestion indicating stability changes in DNA caused by Tau. These findings indicate that Tau alters DNA helicity and integrity and also nicks the DNA. The relevance of these novel intriguing findings regarding the role Tau in neuronal dysfunction is discussed. (C) 2010 Elsevier Ltd. All rights reserved.

Total synthesis of (+/-)-merrilactone A

As a consequence of the advancing age profile of the global population, particularly in developed nations,nerrodegener-ative disorders such as Alzheimers and Parkinsons diseases have emerged as a major public health concern. In this regard, neurotrophic agents, which have been implicated in the maintenance and growth of neurons as well as prevention of neuronal death, are being considered as potential leads for therapeutic development.

Data compression by linear prediction for storage and transmission of EEG signals

The EEG time series has been subjected to various formalisms of analysis to extract meaningful information regarding the underlying neural events. In this paper the linear prediction (LP) method has been used for analysis and presentation of spectral array data for the better visualisation of background EEG activity. It has also been used for signal generation, efficient data storage and transmission of EEG. The LP method is compared with the standard Fourier method of compressed spectral array (CSA) of the multichannel EEG data. The autocorrelation autoregressive (AR) technique is used for obtaining the LP coefficients with a model order of 15. While the Fourier method reduces the data only by half, the LP method just requires the storage of signal variance and LP coefficients. The signal generated using white Gaussian noise as the input to the LP filter has a high correlation coefficient of 0.97 with that of original signal, thus making LP as a useful tool for storage and transmission of EEG. The biological significance of Fourier method and the LP method in respect to the microstructure of neuronal events in the generation of EEG is discussed.