Human papillomavirus molecular prevalence in south China and the impact on vaginal microbiome of unvaccinated women.

The vaginal microbiome (VM) is associated with human papillomavirus (HPV) infection and progression, but a thorough understanding of the relation between HPV infection, and VM needs to be elucidated. From August to December 2022, women who underwent routine gynecological examinations were screened for HPV infection. The distribution of HPV variants and clinical characteristics were collected. Then, a total of 185 participants were enrolled and divided into HPV-negative (HC), high-risk HPV (H), low-risk HPV (L), multiple high-risk HPV (HH), and mixed high-low risk HPV (HL) groups. Samples were collected from the mid-vagina of these 185 participants and sent for 16S rDNA sequencing (V3-V4 region). Among 712 HPV-positive women, the top 3 most frequently detected genotypes were HPV52, HPV58, and HPV16. Among 185 participants in the microbiology study, the ß diversity of the HC group was significantly different from HPV-positive groups (P < 0.001). LEfSe analysis showed that Lactobacillus iners was a potential biomarker for H group, while Lactobacillus crispatus was for L group. Regarding HPV-positive patients, the α diversity of cervical lesion patients was remarkably lower than those with normal cervix (P < 0.05). Differential abundance analysis showed that Lactobacillus jensenii significantly reduced in cervical lesion patients (P < 0.001). Further community state type (CST) clustering displayed that CST IV was more common than other types in HC group (P < 0.05), while CST I was higher than CST IV in H group (P < 0.05). Different HPV infections had distinct vaginal microbiome features. HPV infection might lead to the imbalance of Lactobacillus spp. and cause cervical lesions. IMPORTANCE: In this study, we first investigated the prevalence of different HPV genotypes in south China, which could provide more information for HPV vaccinations. Then, a total of 185 subjects were selected from HPV-negative, high-risk, low-risk, multiple hr-hr HPV infection, and mixed hr-lr HPV infection populations to explore the vaginal microbiome changes. This study displayed that HPV52, HPV58, and HPV16 were the most prevalent high-risk variants in south China. In addition, high-risk HPV infection was featured by Lactobacillus iners, while low-risk HPV infection was by Lactobacillus crispatus. Further sub-group analysis showed that Lactobacillus jensenii was significantly reduced in patients with cervical lesions. Finally, CST clustering showed that CST IV was the most common type in HC group, while CST I accounted the most in H group. In a word, this study for the first time systemically profiled vaginal microbiome of different HPV infections, which may add bricks to current knowledge on HPV infection and lay the foundation for novel treatment/prevention development.

Association of diet and outdoor time with inflammatory bowel disease: a multicenter case-control study using propensity matching analysis in China.

Objective: To investigate the association between dietary and some other environmental factors and the risk of inflammatory bowel diseases (IBD) in Chinese population. Materials and methods: A multicenter case-control study was conducted involving 11 hospitals across China. A total of 1,230 subjects were enrolled consecutively, and diet and environmental factor questionnaires were collected. IBD patients were matched with healthy controls (HC) using propensity-score matching (PSM) at a 1:1 ratio with a caliper value of 0.02. Multivariate conditional logistic regression analyses were performed to evaluate the associations between diet, environmental factors, and IBD. Results: Moderate alcohol and milk consumption, as well as daily intake of fresh fruit, were protective factors for both Crohn's disease (CD) and ulcerative colitis (UC). Conversely, the consumption of eggs and chocolate increased the risk of IBD. Outdoor time for more than 25% of the day was a protective factor only for CD. In eastern regions of China, CD patients had higher egg consumption and less outdoor time, while UC patients consumed more chocolate. IBD patients from urban areas or with higher per capita monthly income consumed more fruit, eggs, and chocolate. Conclusions: This study reveals an association between specific foods, outdoor time, and the emergence of IBD in the Chinese population. The findings emphasize the importance of a balanced diet, sufficient outdoor time and activities, and tailored prevention strategies considering regional variations.

