ARDS and aging: TYMS emerges as a promising biomarker and therapeutic target.

Background: Acute Respiratory Distress Syndrome (ARDS) is a common condition in the intensive care unit (ICU) with a high mortality rate, yet the diagnosis rate remains low. Recent studies have increasingly highlighted the role of aging in the occurrence and progression of ARDS. This study is committed to investigating the pathogenic mechanisms of cellular and genetic changes in elderly ARDS patients, providing theoretical support for the precise treatment of ARDS. Methods: Gene expression profiles for control and ARDS samples were obtained from the Gene Expression Omnibus (GEO) database, while aging-related genes (ARGs) were sourced from the Human Aging Genomic Resources (HAGR) database. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis to understand their roles in ARDS and aging. The Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning pinpointed key modules and marker genes, with ROC curves illustrating their significance. The expression of four ARDS-ARDEGs was validated in lung samples from aged mice with ARDS using qRT-PCR. Gene set enrichment analysis (GSEA) investigated the signaling pathways and immune cell infiltration associated with TYMS expression. Single-nucleus RNA sequencing (snRNA-Seq) explored gene-level differences among cells to investigate intercellular communication during ARDS onset and progression. Results: ARDEGs are involved in cellular responses to DNA damage stimuli, inflammatory reactions, and cellular senescence pathways. The MEmagenta module exhibited a significant correlation with elderly ARDS patients. The LASSO, RRF, and XGBoost algorithms were employed to screen for signature genes, including CKAP2, P2RY14, RBP2, and TYMS. Further validation emphasized the potential role of TYMS in the onset and progression of ARDS. Immune cell infiltration indicated differential proportion and correlations with TYMS expression. SnRNA-Seq and cell-cell communication analysis revealed that TYMS is highly expressed in endothelial cells, and the SEMA3 signaling pathway primarily mediates cell communication between endothelial cells and other cells. Conclusion: Endothelial cell damage associated with aging could contribute to ARDS progression by triggering inflammation. TYMS emerges as a promising diagnostic biomarker and potential therapeutic target for ARDS.

Shell thickness-induced thermal dependence: highly sensitive core-shell CdSe/ZnS/POSS-based temperature probes.

Fluorescence nanothermometry based on quantum dots is a current research hotspot for novel non-contact temperature monitoring, and is of vital significance for the modulation and design of the sensing properties of sensors. Herein, a design strategy to modulate the temperature-sensing characteristics of quantum dots based on the thickness of a shell is proposed. In this study, CdSe/ZnS quantum dot/POSS-based temperature probe films with varying fluorescence characteristics were developed, and the influence of the ZnS shell on temperature sensing was examined by varying the thickness of the ZnS shell. The temperature dependency, linearity, range of applications, and reversibility of quantum dot thin film probes were all considerably regulated by the ZnS shell, according to research on quantum dot/POSS-based films coated with various shell thicknesses. The CdSe/ZnS temperature probe with 4 monolayers (MLs) stood out among the rest due to its strong thermal stability (at least 5 cycles), large usable temperature range (20-80 °C), and excellent temperature sensitivity (R2 > 0.994). The results demonstrated that the temperature sensing performance of quantum dots was the consequence of the combined effect of multiple temperature response properties induced by the thickness of the shell, and the shell control of quantum dots to optimize the temperature sensing performance was an essential approach for the design of temperature probes. This work demonstrates the great potential of the shell in tuning the temperature sensing performance of quantum dots and provides a viable approach for the design of quantum dot temperature probes.

Accuracy of Early Neuroprognostication in Pediatric Severe Traumatic Brain Injury.

