Heme oxygenase-1 regulates cell proliferation via carbon monoxide-mediated inhibition of T-type Ca2+ channels

Induction of the antioxidant enzyme heme oxygenase-1 (HO-1) affords cellular protection and suppresses proliferation of vascular smooth muscle cells (VSMCs) associated with a variety of pathological cardiovascular conditions including myocardial infarction and vascular injury. However, the underlying mechanisms are not fully understood. Over-expression of Cav3.2 T-type Ca2+ channels in HEK293 cells raised basal [Ca2+]i and increased proliferation as compared with non-transfected cells. Proliferation and [Ca2+]i levels were reduced to levels seen in non-transfected cells either by induction of HO-1 or exposure of cells to the HO-1 product, carbon monoxide (CO) (applied as the CO releasing molecule, CORM-3). In the aortic VSMC line A7r5, proliferation was also inhibited by induction of HO-1 or by exposure of cells to CO, and patch-clamp recordings indicated that CO inhibited T-type (as well as L-type) Ca2+ currents in these cells. Finally, in human saphenous vein smooth muscle cells, proliferation was reduced by T-type channel inhibition or by HO-1 induction or CO exposure. The effects of T-type channel blockade and HO-1 induction were non-additive. Collectively, these data indicate that HO-1 regulates proliferation via CO-mediated inhibition of T-type Ca2+ channels. This signalling pathway provides a novel means by which proliferation of VSMCs (and other cells) may be regulated therapeutically

Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach

In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a “learning signal” to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters

Role of f electrons in the Fermi surface of the heavy fermion superconductor beta-YbAlB4.

We present a detailed quantum oscillation study of the Fermi surface of the recently discovered Yb-based heavy fermion superconductor beta-YbAlB4. We compare the data, obtained at fields from 10 to 45 T, to band structure calculations performed using the local density approximation. Analysis of the data suggests that f holes participate in the Fermi surface up to the highest magnetic fields studied. We comment on the significance of these findings for the unconventional superconducting properties of this material

Role of f electrons in the Fermi surface of the heavy fermion superconductor beta-YbAlB4.

We present a detailed quantum oscillation study of the Fermi surface of the recently discovered Yb-based heavy fermion superconductor beta-YbAlB4. We compare the data, obtained at fields from 10 to 45 T, to band structure calculations performed using the local density approximation. Analysis of the data suggests that f holes participate in the Fermi surface up to the highest magnetic fields studied. We comment on the significance of these findings for the unconventional superconducting properties of this material

T-Type Ca2+ Channel Regulation by CO: A Mechanism for Control of Cell Proliferation

T-type Ca(2+) channels regulate proliferation in a number of tissue types, including vascular smooth muscle and various cancers. In such tissues, up-regulation of the inducible enzyme heme oxygenase-1 (HO-1) is often observed, and hypoxia is a key factor in its induction. HO-1 degrades heme to generate carbon monoxide (CO) along with Fe(2+) and biliverdin. Since CO is increasingly recognized as a regulator of ion channels (Peers et al. 2015), we have explored the possibility that it may regulate proliferation via modulation of T-type Ca(2+) channels.Whole-cell patch-clamp recordings revealed that CO (applied as the dissolved gas or via CORM donors) inhibited all 3 isoforms of T-type Ca(2+) channels (Cav3.1-3.3) when expressed in HEK293 cells with similar IC(50) values, and induction of HO-1 expression also suppressed T-type currents (Boycott et al. 2013). CO/HO-1 induction also suppressed the elevated basal [Ca(2+) ](i) in cells expressing these channels and reduced their proliferative rate to levels seen in non-transfected control cells (Duckles et al. 2015).Proliferation of vascular smooth muscle cells (both A7r5 and human saphenous vein cells) was also suppressed either by T-type Ca(2+) channel inhibitors (mibefradil and NNC 55-0396), HO-1 induction or application of CO. Effects of these blockers and CO were non additive. Although L-type Ca(2+) channels were also sensitive to CO (Scragg et al. 2008), they did not influence proliferation. Our data suggest that HO-1 acts to control proliferation via CO modulation of T-type Ca(2+) channels

From Imaging to Functional Traits in Interactions Between Roots and Microbes

The microbes in the rhizosphere constitute very complex communities, in which some are beneficial, others are pathogenic, but the vast majority of microbes are neutral commensals. Methods to unravel the interactions between roots and rhizospheric microbes have involved genetic approaches to determine the molecular bases of plant-microbe recognition and specific adaptive programs for either symbiosis or defense. In addition, imaging techniques have become particularly important to describe and understand the processes that occur within the spatially highly complex environments in and around the roots. Recently developed imaging techniques, in conjunction with appropriate labeling procedures, allow to address functional questions involving tissue-specific gene expression and elemental fluxes in the interactions between roots and rhizospheric microbes. Here, we discuss several imaging techniques from in situ hybridization, that allows the visualization of plant and microbial transcripts, to surface analytical imaging methods that can visualize chemical elements and molecules with micrometer resolution. These spectrometric techniques reveal the distribution of nutrient elements or toxic substances and allow, in combination with stable isotope labeling, to study nutrient fluxes within and between plants and microbes. Finally, we give an example of live-tissue imaging with fluorescent proteins to understand in more detail the process of root colonization through novel transcellular apoplastic compartments. All these techniques have virtually unlimited potential in their applications to other research questions in rhizosphere research