Blockade of endolysosomal acidification suppresses TLR3-mediated proinflammatory signaling in airway epithelial cells.

BACKGROUND: Endolysosomal compartments are acidic and contain low pH-dependent proteases, and these conditions are exploited by respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, for escaping into the cytosol. Moreover, endolysosomes contain various pattern recognition receptors (PRRs), which respond to virus-derived pathogen-associated molecular patterns (PAMPs) by production of proinflammatory cytokines/chemokines. However, excessive proinflammatory responses can lead to a potentially lethal cytokine storm. OBJECTIVES: Here we investigated the endosomal PRR expression profile in primary human small airway epithelial cells (HSAECs), and whether blockade of endolysosomal acidification affects their cytokine/chemokine production after challenge with virus-derived stimulants. METHODS: HSAECs were exposed to stimulants mimicking virus-derived PAMPs, either in the absence or presence of compounds causing blockade of endolysosomal acidification, followed by measurement of cytokine expression and release. RESULTS: We show that Toll-like receptor 3 (TLR3) is the major endosomal PRR expressed by HSAECs, and that TLR3 expression is strongly induced by TLR3 agonists, but not by a range of other PRR agonists. We also demonstrate that TLR3 engagement with its agonists elicits a robust proinflammatory cytokine/chemokine response, which is profoundly suppressed through blockade of endolysosomal acidification, by bafilomycin A1, monensin, or niclosamide. Using TLR3 reporter cells, it was confirmed that TLR3 signaling is strongly induced by Poly(I:C) and that blockade of endolysosomal acidification efficiently blocked TLR3 signaling. Finally, we show that blockade of endolysosomal acidification causes a reduction in the levels of TLR3 mRNA and protein. CONCLUSIONS: These findings show that blockade of endolysosomal acidification suppresses TLR3-dependent cytokine and chemokine production in HSAECs.

The m6A reader IGF2BP2 promotes the progression of esophageal squamous cell carcinoma cells by increasing the stability of OCT4 mRNA.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy with high morbidity and mortality. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) serves as a reader of RNA m6A (N6 methyladenosine) modification to regulate gene expression at the post-transcriptional level. Emerging evidence suggests that IGF2BP2 plays critical roles in tumorigenesis and malignant development. However, the biological function and molecular mechanism of IGF2BP2 in ESCC are not well understood. Here, we found that IGF2BP2 expression was upregulated in esophageal cancer tissues and ESCC cells, and IGF2BP2 overexpression enhanced proliferation, migration, invasion, and stem cell-like properties of ESCC cells. Conversely, the knockdown of IGF2BP2 expression inhibited malignant phenotype of ESCC cells. Mechanistically, IGF2BP2 upregulated octomer-binding transcription factor 4 (OCT4) mRNA expression, and RNA immunoprecipitation (RIP) assay proved that IGF2BP2 could interact with OCT4 mRNA. Moreover, OCT4 was modified at m6A confirmed by methylated m6A RNA immunoprecipitation (Me-RIP)-qPCR assay, and IGF2BP2 knockdown reduced OCT4 mRNA stability. These results suggested that IGF2BP2 served as a reader for m6A-modified OCT4, thus increased OCT4 mRNA expression by regulating its stability. Furthermore, the knockdown of OCT4 could reverse the effects of IGF2BP2 on ESCC cells. In conclusion, these data indicate that IGF2BP2, as a reader for m6A, plays an oncogenic role by regulating OCT4 expression in ESCC, which provides new insights into targeting IGF2BP2/OCT4 axis for the therapy of ESCC.

IQGAP1 overexpression attenuates chemosensitivity through YAP-mediated ferroptosis inhibition in esophageal squamous cell cancer cells.

