Hysteresis in voltage-gated channels

Ion channels constitute a superfamily of membrane proteins found in all living creatures. Their activity allows fast translocation of ions across the plasma membrane down the ion's transmembrane electrochemical gradient, resulting in a difference in electrical potential across the plasma membrane, known as the membrane potential. A group within this superfamily, namely voltage-gated channels, displays activity that is sensitive to the membrane potential. The activity of voltage-gated channels is controlled by the membrane potential, while the membrane potential is changed by these channels' activity. This interplay produces variations in the membrane potential that have evolved into electrical signals in many organisms. These signals are essential for numerous biological processes, including neuronal activity, insulin release, muscle contraction, fertilization and many others. In recent years, the activity of the voltage-gated channels has been observed not to follow a simple relationship with the membrane potential. Instead, it has been shown that the activity of voltage-gated channel displays hysteresis. In fact, a growing number of evidence have demonstrated that the voltage dependence of channel activity is dynamically modulated by activity itself. In spite of the great impact that this property can have on electrical signaling, hysteresis in voltage-gated channels is often overlooked. Addressing this issue, this review provides examples of voltage-gated ion channels displaying hysteretic behavior. Further, this review will discuss how Dynamic Voltage Dependence in voltage-gated channels can have a physiological role in electrical signaling. Furthermore, this review will elaborate on the current thoughts on the mechanism underlying hysteresis in voltage-gated channels.     

Design, synthesis, biological evaluation and QSAR studies of novel bisepipodophyllotoxins as cytotoxic agents

Two moieties of epipodophyllotoxin have been linked at C4-position to provide novel bisepipodophyllotoxin analogues. These have been evaluated for their anticancer potential and DNA-topoisomerase II poisoning activity. Most of these analogues have exhibited promising in vitro anticancer activity against different human tumour cell lines and interestingly 4(')-O-methylated analogues have shown increased cytotoxic activity. Similarly, the DNA-topo II poisoning activity tested for these compounds has not only exhibited the DNA cleavage potential comparable to etoposide, but for some compounds this cleavage potential is superior to etoposide. Further, an interesting structure-activity relationship of these epipodophyllotoxin dimers have been generated on the basis of GI(50) values. The equations indicated that GI(50) activity is strongly dependent on structural and thermodynamic properties. These QSAR results are discussed in conjunction with conformational analysis from molecular modelling studies. QSAR models developed in these studies will be helpful in the future to design novel potent bispodophyllotoxin analogues by minor structural modifications.     

Optical indications of electrical activity and excitation-contraction coupling in the early embryonic heart

Complete understanding of the ontogenesis and early development of electrical activity and its related contraction has been hampered by our inability to apply conventional electrophysiological techniques to the early embryonic heart. Direct intracellular measurement of electrical events in the early embryonic heart is impossible because the cells are too small and frail to be impaled with microelectrodes. Optical signals from voltage-sensitive dyes have provided a new and powerful tool for monitoring changes in membrane potential in a wide variety of living preparations. With this technique it is possible to make optical recordings from cells which are inaccessible to microelectrodes. An additional advantage of the optical method for recording membrane potential activity is that electrical activity can be monitored simultaneously from many sites in a preparation. Thus, applying a multiple-site optical recording method with a 100- or 144-element photodiode array and voltage-sensitive dyes, we have been able to monitor for the first time spontaneous electrical activity in pre-fused cardiac primordia in early chick embryos at the 6- and early 7-somite stages of development; we have been able to determine that the time of initiation of the heartbeat is the middle period of the 9-somite stage. In the rat embryonic heart, the onset of spontaneous electrical activity and contraction occurs at the 3-somite stage. This article describes ionic properties of the spontaneous action potential and genesis of excitation-contraction coupling in the early embryonic chick and rat hearts. In addition, an improved view of the ontogenetic sequence of spontaneous electrical activity and its implications for excitation-contraction coupling in the early embryonic heart are proposed and discussed.     