BACKGROUND: Children with severe traumatic brain injury (sTBI) are at risk for neurological sequelae impacting function. Clinicians are tasked with neuroprognostication to assist in decision-making. We describe a single-center study assessing clinicians' neuroprognostication accuracy. METHODS: Clinicians of various specialties caring for children with sTBI were asked to predict their patients' functioning three to six months postinjury. Clinicians were asked to participate in the study if their patient had survived but not returned to baseline between day 4 and 7 postinjury. The outcome tool utilized was the functional status scale (FSS), ranging from 6 to 30 (best-worst function). Predicted scores were compared with actual scores three to six months postinjury. Lin concordance correlation coefficients were used to estimate agreement between predicted and actual FSS. Outcome was dichotomized as good (FSS 6 to 8) or poor (FSS ≥9). Positive and negative predictive values for poor outcome were calculated. Pessimistic prognostic prediction was defined as predicted worse outcome by ≥3 FSS points. Demographic and clinical variables were collected. RESULTS: A total of 107 surveys were collected on 24 patients. Two children died. Fifteen children had complete (FSS = 6) or near-complete (FSS = 7) recovery. Mean predicted and actual FSS scores were 10.8 (S.D. 5.6) and 8.6 (S.D. 4.1), respectively. Predicted FSS scores were higher than actual scores (P < 0.001). Eight children had collective pessimistic prognostic prediction. CONCLUSIONS: Clinicians predicted worse functional outcomes, despite high percentage of patients with near-normal function at follow-up clinic. Certain patient and provider factors were noted to impact accuracy and need to be studied in larger cohorts.

TPG-functionalized PLGA/PCL nanofiber membrane facilitates periodontal tissue regeneration by modulating macrophages polarization via suppressing PI3K/AKT and NF-κB signaling pathways.

Traditional fibrous membranes employed in guided tissue regeneration (GTR) in the treatment of periodontitis have limitations of bioactive and immunomodulatory properties. We fabricated a novel nTPG/PLGA/PCL fibrous membrane by electrospinning which exhibit excellent hydrophilicity, mechanical properties and biocompatibility. In addition, we investigated its regulatory effect on polarization of macrophages and facilitating the regeneration of periodontal tissue both in vivo and in vitro. These findings showed the 0.5%TPG/PLGA/PCL may inhibit the polarization of RAW 264.7 into M1 phenotype by suppressing the PI3K/AKT and NF-κB signaling pathways. Furthermore, it directly up-regulated the expression of cementoblastic differentiation markers (CEMP-1 and CAP) in periodontal ligament stem cells (hPDLSCs), and indirectly up-regulated the expression of cementoblastic (CEMP-1 and CAP) and osteoblastic (ALP, RUNX2, COL-1, and OCN) differentiation markers by inhibiting the polarization of M1 macrophage. Upon implantation into a periodontal bone defect rats model, histological assessment revealed that the 0.5%TPG/PLGA/PCL membrane could regenerate oriented collagen fibers and structurally intact epithelium. Micro-CT (BV/TV) and the expression of immunohistochemical markers (OCN, RUNX-2, COL-1, and BMP-2) ultimately exhibited satisfactory regeneration of alveolar bone, periodontal ligament. Overall, 0.5%TPG/PLGA/PCL did not only directly promote osteogenic effects on hPDLSCs, but also indirectly facilitated cementoblastic and osteogenic differentiation through its immunomodulatory effects on macrophages. These findings provide a novel perspective for the development of materials for periodontal tissue regeneration.

Mechanism of dexmedetomidine protection against cisplatin induced acute kidney injury in rats.

OBJECTIVE: This study explored the molecular mechanisms by which dexmedetomidine (Dex) alleviates cisplatin (CP)-induced acute kidney injury (AKI) in rats. METHODS: CP-induced AKI models were established, and Dex was intraperitoneally injected at different concentrations into rats in the model groups. Subsequently, rats were assigned to the control, CP, CP + Dex 10 µg/kg, and CP + Dex 25 µg/kg groups. After weighing the kidneys of the rats, the kidney arterial resistive index was calculated, and CP-induced AKI was evaluated. In addition, four serum biochemical indices were measured: histopathological damage in rat kidneys was detected; levels of inflammatory factors, interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor alpha, in kidney tissue homogenate of rats were assessed through enzyme-linked immunosorbent assay (ELISA); and levels of NLRP-3, caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N in kidney tissues of rats were determined via western blotting. RESULTS: Dex treatment reduced nephromegaly and serum clinical marker upregulation caused by CP-induced AKI. In addition, hematoxylin and eosin staining revealed that Dex treatment relieved CP-induced kidney tissue injury in AKI rats. ELISA analyses demonstrated that Dex treatment reduced the upregulated levels of proinflammatory cytokines in the kidney tissue of AKI rats induced by CP, thereby alleviating kidney tissue injury. Western blotting indicated that Dex alleviated CP-induced AKI by inhibiting pyroptosis mediated by NLRP-3 and caspase-1. CONCLUSION: Dex protected rats from CP-induced AKI, and the mechanism may be related to NLRP-3/Caspase-1-mediated pyroptosis.