Chemoresistance is one of the major hindrances to many cancer therapies, including esophageal squamous cell carcinoma (ESCC). Ferroptosis, a new programmed cell death, plays an essential role in chemoresistance. IQ-domain GTPase activating protein 1 (IQGAP1) is a scaffold protein and functions as an oncogene in various human malignancies. However, the underlying effect and molecular mechanisms of IQGAP1 on paclitaxel (PTX) resistance and ferroptosis in ESCC remain to be elucidated. In this study, we found that IQGAP1 was highly expressed in ESCC tissues and could as a potential biomarker for diagnosis and predicting the prognosis of ESCC. Functional studies revealed that IQGAP1 overexpression reduced the sensitivity of ESCC cells to PTX by enhancing ESCC cell viability and proliferation and inhibiting cell death, and protected ESCC cells from ferroptosis, whereas IQGAP1 knockdown exhibited contrary effects. Importantly, reductions of chemosensitivity and ferroptosis caused by IQGAP1 overexpression were reversed with ferroptosis inducer RSL3, while the increases of chemosensitivity and ferroptosis caused by IQGAP1 knockdown were reversed with ferroptosis inhibitor ferrostatin-1 (Fer-1) in ESCC cells, indicating that IQGAP1 played a key role in resistance to PTX through regulating ferroptosis. Mechanistically, we demonstrated that IQGAP1 overexpression upregulated the expression of Yes-associated protein (YAP), the central mediator of the Hippo pathway. YAP inhibitor Verteporfin (VP) could reverse the effects of IQGAP1 overexpression on ESCC chemoresistance and ferroptosis. Taken together, our findings suggest that IQGAP1 promotes chemoresistance by blocking ferroptosis through targeting YAP. IQGAP1 may be a novel therapeutic target for overcoming chemoresistance in ESCC.

An MRI Study of Morphology, Asymmetry, and Sex Differences of Inferior Precentral Sulcus.

Numerous studies utilizing magnetic resonance imaging (MRI) have observed sex and interhemispheric disparities in sulcal morphology, which could potentially underpin certain functional disparities in the human brain. Most of the existing research examines the precentral sulcus comprehensively, with a rare focus on its subsections. To explore the morphology, asymmetry, and sex disparities within the inferior precentral sulcus (IPCS), we acquired 3.0T magnetic resonance images from 92 right-handed Chinese adolescents. Brainvisa was used to reconstruct the IPCS structure and calculate its mean depth (MD). Based on the morphological patterns of IPCS, it was categorized into five distinct types. Additionally, we analyzed four different types of spatial relationships between IPCS and inferior frontal sulcus (IFS). There was a statistically significant sex disparity in the MD of IPCS, primarily observed in the right hemisphere. Females exhibited significantly greater asymmetry in the MD of IPCS compared to males. No statistically significant sex or hemispheric variations were identified in sulcal patterns. Our findings expand the comprehension of inconsistencies in sulcal structure, while also delivering an anatomical foundation for the study of related regions' function.

Synthesis and antitumor activities of novel 3-(6-aminopyridin-3-yl)benzamide derivatives: Inducing cell cycle arrest and apoptosis via AURKB transcription inhibition.

Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC50 value of 0.04 ± 0.01 µM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.

The Association Between Social Support and the Quality of Life of Older Adults in China: The Mediating Effect of Loneliness.

BACKGROUND: Quality of life, social support, and loneliness are common problems among older adults in China , but the relationships among these issues have not been clearly identified. OBJECTIVES: The present study aimed to determine the relationships among Quality of life, social support, and loneliness. METHODS: A total of 560 older adults were randomly selected , the social support rating scale (SSRS), University of California at Los Angeles (UCLA) loneliness scale, and Short-Form 12 (SF-12) were employed to measure their degree of social support, level of loneliness, and quality of life. RESULTS: The average physical component summary (PCS) score was 49.97±16.33, and the average mental component summary (MCS) score was 47.26±11.49. Loneliness plays a partial mediating role between social support and quality of life. CONCLUSION: Loneliness and a lack of social support will affect the quality of life of the older adults. Thus, we need to urgently strengthen the care and support for the older adults and alleviate the loneliness of the older adults in the community.

Optimal Timing of Fractional CO 2 Laser on Cleft Lip Scars: A Single-Blind Randomized Controlled Cohort Study.

