GABAA Receptors in Astrocytes Are Targets for Commonly Used Intravenous and Inhalational General Anesthetic Drugs

Background: Perioperative neurocognitive disorders (PNDs) occur commonly in older patients after anesthesia and surgery. Treating astrocytes with general anesthetic drugs stimulates the release of soluble factors that increase the cell-surface expression and function of GABAA receptors in neurons. Such crosstalk may contribute to PNDs; however, the receptor targets in astrocytes for anesthetic drugs have not been identified. GABAA receptors, which are the major targets of general anesthetic drugs in neurons, are also expressed in astrocytes, raising the possibility that these drugs act on GABAA receptors in astrocytes to trigger the release of soluble factors. To date, no study has directly examined the sensitivity of GABAA receptors in astrocytes to general anesthetic drugs that are frequently used in clinical practice. Thus, the goal of this study was to determine whether the function of GABAA receptors in astrocytes was modulated by the intravenous anesthetic etomidate and the inhaled anesthetic sevoflurane.Methods: Whole-cell voltage-clamp recordings were performed in astrocytes in the stratum radiatum of the CA1 region of hippocampal slices isolated from C57BL/6 male mice. Astrocytes were identified by their morphologic and electrophysiologic properties. Focal puff application of GABA (300 μM) was applied with a Picospritzer system to evoke GABA responses. Currents were studied before and during the application of the non-competitive GABAA receptor antagonist picrotoxin (0.5 mM), or etomidate (100 μM) or sevoflurane (532 μM).Results: GABA consistently evoked inward currents that were inhibited by picrotoxin. Etomidate increased the amplitude of the peak current by 35.0 ± 24.4% and prolonged the decay time by 27.2 ± 24.3% (n = 7, P < 0.05). Sevoflurane prolonged current decay by 28.3 ± 23.1% (n = 7, P < 0.05) but did not alter the peak amplitude. Etomidate and sevoflurane increased charge transfer (area) by 71.2 ± 45.9% and 51.8 ± 48.9% (n = 7, P < 0.05), respectively.Conclusion: The function of astrocytic GABAA receptors in the hippocampus was increased by etomidate and sevoflurane. Future studies will determine whether these general anesthetic drugs act on astrocytic GABAA receptors to stimulate the release of soluble factors that may contribute to PNDs.

Critical current improvement and resistance evaluation of superconducting joint between Bi2223 tapes

We improved the critical current (I c) of the superconducting joint between the Bi2223 tapes by introducing the two-step sintering process. The in-field transport I c of ~ 300 A at 4.2 K and 1 T under a 10−9 Ω criterion was successfully demonstrated. The I c improvement can probably be attributed to the enhancement of the intergrain critical current density for a Bi2223 intermediate layer. Ultra-low in-field joint resistance below 10−14 Ω at 4.2 K and 1 T was also demonstrated using current decay measurement. To our best knowledge, this study is the first to demonstrate a practical level of in-field transport I c and ultra-low in-field joint resistance for the superconducting joint between Bi2223 tapes. We believe that this superconducting joint technology will facilitate development of persistent current mode Bi2223 superconducting magnets.

Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy

ABSTRACTCurrently, protein-coding de novo variants and large copy number variants have been identified as important for ∼30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, treatment-refractory epilepsy, cognitive impairment, and mild dysmorphic features (two affected female full siblings, parents, and one unaffected sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2 protein) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment of the variant revealed it was in the top 0.05% of all conserved bases in the genome, and was predicted damaging by Polyphen2, MutationTaster, and SIFT. It was not present in any controls from public genome databases nor in a joint-call set we generated across 49 individuals with publicly available PacBio HiFi data. This specific missense mutation (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense mutations have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10−5). KCNC2 is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long-read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available.

A Transient Analysis for Amorphous Photoconductors

The study has been carried out for the transient response of photosensors fabricated by amorphous semiconductors under variable levels of excitation when switched off from steady-state. The curves for the entire range of the transient have been plotted in the terms of photoconductivity and they can be converted to current decay curves by multiplying with the applied electric field and the cross-sectional area of the sample. For this purpose, in the calculations, the transit time effect is included. Also, the switching time and gain of the photoconductor have been calculated. It is found that the current gain of the device increases as the density of thermal equilibrium electrons is made higher, compared to that of holes by moving the Fermi level upward. However, this also increased the switching time and its performance, as a switch becomes poorer.

