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Cell Reports. Medicine Jun 2024Infrared spectroscopy is a powerful technique for probing the molecular profiles of complex biofluids, offering a promising avenue for high-throughput in vitro...
Infrared spectroscopy is a powerful technique for probing the molecular profiles of complex biofluids, offering a promising avenue for high-throughput in vitro diagnostics. While several studies showcased its potential in detecting health conditions, a large-scale analysis of a naturally heterogeneous potential patient population has not been attempted. Using a population-based cohort, here we analyze 5,184 blood plasma samples from 3,169 individuals using Fourier transform infrared (FTIR) spectroscopy. Applying a multi-task classification to distinguish between dyslipidemia, hypertension, prediabetes, type 2 diabetes, and healthy states, we find that the approach can accurately single out healthy individuals and characterize chronic multimorbid states. We further identify the capacity to forecast the development of metabolic syndrome years in advance of onset. Dataset-independent testing confirms the robustness of infrared signatures against variations in sample handling, storage time, and measurement regimes. This study provides the framework that establishes infrared molecular fingerprinting as an efficient modality for populational health diagnostics.
PubMed: 38944038
DOI: 10.1016/j.xcrm.2024.101625 -
Ecotoxicology and Environmental Safety Jun 2024As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with...
As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.
PubMed: 38944014
DOI: 10.1016/j.ecoenv.2024.116647 -
Alzheimer's Research & Therapy Jun 2024Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs).... (Comparative Study)
Comparative Study
BACKGROUND
Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs.
METHODS
Single-molecule enzyme-linked assays were used to quantify Aβ42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4- (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples.
RESULTS
The soluble plasma Aβ42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aβ40, Aβ42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions.
CONCLUSION
Soluble plasma Aβ42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aβ release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aβ and tau need correction by NDEVs for better AD risk identification in CN populations.
Topics: Humans; Alzheimer Disease; Extracellular Vesicles; Biomarkers; Female; Male; Amyloid beta-Peptides; Aged; tau Proteins; Peptide Fragments; Aged, 80 and over; Middle Aged; Cohort Studies; Apolipoprotein E4
PubMed: 38943196
DOI: 10.1186/s13195-024-01508-6 -
Nature Communications Jun 2024Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this...
Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.
Topics: Dexamethasone; Humans; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Lung; Cytokines; Critical Illness; Male; Single-Cell Analysis; Female; Middle Aged; T-Lymphocytes; Aged; Lymphocyte Activation
PubMed: 38942804
DOI: 10.1038/s41467-024-49756-2 -
Nature Communications Jun 2024Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and...
Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.
Topics: Down Syndrome; Humans; Chromosomes, Human, Pair 21; Female; Transcriptome; Male; Child; Child, Preschool; Adult; Gene Expression Profiling; Proteome; Adolescent
PubMed: 38942750
DOI: 10.1038/s41467-024-49781-1 -
Biomedicine & Pharmacotherapy =... Jun 2024Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling...
Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling antigen release, typically involving various approaches at the injection site. Yet, strategies for intracellular slow-release of antigens in vaccines are still unexplored. Our study showed that controlling the degradation of antigens in dendritic cells and slowing their transport from early endosomes to lysosomes markedly enhances both antigen-specific T-cell immune responses and germinal center B cell responses. This leads to the establishment of sustained humoral and cellular immunity in vivo imaging and flow cytometry indicated this method not only prolongs antigen retention at the injection site but also enhances antigen concentration in lymph nodes, surpassing traditional Aluminium (Alum) adjuvants. Additionally, we demonstrated that the slow antigen degradation induces stronger follicular helper T cell responses and increases proportions of long-lived plasma cells and memory B cells. Overall, these findings propose that controlling the speed of antigens transport in dendritic cells can significantly boost vaccine efficacy, offering an innovative avenue for developing highly immunogenic next-generation vaccines.
