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Background Wilson's disease (WD) is an autosomal recessive genetic disease caused by ATP7B gene mutations and characterized by copper metabolism disorders. Objective This study aimed to highlight the phenotypic and genetic characteristics of children with WD in Northeast China. Methods We retrospectively analyzed clinical data and gene sequencing results of 65 children with WD from January 1, 2014 to December 31, 2022 in Shengjing Hospital of China Medical University. Results The mean age at the time of the diagnosis of WD was 6.3 ± 3.52 years (range 1.2–15 years). Fifty cases (50/65, 76.9%) were asymptomatic and only found abnormal liver function during physical examination. However, they had negative Kayser–Fleischer (KF) ring with significant difference (p ). Children with acute liver failure had significantly elevated 24hr urinary Cu excretion (p ). We detected a total of 46 gene mutations in ATP7B gene, including 7 novel mutations. The most frequent mutation was p.R778L with an allelic frequency of 38.7%. Phenotype–genotype correlation analysis suggested that p.R778L was significantly associated with lower levels of serum ceruloplasmin and higher zinc levels (p p

Spinal cord stimulation (SCS) evokes fast epidural Evoked Compound Action Potential (ECAPs) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recoding lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and back. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies Significance StatementSpinal cord stimulation (SCS) is an established treatment for chronic pain and has applications to other disorders and neurorehabilitation. Notwithstanding decades of trials and research, questions remain about SCS mechanisms of action - and indicators thereof. Recent technological developments have enabled the detection of Evoked Compound Action Potential (ECAPs) – reflecting synchronous activity of the dorsal column axons activated by SCS. However, ECAP is not a direct measure of sensory processing in the dorsal horn. Here, we identify and characterize a novel electrophysiological signal that is evoked and detectable by epidural SCS electrodes and reflects spinal synaptic currents. This new signal, termed an Evoked Synaptic Activity Potential (ESAP), is thus a novel means with which to interrogate spinal gray matter circuits during SCS.

Rectangular hollow reinforced concrete (RC) columns have been used extensively for bridge structures. Inadequate transverse confinement and thin wall thickness lead to brittle shear failure, whilst limited studies have reported on the shear model. A hollow high-strength concrete and high-strength stirrups (HHSCS) column, which consisted of high-strength materials, were developed in this paper. The prior monotonic loading tests were conducted to investigate the shear performance on eight specimens. The test variables included aspect ratio, axial compression ratio, and transverse reinforcement ratio. The results revealed that all specimens experienced typical shear failure. On the basis of the modified truss-arch model, a theoretical formula was developed for estimating the shear strength of rectangular hollow RC columns. Also, six existing shear strength models were reviewed and compared with the proposed model using the test data including 37 shear-critical rectangular hollow RC columns. The comparison results showed that the proposed model provided high accuracy of shear strength whether shear-critical rectangular hollow RC columns with high-strength or normal-strength materials.

Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS produces analgesia without paresthesia and is thought, therefore, not to activate DC axons, leaving its mechanism unclear. Here we show in rats that kilohertz-frequency SCS activates DC axons but causes them to spike less synchronously than conventional SCS. Spikes desynchronize because axons entrain irregularly when stimulated at intervals shorter than their refractory period, a phenomenon we call overdrive desynchronization. Effects of overdrive desynchronization on evoked compound action potentials were verified in simulations, rats, pigs, and a chronic pain patient. Whereas synchronous spiking in DC axons is necessary for paresthesia, asynchronous spiking is sufficient to produce analgesia. Asynchronous activation of DC axons thus produces paresthesia-free analgesia.

Low-frequency (

Seven energetic salts of 3,6-dinitramino-1,2,4,5-tetrazine (DNAT), named as (NH4)2(DNAT) (1), (NH2NH3)2(DNAT) (2), (NH3OH)2(DNAT) (3), G2(DNAT) (4) (G = guanidine), (AG)2(DNAT) (5) (AG = aminoguani...

3-Nitramino-6-hydroxy-1,2,4,5-tetrazine (NHTZ) and its alkaline earth metal salts (Mg2+(1), Ca2+(2), Sr2+(3), Ba2+(4)) were prepared via 3,6-dinitramino-1,2,4,5-tetrazine for the first time. The electrostatic potentials and HOMO-LUMO orbitals of them were computed to better understand the electronic structure of NHTZ. Structures of the four alkaline earth metal salts were confirmed by elemental analysis, IR spectroscopy, and single-crystal X-ray diffraction. Structural analysis revealed that all compounds have differently dimensional structures, increasing with the radius of metal atoms. Compounds 3 and 4 can be classified as coordination polymers due to their structural features. As the only 3D polymeric structure in this series, compound 4 possesses the highest density and best thermal stability in these compounds. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) measurement shows the excellent thermal stability of these salts, with the thermal decomposition temperatures of 291.1°C (1), 294.1°C (2), 294.9°C (3) and 324.7°C (4). Heat of formation and sensitivity of the four salts were investigated, which suggest 4 as a potential heat-resistant energetic compound instructions for authors.