Natural course of ulcerative colitis in China: Differences from the West?

BACKGROUND AND AIMS: Whether the natural course of ulcerative colitis (UC) in mainland China is similar or different from that in Western countries is unknown, and data on it is limited. We aimed to provide a comprehensive description of the natural course of UC in China and compare it with Western UC patients. METHODS: Based on a prospective Chinese nationwide registry of consecutive patients with inflammatory bowel diseases, the medical treatments and natural history of UC were described in detail, including disease extension, surgery, and neoplasia. The Cox regression model was used to identify factors associated with poor outcomes. RESULTS: A total of 1081 UC patients were included with a median follow-up duration of 5.3 years. The overall cumulative exposure was 99.1% to 5-aminosalicylic acids, 52.1% to corticosteroids, 25.6% to immunomodulators, and 15.4% to biologics. Disease extent at diagnosis was proctitis in 26.9%, left-sided colitis in 34.8%, and extensive colitis in 38.3%. Of 667 patients with proctitis and left-sided colitis, 380 (57.0%) experienced disease extent progression. A total of 58 (5.4%) UC patients underwent colectomy, demonstrating cumulative proportions of surgery at 1, 5, and 10 years after diagnosis of 0.6%, 3.4%, and 8.2%, respectively. In addition, 23 (2.1%) UC patients were diagnosed with neoplasia, demonstrating cumulative proportions of neoplasia at 1, 5, and 10 years after diagnosis of 0.5%, 1.0%, and 3.5%, respectively. CONCLUSIONS: Chinese UC patients had similar cumulative proportions of exposure to IBD-specific treatments but a lower surgical rate than patients in Western countries, indicating a different natural course, and close monitoring needs for UC in China. However, these results must be confirmed in population-based studies because the hospital-based cohort in our study might lead to selection bias.

Pairwise kinship inference and pedigree reconstruction using 91 microhaplotypes.

Kinship inference has been a major issue in forensic genetics, and it remains to be solved when there is no prior hypothesis and the relationships between multiple individuals are unknown. In this study, we genotyped 91 microhaplotypes from 46 pedigree samples using massive parallel sequencing and inferred their relatedness by calculating the likelihood ratio (LR). Based on simulated and real data, different treatments were applied in the presence and absence of relatedness assumptions. The pedigree of multiple individuals was reconstructed by calculating pedigree likelihoods based on real pedigree samples. The results showed that the 91 MHs could discriminate pairs of second-degree relatives from unrelated individuals. And more highly polymorphic loci were needed to discriminate the pairs of second-degree or more distant relative from other degrees of relationship, but correct classification could be obtained by expanding the suspected relationship searched to other relationships with lower LR values. Multiple individuals with unknown relationships can be successfully reconstructed if they are closely related. Our study provides a solution for kinship inference when there are no prior assumptions, and explores the possibility of pedigree reconstruction when the relationships of multiple individuals are unknown.

Digital product import and domestic value-added ratio of export: Theory and demonstration.

Based on the matching of the database of China Industry Business Performance and China Customs Trade from 2000 to 2013, this paper constructs the digital product import index, and adopts the method of panel data modeling to systematically investigate the impact and mechanism of digital product import on the domestic value-added rate of Chinese enterprises' export from the theoretical and empirical aspects. The research finds that the import of digital products significantly promotes the improvement of the domestic value-added rate of enterprises' export, and the core conclusion is still valid after considering the endogeneity of variables, changing the measurement index and estimation method. The mechanism test finds that the import of digital products improves the domestic value-added rate of enterprises' export through two channels: cost markup and relative price. In addition, the heterogeneity test finds that the import of digital products has a stronger effect on the improvement of the domestic value-added rate of enterprises' export in non-export enterprises, pure general trading enterprises, foreign-funded enterprises, labor-intensive enterprises and enterprises in the eastern region.