PubMed: 38941888
DOI: 10.1016/j.biopha.2024.117036 -
Computer Methods and Programs in... Jun 2024In this work, the analysis of the importance of hemodynamic updates on a mechanobiological model of atheroma plaque formation is proposed.
BACKGROUND AND OBJECTIVE
In this work, the analysis of the importance of hemodynamic updates on a mechanobiological model of atheroma plaque formation is proposed.
METHODS
For that, we use an idealized and axisymmetric model of carotid artery. In addition, the behavior of endothelial cells depending on hemodynamical changes is analyzed too. A total of three computational simulations are carried out and their results are compared: an uncoupled model and two models that consider the opposite behavior of endothelial cells caused by hemodynamic changes. The model considers transient blood flow using the Navier-Stokes equation. Plasma flow across the endothelium is determined with Darcy's law and the Kedem-Katchalsky equations, considering the three-pore model, which is also employed for the flow of substances across the endothelium. The behavior of the considered substances in the arterial wall is modeled with convection-diffusion-reaction equations, and the arterial wall is modeled as a hyperelastic Yeoh's material.
RESULTS
Significant variations are noted in both the morphology and stenosis ratio of the plaques when comparing the uncoupled model to the two models incorporating updates for geometry and hemodynamic stimuli. Besides, the phenomenon of double-stenosis is naturally reproduced in the models that consider both geometric and hemodynamical changes due to plaque growth, whereas it cannot be predicted in the uncoupled model.
CONCLUSIONS
The findings indicate that integrating the plaque growth model with geometric and hemodynamic settings is essential in determining the ultimate shape and dimensions of the carotid plaque.
PubMed: 38941860
DOI: 10.1016/j.cmpb.2024.108296 -
Virology Jun 2024An important approach to stopping the AIDS epidemic is the development of a vaccine that elicits antibodies that block virus capture, the initial interactions of HIV-1...
An important approach to stopping the AIDS epidemic is the development of a vaccine that elicits antibodies that block virus capture, the initial interactions of HIV-1 with the target cells, and replication. We utilized a previously developed qRT-PCR-based assay to examine the effects of broadly neutralizing antibodies (bNAbs), plasma from vaccine trials, and monoclonal antibodies (mAbs) on virus capture and replication. A panel of bNAbs inhibited primary HIV-1 replication in PBMCs but not virus capture. Plasma from RV144 and RV305 trial vaccinees demonstrated inhibition of virus capture with the HIV-1 subtype prevalent in Thailand. Several RV305 derived V2-specific mAbs inhibited virus replication. One of these RV305 derived V2-specific mAbs inhibited both virus capture and replication, demonstrating that it is possible to elicit antibodies by vaccination that inhibit virus capture and replication. Induction of a combination of such antibodies may be the key to protection from HIV-1 acquisition.
PubMed: 38941746
DOI: 10.1016/j.virol.2024.110158 -
Alternative Therapies in Health and... Jun 2024Liver failure is a rare, life-threatening disease that has a high mortality rate and affects many organ systems. Bloodstream bacterial infection has played a key role in...
BACKGROUND
Liver failure is a rare, life-threatening disease that has a high mortality rate and affects many organ systems. Bloodstream bacterial infection has played a key role in liver failure patients with plasma exchange-centered artificial liver support systems, but the predicted risk factors of infection have not been fully understood.
OBJECTIVE
We aimed to predict bloodstream bacterial infection in high-risk groups of liver failure patients during a plasma exchange-centered artificial liver support system.
DESIGN
This was a prospective cohort study.
SETTING
This study was performed in Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School.
PARTICIPANTS
118 liver failure patients with plasma exchange-centered artificial liver support system therapy from Nanjing Drum Tower Hospital from November 2019 to November 2020 were selected.
INTERVENTIONS
We used a stepwise binary logistic regression model to select the optimal risk factors of infection with minimum Akaike information criterion, and the Nomogram prognostic model for bloodstream infection was constructed for visualization.
