Advancing skeletal health and disease research with single-cell RNA sequencing.

Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.

Radiomics model based on intratumoral and peritumoral features for predicting major pathological response in non-small cell lung cancer receiving neoadjuvant immunochemotherapy.

Objective: To establish a radiomics model based on intratumoral and peritumoral features extracted from pre-treatment CT to predict the major pathological response (MPR) in patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant immunochemotherapy. Methods: A total of 148 NSCLC patients who underwent neoadjuvant immunochemotherapy from two centers (SRRSH and ZCH) were retrospectively included. The SRRSH dataset (n=105) was used as the training and internal validation cohort. Radiomics features of intratumoral (T) and peritumoral regions (P1 = 0-5mm, P2 = 5-10mm, and P3 = 10-15mm) were extracted from pre-treatment CT. Intra- and inter- class correlation coefficients and least absolute shrinkage and selection operator were used to feature selection. Four single ROI models mentioned above and a combined radiomics (CR: T+P1+P2+P3) model were established by using machine learning algorithms. Clinical factors were selected to construct the combined radiomics-clinical (CRC) model, which was validated in the external center ZCH (n=43). The performance of the models was assessed by DeLong test, calibration curve and decision curve analysis. Results: Histopathological type was the only independent clinical risk factor. The model CR with eight selected radiomics features demonstrated a good predictive performance in the internal validation (AUC=0.810) and significantly improved than the model T (AUC=0.810 vs 0.619, p<0.05). The model CRC yielded the best predictive capability (AUC=0.814) and obtained satisfactory performance in the independent external test set (AUC=0.768, 95% CI: 0.62-0.91). Conclusion: We established a CRC model that incorporates intratumoral and peritumoral features and histopathological type, providing an effective approach for selecting NSCLC patients suitable for neoadjuvant immunochemotherapy.

Critical Solvation Structures Arrested Active Molecules for Reversible Zn Electrochemistry.

Aqueous Zn-ion batteries (AZIBs) have attracted increasing attention in next-generation energy storage systems due to their high safety and economic. Unfortunately, the side reactions, dendrites and hydrogen evolution effects at the zinc anode interface in aqueous electrolytes seriously hinder the application of aqueous zinc-ion batteries. Here, we report a critical solvation strategy to achieve reversible zinc electrochemistry by introducing a small polar molecule acetonitrile to form a "catcher" to arrest active molecules (bound water molecules). The stable solvation structure of [Zn(H2O)6]2+ is capable of maintaining and completely inhibiting free water molecules. When [Zn(H2O)6]2+ is partially desolvated in the Helmholtz outer layer, the separated active molecules will be arrested by the "catcher" formed by the strong hydrogen bond N-H bond, ensuring the stable desolvation of Zn2+. The Zn||Zn symmetric battery can stably cycle for 2250 h at 1 mAh cm-2, Zn||V6O13 full battery achieved a capacity retention rate of 99.2% after 10,000 cycles at 10 A g-1. This paper proposes a novel critical solvation strategy that paves the route for the construction of high-performance AZIBs.

Change of indocyanine green clearance ability and liver function after transcatheter intra-arterial therapies and its impact on outcomes of resectable hepatocellular carcinoma: a retrospective cohort study.