OBJECTIVE: To determine the optimal time to apply a fractional CO 2 laser for the treatment of postsecondary repair scars in patients with cleft lip. METHODS: Forty-two patients with linear scarring after cleft lip repair were recruited from November 2021 to October 2022. A single-blind, randomized, controlled cohort study was conducted to examine the impact of fractional CO 2 laser treatment compared with conventional conservative treatment. Thirty patients started laser treatment at 1 month ( n = 10), 3 months ( n = 10), and 6 months ( n = 10) postoperatively, and 12 patients were in the control group. Each patient was treated with high-energy low-density fractional CO 2 laser treatment 3 times at an interval of 1 month. The Vancouver Scar Scale (VSS) was used for scar evaluation to determine vascularity, pigmentation, pliability, and height. RESULTS: The VSS scores decreased significantly after laser treatment ( p < .05), with the most significant improvement in scars in the group that started treatment 1 month after the surgery. CONCLUSION: Early postoperative fractional CO 2 laser treatment of cleft lip scars is more effective than later treatment.

Mast cell chymase regulates extracellular matrix remodeling-related events in primary human small airway epithelial cells.

BACKGROUND: Mast cells are implicated in the pathogenesis of asthma, but the underlying mechanisms are not fully elucidated. Under asthmatic conditions, mast cells can relocalize to the epithelial layer and may thereby affect the functional properties of the airway epithelial cells. OBJECTIVES: Activated mast cells release large quantities of proteases from their secretory granules, including chymase and tryptase. Here we investigated whether these proteases may affect airway epithelial cells. METHODS: Primary small airway epithelial cells were treated with tryptase or chymase, and the effects on epithelial cell viability, proliferation, migration, cytokine output, and transcriptome were evaluated. RESULTS: Airway epithelial cells were relatively refractory to tryptase. In contrast, chymase had extensive effects on multiple features of the epithelial cells, with a particular emphasis on processes related to extracellular matrix (ECM) remodeling. These included suppressed expression of ECM-related genes such as matrix metalloproteinases, which was confirmed at the protein level. Further, chymase suppressed the expression of the fibronectin gene and also caused degradation of fibronectin released by the epithelial cells. Chymase was also shown to suppress the migratory capacity of the airway epithelial cells and to degrade the cell-cell contact protein E-cadherin on the epithelial cell surface. CONCLUSION: Our findings suggest that chymase may affect the regulation of ECM remodeling events mediated by airway epithelial cells, with implications for the impact of mast cells in inflammatory lung diseases such as asthma.

Mast cell chymase affects the functional properties of primary human airway fibroblasts: Implications for asthma.

BACKGROUND: Mast cells (MCs) have a profound impact on allergic asthma. Under such conditions, MCs undergo degranulation, resulting in the release of exceptionally large amounts of MC-restricted proteases. However, the role of these proteases in asthma is only partially understood. OBJECTIVES: We sought to test our hypothesis that MC proteases can influence the functionality of human lung fibroblasts (HLFs). METHODS: Primary HLFs were treated with MC chymase or tryptase, followed by assessment of parameters related to fibroblast function. RESULTS: HLFs underwent major morphologic changes in response to chymase, showing signs of cellular contraction, but were refractory to tryptase. However, no effects of chymase on HLF viability or proliferation were seen. Chymase, but not tryptase, had a major impact on the output of extracellular matrix-associated compounds from the HLFs, including degradation of fibronectin and collagen-1, and activation of pro-matrix metalloprotease 2. Further, chymase induced the release of various chemotactic factors from HLFs. In line with this, conditioned medium from chymase-treated HLFs showed chemotactic activity on neutrophils. Transcriptome analysis revealed that chymase induced a proinflammatory gene transcription profile in HLFs, whereas tryptase had minimal effects. CONCLUSIONS: Chymase, but not tryptase, has a major impact on the phenotype of primary airway fibroblasts by modifying their output of extracellular matrix components and by inducing a proinflammatory phenotype.

Electronic Modulation and Structural Engineering of Carbon-Based Anodes for Low-Temperature Lithium-Ion Batteries: A Review.

