Severe peripheral nerve injury (PNI) often leads to significant movement disorders and intractable pain. Therefore, promoting nerve regeneration while avoiding neuropathic pain is crucial for the ...clinical treatment of PNI patients. However, established animal models for peripheral neuropathy fail to accurately recapitulate the clinical features of PNI. Additionally, researchers usually investigate neuropathic pain and axonal regeneration separately, leaving the intrinsic relationship between the development of neuropathic pain and nerve regeneration after PNI unclear. To explore the underlying connections between pain and regeneration after PNI and provide potential molecular targets, we performed single-cell RNA sequencing and functional verification in an established rat model, allowing simultaneous study of the neuropathic pain and axonal regeneration after PNI. First, a novel rat model named spared nerve crush (SNC) was created. In this model, two branches of the sciatic nerve were crushed, but the epineurium remained unsevered. This model successfully recapitulated both neuropathic pain and axonal regeneration after PNI, allowing for the study of the intrinsic link between these two crucial biological processes. Dorsal root ganglions (DRGs) from SNC and naïve rats at various time points after SNC were collected for single-cell RNA sequencing (scRNA-seq). After matching all scRNA-seq data to the 7 known DRG types, we discovered that the PEP1 and PEP3 DRG neuron subtypes increased in crushed and uncrushed DRG separately after SNC. Using experimental design scRNA-seq processing (EDSSP), we identified Adcyap1 as a potential gene contributing to both pain and nerve regeneration. Indeed, repeated intrathecal administration of PACAP38 mitigated pain and facilitated axonal regeneration, while Adcyap1 siRNA or PACAP6-38, an antagonist of PAC1R (a receptor of PACAP38) led to both mechanical hyperalgesia and delayed DRG axon regeneration in SNC rats. Moreover, these effects can be reversed by repeated intrathecal administration of PACAP38 in the acute phase but not the late phase after PNI, resulting in alleviated pain and promoted axonal regeneration. Our study reveals that Adcyap1 is an intrinsic protective factor linking neuropathic pain and axonal regeneration following PNI. This finding provides new potential targets and strategies for early therapeutic intervention of PNI.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A two-stage “tandem strategy” for the synthesis of indoles with a high level of substitution on the six-membered ring is described. Benzannulation based on the reaction of cyclobutenones with ...ynamides proceeds via a cascade of four pericyclic reactions to produce multiply substituted aniline derivatives in which the position ortho to the nitrogen can bear a wide range of functionalized substituents. In the second stage of the tandem strategy, highly substituted indoles are generated via acid-, base-, and palladium-catalyzed cyclization and annulation processes.
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IJS, KILJ, NUK, PNG, UL, UM
Epigenetic modifications are involved in the onset, development, and maintenance of pain; however, the precise epigenetic mechanism underlying pain regulation remains elusive. Here it is reported ...that the epigenetic factor chromodomain Y‐like (CDYL) is crucial for pain processing. Selective knockout of CDYL in sensory neurons results in decreased neuronal excitability and nociception. Moreover, CDYL facilitates histone 3 lysine 27 trimethylation (H3K27me3) deposition at the Kcnb1 intron region thus silencing voltage‐gated potassium channel (Kv) subfamily member Kv2.1 transcription. Loss function of CDYL enhances total Kv and Kv2.1 current density in dorsal root ganglia and knockdown of Kv2.1 reverses the pain‐related phenotypes of Cdyl deficiency mice. Furthermore, focal administration of a novel potent CDYL antagonist blunts nociception and attenuates neuropathic pain. These findings reveal that CDYL is a critical regulator of pain sensation and shed light on the development of novel analgesics targeting epigenetic mechanisms.
