CytoGAN: Unpaired staining transfer by structure preservation for cytopathology image analysis.

With the development of digital pathology, deep learning is increasingly being applied to endometrial cell morphology analysis for cancer screening. And cytology images with different staining may degrade the performance of these analysis algorithms. To address the impact of staining patterns, many strategies have been proposed and hematoxylin and eosin (H&E) images have been transferred to other staining styles. However, none of the existing methods are able to generate realistic cytological images with preserved cellular layout, and many important clinical structural information is lost. To address the above issues, we propose a different staining transformation model, CytoGAN, which can quickly and realistically generate images with different staining styles. It includes a novel structure preservation module that preserves the cell structure well, even if the resolution or cell size between the source and target domains do not match. Meanwhile, a stain adaptive module is designed to help the model generate realistic and high-quality endometrial cytology images. We compared our model with ten state-of-the-art stain transformation models and evaluated by two pathologists. Furthermore, in the downstream endometrial cancer classification task, our algorithm improves the robustness of the classification model on multimodal datasets, with more than 20 % improvement in accuracy. We found that generating specified specific stains from existing H&E images improves the diagnosis of endometrial cancer. Our code will be available on github.

SARS-CoV-2 spike protein potentiates platelet aggregation via upregulating integrin αIIbß3 outside-in signaling pathway.

Platelet hyperreactivity is one of the crucial causes of coagulative disorders in patients with COVID-19. Few studies have indicated that integrin αIIbß3 may be a potential target for spike protein binding to platelets. This study aims to investigate whether spike protein interacts with platelet integrin αIIbß3 and upregulates outside-in signaling to potentiate platelet aggregation. In this study, we found that spike protein significantly potentiated platelet aggregation induced by different agonists and platelet spreading in vitro. Mechanism studies revealed that spike protein upregulated the outside-in signaling, such as increased thrombin-induced phosphorylation of ß3, c-Src. Moreover, using tirofiban to inhibit spike protein binding to αIIbß3 or using PP2 to block outside-in signaling, we found that the potentiating effect of spike protein on platelet aggregation was abolished. These results demonstrate that SARS-CoV-2 spike protein directly enhances platelet aggregation via integrin αIIbß3 outside-in signaling, and suggest a potential target for platelet hyperreactivity in patients with COVID-19. HIGHLIGHTS: • Spike protein potentiates platelet aggregation and upregulates αIIbß3 outside-in signaling. • Spike protein interacts with integrin αIIbß3 to potentiate platelet aggregation. • Blocking outside-in signaling abolishes the effect of spike protein on platelets.

BCL6 overexpression in CD4+ T cells induces Tfh-like transdifferentiation and enhances antitumor efficiency of CAR-T therapy in pancreatic cancer.

PDAC is a typical "cold tumor" characterized by low immune cell infiltration and a suppressive immune microenvironment. We previously observed the existence of a rare group of follicular helper T cells (Tfh) that could enhance antitumor immune responses by recruiting other immune cells in PDAC. In this study, we ectopically expressed BCL6 in CD4+ T cells, and successfully induced Tfh-like transdifferentiation in vitro. This strategy provided abundant Tfh-like cells (iTfhs) that can recruit CD8+ T cells like endogenous Tfhs. Subsequently, Chimeric Antigen Receptors (CARs) against both MSL (Mesothelin) and EPHA2 (Ephrin receptor A2) were used to modify iTfh cells, and the CAR-iTfh cells significantly improved infiltration and antitumor cytotoxicity of co-cultured CD8+ T cells. After that, combinatory administration of CAR-iTfh & CAR-CD8 T cell therapy displayed a better effect in repressing the PDAC tumors in xenograft mouse models, compared to conventional CAR-CD4 & CAR-CD8 combinations, and the models received the CAR-iTfh & CAR-CD8 T cells displayed a significantly improved survival rate. Our study revealed the plasticity of Thelper differentiation, expanded the source of Tfh-like cells for cell therapy, and demonstrated a novel and potentially more efficient cellular composition for CAR-T therapy.

Characterization, in vitro elderly digestion, and organoids cell uptake of curcumin-loaded nanoparticles.

