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Agent-based modeling (ABM) is a powerful tool for simulating building users’ dynamic behavior in demand response (DR) programs. However, ABM faces several challenges, particularly in encoding building users’ natural language features and common sense into rules or mathematical equations. To overcome these limitations, this paper proposes an agent framework based on large language models (LLMs) to simulate building users’ air-conditioning setpoint adjustment behavior under DR. This framework leverages LLMs’ natural language processing capabilities to replicate building users’ reasoning and decision-making processes. It consists of five modules: persona, perception, decision, reflection, and memory. Agents are assigned diverse personas through natural language descriptions based on empirical survey data. LLMs drive agents to reason and make decisions based on incentive prices and historical experiences. The results show that the LLM-based agent has common sense derived from natural language-defined personas and exhibits human-like irrational characteristics. This demonstrates the feasibility of replacing rules with natural language in ABM. The LLM-based agent can more effectively model hard-to-parameterize human features and provide decision explanations through LLM outputs. The results show that the inclusion of reflection and memory modules enables the agent to learn from previous decisions and reduce unreasonable choices.

Building users are key participants in demand response (DR) markets, providing significant flexible resources. Due to uncertainty in market clearing prices, various risk-based decision models have been developed to describe their bidding behavior, typically assuming constant risk preferences. However, empirical evidence indicates that users’ risk attitudes vary with the magnitude of load adjustments. To capture this feature, this paper introduces mental accounting theory to model the risk-aware bidding behavior of building users. Total response capacity is divided into three independent mental accounts based on air-conditioning setpoint adjustment magnitude, representing risk-averse, risk-neutral, and risk-seeking behaviors. This framework allows multiple risk preferences to be represented within a unified bidding model. For each account, response quantity and cost models are developed. Bidding strategies under uncertain market clearing prices are formulated by incorporating loss aversion. A multi-agent simulation framework, including building users, a load aggregator, and a grid operator, is established to simulate the market clearing process. A simulation study is conducted using 19 building clusters located in Zhuhai, China. The proposed model is compared with a single-bid model and a step-wise bidding model with constant risk preferences. The results show that it better captures building users’ multiple risk preferences under market clearing price uncertainty. Users tend to secure stable returns through responses with minimal comfort loss, while pursuing excess profits via higher bids for responses involving greater comfort sacrifices.

Background Chronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model. Methods C57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms. Results Huc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy. Conclusion Huc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis. Graphical Abstract

Neuropathic pain is characterized by hyperalgesia and allodynia. Inflammatory response is conducive to tissue recovery upon nerve injury, but persistent and exaggerated inflammation is detrimental and participates in neuropathic pain. Synaptic transmission in the nociceptive pathway, and particularly the balance between facilitation and inhibition, could be affected by inflammation, which in turn is regulated by glial cells. Importantly, glycometabolism exerts a vital role in the inflammatory process. Glycometabolism reprogramming of inflammatory cells in neuropathic pain is characterized by impaired oxidative phosphorylation in mitochondria and enhanced glycolysis. These changes induce phenotypic transition of inflammatory cells to promote neural inflammation and oxidative stress in peripheral and central nervous system. Accumulation of lactate in synaptic microenvironment also contributes to synaptic remodeling and central sensitization. Previous studies mainly focused on the glycometabolism reprogramming in peripheral inflammatory cells such as macrophage or lymphocyte, little attention was paid to the regulation effects of glycometabolism reprogramming on the inflammatory responses in glial cells. This review summarizes the evidences for glycometabolism reprogramming in peripheral inflammatory cells, and presents a small quantity of present studies on glycometabolism in glial cells, expecting to promote the exploration in glycometabolism in glial cells of neuropathic pain.

Varicella-zoster virus reactivation causes neuroinflammation and post-herpetic neuralgia (PHN), in which the mechanism needs to be further explored. Given that Herpes simplex virus type 1 (HSV-1) infection induces a similar neuropathological process, a corresponding model was established for this study. Here we reported that Sirt3 expression decreased in spinal dorsal horn and microglia upon HSV-1 infection-induced neuropathic pain model, which was accompanied by increased mitochondria ROS and disrupted mitophagy. Sirt3 deficiency inhibited the anti-viral innate immunity responses, increased viral loads and mitochondrial ROS production, disrupted mitophagy both in vivo and in vitro. Sirt3 knockdown replicated the cellular responses, while Sirt3 overexpression enhanced the antiviral innate immunity in microglia. Mechanism research revealed that HSV-1 infection disrupted CREB-mediated Sirt3 transcription. AMPK agonist metformin treatment could increase CREB-mediated Sirt3 transcription and enhance anti-viral innate immunity both in vitro and in vivo. In sum, our study reveals the inhibition of CREB-mediated Sirt3 transcription might be the pathology of HSV-1-induced neuropathic pain, which can be blocked by metformin. Graphical Abstract

