Search

Vincristine-induced peripheral neuropathy is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine-induced pain. Our previous studies have shown that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) Nav1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons, we now show an increase in TTX-R current density and a −7.3 mV hyperpolarizing shift in the half-maximal potential (V1/2) of activation of Nav1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from Nav1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel Nav1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia. [ABSTRACT FROM AUTHOR]

This paper describes a study on speaker recognition using the ECAPA-TDNN architecture, which stands for Extended Context-Aware Parallel Aggregations Time-Delay Neural Network. It utilizes X-vectors, a method for extracting speaker features by converting speech into fixed-length vectors, and introduces a squeeze-and-excitation block to model dependencies between channels. In order to better explore temporal relationships in the context of speaker recognition and improve the algorithm's generalization performance in complex acoustic scenarios, this study adds input gates and forget gates to the ECAPA-TDNN architecture, combining them with CIFG (Convolutional LSTM with Input and Forget Gates) modules. These are embedded into a residual structure of multi-layer aggregated features. A sub-center Arcface, an improved loss function based on Arcface, is used for selecting sub-centers for subclass discrimination, retaining advantageous sub-centers to enhance intra-class compactness and strengthen the robustness of the network. Experimental results demonstrate that the improved ECAPA-TDNN-CIFG in this study outperforms the baseline model, yielding more accurate and efficient recognition results. [ABSTRACT FROM AUTHOR]

The similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations.sup.1-4. Comparative analyses of the prefrontal cortex (PFC), a cerebral cortex region involved in higher-order cognition and complex social behaviours, have identified true and potential human-specific structural and molecular specializations.sup.4-8, such as an exaggerated PFC-enriched anterior-posterior dendritic spine density gradient.sup.5. These changes are probably mediated by divergence in spatiotemporal gene regulation.sup.9-17, which is particularly prominent in the midfetal human cortex.sup.15,18-20. Here we analysed human and macaque transcriptomic data.sup.15,20 and identified a transient PFC-enriched and laminar-specific upregulation of cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor-[delta] GRID/GluD-associated synaptic organizer.sup.21-27, during midfetal development that coincided with the initiation of synaptogenesis. Moreover, we found that species differences in level of expression and laminar distribution of CBLN2 are, at least in part, due to Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer. In situ genetic humanization of the mouse Cbln2 enhancer drives increased and ectopic laminar Cbln2 expression and promotes PFC dendritic spine formation. These findings suggest a genetic and molecular basis for the anterior-posterior cortical gradient and disproportionate increase in the Hominini PFC of dendritic spines and a developmental mechanism that may link dysfunction of the NRXN-GRID-CBLN2 complex to the pathogenesis of neuropsychiatric disorders. The authors identify deletions in a retinoic acid signalling responsive genetic element that leads to disproportionate increase of dendritic spines on neurons of the human prefrontal cortex., Author(s): Mikihito Shibata [sup.1] , Kartik Pattabiraman [sup.1] [sup.2] , Sydney K. Muchnik [sup.1] [sup.3] , Navjot Kaur [sup.1] , Yury M. Morozov [sup.1] , Xiaoyang Cheng [sup.4] [sup.5] [sup.6] [...]

Proton exchange membrane fuel cells (PEMFCs) and alkaline membrane fuel cells (AEMFCs) have received great attention as energy devices of the next generation. Accelerating oxygen reduction reaction (ORR) kinetics is the key to improve PEMFC and AEMFC performance. Platinum‐based catalysts are the most widely used catalysts for the ORR, but their high price and low abundance limit the commercialization of fuel cells. Non‐noble metal‐nitrogen‐carbon (M−N−C) is considered to be the most likely material class to replace Pt‐based catalysts, among which Fe−N−C and Co−N−C have been widely studied due to their excellent intrinsic ORR performance and have made great progress in the past decades. With the improvement of synthesis technology and a deeper understanding of the ORR mechanism, some reported Fe−N−C and Co−N−C catalysts have shown excellent ORR activity close to that of commercial Pt/C catalysts. Inspired by the progress, regulation strategies for Fe−N−C and Co−N−C catalysts are summarized in this Review from 5 perspectives: (1) coordinated atoms, (2) environmental heteroatoms and defects, (3) dual‐metal active sites, (4) metal‐based particle promoters, and (5) curved carbon layers. We also make suggestions on some challenges facing Fe−N−C and Co−N−C research. [ABSTRACT FROM AUTHOR]