Curcumin, a bioactive compound, showed versatile in anti-inflammatory and anti-cancer ability, while their biological fate in elderly is unclear. In this study, curcumin-loaded nanoparticles based on octyl succinate hydrate (OSA) starch and sodium caseinate were prepared and the in vitro elderly digestion and absorption fate was investigated. The loading capacity of curcumin-loaded nanoparticles prepared from OSA starch (HI), sodium caseinate (SC) and OSA starch­sodium caseinate (HS) were all higher than 15%. Curcumin release behavior of the three nanoparticles during in vitro digestion conformed to first-order kinetics. Meanwhile, the transport efficiency of curcumin for HI, SC, and HS increased significantly than the free curcumin (near 1-fold), and the permeability were 1.9, 2.0, and 2.0 times, respectively. The gene expressions of TNF-α, SREBP2 and NPC1L1 in the organoids were enhanced than control group. This study provided scientific reference and guidance for encapsulation of curcumin and digestion and absorption properties in elderly.

A deep learning framework for predicting endometrial cancer from cytopathologic images with different staining styles.

Endometrial cancer screening is crucial for clinical treatment. Currently, cytopathologists analyze cytopathology images is considered a popular screening method, but manual diagnosis is time-consuming and laborious. Deep learning can provide objective guidance efficiency. But endometrial cytopathology images often come from different medical centers with different staining styles. It decreases the generalization ability of deep learning models in cytopathology images analysis, leading to poor performance. This study presents a robust automated screening framework for endometrial cancer that can be applied to cytopathology images with different staining styles, and provide an objective diagnostic reference for cytopathologists, thus contributing to clinical treatment. We collected and built the XJTU-EC dataset, the first cytopathology dataset that includes segmentation and classification labels. And we propose an efficient two-stage framework for adapting different staining style images, and screening endometrial cancer at the cellular level. Specifically, in the first stage, a novel CM-UNet is utilized to segment cell clumps, with a channel attention (CA) module and a multi-level semantic supervision (MSS) module. It can ignore staining variance and focus on extracting semantic information for segmentation. In the second stage, we propose a robust and effective classification algorithm based on contrastive learning, ECRNet. By momentum-based updating and adding labeled memory banks, it can reduce most of the false negative results. On the XJTU-EC dataset, CM-UNet achieves an excellent segmentation performance, and ECRNet obtains an accuracy of 98.50%, a precision of 99.32% and a sensitivity of 97.67% on the test set, which outperforms other competitive classical models. Our method robustly predicts endometrial cancer on cytopathologic images with different staining styles, which will further advance research in endometrial cancer screening and provide early diagnosis for patients. The code will be available on GitHub.

The Impact of Harsh Parental Discipline and Emotional Warmth on Adolescent Problem Behaviors.

Purpose: This study, grounded in Social Information Processing Theory, integrates emotional warmth and harsh discipline into a unified model to investigate their differential effects on adolescents' internalized and externalized problem behaviors, as well as to explore the potential divergences in the mediating role of inhibitory control. Patients and Methods: Four hundred and twenty-eight adolescents completed validated scales of Egna Minnen av Barndoms Uppfostran (EMBU), Inhibitory Control and The Youth Self-Report (YSR), Data analysis was performed using SPSS 26.0 and Mplus7.4 to examine the relationship between harsh parental discipline, emotional warmth, adolescent inhibitory control, and internalized and externalized problem behaviors and the mediating effects. Results: The present study revealed that (1) Harsh parental discipline negatively predicted both internalized and externalized problems in adolescents, while emotional warmth from fathers positively predicted internalized problem behaviors; (2) Inhibitory control acted as a mediator in the impact of harsh parental discipline on problem behaviors, while the mediating effect between paternal emotional warmth and internalization issues was not significant. Conclusion: The impact of emotional warmth and harsh discipline on adolescent internalized and externalized problems varied. In families practicing a mixed parenting style, harsh discipline had a more significant effect on adolescents, primarily mediated through inhibitory control.

PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from Mendelian randomization, a retrospective study and basic experiments.