In-situ texturing hollow carbon host anchored with Fe single atoms accelerating solid-phase redox for Li-Se batteries.

Se-based cathodes have caught tremendous attention owing to their comparable volumetric capacity and better electronic conductivity to S cathodes. However, its low utilization ratio and sluggish redox kinetics due to the high reaction barrier of solid-phase transformation from Se to Li2Se limit its practical application. Herein, an in-situ texturing hollow carbon host by gas-solid interface reaction anchored with Fe single-atomic catalyst is designed and prepared for advanced Li-Se batteries. This Se host presents high pore volume of 1.49 cm3 g-1, Fe single atom content of 1.53 wt%, and its specific structure protects single-atomic catalyst from the destructive reaction environment, thus balancing catalytic activity and durability. After Se loading by reduction of H2SeO3, this homogenous Se-based cathode delivers a superior rate capacity of 431.3 mA h g-1 at 4C, and great discharge capacity of 301.8 mA h g-1 after 1000 cycles at 10C, with high Li-ion diffusion coefficient and capacitance-contributed ratio. The distribution of relaxation times analysis verifies solid-phase transformation mechanism of this cathode and density functional theory calculations confirm the adsorption and bidirectionally catalysis effect of Fe single-atomic catalyst. This work provides a new strategy to prepare high-efficient Se cathode associated with non-noble metal single atoms for high-performance Li-Se batteries.

Association between Serum Lactate Dehydrogenase Level and 30-day Mortality in Patients with Intracranial Hemorrhage with Acute Leukemia in the Induction Phase: A Cohort Study.

Objectives This study aimed to identify the association between lactate dehydrogenase (LDH) levels and 30-day mortality in patients with intracranial hemorrhage (ICH) with acute leukemia during the induction phase. Methods This cohort study included patients with acute leukemia with ICH during induction. We evaluated serum LDH levels upon admission. Multivariable Cox regression analyzed the LDH 30-day mortality association. Interaction and stratified analyses based on factors like age, sex, albumin, white blood cell count, hemoglobin level, and platelet count were conducted. Results We selected 91 patients diagnosed with acute leukemia and ICH. The overall 30-day mortality rate was 61.5%, with 56 of the 91 patients succumbing. Among those with LDH levels ≥ 570 U/L, the mortality rate was 74.4% (32 out of 43), which was higher than the 50% mortality rate of the LDH < 570 U/L group (24 out of 48) ( p = 0.017). In our multivariate regression models, the hazard ratios and their corresponding 95% confidence intervals for Log2 and twice the upper limit of normal LDH were 1.27 (1.01, 1.58) and 2.2 (1.05, 4.58), respectively. Interaction analysis revealed no significant interactive effect on the relationship between LDH levels and 30-day mortality. Conclusions Serum LDH level was associated with 30-day mortality, especially in patients with LDH ≥ 570 U/L.

Two-dimensional chiral metal-organic framework nanosheets L-hyp-Ni/Fe@SiO2 composite for HPLC separation.

In this study, we have synthesised a chiral l-hyp-Ni/Fe@SiO2 composite as a chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC) for the first time. This was achieved by coating two-dimensional (2D) chiral metal-organic framework nanosheets (MONs) l-hyp-Ni/Fe onto the surface of activated SiO2 microspheres using the "wrapped in net" method. The separation efficiency of the l-hyp-Ni/Fe chromatographic column was systematically evaluated in normal-phase HPLC (NP-HPLC) and reversed-phase HPLC (RP-HPLC) configurations, employing various racemates as analytes. The findings revealed that 16 chiral compounds were separated using NP-HPLC, and five were separated using RP-HPLC, encompassing alcohols, amines, ketones, esters, alkanes, ethers, amino acids and sulfoxides. Notably, the resolution (Rs) of nine chiral compounds exceeded 1.5, indicating baseline separation. Furthermore, the resolution performance of the l-hyp-Ni/Fe@SiO2-packed column was compared with that of Chiralpak AD-H. It was observed that certain enantiomers, which either could not be resolved or were inadequately separated on the Chiralpak AD-H column, attained separation on the 2D chiral MONs column. These findings suggest a complementary relationship between the two columns in racemate separation, with their combined application facilitating the resolution of a broader spectrum of chiral compounds. In addition, baseline separation was achieved for five positional isomers on the l-hyp-Ni/Fe@SiO2-packed column. The effects of the analyte mass and column temperature on the resolution were also examined. Moreover, during HPLC analysis, the l-hyp-Ni/Fe columns demonstrated commendable repeatability, stability and reproducibility in enantiomer separation. This research not only advances the utilisation of 2D chiral MONs as CSPs but also expands their applications in the separation sciences.

