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Nature Communications Jul 2024Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential...
Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses.
Topics: Receptors, Antigen, T-Cell; Single-Cell Analysis; Humans; SARS-CoV-2; COVID-19; Transcriptome; T-Lymphocytes; Gene Expression Profiling; Antigens, Viral
PubMed: 38956082
DOI: 10.1038/s41467-024-49806-9 -
Cell Death & Disease Jul 2024Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria...
Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein-protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.
Topics: Macrophage Migration-Inhibitory Factors; Mitophagy; Acute Kidney Injury; Ubiquitin-Protein Ligases; Protein Kinases; Sepsis; Animals; Humans; Mitochondria; Kidney Tubules; Epithelial Cells; Apoptosis; Protein Binding; Male; Intramolecular Oxidoreductases
PubMed: 38956064
DOI: 10.1038/s41419-024-06826-z -
Nature Communications Jul 2024Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify...
Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2- or CRL4 -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4-PROTAC-CRL2 ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.
Topics: Humans; Signal Transduction; Proteolysis; Transcription Factors; Cell Cycle Proteins; Ubiquitination; HSP90 Heat-Shock Proteins; Cell Line, Tumor; Apoptosis; Cyclin-Dependent Kinase 9; Nuclear Proteins; Bromodomain Containing Proteins
PubMed: 38956052
DOI: 10.1038/s41467-024-49519-z -
Nature Communications Jul 2024Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal...
Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumoniae. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. Here, we uncover a histone modification induced by S. pneumoniae infection maintained for at least 9 days upon clearance of bacteria with antibiotics. Di-methylation of histone H3 on lysine 4 (H3K4me2) is induced in an active manner by bacterial attachment to host cells. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3 or me1, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses to subsequent infections and promoting infection.
Topics: Histones; Streptococcus pneumoniae; Epithelial Cells; Methylation; Humans; Pneumococcal Infections; Epigenesis, Genetic; Animals; Mice; Lysine; Mice, Inbred C57BL
PubMed: 38956024
DOI: 10.1038/s41467-024-49347-1 -
Mikrochimica Acta Jul 2024CoFe@C was first prepared by calcining the precursor of CoFe-metal-organic framework-74 (CoFe-MOF-74), then an electrochemical sensor for the determination of...
CoFe@C was first prepared by calcining the precursor of CoFe-metal-organic framework-74 (CoFe-MOF-74), then an electrochemical sensor for the determination of neohesperidin dihydrochalcone (NHDC) was constructed, which was stemmed from the novel CoFe@C/Nafion composite film modified glassy carbon electrode (GCE). The CoFe@C/Nafion composite was verified by field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). Electrochemical impedance spectroscopy (EIS) was used to evaluate its electrical properties as a modified material for an electrochemical sensor. Compared with CoFe-MOF-74 precursor modified electrode, CoFe@C/Nafion electrode exhibited a great synergic catalytic effect and extremely increased the oxidation peak signal of NHDC. The effects of various experimental conditions on the oxidation of NHDC were investigated and the calibration plot was tested. The results bespoken that CoFe@C/Nafion GCE has good reproducibility and anti-interference under the optimal experimental conditions. In addition, the differential pulse current response of NHDC was linear with its concentration within the range 0.08 ~ 20 µmol/L, and the linear regression coefficient was 0.9957. The detection limit was as low as 14.2 nmol/L (S/N = 3). In order to further verify the feasibility of the method, it was successfully used to determine the content of NHDC in Chinese medicine, with a satisfactory result, good in accordance with that of high performance liquid chromatography (HPLC).
Topics: Electrodes; Cobalt; Metal-Organic Frameworks; Limit of Detection; Chalcones; Electrochemical Techniques; Drugs, Chinese Herbal; Hesperidin; Fluorocarbon Polymers; Oxidation-Reduction; Carbon; Reproducibility of Results; Iron
PubMed: 38955844
DOI: 10.1007/s00604-024-06525-8 -
Strahlentherapie Und Onkologie : Organ... Jul 2024Glofitamab, an anti-CD20 antibody, is approved as a third-line treatment for relapsed or refractory (r/r) diffuse large-cell B lymphoma (DLBCL), achieving a complete...
