Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.

Targeting the p53-MDM2 pathway to reactivate tumor p53 is a chemotherapeutic approach. However, the involvement of this pathway in CD8+ T cell-mediated antitumor immunity is unknown. Here, we report that mice with MDM2 deficiency in T cells exhibit accelerated tumor progression and a decrease in tumor-infiltrating CD8+ T cell survival and function. Mechanistically, MDM2 competes with c-Cbl for STAT5 binding, reduces c-Cbl-mediated STAT5 degradation and enhances STAT5 stability in tumor-infiltrating CD8+ T cells. Targeting the p53-MDM2 interaction with a pharmacological agent, APG-115, augmented MDM2 in T cells, thereby stabilizing STAT5, boosting T cell immunity and synergizing with cancer immunotherapy. Unexpectedly, these effects of APG-115 were dependent on p53 and MDM2 in T cells. Clinically, MDM2 abundance correlated with T cell function and interferon-γ signature in patients with cancer. Thus, the p53-MDM2 pathway controls T cell immunity, and targeting this pathway may treat patients with cancer regardless of tumor p53 status.

Arginine monomethylation by PRMT7 controls MAVS-mediated antiviral innate immunity.

Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense.

Asymmetric arginine dimethylation of cytosolic RNA and DNA sensors by PRMT3 attenuates antiviral innate immunity.

The cytosolic RNA and DNA sensors initiate type I interferon signaling when binding to RNA or DNA. To effectively protect the host against virus infection and concomitantly avoid excessive interferonopathy at resting states, these sensors must be tightly regulated. However, the key molecular mechanisms regulating these sensors' activation remain elusive. Here, we identify PRMT3, a type I protein arginine methyltransferase, as a negative regulator of cytosolic RNA and DNA sensors. PRMT3 interacts with RIG-I, MDA5, and cGAS and catalyzes asymmetric dimethylation of R730 on RIG-I, R822 on MDA5, and R111 on cGAS. These modifications reduce RNA-binding ability of RIG-I and MDA5 as well as DNA-binding ability and oligomerization of cGAS, leading to the inhibition of downstream type I interferon production. Furthermore, mice with loss of one copy of Prmt3 or in vivo treatment of the PRMT3 inhibitor, SGC707, are more resistant to RNA and DNA virus infection. Our findings reveal an essential role of PRMT3 in the regulation of antiviral innate immunity and give insights into the molecular regulation of cytosolic RNA and DNA sensors' activation.

USP38 promotes deubiquitination of K11-linked polyubiquitination of HIF1α at Lys769 to enhance hypoxia signaling.

HIF1α is one of the master regulators of the hypoxia signaling pathway and its activation is regulated by multiple post-translational modifications (PTMs). Deubiquitination mediated by deubiquitylating enzymes (DUBs) is an essential PTM that mainly modulates the stability of target proteins. USP38 belongs to the ubiquitin-specific proteases (USPs). However, whether USP38 can affect hypoxia signaling is still unknown. In this study, we used quantitative real-time PCR assays to identify USPs that can influence hypoxia-responsive gene expression. We found that overexpression of USP38 increased hypoxia-responsive gene expression, but knockout of USP38 suppressed hypoxia-responsive gene expression under hypoxia. Mechanistically, USP38 interacts with HIF1α to deubiquitinate K11-linked polyubiquitination of HIF1α at Lys769, resulting in stabilization and subsequent activation of HIF1α. In addition, we show that USP38 attenuates cellular ROS and suppresses cell apoptosis under hypoxia. Thus, we reveal a novel role for USP38 in the regulation of hypoxia signaling.

The effect of top-down attention on empathy fatigue.

