Identification of an HLA-A*11:01-restricted neoepitope of mutant PIK3CA and its specific T cell receptors for cancer immunotherapy targeting hotspot driver mutations.

Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy.

D-A Conjugated Polymer/CdS S-Scheme Heterojunction with Enhanced Interfacial Charge Transfer for Efficient Photocatalytic Hydrogen Generation.

Owing to the improved charge separation and maximized redox capability of the system, Step-scheme (S-scheme) heterojunctions have garnered significant research attention for efficient photocatalysis of H2 evolution. In this work, an innovative linear donor-acceptor (D-A) conjugated polymer fluorene-alt-(benzo-thiophene-dione) (PFBTD) is coupled with the CdS nanosheets, forming the organic-inorganic S-scheme heterojunction. The CdS/PFBTD (CP) composite exhibits an impressed hydrogen production rate of 7.62 mmol g-1 h-1 without any co-catalysts, which is ≈14 times higher than pristine CdS. It is revealed that the outstanding photocatalytic performance is attributed to the formation of rapid electron transfer channels through the interfacial Cd─O bonding as evidenced by the density functional theory (DFT) calculations and in situ X-ray photoelectron spectroscopy (XPS) analysis. The charge transfer mechanism involved in S-scheme heterojunctions is further investigated through the photo-irradiated Kelvin probe force microscopy (KPFM) analysis. This work provides a new point of view on the mechanism of interfacial charge transfer and points out the direction of designing superior organic-inorganic S-scheme heterojunction photocatalysts.

Targeting tumor-infiltrating CCR8+ regulatory T cells induces antitumor immunity through functional restoration of CD4+ Tconvs and CD8+ T cells in colorectal cancer.

BACKGROUND: Chemokine (C-C motif) receptor 8 (CCR8) is a chemokine receptor selectively expressed on tumor-infiltrating regulatory T cells (Tregs). Strong immunosuppression mediated by CCR8+ Tregs observed in breast and lung malignancies suggest for their functional significance in cancer therapy. To date, detailed characterization of tumor-infiltrating CCR8+ Tregs cells in colorectal cancer (CRC) is limited. METHODS: To study the presence and functional involvement of CCR8+ Tregs in CRC, we analyzed the proportions of CCR8-expressing T cells in different T cell subsets in tumor and adjacent normal tissues and peripheral blood mononuclear cells (PBMCs) from CRC patients by Flow cytometry. Also, we compared the distribution of CCR8+ T cells in malignant tissues and peripheral lymphoid organs from a subcutaneous CRC murine model. Bioinformatic analysis was performed to address the significance of CCR8 expression levels in CRC prognosis, immune regulatory gene expression profiles and potential molecular mechanisms associated with CCR8+ Tregs in CRC tumors. Further, we administrated an anti-CCR8 monoclonal antibody to CT26 tumor-bearing mice and examined the antitumor activity of CCR8-targeted therapy both in vivo and in an ex vivo confirmative model. RESULTS: Here, we showed that Tregs was predominantly presented in the tumors of CRC patients (13.4 ± 5.8, p < 0.0001) and the CRC subcutaneous murine model (35.0 ± 2.6, p < 0.0001). CCR8 was found to be preferentially expressed on these tumor-infiltrating Tregs (CRC patients: 63.6 ± 16.0, p < 0.0001; CRC murine model: 65.3 ± 9.5, p < 0.0001), which correlated with poor survival. We found that majority of the CCR8+ Tregs expressed activation markers and exhibited strong suppressive functions. Treatment with anti-CCR8 antibody hampered the growth of subcutaneous CRC tumor through effectively restoring the anti-tumor immunity of CD4+ conventional T cells (CD4+ Tconvs) and CD8+ T cells, which was confirmed in the ex vivo examinations. CONCLUSIONS: Collectively, these findings illustrate the importance of CCR8+ Tregs for an immunosuppressive microenvironment in CRC tumors by functional inhibition of CD4+ Tconvs and CD8+ T cells, and suggest for the applicable value of CCR8-targeted therapy for CRC.

Ventral tegmental area dopaminergic circuits participates in stress-induced chronic postsurgical pain in male mice.