This research taking epilepsy as the research object, uses network database resources to inquire and sort out the relevant genes, and uses the biological pathways involved in genes to successfully construct a local gene network. The coupling of the metabolic module proves that there is a complex connection between epilepsy and the nutritional metabolism module. To a certain extent, it reflects the important influence of nutritional metabolism on epilepsy, and also provides a basis for the prevention and treatment of epilepsy through diet and the development of new therapeutic drugs.

OBJECTIVES Clinical high-frequency spinal cord stimulation (hfSCS) (>250 Hz) applied at subperception amplitudes reduces leg and low back pain. This study investigates, via labeling for c-fos-a marker of neural activation, whether 500 Hz hfSCS applied at amplitudes above and below the dorsal column (DC) compound action potential (CAP) threshold excites dorsal horn neurons. MATERIALS AND METHODS DC CAP thresholds in rats were determined by applying single biphasic pulses of SCS to T12 -T13 segments using pulse widths of 40 or 200 μsec via a ball electrode placed over the left DC and increasing amplitude until a short latency CAP was observed on the L5 DC and sciatic nerve. The result of this comparison allowed us to substitute sciatic nerve CAP for DC CAP. SCS at T12 -T13 was applied continuously for two hours using: sham or hfSCS at 500 Hz SCS, 40 μsec pulse width, and 50, 70, 90, or 140% CAP threshold. Spinal cord slices from T11 -L1 were immunolabeled for c-fos, and the number of c-fos-positive cells was quantified. RESULTS 500 Hz hfSCS applied at 90 and 140% CAP threshold produced substantial (≥6 c-fos + neurons on average per slice per segment) c-fos expression in more segments between T11 and L1 than did sham stimulation (p < 0.025, 90% CAP; p < 0.001, 140% CAP, Fisher's Exact Tests) and resulted in more c-fos-positive neurons on average per slice per segment ipsilateral to than contralateral to the SCS electrode at 70, 90, and 140% CAP threshold (p < 0.01, Wilcoxon Signed Rank Tests). CONCLUSIONS The finding of enhanced c-fos expression in the ipsilateral superficial dorsal horn provides evidence for activation/modulation of neuronal circuitry associated with subperception hfSCS.

The alkali metal salts of 3,6-dinitramino-1,2,4,5-tetrazine (DNAT, 1), Li2(H2O)4(DNAT) (2), Na2(H2O)3(DNAT) (3), K2(H2O)(DNAT) (4), Rb2(DNAT) (5) and Cs2(DNAT) (6) were synthesized and characterized by elemental analysis, IR spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and single-crystal X-ray diffraction. All of these alkali metal salts possess higher thermal stability (from 240.9 °C to 260.0 °C) than that of DNAT substrate (108.3 °C) due to their numerous coordination bonds and the three-dimensional network structures of the complexes. The number of coordination water molecules, the atomic radius of metal and the different packing forms of the crystal structure contribute to the different thermal stabilities of the alkali metal salts. The experimental (constant-volume) energy of combustion values range from 1331 to 1531 kJ mol−1. The compounds 1, 4, 5, and 6 are sensitive to impact and friction.

Two energetic complexes, Fe2II(DTMone)2(H2O)6 (1) and Fe2IIIO(DTMone)2(H2O)12 (2) [H2DTMone = di(1H-tetrazol-5-yl) methanone] were synthesized and characterized by FT-IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction. The coordination complex (1) and (2) belong to the P21/n and P1 space group, respectively. Both Iron cations are six-coordinated in octahedral fashion, by N atoms and O atoms. However, the O atoms of (2) have one free atom which is different from (1). The structure of complex (2) is analogous to two dimension structure due to the oxygen ligands participating in the coordination. Their thermal stabilities were investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Additionally, the DSC measurements display that the dehydrated polymers possess excellent thermal stability, and the thermal decomposition peak temperature is as high as 285 °C. The sensitivities to external stimuli were determined with BAM standard methods as for impact >40 J (TNT,15J) and for friction >360 N.

