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1.
Cell ; 187(11): 2855-2874.e19, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38657603

ABSTRACT

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.


Subject(s)
Embryo, Mammalian , Gastrulation , Gene Expression Regulation, Developmental , Imaging, Three-Dimensional , Humans , Embryo, Mammalian/metabolism , Transcriptome/genetics , Gastrula/metabolism , Gastrula/embryology , Signal Transduction , Cell Lineage , Gene Expression Profiling , Body Patterning/genetics
2.
Cell ; 187(3): 764-781.e14, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38306985

ABSTRACT

Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.


Subject(s)
Metabolomics , Pregnancy , Animals , Female , Humans , Pregnancy/metabolism , Corticosterone/metabolism , Metabolome/physiology , Placenta/metabolism , Pre-Eclampsia , Primates/metabolism
3.
Cell ; 186(10): 2078-2091.e18, 2023 05 11.
Article in English | MEDLINE | ID: mdl-37172562

ABSTRACT

Neural tube (NT) defects arise from abnormal neurulation and result in the most common birth defects worldwide. Yet, mechanisms of primate neurulation remain largely unknown due to prohibitions on human embryo research and limitations of available model systems. Here, we establish a three-dimensional (3D) prolonged in vitro culture (pIVC) system supporting cynomolgus monkey embryo development from 7 to 25 days post-fertilization. Through single-cell multi-omics analyses, we demonstrate that pIVC embryos form three germ layers, including primordial germ cells, and establish proper DNA methylation and chromatin accessibility through advanced gastrulation stages. In addition, pIVC embryo immunofluorescence confirms neural crest formation, NT closure, and neural progenitor regionalization. Finally, we demonstrate that the transcriptional profiles and morphogenetics of pIVC embryos resemble key features of similarly staged in vivo cynomolgus and human embryos. This work therefore describes a system to study non-human primate embryogenesis through advanced gastrulation and early neurulation.


Subject(s)
Neural Tube Defects , Neurulation , Tissue Culture Techniques , Animals , Humans , Blastocyst , Embryo, Mammalian , Embryonic Development , Macaca fascicularis , Neural Tube Defects/genetics , Neural Tube Defects/pathology , Tissue Culture Techniques/methods
4.
Nature ; 612(7941): 732-738, 2022 12.
Article in English | MEDLINE | ID: mdl-36517595

ABSTRACT

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.


Subject(s)
Gastrulation , Macaca fascicularis , Organogenesis , Single-Cell Analysis , Animals , Humans , Mice , Gastrulation/genetics , Macaca fascicularis/embryology , Macaca fascicularis/genetics , Organogenesis/genetics , Embryoid Bodies , Gene Expression Profiling , Primitive Streak/cytology , Primitive Streak/embryology , Neural Tube/cytology , Neural Tube/embryology , Neural Crest/cytology , Neural Crest/embryology , Hippo Signaling Pathway , Mesoderm/cytology , Mesoderm/embryology , Stem Cells
5.
Nature ; 585(7825): 404-409, 2020 09.
Article in English | MEDLINE | ID: mdl-32848249

ABSTRACT

To implant in the uterus, the mammalian embryo first specifies two cell lineages: the pluripotent inner cell mass that forms the fetus, and the outer trophectoderm layer that forms the placenta1. In many organisms, asymmetrically inherited fate determinants drive lineage specification2, but this is not thought to be the case during early mammalian development. Here we show that intermediate filaments assembled by keratins function as asymmetrically inherited fate determinants in the mammalian embryo. Unlike F-actin or microtubules, keratins are the first major components of the cytoskeleton that display prominent cell-to-cell variability, triggered by heterogeneities in the BAF chromatin-remodelling complex. Live-embryo imaging shows that keratins become asymmetrically inherited by outer daughter cells during cell division, where they stabilize the cortex to promote apical polarization and YAP-dependent expression of CDX2, thereby specifying the first trophectoderm cells of the embryo. Together, our data reveal a mechanism by which cell-to-cell heterogeneities that appear before the segregation of the trophectoderm and the inner cell mass influence lineage fate, via differential keratin regulation, and identify an early function for intermediate filaments in development.


Subject(s)
Cell Lineage , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Keratins/metabolism , Actins/metabolism , Animals , Cell Division , Chromatin Assembly and Disassembly , Chromosomal Proteins, Non-Histone/metabolism , Ectoderm/cytology , Embryo, Mammalian/embryology , Female , Humans , Intermediate Filaments/metabolism , Mice , Microtubules/metabolism , Multiprotein Complexes/metabolism , Trophoblasts/cytology
6.
Brain ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701344

ABSTRACT

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

7.
Int J Cancer ; 154(12): 2031-2042, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38500385

ABSTRACT

Tumor-associated myeloid cells (TAMCs) play a crucial role in orchestrating the dynamics of the tumor immune microenvironment. This heterogeneous population encompasses myeloid-derived suppressor cells, tumor-associated macrophages and dendritic cells, all of which contribute to the establishment of an immunosuppressive milieu that fosters tumor progression. Tumor-derived exosomes (TEXs), small extracellular vesicles secreted by tumor cells, have emerged as central mediators in intercellular communication within the tumor microenvironment. In this comprehensive review, we explore the intricate mechanisms through which TEXs modulate immune-suppressive effects on TAMCs and their profound implications in cancer progression. We delve into the multifaceted ways in which TEXs influence TAMC functions, subsequently affecting tumor immune evasion. Furthermore, we elucidate various therapeutic strategies aimed at targeting TEX-mediated immune suppression, with the ultimate goal of bolstering antitumor immunity.