Regulation of afferent transmission in the feeding circuitry of Aplysia

Although feeding in Aplysia is mediated by a central pattern generator (CPG), the activity of this CPG is modified by afferent input. To determine how afferent activity produces the widespread changes in motor programs that are necessary if behavior is to be modified, we have studied two classes of feeding sensory neurons. We have shown that afferent-induced changes in activity are widespread because sensory neurons make a number of synaptic connections. For example, sensory neurons make monosynaptic excitatory connections with feeding motor neurons. Sensori-motor transmission is, however, regulated so that changes in the periphery do not disrupt ongoing activity. This results from the fact that sensory neurons are also electrically coupled to feeding interneurons. During motor programs sensory neurons are, therefore, rhythmically depolarized via central input. These changes in membrane potential profoundly affect sensori-motor transmission. For example, changes in membrane potential alter spike propagation in sensory neurons so that spikes are only actively transmitted to particular output regions when it is behaviorally appropriate. To summarize, afferent activity alters motor output because sensory neurons make direct contact with motor neurons. Sensori-motor transmission is, however, centrally regulated so that changes in the periphery alter motor programs in a phase-dependent manner.     

Antimutagenicity profiles for some model compounds

The concept of activity profile listings and plots, already applied successfully to the display of mutagenicity data, has been modified for application to antimutagenicity data. The activity profiles are bar graphs that have been organized in two general ways: for antimutagens that have been tested in combination with a given mutagen and for mutagens that have been tested in combination with a given antimutagen. Doses from both the mutagen and the antimutagen are displayed and plotted together with results on enhancement or inhibition of mutagenic activity. The short-term tests that have been used extensively to identify mutagens and potential carcinogens are increasingly being used to identify antimutagens and potential anticarcinogens. Three model mutagens, N-methyl-N'-nitro-N-nitrosoguanidine, aflatoxin B1 and benzo[a]pyrene, and 4 model antimutagens, butylated hydroxyanisole, butylated hydroxytoluene, glutathione and disulfiram, were selected from the data surveyed in the published literature. It is not clear at the present time whether the inhibition of carcinogen-induced mutation is a good indicator of anticarcinogenic properties, and further research is needed. Nevertheless, the activity profiles are useful for the assessment of the available antimutagenesis data by providing rapid visualization of considerable dose information and experimental results.     

Novel small molecule activators of the Trk family of receptor tyrosine kinases

The Tropomyosin-related kinase (Trk) receptors are a subset of the receptor tyrosine kinase family with an important functionality in the regulation of neurotrophic signaling in the peripheral and central nervous system. As the receptors are able to mediate neuronal survival by associating with their respective neurotrophin ligands, many studies have focused on the therapeutic potential of generating small-molecule mimetic compounds that elicit agonistic effects similar to those of the natural protein ligands. To this end, various structure-based studies have led to the generation of bivalent peptide-based agonists and antibodies that selectively initiate Trk receptor signaling; however, these compounds do not possess the ideal characteristics of a potential drug. Additionally, the reliance of structure-based data to generate the compound libraries, limits the potential identification of novel chemical structures with desirable activity. Therefore, subsequent investigations utilized a cell-based apoptotic screen to facilitate the analysis of large, diverse chemical libraries of small molecules and quickly identify compounds with Trk-dependent anti-apoptotic activity. Herein, we describe the Trk agonists that have been identified by this screening methodology and summarize their in vitro and in vivo neurotrophic activity as well as their efficacy in various neurological disease models, implicating their future utility as therapeutic compounds. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.     

Technical methods to improve yield,activity and stability in the development of microbial lipases

Lipases are ubiquitous biocatalysts that catalyze various reactions in organic solvents or in solvent-free systems and are increasingly applied in various industrial fields. In view of the excellent catalytic activities and the huge application potential, more than 20 microbial lipases have been realized in large-scale commercial production. The potential for commercial exploitation of a microbial lipase is determined by its yield, activity, stability and other characteristics. This review will survey the various technical methods that have been developed to enhance yield, activity and stability of microbial lipases from four aspects, including improvements in lipase-producing strains, modification of lipase genes, fermentation engineering of lipases and downstream processing technology of lipase products.     