Baicalein inhibits biofilm formation of avian pathogenic Escherichia coli in vitro mainly by affecting adhesion.

Avian pathogenic Escherichia coli (APEC) is a widespread bacterium that causes significant economic losses to the poultry industry. APEC biofilm formation may result in chronic, persistent, and recurrent infections in clinics, making treatment challenging. Baicalein is a natural product that exhibits antimicrobial and antibiofilm activities. This study investigates the inhibitory effect of baicalein on APEC biofilm formation at different stages. The minimum inhibitory concentration (MIC) of baicalein on APEC was determined, and the growth curve of APEC biofilm formation was determined. The effects of baicalein on APEC biofilm adhesion, accumulation, and maturation were observed using optical microscopy, confocal laser scanning microscopy, and scanning electron microscopy. The biofilm inhibition rate of baicalein was calculated at different stages. The MIC of baicalein against APEC was 256 µg/mL. The process of APEC biofilm maturation takes approximately 48 h after incubation, with initial adhesion completed at 12 h, and cell accumulation finished at 24 h. Baicalein had a significant inhibitory effect on APEC biofilm formation at concentrations above 1 µg/mL (p < 0.01). Notably, baicalein had the highest rate of biofilm formation inhibition when added at the adhesion stage. Therefore, it can be concluded that baicalein is a potent inhibitor of APEC biofilm formation in vitro and acts, primarily by inhibiting cell adhesion. These findings suggests that baicalein has a potential application for inhibiting APEC biofilm formation and provides a novel approach for the prevention and control APEC-related diseases.

Exploration of identifying individual tumor tissue based on probabilistic model.

Variations in the tumor genome can result in allelic changes compared to the reference profile of its homogenous body source on genetic markers. This brings a challenge to source identification of tumor samples, such as clinically collected pathological paraffin-embedded tissue and sections. In this study, a probabilistic model was developed for calculating likelihood ratio (LR) to tackle this issue, which utilizes short tandem repeat (STR) genotyping data. The core of the model is to consider tumor tissue as a mixture of normal and tumor cells and introduce the incidence of STR variants (φ) and the percentage of normal cells (Mxn) as a priori parameters when performing calculations. The relationship between LR values and φ or Mxn was also investigated. Analysis of tumor samples and reference blood samples from 17 colorectal cancer patients showed that all samples had Log 10(LR) values greater than 1014. In the non-contributor test, 99.9% of the quartiles had Log 10(LR) values less than 0. When the defense's hypothesis took into account the possibility that the tumor samples came from the patient's relatives, LR greater than 0 was still obtained. Furthermore, this study revealed that LR values increased with decreasing φ and increasing Mxn. Finally, LR interval value was provided for each tumor sample by considering the confidence interval of Mxn. The probabilistic model proposed in this paper could deal with the possibility of tumor allele variability and offers an evaluation of the strength of evidence for determining tumor origin in clinical practice and forensic identification.

Soil warming-induced reduction in water content enhanced methane uptake at different soil depths in a subtropical forest.

Global warming can significantly impact soil CH4 uptake in subtropical forests due to changes in soil moisture, temperature sensitivity of methane-oxidizing bacteria (MOB), and shifts in microbial communities. However, the specific effects of climate warming and the underlying mechanisms on soil CH4 uptake at different soil depths remain poorly understood. To address this knowledge gap, we conducted a soil warming experiment (+4 °C) in a natural forest. From August 2020 to October 2021, we measured soil temperature, soil moisture, and CH4 uptake rates at four different soil depths: 0-10 cm, 10-20 cm, 20-40 cm, and 40-60 cm. Additionally, we assessed the soil MOB community structure and pmoA gene (with qPCR) at the 0-10 and 10-20 cm depths. Our findings revealed that warming significantly enhanced soil net CH4 uptake rate by 12.28 %, 29.51 %, and 61.05 % in the 0-10, 20-40, and 40-60 cm soil layers, respectively. The warming also led to reduced soil moisture levels, with more pronounced reductions observed at the 20-40 cm depth compared to the 0-20 cm depth. At the 0-10 cm depth, warming increased the relative abundance of upland soil cluster α (a type of MOB) and decreased the relative abundance of Methylocystis, but it did not significantly increase the pmoA gene copies. Our structural equation model analysis indicated that warming directly regulated soil CH4 uptake rate through the decrease in soil moisture, rather than through changes in the pmoA gene and MOB community structure at the 0-20 cm depth. In summary, our results demonstrate that warming enhances soil CH4 uptake at different depths, with soil moisture playing a crucial role in this process. Under warming conditions, the drier soil pores allow for better CH4 penetration, thereby promoting more efficient activity of MOB.

