miR-92a-3p promotes pulmonary fibrosis progression by regulating KLF2-mediated endothelial-to-mesenchymal transition.

Pulmonary fibrosis (PF) is a chronic lung disease that has a poor prognosis and a serious impact on the quality of life of patients. Here, we investigated the potential role of miR-92a-3p in PF. The mRNA level of miR-92a-3p was significantly increased in both the lung tissues of bleomycin (BLM)--treated mice and pulmonary microvascular endothelial cells (PMVECs). Overexpressing miR-92a-3p increased the mRNA and protein levels of α­SMA, vimentin, and Col-1 but downregulated E-cadherin. Additionally, the protein and mRNA expression levels of KLF2 were significantly decreased in the lung tissues of BLM-treated mice, suggesting that KLF2 participated in the progression of BLM-induced PF. Downregulating miR-92a-3p upregulated the expression of KLF2 and inhibited the endothelial-to-mesenchymal transition (EndoMT) process, thus alleviating PF in vivo. Altogether, a miR-92a-3p deficiency could significantly reduce the development of myofibroblasts and ameliorate PF progression.

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib.

Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

Water-sensitive fluorescent microgel inks to produce verifiable information for highly secured anti-counterfeiting.

The decryption and verification of encrypted information via a simple and efficient method is always difficult and challenging in the field of information security. Herein, a series of water-sensitive fluorescent microgels are fabricated for highly secured anti-counterfeiting with authenticity identification. The initial negatively charged microgels (MG) are made up of N-isopropylacrylamide (NIPAM), acrylic acid (AAc) and anthracen-9-yl acrylate (9-ANA, blue fluorescent monomer). The prepared MGs can bind cationic fluorescent dyes such as 5-aminofluorescein (FITC, green fluorescent dye) and rhodamine B (Rh B, red fluorescent dye) via electrostatic interaction, emitting multi-fluorescent colors based on the fluorescence resonance energy transfer (FRET) process. Furthermore, the fluorescence colors of MG-derived systems can be rapidly changed by swelling in water, which can block the FRET process and change the aggregation state of dyes. With the assistance of inkjet printing, multi-color security patterns can be designed and encoded, which can be revealed by UV irradiation and further verified by water stimulation. This study has pioneered a novel strategy to verify the authenticity of decrypted information, which greatly improves the security level of information.

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived ß cells.

Human pluripotent stem cell-derived ß cells (hPSC-ß cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-ß cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-ß cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-ß cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for ß cell maturation. Limiting intracellular accumulation of ceramides in hPSC-ß cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic ß cells and highlight the importance of ceramide homeostasis in function acquisition.

A novel hydrophobic carborane-hybrid microporous material for reversed C2H6 adsorption and efficient C2H4/C2H6 separation under humid conditions.

Since ethylene (C2H4) is important feedstock in the chemical industry, developing economical and energy-efficient adsorption separation techniques based on ethane (C2H6)-selective adsorbents to replace the energy-intensive cryogenic distillation is highly demanded, which however remains a daunting challenge. While previous anionic boron cluster hybrid microporous materials display C2H4-selective features, we herein reported that the incorporation of a neutral para-carborane backbone and aliphatic 1,4-diazabicyclo[2.2.2]octane (DABCO) enables the reversed adsorption of C2H6 over C2H4. The generated carborane-hybrid microporous material ZNU-10 (ZNU = Zhejiang Normal University) is highly stable in humid air and maintains good C2H6/C2H4 separation performance under high humidity. Gas loaded single crystal structure and density-functional theory (DFT) calculations revealed that the weakly polarized carborane and DABCO within ZNU-10 induce more specific C-Hδ+⋯Hδ--B dihydrogen bonds and other van der Waals interactions with C2H6, while the suitable pore space allows the high C2H6 uptake. Approximately 14.5 L kg-1 of polymer grade C2H4 can be produced from simulated C2H6/C2H4 (v/v 10/90) mixtures under ambient conditions in a single step, comparable to those of many popular materials.

Saliva and tongue microbiota in burning mouth syndrome: An exploratory study of potential roles.