Integration of Multiple Signaling Regulates through Apoptosis the Differential Osteogenic Potential of Neural Crest-Derived and Mesoderm-Derived Osteoblasts

Neural crest-derived (FOb) and mesoderm-derived (POb) calvarial osteoblasts are characterized by distinct differences in their osteogenic potential. We have previously demonstrated that enhanced activation of endogenous FGF and Wnt signaling confers greater osteogenic potential to FOb. Apoptosis, a key player in bone formation, is the main focus of this study. In the current work, we have investigated the apoptotic activity of FOb and POb cells during differentiation. We found that lower apoptosis, as measured by caspase-3 activity is a major feature of neural crest-derived osteoblast which also have higher osteogenic capacity. Further investigation indicated TGF-β signaling as main positive regulator of apoptosis in these two populations of calvarial osteoblasts, while BMP and canonical Wnt signaling negatively regulate the process. By either inducing or inhibiting these signaling pathways we could modulate apoptotic events and improve the osteogenic potential of POb. Taken together, our findings demonstrate that integration of multiple signaling pathways contribute to imparting greater osteogenic potential to FOb by decreasing apoptosis.     

植物抗毒素研究进展及其作为食品功能性成分的应用前景

植物抗毒素是植物受到外界刺激或感染病菌后合成并积累的具有抗逆活性的小分子化合物.过去对它的研究集中在其生成机理以及作为植物免疫体系组成成分、起到抗病作用等方面.新近的研究表明,植物抗毒素对人体同样具有多重生物学功效,如抗氧化、抗炎、抗癌等.由此,植物抗毒素作为植物次生代谢产物的重要组成部分,在功能食品和膳食补充剂领域有着广阔的应用前景.本文综述了近年来关于植物抗毒素的种类、活性及在植物体内诱生和积累等方面的研究,为食品功能因子的选择性拓展提供依据和指导.     

The evolution of ATPase activity in SMC proteins

The SMC (structural maintenance of chromosomes) proteins are a highly conserved and ubiquitous family of ATPases, found in nearly all living organisms examined, where they play crucial roles in transmission of the hereditary material. However, the extent to which efficient ATP hydrolysis is required for SMC function has been a matter of some debate. Here we investigate the potential functional significance of ATP binding and hydrolysis in different eukaryotic SMC proteins, both by comparing the conservation of conserved ATPase motifs and by exploring potential coevolution between associated domains. In this way, we have been able to account for the reduced requirement for ATPase activity in cohesin's SMC3 and demonstrate the greater apparent conservation requirements for such activity in condensin SMC proteins. Finally, we explore possible interactions between the SMC and non-SMC components of the condensin complex that are required for full condensin activity and may modulate ATPase activity in the holocomplex.     

Electrophysiology of the isolated central nervous system of the northern octopus Eledone cirrhosa

A successful preparation has been devised for maintaining the octopus brain in a viable condition to allow microelectrode studies of individual nerve cells. Impalements of cells within the sub‐oesophageal mass reveal that three populations of neurones are present These have different resting potentials, ranging from approximately 60 mV down to under 30 mV. Spontaneous activity is recorded from many neurones but some are silent and others exhibit only synaptic noise. Electrical stimulation of silent cells may lead to no response (large resting potential cells) or provoke trains of impulses (30–45 mV cells). Typical action potentials have durations of 20 msec. IPSP and EPSP activity may be observed. Burster cells or oscillators are located in one specific region, and a variety of activity may be recorded. These periodic bursts may be modified by hyperpolarisation so that spiking ceases but the underlying oscillatory potential remains. Some units exhibit two spike sizes, often uncorrelated in discharge.     