Antibiotics influence the risk of anti-drug antibody formation during anti-TNF therapy in Chinese inflammatory bowel disease patients.

Aims: The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD. Methods: A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development. Results: Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used ß-lactam-ß-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270, p = 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089, p = 0.004) during 12 months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924, p = 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85 µg/mL, p < 0.0001; adalimumab: 0.45 vs. 7.55 µg/mL, p = 0.0121). Conclusion: ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.

Ovary metabolome and cecal microbiota changes in aged laying hens supplemented with vitamin E.

This study was aimed to evaluate the effect of vitamin E (VE) on laying performance, VE deposition, antioxidant capacity, immunity, follicle development, estrogen secretion, ovary metabolome, and cecal microbiota of laying hens. One hundred and twenty XinYang Black-Feathered laying hens (70 wk old) were randomly assigned to 2 groups (6 replicates of 20 birds), and fed a basal diet (containing 20 mg/kg VE, control (CON) group) and a basal diet supplemented with 20 mg/kg VE (VE group). The experiment lasted for 10 wk. Results showed that VE supplementation increased laying performance, antioxidant capacity, and immunity, as evidenced by increased (P < 0.05) performance (laying rate), antioxidant (glutathione peroxidase, total superoxide dismutase, total antioxidant capacity, and catalase) and immune (immunoglobulins) parameters, and decreased (P < 0.05) feed/egg ratio and malondialdehyde. Meanwhile, VE group had higher (P < 0.05) pregrade follicles, ovary index and serum estrogen levels than CON group. 16S rRNA sequencing showed that VE supplementation altered the cecal microbiota composition by increasing Bacteroides, Rikenellaceae_RC9_gut_group, Prevotellaceae_UCG-001 and Megamonas abundances and reducing Christensenellaceae_R-7_group abundance (at genus level), which are mainly associated with the production of short-chain fatty acids. Metabolomic profiling of the ovary revealed that the major metabolites altered by VE supplementation were mainly related to follicle development, estrogen secretion, anti-inflammatory, antioxidant, phototransduction, bile acid synthesis, and nutrient transport. Furthermore, changes in cecal microbiota (at genus level) and ovary metabolites were highly correlated with laying performance, antioxidant, and immune parameters. In summary, VE contributed to the laying performance of aged laying hens by enhancing antioxidant, immune, and ovarian functions, promoting follicle development and estrogen secretion, and regulating gut microbiota and ovary metabolites. These findings will provide a new perspective on the mechanisms of egg production in aged poultry ovaries.

The Graphene Quantum Dots Gated Nanoplatform for Photothermal-Enhanced Synergetic Tumor Therapy.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5-10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

Peptidylprolyl isomerase D circular RNA sensitizes breast cancer to trastuzumab through remodeling HER2 N4-acetylcytidine modification.