BACKGROUND: Chronic postsurgical pain (CPP) markedly impairs patients' quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS. METHODS: We conducted CSDS on C57BL/6 J wild-type male mice (n = 12-16 mice/group) and DAT-cre male mice (n = 10-12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC. RESULTS: The ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC. CONCLUSION: CSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

Nanostructured, Biodoping-Activated Fungi-Modified Wood for Enhanced Cd2+ Removal: Performances and Insight on Adsorption Mechanisms.

Nanostructured activated carbon (AC) adsorbents derived from woody biomass have garnered attention for their potential usage to remove toxic substances from the environment due to their high specific surface area, superior micro/mesoporosity, and tunable surface chemistry profile. However, chemical dopants widely used to enhance the chemical reactivity with heavy metals would pollute the environment and conflict with the vision of a cleaner and sustainable environment. Herein, we report a facile, green, and sustainable approach using fungi modification combined with alkali activation to produce AC for heavy metal removal. The decayed wood-derived AC (DAC) exhibited a high specific surface area of 2098 m2/g, and the content of O and N functional groups was 18 and 2.24%, respectively. It showed remarkable adsorption capacity toward Cd2+ of 148.7 mg/g, which was much higher than most reported Cd2+ adsorbents. Such excellent adsorption capacity was primarily based on enhanced physical adsorption (pore filling, π-π) and chemical adsorption (functional group complexation, ion exchange, and precipitation). Additionally, the DAC showed rapid kinetics and remarkable applicability in both dynamic environments and actual water samples. These results suggest that decayed wood has excellent potential for efficient use in the removal of Cd2+ from wastewater. Furthermore, these results indicate that decayed wood can be cleanly produced into high efficiency heavy metal adsorbents to realize value-added utilization of decayed wood.

Sex-Biased Expression and Response of microRNAs in Neurological Diseases and Neurotrauma.

Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and pathological factors that impact the sex disparity in neurological diseases. MicroRNAs (miRNAs) are a powerful class of gene expression regulator that are extensively involved in mediating biological pathways. Emerging evidence demonstrates that miRNAs play a crucial role in the sex dimorphism observed in various human diseases, including neurological diseases. Understanding the sex differences in miRNA expression and response is believed to have important implications for assessing the risk of neurological disease, defining therapeutic intervention strategies, and advancing both basic research and clinical investigations. However, there is limited research exploring the extent to which miRNAs contribute to the sex disparities observed in various neurological diseases. Here, we review the current state of knowledge related to the sexual dimorphism in miRNAs in neurological diseases and neurotrauma research. We also discuss how sex chromosomes may contribute to the miRNA sexual dimorphism phenomenon. We attempt to emphasize the significance of sexual dimorphism in miRNA biology in human diseases and to advocate a gender/sex-balanced science.

Molecularly Tunable Heterostructured Co-Polymers Containing Electron-Deficient and -Rich Moieties for Visible-Light and Sacrificial-Agent-Free H2O2 Photosynthesis.

As an alternative to hydrogen peroxide (H2O2) production by complex anthraquinone oxidation process, photosynthesis of H2O2 from water and oxygen without sacrificial agents is highly demanded. Herein, a covalently connected molecular heterostructure is synthesized via sequential C-H arylation and Knoevenagel polymerization reactions for visible-light and sacrificial-agent-free H2O2 synthesis. The subsequent copolymerization of the electron-deficient benzodithiophene-4,8-dione (BTD) and the electron-rich biphenyl (B) and p-phenylenediacetonitrile (CN) not only expands the π-conjugated domain but also increases the molecular dipole moment, which largely promotes the separation and transfer of the photoinduced charge carriers. The optimal heterostructured BTDB-CN0.2 manifested an impressive photocatalytic H2O2 production rate of 1920 µmol g-1 h-1, which is 2.2 and 11.6 times that of BTDB and BTDCN. As revealed by the femtosecond transient absorption (fs-TA) and theoretical calculations, the linkage serves as a channel for the rapid transfer of photogenerated charge carriers, enhancing the photocatalytic efficiency. Further, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) uncovers that the oxygen reduction reaction occurs through the step one-electron pathway and the mutual conversion between C=O and C-OH with the anchoring of H+ during the catalysis favored the formation of H2O2. This work provides a novel perspective for the design of efficient organic photocatalysts.

