Small-conductance (KCa2.1-2.3) and intermediate-conductance (KCa3.1) calcium-activated K(+) channels are critically involved in modulating calcium-signaling cascades and membrane potential in both ...excitable and nonexcitable cells. Activators of these channels constitute useful pharmacological tools and potential new drugs for the treatment of ataxia, epilepsy, and hypertension. Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra2,1-dthiazol-2-ylamine (SKA-20) and naphtho1,2-dthiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC(50) values of 430 nM and 2.9 microM, KCa2.2 with an EC(50) value of 1.9 microM, KCa2.3 with EC(50) values of 1.2 and 2.9 microM, and KCa3.1 with EC(50) values of 115 and 260 nM. Likewise, SKA-20 and SKA-31 activated native KCa2.3 and KCa3.1 channels in murine endothelial cells, and the more "drug-like" SKA-31 (half-life of 12 h) potentiated endothelium-derived hyperpolarizing factor-mediated dilations of carotid arteries from KCa3.1(+/+) mice but not from KCa3.1(-/-) mice. Administration of 10 and 30 mg/kg SKA-31 lowered mean arterial blood pressure by 4 and 6 mm Hg in normotensive mice and by 12 mm Hg in angiotensin-II-induced hypertension. These effects were absent in KCa3.1-deficient mice. In conclusion, with SKA-31, we have designed a new pharmacological tool to define the functional role of the KCa2/3 channel activation in vivo. The blood pressure-lowering effect of SKA-31 suggests KCa3.1 channel activation as a new therapeutic principle for the treatment of hypertension.
This article discusses theoretical aspects of studies on viviparous organisms and provides new approaches to understanding the evolution of viviparity. Viviparity is considered here not as a “great ...biological advantage,” but as the simplest way of birth, that in terms of biodiversity is in the minority; it is realized only in cases in which, due to various reasons, laying eggs is impossible or poorly compatible with newly acquired morphological and/or physiological characteristics. Aberrations of the reproductive sphere, changes in its ancestral state and changes leading to viviparity, can be divided into three main groups: (1) the appearance of oogamy in the ancient colonial protists and multicellular organisms before the appearance of any mechanisms for extrusion of immobile oogamete (or zigote); (2) evolutionary conversions from external to internal fertilization in organisms that have no specialized oviducts with accessory glands and spermathecae; (3) abnormalities in well-developed female reproductive systems: the loss of insect reproductive organs (in cases of paedogenesis, neoteny, or paedomoprhosis), larval meiosis, change of fertilization area from ectodermal parts of oviducts to intragonadal fertilization. All the above mentioned evolutionary rearrangements are considered from the point of view of an analytical review of viviparity in the largest biological taxa from archaic multicellular organisms to the most advanced groups of invertebrate and vertebrate animals.
A new species and a new monotypic genus of legless mealybug, Orbuspedum machinator gen. et sp. nov., are described and illustrated, based on material collected from bamboo twigs in southern Thailand. ...Larvae and females of the new species each live inside an individual conical domicile constructed from densely packed fungal hyphae of the sooty mould Capnodium sp., mixed with small quantities of wax, secreted by the mealybug. The domicile is enlarged as the insect grows; the insect irrigates the hyphae with honeydew through a small orifice at the apex of the domicile. While the insect produces honeydew and feeds the fungus, the fungus grows around the insect, protects it from predators, and buttresses the soft apodal body of the mealybug. Such a remarkable example of mutualistic symbiosis between an animal and a fungus is reported for the first time.
www.zoobank.org/urn:lsid:zoobank.org:pub:C0A84631-C6A0-4177-BC50-A71D6281107F
The results of modeling and optimization of a composite scintillator for recording thermal neutrons are presented. The interaction of thermal neutrons and γ-quanta with composites consisting of ...fragments of a glass scintillator containing
6
Li was observed. The aim of the research was to determine the structure of a composite with high sensitivity to thermal neutrons and to provide effective suppression of signals from γ‑quanta. During the simulation, the optimal structural parameters of the composite were determined, such as the size of the fragments and the concentration of glass. According to the presented simulation results, optimized composites under thermal neutron irradiation can provide a neutron detection efficiency of at least 50% with a sensitivity to γ-quanta at the level η < 10
–6
.
Knockout of the mitochondrial complex I protein, NDUFS4, profoundly increases sensitivity of mice to volatile anesthetics. In mice carrying an Ndufs4lox/lox gene, adeno-associated virus expressing ...Cre recombinase was injected into regions of the brain postulated to affect sensitivity to volatile anesthetics. These injections generated otherwise phenotypically wild type mice with region-specific, postnatal inactivation of Ndufs4, minimizing developmental effects of gene loss. Sensitivities to the volatile anesthetics isoflurane and halothane were measured using loss of righting reflex (LORR) and movement in response to tail clamp (TC) as endpoints. Knockdown (KD) of Ndufs4 in the vestibular nucleus produced resistance to both anesthetics for movement in response to TC. Ndufs4 loss in the central and dorsal medial thalami and in the parietal association cortex increased anesthetic sensitivity to both TC and LORR. Knockdown of Ndufs4 only in the parietal association cortex produced striking hypersensitivity for both endpoints, and accounted for half the total change seen in the global KO (Ndufs4(KO)). Excitatory synaptic transmission in the parietal association cortex in slices from Ndufs4(KO) animals was hypersensitive to isoflurane compared to control slices. We identified a direct neural circuit between the parietal association cortex and the central thalamus, consistent with a model in which isoflurane sensitivity is mediated by a thalamic signal relayed through excitatory synapses to the parietal association cortex. We postulate that the thalamocortical circuit is crucial for maintenance of consciousness and is disrupted by the inhibitory effects of isoflurane/halothane on mitochondria.
