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Background Chemokine axis chemokine C-X-C motif ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) is an emerging pain modulator, but mechanisms for its involvement in neuropathic pain remain unclear. Here, we aimed to study whether CXCL12/CXCR4 axis modulated the development of neuropathic pain via glial mechanisms. In this study, two mouse models of neuropathic pain, namely partial sciatic nerve ligation (pSNL) model and chronic post-ischemia pain (CPIP) model, were used. Results In the dorsal horn of L3–L5 segment of spinal cord, CXCL12 and CXCR4 were expressed in both astrocyte and microglia in normal mice. In the pSNL or CPIP model, the expression level of CXCL12 in the ipsilateral L3–L5 segment of mice spinal cord was increased in an astrocyte-dependent manner on post-operative day (POD) 3. Intrathecal administration of CXCL12 with AMD3100 (CXCR4 antagonist) or minocycline (microglia activation inhibitor), but not fluorocitrate (astrocyte activation inhibitor), reversed CXCL12-indued mechanical allodynia in naïve mice. In these models, AMD3100 and AMD3465 (CXCR4 antagonist), administered daily from 1 h before surgery and up to POD 3, attenuated the development of mechanical allodynia. Moreover, AMD3100 administered daily from 1 h before surgery and up to POD 3 downregulated mRNA levels of tumor necrosis factor alpha, interleukin 1β, and interleukin 6 in the ipsilateral L3–L5 segment of spinal cord in the pSNL and CPIP models on POD 3. Conclusion This study demonstrates the crosstalk between astrocytic CXCL12 and microglial CXCR4 in the pathogenesis of neuropathic pain using pSNL and CPIP models. Our results offer insights for the future research on CXCL12/CXCR4 axis and neuropathic pain therapy.

Cancer immunotherapy has revolutionized oncology by leveraging the immune system to combat tumors. Among various biomarkers, neoantigens and tumor mutational burden (TMB) have emerged as critical factors in tailoring personalized treatments. Neoantigens are tumor-specific peptides displayed on cancer cell surfaces, derived from somatic mutations. Recognized as \"non-self\" by the immune system, they trigger T-cell responses and enable therapies like personalized vaccines and adoptive T-cell transfer. Critically, neoantigen potential correlates with TMB, which quantifies the total somatic mutations within a tumor genome. A higher TMB generally correlates with a greater likelihood of generating immunogenic neoantigens, making it a predictive biomarker for the efficacy of immune checkpoint inhibitors (ICI). Progress in high-throughput sequencing, bioinformatics, and immuno-peptidomics has significantly enhanced the accuracy of neoantigen prediction, including assessments of major histocompatibility complex (MHC) binding affinity and T-cell receptor recognition. Clinically, neoantigen-based therapies have shown efficacy in early trials, with strategies such as mRNA vaccines demonstrating synergy with ICI by boosting T-cell activation and overcoming immune suppression. Combining neoantigen-based therapies with chemotherapy and radiotherapy harnesses synergistic mechanisms to enhance efficacy, overcome resistance, and emerge as a pivotal oncology research focus. The integration of TMB into clinical practice has received regulatory approval as a biomarker for stratifying patients for ICI therapies. Furthermore, advanced methodologies like liquid biopsy and single-cell technologies have streamlined TMB measurement, improving its predictive value for personalized immunotherapy. Collectively, neoantigens and TMB have optimized the evolution of precision immuno-oncology by providing frameworks that maximize therapeutic efficacy, overcome resistance mechanisms, and advance durable cancer remission.​

Background Chemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling. Methods miRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway. Results CXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3′ UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR-23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naïve mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice. Conclusions miR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity.

Extensive experiments illustrate that moments and their derivations can act as effective fingerprint features for specific emitter identification. Nevertheless, the lack of mechanistic explanation restricts the moment-based fingerprint features to a trial-based and data-driven technique. To make up for theoretical weakness and enhance generalization ability, we analytically investigate how intentional modulation and unintentional modulation affect moments. A framework for extracting moment-based fingerprint features is proposed through fine-segmenting slices. Fingerprint features are extracted, followed by segmenting signals into a combination of sinewaves and calculating their moments. The proposed framework shows advantages in mechanism interpretability and generalizing ability. Simulations and experiments verified the correctness and effectiveness of the proposed framework.