Background: Current evidences suggest that Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) exhibit a protective influence on acute coronary syndrome (ACS). Nevertheless, further investigation is required to comprehend the impact and mechanisms of these pharmaceutical agents on inflammatory factors and arterial stiffness (AS) in patients with ACS. Consequently, the objective of this study is to ascertain the influence of PCSK9i on arterial stiffness in ACS patients and elucidate the underlying mechanisms behind their actions. Methods: This study employed Mendelian randomization (MR) analysis to examine the association between genetic prediction of PCSK9 inhibition and arterial stiffness. Data of 71 patients with ACS were retrospectively collected, including PCSK9i group (n = 36, PCSK9 inhibitors combined with statins) and control group (n = 35, statins only). Blood lipid levels, inflammatory markers and pulse wave velocity (PWV) data were collected before treatment and at 1 and 6 months after treatment for analysis. Additionally, cell experiments were conducted to investigate the impact of PCSK9i on osteogenesis of vascular smooth muscle cells (VSMCs), utilizing western blot (WB), enzyme-linked immunosorbent assay (ELISA), and calcification index measurements. Results: The results of the MR analysis suggest that genetic prediction of PCSK9 inhibition has potential to reduce the PWV. Following treatment of statins combined with PCSK9 inhibitors for 1 and 6 months, the PCSK9i group exhibited significantly lower levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen (FIB) and procalcitonin (PCT) compared to the control group (p < 0.05). Additionally, PWV in the PCSK9i group demonstrated significant reduction after 6 months of treatment and was found to be associated with the circulating CRP level. In cell experiments, PCSK9i pretreatment ameliorated osteogenesis of VSMCs through reducing the deposition of calcium ions, alkaline phosphatase (ALP) activity, and expression of runt-related transcription factor 2 (RUNX2). Conclusion: PCSK9i have potential to enhance arterial stiffness in ACS patients. Specifically, at the clinical level, this impact may be attributed to alterations in circulating CRP levels. At the cellular level, it is associated with the signaling pathway linked to RUNX2.

ZIF-8-Modified Black Phosphorus Nanosheets Incorporated into Injectable Dual-Component Hydrogels for Enhanced Photothermal Antibacterial and Osteogenic Activities.

The development of growth factor-free biomaterials for bone tissue regeneration with anti-infection and anti-inflammatory activities remains challenging. Black phosphorus nanosheets (BPNs), with distinctive attributes, including photothermal conversion and calcium ion chelation, offer potential for use in bone tissue engineering and infection prevention. However, BPNs are prone to oxidation and degradation in aqueous environments, and methods to stabilize BPNs for long-term bone repair remain insufficient. Herein, zeolitic imidazolate framework-8 (ZIF-8) was used to stabilize BPNs via in situ crystallization onto the surface of BPNs (BP@ZIF-8 nanocomposite). A novel injectable dual-component hydrogel comprising gelatin methacryloyl (GelMA) and methacrylate-modified hyaluronic acid (HAMA) was used as a BP@ZIF-8 nanocomposite carrier (GelMA/HAMA/BP@ZIF-8). The BP@ZIF-8 nanocomposite could effectively protect internal BPNs from oxidation and enhance the long-term photothermal performance of the hydrogel in both in vitro and in vivo settings. The GelMA/HAMA/BP@ZIF-8 hydrogel was injectable and exhibited outstanding performance for photothermal conversion, mechanical strength, and biodegradability, as well as excellent photothermal antibacterial activity against Staphylococcus aureus and Escherichia coli in vitro and in an in vivo rat model. The GelMA/HAMA/BP@ZIF-8 hydrogel also provided a microenvironment conducive to osteogenic differentiation, promoting the transformation of M2 macrophages and inhibiting inflammatory responses. Furthermore, the hydrogel promoted bone regeneration and had a synergistic effect with near-infrared irradiation in a rat skull-defect model. Transcriptome sequencing analysis revealed that the PI3K-AKT- and calcium-signaling pathways may be involved in promoting osteogenic differentiation induced by the GH-BZ hydrogel. This study presents an innovative, multifaceted solution to the challenges of bone tissue regeneration with antibacterial and anti-inflammatory effects, providing insights into the design of smart biomaterials with dual therapeutic capabilities.

LncRNA lnc-SPRR2G-2 contributes to keratinocyte hyperproliferation and inflammation in psoriasis by activating the STAT3 pathway and downregulating KHSRP.