Lithium-ion batteries (LIBs) have become the preferred battery system for portable electronic devices and transportation equipment due to their high specific energy, good cycling performance, low self-discharge, and absence of memory effect. However, excessively low ambient temperatures will seriously affect the performance of LIBs, which are almost incapable of discharging at -40~-60 °C. There are many factors affecting the low-temperature performance of LIBs, and one of the most important is the electrode material. Therefore, there is an urgent need to develop electrode materials or modify existing materials in order to obtain excellent low-temperature LIB performance. A carbon-based anode is one candidate for use in LIBs. In recent years, it has been found that the diffusion coefficient of lithium ion in graphite anodes decreases more obviously at low temperatures, which is an important factor limiting its low-temperature performance. However, the structure of amorphous carbon materials is complex; they have good ionic diffusion properties, and their grain size, specific surface area, layer spacing, structural defects, surface functional groups, and doping elements may have a greater impact on their low-temperature performance. In this work, the low-temperature performance of LIBs was achieved by modifying the carbon-based material from the perspectives of electronic modulation and structural engineering.

Health technology assessment of medical devices: current landscape, challenges, and a way forward.

BACKGROUND: Health Technology Assessment (HTA) has been widely recognized as informing healthcare decision-making, and interest in HTA of medical devices has been steadily increasing. How does the assessment of medical devices differ from that of drug therapies, and what innovations can be adopted to overcome the inherent challenges in medical device HTA? METHOD: HTA Accelerator Database was used to describe the landscape of HTA reports for medical devices from HTA bodies, and a literature search was conducted to understand the growth trend of relevant HTA publications in four case studies. Another literature review was conducted for a narrative synthesis of the characteristic differences and challenges of HTA in medical devices. We further conducted a focused Internet search of guidelines and a narrative review of methodologies specific to the HTA of medical devices. MAIN BODY: The evidence of HTA reports and journal publications on medical devices around the world has been growing. The challenges in assessing medical devices include scarcity of well-designed randomized controlled trials, inconsistent real-world evidence data sources and methods, device-user interaction, short product lifecycles, inexplicit target population, and a lack of direct medical outcomes. Practical solutions in terms of methodological advancement of HTA for medical devices were also discussed in some HTA guidelines and literature. CONCLUSION: To better conduct HTA on medical devices, we recommend considering multi-source evidence such as real-world evidence; standardizing HTA processes, methodologies, and criteria; and integrating HTA into decision-making.

Repair of Asymmetric Bilateral Cleft lip: 1 Stage or 2 Stage.

OBJECTIVE: To verify the advantages and indications of 1-stage and 2-stage repair for asymmetric bilateral cleft lip (BCL). DESIGN: Retrospective study. SETTING: From January 2004 to December 2016 in our department. PATIENTS: Patients with BCL. MAIN OUTCOME MEASURE(S): Over 6 months after the operation, the surgery outcomes were evaluated and graded by 2 experienced surgeons. RESULTS: The result of surgery was evaluated using the scoring method of Mortier et al and Anastassov and Chipkov. Among 133 patients with asymmetric BCL, 61 (45.9%) had 1-stage repair and 72 (54.1%) had 2-stage repair. Sixty-eight (51.1%) patients had complete-incomplete cleft lip (CL), and those who underwent 1-stage repair showed a trend of better outcome (P = .028). Fifty (37.6%) patients with incomplete-microform CL showed no significant difference between the outcomes of 2 surgery plans (P = .253). In 15 (11.3%) patients with complete-microform CL, only one had 1-stage repair with a score of 8.5. The other 14 patients with 2-stage repair were scored 3.68 ± 1.28. Two-stage repair was preferable when the deformity degree was very different on 2 sides, as it could reduce unnecessary scar tissue and extend the nasal columella. One-stage repair could help to achieve the anatomical reduction of the orbicularis oris and a better contour of the vermilion tubercle. CONCLUSION: One-stage repair is recommended for patients with complete-incomplete CL and incomplete-microform CL. Two-stage repair for patients with complete-microform CL is preferred in our center, but more studies are required to support this conclusion.

