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Abstract Background Acetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure. Macrophages are key players in liver restoration following APAP-induced liver injury. Thromboxane A2 (TXA2) and its receptor, thromboxane prostanoid (TP) receptor, have been shown to be involved in tissue repair. However, whether TP signaling plays a role in liver repair after APAP hepatotoxicity by affecting macrophage function remains unclear. Methods Male TP knockout (TP −/−) and C57BL/6 wild-type (WT) mice were treated with APAP (300 mg/kg). In addition, macrophage-specific TP-knockout (TP △mac) and control WT mice were treated with APAP. We explored changes in liver inflammation, liver repair, and macrophage accumulation in mice treated with APAP. Results Compared with WT mice, TP −/− mice showed aggravated liver injury as indicated by increased levels of alanine transaminase (ALT) and necrotic area as well as delayed liver repair as indicated by decreased expression of proliferating cell nuclear antigen (PCNA). Macrophage deletion exacerbated APAP-induced liver injury and impaired liver repair. Transplantation of TP-deficient bone marrow (BM) cells to WT or TP −/− mice aggravated APAP hepatotoxicity with suppressed accumulation of macrophages, while transplantation of WT-BM cells to WT or TP −/− mice attenuated APAP-induced liver injury with accumulation of macrophages in the injured regions. Macrophage-specific TP −/− mice exacerbated liver injury and delayed liver repair, which was associated with increased pro-inflammatory macrophages and decreased reparative macrophages and hepatocyte growth factor (HGF) expression. In vitro, TP signaling facilitated macrophage polarization to a reparative phenotype. Transfer of cultured BM-derived macrophages from control mice to macrophage-specific TP −/− mice attenuated APAP-induced liver injury and promoted liver repair. HGF treatment mitigated APAP-induced inflammation and promoted liver repair after APAP-induced liver injury. Conclusions Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury, which is associated with reduced accumulation of reparative macrophages and the hepatotrophic factor HGF. Specific activation of TP signaling in macrophages may be a potential therapeutic target for liver repair and regeneration after APAP hepatotoxicity.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that induces cytokine hypersecretion. Receptor activity-modifying protein (RAMP) 1, a subunit of the calcitonin gene-related peptide (CGRP) receptor, regulates the production of cytokines. This study examined the role of RAMP1 signaling during lipopolysaccharide (LPS)-induced acute lung injury (ALI). LPS administration to wild-type (WT) mice depleted alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) and neutrophils. RAMP1-deficient (RAMP1−/−) mice exhibited higher lung injury scores, cytokine levels, and cytokine-producing neutrophil infiltration. RAMP1-deficient AMs produced more cytokines in response to LPS than WT AMs. Adoptive transfer of RAMP1-deficient AMs to RAMP1−/− mice increased cytokine levels and neutrophil accumulation compared to the transfer of WT AMs. RAMP1−/− mice had reduced MDM recruitment and lower pro-inflammatory and reparative macrophage profiles. Cultured bone marrow (BM)-derived RAMP1-deficient macrophages stimulated with LPS showed decreased expression of pro-inflammatory and pro-repairing genes. CGRP administration to WT mice reduced cytokine production and neutrophil accumulation. These findings indicate that RAMP1 signaling mitigates LPS-induced ALI by inactivating AMs and promoting inflammatory and repair activities of MDMs. Targeting RAMP1 signaling presents a potential therapeutic approach for the treatment of ARDS.

Abstract Cyclic phosphatidic acid (cPA) is a lipid mediator, which regulates adipogenic differentiation and glucose homeostasis by suppressing nuclear peroxisome proliferator-activated receptor γ (PPARγ). Glycerophosphodiesterase 7 (GDE7) is a Ca2+-dependent lysophospholipase D that localizes in the endoplasmic reticulum. Although mouse GDE7 catalyzes cPA production in a cell-free system, it is unknown whether GDE7 generates cPA in living cells. Here, we demonstrate that human GDE7 possesses cPA-producing activity in living cells as well as in a cell-free system. Furthermore, the active site of human GDE7 is directed towards the luminal side of the endoplasmic reticulum. Mutagenesis revealed that amino acid residues F227 and Y238 are important for catalytic activity. GDE7 suppresses the PPARγ pathway in human mammary MCF-7 and mouse preadipocyte 3T3-L1 cells, suggesting that cPA functions as an intracellular lipid mediator. These findings lead to a better understanding of the biological role of GDE7 and its product, cPA.