Understanding the cellular mechanisms of kHz electrical stimulation is of broad interest in neuromodulation including forms of transcranial electrical stimulation (tES), interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membranes suggests minimal neuronal polarization in respond to charge-balanced kHz stimulation. The hippocampal brain slice model is among the most studied systems in neuroscience and exhaustively characterized in screening the effects of electrical stimulation. High-frequency electric fields of varied amplitudes (1-150 V/m), waveforms (sinusoidal, symmetrical pule, asymmetrical pulse) and frequencies (1 and10 kHz) were tested. Changes in single or paired-pulse field excitatory post-synaptic potentials (fEPSP) in CA1 were measured in response to radial- and tangential-directed electric fields, with brief (30 s) or long (30 min) application times. The effects of kHz stimulation on ongoing endogenous network activity were tested in carbachol-induced gamma oscillation of CA3a and CA3c. Across 23 conditions evaluated, no significant changes in fEPSP were resolved, while responses were detected for within-slice control DC fields. 1 kHz sinusoidal and pulse stimulation (≥60 V/m), but not 10 kHz induced changes in oscillating neuronal network. We thus report no responses to low-amplitude 1 kHz or any 10 kHz fields, suggesting that any brain sensitivity to these fields is via yet to be-determined mechanism(s) of action which were not identified in our experimental preparation.SIGNIFICANCE STATEMENT There a large mismatch between enthusiasm for clinical treatments using kHz frequency electrical stimulation and the understanding of kHz mechanisms of action. Indeed, the well-established low-pass properties of cell membranes should attenuate any response to kHz stimulation. This study presents the largest and broadest characterization of the cellular effects of kHz stimulation using the most established animal model to detect CNS sensitivity to electric fields: Our work systematically evaluated sensitivity of hippocampal synaptic function and oscillatory network activity in response to kHz. Only at low kHz (1 kHz but not 10 kHz) with high intensity and during oscillations responses were detected. This systematic and largely negative experimental series suggest kHz neuromodulation operates via yet to be determined mechanisms.

This article studies the effects of some basic parameters of a parallel-axis helix gear stage on wind turbine gearbox vibration in a case study: a multibody dynamic model is constructed to simulate the drive train of a faulted multistage wind turbine gearbox with serious vibrations. The significant vibration behaviour of the drive train for typical excitations is calculated, and the results according to specified geometric parameters of the gears are analysed in detail to investigate effective solutions for vibration reduction. The results indicate that the helix angle and numbers of teeth of a gear pair are the most significant factors for solving the problem. The effectiveness of the proposed solutions and relevant mechanisms are discussed and validated by a prototype vibration test.

Background Kilohertz-frequency electric field stimulation (kEFS) applied to the spinal cord can reduce chronic pain without causing the buzzing sensation (paresthesia) associated with activation of dorsal column fibers. This suggests that high-rate spinal cord stimulation (SCS) has a mode of action distinct from conventional, parasthesia-based SCS. A recent study reported that kEFS hyperpolarizes spinal neurons, yet this potentially transformative mode of action contradicts previous evidence that kEFS induces depolarization and was based on patch clamp recordings whose accuracy in the presence of kEFS has not been verified. Objectives We sought to elucidate the basis for kEFS-induced hyperpolarization and to validate the effects of kEFS observed in patch clamp recordings by comparing with independent optical methods. Methods Using patch clamp electrophysiology and voltage-sensitive dye (VSD) imaging, we measured the response to kEFS applied in vitro to hippocampal and spinal neurons. Results The kEFS-induced hyperpolarization observed with current clamp recordings was corroborated by VSD imaging and rheobase measurements in patched neurons. However, no hyperpolarization was observed when imaging unpatched neurons or when recording with a voltage-follower amplifier rather than with a patch clamp amplifier (PCA). We found that EFS induced an artifactual current in PCAs that was injected back into current clamped neurons. The artifactual current induced by single, charge-balanced EFS pulses caused modest hyperpolarization, but these unitary hyperpolarizations accumulated when EFS pulses were repeated at kilohertz frequencies. Conclusion Our results rule out hyperpolarization as the mechanism underlying kEFS-mediated analgesia and highlight the risk of recording artifacts caused by extracellular electrical stimulation.

Two nitrogen-rich energetic salts (NH4)2(bto) (1) and (NH3OH)2(bto)·H2O (2) [H2bto = Bis (1H-tetrazol-5-yl) methanone oxime] were synthesized by an improved method in which water was used as solvent. These compounds were characterized by FT-IR spectroscopy, elemental analysis and single crystal X-ray diffraction. Their crystal structures were confirmed to belong to monoclinic system with space group P21 for 1 and Pc for 2, respectively. The detailed thermal behaviours were investigated by using differential scanning calorimetry (DSC) and thermogravimetric method (TG) (decomposition temperature >250 °C). The enthalpies of formation were calculated through the experimental values of combustion enthalpy. In addition, the sensitivities toward impact and friction were tested with standard methods, and those results indicated that two compounds are all insensitive (impact >40 J and friction >360 N). In short, both of the compounds show potential usages as energetic materials. The improved process opens a door for exploring nitrogen-rich salts based on Bis (1H-tetrazol-5-yl) methanone oxime.

Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes when contacting the caudal thoracic DC and at 200 or 600 μm above. Antidromic responses recorded distally from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 μm above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 8) caudal segments sampled. Whereas A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically mediated dorsal root reflexes were observed in more distant (lumbar) segments. In sum, clinically analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a nonprimary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.NEW & NOTEWORTHY Spinal cord stimulation (SCS) is used clinically to control pain. To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.

Characterizing the cellular targets of kHz (1–10 kHz) electrical stimulation remains a pressing topic in neuromodulation because expanding interest in clinical application of kHz stimulation has surpassed mechanistic understanding. The presumed cellular targets of brain stimulation do not respond to kHz frequencies according to conventional electrophysiology theory. Specifically, the low‐pass characteristics of cell membranes are predicted to render kHz stimulation inert, especially given the use of limited‐duty‐cycle biphasic pulses. Precisely because kHz frequencies are considered supra‐physiological, conventional instruments designed for neurophysiological studies such as stimulators, amplifiers and recording microelectrodes do not operate reliably at these high rates. Moreover, for pulsed waveforms, the signal frequency content is well above the pulse repetition rate. Thus, the very tools used to characterize the effects of kHz electrical stimulation may themselves be confounding factors. We illustrate custom equipment design that supports reliable electrophysiological recording during kHz‐rate stimulation. Given the increased importance of kHz stimulation in clinical domains and compelling possibilities that mechanisms of actions may reflect yet undiscovered neurophysiological phenomena, attention to suitable performance of electrophysiological equipment is pivotal. [Image: see text]

Nitrogen-rich energetic salts and cocrystal have attracted considerable attention in recent years. To assess the formation of cocrystal or salt, acid dissociation constant (pKa) values of the isomeric co-formers were calculated in this work and significant differences were observed. Two salts and one cocrystal based on H2BT (1H, 1′H-5,5′-bitetrazole), DATr (4,5-diamino-4H-1,2,4-triazole), 1MAT (1-methyl-5-aminotetrazole) and 2MAT (2-methyl-5-aminotetrazole) were synthesized, which corresponding to the different pKa values of three isomeric coformers. Single crystal structure analysis reveals that all compounds are formed by layered stacking structure with π-π stacking and rich hydrogen bonds, resulting in the insensitivity towards impact and friction (impact sensitivity > 40 J, friction sensitivity > 360 N). To the best of our knowledge, it is the first time to report the cocrystal of H2BT. The study results provide a utility method to seek for suitable coformers and design energetic cocrystal through the calculation of pKa.

Four alkaline earth metal salts (Mg2+(1), Ca2+(2), Sr2+(3), Ba2+(4)) of 3,6-dinitramino-1,2,4,5-tetrazine were synthesized and characterized by elemental analysis, IR spectroscopy, and single-crystal X-ray diffraction. Structural analysis revealed that all compounds have differently reticular structures, where each metal is bound in a specific and characteristic fashion. Thermal behaviors investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) show that all of these salts possess better thermal stability compared to neutral 3,6-dinitramino-1,2,4,5-tetrazine, with the thermal decomposition temperatures of 162 °C (1), 262.1 °C (2), 268 °C (3) and 267 °C (4), respectively, due to their plenty of coordinate bonds and intermolecular H-bonds. Besides, the kinetic parameters have been determined by non-isothermal kinetics at various heating rates. All these salts are insensitive to the stimulation of impact and friction (impact sensitivity > 40 J, friction sensitivity > 360 N), which can be considered as potential eco-friendly insensitive energetic compounds.

Lysophosphatidic acid (LPA), which is one of the intermediate products of membrane phospholipid metabolism, is a bioactive phospholipid that possesses diverse activities. In the present study, the effects of LPA on neointimal formation following vascular injury were investigated. A carotid artery balloon injury model was employed in the present study, and following vascular injury, rats received an intraperitoneal injection of 1 mg/kg LPA. Subsequently, histopathological alterations were assessed by hematoxylin and eosin staining, the expression levels of proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry, apoptosis was assessed via a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and the expression levels of apoptosis-associated and autophagy-associated proteins were detected by western blotting. In addition, inflammatory and oxidative stress-associated factors were assessed by reverse transcription-quantitative polymerase chain reaction or corresponding kits. The results of the present study demonstrated that LPA enhanced vascular injury-induced neointimal hyperplasia. LPA further elevated the expression levels of PCNA in the injured carotid artery tissues. LPA exhibited no effect on apoptosis in carotid artery tissues, whereas it modulated autophagy in the injured carotid artery tissues. Furthermore, LPA enhanced vascular injury-induced inflammation and oxidative stress. The present study demonstrated that LPA may enhance neointimal hyperplasia following vascular injury by modulating proliferation, autophagy, inflammation and oxidative stress, but not apoptosis. Furthermore LPA may contribute to the pathology of atherosclerosis and may be considered a promising therapeutic target for the treatment of atherosclerosis.