BACKGROUND: Indocyanine green (ICG) clearance test is a classical measurement of hepatic reserve, which involves surgical safety and patient recovery of hepatocellular carcinoma (HCC). The authors aim to compare effects of hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE) on liver function and outcomes of subsequent hepatectomy. MATERIAL AND METHODS: HCC patients receiving HAIC/TACE in SYSUCC with repeated ICG clearance tests were retrospectively enrolled. ICG eliminating rate (ICG-K), ICG retention rate at 15 min (ICG-R15) and ordinary laboratory tests were collected. Peri-therapeutic changes of values were compared between the groups. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) were employed to validate findings. Post-hepatectomy liver failure (PHLF), overall survival (OS) and recurrence-free survival (RFS) were analyzed in patients with subsequent curative hepatectomy. RESULTS: Two hundred and four patients treated with HAIC ( n =130) and TACE ( n =74) were included. ΔICG-R15 was greater in the HAIC arm before matching (mean, 3.8% vs. 0.7%, P <0.001), after PSM (mean, 4.7% vs. 1.1%, P =0.014) and IPTW (mean, 2.0% vs. -3.6%, P <0.001). No difference was found for ΔALB, ΔALBI, ΔTBIL, ΔALT, ΔAST and ΔPT-INR. Multivariable analyses revealed elder age, cirrhosis, HAIC, greater ΔTBIL and ΔALBI were associated with deteriorating ICG-R15. Among those (105 for HAIC and 48 for TACE) receiving hepatectomy, occurrence of grade B/C PHLF (4.8% vs. 8.3%, P =0.616), OS (median, unreached vs. unreached, P =0.94) and RFS (median, 26.7 vs. 17.1 months, P =0.096) were comparable between the two arms. In subgroup analyses, preoperative HAIC yield superior RFS (median, 26.7 vs. 16.2 months, P =0.042) in patients with baseline ICG-R15 less than or equal to 10%. CONCLUSION: Preoperative FOLFOX-HAIC caused apparent impairment of ICG clearance ability than TACE yet comparable impact on liver function and post-hepatectomy outcomes.

Screening of coexpression genes of immune cells in breast cancer tissues.

This study aimed to investigate immune cell infiltration (ICI) in breast cancer tissues and its impact on the prognosis of patients. The whole transcriptome sequencing data sets of breast tissue (GSE126125, GSE190275 and GSE45498) were downloaded from Gene Expression Omnibus database. Data sets, including 281 breast cancer tissue samples and 59 normal breast tissue samples. In this study, the CIBERSORT algorithm was used to calculate the infiltration content of 22 immune cells subtypes in breast cancer tissues and normal breast tissues. The ICI between normal and breast cancer tissue samples was examined through the Rank-sum test. Furthermore, Kaplan-Meier and the log-rank test were used for survival analysis. Univariate and multivariate COX analysis was used to screen the prognostic risk factors of breast cancer based on ICI. The correlation between 22 kinds of immune cells was analyzed by the Pearson test. The results of univariate COX analysis indicated that resting dendritic cells, eosinophils, resting mast cells, monocytes, and memory CD4 T cells resting were protective factors for the prognosis of breast cancer patients (hazard ratio [HR] < 1, P < .05). The activation of macrophage M0 and mast cells were also prognostic risk factors for breast cancer patients (HR > 1, P < .05). Besides, multivariate COX analysis showed that resting mast cells were independent protective factors for the prognosis of breast cancer patients (HR < 1, P < .05). Macrophage M0 and mast cell activation were independent risk factors for the prognosis of breast cancer patients (HR > 1, P < .05). High infiltration of macrophage M0 and activated mast cells is associated with poor prognosis. Meanwhile, macrophage M0 and activated mast cells promote breast cancer progression. Low infiltration of resting mast cells is associated with poor prognosis, which inhibits breast cancer progression.

An Easily Overlooked Disease: Hemophagocytic Syndrome.

BACKGROUND: Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a heterogenic syndrome, which leads to an acute, life-threatening inflammatory reaction. We report a case of rapid death due to HLH induced by chronic, active Epstein-Barr virus (EBV) infection. METHODS: Appropriate laboratory tests, abdominal ultrasonography, and cervical lymph node biopsy. RESULTS: Hemoglobin and platelet counts decreased, fasting triglyceride increased to 2.32 mmol/L, ferritin > 1,500 ng/mL, soluble CD25 (interleukin-2 receptor) > 2,400 U/mL, and abdominal ultrasound indicated splenomegaly, meeting the diagnostic criteria of HLH. A biopsy of the left cervical lymph node revealed chronic, active EBV infection. CONCLUSIONS: HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential.

Efficacy of neoadjuvant therapy for lung squamous cell carcinoma and lung adenocarcinoma: A retrospective comparative study.

