-
BMC Psychiatry Jul 2024Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical...
BACKGROUND
Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS).
METHODS
The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC).
RESULTS
The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels.
CONCLUSIONS
These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.
Topics: Humans; Schizophrenia; Female; Male; Tumor Necrosis Factor-alpha; Psychomotor Agitation; Adult; Receptors, Tumor Necrosis Factor, Type I; Young Adult; Psychiatric Status Rating Scales
PubMed: 38956509
DOI: 10.1186/s12888-024-05796-y -
Scientific Reports Jul 2024Environmental temperature strongly influences the adaptation dynamics of amphibians, whose limited regulation capabilities render them susceptible to thermal...
Environmental temperature strongly influences the adaptation dynamics of amphibians, whose limited regulation capabilities render them susceptible to thermal oscillations. A central element of the adaptive strategies is the transcription factors (TFs), which act as master regulators that orchestrate stress responses, enabling species to navigate the fluctuations of their environment skillfully. Our study delves into the intricate relationship between TF expression and thermal adaptation mechanisms in the Rhinella spinulosa populations. We sought to elucidate the dynamic modulations of TF expression in prometamorphic and metamorphic tadpoles that inhabit two thermally contrasting environments (Catarpe and El Tatio Geyser, Chile) and which were exposed to two thermal treatments (25 °C vs. 20 °C). Our findings unravel an intriguing dichotomy in response strategies between these populations. First, results evidence the expression of 1374 transcription factors. Regarding the temperature shift, the Catarpe tadpoles show a multifaceted approach by up-regulating crucial TFs, including fosB, atf7, and the androgen receptor. These dynamic regulatory responses likely underpin the population's ability to navigate thermal fluctuations effectively. In stark contrast, the El Tatio tadpoles exhibit a more targeted response, primarily up-regulating foxc1. This differential expression suggests a distinct focus on specific TFs to mitigate the effects of temperature variations. Our study contributes to understanding the molecular mechanisms governing thermal adaptation responses and highlights the resilience and adaptability of amphibians in the face of ever-changing environmental conditions.
Topics: Animals; Transcription Factors; Temperature; Larva; Adaptation, Physiological; Bufonidae; Anura; Acclimatization; Chile
PubMed: 38956427
DOI: 10.1038/s41598-024-66127-5 -
Scientific Reports Jul 2024Increasing evidence has shown that many environmental and toxic factors can cause testicular damage, leading to testicular ferroptosis and subsequent male reproductive...
Increasing evidence has shown that many environmental and toxic factors can cause testicular damage, leading to testicular ferroptosis and subsequent male reproductive disorders. Melatonin is a major hormone and plays an vital role in regulating male reproduction. However, there is a lack of research on whether Mel can alleviate testicular cell ferroptosis and its specific mechanism. In this study, the results indicated that Mel could enhance the viability of swine testis cells undergoing ferroptosis, reduce LDH enzyme release, increase mitochondrial membrane potential, and affect the expression of ferroptosis biomarkers. Furthermore, we found that melatonin depended on melatonin receptor 1B to exert these functions. Detection of MMP and ferroptosis biomarker protein expression confirmed that MT2 acted through the downstream Akt signaling pathway. Moreover, inhibition of the Akt signaling pathway can eliminate the protective effect of melatonin on ferroptosis, inhibit AMPK phosphorylation, reduce the expression of mitochondrial gated channel (VDAC2/3), and affect mitochondrial DNA transcription and ATP content. These results suggest that melatonin exerts a beneficial effect on mitochondrial function to mitigate ferroptosis through the MT2/Akt signaling pathway in ST cells.
Topics: Animals; Melatonin; Male; Ferroptosis; Proto-Oncogene Proteins c-akt; Signal Transduction; Mitochondria; Swine; Testis; Receptor, Melatonin, MT2; Membrane Potential, Mitochondrial
PubMed: 38956409
DOI: 10.1038/s41598-024-65666-1 -
Scientific Reports Jul 2024Benralizumab, a monoclonal antibody targeting IL-5 receptors, reduces exacerbations and oral corticosteroid requirements for severe, uncontrolled eosinophilic asthma. In...
Benralizumab, a monoclonal antibody targeting IL-5 receptors, reduces exacerbations and oral corticosteroid requirements for severe, uncontrolled eosinophilic asthma. In Japan, geographic disparities in asthma outcomes suggest differential prescribing and access. This study aimed to quantify regional prescribing variations for benralizumab nationwide. Using Japan's National Database (NDB) of insurance claims (2009-2019), benralizumab standardized claim ratios (SCRs) were calculated for 47 prefectures. Correlations between SCRs and other biologics' SCRs, economic variables like average income, and physician densities were evaluated through univariate analysis and multivariate regressions. Income-related barriers to optimal prescribing were examined. Wide variation emerged in benralizumab SCRs, from 40.1 to 184.2 across prefectures. SCRs strongly correlated with omalizumab (r = 0.61, p < 0.00001) and mepolizumab (r = 0.43, p = 0.0024). Average monthly income also positively correlated with benralizumab SCRs (r = 0.45, p = 0.0016), whereas lifestyle factors were insignificant. Respiratory specialist density modestly correlated with SCRs (r = 0.29, p = 0.047). In multivariate regressions, average income remained the most robust predictor (B = 0.74, p = 0.022). Benralizumab SCRs strongly associate with income metrics more than healthcare infrastructure/population factors. Many regions show low SCRs, constituting apparent prescribing gaps. Access barriers for advanced asthma therapies remain inequitable among Japan's income strata. Addressing affordability alongside specialist allocation can achieve better prescribing quality and asthma outcomes.