OBJECTIVES: Burning mouth syndrome (BMS) is a chronic orofacial pain disorder with unclear etiology, in which the tongue is most commonly affected. This study aims to provide implication of the possible relationship between oral microbiota and the pathogenesis of BMS. MATERIALS AND METHODS: Saliva and tongue swabs of 15 primary BMS patients and 10 healthy controls were collected and assessed by 16S rRNA gene amplicon sequencing. The microbiota compositions were compared and bioinformatic analysis was conducted. RESULTS: Differences in microbiota compositions between BMS patients and healthy controls were revealed in both saliva and tongue samples. In saliva, Streptococcus, Rothia, and Neisseria were the predominant genus at the taxonomic level in BMS patients. In tongue samples, Prevotella, Streptococcus, and Neisseria were the dominant genus at the taxonomic level in BMS patients. LEfSe analysis and linear discriminant analysis score showed that Actinobacteria were the predominant phylum in saliva, and Selenomonas were enriched in the dorsum of the tongue of BMS patients. CONCLUSIONS: This study for the first-time reported saliva and tongue microbiota profiles were distinguished from that of healthy controls, indicating a necessity for further research on the possible relationship between oral microbes and the pathogenesis of BMS.

Surveillance and Resistance of Community-Onset Extended-Spectrum ß-Lactamase-Producing Escherichia coli and Klebsiella pneumonia in Oral and Maxillofacial Surgery Site Infections.

Background: The prevalence of community-onset infections of extended spectrum ß-lactamase (ESBL)-producing strains has increased globally, yet surveillance and resistance in patients with oral and maxillofacial surgery site infections is less investigated. Patients and Methods: A retrospective cohort study was performed to investigate risk factors and resistance of ESBL-producing Escherichia coli (ESBL-EC) and ESBL-producing Klebsiella pneumonia (ESBL-KP) among community-onset patients with oral and maxillofacial surgery during January 2010 to December 2016. Demographic features, predisposing factors, clinical outcomes, and antibiotic agent costs were analyzed. Antimicrobial susceptibility testing of nine antimicrobial agents against ESBL-KP and ESBL-EC were measured. Results: Among 2,183 cultures from infection sites in patients with oral and maxillofacial surgery site (45 cases [2.06%]) were confirmed with community-onset ESBL-KP (24; 1.10%) or ESBL-EC (21; 0.96%) infection. Multivariable analysis showed the independent risk factors for ESBL-producing bacterial infection were prior history of hospitalization (adjusted odds ratio [aOR], 10.984; 95% confidence interval [CI], 5.965-59.879; p = 0.025) and malignant condition (aOR, 3.373; 95% CI 2.947-7.634; p = 0.024). Based on antimicrobial susceptibility testing, 57.8% ESBL-KP and ESBL-EC were found receiving inappropriate antimicrobial therapy, and antibiotic agent costs were higher than non-ESBL-producing bacterial infections ($493.8 ± $367.3 vs. $304.1 ± $334.7; p = 0.031). Conclusions: Infections caused by ESBL-KP and ESBL-EC among patients in sites with oral and maxillofacial surgery are associated with prior history of hospitalization and malignant conditions. Prompt detection and appropriate antibiotic administration for community-onset infections of ESBLs are necessary for such populations.

A type I and type II chemical biology toolbox to overcome the hypoxic tumour microenvironment for photodynamic therapy.

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality employed for the treatment of various types of cancers, localized infections, and other diseases. Upon illumination, the photo-excited photosensitizer generates singlet oxygen and other reactive species, thereby inducing cytotoxicity in the target cells. The hypoxic tumour microenvironment (TME), however, poses a limitation on the supply of oxygen in tumour tissues. Moreover, under such conditions, tumour metastasis and drug resistance frequently occur, further compromising the efficacy of PDT in combating tumours. Traditionally, type I photosensitizers with lower oxygen consumption demonstrate significant potential in overcoming hypoxic environments and play a crucial role in determining the therapeutic efficacy of PDT because type I photosensitizers can generate highly cytotoxic free radicals. In comparison, type II photosensitizers exhibit high oxygen dependence. The rate of reactive oxygen species (ROS) generation in the type II process is significantly higher than that in the type I process. Thus, the efficiency and selectivity of PDT depend on the properties of the photosensitizer. Here, the recent development and application of type I and type II photosensitizers, mainly in the past year, are summarized. The design methods, electronic structures, photophysical properties, lipophilic properties, electric charge, and other molecular characteristics of these photosensitizers are discussed in detail. These modifications alter the microstructure of photosensitizers and directly impact the results of PDT. The main content of this paper will have a positive promoting and inspiring effect on the future development of PDT.