The single‐atom Fe−N−C is a prominent material with exceptional reactivity in areas of sustainable energy and catalysis research. It is challenging to obtain the dense Fe‐N4 site without the Fe nanoparticles (NPs) sintering during the Fe−N−C synthesis via high‐temperature pyrolysis. Thus, a novel approach is devised for the Fe−N−C synthesis at low temperatures. Taking FeCl2 as Fe source, a hydrogen environment can facilitate oxygen removal and dichlorination processes in the synthesis, efficiently favouring Fe‐N4 site formation without Fe NPs clustering at as low as 360 °C. We shed light on the reaction mechanism about hydrogen promoting Fe‐N4 formation in the synthesis. By adjusting the temperature and duration, the Fe‐N4 structural evolution and site density can be precisely tuned to directly influence the catalytic behaviour of the Fe−N−C material. The FeNC‐H2‐360 catalyst demonstrates a remarkable Fe dispersion (8.3 wt %) and superior acid ORR activity with a half‐wave potential of 0.85 V and a peak power density of 1.21 W cm−2 in fuel cell. This method also generally facilitates the synthesis of various high‐performance M−N−C materials (M=Fe, Co, Mn, Ni, Zn, Ru) with elevated single‐atom loadings. [ABSTRACT FROM AUTHOR]

Iron‐nitrogen‐carbon (Fe‐N‐C) catalysts for the oxygen reduction reaction (ORR) in proton exchange membrane fuel cells (PEMFCs) have seriously been hindered by their poor ORR performance of Fe‐N‐C due to the low active site density (SD) and site utilization. Herein, we reported a melamine‐assisted vapor deposition approach to overcome these hindrances. The melamine not only compensates for the loss of nitrogen caused by high‐temperature pyrolysis but also effectively etches the carbon substrate, increasing the external surface area and mesoporous porosity of the carbon substrate. These can provide more useful area for subsequent vapor deposition on active sites. The prepared 0.20Mela‐FeNC catalyst shows a fourfold higher SD value and site utilization than the FeNC without the treatment of melamine. As a result, 0.20Mela‐FeNC catalyst exhibits a high ORR activity with a half‐wave potential (E1/2) of 0.861 V and 12‐fold higher ORR mass activity than the FeNC in acidic media. As the cathode in a H2‐O2 PEMFCs, 0.20Mela‐FeNC catalyst demonstrates a high peak power density of 1.30 W cm−2, outstripping most of the reported Fe‐N‐C catalysts. The developed melamine‐assisted vapor deposition approach for boosting the SD and utilization of Fe‐N‐C catalysts offers a new insight into high‐performance ORR electrocatalysts. [ABSTRACT FROM AUTHOR]

To achieve the Fe−N−C materials with both high activity and durability in proton exchange membrane fuel cells, the attack of free radicals on Fe−N4 sites must be overcome. Herein, we report a strategy to effectively eliminate radicals at the source to mitigate the degradation by anchoring CeO2 nanoparticles as radicals scavengers adjacent (Scaad‐CeO2) to the Fe−N4 sites. Radicals such as ⋅OH and HO2⋅ that form at Fe−N4 sites can be instantaneously eliminated by adjacent CeO2, which shortens the survival time of radicals and the regional space of their damage. As a result, the CeO2 scavengers in Fe−NC/Scaad‐CeO2 achieved ∼80 % elimination of the radicals generated at the Fe−N4 sites. A fuel cell prepared with the Fe−NC/Scaad‐CeO2 showed a smaller peak power density decay after 30,000 cycles determined with US DOE PGM‐relevant AST, increasing the decay of Fe−NCPhen from 69 % to 28 % decay. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons. Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV1.7. [ABSTRACT FROM AUTHOR]

Abstract: Gain-of-function and loss-of-function mutations in Nav1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Nav1.7 in the peripheral nervous system and its role in human pain signaling make Nav1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and because of the lack of subtype-selective molecular modulators, the role of Nav1.7 in the perception of pain remains poorly understood. Scorpion venom is an excellent source of bioactive peptides that modulate various ion channels, including voltage-gated sodium (Nav) channels. Here, we demonstrate that Buthus martensii Karsch scorpion venom (BV) elicits pain responses in mice through direct enhancement of Nav1.7 activity and have identified Makatoxin-3, an α-like toxin, as a critical component for BV-mediated effects on Nav1.7. Blocking other Nav subtypes did not eliminate BV-evoked pain responses, supporting the pivotal role of Nav1.7 in BV-induced pain. Makatoxin-3 acts on the S3-S4 loop of voltage sensor domain IV (VSD4) of Nav1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure-function relationships for the toxin-channel interactions, which are distinct from those of other well-studied α toxins. This study not only reveals a new mechanism underlying BV-evoked pain but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin-Nav1.7 interactions, which facilitates the design of novel Nav1.7 selective modulators. [ABSTRACT FROM AUTHOR]