Prolonged exposure to others' suffering can lead to empathy fatigue, especially when individuals struggle to effectively regulate their empathic capacity. Shifting active attention away from emotional components toward cognitive components of others' suffering is an effective strategy for mitigating empathy fatigue. This research investigated how top-down attentional manipulation modulates empathy fatigue in both auditory (Study 1) and visual (Study 2) modalities. Participants completed two tasks in both studies: (i) the attention to cognitive empathy task (A-C task) and (ii) the attention to emotional empathy task (A-E task). Each task included three blocks (Time Block 1, Time Block 2, and Time Block 3) designed to induce empathy fatigue. Study 1 revealed that the A-C task reduced empathy fatigue and N1 amplitudes than the A-E task in Time Block 3, indicating that attention to cognitive empathy might decrease auditory empathy fatigue. Study 2 indicates that the A-C task caused a longer N2 latency than the A-E task, signifying a decelerated emotional empathic response when attention was on cognitive empathy in the visual modality. Overall, prioritizing cognitive empathy seems to conserve mental resources and reduce empathy fatigue. This research documented the relationship between top-down attention and empathy fatigue and the possible neural mechanism.

Single Crystal Seed Induced Epitaxial Growth Stabilizes α-FAPbI3 in Perovskite Solar Cells.

FAPbI3 stands out as an ideal candidate for the photoabsorbing layer of perovskite solar cells (PSCs), showcasing outstanding photovoltaic properties. Nonetheless, stabilizing photoactive α-FAPbI3 remains a challenge due to the lower formation energy of the competitive photoinactive δ-phase. In this study, we employ tetraethylphosphonium lead tribromide (TEPPbBr3) single crystals as templates for the epitaxial growth of PbI2. The strategic use of TEPPbBr3 optimizes the evolution of intermediates and the crystallization kinetics of perovskites, leading to high-quality and phase-stable α-FAPbI3 films. The TEPPbBr3-modified perovskite exhibits optimized carrier dynamics, yielding a champion efficiency of 25.13% with a small voltage loss of 0.34 V. Furthermore, the target device maintains 90% of its initial PCE under maximum power point (MPP) tracking over 1000 h. This work establishes a promising pathway through single crystal seed based epitaxial growth for achieving satisfactory crystallization regulation and phase stabilization of α-FAPbI3 perovskites toward high-efficiency and stable PSCs.

Origin of Water-Stable CsPbX3 Quantum Dots Assisted by Zwitterionic Ligands and Sequential Strategies for Enhanced Luminescence Based on Crystal Evolution.

Water stability is a crucial issue always addressed for commercial practical application of perovskite quantum dots (QDs). Recent advances in ligand engineering for in situ synthesis of water-stable perovskite QDs have attracted growing interest. However, the exact mechanism remains unclear. Here, the function of 4-bromobutyric acid (BBA) and oleylamine (OLA) is systematically studied in water-stable CsPbX3 (X = Br and I) QDs and confirms that the zwitterionic ligands generated in situ by BBA and OLA are anchored on the QDs surface, thus preventing water from penetrating into the QDs. Cs4PbBr6 intermediate crystal found in the crystal structure evolution process of CsPbX3 QD further reveals a complete crystallization process: PbX2 + CsX + Br- → Cs4PbBr6 crystals + X-→ CsPbX3 QDs + Br-. Furthermore, it is found that the solvent coordination of the precursor solution has a significant effect on the crystallinity of Cs4PbBr6 intermediate crystal, while the Rb+ doping can effectively passivate the surface defects of CsPbX3 QDs, thereby jointly achieving photoluminescence quantum yields (PLQY) of 94.6% for CsPbBr3 QDs (88.2% for CsPbI3 QDs). This work provides new insights and guiding ideas for the green synthesis of high-quality and water-stable perovskite QDs.

A Versatile Strategy for Concurrent Passive Daytime Radiative Cooling and Sustainable Energy Harvesting.