Psoriasis is a chronic inflammatory disease characterized by increased keratinocyte proliferation and local inflammation. Long noncoding RNAs (lncRNAs) play important regulatory roles in many immune-mediated diseases, including psoriasis. In this study, we aimed to investigate the role and mechanism of lnc-SPRR2G-2 (SPRR2G) in M5-treated psoriatic keratinocytes. Fluorescence in situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) showed that lnc-SPRR2G-2 was significantly upregulated in psoriasis tissues and psoriatic keratinocytes. In psoriatic keratinocytes, functional and molecular experiment analyses demonstrated that SPRR2G regulated proliferation, cell cycle and apoptosis, and induced the expression of S100 calcium binding protein A7 (S100A7), interleukin (IL)-1ß, IL-8 and C-X-C motif chemokine ligand 10 (CXCL10). The function of SPRR2G in psoriasis is related to the STAT3 signaling pathway and can be inhibited by a STAT3 inhibitor. Moreover, KH-type splicing regulatory protein (KHSRP) was proved to be regulated by lnc-SPRR2G-2 and to control the mRNA decay of psoriasis-related cytokines (p < 0.05). In summary, we reported the functions of lnc-SPRR2G-2 and KHSRP in psoriasis. Our findings provide new insights for the further exploration of the pathogenesis and treatment of psoriasis.

Effect of pH, protein/polysaccharide ratio and preparation method on the stability of lactoferrin-polysaccharide complexes.

In this study, carrageenan (CG), xanthan gum (XG) and locust bean gum (LBG), which can be used in infant formulas in China national standards, were selected to prepare LF-polysaccharide complexes to improve the stability of lactoferrin. The results showed that LF interacted more strongly with polysaccharides and did not affect the LF structure to a large extent when the pH and protein/polysaccharide mass ratio were 7 and 10:1 for LF-CG, 8 and 5:1 for LF-XG, 7 and 15:1 for LF-LBG. The zeta potential and fluorescence intensity of the LF-polysaccharide complexes displayed a decreasing trend with the increase in pH. When pH < 6, LF-CG and LF-XG exhibited precipitation and increased UV absorbance. Complexation between LF and CG/XG mainly attributed to electrostatic interactions, while LF and LBG form complexes based on hydrogen bonding or hydrophobic interactions. This study could provide a reference for the practical application of LF in infant formula.

Noninvasive pressure-strain loop quantitative assessment of left ventricular function in anemic preterm infants with different modes of respiratory support.

To investigate noninvasive pressure-strain loop (PSL) combined with two-dimensional speck tracking imaging and left ventricular pressure measurement in the evaluation of cardiac function changes in anemia of prematurity (AOP) with different modes of respiratory support, and to explore its value in detecting subclinical myocardial injury in preterm infants. This retrospective study included 79 preterm infants with anemia, according to different modes of respiratory support, who were divided into invasive respiratory support group (39 cases) and noninvasive respiratory support group (40 cases). A control group of 40 nonanemic preterm infants with matched age, sex, and gestational age were also included. Complete echocardiography was performed for each included infant. There are PSL parameters that used to evaluate cardiac function, including global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) among the three groups were compared. Compared with the control group, the value of GWI, GCW, and GWE were significantly lower and GWW was higher in the AOP groups (P < 0.05), and GWI, GCW and GWE were much significantly lower in the invasive respiratory support group than in the noninvasive respiratory support group (P < 0.05). There was no significant difference in GLS among the three groups (P > 0.05). Noninvasive PSL analysis can quantitatively assess myocardial work in AOP with different respiratory support, which is more sensitive than other conventional echocardiographic indices. This technique may provide a new method for monitoring subclinical myocardial injury with AOP.

CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche.

Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid-liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion-related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion-driven diseases.

Metabolic landscape of head and neck squamous cell carcinoma informs a novel kynurenine/Siglec-15 axis in immune escape.