A Unique Combination of Mn2+ and Aluminum Adjuvant Acted the Synergistic Effect.

Introduction: The development of combinatorial adjuvants is a promising strategy to boost vaccination efficiency. Accumulating evidence indicates that manganese exerts strong immunocompetence and will become an enormous potential adjuvant. Here, we described a novel combination of Mn2+ plus aluminum hydroxide (AH) adjuvant that significantly exhibited the synergistic immune effect. Methodology. Initially, IsdB3 proteins as the immune-dominant fragment of IsdB proteins derived from Staphylococcus aureus (S. aureus) were prepared. IsdB3 proteins were identified by western blotting. Furthermore, we immunized C57/B6 mice with IsdB3 proteins plus Mn2+ and AH adjuvant. After the second immunization, the proliferation of lymphocytes was measured by the cell counting kit-8 (CCK-8) and the level of IFN-γ, IL-4, IL-10, and IL-17 cytokine from spleen lymphocytes in mice and generation of the antibodies against IsdB3 in serum was detected with ELISA, and the protective immune response was assessed through S. aureus challenge. Results: IsdB3 proteins plus Mn2+ and AH obviously stimulated the proliferation of spleen lymphocytes and increased the secretion of IFN-γ, IL-4, IL-10, and IL-17 cytokine in mice, markedly enhanced the generation of the antibodies against IsdB3 in serum, observably decreased bacterial load in organs, and greatly improved the survival rate of mice. Conclusion: These data showed that the combination of Mn2+ and AH significantly acted a synergistic effect, reinforced the immunogenicity of IsdB3, and offered a new strategy to increase vaccine efficiency.

A Better Fruit Quality of Grafted Blueberry Than Own-Rooted Blueberry Is Linked to Its Anatomy.

To further clarify the impact of different rootstocks in grafted blueberry, fruit quality, mineral contents, and leaf gas exchange were investigated in 'O'Neal' blueberry (Vaccinium corymbosum) grafted onto 'Anna' (V. corymbosum) (AO), 'Sharpblue' (V. corymbosum) (SO), 'Baldwin' (V. virgatum) (BO), 'Plolific' (V. virgatum) (PO), and 'Tifblue' (V. virgatum) (TO) rootstocks and own-rooted 'O'Neal' (NO), and differences in anatomic structures and drought resistance were determined in AO, TO, and NO. The findings revealed that fruit quality in TO and PO was excellent, that of BO and SO was good, and that of AO and NO was medium. 'Tifblue' and 'Plolific' rootstocks significantly increased the levels of leaf phosphorus and net photosynthetic rate of 'O'Neal', accompanied by a synchronous increase in their transpiration rates, stomatal conductance, and intercellular CO2. Additionally, the comprehensive evaluation scores from a principal component analysis based on anatomic structure traits from high to low were in the order TO > AO > NO. The P50 (xylem water potential at 50% loss of hydraulic conductivity) values of these grafted plants descended in the order NO > AO > TO, and the branch hydraulic conductivity of TO and sapwood hydraulic conductivity of TO and AO were significantly lower than those of NO. Thus, TO plants exhibited the strongest drought resistance, followed by AO, and NO, and this trait was related to the effects of different rootstocks on the fruit quality of 'O'Neal' blueberry. These results provided a basis for a deeper understanding of the interaction between rootstocks and scions, as well mechanisms to improve blueberry fruit quality.

Transanal fistula repair for the treatment of rectovestibular fistula with normal anus in female children: a 5-year single-center experience.