Preoperative neoadjuvant therapy is widely used in cancer treatment; however, its efficacy in different subtypes of non-small cell lung cancer (NSCLC) is unknown. The present study compared the clinical efficacy of preoperative neoadjuvant therapy for two major NSCLC subtypes. Patients with NSCLC who underwent preoperative neoadjuvant therapy between January 2016 and August 2022 were reviewed. Patients were stratified according to histology and treatment strategy. Retrospective analysis was performed by comparing the basic clinical characteristics of the patients, clinicopathological characteristics of the tumors, imaging data and pathological responses to treatment. A total of 36 cases of lung squamous cell carcinoma (LUSC) and 31 cases of lung adenocarcinoma (LUAD) were included. After neoadjuvant chemotherapy combined with immunotherapy, the pathological response rates were higher for patients with LUSC than LUAD, but there was no statistically significant difference between the two subgroups (P=0.06). However, the pathological complete response rates after neoadjuvant chemotherapy combined with immunotherapy were significantly higher for LUSC than those after chemotherapy alone (P=0.01). These preliminary findings suggested that preoperative chemotherapy combined with immunotherapy could improve the pathological response of patients, particularly in those with LUSC. The present study provided new insights into the treatment of NSCLC.

Depression in Alzheimer's Disease: Epidemiology, Mechanisms, and Treatment.

Depression and Alzheimer's disease (AD) are substantial public health concerns. In the past decades, a link between the 2 disease entities has received extensive acknowledgment, yet the complex nature of this relationship demands further clarification. Some evidence indicates that midlife depression may be an AD risk factor, while a chronic course of depression in late life may be a precursor to or symptom of dementia. Recently, multiple pathophysiological mechanisms have been proposed to underlie the bidirectional relationship between depression and AD, including genetic predisposition, immune dysregulation, accumulation of AD-related biomarkers (e.g., amyloid-ß and tau), and alterations in brain structure. Accordingly, numerous therapeutic approaches, such as pharmacology treatments, psychotherapy, and lifestyle interventions, have been suggested as potential means of interfering with these pathways. However, the current literature on this topic remains fragmented and lacks a comprehensive review characterizing the association between depression and AD. In this review, we aim to address these gaps by providing an overview of the co-occurrence and temporal relationship between depression and AD, as well as exploring their underlying mechanisms. We also examine the current therapeutic regimens for depression and their implications for AD management and outline key challenges facing the field.

Aligning Standards Communities for Omics Biodiversity Data: Sustainable Darwin Core-MIxS Interoperability.

The standardization of data, encompassing both primary and contextual information (metadata), plays a pivotal role in facilitating data (re-)use, integration, and knowledge generation. However, the biodiversity and omics communities, converging on omics biodiversity data, have historically developed and adopted their own distinct standards, hindering effective (meta)data integration and collaboration. In response to this challenge, the Task Group (TG) for Sustainable DwC-MIxS Interoperability was established. Convening experts from the Biodiversity Information Standards (TDWG) and the Genomic Standards Consortium (GSC) alongside external stakeholders, the TG aimed to promote sustainable interoperability between the Minimum Information about any (x) Sequence (MIxS) and Darwin Core (DwC) specifications. To achieve this goal, the TG utilized the Simple Standard for Sharing Ontology Mappings (SSSOM) to create a comprehensive mapping of DwC keys to MIxS keys. This mapping, combined with the development of the MIxS-DwC extension, enables the incorporation of MIxS core terms into DwC-compliant metadata records, facilitating seamless data exchange between MIxS and DwC user communities. Through the implementation of this translation layer, data produced in either MIxS- or DwC-compliant formats can now be efficiently brokered, breaking down silos and fostering closer collaboration between the biodiversity and omics communities. To ensure its sustainability and lasting impact, TDWG and GSC have both signed a Memorandum of Understanding (MoU) on creating a continuous model to synchronize their standards. These achievements mark a significant step forward in enhancing data sharing and utilization across domains, thereby unlocking new opportunities for scientific discovery and advancement.

Mollusca collected by Agassiz trawl from the 2016 SO-AntEco (JR15005) expedition to the South Orkney Islands, Antarctica - data.