An enigma of modern medicine has persisted for over 150 years. The mechanisms by which volatile anesthetics (VAs) produce their effects (loss of consciousness, analgesia, amnesia, and immobility) ...remain an unsolved mystery. Many attractive putative molecular targets have failed to produce a significant effect when genetically tested in whole-animal models 1–3. However, mitochondrial defects increase VA sensitivity in diverse organisms from nematodes to humans 4–6. Ndufs4 knockout (KO) mice lack a subunit of mitochondrial complex I and are strikingly hypersensitive to VAs yet resistant to the intravenous anesthetic ketamine 7. The change in VA sensitivity is the largest reported for a mammal. Limiting NDUFS4 loss to a subset of glutamatergic neurons recapitulates the VA hypersensitivity of Ndufs4(KO) mice, while loss in GABAergic or cholinergic neurons does not. Baseline electrophysiologic function of CA1 pyramidal neurons does not differ between Ndufs4(KO) and control mice. Isoflurane concentrations that anesthetize only Ndufs4(KO) mice (0.6%) decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) only in Ndufs4(KO) CA1 neurons, while concentrations effective in control mice (1.2%) decreased sEPSC frequencies in both control and Ndufs4(KO) CA1 pyramidal cells. Spontaneous inhibitory postsynaptic currents (sIPSCs) were not differentially affected between genotypes. The effects of isoflurane were similar on evoked field excitatory postsynaptic potentials (fEPSPs) and paired pulse facilitation (PPF) in KO and control hippocampal slices. We propose that CA1 presynaptic excitatory neurotransmission is hypersensitive to isoflurane in Ndufs4(KO) mice due to the inhibition of pre-existing reduced complex I function, reaching a critical reduction that can no longer meet metabolic demands.
•VGLUT2-specific loss of NDUFS4 causes whole-animal anesthetic hypersensitivity•Isoflurane depresses hippocampal sEPSC frequencies selectively in Ndufs4(KO) mice•sIPSCs are not affected by NDUFS4 loss•The Ndufs4 mutation selectively affects presynaptic function in excitatory neurons
Ndufs4(KO) mice are very hypersensitive to volatile anesthetics. Zimin et al. show that VGLUT2-specific Ndufs4(KO) mice recapitulated the phenotype, while GABAergic and cholinergic Ndufs4(KO) did not. Isoflurane selectively inhibited excitatory neurotransmission in the CA1 of the hippocampus of Ndufs4(KO) at a dose that did not affect controls.
The problem of scattering of a plane electromagnetic wave by a 2D periodic structure formed by absorbing spherical radially inhomogeneous dielectric elements is considered. The elements have the type ...of electromagnetic black holes located on a semi-infinite substrate. The numerical algorithm of the solution is developed. The algorithm is based on the hybrid projection method and takes into account the peculiarities of the black hole construction. The algorithm is generalized to the case, when black holes are situated on a perfectly conducting screen. New expressions for calculating the power absorbed by the structure elements are derived. The numerical results characterizing the efficiency of the structure absorption are presented.
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The characteristics of neutron scintillation detectors built on monolithic and heterogeneous scintillators containing
6
Li were studied. The detectors were tested on a thermal neutron beam and on a ...stand with a source of γ-quanta
60
Co. To process the signals received from the detector with a monolithic scintillator, three different γ-radiation discrimination algorithms were used: registration of pulses at a constant threshold and selection according to the pulse shape using two digital signal separation methods: charge integration and pulse duration measurement. For a homogeneous scintillator, pulse shape selection methods work approximately the same when separating thermal neutrons and γ-quanta and are significantly inferior to the method of registration at a constant threshold. In this case, the quality of the
n
/γ separation is worse than the result obtained with a heterogeneous scintillator when recording at a constant threshold. The purpose of the work is to compare the results of using digital methods for discrimination of gamma-quanta with the results obtained using heterogeneous scintillators.
Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms ...of amyloid-β protein (Aβ), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar Aβ, a major component of amyloid plaques in AD brains. Here we report that amyloid-β oligomer (AβO), at 5–50 nm, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca2+-activated potassium channel KCa3.1. AβO treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor κB. Interestingly, although increasing nitric oxide (NO) production, AβO did not increase several proinflammatory mediators commonly induced by lipopolyliposacharides or fibrillar Aβ, suggesting that AβO stimulates both common and divergent pathways of microglia activation. AβO at low nanomolar concentrations, although not neurotoxic, induced indirect, microglia-mediated damage to neurons in dissociated cultures and in organotypic hippocampal slices. The indirect neurotoxicity was prevented by (i) doxycycline, an inhibitor of microglia activation; (ii) TRAM-34, a selective KCa3.1 blocker; and (iii) two inhibitors of inducible NO synthase, indicating that KCa3.1 activity and excessive NO release are required for AβO-induced microglial neurotoxicity. Our results suggest that AβO, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.
![Naphtho[1,2-d]thiazol-2-yla...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1521-0111_0026-895X/small "Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure")
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