Prophylactic anticoagulation is a standard strategy for patients undergoing total hip arthroplasty (THA) to prevent deep venous thromboembolism (DVT) and pulmonary embolism (PE). Nevertheless, some patients still experience these complications during their hospital stay. Current risk assessment methods like the Caprini and Geneva scores are not specifically designed for THA and may not accurately predict DVT or PE postoperatively. This study used machine learning techniques to establish models for early diagnosis of DVT and PE in patients undergoing THA. Data were collected from 1481 patients who received perioperative prophylactic anticoagulation. Model establishment and parameter tuning were performed using a training set and evaluated using a test set. Among the models, extreme gradient boosting (XGBoost) performed the best, with an area under the receiver operating characteristic curve (AUC) of 0.982, sensitivity of 0.913, and specificity of 0.998. The main features used in the XGBoost model were direct and indirect bilirubin, partial activation prothrombin time, prealbumin, creatinine, D-dimer, and C-reactive protein. Shapley Additive Explanations analysis was conducted to further analyze these features. This study presents a model for early diagnosis DVT or PE after THA and demonstrates bilirubin could be a potential predictor in the assessment of DVT or PE. Compared to traditional risk assessment, XGBoost has a high sensitivity and specificity to predict DVT and PE in the clinical setting. Furthermore, the results of this study were converted into a web calculator that can be used in clinical practice.

Background This study aimed to assess changes in quality of sleep (QoS) in isolated metastatic patients with spinal cord compression following two different surgical treatments and identify potential contributing factors associated with QoS improvement. Methods We reviewed 49 patients with isolated spinal metastasis at our spinal tumor center between December 2017 and May 2021. Total en bloc spondylectomy (TES) and palliative surgery with postoperative stereotactic radiosurgery (PSRS) were performed on 26 and 23 patients, respectively. We employed univariate and multivariate analyses to identify the potential prognostic factors affecting QoS. Results The total Pittsburgh Sleep Quality Index (PSQI) score improved significantly 6 months after surgery. Univariate analysis indicated that age, pain worsening at night, decrease in visual analog scale (VAS), increase in Eastern Cooperative Oncology Group performance score (ECOG-PS), artificial implant in focus, and decrease in epidural spinal cord compression (ESCC) scale values were potential contributing factors for QoS. Multivariate analysis indicated that the ESCC scale score decreased as an independent prognostic factor. Conclusions Patients with spinal cord compression caused by the metastatic disease had significantly improved QoS after TES and PSRS treatment. Moreover, a decrease in ESCC scale value of > 1 was identified as a favorable contributing factor associated with PSQI improvement. In addition, TES and PSRS can prevent recurrence by achieving efficient local tumor control to improve indirect sleep. Accordingly, timely and effective surgical decompression and recurrence control are critical for improving sleep quality.

Postherpetic neuralgia (PHN) is characterized by neural injury and neuroinflammation resulting from viral infection and reactivation. Herpes simplex virus type 1 (HSV-1) is capable of inducing virus-associated PHN-like neuropathic pain and has been widely used as a model for studying virus-induced neuroinflammatory pain. However, the immune mechanisms underlying virus-induced neuroinflammation and pain remain incompletely understood. In this study, we used an HSV-1-induced neuroinflammatory pain model and observed reduced Lapf expression following HSV-1 infection through transcriptome sequencing, which was further confirmed to be localized in microglia of the spinal dorsal horn by immunofluorescence staining. Lapf microglia-specific deficiency aggravated neuroinflammation and promoted mechanical allodynia by impairing antiviral innate immunity both in vivo and in vitro. Overexpression of Lapf in microglia strengthened antiviral innate immunity and suppressed HSV-1 replication. Mechanistically, transcriptome sequencing of Lapf microglia-specific deficient mice identified lysosomal endocytosis as a critical pathway in LAPF-mediated antiviral innate immunity. Lapf deficiency decreased lysosomal acidity, resulting in reduced TLR9 activation, thereby impairing viral DNA sensing and IFN-I production. Lapf deficiency also reduced lysosomal membrane stability, facilitating the escape of HSV-1 DNA into the cytoplasm, where it could amplify and reactivate. Conversely, Lapf overexpression enhanced lysosomal acidity and membrane stability, promoting TLR9 activation and antiviral innate immunity. Furthermore, Lapf deficiency markedly reduced the phosphorylation of STING, TBK1, and IRF3, whereas Lapf overexpression restored cGAS-STING signaling. This effect was abolished by lysosomal acidification inhibitor chloroquine (CQ), supporting that LAPF promotes lysosomal acidification-dependent antiviral immunity via TLR9 and cGAS-STING pathways. Pharmacological enhancement of LAPF activity using the dephosphorylation inhibitor SHP099 alleviated neuroinflammation and mechanical allodynia in HSV-1-induced neuroinflammatory pain model mice, suggesting potential therapeutic implications. In conclusion, our findings demonstrate that LAPF enhances lysosomal acidification to promote dual antiviral innate immune responses via TLR9 and cGAS-STING pathways in HSV-1 infection, thereby attenuating HSV-1-induced neuroinflammatory pain. These results provide mechanistic insights and potential therapeutic targets for virus-associated neuroinflammatory pain.