Background: This dataset contributes to the knowledge of macro- and megafaunal Mollusca associated with a range of benthic habitat types in the South Orkney Islands, Antarctica, an exceptionally diverse region of the Southern Ocean. The information presented is derived from Agassiz trawl samples collected on the archipelago's shelf plateau and slope, within and outside of the South Orkney Islands Southern Shelf Marine Protected Area (SOISS MPA). Sampling was conducted in the framework of the British Antarctic Survey/SCAR "South Orkneys - State of the Antarctic Ecosystem" (SO-AntEco) project aboard RRS James Clark Ross during expedition JR15005 in Austral summer 2016. This dataset is published by the British Antarctic Survey under the licence CC-BY 4.0. We would appreciate it if you could follow the guidelines from the SCAR Data Policy (SCAR 2023) when using the data. If you have any questions regarding this dataset, do not hesitate to contact us via the contact information provided in the metadata or via data-biodiversity-aq@naturalsciences.be. Issues with the dataset can be reported at https://github.com/biodiversity-aq/data-publication/. This dataset is part of the Biodiversity, Evolution and Adaptation Project of the Environmental Change and Evolution Program of the British Antarctic Survey. The cruise report of the expedition is available at https://www.bodc.ac.uk/resources/inventories/cruise_inventory/reports/jr15005.pdf. New information: We report occurrences of Mollusca from individual samples taken with a 2 m-wide Agassiz trawl (AGT) in the framework of the February - March 2016 research expedition JR15005 of RRS James Clark Ross to the SOISS MPA and adjacent shelf and slope areas. Of 78 successful AGT deployments, 44 trawls at depths ranging from 235-2194 m yielded living Mollusca, totalling 2276 individuals, 67 morphospecies and 163 distributional records. One hundred and fifteen empty shells were also collected and recorded in the dataset. Three morphospecies (one Bivalvia and two Gastropoda) were sampled exclusively as empty shells, yielding a total of 70 morphospecies and 2391 specimens represented in the dataset. All specimens were preserved in 96% undenatured ethanol and are stored as vouchers in the collections of the British Antarctic Survey (BAS), Cambridge, United Kingdom. The publication of this dataset aims at increasing the knowledge on the biodiversity, abundance and geographical and bathymetric distribution of larger-sized epi- and shallow infaunal Mollusca of the South Orkney Islands.

Deep Learning-Based Recognition of Cervical Squamous Interepithelial Lesions.

Cervical squamous intraepithelial lesions (SILs) are precursor lesions of cervical cancer, and their accurate diagnosis enables patients to be treated before malignancy manifests. However, the identification of SILs is usually laborious and has low diagnostic consistency due to the high similarity of pathological SIL images. Although artificial intelligence (AI), especially deep learning algorithms, has drawn a lot of attention for its good performance in cervical cytology tasks, the use of AI for cervical histology is still in its early stages. The feature extraction, representation capabilities, and use of p16 immunohistochemistry (IHC) among existing models are inadequate. Therefore, in this study, we first designed a squamous epithelium segmentation algorithm and assigned the corresponding labels. Second, p16-positive area of IHC slides were extracted with Whole Image Net (WI-Net), followed by mapping the p16-positive area back to the H&E slides and generating a p16-positive mask for training. Finally, the p16-positive areas were inputted into Swin-B and ResNet-50 to classify the SILs. The dataset comprised 6171 patches from 111 patients; patches from 80% of the 90 patients were used for the training set. The accuracy of the Swin-B method for high-grade squamous intraepithelial lesion (HSIL) that we propose was 0.914 [0.889-0.928]. The ResNet-50 model for HSIL achieved an area under the receiver operating characteristic curve (AUC) of 0.935 [0.921-0.946] at the patch level, and the accuracy, sensitivity, and specificity were 0.845, 0.922, and 0.829, respectively. Therefore, our model can accurately identify HSIL, assisting the pathologist in solving actual diagnostic issues and even directing the follow-up treatment of patients.

Fractional flow reserve measured via left internal mammary artery after coronary artery bypass grafting: Two case reports.