BACKGROUND: Metabolic reprograming and immune escape are two hallmarks of cancer. However, how metabolic disorders drive immune escape in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, the aim of the present study was to investigate the metabolic landscape of HNSCC and its mechanism of driving immune escape. METHODS: Analysis of paired tumor tissues and adjacent normal tissues from 69 HNSCC patients was performed using liquid/gas chromatography-mass spectrometry and RNA-sequencing. The tumor-promoting function of kynurenine (Kyn) was explored in vitro and in vivo. The downstream target of Kyn was investigated in CD8+ T cells. The regulation of CD8+ T cells was investigated after Siglec-15 overexpression in vivo. An engineering nanoparticle was established to deliver Siglec-15 small interfering RNA (siS15), and its association with immunotherapy response were investigated. The association between Siglec-15 and CD8+ programmed cell death 1 (PD-1)+ T cells was analyzed in a HNSCC patient cohort. RESULTS: A total of 178 metabolites showed significant dysregulation in HNSCC, including carbohydrates, lipids and lipid-like molecules, and amino acids. Among these, amino acid metabolism was the most significantly altered, especially Kyn, which promoted tumor proliferation and metastasis. In addition, most immune checkpoint molecules were upregulated in Kyn-high patients based on RNA-sequencing. Furthermore, tumor-derived Kyn was transferred into CD8+ T cells and induced T cell functional exhaustion, and blocking Kyn transporters restored its killing activity. Accroding to the results, mechanistically, Kyn transcriptionally regulated the expression of Siglec-15 via aryl hydrocarbon receptor (AhR), and overexpression of Siglec-15 promoted immune escape by suppressing T cell infiltration and activation. Targeting AhR in vivo reduced Kyn-mediated Siglec-15 expression and promoted intratumoral CD8+ T cell infiltration and killing capacity. Finally, a NH2-modified mesoporous silica nanoparticle was designed to deliver siS15, which restored CD8+ T cell function status and enhanced anti-PD-1 efficacy in tumor-bearing immunocompetent mice. Clinically, Siglec-15 was positively correlated with AhR expression and CD8+PD-1+ T cell infiltration in HNSCC tissues. CONCLUSIONS: The findings describe the metabolic landscape of HNSCC comprehensively and reveal that the Kyn/Siglec-15 axis may be a novel potential immunometabolism mechanism, providing a promising therapeutic strategy for cancers.

Co-culture of STRO1 + human gingival mesenchymal stem cells and human umbilical vein endothelial cells in 3D spheroids: enhanced in vitro osteogenic and angiogenic capacities.

Stem cell spheroid is a promising graft substitute for bone tissue engineering. Spheroids obtained by 3D culture of STRO1+ Gingival Mesenchymal Stem Cells (sGMSCs) (sGMSC spheroids, GS) seldom express angiogenic factors, limiting their angiogenic differentiation in vivo. This study introduced a novel stem cell spheroid with osteogenic and angiogenic potential through 3D co-culture of sGMSCs and Human Umbilical Vein Endothelial Cells (HUVECs) (sGMSC/HUVEC spheroids, GHS). GHS with varying seeding ratios of sGMSCs to HUVECs (GHR) were developed. Cell fusion within the GHS system was observed via immunofluorescence. Calcein-AM/PI staining and chemiluminescence assay indicated cellular viability within the GHS. Furthermore, osteogenic and angiogenic markers, including ALP, OCN, RUNX2, CD31, and VEGFA, were quantified and compared with the control group comprising solely of sGMSCs (GS). Incorporating HUVECs into GHS extended cell viability and stability, initiated the expression of angiogenic factors CD31 and VEGFA, and upregulated the expression of osteogenic factors ALP, OCN, and RUNX2, especially when GHS with a GHR of 1:1. Taken together, GHS, derived from the 3D co-culture of sGMSCs and HUVECs, enhanced osteogenic and angiogenic capacities in vitro, extending the application of cell therapy in bone tissue engineering.

Associations between parental autonomy support and depressive symptoms among Chinese college students: the chain-mediating effects of mindfulness and self-esteem.

