TRPV1+ neurons alter Staphylococcus aureus skin infection outcomes by affecting macrophage polarization and neutrophil recruitment.

BACKGROUND: The interaction between the nervous system and the immune system can affect the outcome of a bacterial infection. Staphylococcus aureus skin infection is a common infectious disease, and elucidating the relationship between the nervous system and immune system may help to improve treatment strategies. RESULTS: In this study, we found that the local release of calcitonin gene-related peptide (CGRP) increased during S. aureus skin infection, and S. aureus could promote the release of CGRP from transient receptor potential cation channel subfamily V member 1 (TRPV1+) neurons in vitro. The existence of TRPV1+ neurons inhibited the recruitment of neutrophils to the infected region and regulated the polarization of macrophages toward M2 while inhibiting polarization toward M1. This reduces the level of inflammation in the infected area, which aggravates the local infection. Furthermore, this study demonstrates that TRPV1 may be a target for the treatment of S. aureus skin infections and that botulinum neurotoxin A (BoNT/A) and BIBN4096 may reverse the inhibited inflammatory effect of CGRP, making them potential therapeutics for the treatment of skin infection in S. aureus. CONCLUSIONS: In S. aureus skin infection, TRPV1+ neurons inhibit neutrophil recruitment and regulate macrophage polarization by releasing CGRP. BoNT/A and BIBN4096 may be potential therapeutic agents for S. aureus skin infection.

The Combination of Anti-CD47 Antibody with CTLA4 Blockade Enhances Anti-Tumor Immunity in Non-Small Cell Lung Cancer via Normalization of Tumor Vasculature and Reprogramming of the Immune Microenvironment.

In solid tumors, the formidable anti-tumor impact resulting from blocking the "don't eat me" signal, arising from CD47-SIRPα interaction, is constrained, especially compared to its efficacy in hematopoietic malignancies. Activating macrophage anti-tumor activity not only necessitates the inhibition of the "don't eat me" signal, but also the activation of the "eat me" (pre-phagocyte) signal. Intriguingly, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody (Ab) has been identified to stimulate Fc receptor-mediated active phagocytes in the tumor microenvironment, thereby generating "eat me" signals. This study postulates that concurrently targeting CD47 and CTLA4 could intensify the anti-tumor effects by simultaneously blocking the "don't eat me" signal while triggering the "eat me" signal. The experimental data from this investigation confirm that the combined targeting of CD47 and CTLA4 enhances immunity against solid tumors in LLC cell-transplanted tumor-bearing mice. This effect is achieved by reducing myeloid-derived suppressor cell infiltration while increasing the presence of effector memory CD8+ T cells, NK1.1+ CD8+ T cells, and activated natural killer T cells. Meanwhile, combination therapy also alleviated anemia. Mechanistically, the anti-CD47 Ab is shown to upregulate CTLA4 levels in NSCLC cells by regulating Foxp1. Furthermore, targeting CD47 is demonstrated to promote tumor vascular normalization through the heightened infiltration of CD4+ T cells. These findings suggest that the dual targeting of CD47 and CTLA4 exerts anti-tumor effects by orchestrating the "eat me" and "don't eat me" signals, reshaping the immune microenvironment, and fostering tumor vascular normalization. This combined therapeutic approach emerges as a potent strategy for effectively treating solid tumors.

Detection of rare microorganisms in bone and joint infections by metagenomic next-generation sequencing.

Aims: This aim of this study was to analyze the detection rate of rare pathogens in bone and joint infections (BJIs) using metagenomic next-generation sequencing (mNGS), and the impact of mNGS on clinical diagnosis and treatment. Methods: A retrospective analysis was conducted on 235 patients with BJIs who were treated at our hospital between January 2015 and December 2021. Patients were divided into the no-mNGS group (microbial culture only) and the mNGS group (mNGS testing and microbial culture) based on whether mNGS testing was used or not. Results: A total of 147 patients were included in the no-mNGS group and 88 in the mNGS group. The mNGS group had a higher detection rate of rare pathogens than the no-mNGS group (21.6% vs 10.2%, p = 0.016). However, the mNGS group had lower rates of antibiotic-related complications, shorter hospital stays, and higher infection control rates compared with the no-mNGS group (p = 0.017, p = 0.003, and p = 0.028, respectively), while there was no significant difference in the duration of antibiotic use (p = 0.957). In culture-negative cases, the mNGS group had lower rates of antibiotic-related complications, shorter hospital stays, and a higher infection control rate than the no-mNGS group (p = 0.036, p = 0.033, p = 0.022, respectively), while there was no significant difference in the duration of antibiotic use (p = 0.748). Conclusion: mNGS improves detection of rare pathogens in BJIs. mNGS testing reduces antibiotic-related complications, shortens hospital stay and antibiotic use duration, and improves treatment success rate, benefits which are particularly evident in culture-negative cases.