High-temperature-tolerable superconducting Nb-alloy and its application to Pb- and Cd-free superconducting joints between NbTi and Nb3Sn wires

For more than 30 years, Pb–Bi alloy and Wood's metal (50% Bi, 26.7% Pb, 13.3% Sn, and 10% Cd) have been used as representative superconducting solder intermedia to establish superconducting joints between NbTi and Nb3Sn wires in high-field nuclear magnetic resonance magnet systems. However, the use of Pb and Cd has been severely restricted by environmental regulations, such as the Restriction of Hazardous Substances Directive. Herein, a novel method of forming a superconducting joint between NbTi and Nb3Sn wires without Pb and Cd has been proposed. This approach is based on metallurgical bonding processes using a superconducting Nb-alloy intermedium, whose fine microstructure is maintained even after exposure to temperatures higher than 650 °C. Further, fine crystal defects become sources of magnetic flux pinning centers. Among transition elements close to Nb, Hf is considered the most suitable additive for realizing high-temperature-tolerable (HTT) superconducting Nb-alloy intermedia. Utilizing the HTT characteristic of Nb–Hf, a superconducting joint between Nb3Sn filaments and one end of the Nb–Hf alloy core was created by forming a superconducting Nb3Sn layer at the interface through a chemical reaction. The other end of the Nb–Hf alloy core was cold-pressed with NbTi filaments, to connect their active new surfaces to each other in order to create a superconducting joint. Ultimately, a superconducting joint between NbTi and Nb3Sn wires was realized with a high critical magnetic field (Bc2) of more than 1 T. The formation of the superconducting joint was confirmed by current decay measurements. This method of forming a superconducting joint is promising for application in environmentally friendly nuclear magnetic resonance magnet systems. Graphical abstract

High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology

Incorporation of noncanonical amino acids (ncAAs) can endow proteins with novel functionalities, such as crosslinking or fluorescence. In ion channels, the function of these variants can be studied with great precision using standard electrophysiology, but this approach is typically labor intensive and low throughput. Here, we establish a high-throughput protocol to conduct functional and pharmacological investigations of ncAA-containing human acid-sensing ion channel 1a (hASIC1a) variants in transiently transfected mammalian cells. We introduce 3 different photocrosslinking ncAAs into 103 positions and assess the function of the resulting 309 variants with automated patch clamp (APC). We demonstrate that the approach is efficient and versatile, as it is amenable to assessing even complex pharmacological modulation by peptides. The data show that the acidic pocket is a major determinant for current decay, and live-cell crosslinking provides insight into the hASIC1a–psalmotoxin 1 (PcTx1) interaction. Further, we provide evidence that the protocol can be applied to other ion channels, such as P2X2 and GluA2 receptors. We therefore anticipate the approach to enable future APC-based studies of ncAA-containing ion channels in mammalian cells.

Lepton Flavor Violating $h\to\tau\mu$ decay induced by leptoquarks

The flavor changing neutral current decay $h\to\tau\mu$ is studied in a renormalizable scalar leptoquark model with no proton decay. Analytical expressions for the one-loop level contributions of a scalar leptoquark to the decay width of the process $h\to\tau\mu$ are presented. We find a viable model parameter space via the current constraints on the muon ($g-2$), the decay $\tau\to\mu\gamma$, the LHC Higgs boson data and the direct leptoquark searches at the LHC. Then, we evaluate branching ratio of the decay $h\to\tau\mu$induced by leptoquarks; we find that it is of the order of $10^{-8}-10^{-7}$ ($10^{-8}$; $10^{-9}-10^{-8}$)for a scalar leptoquark mass equal to $m_{\Omega_{5/3}}=1$ TeV ($m_{\Omega_{5/3}}=2$; $m_{\Omega_{5/3}}=10$ TeV). Finally, we evaluate the number of events produced at future hadron colliders from both the $h\to\tau\mu$ decay and the potential Standard Model background finding a potentialevidence for the $h\to\tau\mu$ decay.

Microscale Schottky superlubric generator with high direct-current density and ultralong life

Miniaturized or microscale generators that can effectively convert weak and random mechanical energy into electricity have significant potential to provide solutions for the power supply problem of distributed devices. However, owing to the common occurrence of friction and wear, all such generators developed so far have failed to simultaneously achieve sufficiently high current density and sufficiently long lifetime, which are crucial for real-world applications. To address this issue, we invent a microscale Schottky superlubric generator (S-SLG), such that the sliding contact between microsized graphite flakes and n-type silicon is in a structural superlubric state (an ultra-low friction and wearless state). The S-SLG not only generates high current (~210 Am−2) and power (~7 Wm−2) densities, but also achieves a long lifetime of at least 5,000 cycles, while maintaining stable high electrical current density (~119 Am−2). No current decay and wear are observed during the experiment, indicating that the actual persistence of the S-SLG is enduring or virtually unlimited. By excluding the mechanism of friction-induced excitation in the S-SLG, we further demonstrate an electronic drift process during relative sliding using a quasi-static semiconductor finite element simulation. Our work may guide and accelerate the future use of S-SLGs in real-world applications.