Introduction: Despite extensive research on contextual factors will relieve college students' depressive symptoms, significant gaps remain in understanding the underlying mechanisms of this relationship, particularly through individual strength factors such as mindfulness and self-esteem. Based on self-determination theory, we explore the association between parental autonomy support and depressive symptoms among Chinese college students and whether mindfulness and self-esteem serve as mediators. Methods: A total of 1,182 Chinese college students aged 16 to 27 years (Mage = 20.33, SD = 1.63; female = 55.7%) participated in this research. Questionnaires pertaining to parental autonomy support, mindfulness, self-esteem, and depressive symptoms were administered. Results: The results revealed that depressive symptoms were negatively correlated with both paternal and maternal autonomy support, with mindfulness and self-esteem acting as chain-mediators. Specifically, mindfulness and self-esteem were positively impacted by parental autonomy support, whereas depressive symptoms were negatively impacted by mindfulness and self-esteem. Furthermore, paternal and maternal autonomy support significantly impacted depressive symptoms via both direct and indirect pathways. Indirect effects included three paths: mediation through mindfulness, mediation through self-esteem, and mediation through the mindfulness and self-esteem chain. Discussion: The study highlights the fundamental mechanisms that account for the association between Chinese college students' parental autonomy support and depressive symptoms, these insights can be used to prevent and manage mental health problems among Chinese college students. For example, parents' autonomy support can directly reduce depressive symptoms, but we can also indirectly promote college students' mental health by emphasizing the mediation role of students' mindfulness and self-esteem.

1,25-Dihydroxyvitamin D3 attenuates platelet aggregation potentiated by SARS-CoV-2 spike protein via inhibiting integrin αIIbß3 outside-in signaling.

Platelet hyperreactivity contributes to the pathogenesis of COVID-19, which is associated with a hypercoagulability state and thrombosis disorder. It has been demonstrated that Vitamin D deficiency is associated with the severity of COVID-19 infection. Vitamin D supplement is widely used as a dietary supplement due to its safety and health benefits. In this study, we investigated the direct effects and underlying mechanisms of 1,25(OH)2D3 on platelet hyperreactivity induced by SRAS-CoV-2 spike protein via Western blot and platelet functional studies in vitro. Firstly, we found that 1,25(OH)2D3 attenuated platelet aggregation and Src-mediated signaling. We further observed that 1,25(OH)2D3 attenuated spike protein-potentiated platelet aggregation in vitro. Mechanistically, 1,25(OH)2D3 attenuated spike protein upregulated-integrin αIIbß3 outside-in signaling such as platelet spreading and the phosphorylation of ß3, c-Src and Syk. Moreover, using PP2, the Src family kinase inhibitor to abolish spike protein-stimulated platelet aggregation and integrin αIIbß3 outside-in signaling, the combination of PP2 and 1,25(OH)2D3 did not show additive inhibitory effects on spike protein-potentiated platelet aggregation and the phosphorylation of ß3, c-Src and Syk. Thus, our data suggest that 1,25(OH)2D3 attenuates platelet aggregation potentiated by spike protein via downregulating integrin αIIbß3 outside-in signaling.

Resveratrol Improves Hyperuricemia and Ameliorates Renal Injury by Modulating the Gut Microbiota.

Resveratrol (RES) has been reported to prevent hyperuricemia (HUA); however, its effect on intestinal uric acid metabolism remains unclear. This study evaluated the impact of RES on intestinal uric acid metabolism in mice with HUA induced by a high-fat diet (HFD). Moreover, we revealed the underlying mechanism through metagenomics, fecal microbiota transplantation (FMT), and 16S ribosomal RNA analysis. We demonstrated that RES reduced the serum uric acid, creatinine, urea nitrogen, and urinary protein levels, and improved the glomerular atrophy, unclear renal tubule structure, fibrosis, and renal inflammation. The results also showed that RES increased intestinal uric acid degradation. RES significantly changed the intestinal flora composition of HFD-fed mice by enriching the beneficial bacteria that degrade uric acid, reducing harmful bacteria that promote inflammation, and improving microbial function via the upregulation of purine metabolism. The FMT results further showed that the intestinal microbiota is essential for the effect of RES on HUA, and that Lactobacillus may play a key role in this process. The present study demonstrated that RES alleviates HFD-induced HUA and renal injury by regulating the gut microbiota composition and the metabolism of uric acid.

Research progress on incomplete partition type 3 inner ear malformation.