Enhancing the catalytic activity of the MnNC catalyst by regulating the coordination environment.

The catalytic activity is largely determined by the coordination environment of the active sites. The catalytic activity of MnNC was much enhanced by the regulation of the coordination environment. The introduction of optimal epoxy to the vicinity of the Mn centers improved its half-wave potential by ∼300 mV.

Engineered exosomes and composite biomaterials for tissue regeneration.

Exosomes, which are small vesicles enclosed by a lipid bilayer and released by many cell types, are widely dispersed and have garnered increased attention in the field of regenerative medicine due to their ability to serve as indicators of diseases and agents with therapeutic potential. Exosomes play a crucial role in mediating intercellular communication through the transfer of many biomolecules, including proteins, lipids, RNA, and other molecular constituents, between cells. The targeted transport of proteins and nucleic acids to specific cells has the potential to enhance or impair specific biological functions. Exosomes have many applications, and they can be used alone or in combination with other therapeutic approaches. The examination of the unique attributes and many functions of these factors has emerged as a prominent field of study in the realm of biomedical research. This manuscript summarizes the origins and properties of exosomes, including their structural, biological, physical, and chemical aspects. This paper offers a complete examination of recent progress in tissue repair and regenerative medicine, emphasizing the possible implications of these methods in forthcoming tissue regeneration attempts.

How to make full use of dental pulp stem cells: an optimized cell culture method based on explant technology.

Introduction: Dental pulp stem cells from humans possess self-renewal and versatile differentiation abilities. These cells, known as DPSC, are promising for tissue engineering due to their outstanding biological characteristics and ease of access without significant donor site trauma. Existing methods for isolating DPSC mainly include enzyme digestion and explant techniques. Compared with the enzymatic digestion technique, the outgrowth method is less prone to cell damage and loss during the operation, which is essential for DPSC with fewer tissue sources. Methods: In order to maximize the amount of stem cells harvested while reducing the cost of DPSC culture, the feasibility of the optimized explant technique was evaluated in this experiment. Cell morphology, minimum cell emergence time, the total amount of cells harvested, cell survival, and proliferative and differentiation capacity of DPSC obtained with different numbers of explant attachments (A1-A5) were evaluated. Results: There was a reduction in the survival rate of the cells in groups A2-A5, and the amount of harvested DPSC decreased in A3-A5 groups, but the DPSC harvested in groups A1-A4 had similar proliferative and differentiation abilities. However, starting from group A5, the survival rate, proliferation and differentiation ability of DPSC decreased significantly, and the adipogenic trend of the cells became more apparent, indicating that the cells had begun to enter the senescence state. Discussion: The results of our study demonstrated that the DPSC obtained by the optimized explant method up to 4 times had reliable biological properties and is available for tissue engineering.

Bioprinted research models of urological malignancy.

Urological malignancy (UM) is among the leading threats to health care worldwide. Recent years have seen much investment in fundamental UM research, including mechanistic investigation, early diagnosis, immunotherapy, and nanomedicine. However, the results are not fully satisfactory. Bioprinted research models (BRMs) with programmed spatial structures and functions can serve as powerful research tools and are likely to disrupt traditional UM research paradigms. Herein, a comprehensive review of BRMs of UM is presented. It begins with a brief introduction and comparison of existing UM research models, emphasizing the advantages of BRMs, such as modeling real tissues and organs. Six kinds of mainstream bioprinting techniques used to fabricate such BRMs are summarized with examples. Thereafter, research advances in the applications of UM BRMs, such as culturing tumor spheroids and organoids, modeling cancer metastasis, mimicking the tumor microenvironment, constructing organ chips for drug screening, and isolating circulating tumor cells, are comprehensively discussed. At the end of this review, current challenges and future development directions of BRMs and UM are highlighted from the perspective of interdisciplinary science.

A Peel Test Method to Characterize the Decay Law of Prepreg Tape Tack at Different Temperatures.