Deep learning (DL)-based specific emitter identification (SEI) technique can automatically extract radio frequency (RF) fingerprint features in RF signals to distinguish between legal and illegal devices and enhance the security of wireless network. However, deep neural network (DNN) can easily be fooled by adversarial examples or perturbations of the input data. If a malicious device emits signals containing a specially designed adversarial samples, will the DL-based SEI still work stably to correctly identify the malicious device? To the best of our knowledge, this research is still blank, let alone the corresponding defense methods. Therefore, this paper designs two scenarios of attack and defense and proposes the corresponding implementation methods to specializes in the robustness of DL-based SEI under adversarial attacks. On this basis, detailed experiments are carried out based on the real-world data and simulation data. The attack scenario is that the malicious device adds an adversarial perturbation signal specially designed to the original signal, misleading the original system to make a misjudgment. Experiments based on three different attack generation methods show that DL-based SEI is very vulnerability. Even if the intensity is very low, without affecting the probability density distribution of the original signal, the performance can be reduced to about 50%, and at −22 dB it is completely invalid. In the defense scenario, the adversarial training (AT) of DL-based SEI is added, which can significantly improve the system’s performance under adversarial attacks, with ≥60% improvement in the recognition rate compared to the network without AT. Further, AT has a more robust effect on white noise. This study fills the relevant gaps and provides guidance for future research. In the future research, the impact of adversarial attacks must be considered, and it is necessary to add adversarial training in the training process.

Conventional reconnaissance camera systems have been flown on manned aircraft, where the weight, size, and power requirements are not stringent. However, today, these parameters are important for unmanned aerial vehicles (UAVs). This article provides a solution to the design of airborne large aperture infrared optical systems, based on a monocentric lens that can meet the strict criteria of aerial reconnaissance UAVs for a wide field of view (FOV) and lightness of airborne electro-optical pod cameras. A monocentric lens has a curved image plane, consisting of an array of microsensors, which can provide an image with 368 megapixels over a 100° FOV. We obtained the initial structure of a five-glass (5GS) asymmetric monocentric lens with an air gap, using ray-tracing and global optimization algorithms. According to the design results, the ground sampling distance (GSD) of the system is 0.33 m at 3000 m altitude. The full-field modulation transfer function (MTF) value of the system is more than 0.4 at a Nyquist frequency of 70 lp/mm. We present a primary thermal control method, and the image quality was steady throughout the operating temperature range. This compactness and simple structure fulfill the needs of uncrewed airborne lenses. This work may facilitate the practical application of monocentric lens in UAVs.

Chronic pain following nerve injury (neuropathic pain), is notoriously difficult to treat, with current analgesics showing limited efficacy and adverse or dangerous side effects. One new candidate analgesic target is the TRPM8 ion channel, identified as the peripheral detector for innocuous cool sensation and reported to attenuate spinal cord pain processing by processes involving inhibitory metabotropic glutamate (mGlu) receptors. Highly selective Group II/III mGluR antagonists and allosteric modulators were used in a nerve injury model to identify the specific receptor subtypes mediating TRPM8-mediated attenuation of nociceptive (pain) processing through peptidergic and non-peptidergic afferent inputs (associated with thermal and mechanical nociception respectively). Integrated experimental approaches involved immunofluorescence histochemistry, functional Ca fluorescence responses of synaptoneurosomes and reflex pain behaviours. Differential expression of TRPV1 and MrgprD was demonstrated in peptidergic and non-peptidergic afferents and their selective activation by capsaicin and β-alanine characterised to interrogate transmission at the first central synapses from these afferents in dorsal spinal cord synaptoneurosomes. TRPM8-evoked attenuation of nerve injury-induced increments in capsaicin responses was selectively modified by mGlu -targetting agents whereas the equivalent effect on β-alanine responses was selectively modified by mGlu -targetting agents. Other Group II/III mGluR subtypes appeared not to be involved. Reflex pain behaviour assessments correspondingly pointed to mGlu and mGlu being selectively involved in TRPM8 attenuation of thermal and mechanical hypersensitivity respectively. Spinal administration of mGlu and mGlu antagonists impacted TRPM8 attenuation of nerve injury-induced synaptic hypersensitivity at spinal and also supraspinal regions of the CNS associated with pain processing. Our findings clarify the roles of specific Group II/III mGluRs in the antinociceptive effects of TRPM8 activation against nerve injury-induced hypersensitivity. The mGluRs involved in impacting peptidergic (thermal-associated) nociceptive inputs and non-peptidergic (mechanical-associated) nociceptive inputs appear quite distinct - mGlu and mGlu , respectively. This provides robust evidence to support the fundamental concept of distinct parallel processing and differential modulation of these classes of inputs. This work extends our understanding of the basis for TRPM8 analgesia, identifies distinct modality-specific processes and points to the possibility of refined therapeutic interventions using mGluR modulators as adjunct promoters of particular elements of analgesia.