Human epidermal growth factor receptor 2 (HER2) overexpression and activation are crucial for trastuzumab resistance in HER2-positive breast cancer; however, the potential regulatory mechanism of HER2 is still largely undetermined. In this study, a novel circular RNA derived from peptidylprolyl isomerase D (PPID) is identified as a negative regulator of trastuzumab resistance. Circ-PPID is highly stable and significantly downregulated in trastuzumab-resistant cells and tissues. Restoration of circ-PPID markedly enhances HER2-positive breast cell sensitivity to trastuzumab in vitro and in vivo. Circ-PPID directly binds to N-acetyltransferase 10 (NAT10) in the nucleus and blocks the interaction between NAT10 and HER2 mRNA, reducing N4-acetylcytidine (ac4C) modification on HER2 exon 25, leading to HER2 mRNA decay. Intriguingly, the subcellular localization of circ-PPID differs between trastuzumab-sensitive and -resistant cells. Circ-PPID in trastuzumab-resistant cells is located more in the cytoplasm, mainly due to the upregulation of Exportin 4 (XPO4), which results in the loss of spatial conditions for circ-PPID to bind to nuclear NAT10. Taken together, our data suggest that circ-PPID is a previously unappreciated ac4C-dependent HER2 epigenetic regulator, providing a promising therapeutic direction for overcoming trastuzumab resistance in clinical setting.

Using simulated microhaplotype genotyping data to evaluate the value of machine learning algorithms for inferring DNA mixture contributor numbers.

Inferring the number of contributors (NoC) is a crucial step in interpreting DNA mixtures, as it directly affects the accuracy of the likelihood ratio calculation and the assessment of evidence strength. However, obtaining the correct NoC in complex DNA mixtures remains challenging due to the high degree of allele sharing and dropout. This study aimed to analyze the impact of allele sharing and dropout on NoC inference in complex DNA mixtures when using microhaplotypes (MH). The effectiveness and value of highly polymorphic MH for NoC inference in complex DNA mixtures were evaluated through comparing the performance of three NoC inference methods, including maximum allele count (MAC) method, maximum likelihood estimation (MLE) method, and random forest classification (RFC) algorithm. In this study, we selected the top 100 most polymorphic MH from the Southern Han Chinese (CHS) population, and simulated over 40 million complex DNA mixture profiles with the NoC ranging from 2 to 8. These profiles involve unrelated individuals (RM type) and related pairs of individuals, including parent-offspring pairs (PO type), full-sibling pairs (FS type), and second-degree kinship pairs (SE type). Our results indicated that how the number of detected alleles in DNA mixture profiles varied with the markers' polymorphism, kinship's involvement, NoC, and dropout settings. Across different types of DNA mixtures, the MAC and MLE methods performed best in the RM type, followed by SE, FS, and PO types, while RFC models showed the best performance in the PO type, followed by RM, SE, and FS types. The recall of all three methods for NoC inference were decreased as the NoC and dropout levels increased. Furthermore, the MLE method performed better at low NoC, whereas RFC models excelled at high NoC and/or high dropout levels, regardless of the availability of a priori information about related pairs of individuals in DNA mixtures. However, the RFC models which considered the aforementioned priori information and were trained specifically on each type of DNA mixture profiles, outperformed RFC_ALL model that did not consider such information. Finally, we provided recommendations for model building when applying machine learning algorithms to NoC inference.

The novel ß-TrCP protein isoform hidden in circular RNA confers trastuzumab resistance in HER2-positive breast cancer.

Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a major hurdle to clinical treatment. In the present study, we identify a circular RNA intimately linked to trastuzumab resistance. circ-ß-TrCP, derived from the back-splicing of ß-TrCP exon 7 and 13, confers trastuzumab resistance by regulating NRF2-mediated antioxidant pathway in a KEAP1-independent manner. Concretely, circ-ß-TrCP encodes a novel truncated 343-amino acid peptide located in the nucleus, referred as ß-TrCP-343aa, which competitively binds to NRF2, blocks SCFß-TrCP-mediated NRF2 proteasomal degradation, and this protective effect of ß-TrCP-343aa on NRF2 protein requires GSK3 activity. Subsequently, the elevated NRF2 transcriptionally upregulates a cohort of antioxidant genes, giving rise to trastuzumab resistance. Moreover, the translation ability of circ-ß-TrCP is inhibited by eIF3j under both basal and oxidative stress conditions, and eIF3j is transcriptionally repressed by NRF2, thus forming a positive feedback circuit between ß-TrCP-343aa and NRF2, expediting trastuzumab resistance. Collectively, our data demonstrate that circ-ß-TrCP-encoded ß-TrCP protein isoform drives HER2-targeted therapy resistance in a NRF2-dependent manner, which provides potential therapeutic targets for overcoming trastuzumab resistance.