Glofitamab, an anti-CD20 antibody, is approved as a third-line treatment for relapsed or refractory (r/r) diffuse large-cell B lymphoma (DLBCL), achieving a complete response in nearly 40% of patients. This humanized IgG1 bispecific monoclonal antibody binds to CD20 on malignant B lymphocytes and to CD3 on cytotoxic T cells. This dual binding forms an immunological synapse, activating T lymphocytes and leading to the lysis of tumor cells. Salvage radiotherapy is also effective for r/r DLBCL, but its combination with systemic treatments like glofitamab may increase radiation-induced toxicity. We report the first case of a patient with r/r DLBCL receiving concurrent salvage radiotherapy and glofitamab. A 68-year-old female diagnosed with stage IV DLBCL underwent initial treatment with R-CHOP, then Car-T cell therapy, followed by glofitamab for recurrence. Upon early metabolic progression detected by 18FDG-PET/CT, salvage radiotherapy was administered to the refractory site concurrently with glofitamab. The patient experienced mild para-spinal pain post-radiotherapy but no other significant toxicities. Three months post-treatment, she showed a complete metabolic response with no radiotherapy toxicity, as evidenced by PET-CT, and no signs of radiation pneumonitis. This case indicates that combining glofitamab with salvage radiotherapy is tolerable and suggests potential efficacy, warranting further investigation in prospective studies for r/r DLBCL.
PubMed: 38955824
DOI: 10.1007/s00066-024-02256-0 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jun 2024This study aims to explore the diagnostic value of inflammation-related genes in peripheral blood mononuclear cells in bronchopulmonary dysplasia (BPD). By using...
This study aims to explore the diagnostic value of inflammation-related genes in peripheral blood mononuclear cells in bronchopulmonary dysplasia (BPD). By using bioinformatics analysis, three datasets including GSE32472, GSE125873, and GSE220135, which contain whole-genome expression profile data of 251 neonates, were included. The GSE32472 dataset was used as a training dataset to detect differentially expressed genes between non-BPD and BPD neonates in peripheral blood mononuclear cells. The gene enrichment analysis (GSEA) was used to detect the pathway enrichment of up-regulated genes in BPD newborns. The main regulatory factors analysis (MRA) algorithm was used to filter the main regulatory genes in the inflammation-related pathway (GO:0006954). After obtaining the main regulatory genes, the expression of the main regulatory genes in the GSE32472, GSE125873, and GSE220135 datasets was detected. Through the logistic regression model, risk scoring was conducted for neonates, and the risk scores of non-BPD and BPD neonates were compared. Lastly, the classification performance of the model was evaluated using the area under the curve (AUC). The results showed that compared with non-BPD neonates, there were 486 up-regulated genes and 433 down-regulated genes in the peripheral blood mononuclear cells of BPD neonates. The inflammation-related pathway was highly enriched in the up-regulated genes. Ultimately, phospholipase C beta 1 (PLCB1), nidogen 1 (NID1), serum response factor binding protein 1 (SRFBP1), centrosomal protein 72 (CEP72), excision repair cross complementation group 6 like (ERCC6L), and peptidylprolyl isomerase like 1 (PPIL1) were identified as the main regulatory genes. The prediction model's calculation formula for risk score was PLCB1×0.26+NID1×0.97+SRFBP1×1.58+CEP72×(-0.36)+ERCC6L×2.14+PPIL1×0.67. The AUCs in the GSE32472 test dataset, GSE125873 dataset, and GSE220135 dataset were 0.88, 0.86, and 0.89, respectively. This prediction model could distinguish between non-BPD and BPD neonates. In conclusion, the prediction model based on inflammation-related pathway genes has a certain diagnostic value for BPD.
Topics: Humans; Bronchopulmonary Dysplasia; Infant, Newborn; Inflammation; Leukocytes, Mononuclear; Gene Expression Profiling; Computational Biology
PubMed: 38955739
DOI: 10.3760/cma.j.cn112150-20231012-00257 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jun 2024To investigate the association of urinary cadmium levels with peripheral leukocyte classification counts among middle-aged and older adults aged 40 to 89 years in...