Developing versatile systems that can concurrently achieve energy saving and energy generation is critical to accelerate carbon neutrality. However, challenges on designing highly effective, large scale, and multifunctional photonic film hinder the concurrent combination of passive daytime radiative cooling (PDRC) and utilization of sustainable clean energies. Herein, a versatile scalable photonic film (Ecoflex@h-BN) with washable property and excellent mechanical stability is developed by combining the excellent scattering efficiency of the hexagonal boron nitride (h-BN) nanoplates with the high infrared emissivity and ideal triboelectric negative property of the Ecoflex matrix. Strikingly, sufficiently high solar reflectance (0.92) and ideal emissivity (0.97) endow the Ecoflex@h-BN film with subambient cooling effect of ≈9.5 °C at midday during the continuous outdoor measurements. In addition, the PDRC Ecoflex@h-BN film-based triboelectric nanogenerator (PDRC-TENG) exhibits a maximum peak power density of 0.5 W m-2 . By reasonable structure design, the PDRC-TENG accomplishes effective wind energy harvesting and can successfully drive the electronic device. Meanwhile, an on-skin PDRC-TENG is fabricated to harvest human motion energy and monitor moving states. This research provides a novel design of a multifunctional PDRC photonic film, and offers a versatile strategy to realize concurrent PDRC and sustainable energies harvesting.

Carbon Corrosion Induced by Surface Defects Accelerates Degradation of Platinum/Graphene Catalysts in Oxygen Reduction Reaction.

Graphene supported electrocatalysts have demonstrated remarkable catalytic performance for oxygen reduction reaction (ORR). However, their durability and cycling performance are greatly limited by Oswald ripening of platinum (Pt) and graphene support corrosion. Moreover, comprehensive studies on the mechanisms of catalysts degradation under 0.6-1.6 V versus RHE (Reversible Hydrogen Electrode) is still lacking. Herein, degradation mechanisms triggered by different defects on graphene supports are investigated by two cycling protocols. In the start-up/shutdown cycling (1.0-1.6 V vs. RHE), carbon oxidation reaction (COR) leads to shedding or swarm-like aggregation of Pt nanoparticles (NPs). Theoretical simulation results show that the expansion of vacancy defects promotes reaction kinetics of the decisive step in COR, reducing its reaction overpotential. While under the load cycling (0.6-1.0 V vs. RHE), oxygen containing defects lead to an elevated content of Pt in its oxidation state which intensifies Oswald ripening of Pt. The presence of vacancy defects can enhance the transfer of electrons from graphene to the Pt surface, reducing the d-band center of Pt and making it more difficult for the oxidation state of platinum to form in the cycling. This work will provide comprehensive understanding on Pt/Graphene catalysts degradation mechanisms.

A Novel Multifunctional Photonic Film for Colored Passive Daytime Radiative Cooling and Energy Harvesting.

Passive daytime radiative cooling (PDRC) materials with sustainable energy harvesting capability is critical to concurrently reduce traditional cooling energy utilized for thermal comfort and transfer natural clean energies into electricity. Herein, a versatile photonic film (Ecoflex@BTO@UAFL) based on a novel fluorescent luminescence color passive radiative cooling with triboelectric and piezoelectric effect is developed by filling the dielectric BaTiO3 (BTO) nanoparticles and ultraviolet absorption fluorescent luminescence (UAFL) powder into the elastic Ecoflex matrix. Test results demonstrate that the Ecoflex@BTO@UAFL photonic film exhibits a maximum passive radiative cooling effect of ∽10.1 °C in the daytime. Meanwhile, its average temperature drop in the daytime is ~4.48 °C, which is 0.91 °C higher than that of the Ecoflex@BTO photonic film (3.56 °C) due to the addition of UAFL material. Owing to the high dielectric constant and piezoelectric effect of BTO nanoparticles, the maximum power density (0.53 W m-2, 1 Hz @ 10 N) of the Ecoflex@BTO photonic film-based hybrid nanogenerator is promoted by 70.9% compared to the Ecoflex film-based TENG. This work provides an ingenious strategy for combining PDRC effects with triboelectric and piezoelectric properties, which can spontaneously achieve thermal comfort and energy conservation, offering a new insight into multifunctional energy saving.

π-π Stacking at the Perovskite/C60 Interface Enables High-Efficiency Wide-Bandgap Perovskite Solar Cells.