Topics: Humans; Asthma; Japan; Antibodies, Monoclonal, Humanized; Male; Anti-Asthmatic Agents; Female; Middle Aged; Adult; Aged; Practice Patterns, Physicians'
PubMed: 38956390
DOI: 10.1038/s41598-024-65407-4 -
Scientific Reports Jul 2024Targeting intracellular inhibiting proteins has been revealed to be a promising strategy to improve CD8 T cell anti-tumor efficacy. Here, we are focusing on...
Targeting intracellular inhibiting proteins has been revealed to be a promising strategy to improve CD8 T cell anti-tumor efficacy. Here, we are focusing on intracellular inhibiting proteins specific to TCR signaling: DOK1 and DOK2 expressed in T cells. We hypothesized that depletion of intracellular inhibition checkpoint DOK1 and DOK2 could improve CD8 T-cell based cancer therapies. To evaluate the role of DOK1 and DOK2 depletion in physiology and effector function of CD8 T lymphocytes and in cancer progression, we established a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) in WT and Dok1/Dok2 DKO (double KO) mice. We showed that both DOK1 and DOK2 depletion in CD8 T cells after an in vitro pre-stimulation induced a higher percentage of effector memory T cells as well as an up regulation of TCR signaling cascade- induced by CD3 mAbs, including the increased levels of pAKT and pERK, two major phosphoproteins involved in T cell functions. Interestingly, this improved TCR signaling was not observed in naïve CD8 T cells. Despite this enhanced TCR signaling essentially shown upon stimulation via CD3 mAbs, pre-stimulated Dok1/Dok2 DKO CD8 T cells did not show any increase in their activation or cytotoxic capacities against melanoma cell line expressing hgp100 in vitro. Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8 T cells. Indeed, our results allow us to conclude that DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.
Topics: Animals; CD8-Positive T-Lymphocytes; RNA-Binding Proteins; Signal Transduction; Mice; Adaptor Proteins, Signal Transducing; Phosphoproteins; DNA-Binding Proteins; Immunologic Memory; Receptors, Antigen, T-Cell; Mice, Knockout; Cell Line, Tumor; Mice, Transgenic
PubMed: 38956389
DOI: 10.1038/s41598-024-66075-0 -
Nature Immunology Jul 2024Group 1 innate lymphoid cells (ILC1s) are cytotoxic and interferon gamma-producing lymphocytes lacking antigen-specific receptors, which include ILC1s and natural killer...
Group 1 innate lymphoid cells (ILC1s) are cytotoxic and interferon gamma-producing lymphocytes lacking antigen-specific receptors, which include ILC1s and natural killer (NK) cells. In mice, ILC1s differ from NK cells, as they develop independently of the NK-specifying transcription factor EOMES, while requiring the repressor ZFP683 (ZNF683 in humans) for tissue residency. Here we identify highly variable ILC1 subtypes across tissues through investigation of human ILC1 diversity by single-cell RNA sequencing and flow cytometry. The intestinal epithelium contained abundant mature EOMES ILC1s expressing PRDM1 rather than ZNF683, alongside a few immature TCF7PRDM1 ILC1s. Other tissues harbored NK cells expressing ZNF683 and EOMES transcripts; however, EOMES protein content was variable. These ZNF683 NK cells are tissue-imprinted NK cells phenotypically resembling ILC1s. The tissue ILC1-NK spectrum also encompassed conventional NK cells and NK cells distinguished by PTGDS expression. These findings establish a foundation for evaluating phenotypic and functional changes within the NK-ILC1 spectrum in diseases.
PubMed: 38956380
DOI: 10.1038/s41590-024-01885-y -
Nature Immunology Jul 2024The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to...
The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56 state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56 state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.
PubMed: 38956379
DOI: 10.1038/s41590-024-01884-z -
Nature Biotechnology Jul 2024Antigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC...
Antigen discovery technologies have largely focused on major histocompatibility complex (MHC) class I-restricted human T cell receptors (TCRs), leaving methods for MHC class II-restricted and mouse TCR reactivities relatively undeveloped. Here we present TCR mapping of antigenic peptides (TCR-MAP), an antigen discovery method that uses a synthetic TCR-stimulated circuit in immortalized T cells to activate sortase-mediated tagging of engineered antigen-presenting cells (APCs) expressing processed peptides on MHCs. Live, tagged APCs can be directly purified for deconvolution by sequencing, enabling TCRs with unknown specificity to be queried against barcoded peptide libraries in a pooled screening context. TCR-MAP accurately captures self-reactivities or viral reactivities with high throughput and sensitivity for both MHC class I-restricted and class II-restricted TCRs. We elucidate problematic cross-reactivities of clinical TCRs targeting the cancer/testis melanoma-associated antigen A3 and discover targets of myocarditis-inciting autoreactive T cells in mice. TCR-MAP has the potential to accelerate T cell antigen discovery efforts in the context of cancer, infectious disease and autoimmunity.
