Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions.

Voltage-gated K(+) (Kv) channel activation depends on interactions between voltage sensors and an intracellular activation gate that controls access to a central pore cavity. Here, we hypothesize that this gate is additionally responsible for closed-state inactivation (CSI) in Kv4.x channels. These Kv channels undergo CSI by a mechanism that is still poorly understood. To test the hypothesis, we deduced the state of the Kv4.1 channel intracellular gate by exploiting the trap-door paradigm of pore blockade by internally applied quaternary ammonium (QA) ions exhibiting slow blocking kinetics and high-affinity for a blocking site. We found that inactivation gating seemingly traps benzyl-tributylammonium (bTBuA) when it enters the central pore cavity in the open state. However, bTBuA fails to block inactivated Kv4.1 channels, suggesting gated access involving an internal gate. In contrast, bTBuA blockade of a Shaker Kv channel that undergoes open-state P/C-type inactivation exhibits fast onset and recovery inconsistent with bTBuA trapping. Furthermore, the inactivated Shaker Kv channel is readily blocked by bTBuA. We conclude that Kv4.1 closed-state inactivation modulates pore blockade by QA ions in a manner that depends on the state of the internal activation gate

Sustainable management model based on renewable energies for the first capital of the Californias, Loreto, Mexico

The Mexican state of Baja California Sur has a high rate of population growth. It is also one of the states that are most vulnerable to climate change. Due to its location on the southern side of a roughly 900-mile long peninsula, and its natural separation from mainland Mexico, its power transmission networks are completely independent of the rest of the country. Thus, nearly all the energy used to generate electricity must be shipped to the state in the form of fossil fuels. The importation of energy supplies from the mainland results in higher costs for the state than in other areas of the country, causes greater environmental damage, and prevents a steady supply of energy to the state. This study’s objective is to propose a sustainable management model and to provide a reference to feasible sites available that could serve the Loreto region. An analytical model has been developed with multiple criteria and geographic information systems. This will allow for a wide range of spatial analysis of information covering the calculation of slopes, orientation, irradiation, infrastructure, etc. The municipal region of Loreto has roughly 288 square kilometres of land deemed suitable for the installation of solar plants. This area comprises 1.62% of the municipality. In 2016, the maximum electrical power demand for the entire state of Baja California Sur was 628 Megawatts per hour according to the Federal Electricity Commission (CFE). Loreto’s electrical capacity is currently 17 MWh. Based on calculations that one photovoltaic plant located on two acres of land can produce one MWh, solar plants in the region could, theoretically, produce up to 14,403.35 MWh. Clearly, this potential capacity would be well above the demands of the municipality, which encompasses 3.8% of the state territory

Spectral Identification of an Ancient Supernova using Light Echoes in the LMC

We report the successful identification of the type of the supernova responsible for the supernova remnant SNR 0509-675 in the Large Magellanic Cloud (LMC) using Gemini spectra of surrounding light echoes. The ability to classify outbursts associated with centuries-old remnants provides a new window into several aspects of supernova research and is likely to be successful in providing new constraints on additional LMC supernovae as well as their historical counterparts in the Milky Way Galaxy (MWG). The combined spectrum of echo light from SNR 0509-675 shows broad emission and absorption lines consistent with a supernova (SN) spectrum. We create a spectral library consisting of 26 SNe Ia and 6 SN Ib/c that are time-integrated, dust-scattered by LMC dust, and reddened by the LMC and MWG. We fit these SN templates to the observed light echo spectrum using $\chi^2$ minimization as well as correlation techniques, and we find that overluminous 91T-like SNe Ia with \dm15<0.9 match the observed spectrum best.Comment: 12 pages, 18 Figures, to be published in Ap

Targeting apoptosis for optical imaging of infection

PURPOSE: Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo. A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging. METHODS: Bacterial infection and sterile inflammation were induced in separate groups (n = 5) of mice. PS was targeted with a NIR fluorophore, PSVue(®)794 (2.7 pmol). Imaging was performed (ex = 730 nm, em = 830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity. RESULTS: Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post-injection, the lesion to background intensity ratios in the foci of infection (6.6 ± 0.2) were greater than those in inflammation (3.2 ± 0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS. CONCLUSIONS: Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7-14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection

Positive Allosteric Modulation of Kv Channels by Sevoflurane: Insights into the Structural Basis of Inhaled Anesthetic Action.

Inhalational general anesthesia results from the poorly understood interactions of haloethers with multiple protein targets, which prominently includes ion channels in the nervous system. Previously, we reported that the commonly used inhaled anesthetic sevoflurane potentiates the activity of voltage-gated K+ (Kv) channels, specifically, several mammalian Kv1 channels and the Drosophila K-Shaw2 channel. Also, previous work suggested that the S4-S5 linker of K-Shaw2 plays a role in the inhibition of this Kv channel by n-alcohols and inhaled anesthetics. Here, we hypothesized that the S4-S5 linker is also a determinant of the potentiation of Kv1.2 and K-Shaw2 by sevoflurane. Following functional expression of these Kv channels in Xenopus oocytes, we found that converse mutations in Kv1.2 (G329T) and K-Shaw2 (T330G) dramatically enhance and inhibit the potentiation of the corresponding conductances by sevoflurane, respectively. Additionally, Kv1.2-G329T impairs voltage-dependent gating, which suggests that Kv1.2 modulation by sevoflurane is tied to gating in a state-dependent manner. Toward creating a minimal Kv1.2 structural model displaying the putative sevoflurane binding sites, we also found that the positive modulations of Kv1.2 and Kv1.2-G329T by sevoflurane and other general anesthetics are T1-independent. In contrast, the positive sevoflurane modulation of K-Shaw2 is T1-dependent. In silico docking and molecular dynamics-based free-energy calculations suggest that sevoflurane occupies distinct sites near the S4-S5 linker, the pore domain and around the external selectivity filter. We conclude that the positive allosteric modulation of the Kv channels by sevoflurane involves separable processes and multiple sites within regions intimately involved in channel gating

The TSC-mTOR pathway regulates macrophage polarization

Macrophages are able to polarize to proinflammatory M1 or alternative M2 states with distinct phenotypes and physiological functions. How metabolic status regulates macrophage polarization remains not well understood, and here we examine the role of mTOR (Mechanistic Target of Rapamycin), a central metabolic pathway that couples nutrient sensing to regulation of metabolic processes. Using a mouse model in which myeloid lineage specific deletion of Tsc1 (Tsc1Δ/Δ) leads to constitutive mTOR Complex 1 (mTORC1) activation, we find that Tsc1Δ/Δ macrophages are refractory to IL-4 induced M2 polarization, but produce increased inflammatory responses to proinflammatory stimuli. Moreover, mTORC1-mediated downregulation of Akt signaling critically contributes to defective polarization. These findings highlight a key role for the mTOR pathway in regulating macrophage polarization, and suggest how nutrient sensing and metabolic status could be “hard-wired” to control of macrophage function, with broad implications for regulation of Type 2 immunity, inflammation, and allergy