The tack of prepreg is a key factor affecting the automatic tape laying process. During the manufacturing process of large composite parts, prepreg material may be stored at room temperature for several days, resulting in a decrease in its tack. In this study, a new tack test tool was designed, and the decay rate of prepreg tack at different temperatures was tested. We proposed a prepreg tack decay model, which assumes that the main factor in tack decay is the reduction in resin chain activity during storage. The maximum deviation between the model calculation results and the experimental results of the tack decay rate is 9.7%. This study also proposed a new statistical unit for prepreg tack, which can establish the relationship between the tack of prepreg and its remaining storage time and reduce prepreg management costs.

The cavitation characteristics of aerospace high-speed centrifugal pumps with different tip clearance.

This study investigates the Tip Clearance Cavitation (TCC) characteristics of three different Tip Clearances (TC) (0.4, 0.6, 0.8) and five inlet negative pressure conditions Pj = (- 20-60)kPa to improve the reliability of the aerospace high-speed centrifugal pump during in-orbit operation, based on the premise of good agreement between the TC 0.6 test curve and the simulation performance curve. Under negative pressure and high-speed conditions, the variation gradient of cavitation characteristics with various inlet negative pressures is non-linear and has a sudden change, but the trend becomes stable after the inlet negative pressure drops to a certain stage. The tip clearance cavitation characteristics vary from the blade surface cavitation characteristics due to the difference in forces on both sides. This study is a proper starting point for the design of aerospace power pumps.

Elafibranor emerged as a potential chemotherapeutic drug for non-muscle invasive bladder cancer.

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 µM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.

Bi-Constraints Diffusion: A Conditional Diffusion Model with Degradation Guidance for Metal Artifact Reduction.

In recent years, score-based diffusion models have emerged as effective tools for estimating score functions from empirical data distributions, particularly in integrating implicit priors with inverse problems like CT reconstruction. However, score-based diffusion models are rarely explored in challenging tasks such as metal artifact reduction (MAR). In this paper, we introduce the BiConstraints Diffusion Model for Metal Artifact Reduction (BCDMAR), an innovative approach that enhances iterative reconstruction with a conditional diffusion model for MAR. This method employs a metal artifact degradation operator in place of the traditional metal-excluded projection operator in the data-fidelity term, thereby preserving structure details around metal regions. However, scorebased diffusion models tend to be susceptible to grayscale shifts and unreliable structures, making it challenging to reach an optimal solution. To address this, we utilize a precorrected image as a prior constraint, guiding the generation of the score-based diffusion model. By iteratively applying the score-based diffusion model and the data-fidelity step in each sampling iteration, BCDMAR effectively maintains reliable tissue representation around metal regions and produces highly consistent structures in non-metal regions. Through extensive experiments focused on metal artifact reduction tasks, BCDMAR demonstrates superior performance over other state-of-the-art unsupervised and supervised methods, both quantitatively and in terms of visual results.

Attenuation of palmitic acid-induced lysyl oxidase overexpression in the ovary contributes to the improvement of ovulation in obesity by metformin.