The Preventive and Control Recommendations on Patient With Cleft Lip and Palate During COVID-19 Pandemic in Shanghai.

ABSTRACT: As Corona Virus Disease 2019 (COVID-19) has been gradually controlled domestically, various industries began to resume production in an orderly way. Attention should be paid to the disease and population characteristics of patients with cleft lip with/without palate during diagnosis and treatment. This article summarized and provided prevention and control recommendations on management strategies during hospitalization and protective measures of patients and healthcare workers, hoping to minimize the spread of disease and create a relatively safe environment for medical work.

Experiment of Mechanical Properties of a Customized Distractor Based on Three-Dimensional Printing Technology.

ABSTRACT: This study aimed to design and fabricate a customized distractor based on 3D printing technology and compare its mechanical properties with conventional distractor. The investigators designed and implemented a study composed of conventional and customized distractors. The design of customized distractor was based on the specification of conventional mandibular distractors and was fabricated using selective laser melting (SLM) technology. The same type of conventional distractors served as control group. Vickers-hardness test, three-point bending test and welding strength test were carried out for the conventional and customized distractor respectively and data was analyzed with t test using SPSS13.0 software package. The sample was composed of 18 distractors grouped as follows: customized distractor (n = 9) and conventional distractor (n = 9). The customized distractor showed better result than the conventional distractor in mechanical property tests, with statistically significant differences in Vickers-hardness and maximum load (P < 0.05), and no significant differences in yield strength and welding strength (P > 0.05). The results of this study suggest indicated that compared to the conventional distractor, the customized distractor had better mechanical properties and could be used in maxillofacial distraction osteogenesis.

Mucilaginibacter hurinus sp. nov., isolated from briquette warehouse soil.

A novel bacterial strain, designated ZR32T, was isolated from briquette warehouse soil in Ulsan (Korea). The strain was aerobic, showing pink-colored colonies on R2A agar. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ZR32T was closely related to Mucilaginibacter soli R9-65T (97.0%), Mucilaginibacter gynuensis YC7003T (96.9%), and Mucilaginibacter lutimaris BR-3T (96.8%). The values of DNA-DNA relatedness related two highest strains M. soli R9-65T and M. gynuensis YC7003T were 31.2 ± 6.9% and 19.7 ± 0.3%, respectively. Its genome size was 3.9 Mb, comprising 3402 predicted genes. The DNA G+C content of strain ZR32T was 43.0 mol%. The major cellular fatty acids (> 5% of total) were summed feature 3 (C16:1ω6c and/or C16:1ω7c), C16:0, C16:1ω5c, iso-C15:0, iso-C17:0 3-OH, and C17:1ω9c. The major respiratory quinine was menaquinone-7 (MK-7). The major polar lipids were phosphatidylethanolamine, two unidentified phospholipids, one unidentified sphingolipid, and one unidentified polar lipid. Strain ZR32T showed distinctive characteristics such as the temperature and pH for growth ranges, being positive for ß-glucosidase, salicin production, negative for N-acetyl-glucosamine assimilation, being resistant to carbenicillin and piperacillin to related species. On the basis of phenotypic, chemotaxonomic, and phylogenetic data, strain ZR32T represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter hurinus sp. nov. is proposed. The type strain is ZR32T (= KCTC 62193 = CCTCC AB 2017285).

Ectopic Parotid Main Duct on Buccal Mucosa: A Case Report and Literature Review.

Ectopic parotid main duct (Stensen's duct) orifice is a rare anatomic abnormality of the salivary gland. We report a case in which the patient's left Stensen's duct opened on the left buccal skin. After surgery to perform parotid duct transposition, the buccal fistula was closed, and the saliva secreted by the parotid gland could overflow smoothly through the new orifice throughout a 3-year follow-up period. We also performed a review of the current relevant data.

The Effectiveness of 595-nm Pulsed Dye Laser for the Treatment of Bilateral Cleft-Lip Scars in Asian Patients: A 6-Month Prospective, Randomized, Self-Controlled Trial.