Prediction of short- and long-term outcomes using pre-operative ventricular size in infants with post-hemorrhagic ventricular dilation.

PURPOSE: Post-hemorrhagic ventricular dilation (PHVD) leads to developmental delays in premature infants, yet the optimal timing of neurosurgical interventions is unknown. Neuroimaging modalities have emerged to delineate injury and follow the progression of PHVD. Fronto-temporal horn ratio (FTHR) is used as a marker of ventricular dilation and can be a standardized tool to direct the timing of neurosurgical intervention. Our study determined a pre-operative FTHR measurement threshold to predict short- and long-term outcomes. METHODS: This is a retrospective cohort study of premature infants with severe intraventricular hemorrhage (IVH) who developed PHVD requiring neurosurgical intervention and were treated in a level IV NICU between 2012 and 2019. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analyses were performed to evaluate the accuracy of pre-operative FTHR for predicting developmental delay. In-hospital outcomes and developmental assessments were analyzed. RESULTS: We reviewed 121 charts of infants with IVH and identified 43 infants with PHVD who required neurosurgical intervention. We found FTHR measurements were an excellent predictor of cognitive and motor delay with an AUC of 0.89 and 0.88, respectively. An average pre-operative FTHR of ≥ 0.67 was also associated with worse lung and feeding outcomes. There was excellent inter-observer reliability of individual components of FTHR measurements. CONCLUSIONS: Early intervention for PHVD is ideal but not always practical. Identification of ventricular size thresholds associated with better outcomes is needed to direct timing of neurosurgical intervention.

S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages.

BACKGROUND: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection. METHODS: Biotin-switch assay combined with liquid chromatography-tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and Apoe-/- mice infused with angiotensin II. Angiotensin II-induced aortic aneurysm model and ß-aminopropionitrile-induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis. RESULTS: Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and Apoe-/- mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis. CONCLUSIONS: SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.

Effects of KLF11 on Vascular Smooth Muscle Cells and its Underlying Mechanisms in Intracranial Aneurysm.

Vascular smooth muscle cells (VSMCs) affect the phenotypic changes in intracranial aneurysm (IA). They exhibit enhanced dissociation and migration and play a key role in IA pathogenesis. KLF transcription factor 11 (KLF11), a member of the KLF family, significantly affects the cancer cell proliferation, differentiation, and apoptosis. However, its expression, biological functions, and latent action mechanisms in IA remain unclear. This study aimed to analyze the effects of KLF11 on H2O2-induced human brain VSMCs (HBVSMCs) in IA. We determined the mRNA levels of KLF11 in 15 paired arterial wall tissues of patients with IA and healthy volunteers. HBVSMCs were stimulated with H2O2 for 6 h to establish an IA model in vitro. Cell viability, apoptosis, and inflammatory cytokine (interleukin [IL-1ß, tumor necrosis factor-α, and IL-6) levels were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide, flow cytometry, and enzyme-linked immunosorbent assays, respectively. KLF11 expression was determined via quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence analyses. Furthermore, p-p38, p38, cleaved-caspase 3, and caspase 3 levels were determined via western blotting. KLF11 levels were downregulated in the arterial wall tissues of patients with IA than in those of the control group. KLF11 upregulation by KLF11-plasmid promoted the cell viability, reduced apoptosis, decreased cleaved-caspase 3 expression, and inhibited the secretion of inflammatory factors in H2O2-induced HBVSMCs. KLF11-plasmid remarkably reduced p-p38 expression and p-p38/p-38 ratio; however, these effects were reversed by P79350 treatment. Overall, KLF11 upregulation improved the HBVSMC functions and exerted protective effects against IA, suggesting its potential for IA treatment.