STUDY QUESTION: Does palmitic acid (PA), the most common saturated free fatty acid (FFA) in individuals with obesity, contribute to anovulation through upregulation of the collagen-crosslinking enzyme lysyl oxidase (LOX) in the ovary? SUMMARY ANSWER: Increased PA in individuals with obesity can cause LOX upregulation via the activation of hypoxia-inducible factor-1α (HIF-1α), resulting in abnormal collagen deposition in the ovary and anovulation, which can be ameliorated by metformin therapy. WHAT IS KNOWN ALREADY: The underlying cause of anovulation in individuals with obesity is poorly defined, and accumulating evidence indicates that hormonal disturbance, insulin resistance, and inflammation may all play a role in the development of ovulation disorders in individuals with obesity. However, it remains to be determined whether PA plays a role in the regulation of LOX expression, thus disrupting ovarian extracellular matrix (ECM) remodelling in the ovary and resulting in impaired ovulation in individuals with obesity. STUDY DESIGN SIZE DURATION: PA concentration and LOX protein abundance and activity in follicular fluid and ovarian tissue were compared between control (n = 21) subjects, patients with obesity with ovulation (n = 22), and patients with obesity with anovulation (n = 16). The effect of PA on LOX protein expression, and the underlying mechanism, was examined in primary human granulosa cells in vitro. The improvements in obesity conditions induced by LOX inhibition combined with metformin were investigated in a high-fat diet-induced obese rat model. PARTICIPANTS/MATERIALS SETTING METHODS: The abundance of PA concentration and LOX activity was measured via a LOX activity assay and ELISA, respectively. The effect of PA on LOX protein expression was examined in the presence or absence of inhibitors of signalling molecules and siRNA-mediated knockdown of the putative transcription factor. Chromatin immunoprecipitation assays were subsequently conducted to further identify the responsible transcription factor. The role of metformin in the treatment of anovulation by LOX inhibition was investigated in a high-fat diet (HFD)-induced obese rat model. The numbers of retrieved total oocytes and metaphase II oocytes were recorded upon ovarian stimulation. Masson's trichrome staining was used to measure the total collagen content, and immunohistochemical staining and western blotting were used to measure LOX, HIF-1α, and collagen I and IV in the ovary. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly increased FFA, LOX, and collagen abundance were observed in the ovaries of obese women with anovulation, compared to healthy controls or obese women with ovulation. In a HFD-induced obese rat model, metformin corrected the distortion of ovarian morphology by decreasing LOX and collagen protein abundance in the ovary and improving oestrous cyclicity and ovulation. PA increased LOX expression via the activation of HIF-1α in human granulosa cells, which was attenuated by metformin. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Several other saturated and polyunsaturated FFAs, such as stearic acid and arachidonic acid, are also increased in the blood of individuals with obesity, and increased levels of other FFAs may also contribute to the development of anovulation in individuals with obesity, which needs to be further verified in the future. WIDER IMPLICATIONS OF THE FINDINGS: Elevated PA in individuals with obesity can cause LOX dysregulation via activation of HIF-1α, resulting in abnormal collagen deposition in the ovary and anovulation. This dysregulation can be ameliorated by metformin therapy through its local effect on ECM remodelling in the ovary, which is independent of its systemic effect on insulin sensitivity and chronic inflammation. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Natural Science Foundation of China (grant numbers 82101730, 82130046, and 31900598) and Innovative Research Team of High-level local Universities in Shanghai (SHSMU-ZLCX20210201). All the authors declare no conflicts of interest in relation to this work.

Disturbance of Fetal Growth by Azithromycin Through Induction of ER Stress in the Placenta.

Aim: Azithromycin (AZM) is widely used to treat mycoplasma infection in pregnancy. However, there is no adequate evaluation of its side effect on the placenta. In this study, using human placental syncytiotrophoblasts and a mouse model, we investigated whether AZM use in pregnancy might adversely affect placental function and pregnancy outcome. Results: Transcriptomic analysis of AZM-treated human placental syncytiotrophoblasts showed increased expression of endoplasmic reticulum (ER) stress-related genes and decreased expression of genes for hormone production and growth factor processing. Verification studies showed that AZM increased the abundance of ER stress mediators (phosphorylated eIF2α, activating transcription factor 4 [ATF4], and C/EBP Homologous Protein [CHOP]) and decreased the abundance of enzymes involved in progesterone and estradiol synthesis (STS, CYP11A1, and CYP19A1) and insulin-like growth factor binding protein (IGFBP) cleavage (PAPPA and ADAM12) in human placental syncytiotrophoblasts. Inhibition of ER stress blocked AZM-induced decreases in the expression of CYP19A1, CYP11A1, PAPPA, and ADAM12, suggesting that the inhibition of AZM on those genes' expression was secondary to AZM-induced ER stress. Further mechanism study showed that increased ATF4 in ER stress might repressively interact with C/EBPα to suppress the expression of those genes, including CEBPA itself. Mouse studies showed that AZM administration decreased fetal weights along with increased ER stress mediators and decreased levels of insulin-like growth factor, estrogen, and progesterone in the maternal blood, which could be alleviated by inhibition of ER stress. Innovation and Conclusion: These findings first support the fact that AZM, often used during pregnancy, may affect fetal growth by inhibiting crucial enzymes for estrogen and progesterone synthesis and disrupting crucial proteases for IGFBP cleavage via inducing ER stress in placental syncytiotrophoblasts.