Enterohemorrhagic Escherichia coli O157:H7 antigens produced in transgenic lettuce effective as an oral vaccine in mice.

KEY MESSAGE: Transgene with recombination sites to address biosafety concerns engineered into lettuce to produce EspB and γ-intimin C280 for oral vaccination against EHEC O157:H7. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a food-borne pathogen where ruminant farm animals, mainly bovine, serve as reservoirs. Bovine vaccination has been used to prevent disease outbreaks, and the current method relies on vaccines subcutaneously injected three times per year. Since EHEC O157:H7 colonizes mucosal surfaces, an oral vaccine that produces an IgA response could be more convenient. Here, we report on oral vaccination against EHEC O157:H7 in mice orally gavaged with transgenic lettuce that produces EHEC O157:H7 antigens EspB and γ-intimin C280. Younger leaves accumulated a higher concentration of antigens; and in unexpanded leaves of 30-day-old T2 plants, EspB and γ-intimin C280 were up to 32 and 51 µg/g fresh weight, respectively. Mice orally gavaged with lettuce powders containing < 3 µg antigens for 6 days showed a mucosal immune response with reduced colonization of EHEC O157:H7. This suggests that the transgenic lettuce has potential to be used for bovine vaccination. To promote the biosafety of crop plants producing medically relevant proteins, recombination sites were built into our transgenic lines that would permit optional marker removal by Cre-lox recombination, as well as transgene deletion in pollen by CinH-RS2 recombination. The ability to upgrade the transgenic lettuce by stacking additional antigen genes or replacing older genes with newer versions would also be possible through the combined use of Bxb-att and Cre-lox recombination systems.

Role of miR­let­7c­5p/c­myc signaling axis in the committed differentiation of leukemic THP­1 cells into monocytes/macrophages.

In a preliminary experiment, it was found that c-myc expression was decreased following the differentiation of THP-1 cells into monocytes/macrophages induced by phorbol 12-myristate 13 acetate (PMA) + lipopolysaccharide (LPS) + interferon (IFN)-γ. The expression of miR-let-7c-5p was then found to be elevated by cross-sectional analysis using TargetScan and PubMed and differential microarray analysis. The present study aimed to investigate the role of the miR-let-7c-5p/c-myc signaling axis in the committed differentiation of THP-1 leukemic cells into monocytes/macrophages induced by PMA + LPS + IFN-γ. Human THP-1 leukemic cells were induced to differentiate into monocytes/macrophages by PMA + LPS + IFN-γ. Following induction for 48 h, the growth density of the THP-1 cells was observed directly under an inverted microscope, cell proliferation was measured using Cell Counting Kit-8 assay and the cell cycle and the expression of differentiation-related antigens (CD11b and CD14) were measured using flow cytometry. The mRNA expression of miR-let-7c-5p and c-myc was detected using reverse transcription-quantitative PCR and the protein expression of c-myc was detected using western blot analysis. Dual luciferase reporter gene analysis was used to detect the targeted binding of miR-let-7c-5p on the 3'UTR of c-myc. The relative expression of miR-let-7c-5p and c-myc genes in THP-1 cells induced by PMA + LPS + IFN-γ was found to be up- and downregulated respectively, and expression of miR-let-7c-5p was negatively correlated with the expression of c-myc gene. Dual luciferase reporter gene assays confirmed that miR-let-7c-5p targeted the 3'UTR of c-myc and inhibited luciferase activity. Following transfection with miR-let-7c-5p mimics, the expression of c-myc was markedly downregulated and the proliferative ability of the THP-1 cells was decreased, while the expression rate of CD11b and CD14 was significantly increased. The rescue experiment revealed that the effects of miR-let-7c-5p mimics on the proliferation and differentiation of THP-1 cells were attenuated by transfection with c-myc overexpression vector. Together, the findings of the present study demonstrated that miR-let-7c-5p can target the 3'UTR region of c-myc and that the miR-let-7c-5p/c-myc signaling axis is one of the critical pathways involved in the directional differentiation of leukemic cells into monocytes/macrophages.