In vivo biodistribution and ototoxicity assessment of cationic liposomal-ceftriaxone via noninvasive trans-tympanic delivery in chinchilla models: Implications for otitis media therapy.

OBJECTIVES: We report the in vivo biodistribution and ototoxicity of cationic liposomal-ceftriaxone (CFX) delivered via ear drop formulation in adult chinchilla. METHODS: CFX was encapsulated in liposomes with size of ∼100 nm and surface charge of +20 mV. 100 µl liposomes or free drug was applied twice daily in both external ear canals of adult chinchillas for either 3 or 10 days. Study groups included free ceftriaxone (CFX, Day 3: n = 4, Day 10: n = 8), liposomal ceftriaxone (CFX-Lipo, Day 3: n = 4, Day 10: n = 8), and a systemic control group (Day 3: n = 4, Day 10: n = 4). Ceftriaxone delivery to the middle ear and systemic circulation was quantified by HPLC assays. Liposome transport was visualized via confocal microscopy. Auditory brainstem response (ABR) tests and cochlear histology were used to assess ototoxicity. RESULTS: Liposomal ceftriaxone (CFX-Lipo) displayed a ∼658-fold increase in drug delivery efficiency in the middle ear relative to the free CFX (8.548 ± 0.4638% vs. 0.013 ± 0.0009%, %Injected dose, Mean ± SEM). CFX measured in blood serum (48.2 ± 7.78 ng/ml) following CFX-Lipo treatment in ear was 41-fold lower compared to systemic free-CFX treatment (1990.7 ± 617.34 ng/ml). ABR tests and histological analysis indicated no ototoxicity due to the treatment. CONCLUSION: Cationic liposomal encapsulation results in potent drug delivery across the tympanic membrane to the middle ear with minimal systemic exposure and no ototoxicity.

Histomorphological analysis of perfusion parameters and CNS lymphatic vessels in mice: an experimental method study.

To investigate the distribution and characteristics of lymphatic vessels within the central nervous system, we focus on the meninges of the spinal cord and brain parenchyma in mice. Additionally, we aim to provide experimental methods for obtaining optimal imaging and clear structures of lymphatic vessels, while optimizing the perfusion parameters to improve histomorphological quality. Male C57BL/6J mice were randomly divided into four groups, with each group assigned a specific perfusion parameter based on perfusion volumes and temperatures. Immunofluorescence staining of lymphatics and blood vessels was performed on both meningeal and the brain tissue samples. Statistical analysis was performed using one-way analysis of variance to compare the groups, and a significant level of P < 0.05 was considered statistically significant. Our study reports the presence of lymphatic vessels in the meninges of the spinal cord and brain parenchyma in mice. We highlight the crucial role of high perfusion volume of paraformaldehyde with low temperature in fixation for achieving optimal results. We provide experimental methods for obtaining optimal imaging and clear structures of lymphatic vessels in the meninges of the spinal cord and brain parenchyma in mice, which contribute to our understanding of the distribution and characteristics of lymphatic vessels within the central nervous system. Further research is warranted to explore the functional implications of these lymphatic vessels and their potential therapeutic significance in neurodegenerative and neuroinflammatory diseases.

Inhaled fosamprenavir for laryngopharyngeal reflux: Toxicology and fluid dynamics modeling.