Immune thrombocytopenia (ITP) carries bleeding and thrombotic risks; however, thromboses associated with ITP have not been histologically examined. This report presents optical coherence tomography images of the culprit lesion and histology of coronary aspirates in very late stent thrombosis complicating severe ITP, providing evidence of platelet-rich thrombus formation. (Level of Difficulty: Advanced.)

Neuromodulation techniques for modulating brain activity can affect performance in a variety of behaviors. Techniques including transcranial alternating current stimulation and random noise stimulation can modulate neural oscillations. However, the intervention effect of neuromodulation approaches on motor learning is poor, partly because the electroencephalography (EEG) power spectra associated with the motor learning process has not yet been fully elucidated. Therefore, we investigated the characteristics of EEG power spectra in the process of motor learning in 15 right-handed healthy participants (5 females; mean age = 22.8 ± 3.0 years). The motor task was a ball-rotation task in which participants rotated two balls in the palm of their left hand. Participants performed a pre-test, the motor learning tasks, and a post-test. In the motor learning tasks, twenty 60 s trials were performed in the clockwise (CW) direction. Before and after the motor learning tasks, CW and counterclockwise (CCW; control condition) tasks were performed for 60 s each as pre- and post-tests. Therefore, CW direction was set as a motor learning task, while CCW was a test-only control task. EEG was recorded during the tests and tasks, and the power spectra in the alpha, beta, and gamma oscillations were calculated and compared between pre- and post-tests. The results showed that in the CW post-test, the power of the gamma band in the left parietal areas and the right frontal area was significantly higher than in the pre-test. In the CCW, there was no significant difference in each band at each area between the pre- and post-tests. Our findings reveal the characteristics of the EEG spectra related to the motor learning process. These results may help to establish more effective neuromodulation approaches to modifying neural oscillations in motor learning, including in rehabilitation fields.

Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome these limitations, we conjugated the zwitterionic near-infrared fluorophore ZW800-PEG to human serum albumin (HSA), creating HSA-ZW800-PEG. This conjugation notably improves chemical, physical, and optical stability under physiological conditions, addressing issues commonly encountered with small molecules in biological applications. Additionally, the high molecular weight and extinction coefficient of HSA-ZW800-PEG enhances biodistribution and tumor targeting through the enhanced permeability and retention effect. The unique distribution and elimination dynamics, along with the significantly extended blood half-life of HSA-ZW800-PEG, contribute to improved tumor targetability in both subcutaneous and orthotopic xenograft tumor-bearing animal models. This modification not only influences the pharmacokinetic profile, affecting retention time and clearance patterns, but also enhances bioavailability for targeting tissues. Our study guides further development and optimization of targeted imaging agents and drug-delivery systems.

Abstract Background In Japan, engineering controls for preparing injectable anticancer drugs are inadequate and compliance with appropriate preparation procedures is vital. In this study, we evaluated the effects of adherence to appropriate anticancer drug formulation and packaging procedures on reducing anticancer drug dispersal in clinical practice, especially in Japan. Methods We quantitatively evaluated the effectiveness of implementing procedures that were experimentally verified to help reduce the amount of anticancer drug dispersed during preparation based on procedures described in the “Anticancer Drug Preparation Manual.” The target facilities were four regional hub hospitals in the Kanto area. Contamination of sheets and gloves with 5-fluorouracil (5-FU) and gemcitabine (GEM) in a safety cabinet during formulation was evaluated using wipe tests. Subsequently, the proper preparation procedure was shown on a video, training was provided, and the wipe tests were repeated. Results Forty-one and 39 pharmacists were engaged in drug preparation before and after intervention, respectively. 5-FU had the highest dispersal per prepared vial on the sheet before intervention. The dispersal amount per prepared vial decreased significantly (P = 0.01) after intervention. The amount of GEM dispersed before and after intervention did not differ significantly. However, the percentage of sheets below the detection limit after intervention was 62%, increasing from 46% before intervention. The amount dispersed on gloves was not significantly reduced by proper preparation technique. Although not explicitly noticeable and quantifiable, pharmacists must consider that a significant amount of anticancer drug is dispersed on gloves despite following appropriate preparation procedures. Conclusions Quantitative amounts of anticancer drugs dispersed in the preparations of 5-FU and GEM were found in our study. The difference in the amount of contamination before and after intervention was significantly reduced only for the contamination of sheets with 5-FU. There was no decrease in the amount of glove contamination. There was also no difference between medical facilities. Despite following appropriate preparation procedures, dispersed amounts cannot be maintained below the detection limit, indicating the need for a combination of education and engineering controls.