BACKGROUND: The fractional flow reserve (FFR) has made the treatment of coronary heart disease more precise. However, there are few reports on the measurement of FFR via the left internal mammary artery (LIMA). Herein, we described the determination of further treatments by measuring FFR via the LIMA in 2 cases after coronary artery bypass grafting (CABG). CASE SUMMARY: Case 1 was a 66-year-old male who was admitted due to "chest tightness after CABG." The patient underwent CABG 7 years prior due to coronary heart disease. Coronary artery angiography showed complete occlusion of the left anterior descending artery (LAD), and subtotal occlusion of the third segment of the right coronary artery. On arterial angiography, there was 85% stenosis at the distal end of the anastomosis of the LIMA-LAD graft. FFR via LIMA was determined at 0.75. Thus, balloon dilation was performed in Case 1. FFR after balloon dilation was 0.94. Case 2 was a 60-year-old male who was admitted due to "chest tightness after CABG." The patient underwent CABG 6 years prior due to coronary heart disease. There was 60% segmental stenosis in the middle segment of LAD and 75% anastomotic stenosis. FFR measured via LIMA was 0.83 (negative); thus the intervention was not performed. Case 2 was given drug treatments. At the 3-mo follow-up, there was no recurrence of chest tightness or shortness of breath in both cases. They are currently under continual follow-up. CONCLUSION: We provided evidence that FFR measurement via grafted blood vessels, especially LIMA, after CABG is a good method to determine the intervention course.

Srgap2 suppression ameliorates retinal ganglion cell degeneration in mice.

Slit-Robo GTPase-activating protein 2 (SRGAP2) plays important roles in axon guidance, neuronal migration, synapse formation, and nerve regeneration. However, the role of SRGAP2 in neuroretinal degenerative disease remains unclear. In this study, we found that SRGAP2 protein was first expressed in the retina of normal mice at the embryonic stage and was mainly located in the mature retinal ganglion cell layer and the inner nuclear layer. SRGAP2 protein in the retina and optic nerve increased after optic nerve crush. Then, we established a heterozygous knockout (Srgap2+/-) mouse model of optic nerve crush and found that Srgap2 suppression increased retinal ganglion cell survival, lowered intraocular pressure, inhibited glial cell activation, and partially restored retinal function. In vitro experiments showed that Srgap2 suppression activated the mammalian target of rapamycin signaling pathway. RNA sequencing results showed that the expression of small heat shock protein genes (Cryaa, Cryba4, and Crygs) related to optic nerve injury were upregulated in the retina of Srgap2+/- mice. These results suggest that Srgap2 suppression reduced the robust activation of glial cells, activated the mammalian target of rapamycin signaling pathway related to nerve protein, increased the expression of small heat shock protein genes, inhibited the degeneration of retinal ganglion cells, and partially restored optic nerve function.

Protective effect of Lactiplantibacillus pentosus CQZC01 in Kunming mice of subacute alcoholic liver injury.

To decrease the climbing rate of alcoholic liver disease, the protective effect in subacute alcoholic liver injury of newly isolated Lactiplantibacillus pentosus CQZC01 has been investigated. Lactiplantibacillus pentosus CQZC01 (1 × 109 CFU/kgbw) administered orally could keep weight of mice at 30.54 ± 1.15 g; alleviate alcoholic damage on hepatic morphology; decrease the activities of hyaluronidase (147 ± 19 U/L), procollagen III (4.82 ± 0.54 ng/mL), alanine transaminase (10.66 ± 2.32 U/L), and aspartate aminotransferase (15.18 ± 1.98 U/L); enhance the activities of alcohol dehydrogenase (65.15 ± 3.2 U/mgprot), aldehyde dehydrogenase (16.50 ± 0.96 U/mgprot), superoxide dismutase (623 ± 39 U/mgprot), and glutathione (19.54 ± 2.46 µmol/gprot); and decrease liver total cholesterol (3.59 ± 0.50 mmol/gprot) and triglyceride (0.88 ± 0.24 mmol/gprot) (p < 0.05). Moreover, L. pentosus CQZC01 elevated the level of interleukin-10 (IL-10; 807 ± 44 pg/mL) but significantly decreased the levels of IL-1ß (29.75 ± 5.27pg/mL), IL-6 (58 ± 8 pg/mL), and tumor necrosis factor-α (TNF-α, 564 ± 13 pg/mL). Liver malondialdehyde was also significantly decreased by treatment with L. pentosus CQZC01 from 3.61 ± 0.14  to 2.03 ± 0.49 nmol/mgprot. The relative expression of C-Jun N-terminal kinase, extracellular regulated protein kinases, and cyclooxygenase-1 was downregulated, and the SOD1, SOD2, peroxisome proliferator-activated receptor-α, glutathione peroxidase, catalase, nuclear factor erythroid-2-related factor 2, heme oxygenase-1 and nicotinamide adenine dinucleotide phosphate were upregulated by L. pentosus CQZC01. The overall protective effect of L. pentosus CQZC01 was comparable to commercial Lactobacillus delbrueckii subsp. Bulgaricus. Lactobacillus pentosus CQZC01 might be a suitable hepatoprotective measure for people who frequently ingest alcoholic drinks. PRACTICAL APPLICATION: L. pentosus CQZC01 can alleviate subacute alcoholic liver injury by raising the antioxidant status and upregulating the antioxidant-related genes.