Spontaneous brain activity observed with functional magnetic resonance imaging as a potential biomarker in neuropsychiatric disorders

As functional magnetic resonance imaging (fMRI) studies have yielded increasing amounts of information about the brain’s spontaneous activity, they have revealed fMRI’s potential to locate changes in brain hemodynamics that are associated with neuropsychiatric disorders. In this paper, we review studies that support the notion that changes in brain spontaneous activity observed by fMRI can be used as potential biomarkers for diagnosis and treatment evaluation in neuropsychiatric disorders. We first review the methods used to study spontaneous activity from the perspectives of (1) the properties of local spontaneous activity, (2) the spatial pattern of spontaneous activity, and (3) the topological properties of brain networks. We also summarize the major findings associated with major neuropsychiatric disorders obtained using these methods. Then we review the pilot studies that have used spontaneous activity to discriminate patients from normal controls. Finally, we discuss current challenges and potential research directions to further elucidate the clinical use of spontaneous brain activity in neuropsychiatric disorders.     

Inhibitory effect of lead ions on cells of some strains of Pseudomonas species bacteria

The inhibition effect of ionic lead on membrane ATPase activity, transmembrane potential (delta psi) and permeability level of the Pb-sensitive P. fluorescens B894 and Pb-resistant P. fluorescens B4252 bacteria cells have been studied. It have been shown that decreasing ATPase activity and transmembrane potential values and the increasing of permeability by lead are higher for Pb-sensitive strain then for Pb-resistant. It is suggested that mechanism of the ionic lead toxic effect deals with plasma membrane biochemical parameters (ATPase activity, value of delta psi) alterations and interruption of it barrier function.     

Investigation of immunomodulatory and anti-inflammatory effects of eriodictyol through its cellular anti-oxidant activity

Many studies have been performed to assess the potential utility of natural products as immunomodulatory agents to enhance host responses against infection or to ameliorate immune-based pathologies. To determine whether eriodictyol has immunomodulatory effects and clarify which types of immune effector cells are stimulated in vitro, we investigated the stimulatory effect of eriodictyol on spleen cells isolated from BALB/c mice. Eriodictyol significantly stimulated splenocyte proliferation. However, only B lymphocytes (not T lymphocytes) could be stimulated by eriodictyol in a dose-related manner. Studies assessing potential effect of eriodictyol on innate immunity reported that eriodictyol enhanced significantly the killing activity of natural killer (NK) cells, T lymphocytes, and macrophages. We also demonstrated that eriodictyol inhibited nitric oxide (NO) production and lysosomal enzyme activity in murine peritoneal macrophages cultured ex-vivo, suggesting a potential anti-inflammatory effect in situ. Eriodictyol revealed also a cellular anti-oxidant activity in splenocytes and macrophages. Furthermore, eriodictyol increased catalase activity in spleen cells. From this data, it can be concluded that eriodictyol exhibited an immunomodulatory effect that could be ascribed in part to a cytoprotective effect related to its anti-oxidant activity.     

Coupling in secondary transport. Effect of electrical potentials on the kinetics of ion linked co-transport.

In a previous paper kinetic equations of secondary active transport by cotransport have been derived. In the present paper these equations have been expanded by including the effect of an electrical potential difference in order to make them applicable to the more realistic systems of secondary active transport driven by the gradients of Na+ or H+. Thermodynamically an electrical potential difference is as a driving force fully exchangeable with an equivalent chemical potential difference. This is not necessarily so for the kinetics of co-transport. It is not always the same whether a given difference in electrochemical activity of the driver ion is mainly osmotic, i.e. due to difference in concentration, or electric, i.e. due to a difference in the electrochemical activity coefficient. In most cases a difference in concentration is more effective in driving co-transport than is an equivalent difference in electrical potential leading to the same difference in electrical activity. The effectiveness of the latter highly depends on the model, whether it is of the affinity type or of the velocity type, but also on whether the loaded or the unloaded carrier bears an electrical charge. With the same electrical potential difference co-transport is as a rule faster if the ternary complex rather than the empty carrier is charged. Also the "standard parameters", (see Glossary, page 62) Jmax and Km, of the overall transport respond differently to the introduction of an electrical potential difference, depending on the model. So an electrical potential difference will mostly affect Km if the loaded carrier is ionic, and mostly Jmax if the empty carrier is ionic, provided that the mobility of the loaded carrier is greater than that of the empty one. On the other hand, distinctive criteria between affinity type and velocity type models are partly affected by an electrical potential difference. If the translocation steps of loaded and unloaded carrier are no longer rate limiting for the overall transport, electrical effects on the transport rate are bound to vanish as does the activation by co-transport.     

