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Objective: Neuropathic pain poses a persistent challenge in clinical management. Neuromodulation has emerged as a last‐resort therapy. Conventional spinal cord stimulation (Con SCS) often causes abnormal sensations and provides short analgesia, whereas high‐frequency spinal cord stimulation (HF SCS) is a newer therapy that effectively alleviates pain without paresthesia. However, the modes of action of 10kHz HF SCS (HF10 SCS) in pain relief remain unclear. To bridge this knowledge gap, we employed preclinical models that mimic certain features of clinical SCS to explore the underlying mechanisms of HF10 SCS. Addressing these issues would provide the scientific basis for improving and evaluating the effectiveness, reliability, and practicality of different frequency SCS in clinical settings. Methods: We established a preclinical SCS model to examine its effects in a neuropathic pain rat model. We conducted bulk and single‐cell RNA sequencing in the spinal dorsal horn (SDH) to examine cellular and molecular changes under different treatments. We employed genetic manipulations through intrathecal injection of a lentiviral system to explore the SCS‐mediated signaling axis in pain. Various behavioral tests were performed to evaluate pain conditions under different treatments. Results: We found that HF10 SCS significantly reduces immune responses in the SDH by inactivating the Kaiso‐P2X7R pathological axis in microglia, promoting long‐lasting pain relief. Targeting Kaiso‐P2X7R in microglia dramatically improved efficacy of Con SCS treatment, leading to reduced neuroinflammation and long‐lasting pain relief. Interpretation: HF10 SCS could improve the immunopathologic state in the SDH, extending its benefits beyond symptom relief. Targeting the Kaiso‐P2X7R axis may enhance Con SCS therapy and offer a new strategy for pain management. ANN NEUROL 2024;95:966–983 [ABSTRACT FROM AUTHOR]

In order to investigate the mechanical properties and permeability characteristics of sandstone during damage evolution under hydromechanical condition, a series of coupled hydro-mechanical triaxial tests on sandstone specimens were conducted based on the Rock Top 50HT full-stress multi-field coupling triaxial test system. Variations in permeability as a function of confining pressure, seepage pressure gradient, and volumetric strain during damage evolution were obtained. The results show that: (1) When the confining pressure is constant and the specimen is gradually changed from a dry to a saturated state, the failure mode of sandstone changes from shear failure to single-slope shear failure. (2) There are four distinctive stages in the permeability evolution of sandstone: gradual decrease, steady development, gradual increase, and rapid growth. These stages correspond to the complete stress–strain curve under the respective working conditions. (3) Employing the Weibull distribution formula, this study investigates the evolution of fracture damage under varying working conditions and determines the permeability evolution relationships associated with damage variables. This exploration reveals an intrinsic link between permeability and damage variables. These findings enhance our understanding of the interplay between stress, deformation, permeability, and damage evolution in seepage-stress coupled sandstone. The results contribute valuable insights to the field of rock mechanics and hold implications for diverse geotechnical and engineering applications. [ABSTRACT FROM AUTHOR]

Background: The behaviors and ontogeny of Aedes aegypti are closely related to the spread of diseases caused by dengue (DENV), chikungunya (CHIKV), Zika (ZIKV), and yellow fever (YFV) viruses. During the life cycle, Ae. aegypti undergoes drastic morphological, metabolic, and functional changes triggered by gene regulation and other molecular mechanisms. Some essential regulatory factors that regulate insect ontogeny have been revealed in other species, but their roles are still poorly investigated in the mosquito. Results: Our study identified 6 gene modules and their intramodular hub genes that were highly associated with the ontogeny of Ae. aegypti in the constructed network. Those modules were found to be enriched in functional roles related to cuticle development, ATP generation, digestion, immunity, pupation control, lectins, and spermatogenesis. Additionally, digestion-related pathways were activated in the larvae and adult females but suppressed in the pupae. The integrated protein‒protein network also identified cilium-related genes. In addition, we verified that the 6 intramodular hub genes encoding proteins such as EcKinase regulating larval molt were only expressed in the larval stage. Quantitative RT‒PCR of the intramodular hub genes gave similar results as the RNA-Seq expression profile, and most hub genes were ontogeny-specifically expressed. Conclusions: The constructed gene coexpression network provides a useful resource for network-based data mining to identify candidate genes for functional studies. Ultimately, these findings will be key in identifying potential molecular targets for disease control. [ABSTRACT FROM AUTHOR]

Arylalkylamine N‐acetyltransferase (aaNAT), considered a potential new insecticide target, catalyzes the acetylation of arylalkylamine substrates such as serotonin and dopamine and, hence, mediates diverse functions in insects. However, the origin of insect aaNATs (iaaNATs) and the evolutionary process that generates multiple aaNATs in mosquitoes remain largely unknown. Here, we have analyzed the genomes of 33 species to explore and expand our understanding of the molecular evolution of this gene family in detail. We show that aaNAT orthologs are present in Bacteria, Cephalochordata, Chondrichthyes, Cnidaria, Crustacea, Mammalia, Placozoa, and Teleoste, as well as those from a number of insects, but are absent in some species of Annelida, Echinozoa, and Mollusca as well as Arachnida. Particularly, more than 10 aaNATs were detected in the Culicinae subfamily of mosquitoes. Molecular evolutionary analysis of aaNAT/aaNAT‐like genes in mosquitoes reveals that tandem duplication events led to gene expansion in the Culicinae subfamily of mosquitoes more than 190 million years ago. Further selection analysis demonstrates that mosquito aaNATs evolved under strongly positive pressures that generated functional diversity following gene duplication events. Overall, this study may provide novel insights into the molecular evolution of the aaNAT family in mosquitoes. [ABSTRACT FROM AUTHOR]

In order to obtain the optimal spacing of closely spaced footings under cyclic dynamic loading, dynamic model tests of closely spaced footings were carried out on unreinforced and reinforced sand foundations. The influence of the center point spacing (S) of closely spaced footings on the bearing capacity of the foundation under cyclic dynamic load is discussed. The test results show the following: (1) The dynamic load peak of the unreinforced and reinforced sand foundation is the largest when S/B = 2.0 (B is the width of footing), and the ultimate bearing capacity of the reinforced sand foundation is 20% higher than that of unreinforced sand foundation. (2) The vertical soil pressure at different positions of closely spaced footings with different spacing ratios (S/B) on the reinforced sand foundation is lower than that of unreinforced sand foundation, and the vertical soil pressure at different buried depths ('1-3', '2-3', '3-3' positions) at the center of closely spaced footings are smaller than that below the footings ('1-2', '2-2', '3-2' positions). (3) When S/B = 2.0, the strain of geogrid and the peak acceleration at the center of the closely spaced footings are the smallest, indicating that the sand foundation has little transient change under this spacing. From the aspects of ultimate bearing capacity design and engineering economic benefits, it is suggested that the spacing between closely spaced footings should be arranged according to two times the width of the footing (S/B = 2.0). [ABSTRACT FROM AUTHOR]