Chromodomain Y‐like (CDYL) in peripheral sensory neurons is indispensable for pain sensation. Downregulation of peripheral CDYL decreases neuronal excitability and elevates pain threshold. One of the critical mechanisms is that loss of CDYL represses histone 3 lysine 27 trimethylation (H3K27me3) deposition at Kcnb1 intron region and facilitates its transcription. More importantly, focal delivery of a novel CDYL antagonist successfully attenuates neuropathic pain, providing probability for clinical translation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In recent years, with the increase of the depth of open-pit mining, the pollution level has been on the rise due to harmful gases and dust occurring in the process of mining. In order to accelerate ...the diffusion of these air pollutants, the distributed regularity of the rock face temperature which is directly related to the air ventilation in deep open-pit mines should be studied. Here, we establish the key factors influencing the rock face temperature in a deep open-pit mine. We also present an empirical model of the rock face temperature variation in the deep open-pit mine, of which the performance is interestingly high compared with that of the field test. This study lays a foundation to study the ventilation thermodynamic theory in the deep open-pit mine, which is of great importance for theoretical studies and engineering applications of solving air pollution problem in deep open-pit mines.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Modern radar is a typical millisecond pulse power load (MPPL), which contains a large number of power electronic devices. If the MPPL is connected to the power system, it will cause serious voltage ...distortion problems. The working mode of the radar pulse load will directly affect the voltage distortion. In order to analyze the influence of MPPL on the system voltage distortion, a harmonic source model of MPPL were proposed based on the switching functions. At the same time, in order to evaluate the degree of voltage distortion, an improved voltage distortion evaluation index-Waveform Relative Deviation Rate (WRDR) is proposed. The harmonic source model is based on the equivalent topology of MPPL, which can theoretically explain the cause of the sub-harmonic and inter-harmonic currents, and can reflect the influence of the parameters of MPPL on its harmonic characteristics. The simulation and experimental results prove that the harmonic source model can be used to calculate the distribution and magnitude of the harmonic current of MPPL, and to explain the cause of voltage distortion. Finally, the improved voltage distortion evaluation index is used to analyze and summarize the influence of MPPL on voltage distortion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hanging glaciers hold the absolute dominant number in West China and their changes had important influences on local hydrology, sea-level rise and natural hazards (snow/ice avalanches). However, ...logistic and operational difficulties have resulted in the lack of in-situ-measured data, leaving us with poor knowledge of the changing behaviors of this type of glacier. Here, we presented the spatiotemporal pattern of seasonal and annual mass changes of a mid-latitude hanging glacier in the Tien Shan based on repeated terrestrial laser scanning (TLS) surveys during the period 2016–2018. The distributed glacier surface elevation changes exhibited highly spatiotemporal variability, and the winter elevation changes showed slight surface lowering at the upper elevations and weak thickening at the glacier terminus, which was contrary to altitudinal elevation changing patterns at the summer and annual scales. Mass balance processes of the hanging glacier mainly occurred during summer and the winter mass balance was nearly balanced (−0.10 ± 0.15 m w.e.). The glacier exhibited more rapid mass loss than adjacent other morphological glacier and the estimated response time of the glacier to climate change was very short (6–9 years), indicating hanging glaciers will experience rapid wastage and disappearance in the future even with climate change mitigation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RATIONALE:βARs (β-adrenergic receptors) are prototypical GPCRs (G protein–coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β1AR signaling mediates a global ...response, including both L-type Ca channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, β2AR mediates local signaling with little effect on the function of SR proteins.
OBJECTIVE:To investigate the signaling relationship between β1ARs and β2ARs.
METHOD AND RESULTS:Using whole-cell patch-clamp analyses combined with confocal Ca imaging, we found that the activation of compartmentalized β2AR signaling was able to convert the β1AR signaling from global to local mode, preventing β1ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of β2AR, GRK2 (GPCR kinase-2), βarr1 (β-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the β1AR C terminus, a component of the putative βarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by β2AR activation.
CONCLUSIONS:β2AR stimulation compartmentalizes β1AR signaling into nanoscale local domains in a phosphodiesterase-4–dependent manner by targeting the C terminus of β1ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient β1AR response of sympathetic excitation.
The first synthesis of the tetracyclic aromatic compound furo2,3-gthieno2,3-eindole (“FTI”) is described. The synthetic strategy features a photochemical benzannulation based on the reaction of ...an α-diazo ketone and ynamide which assembles a benzothiophene equipped with substituents that enable subsequent cyclizations to generate the nitrogen and oxygen heterocyclic rings.
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IJS, KILJ, NUK, PNG, UL, UM
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![Furo[2,3‑g]thieno[2,3‑e]ind...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1523-7060/small "Furo[2,3‑g]thieno[2,3‑e]indole: Application of an Ynamide-Based Benzannulation Strategy to the Synthesis of a Tetracyclic Heteroaromatic Compound")