Reversed windshield-wiper effect leads to failure of cement-augmented pedicle screw: Biomechanical mechanism analysis by finite element experiment.

The failure mode of cement-augmented pedicle screw (CAPS) was different from common pedicle screw. No biomechanical study of this failure mode named as "reversed windshield-wiper effect" was reported. To investigate the mechanisms underlying this failure mode, a series of finite element models of CAPS and PS were modified on L4 osseous model. Nine models were created according to the cement volume at 0.5 mL interval (range: 1-5 mL). Pullout load and cranio-caudal loads were applied on the screws. Stress and instantaneous rotation center (IRC) of the vertebra were observed. Under cranio-caudal load, the stress concentrated on the screw tip and pedicle region. The maximal stress (MS) at the screw tip region was +2.143 MPa higher than pedicle region. With cement volume increasing, the maximal stress (MS) at the screw tip region decreased dramatically, while MS at pedicle region was not obviously affected. As dose increased to 1.5 mL, the MS at pedicle region became higher than screw tip region and the maximal stress difference was observed at 3.5 mL. IRC of the vertebra located at the facet joint region in PS model. While IRC in CAPS models shifted anteriorly closer to the vertebral body with the increasing of cement volume. Under axial pull-out load, the maximal stress (MS) of cancellous bone in CAPS models was 29.53-50.04% lower than that 2.228 MPa in PS model. MS in the screw-bone interface did not change significantly with cement volume increasing. Therefore, the possible mechanism is that anterior shift of IRC and the negative difference value of MS between screw tip and pedicle region due to cement augmentation, leading to the screw rotate around the cement-screw complex as the fulcrum point.

IL-11 drives the phenotypic transformation of tracheal epithelial cells and fibroblasts to enhance abnormal repair after tracheal injury.

Tracheal stenosis (TS) is a multifactorial and heterogeneous disease that can easily lead to respiratory failure and even death. Interleukin-11 (IL-11) has recently received increased attention as a fibrogenic factor, but its function in TS is uncertain. This study aimed to investigate the role of IL-11 in TS regulation based on clinical samples from patients with TS and a rat model of TS produced by nylon brush scraping. Using lentiviral vectors expressing shRNA (lentivirus-shRNA) targeting the IL-11 receptor (IL-11Rα), we lowered IL-11Rα levels in the rat trachea. Histological and immunostaining methods were used to evaluate the effects of IL-11Rα knockdown on tracheal injury, molecular phenotype, and fibrosis in TS rats. We show that IL-11 was significantly elevated in circulating serum and granulation tissue in patients with TS. In vitro, TGFß1 dose-dependently stimulated IL-11 secretion from human tracheal epithelial cells (Beas-2b) and primary rat tracheal fibroblasts (PRTF). IL-11 transformed the epithelial cell phenotype to the mesenchymal cell phenotype by activating the ß-catenin pathway. Furthermore, IL-11 activated the atypical ERK signaling pathway, stimulated fibroblasts proliferation, and transformed fibroblasts into alpha-smooth muscle actin (α-SMA) positive myofibroblasts. IL-11-neutralizing antibodies (IL-11NAb) or ERK inhibitors (U0126) inhibited IL-11 activity and downregulated fibrotic responses involving TGFß/SMAD signaling. In vivo, IL-11Rα knockdown rats showed unobstructed tracheal lumen, relatively intact epithelial structure, and significantly reduced granulation tissue proliferation and collagen fiber deposition. Our findings confirm that IL-11 may be a target for future drug prevention and treatment of tracheal stenosis.

Role of mitochondrial metabolism in immune checkpoint inhibitors-related myocarditis.