Synergistic Amplification of Ferroptosis with Liposomal Oxidation Catalyst and Gpx4 Inhibitor for Enhanced Cancer Therapy.

As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H2 O2 or relatively high pH value for Fenton reaction-dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid-based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction-independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG2K -DSPE-modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe2+ , and subsequently the formed iron redox pair (Fe2+ /Fe3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction-independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor-killing ability with negligible side effect. Consequently, this two-pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.

Multiscale Microflower Structured Superhydrophobic Surface via Electrostatic Air Spray.

Superhydrophobic surfaces with microstructures and multifunctionality have attracted intense research interest. Herein, a multiscale microflower structured surface (MMSS) was successfully fabricated by electrostatic air spray. To systematically study the preparation process, the influences of different electrostatic voltages, solution ratios, soaking time, spray distances, and spray time on surface morphology and hydrophobicity were analyzed. The surface has good superhydrophobic properties with a water contact angle of 162.3°, which allows the surface to be self-cleaning and antifouling. The surface hydrophobicity can be maintained after various mechanical and chemical damages. To overcome the limitation that existing droplet manipulation relies on special materials and surfaces, a new and universal droplet transport method is presented to successfully perform nondestructive droplet manipulations, which relies on external forces and droplet deformation to drive droplets. Therefore, this paper represents a different approach from previous studies of superhydrophobic surfaces and provides a new way to achieve dynamic droplet manipulations. These results indicate that the multifunctional MMSS will be widely used in industrial droplet transportation and self-cleaning applications.

Case report: Sudden unexpected death due to tuberculous myocarditis involving sinus node at autopsy.

Tuberculous myocarditis (TM) is an extremely rare manifestation of Mycobacterium tuberculosis (TB) infection. Although TM is a critical cause of sudden cardiac death, only a few cases have been reported. We report the case of an older patient with pulmonary TB with a history of fever, chest tightness, paroxysmal palpitations, and electrocardiographic evidence of sinus node conduction abnormalities on admission. Although emergency physicians observed these unusual clinical manifestations, no timely differential diagnosis was made nor interventions were performed. A definitive diagnosis of TM and histopathological findings compatible with sinus node involvement were made based on autopsy outcomes. Herein, we describe the clinical presentation and pathological features of a rare form of Mycobacterium TB. In addition, we provide an overview of issues related to the diagnosis of myocardial TB.

Intestinal fungi and antifungal secretory immunoglobulin A in Crohn's disease.

The human gastrointestinal tract harbors trillions of commensal microorganisms. Emerging evidence points to a possible link between intestinal fungal dysbiosis and antifungal mucosal immunity in inflammatory bowel disease, especially in Crohn's disease (CD). As a protective factor for the gut mucosa, secretory immunoglobulin A (SIgA) prevents bacteria from invading the intestinal epithelium and maintains a healthy microbiota community. In recent years, the roles of antifungal SIgA antibodies in mucosal immunity, including the regulation of intestinal immunity binding to hyphae-associated virulence factors, are becoming increasingly recognized. Here we review the current knowledge on intestinal fungal dysbiosis and antifungal mucosal immunity in healthy individuals and in patients with CD, discuss the factors governing antifungal SIgA responses in the intestinal mucosa in the latter group, and highlight potential antifungal vaccines targeting SIgA to prevent CD.