Interface passivation is a key method for improving the efficiency of perovskite solar cells, and 2D/3D perovskite heterojunction is the mainstream passivation strategy. However, the passivation layer also produces a new interface between 2D perovskite and fullerene (C60), and the properties of this interface have received little attention before. Here, the underlying properties of the 2D perovskite/C60 interface by taking the 2D TEA2PbX4 (TEA = C6H10NS; X = I, Br, Cl) passivator as an example are systematically expounded. It is found that the 2D perovskite preferentially exhibits (002) orientation with the outermost surface featuring an oriented arrangement of TEACl, where the thiophene groups face outward. The outward thiophene groups further form a strong π-π stacking system with C60 molecule, strengthening the interaction force with C60 and facilitating the creation of a superior interface. Based on the vacuum-assisted blade coating, wide-bandgap (WBG, 1.77 eV) perovskite solar cells achieved impressive records of 19.28% (0.09 cm2) and 18.08% (1.0 cm2) inefficiency, respectively. This research not only provides a new understanding of interface processing for future perovskite solar cells but also lays a solid foundation for realizing efficient large-area devices.

Preclinical Pharmacology Characterization of Sovleplenib (HMPL-523), an Orally Available Syk Inhibitor.

Spleen tyrosine kinase (Syk) is an intracellular tyrosine kinase involved in the signal transduction in immune cells mainly. Its aberrant regulation is associated with diversified allergic disorders, autoimmune diseases and B cell malignancies. Therefore, inhibition of Syk is considered a reasonable approach to treat autoimmune/inflammatory diseases and B cell malignancies. Here we described the preclinical characterization of sovleplenib, a novel, highly potent and selective, oral Syk inhibitor, in several rodent autoimmune disease models. Sovleplenib potently inhibited Syk activity in a recombinant enzymatic assay and Syk-dependent cellular functions in various immune cell lines and human whole blood in vitro. Furthermore, sovleplenib, by oral administration, demonstrated strong in vivo efficacies in murine models of immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and chronic graft-versus-host disease (cGVHD), and a rat model of collagen induced arthritis (CIA) respectively, in a dose-dependent manner. Collectively, these results clearly supported sovleplenib as a therapeutic agent in the treatment of autoimmune diseases. Sovleplenib is being globally developed for ITP (Phase III, NCT05029635, Phase Ib/II, NCT03951623), wAIHA (Phase II/III, NCT05535933) and B-cell lymphoma (Phase I, NCT02857998, NCT03779113). SIGNIFICANCE STATEMENT: Syk is a key mediator of signaling pathways downstream of a wide array of receptors important for immune functions, including the B cell receptor, immunoglobulin receptors bearing Fc receptors. Inhibition of Syk could provide a novel therapeutic approach for autoimmune diseases and hematologic malignancies. The manuscript describes the preclinical pharmacology characterization of sovleplenib, a novel Syk inhibitor, in enzymatic and cellular assays in vitro and several murine autoimmune disease models in vivo.

Ultra-thin sub-diffraction metalens with a wide field-of-view for UV focusing.

In recent years, wide field-of-view imaging technology based on a metasurface has been widely applied. However, works on the reported sub-diffraction metalens with a wide field-of-view indicate that multiple structures are essential to effectively eliminate aberrations, which results in a heavy device thickness and weakens the advantage of an ultra-thin metasurface. To solve this problem, according to the super-oscillation theory and the translational symmetry of quadratic phase, as well as the principle of virtual aperture diaphragm based on wave vector filter, this Letter demonstrates a sub-diffraction metalens combined with a single quadratic metalens and a wave vector filter. Our design not only realizes the super-resolution effects of 0.74 to 0.75 times the diffraction limit in the wide field-of-view of nearly 180° for the first time to our knowledge but also compresses the device thickness to the subwavelength order in principle. The proposed ultra-thin sub-diffraction metalens with a wide field-of-view is expected to be applied in the fields of super-resolution fast scanning imaging, information detection, small target recognition, and so on.

A muti-modal feature fusion method based on deep learning for predicting immunotherapy response.