Specific Activation of Dopamine Receptor D1 Expressing Neurons in the PrL Alleviates CSDS-Induced Anxiety-Like Behavior Comorbidity with Postoperative Hyperalgesia in Male Mice.

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.

A novel fullerene composite material for directional oil control and antioxidant.

BACKGROUND: There are very few cosmetic ingredients that can target oil control and extend the wear time. Fullerenes have been reported to have excellent antioxidant capacity and a variety of biological activities, such as quenching free radicals, inhibiting lipid peroxidation, and promoting lipid flocculation. OBJECTIVE: The purpose of applying foundation makeup on the face is to make the skin color even, but the secretion and oxidation of skin oil will make the makeup mottled and dull. In order to solve this problem, a fullerene composite material that can directionally absorb oil and resist oil oxidation has been developed. METHODS: Fullerenes and hydroxyapatite composite was prepared by high pressure homogenization under alkaline condition. The indicated morphology and structure were characterized by SEM, UV-Vis, Raman, and XRD. The oil absorption capacity was determined by adding the C60-hydroxyapatite composite to a mixed solution of hexane and oil, shaking for 1 h, filtering, analyzed by GC-MS, and calculating the oil absorption by external standard method. Artificial sebum was prepared by adding different mass of water and oleic acid to screen the optimum ratio. C60-hydroxyapatite mixture and C60-hydroxyapatite composite were added to the artificial sebum to test the oil-absorbing capacity of the materials. The hydroxyl radical scavenging ability of C60-hydroxyapatite composite containing different fullerene contents was measured by X-band ESR spectroscopy, and the long-term radical scavenging ability of the composites was tested in comparison with VC. Antioxidant experiment is adding C60-hydroxyapatite composite material, and hydroxyapatite to oleic acid, then the UV light irradiation is aimed to accelerate the oxidation of oleic acid. Oleic acid act as a control group, and make the detection of oleic acid peroxide value after 7 days. The safety of the materials was tested by using culture media to soak the C60-hydroxyapatite composite for 24 h and then used to culture cells. RESULTS: The characterization of SEM, UV-Vis, Raman, and XRD showed that fullerene clusters were dispersed on the surface of hydroxyapatite stably, and they formed a stable composite. The adsorption rates of C60-hydroxyapatite composites for oleic acid, phenyl trimethicone, caprylic capric glyceride, isooctyl palmitate, mineral oil, olive oil, and dimethicone were 60.5%, 9.3%, 9.15%, 5.24%, 2.94%, 1.01%, and 0%, respectively. The flocculation amount of artificial sebum was 5.9 g per gram of C60-hydroxyapatite mixture and 24.2 g per gram of C60-hydroxyapatite composite. C60-hydroxyapatite composites have excellent quenching ability for hydroxyl radicals. When the fullerene content is 1, 2, 3, and 4 mg/kg, the quenching rates are 25.02%, 39.57%, 49.75%, and 62.24%, respectively. The quenching effect was enhanced with the increase of fullerene content, and it had strong long-term antioxidant properties. It can also be proved that C60-hydroxyapatite composites have strong antioxidant capacity through antioxidant experiments. The peroxide value of oleic acid on Day 0 was 2.8, and after 7 days of UV irradiation, the peroxide values of blank control, hydroxyapatite group, C60-hydroxyapatite composite containing 0.5% and 1% fullerenes four groups of materials were 8.02 meq O2/kg, 7.98 meq O2/kg, 7.11 meq O2/kg, and 6.87 meq O2/kg, respectively. The cell activity was 20.94% and 99.2% after the cells were cultured for 24 h using C60-hydroxyapatite composite and hydroxyapatite extracts, respectively, and the addition of fullerene was able to significantly increase the cell activity. CONCLUSION: Fullerene hydroxyapatite complex has excellent directional oil absorption characteristics, which can effectively remove free radicals and reduce skin oil oxidation.