Abstract Background Congenital myasthenia syndrome is a heterogeneous disease with impaired neuromuscular transmission. Case presentation This report describes a 13-year-old child with congenital myasthenia syndrome who underwent surgery for scoliosis under general anesthesia. We used a small dose of rocuronium, neuromuscular transmission monitoring, and non-invasive positive pressure ventilation for postoperative respiratory management. There were no respiratory complications during the perioperative period. Conclusion As there are only a few reports on the anesthetic management of patients with congenital myasthenia syndrome, we applied the principles of managing autoimmune myasthenia gravis. The postoperative management described herein can prevent respiratory complications in patients with congenital myasthenia syndrome.

Platinum-based anticancer agents have revolutionized oncological treatments globally. However, their therapeutic efficacy is often accompanied by systemic toxicity. Carboplatin, recognized for its relatively lower toxicity profile than cisplatin, still presents off-target toxicities, including dose-dependent cardiotoxicity, neurotoxicity, and myelosuppression. In this study, we demonstrate a delivery strategy of carboplatin to mitigate its off-target toxicity by leveraging the potential of zwitterionic nanocarrier, H-dot. The designed carboplatin/H-dot complex (Car/H-dot) exhibits rapid drug release kinetics and notable accumulation in proximity to tumor sites, indicative of amplified tumor targeting precision. Intriguingly, the Car/H-dot shows remarkable efficacy in eliminating tumors across insulinoma animal models. Encouragingly, concerns linked to carboplatin-induced cardiotoxicity are effectively alleviated by adopting the Car/H-dot nanotherapeutic approach. This pioneering investigation not only underscores the viability of H-dot as an organic nanocarrier for platinum drugs but also emphasizes its pivotal role in ameliorating associated toxicities. Thus, this study heralds a promising advancement in refining the therapeutic landscape of platinum-based chemotherapy.

Abstract Self-related stimuli are important cues for people to recognize themselves in the external world and hold a special status in our perceptual system. Self-voice plays an important role in daily social communication and is also a frequent input for self-identification. Although many studies have been conducted on the acoustic features of self-voice, no research has ever examined the spatial aspect, although the spatial perception of voice is important for humans. This study proposes a novel perspective for studying self-voice. We investigated people’s distance perception of their own voice when the voice was heard from an external position. Participants heard their own voice from one of four speakers located either 90 or 180 cm from their sitting position, either immediately after uttering a short vowel (i.e., active session) or hearing the replay of their own pronunciation (i.e., replay session). They were then asked to indicate which speaker they heard the voice from. Their voices were either pitch-shifted by ± 4 semitones (i.e., other-voice condition) or unaltered (i.e., self-voice condition). The results of spatial judgment showed that self-voice from the closer speakers was misattributed to that from the speakers further away at a significantly higher proportion than other-voice. This phenomenon was also observed when the participants remained silent and heard prerecorded voices. Additional structural equation modeling using participants’ schizotypal scores showed that the effect of self-voice on distance perception was significantly associated with the score of delusional thoughts (Peters Delusion Inventory) and distorted body image (Perceptual Aberration Scale) in the active speaking session but not in the replay session. The findings of this study provide important insights for understanding how people process self-related stimuli when there is a small distortion and how this may be linked to the risk of psychosis.