Immunotherapies, especially the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, have revolutionized the therapeutic strategies of various cancers. As for colorectal cancer (CRC), the current clinical application of PD-1/PD-L1 inhibitors are mainly used according to the mutation pattern, which is categorized into deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H) and proficient mismatch repair (pMMR), or non-high levels of microsatellite instability (non-MSI-H). PD-1/PD-L1 inhibitors have been proven to have favorable outcomes against dMMR/MSI-H CRC because of more T-cell infiltration into tumor tissues. Nevertheless, the effectiveness of PD-1/PD-L1 inhibitors in pMMR/non-MSI-H CRC is still uncertain. Because of the quite-lower proportion of dMMR/MSI-H in CRC, PD-1/PD-L1 inhibitors have been reported to combine with other antitumor treatments including chemotherapy, radiotherapy, and targeted therapy for better therapeutic effect in recent clinical trials. Neoadjuvant therapy, mainly including chemotherapy and radiotherapy, not only can reduce clinical stage but also benefit from local control, which can improve clinical symptoms and the quality of life. Adding immunotherapy into neoadjuvant therapy may change the treatment strategy of primary resectable or some metastatic CRC. In this review, we focus on the development of neoadjuvant anti-PD-1/PD-L1 therapy and discuss the future perspectives in CRC.

Keywords: TCR signaling, ZDHHC21, Themis, S-palmitoylation, Homeostatic balance

Immune checkpoint therapy, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, has achieved remarkable results in treating various tumors. However, most cancer patients show a low response rate to PD-1/PD-L1 blockade, especially those with microsatellite stable/mismatch repair-proficient colorectal cancer subtypes, which indicates an urgent need for new approaches to augment the efficacy of PD-1/PD-L1 blockade. Cholesterol metabolism, which involves generating multifunctional metabolites and essential membrane components, is also instrumental in tumor development. In recent years, inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase that regulates cholesterol metabolism, has been demonstrated to be a method enhancing the antitumor effect of PD-1/PD-L1 blockade to some extent. Mechanistically, PCSK9 inhibition can maintain the recycling of major histocompatibility protein class I, promote low-density lipoprotein receptor-mediated T-cell receptor recycling and signaling, and modulate the tumor microenvironment (TME) by affecting the infiltration and exclusion of immune cells. These mechanisms increase the quantity and enhance the antineoplastic effect of cytotoxic T lymphocyte, the main functional immune cells involved in anti-PD-1/PD-L1 immunotherapy, in the TME. Therefore, combining PCSK9 inhibition therapy with anti-PD-1/PD-L1 immunotherapy may provide a novel option for improving antitumor effects and may constitute a promising research direction. This review concentrates on the relationship between PCSK9 and cholesterol metabolism, systematically discusses how PCSK9 inhibition potentiates PD-1/PD-L1 blockade for cancer treatment, and highlights the research directions in this field.