PURPOSE: The purpose of this study was to review a 5-year operative experience of transanal fistula repair for the treatment of rectovestibular fistula with a normal anus in female children. METHODS: In this study, we conducted a retrospective review of children diagnosed with rectovestibular fistula with normal anus who underwent transanal fistula repair in the department of General Surgery, Children's Hospital of Chongqing Medical University. Clinical data were retrospectively analyzed. RESULTS: A total of 56 female children were included in the study. The patients' ages ranged from 1 year 10 months to 15 years 11 months, with an average age of 5 years 1 month. These children had a clear history of gas or loose stool leakage through the vestibular area, with or without a history of vestibular infection. All patients had a normal anus and underwent transanal fistula repair. Follow-up was conducted through telephone or outpatient visits for a duration of 10 months to 5 years (average follow-up duration 19 months). Three patients experienced minimal secretion from the external orifice of the vestibular fistula within two weeks after the operation, but were successfully treated with sitting bath therapy without any relapse. Another three cases had a recurrence of the fistula, and two of them underwent transanal fistula repair at our center again, resulting in a successful cure after reoperation. The remaining case has not yet undergone reoperation. In the long-term follow-up, all the children had satisfactory anal appearance, with no fecal incontinence, anorectal stenosis, or fistula infection. CONCLUSION: Transanal fistula repair is a simple, safe, and effective surgical method to treat female children with rectovestibular fistula with a normal anus.

Candida albicans-myeloid cells-T lymphocytes axis in the tumor microenvironment of oral tumor-bearing mice.

Candida albicans (C. albicans) is associated with the development of oral cancer. Here, we report the altered tumor microenvironment in oral tumor-bearing mice caused by C. albicans infection. Single-cell RNA sequencing showed that C. albicans infection influenced the tumor microenvironment significantly. Specifically, C. albicans infection reduced the CD8+ T cells but increased the IL-17A+ CD4+ T cells and IL-17A+ γδ T cells in oral tumor. The neutralization of IL-17A or TCR γ/δ alleviated the tumor progression caused by C. albicans infection. Additionally, C. albicans infection promoted the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor, especially polymorphonuclear (PMN)-MDSCs, which infiltration was reduced after the neutralization of CCL2. Thus, our findings reveal the myeloid cells-T lymphocytes axis in oral tumor microenvironment with C. albicans infection, which helps to understand the mechanisms for C. albicans promoting oral cancer from the perspective of immune microenvironment.

A living neutrophil Biorobot synergistically blocks multifaceted inflammatory pathways in macrophages to effectively neutralize cytokine storm.

Cytokine storm is a potentially life-threatening immune response typically correlated with lung injury, particularly in people with underlying disease states, such as pneumonia. Therefore, the prompt treatment of cytokine storm is essential for successful recovery from a potentially fatal condition. Herein, a living anti-inflammatory Biorobot (firefighter), composed of neutrophils encapsulating mannose-decorated liposomes of the NF-κB inhibitor TPCA-1 and STING inhibitor H-151 (M-Lip@TH, inflammatory retardant), is developed for alleviating hyperinflammatory cytokine storm through targeting multiple inflammatory pathways in macrophages. Biorobot fully inherits the chemotaxis characteristics of neutrophils, and efficiently delivers and releases therapeutic M-Lip@TH at the inflammatory site. Subsequently, M-Lip@TH selectively targets macrophages and simultaneously blocks the transcription factor NF-κB pathway and STING pathway, thereby preventing the overproduction of cytokines. Animal studies show that Biorobot selectively targets LPS-induced acute lung injury, and not only inhibits the NF-κB pathway to suppress the release of various pro-inflammatory cytokines and chemokines, but also blocks the STING pathway to prevent an overactive immune response, which helps to neutralize cytokine storms. Particularly, Biorobot reduces lung inflammation and injury, improves lung function, and increases the survival rates of pneumonia mice. Therefore, Biorobot represents a rational combination therapy against cytokine storm, and may provide insights into the treatment of diseases involving overactive immune responses.

Panobinostat sensitizes AraC-resistant AML cells to the combination of azacitidine and venetoclax.

The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.

The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia.

Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity. Deletion of OGDH, which encodes αKGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for αKGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced the translation of MCL1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitive to ONC213 in vivo. Collectively, these findings support further development of ONC213 for treating AML. SIGNIFICANCE: In AML cells, ONC213 suppresses αKGDH, which induces a unique mitochondrial stress response, and reduces MCL1 to decrease oxidative phosphorylation and elicit potent antileukemia activity. See related commentary by Boët and Sarry, p. 950.