Background Hyperglycemia‐induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear. Objective To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia‐induced neuroinflammation and DNP and to explore potential therapeutic interventions. Method and Results Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA‐sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia‐induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high‐glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy‐lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia‐induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia‐induced Sirt3 downregulation. Conclusion Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP. Li et al. have addressed the critical role of hyperglycemia‐induced neuroinflammation in the pathogenesis of diabetic neuropathic pain (DNP), a significant and growing global health concern due to the rising prevalence of diabetes. Metformin can decrease neuroinflammation and DNP, and this effect depends on its regulation of Sirt3 protein level.

Background: Peripheral nerve injury (PNI) frequently causes persistent sensory and motor deficits with limited therapeutic options. While Ptbp1‐mediated astrocyte reprogramming shows promise in central nervous system repair, its role in PNI—particularly regarding spinal cord astrocytes and dorsal root ganglia (DRG) satellite glial cells (SGCs)—remains unexplored.Aims: This study aimed to determine whether Ptbp1 knockdown in glial cells enhances functional recovery after sciatic nerve injury (SNI) by dual mechanisms: (1) converting spinal cord astrocytes to motor neurons and polarizing them toward neuroprotective A2 phenotype, and (2) activating regenerative signaling pathways in DRG SGCs.Materials & Methods: C57BL/6J mice underwent SNI followed by intrathecal injection of AAV‐GFAP‐CasRx‐Ptbp1 (targeting Ptbp1 in astrocytes/SGCs) or control virus. Primary astrocytes and SGCs were transfected with Ptbp1 siRNA in vitro. Assessments included functional recovery (Basso Mouse Scale, Louisville Swim Score, Hargreaves test, von Frey assay), axonal regeneration (HE/β3‐tubulin/SCG‐10 staining), transcriptome/ATAC sequencing, and molecular analyses (immunofluorescence for DCX/Islet1/ntng2‐NGL‐2; Western blot for Ptbp1/GDNF/C3).Results: Ptbp1 was upregulated in spinal cord astrocytes and DRG SGCs post‐SNI. Its knockdown accelerated motor/sensory functional recovery and axonal regeneration. Mechanistically, in the spinal cord, Ptbp1 depletion induced astrocyte‐to‐motor neuron conversion (upregulation of DCX/Islet1/Map2) and polarized astrocytes toward A2 phenotype (upregulation of S100a10/GDNF; downregulation of C3). In DRG, it activated the ntng2/NGL‐2 pathway in SGCs, enhancing sensory axon regeneration (upregulation of ATF3/GAP43). Ntng2 blockade abolished sensory regeneration, confirming pathway dependence.Discussion: Ptbp1 knockdown promotes PNI repair through spatially distinct mechanisms: spinal cord astrocyte reprogramming/A2 polarization synergizes with DRG SGC‐mediated ntng2/NGL‐2 activation. While astrocyte‐to‐neuron conversion was limited, dominant A2 polarization provided neuroprotection. The absence of SGC transdifferentiation highlights cell‐type‐specific responses. Limitations include low conversion efficiency and interspecies regenerative differences.Conclusion: Targeting Ptbp1 in glial cells accelerates PNI recovery by dual regenerative mechanisms: motor function restoration via astrocyte‐derived neuron replenishment and A2 polarization, coupled with sensory repair through ntng2/NGL‐2 pathway activation. This establishes Ptbp1 as a promising therapeutic target for nerve injuries. Knockdown of Ptbp1 in spinal cord astrocytes promotes motor function recovery after sciatic nerve injury by inducing their transdifferentiation into motor neurons and polarization toward the neuroprotective A2 phenotype. Concurrently, Ptbp1 depletion in dorsal root ganglion satellite glial cells enhances sensory axon regeneration through the activation of the ntng2/NGL‐2 signaling pathway.