PubMed: 38956325
DOI: 10.1038/s41587-024-02248-6 -
Communications Biology Jul 2024G protein-coupled receptors (GPCRs) are mainly regulated by GPCR kinase (GRK) phosphorylation and subsequent β-arrestin recruitment. The ubiquitously expressed GRKs are...
G protein-coupled receptors (GPCRs) are mainly regulated by GPCR kinase (GRK) phosphorylation and subsequent β-arrestin recruitment. The ubiquitously expressed GRKs are classified into cytosolic GRK2/3 and membrane-tethered GRK5/6 subfamilies. GRK2/3 interact with activated G protein βγ-subunits to translocate to the membrane. Yet, this need was not linked as a factor for bias, influencing the effectiveness of β-arrestin-biased agonist creation. Using multiple approaches such as GRK2/3 mutants unable to interact with Gβγ, membrane-tethered GRKs and G protein inhibitors in GRK2/3/5/6 knockout cells, we show that G protein activation will precede GRK2/3-mediated β-arrestin2 recruitment to activated receptors. This was independent of the source of free Gβγ and observable for Gs-, Gi- and Gq-coupled GPCRs. Thus, β-arrestin interaction for GRK2/3-regulated receptors is inseparably connected with G protein activation. We outline a theoretical framework of how GRK dependence on free Gβγ can determine a GPCR's potential for biased agonism. Due to this inherent cellular mechanism for GRK2/3 recruitment and receptor phosphorylation, we anticipate generation of β-arrestin-biased ligands to be mechanistically challenging for the subgroup of GPCRs exclusively regulated by GRK2/3, but achievable for GRK5/6-regulated receptors, that do not demand liberated Gβγ. Accordingly, GRK specificity of any GPCR is foundational for developing arrestin-biased ligands.
Topics: Humans; GTP-Binding Protein gamma Subunits; HEK293 Cells; GTP-Binding Protein beta Subunits; G-Protein-Coupled Receptor Kinases; Receptors, G-Protein-Coupled; Phosphorylation; Animals; Signal Transduction
PubMed: 38956302
DOI: 10.1038/s42003-024-06490-1 -
Scientific Reports Jul 2024In the current study, we aimed to investigate whether disulfiram (DSF) exerts a neuroprotective role in cerebral ischemiareperfusion (CI-RI) injury by modulating...
In the current study, we aimed to investigate whether disulfiram (DSF) exerts a neuroprotective role in cerebral ischemiareperfusion (CI-RI) injury by modulating ferredoxin 1 (FDX1) to regulate copper ion (Cu) levels and inhibiting inflammatory responses. To simulate CI-RI, a transient middle cerebral artery occlusion (tMCAO) model in C57/BL6 mice was employed. Mice were administered with or without DSF before and after tMCAO. Changes in infarct volume after tMCAO were observed using TTC staining. Nissl staining and hematoxylin-eosin (he) staining were used to observe the morphological changes of nerve cells at the microscopic level. The inhibitory effect of DSF on initial inflammation was verified by TUNEL assay, apoptosis-related protein detection and iron concentration detection. FDX1 is the main regulatory protein of copper death, and the occurrence of copper death will lead to the increase of HSP70 stress and inflammatory response. Cuproptosis-related proteins and downstream inflammatory factors were detected by western blotting, immunofluorescence staining, and immunohistochemistry. The content of copper ions was detected using a specific kit, while electron microscopy was employed to examine mitochondrial changes. We found that DSF reduced the cerebral infarction volume, regulated the expression of cuproptosis-related proteins, and modulated copper content through down regulation of FDX1 expression. Moreover, DSF inhibited the HSP70/TLR-4/NLRP3 signaling pathway. Collectively, DSF could regulate Cu homeostasis by inhibiting FDX1, acting on the HSP70/TLR4/NLRP3 pathway to alleviate CI/RI. Accordingly, DSF could mitigate inflammatory responses and safeguard mitochondrial integrity, yielding novel therapeutic targets and mechanisms for the clinical management of ischemia-reperfusion injury.
Topics: Animals; Reperfusion Injury; Disulfiram; Mice; Copper; Homeostasis; Mice, Inbred C57BL; Male; Inflammation; Down-Regulation; Infarction, Middle Cerebral Artery; Disease Models, Animal; Iron-Sulfur Proteins; Brain Ischemia; Apoptosis; Mitochondria; Neuroprotective Agents; Toll-Like Receptor 4
PubMed: 38956251
DOI: 10.1038/s41598-024-64981-x