Inflammatory activity and hypoxia in atherosclerotic plaques are associated with plaque instability and thrombotic complications. Recent studies show that vascular cell metabolism affects atherogenesis and thrombogenicity. This study aimed to identify the metabolites in macrophage-rich unstable plaques that modulate atherogenesis and serve as potential markers of plaque instability. Atherosclerotic plaques were induced by balloon injury in the iliofemoral arteries of rabbits fed on a conventional or 0.5% cholesterol diet. At 3 months post-balloon injury, the arteries and cardiac tissues were subjected to histological, quantitative real-time polymerase chain reaction, and metabolomic analyses. The identified metabolite-related proteins were immunohistochemically analyzed in stable and unstable plaques from human coronary arteries. The factors modulating the identified metabolites were examined in macrophages derived from human peripheral blood mononuclear cells. Metabolomic analysis revealed that choline and guanine levels in macrophage-rich arteries were upregulated compared with those in non-injured arteries and cardiac tissues. Vascular choline levels, but not guanine levels, were positively correlated with the areas immunopositive for macrophages and tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP) 9 mRNA levels in injured arteries. In human coronary arteries, choline transporter-like protein (CTL) 1 was mainly localized to macrophages within plaques. The area that was immunopositive for CTL1 in unstable plaques was significantly higher than that in stable plaques. Intracellular choline levels were upregulated upon stimulation with TNF-α but were downregulated under hypoxia in cultured macrophages. Administration of choline upregulated the expression of TNF-α and CTL1 mRNA in cultured macrophages. The transfection of CTL1 small interfering RNA decreased CTL1, TNF-α, and MMP9 mRNA levels in cultured macrophages. These results suggest that choline metabolism is altered in macrophage-rich atherosclerotic lesions and unstable plaques. Thus, CTL1 may be potential markers of plaque instability.

Optical tissue phantoms (OTPs) have been extensively applied to the evaluation of imaging systems and surgical training. Due to their human tissue‐mimicking characteristics, OTPs can provide accurate optical feedback on the performance of image‐guided surgical instruments, simulating the biological sizes and shapes of human organs, and preserving similar haptic responses of original tissues. This review summarizes the essential components of OTPs (i.e., matrix, scattering and absorbing agents, and fluorophores) and the various manufacturing methods currently used to create suitable tissue‐mimicking phantoms. As photobleaching is a major challenge in OTP fabrication and its feedback accuracy, phantom photostability and how the photobleaching phenomenon can affect their optical properties are discussed. Consequently, the need for novel photostable OTPs for the quantitative evaluation of surgical imaging devices is emphasized.

Abstract Adaptive motor learning refers to the ability to adjust to novel disturbances in the environment as a way of minimizing sensorimotor errors. It is known that such processes show large individual differences and are linked to multiple perceptual and cognitive processes. On the other hand, the sense of agency refers to the subjective feeling of control during voluntary motor control. Is the sense of agency just a by-product of the control outcome, or is it actually important for motor control and learning? To answer this question, this study takes an approach based on individual differences to investigate the relationship between the sense of agency and learnability in sensorimotor adaptation. Specifically, we use an adaptive motor learning task to measure individual differences in the efficiency of motor learning. Regarding the sense of agency, we measure the perceptual sensitivity of detecting an increase or a decrease in control when the actual level of control gradually increases or decreases, respectively. The results of structure equation modelling reveal a significant influence of perceptual sensitivity to increased control on motor learning efficiency. On the other hand, the link between perceptual sensitivity to decreased control and motor learning is nonsignificant. The results show that the sense of agency in detecting increased control is associated with the actual ability of sensorimotor adaptation: people who are more sensitive in detecting their control in the environment can also more quickly adjust their behaviors to novel disturbances to acquire better control, compared to people who have a less sensitive sense of agency. Finally, the results also reveal that the processes of increasing control and decreasing control may be partially independent.

Aim: To clarify whether there is any association between the extent of Chlamydia pneumoniae (C. pneumoniae ) infection and plaque instability or post–directional coronary atherectomy (DCA) restenosis, we determined the frequency of C. pneumoniae infection and its localization in symptomatic coronary atherosclerotic plaques using specimens obtained from DCA. Methods and results: Immunohistochemistry (IHC) and real-time polymerase chain reaction (RT-PCR) revealed the existence of C. pneumoniae in all 50 specimens of coronary atherosclerotic plaques obtained by DCA. C. pneumoniae –positive cell ratio determined with IHC or copy numbers of C. pneumoniae DNA detected by RT-PCR did not differ significantly between patients with stable angina pectoris and those with acute coronary syndrome (IHC: 16.4 ± 7.6% vs 18.0 ± 7.1%, P = .42; RT-PCR: no. of cases with high copy numbers 12/25 vs 10/25, P = .78), or between patients with subsequent post-DCA restenosis and those without (IHC: 17.1 ± 8.0% vs 18.0 ± 7.4%, P = .74; RT-PCR: 5/12 vs 10/21, P = 1.00). Conclusions: C. pneumoniae was highly prevalent in coronary atherosclerotic plaques of patients who underwent DCA. However, the extent of C. pneumoniae infection in coronary atherosclerotic plaques was not associated with plaque instability or post-DCA restenosis.