Glutathione determines chronic myeloid leukemia vulnerability to an inhibitor of CMPK and TMPK.

Bcr-Abl transformation leads to chronic myeloid leukemia (CML). The acquirement of T315I mutation causes tyrosine kinase inhibitors (TKI) resistance. This study develops a compound, JMF4073, inhibiting thymidylate (TMP) and cytidylate (CMP) kinases, aiming for a new therapy against TKI-resistant CML. In vitro and in vivo treatment of JMF4073 eliminates WT-Bcr-Abl-32D CML cells. However, T315I-Bcr-Abl-32D cells are less vulnerable to JMF4073. Evidence is presented that ATF4-mediated upregulation of GSH causes T315I-Bcr-Abl-32D cells to be less sensitive to JMF4073. Reducing GSH biosynthesis generates replication stress in T315I-Bcr-Abl-32D cells that require dTTP/dCTP synthesis for survival, thus enabling JMF4073 susceptibility. It further shows that the levels of ATF4 and GSH in several human CML blast-crisis cell lines are inversely correlated with JMF4073 sensitivity, and the combinatory treatment of JMF4073 with GSH reducing agent leads to synthetic lethality in these CML blast-crisis lines. Altogether, the investigation indicates an alternative option in CML therapy.

NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.

Wireless Optogenetic Targeting Nociceptors Helps Host Cells Win the Competitive Colonization in Implant-Associated Infections.

The role of nociceptive nerves in modulating immune responses to harmful stimuli via pain or itch induction remains controversial. Compared to conventional surgery, various implant surgeries are more prone to infections even with low bacterial loads. In this study, an optogenetic technique is introduced for selectively activating peripheral nociceptive nerves using a fully implantable, wirelessly rechargeable optogenetic device. By targeting nociceptors in the limbs of awake, freely moving mice, it is found that activation induces anticipatory immunity in the innervated territory and enhances the adhesion of various host cells to the implant surface. This effect mediates acute immune cell-mediated killing of Staphylococcus aureus on implants and enables the host to win "implant surface competition" against Staphylococcus aureus. This finding provides new strategies for preventing and treating implant-associated infections.

The Outcome of under 10 mm Single-Incision Surgery Using a Non-Specialized Volar Plate in Distal Radius Fractures: A Retrospective Comparative Study.

BACKGROUND: The distal radius fracture is a common orthopedic injury. We aimed to share the surgical steps and investigate the outcomes of treating distal radius fractures with wounds ≤10 mm using a globally accessible locking plate. METHODS: We collected 46 patients who underwent surgery via a <10 mm wound, with a control group consisting of 40 patients who underwent conventional procedures. Both groups were treated using the same volar plate. We compared the radiographic reduction quality, including volar tilt angle, radial inclination angle, and ulna variance. Additionally, clinical outcomes, such as pain assessed using VAS, Q-Dash score, and PRWE, were evaluated. Patient satisfaction with the wound was also analyzed. The follow-up time for the clinical outcomes was 24.2 ± 13.47 months. RESULTS: There were no differences in the quality of reduction in parameters such as the volar tilt angle (p = 0.762), radial inclination angle (p = 0.986), and ulna variance (p = 0.166). Both groups exhibited comparable results in pain VAS (p = 0.684), Q-Dash score (p = 0.08), and PRWE (p = 0.134). The ≤10 mm incision group displayed an increase in satisfaction with the wound (p < 0.001). CONCLUSIONS: Treating distal radius fractures with a <10 mm wound using a non-specialized locking plate is a feasible approach. It does not compromise the quality of fracture reduction or functional scores and improves wound satisfaction.