Objectives: Approximately 25% of Americans suffer from laryngopharyngeal reflux (LPR), a disease for which no effective medical therapy exists. Pepsin is a predominant source of damage during LPR and a key therapeutic target. Fosamprenavir (FOS) inhibits pepsin and prevents damage in an LPR mouse model. Inhaled FOS protects at a lower dose than oral; however, the safety of inhaled FOS is unknown and there are no inhalers for laryngopharyngeal delivery. A pre-Good Lab Practice (GLP) study of inhaled FOS was performed to assess safety and computational fluid dynamics (CFD) modeling used to predict the optimal particle size for a laryngopharyngeal dry powder inhaler (DPI). Methods: Aerosolized FOS, amprenavir (APR), or air (control) were provided 5 days/week for 4 weeks (n = 6) in an LPR mouse model. Organs (nasal cavity, larynx, esophagus, trachea, lung, liver, heart, and kidney) were assessed by a pathologist and bronchoalveolar lavage cytokines and plasma cardiotoxicity markers were assessed by Luminex assay. CFD simulations were conducted in a model of a healthy 49-year-old female. Results: No significant increase was observed in histologic lesions, cytokines, or cardiotoxicity markers in FOS or APR groups relative to the control. CFD predicted that laryngopharyngeal deposition was maximized with aerodynamic diameters of 8.1-11.5 µm for inhalation rates of 30-60 L/min. Conclusions: A 4-week pre-GLP study supports the safety of inhaled FOS. A formal GLP assessment is underway to support a phase I clinical trial of an FOS DPI for LPR. Level of Evidence: NA.

17ß-estradiol Attenuates the Middle Ear Inflammatory Response to Nontypeable Haemophilus influenzae.

OBJECTIVES: 17ß-estradiol (E2) is a steroidal hormone with immunomodulatory functions that play a role in infectious and inflammatory diseases. E2 was recently identified as the leading upstream regulator of differentially expressed genes in a comparative RNA sequencing study of pediatric patients with otitis media (OM) versus OM-free counterparts and may therefore play a role in the inflammatory response to bacterial otopathogens during pediatric OM. This study examined the effect of E2 on bacterial-induced inflammatory cytokine expression in an in vitro pediatric OM model. METHODS: An immortalized middle ear (ME) epithelial cell line, ROM-SV40, was developed from a pediatric recurrent OM patient. The culture was exposed to E2 at physiological levels for 1-48 h prior to 6 h-stimulation with nontypeable Haemophilus influenzae (NTHi) whole cell lysate. TNFA, IL1B, IL6, and IL8 were assayed by qPCR and ELISA. RESULTS: E2 pretreatment (24 h) abrogated NTHi induction of IL6; a longer pretreatment (1-10 nM, 48 h) abrogated IL1B induction (p < 0.05). E2 pretreatment (5 nM, 48 h) abrogated NTHi-induced IL8 secretion (p = 0.017). CONCLUSION: E2 pretreatment partially rescued NTHi-induced cytokine production by ME epithelia. These data support a role for E2 in moderating the excessive inflammatory response to middle ear infection that contributes to OM pathophysiology. LEVELS OF EVIDENCE: NA Laryngoscope, 2024.

MicrobeTCM: A comprehensive platform for the interactions of microbiota and traditional Chinese medicine.

Thanks to the advancements in bioinformatics, drugs, and other interventions that modulate microbes to treat diseases have been emerging continuously. In recent years, an increasing number of databases related to traditional Chinese medicine (TCM) or gut microbes have been established. However, a database combining the two has not yet been developed. To accelerate TCM research and address the traditional medicine and micro ecological system connection between short board, we have developed the most comprehensive micro-ecological database of TCM. This initiative includes the standardization of the following advantages: (1) A repeatable process achieved through the standardization of a retrieval strategy to identify literature. This involved identifying 419 experiment articles from PubMed and six authoritative databases; (2) High-quality data integration achieved through double-entry extraction of literature, mitigating uncertainties associated with natural language extraction; (3) Implementation of a similar strategy aiding in the prediction of mechanisms of action. Leveraging drug similarity, target entity similarity, and known drug-target entity association, our platform enables the prediction of the effects of a new herb or acupoint formulas using the existing data. In total, MicrobeTCM includes 171 diseases, 725 microbes, 1468 herb-formulas, 1032 herbs, 15780 chemical compositions, 35 acupoint-formulas, and 77 acupoints. For further exploration, please visit https://www.microbetcm.com.

Effective disinfecting of negative pressure pipelines of DCUs reduces the risk of cross infection in dental care.