To investigate the association of urinary cadmium levels with peripheral leukocyte classification counts among middle-aged and older adults aged 40 to 89 years in selected areas of China. The research was based on the survey of the impact of soil quality of agricultural land on human health in typical areas conducted in 2019-2020. A total of 5 600 middle-aged and older adults aged 40 to 89 years were included by using a multi-stage stratified random sampling method. Baseline characteristics of the subjects were collected and physical examinations were performed. Random midstream urine was collected to measure urinary cadmium and urinary creatinine and fasting venous blood was collected to measure the leukocyte count, neutrophil count, lymphocyte count, monocyte count and eosinophil count. The linear mixed effect model was used to analyse the association of urinary cadmium levels with leukocyte classification counts, and the dose-response relationship between them was analyzed by using the restricted cubic spline (RCS) function. The age of the subjects was (63.17±12.02) years; 2 851 (50.91%) were males; and the (, ) of urinary creatinine-corrected urinary cadmium levels was 2.69 (1.52, 4.69) μg/g·creatinine. After adjusting for confounding factors, the results of linear mixed effects model analysis showed that for each 1-unit increase in urinary creatinine-corrected urinary cadmium level, the percentage change [% (95%)] of leukocyte count and lymphocyte count was -1.70% (-2.61%, -0.79%) and -1.57% (-2.86%, -0.26%), respectively. RCS function showed a negative linear relationship between urinary creatinine-corrected urinary cadmium levels and leukocyte counts and lymphocyte counts, respectively (all >0.05). Urinary cadmium levels are negatively associated with leukocyte count and lymphocyte count among middle-aged and older adults aged 40 to 89 years in selected areas of China.
Topics: Humans; Cadmium; Middle Aged; China; Aged; Male; Leukocyte Count; Female; Adult; Aged, 80 and over; Creatinine
PubMed: 38955731
DOI: 10.3760/cma.j.cn112150-20240222-00137 -
Zhonghua Yu Fang Yi Xue Za Zhi [Chinese... Jun 2024To investigate the effects of subcutaneous immunotherapy (SCIT) on patients' immune markers and metabolic levels in the early stage of allergen treatment, and to gain...
To investigate the effects of subcutaneous immunotherapy (SCIT) on patients' immune markers and metabolic levels in the early stage of allergen treatment, and to gain insight into the role of SCIT in regulating immune responses and metabolic levels, so as to provide reference data for the further discovery of potential biomarkers. A longitudinal study was used to include 40 subjects who underwent SCIT with dust mite allergens in the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University between November 2017 and February 2022, including 20 subjects each of single mite subcutaneous immunotherapy (SM-SCIT) and double mite subcutaneous immunotherapy (DM-SCIT). In this study, levels of dust mite allergen-specific antibodies and polyunsaturated fatty acid metabolism were measured before and 12 months after treatment, while pulmonary function tests were performed. The therapeutic effects of the patients were followed up by visual analogue scale (VAS), asthma control test (ACT) and total medication scores (TMS). The results were statistically analyzed using -test and Mann-Whitney -test. After 12 months of treatment with SCIT, both groups showed a significant decrease in total VAS score (SM-SCIT:=-2.298, <0.05; DM-SCIT:=-3.411, <0.001); total ACT score (SM-SCIT:=-2.054, <0.05; DM-SCIT:=-2.014, <0.05) and total medication scores (SM-SCIT:=-3.799, <0.000 1; DM-SCIT:=-3.474, <0.001) were significantly higher, in addition to significantly higher MMEF75/25 values in the DM-SCIT group (=-2.253, <0.05). There was no significant change in sIgE in the SM-SCIT group (>0.05), and the sIgG4 levels of the Der p, Der f, p 1, p 2, f 2, and p 21 fractions were significantly elevated (-2.651, -3.771, -2.949, -2.912, -2.725, -2.128, and -3.285, respectively, all <0.05); The sIgE of Der p 2, f 2, p 7 and p 23 fractions(=-2.651, -3.771, -2.949, -2.912, -2.725, -2.128, -3.285, all <0.05) and the sIgG4 levels of the Der p, Der f, p 1, p 2, f 1, f 2, p 10, p 21 and p 23 fractions (=-3.808, -3.845, -3.061, -2.688, -2.464, -3.211, -2.371, -2.091, -2.427, all <0.05) of the DM-SCIT group were significantly elevated. Metabolomics analysis showed that arachidonic acid, docosahexaenoic acid, docosapentaenoic acid, eicosapentaenoic acid, 5, 9, 12-octadecatrienoic acid, 5(S)-hydroxylated eicosatetraenoic acid, and dihomo-gamma-linolenic acid were significantly elevated at the beginning of the treatment period after SM-SCIT treatment ( of -2.191, -2.497, -1.988, -2.090, -2.19, -2.803, -2.073, all <0.05); 5(S)-hydroxylated eicosatetraenoic acid showed elevated and alpha-linolenic acid, eicosadienoic acid, and eicosapentaenoic acid were significantly decreased in the DM-SCIT group after treatment (=-1.988, -2.090, -2.497, -1.988, respectively, all <0.05). Correlation analysis showed that arachidonic acid was significantly negatively correlated with changes in dust mite-specific IgG4 (-0.499, <0.05), and that alpha-linolenic acid, 5, 9, 12-octadecatrienoic acid, and eicosapentaenoic acid were positively correlated with the ΔsIgG4 of the dust mite der p 2 (=0.451, 0.420, 0.474, respectively; all <0.05). Significant changes in allergen-specific antibody levels and polyunsaturated fatty acid metabolism levels occur during SCIT, and the two may interact and influence each other.
Topics: Humans; Fatty Acids, Unsaturated; Animals; Desensitization, Immunologic; Asthma; Pyroglyphidae; Longitudinal Studies; Antigens, Dermatophagoides; Allergens; Child; Injections, Subcutaneous; Immunoglobulin E
PubMed: 38955724
DOI: 10.3760/cma.j.cn112150-20240124-00083 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Jul 2024To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. The data from 3 422 patients with invasive breast cancer which...
To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. The data from 3 422 patients with invasive breast cancer which archived in Peking Union Medical College Hospital between April 2019 and July 2022 were retrospectively reviewed. Among them, 136 patients were treated with neoadjuvant chemotherapy. The tumor size, histological type, tumor differentiation, lymph node metastasis, Ki-67 index, the status of estrogen receptor, progesterone receptor and HER2 as well as pathological complete response (pCR) rate were collected. The HER2 status of 3 286 patients without neoadjuvant therapy, 616 (616/3 286, 18.7%) score 0, 1 047 (1 047/3 286, 31.9%) score 1+, 1 099 (1 099/3 286,33.4%) score 2+ and 524 (524/3 286,15.9%) score 3+ by immunohistochemistry (IHC). Among the 1 070 IHC 2+ cases, 161 were classified as HER2 positive by reflex fluorescence in situ hybridization (FISH) assay. In our cohort, 1 956 cases of HER2-low (IHC 1+ and IHC 2+/FISH-) breast cancer were identified. Compared to the HER2 IHC 0 group, HER2-low tumors more frequently occurred in patients with hormone receptor (HR) positive (<0.001), Ki-67 index below 35% (<0.001), well or moderate differentiation (<0.001) and over the age of 50 (=0.008). However, there were no significant differences in histological type, tumor size, and lymph node metastasis between HER2-low and HER2 IHC 0 group. For patients who had neoadjuvant therapy, the pCR rate in the patients with HER2-low was lower than those with HER2 IHC 0 (13.3%, 23.9%), but there was no significant difference. Although HER2-low breast cancers showed a slightly lower pCR rate than HER2 IHC 0 tumors, no remarkable difference was observed between tumors with HER2-low and HER2 IHC 0 regardless of hormone receptor status. The clinicopathological features of HER2-low breast cancers are different from those with HER2 IHC 0. It is necessary to accurately distinguish HER2-low breast cancer from HER2 IHC 0 and to reveal whether HER2-low tumor is a distinct biological entity.
Topics: Humans; Breast Neoplasms; Receptor, ErbB-2; Female; Retrospective Studies; Lymphatic Metastasis; Receptors, Estrogen; Receptors, Progesterone; Neoadjuvant Therapy; In Situ Hybridization, Fluorescence; Immunohistochemistry; Middle Aged; Adult; Ki-67 Antigen
PubMed: 38955700
DOI: 10.3760/cma.j.cn112151-20240315-00167