Immune checkpoint therapy (ICT) has greatly improved the survival of cancer patients in the past few years, but only a small number of patients respond to ICT. To predict ICT response, we developed a multi-modal feature fusion model based on deep learning (MFMDL). This model utilizes graph neural networks to map gene-gene relationships in gene networks to low dimensional vector spaces, and then fuses biological pathway features and immune cell infiltration features to make robust predictions of ICT. We used five datasets to validate the predictive performance of the MFMDL. These five datasets span multiple types of cancer, including melanoma, lung cancer, and gastric cancer. We found that the prediction performance of multi-modal feature fusion model based on deep learning is superior to other traditional ICT biomarkers, such as ICT targets or tumor microenvironment-associated markers. In addition, we also conducted ablation experiments to demonstrate the necessity of fusing different modal features, which can improve the prediction accuracy of the model.

Upregulated LncRNA H19 Sponges MiR-106a-5p and Contributes to Aldosterone-Induced Vascular Calcification via Activating the Runx2-Dependent Pathway.

BACKGROUND: Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS: We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS: H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS: Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.

Excessive dietary iron exposure increases the susceptibility of largemouth bass (Micropterus salmoides) to Aeromonas hydrophila by interfering with immune response, oxidative stress, and intestinal homeostasis.

Iron is an essential cofactor in the fundamental metabolic pathways of organisms. Moderate iron intake can enhance animal growth performance, while iron overload increases the risk of pathogen infection. Although the impact of iron on the pathogen-host relationship has been confirmed in higher vertebrates, research in fish is extremely limited. The effects and mechanisms of different levels of iron exposure on the infection of Aeromonas hydrophila in largemouth bass (Micropterus salmoides) remain unclear. In this study, experimental diets were prepared by adding 0, 800, 1600, and 3200 mg/kg of FeSO4∙7H2O to the basal feed, and the impact of a 56-day feeding period on the mortality rate of largemouth bass infected with A. hydrophila was analyzed. Additionally, the relationships between mortality rate and tissue iron content, immune regulation, oxidative stress, iron homeostasis, gut microbiota, and tissue morphology were investigated. The results showed that the survival rate of largemouth bass infected with A. hydrophila decreased with increasing iron exposure levels. Excessive dietary iron intake significantly increased iron deposition in the tissues of largemouth bass, reduced the expression and activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, increased the content of lipid peroxidation product malondialdehyde, and thereby induced oxidative stress. Excessive iron supplementation could influence the immune response of largemouth bass by upregulating the expression of pro-inflammatory cytokines in the intestine and liver, while downregulating the expression of anti-inflammatory cytokines. Additionally, excessive iron intake could also affect iron metabolism by inducing the expression of hepcidin, disrupt intestinal homeostasis by interfering with the composition and function of the gut microbiota, and induce damage in the intestinal and hepatic tissues. These research findings provide a partial theoretical basis for deciphering the molecular mechanisms underlying the influence of excessive iron exposure on the susceptibility of largemouth bass to pathogenic bacteria.

Direct synthesis of N-functionalized indoles through isomerization of azomethine ylides.

An unexpected isomerization of azomethine ylides generated in situ from isatin with indoline-2-carboxylic acid has been disclosed, providing direct access to N-functionalized indole scaffolds. This protocol has good functional group tolerance and provides various 3-(1H-indol-1-yl)indolin-2-one derivatives in moderate to high yields simply by using alcohol as the solvent, with no additional additive being required.

The influence of aggressive exercise on responses to self-perceived and others' pain.

Previous studies have reported relationships between exercise and pain. However, little is known about how aggressive exercise modulates individuals' responses to their own and others' pain. This present study addresses this question by conducting 2 studies employing event-related potential (ERP). Study 1 included 38 participants whose self-perceived pain was assessed after intervention with aggressive or nonaggressive exercises. Study 2 recruited 36 participants whose responses to others' pain were assessed after intervention with aggressive or nonaggressive exercise. Study 1's results showed that P2 amplitudes were smaller, reaction times were longer, and participants' judgments were less accurate in response to self-perceived pain stimuli, especially to high-pain stimuli, after intervention with aggressive exercise compared to nonaggressive exercise. Results of study 2 showed that both P3 and LPP amplitudes to others' pain were larger after intervention with aggressive exercise than with nonaggressive exercise. These results suggest that aggressive exercise decreases individuals' self-perceived pain and increases their empathic responses to others' pain.