Background: Immune checkpoint inhibitor-related myocarditis is the deadliest complication of immunotherapy. However, the underlying pathophysiological mechanisms of its occurrence and development remain unclear. Due to the long-term lack of effective early diagnosis and treatment options, it is of great significance to understand the pathophysiological mechanism of immune checkpoint inhibitor-related myocarditis. Methods: Tissue samples from three patients with immune checkpoint inhibitor-related myocarditis and three control tissue samples were collected for protein analysis. Differentially expressed proteins were screened out using quantitative proteomics technology based on TMT markers. Protein-protein interaction (PPI) and Gene Ontology (GO) functional enrichment analyses of cross-factors were subsequently performed. Combined with the PD-L1 subcellular organelle- level protein interaction network, we searched for hub proteins involved in immune checkpoint inhibitor-related myocarditis and explored potential drug sensitivity and disease correlation. Results: A total of 306 differentially expressed proteins were identified in immune checkpoint inhibitor-related myocarditis. Enrichment analysis showed that the differentially expressed proteins were closely related to mitochondrial metabolism. By analyzing mitochondria-related proteins and PD-L1-related proteins, we found four hub proteins, mammalian target of rapamycin (mTOR), Glycogen synthase kinase 3ß (GSK3ß), Protein tyrosine phosphatase non-receptor type 11 (PTPN11), and Mitofusin 2 (MFN2), indicating that they are closely related to immune checkpoint inhibitor-related myocarditis. Finally, we explored potential drugs for the treatment of immune checkpoint inhibitor-related myocarditis. Conclusion: Mitochondrial metabolism is involved in the process of immune checkpoint inhibitor-related myocarditis, and we identified four hub proteins, which may become new biomarkers for the early diagnosis and treatment of immune checkpoint inhibitor-related myocarditis.

Occupational characteristics and incident anxiety and depression: A prospective cohort study of 206,790 participants.

BACKGROUND: This study aimed to analyze the impact of a wide spectrum of occupational characteristics on the incidence of anxiety and depression, and to determine the features affecting adaptation to specific characteristics. METHODS: Participants in paid employment or self-employed at baseline in UKB were included, with occupational characteristics extracted from O*NET. Cox-proportional-hazard models were conducted in the main analyses and subgroup analyses. RESULTS: Direct work with the public and exposure to disease/infections were first time demonstrated to be risk factors for both anxiety and depression, along with occupations involving more physical activities and dealing with unpleasant/physically aggressive people. Protective factors for both: time spent sitting, communication, decision making, creativity and reasoning, and responsibility in work. Protective factors for anxiety only: Coordinating/leading, fluency of ideas, originality, problem sensitivity, decision latitude, and time pressure. Risk factor for depression only: Exposure to contaminants. Females were found more sensitive to dealing with unpleasant/physically aggressive people. The impact of exposure to disease/infections was more significant among those with lower education levels. Those with BMI over 24 were more sensitive to the risk factors. LIMITATIONS: The short-term effect of the above exposures remained unclear. The scores of occupational characteristics were based on self-reported questionnaires. There was the potential for undiagnosed anxiety or depression events. The participants included only those aged from 40 to 69. Participants included in this cohort were mainly White British. CONCLUSIONS: Our findings advocate closer monitoring of the mental health of workers with risk work-related factors.

Serum levels of angiotensin-converting enzyme 2 in children with Kawasaki disease.

Kawasaki disease (KD) has replaced rheumatic fever as the main cause of acquired heart disease in Japanese, American, and Chinese children. Polymorphisms in angiotensin-converting enzyme may be associated with susceptibility to KD, but the association of angiotensin-converting enzyme 2 (ACE2) with vascular endothelial injury in KD and the possibility for prognosis of vascular injury in KD by evaluating changes in serum ACE2 have not yet been assessed. Thus, this study aimed to investigate ACE2 levels in patients with KD to further explore the relationship between ACE2 and vascular injury in KD. Blood samples were collected from 49 children with KD before intravenous immunoglobulin treatment and 28 healthy children in the same period as the control group. Clinical data were collected from the patients and serum ACE2 levels of all participants were measured using an enzyme-linked immunosorbent assay. Serum ACE2 levels were significantly higher in the KD group than in the control group, and were negatively correlated with platelet levels in patients with KD. Serum ACE2 levels are related to the pathogenesis of KD and may be used as a potential serum marker for KD diagnosis.