Objective: This study is the first prospective within-patient self-controlled research seeking to investigate the safety and efficacy of 595 nm pulsed-dye laser (PDL) for the treatment of cleft-lip scars. Approach: This prospective, randomized, self-controlled study is based on the clinical records of the patients who received laser-assisted treatment due to bilateral cleft-lip scars. The bilateral scars were randomly assigned to the 595 nm PDL group with five consecutive sessions at 2-week intervals or control group in a blinded manner of evaluators, with subsequent follow-up for 6 months after the final treatment. Clinical efficacy and safety outcomes were evaluated by Vancouver Scar Scale (VSS), Patient Scar Assessment Questionnaire (PSAQ), and other objective evaluations. Results: A total of 18 patients were included. The 595 nm PDL-treated sides showed statistically significant improvement in VSS after treatment at follow-up compared with the baseline (p < 0.05). Interestingly, the 595 nm-PDL-treated side achieved significantly better improvement in scar pigmentation and pliability (p < 0.05). Though there was statistically significant difference between two groups (p < 0.05), the gap in overall PSAQ is not obvious. And comparison by area and coloring evaluation (E/M index) also suggests that the responses of scars to treatment by PDL were slightly improved (p < 0.05). Innovation and Conclusion: It is the first time to apply the 595nm PDL for cleft-lip scars. It would be a better choice for the early treatment of red scar with proliferative tendency after cleft-lip surgery.

A carbonyl-rich conjugated organic compound for aqueous rechargeable Na+ storage with wide voltage window workability.

Organic compounds have become an important electrode material for aqueous electrochemical energy storage. However, organic electrodes still face poor performance in aqueous batteries due to insufficient electrochemical activity. In this work, a novel conjugated quinone compound containing a rich carbonyl group was designed. The quinone compound was synthesized by a simple dehydration reaction of pyrene-4,5,9,10-tetrone (PTO) and 1,2-diaminoanthraquinone (1,2-AQ); it contains 4 pyrazines (CN) from AQ and 4 carbonyl groups (CO), as well as a large number of active sites and the excellent conductivity brought by its conjugated structure ensures the high theoretical capacity of PTO-AQ. In the context of aqueous sodium ion batteries (ASIBs), the electrode material known as PTO-AQ exhibits a notable reversible discharge capacity of 117.9 mAh/g when subjected to a current density of 1 A/g; impressively, it maintained a capacity retention rate of 74.3 % even after undergoing 500 charge and discharge cycles, a performance significantly surpassing that of pristine PTO and AQ. Notably, PTO-AQ exhibits a wide operating voltage range (-1.0-0.5 V) and a cycle life of up to 10,000 cycles. In situ Raman and ex situ measurements were used to analyze the structural changes of PTO-AQ during charge and discharge and the energy storage mechanism in NaAC. The effective promotion of Na+ storage brought by a rich carbonyl group was obtained. The structural energy level and electrostatic potential of PTO-AQ were calculated, and the active center distribution of PTO-AQ was obtained. This work serves as a guide for designing high-performance aqueous organic electrode materials that operate across a wide voltage range while also explaining their energy storage mechanism.

A non-canonical visual cortical-entorhinal pathway contributes to spatial navigation.

Visual information is important for accurate spatial coding and memory-guided navigation. As a crucial area for spatial cognition, the medial entorhinal cortex (MEC) harbors diverse spatially tuned cells and functions as the major gateway relaying sensory inputs to the hippocampus containing place cells. However, how visual information enters the MEC has not been fully understood. Here, we identify a pathway originating in the secondary visual cortex (V2) and directly targeting MEC layer 5a (L5a). L5a neurons served as a network hub for visual processing in the MEC by routing visual inputs from multiple V2 areas to other local neurons and hippocampal CA1. Interrupting this pathway severely impaired visual stimulus-evoked neural activity in the MEC and performance of mice in navigation tasks. These observations reveal a visual cortical-entorhinal pathway highlighting the role of MEC L5a in sensory information transmission, a function typically attributed to MEC superficial layers before.