Antimicrobial peptides (AMPs): A promising class of antimicrobial compounds

Antimicrobial peptides (AMPs) are compounds, which have inhibitory activity against microorganisms. In the last decades, AMPs have become powerful alternative agents that have met the need for novel anti-infectives to overcome increasing antibiotic resistance problems. Moreover, recent epidemics and pandemics are increasing the popularity of AMPs, due to the urgent necessity for effective antimicrobial agents in combating the new emergence of microbial diseases. AMPs inhibit a wide range of microorganisms through diverse and special mechanisms by targeting mainly cell membranes or specific intracellular components. In addition to extraction from natural sources, AMPs are produced in various hosts using recombinant methods. More recently, the synthetic analogues of AMPs, designed with some modifications, are predicted to overcome the limitations of stability, toxicity and activity associated with natural AMPs. AMPs have potential applications as antimicrobial agents in food, agriculture, environment, animal husbandry and pharmaceutical industries. In this review, we have provided an overview of the structure, classification and mechanism of action of AMPs, as well as discussed opportunities for their current and potential applications.     

Hyperpolarization-activated currents control the excitability of principal neurons in the basolateral amygdala

Anxiety is thought to be influenced by neuronal excitability in basolateral nucleus of the amygdala (BLA). However, molecules that are critical for regulating excitability of BLA neurons are yet to be determined. In the present study, we have examined whether hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which mediate the depolarizing cation current, can control the neuronal excitability. HCN channel-like activity appeared to be detected in BLA principal neurons. ZD7288, a specific blocker for HCN channels, increased the input resistance of membrane, hyperpolarized resting membrane potential, and enhanced action potential firing in BLA principal neurons. The blockade of HCN channels facilitated temporal summation of repetitively evoked excitatory postsynaptic potentials, suggesting that suppression of HCN channel activity in principal neurons can accelerate the propagation of synaptic responses onto the axon hillock. Thus, our findings have laid foundation for studies to reveal how HCN channel activity in BLA principal neurons regulates anxiety in vivo.     

Iron-Rich Diagenetic Minerals are Biomarkers of Microbial Activity in Antarctic Rocks

The cold, dry ecosystems of Antarctica have been shown to harbor traces left behind by microbial activity within certain types of rocks, but only two indirect biomarkers of cryptoendolithic activity in the Antarctic cold desert zone have been described to date. These are the geophysical and geochemical bioweathering patterns macroscopically observed in sandstone rock. Here we show that in this extreme environment, minerals are biologically transformed, and as a result, Fe-rich diagenetic minerals in the form of iron hydroxide nanocrystals and biogenic clays are deposited around chasmoendolithic hyphae and bacterial cells. Thus, when microbial life decays, these characteristic neocrystalized minerals act as distinct biomarkers of previous endolithic activity. The ability to recognize these traces may have potential astrobiological implications because the Antarctic Ross Desert is considered a terrestrial analogue of a possible ecosystem on early Mars.     

College physical education: an unrecognized agent of change in combating inactivity-related diseases

Physical activity patterns during the young adult years are likely to be important influences on habitual physical activity during overall adult life and, consequently, have significant implications for long-term health outcomes. The potential reach and impact of college physical education on the promotion of physical activity to a large segment of the American population has been largely unrecognized. Over the last generation, many colleges and universities have reduced or eliminated their physical education requirements. Nonetheless, physical education can make important contributions in the primary prevention of inactivity-related chronic diseases and to the general education of the college student. Awareness and advocacy are needed to strengthen college physical education programs.