Objectives: Microbial contamination of various accessory parts of the dental chair units (DCUs) is an essential source of cross infection, while the accessories of the crucial suction function are usually overlooked. In this study, we aim to find an effective disinfectant and a cost-effective method to remove bacterioplankton and bacterial biofilm deposited in the negative pressure suction pipelines to control cross infection during dental treatment. Methods: Double-chain quaternary ammonium salt disinfectant (Orotol Plus®), 3% hydrogen peroxide solution plus multi-enzyme cleaning agent and chlorine disinfectant are used to clean and disinfect the negative pressure pipelines of DCUs. Microbiological examinations, air condition detection, corrosion tests and gene sequencing are performed. Results: Little bacteria grow in the pipelines disinfected with double-chain quaternary ammonium salt disinfectants, destruction of biofilms in these pipelines appears, and multi-resistant bacteria cannot be detected. Minimal damage to metal sheets and fittings is caused by double-chain quaternary ammonium salt disinfectants. Conclusion: Double-chain quaternary ammonium salt disinfectant has excellent bactericidal ability and anti-biofilm effect, and it is less corrosive to the fittings of the pipelines. Thus, the double-chain quaternary ammonium salt disinfectant is a potential novel disinfectant for negative pressure suction pipelines of DCUs to control cross infection during dental treatment. Clinical significance: It is essential to add all these data to our dental practice to control cross infection with a broader landscape.

Aletrisguangxiensis (Nartheciaceae), a new species from Guangxi, China.

Aletrisguangxiensis Y. Nong & Y. F. Huang (Nartheciaceae), a new species from Guangxi, China, is described and illustrated. This new species is most similar to A.scopulorum, but it can be easily distinguished by its sparsely glandular, 5-18 cm long scape, glandular inflorescence axis, distinctly pedicellate flowers, sparsely glandular, 5-10 mm long pedicel, bract borne at base of pedicel, glabrous perianth divided to the base, strongly recurved or revolute perianth lobes and turbinate, obovoid to oblong-obovoid capsule. An identification key for 24 species and 1 hybrid of Aletris is also provided.

Hyperoxia-induced airflow restriction and Renin-Angiotensin System expression in a bronchopulmonary dysplasia mouse model.

Mechanisms underlying hyperoxia-induced airflow restriction in the pediatric lung disease Bronchopulmonary dysplasia (BPD) are unclear. We hypothesized a role for Renin-Angiotensin System (RAS) activity in BPD. RAS is comprised of a pro-developmental pathway consisting of angiotensin converting enzyme-2 (ACE2) and angiotensin II receptor type 2 (AT2), and a pro-fibrotic pathway mediated by angiotensin II receptor type 1 (AT1). We investigated associations between neonatal hyperoxia, airflow restriction, and RAS activity in a BPD mouse model. C57 mouse pups were randomized to normoxic (FiO2 = 0.21) or hyperoxic (FiO2 = 0.75) conditions for 15 days (P1-P15). At P15, P20, and P30, we measured airflow restriction using plethysmography and ACE2, AT1, and AT2 mRNA and protein expression via polymerase chain reaction and Western Blot. Hyperoxia increased airflow restriction P15 and P20, decreased ACE2 and AT2 mRNA, decreased AT2 protein, and increased AT1 protein expression. ACE2 mRNA and protein remained suppressed at P20. By P30, airflow restriction and RAS expression did not differ between groups. Hyperoxia caused high airflow restriction, increased pulmonary expression of the pro-fibrotic RAS pathway, and decreased expression of the pro-developmental in our BPD mouse model. These associated findings may point to a causal role for RAS in hyperoxia-induced airflow restriction.

NRF2 mutation enhances the immune escape of hepatocellular carcinoma by reducing STING activation.

The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor usually hyperactivated in hepatocellular carcinoma (HCC). In addition, about 14 % of HCC patients carry mutation in NRF2 or Kelch-like ECH-associated protein 1 (Keap1), a NRF2 inhibitor, both of which lead to constitutive activation of NRF2. It has been widely reported that NRF2 plays important roles in the proliferation, differentiation and metastasis of tumor cells. But as an important gene involved in antioxidation and anti-inflammation, little studies have focused on its role in tumor immune escape. Here we found that NRF2 gain-of-function mutation leads to reduced expression of STING and decreased infiltration of peripheral immune cells through which way it helps the tumor cells to evade from immune surveillance. This phenomenon can be reversed by STING overexpression. Our study also revealed that NRF2 mutation greatly reduced the effect of STING activating based immunotherapy. It is important to simultaneously inhibit the activity of NRF2 when using STING agonist for the treatment of HCC patients carrying NRF2 mutation.