PRIMARY OUTCOME MEASURES
Risk factors of bloodstream infection (2) predictive accuracy of the constructed nomogram model.
RESULTS
Among the 118 liver failure patients, 22 (18.64%) were diagnosed with bloodstream bacterial infection. The univariable and multivariate logistic regression analyses suggested that culture level, glucocorticoids use, number of punctures, blood platelet counts, white blood cell counts, and indwelling catheter time were the sex predictors of bloodstream infection for liver failure patients during plasma exchange-centered artificial liver support system (P = .042, P = .013, P = .025, P = .003, P = .024 and P = .026). The nomogram predictive model was established with high prediction accuracy, of which the area under the curve was 0.935 (95% confidence interval: 0.884-0.986), the sensitivity was 0.955, and the specificity was 0.854.
CONCLUSION
The constructed nomogram prognostic model can recognize the risk factors and accurately predict bloodstream infection for liver failure patients during plasma exchange-centered artificial liver support system.
PubMed: 38940794
DOI: No ID Found -
Frontiers in Bioscience (Landmark... May 2024Osteosarcoma (OS) is a primary malignant bone tumor in the pediatric and adolescent populations. Long non-coding RNAs (LncRNAs), such as plasma-cytoma variant...
BACKGROUND
Osteosarcoma (OS) is a primary malignant bone tumor in the pediatric and adolescent populations. Long non-coding RNAs (LncRNAs), such as plasma-cytoma variant translocation 1 (PVT1), have emerged as significant regulators of OS metastasis. Recent studies have indicated that activation of signal transducer and activator of transcription 3 (STAT3) signaling, which might be controlled by PVT1, inhibits ferroptosis to promote the malignant progression of cancer. Therefore, the present study aimed to determine the role of PVT1 in OS pathogenesis and investigate whether PVT1 affects OS progression by regulating STAT3/GPX4 pathway-mediated ferroptosis.
METHODS
The human OS cell line MG63 were transfected with sh-PVT1 plasmid to inhibit PVT1 expression, with or without co-transfection with a STAT3 overexpression plasmid. The expression of PVT1 was determined by real-time quantitative polymerase chain reaction (RT-qPCR). The proliferation, migration, invasion, and apoptosis of MG63 cells were determined using the cell counting kit-8 (CCK8), Transwell assay, and flow cytometry. The levels of malondialdehyde (MDA), Fe2+, and glutathione (GSH) were determined by ELISA kits, whereas reactive oxygen species (ROS) level was determined by immunofluorescence. The protein expression levels of STAT3, p-STAT3, and glutathione peroxidase 4 (GPX4) were detected by western blot (WB).
RESULTS
PVT1 expression was significantly increased in MG63 cells. When knocking down PVT1 with sh-PVT1 plasmid, the proliferation, migration, and invasion of MG63 cells were markedly inhibited, while the rate of apoptosis was upregulated. Further investigation revealed that MG63 cells with PVT1 knockdown exhibited elevated levels of MDA, Fe2+, and ROS. In addition, the inhibition of PVT1 expression resulted in decreased levels of GSH and inhibited expression of p-STAT3 and GPX4. When sh-PVT1 was co-transfected with STAT3 overexpression plasmid in MG63 cells, the increased levels of MDA, Fe2+, and ROS were downregulated, and the decreased expressions of GSH, p-STAT3, and GPX4 were upregulated.
CONCLUSION
PVT1 promotes OS metastasis by activating the STAT3/GPX4 pathway to inhibit ferroptosis. Targeting PVT1 might be a novel therapeutic strategy for OS treatment.
Topics: Humans; Osteosarcoma; RNA, Long Noncoding; Ferroptosis; STAT3 Transcription Factor; Cell Line, Tumor; Bone Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Cell Proliferation; Reactive Oxygen Species; Signal Transduction; Cell Movement; Disease Progression; Apoptosis; Gene Expression Regulation, Neoplastic
PubMed: 38940027
DOI: 10.31083/j.fbl2906207