Relationship between burning mouth disorder and gastroesophageal reflux disease: A scoping review.

OBJECTIVE: This study aims to provide a scoping review and attempts to uncover the possible association between burning mouth disorder and gastroesophageal reflux disease. METHODS: PubMed, EMBASE, Web of Science, the Cochrane Library, Ovid, Scopus, and a search platform (EBSCOhost) were searched from their inception to August 22, 2023. RESULTS: After screening 2795 records, 18 articles were included in the final review, comprising cross-sectional studies (n = 9), case-control studies (n = 5), case reports (n = 2), case series (n = 1), and experimental study (n = 1). The prevalence of gastroesophageal reflux disease and its extraesophageal manifestations of laryngopharyngeal reflux in burning mouth patients was reported 3.39%-23.4% and 50%-93.8%, respectively, while oral burning was reported in 9%-45% of patients with gastroesophageal reflux disease. In case-control studies, gastroesophageal reflux disease was more prevalent in patients with burning mouth disorder compared with controls. Burning mouth would be resolved after antireflux therapy in laryngopharyngeal reflux patients in case series. PH value and saliva alternation might be the possible mechanisms. CONCLUSION: The possibility of the correlation between burning mouth disorder and gastroesophageal reflux disease still needs to be clearly demonstrated through better-conducted studies. The link between them is worth to be explored in future research.

Projection-defined median raphe Pet+ subpopulations are diversely implicated in seizure.

The raphe nuclei, the primary resource of forebrain 5-HT, play an important but heterogeneous role in regulating subcortical excitabilities. Fundamental circuit organizations of different median raphe (MR) subsystems are far from completely understood. In the present study, using cell-specific viral tracing, Ca2+ fiber photometry and epilepsy model, we map out the forebrain efferent and afferent of different MR Pet+ subpopulations and their divergent roles in epilepsy. We found that PetMR neurons send both collateral and parallel innervations to different downstream regions through different subpopulations. Notably, CA3-projecting PetMR subpopulations are largely distinct from habenula (Hb)-projecting PetMR subpopulations in anatomical distribution and topological organization, while majority of the CA3-projecting PetMR subpopulations are overlapped with the medial septum (MS)-projecting PetMR subpopulations. Further, using Ca2+ fiber photometry, we monitor activities of PetMR neurons in hippocampal-kindling seizure, a classical epilepsy model with pathological mechanisms caused by excitation-inhibition imbalance. We found that soma activities of PetMR neurons are heterogeneous during different periods of generalized seizures. These divergent activities are contributed by different projection-defined PetMR subpopulations, manifesting as increased activities in CA3 but decreased activity in Hb resulting from their upstream differences. Together, our findings provide a novel framework of MR subsystems showing that projection-defined MR Pet+ subpopulations are topologically heterogenous with divergent circuit connections and are diversely implicated in seizures. This may help in the understanding of heterogeneous nature of MR 5-HTergic subsystems and the paradox roles of 5-HTergic systems in epilepsy.

Estimating residual undifferentiated cells in human chemically induced pluripotent stem cell derived islets using lncRNA as biomarkers.

Human pluripotent stem cells (hPSCs) can generate insulin-producing beta cells for diabetes treatment, but residual undifferentiated cells may cause tumors. We developed a highly sensitive assay to detect these cells in islet cells derived from human chemically induced pluripotent stem cells (hCiPSCs), which are transgene-free and safer. We used RNA-seq data to find protein-coding and non-coding RNAs that were only expressed in hCiPSCs, not in islet cells. We confirmed these biomarkers by RT-qPCR and ddPCR. We chose long non-coding RNA (lncRNA) markers, which performed better than protein-coding RNA markers. We found that LNCPRESS2, LINC00678 and LOC105370482 could detect 1, 1 and 3 hCiPSCs in 106 islet cells by ddPCR, respectively. We tested our method on several hCiPSC lines, which could quantify 0.0001% undifferentiated cell in 106 islet cells by targeting hCiPSCs-specific lncRNA transcripts, ensuring the safety and quality of hCiPSC-derived islet cells for clinical use.