PURPOSE: This review aims to provides a comprehensive overview of the latest research progress on IP-III inner ear malformation, focusing on its geneticbasis, imaging features, cochlear implantation, and outcome. METHODS: Review the literature on clinical and genetic mechanisms associated with IP-III. RESULTS: Mutations in the POU3F4 gene emerge as the principal pathogenic contributors to IP-III anomalies, primarily manifesting through inner ear potential irregularities leading to deafness. While cochlear implantation stands as the primary intervention for restoring hearing, the unique nature of the inner ear anomaly escalates the complexity of surgical procedures and postoperative results. Hence, meticulous preoperative assessment to ascertain surgical feasibility and postoperative verification of electrode placement are imperative. Additionally, gene therapy holds promise as a prospective treatment modality. CONCLUSIONS: IP-III denotes X-linked recessive hereditary deafness, with cochlear implantation currently serving as the predominant therapeutic approach. Clinicians are tasked with preoperative assement and individualized postoperative rehabilitation.

Ectopic CXCR2 expression cells improve the anti-tumor efficiency of CAR-T cells and remodel the immune microenvironment of pancreatic ductal adenocarcinoma.

BACKGROUND: Recent progressions in CAR-T cell therapy against pancreatic ductal adenocarcinoma (PDAC) remain disappointing, which are partially attributed to the immunosuppressive microenvironment including macrophage-mediated T cell repletion. METHODS: We first characterized the expression patterns of macrophage-relevant chemokines and identified CXCR2 as the key factor regulating T cell trafficking and tumor-specific accumulation in PDAC microenvironment. After that, we synthesized and introduced a CXCR2 expression cascade into Claudin18.2 CAR-T cells and compared the behaviors of CAR-T cells in vitro and in vivo. The therapeutic potential of CXCR2 CAR-T was evaluated in two different allogeneic models: subcutaneous allografts and metastatic PDAC models. RESULTS: The results showed that CXCR2 CAR-T not only reduced the size of allografted PDAC tumors, but also completely eliminated the formation of metastases. Lastly, we investigated the tumor tissues and found that expression of ectopic CXCR2 significantly improved tumor-targeted infiltration and residence of T cells and reduced the presence of MDSCs and CXCR2 + macrophages in PDAC microenvironment. CONCLUSION: Our studies suggested that ectopic CXCR2 played a significant and promising role in improving the efficiency of CAR-T therapy against primary and metastatic PDAC and partially reversed the immune-suppressive microenvironment.

Pentraxin 3 exacerbates psoriasiform dermatitis through regulation of macrophage polarization.

OBJECTIVE: To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice. METHODS: An Imiquimod (IMQ)-induced murine psoriatic model was created using Ptx3-KO (Ptx3-/-) and wild-type (Ptx3+/+) mice. Skin lesion severity and expression of inflammatory mediators (IL-6 and TNFα) were assessed using PASI score and ELISA, respectively. Cutaneous tissues from the two mice groups were subjected to histological analyses, including HE staining, Masson staining, and Immunohistochemistry (IHC). The PTX3, iNOS, COX2, and Arg1 expressions were quantified and compared between the two groups. We used RNA-seq to clarify the underlying mechanisms of the disease. Flow cytometry was used to analyze systemic Th17 cell differentiation and macrophage polarization. RESULT: The psoriatic region exhibited a higher PTX3 expression than the normal cutaneous area. Moreover, PTX3 was upregulated in HaCaT cells post-TNFα stimulation. Upon IMQ stimulation, Ptx3-/- mice displayed a lower degree of the psoriasiform dermatitis phenotype compared to Ptx3+/+ mice. Consistent with the RNA-seq results, further experiments confirmed that compared to the wild-type group, the PTX3-KO group exhibited a generally lower IL-6, TNFα, iNOS, and COX2 expression and a contrasting trend in macrophage polarization. However, no significant difference in Th17 cell activation was observed between the two groups. CONCLUSIONS: This study revealed that PTX3 was upregulated in psoriatic skin tissues and TNFα-stimulated HaCaT cells. We also discovered that PTX3 deficiency in mice ameliorated the psoriasiform dermatitis phenotype upon IMQ stimulation. Mechanistically, PTX3 exacerbates psoriasiform dermatitis by regulating macrophage polarization rather than Th17 cell differentiation.