Subject(s)
Exosomes , Myeloid-Derived Suppressor Cells , Neoplasms , Humans , Exosomes/pathology , Neoplasms/pathology , Immunosuppression Therapy , Myeloid Cells , Tumor Microenvironment
8.
Anal Chem ; 96(1): 220-228, 2024 01 09.
Article in English | MEDLINE | ID: mdl-38109169

ABSTRACT

Nucleic acid detection of pathogens in a point-of-need (PON) manner is of great significance yet remains challenging for sensitive and accurate visual discrimination. Here, we report a CRISPR-Cas12a-mediated lateral flow assay for PON detection of Salmonella typhimurium (S.ty) that is a prevailing pathogen disseminated through tainted food. The variation of the fluorescence color of the test line is exploited to interpret the results, enabling the discrimination between positive and negative samples on the basis of a hue-recognition mechanism. By leveraging the cleavage activity of Cas12a and hue-recognition readout, the assay facilitated by recombinase polymerase amplification can yield a visual detection limit of 1 copy µL-1 for S.ty genomic DNA within 1 h. The assay also displays a high specificity toward S.ty in fresh chicken samples, as well as a sensitivity 10-fold better than that of the commercial test strip. Moreover, a semiquantitative detection of S.ty ranging from 0 to 4 × 103 CFU/mL by the naked eye is made possible, thanks to the easily discernible color change of the test line. This approach provides an easy, rapid, accurate, and user-friendly solution for the PON detection of Salmonella and other pathogens.


Subject(s)
CRISPR-Cas Systems , Salmonella typhimurium , Animals , CRISPR-Cas Systems/genetics , Salmonella typhimurium/genetics , Biological Assay , Chickens , Food , Nucleic Acid Amplification Techniques
9.
Breast Cancer Res Treat ; 207(2): 417-434, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38834774

ABSTRACT

BACKGROUND: Adhesion G protein-coupled receptors (aGPCRs), a distinctive subset of the G protein-coupled receptor (GPCR) superfamily, play crucial roles in various physiological and pathological processes, with implications in tumor development. Despite the global prevalence of breast cancer (BRCA), specific aGPCRs as potential drug targets or biomarkers remain underexplored. METHODS: UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, cBiopportal, String, GeneMANIA, DAVID, Timer, Metascape, and qPCR were applied in this work. RESULTS: Our analysis revealed significantly increased transcriptional levels of ADGRB2, ADGRC1, ADGRC2, ADGRC3, ADGRE1, ADGRF2, ADGRF4, and ADGRL1 in BRCA primary tumors. Further analysis indicated a significant correlation between the expressions of certain aGPCRs and the pathological stage of BRCA. High expression of ADGRA1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, and ADGRG7 was significantly correlated with poor overall survival (OS) in BRCA patients. Additionally, high expression of ADGRF2 and ADGRF4 indicated inferior recurrence-free survival (RFS) in BRCA patients. The RT-qPCR experiments also confirmed that the mRNA levels of ADGRF2 and ADGRF4 were higher in BRCA cells and tissues. Functional analysis highlighted the diverse roles of aGPCRs, encompassing GPCR signaling and metabolic energy reserves. Moreover, aGPCRs may exert influence or actively participate in the development of BRCA through their impact on immune status. CONCLUSION: aGPCRs, particularly ADGRF2 and ADGRF4, hold promise as immunotherapeutic targets and prognostic biomarkers in BRCA.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms , Gene Expression Regulation, Neoplastic , Receptors, G-Protein-Coupled , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Prognosis , Molecular Targeted Therapy , Cell Line, Tumor , Gene Expression Profiling , Kaplan-Meier Estimate
10.
J Virol ; 97(12): e0150123, 2023 Dec 21.
Article in English | MEDLINE | ID: mdl-37982618

ABSTRACT

IMPORTANCE: The type-I interferon (IFN-I) signaling pathway is the first line of antiviral innate immunity. It must be precisely regulated against virus-induced damage. The tightly regulated mechanisms of action of host genes in the antiviral innate immune signaling pathway are still worth studying. Here, we report a novel role of DLG1 in positively regulating the IκB kinase epsilon (IKKε)-mediated IFN-I signaling response against negative-stranded RNA virus replication, whereas the RNA virus inhibits the expression of DLG1 for immune escape. Importantly, the E3 ligase March2 interacts with and promotes K27-linked polyubiquitination of IKKε, and p62 is a cargo receptor that recognizes ubiquitinated IKKε for eventual autophagic degradation. Together, the current findings elucidate the role of DLG1 in the antiviral IFN-I signaling pathway and viral infection repression.


Subject(s)
Autophagy , Discs Large Homolog 1 Protein , I-kappa B Kinase , Immunity, Innate , Negative-Sense RNA Viruses , Sequestosome-1 Protein , Virus Diseases , Humans , Discs Large Homolog 1 Protein/metabolism , I-kappa B Kinase/metabolism , Immunity, Innate/immunology , Negative-Sense RNA Viruses/growth & development , Negative-Sense RNA Viruses/immunology , Polyubiquitin/metabolism , Sequestosome-1 Protein/antagonists & inhibitors , Signal Transduction , Virus Diseases/immunology , Animals , Cell Line
11.
J Med Virol ; 96(8): e29845, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39119969

ABSTRACT

Hemorrhagic fever with renal syndrome (HFRS) and severe fever with thrombocytopenia syndrome (SFTS) are both endemic in rural areas and some characteristics are similar between HFRS and SFTS, which usually lead to misdiagnosis. In this study, we summarized and compared some characteristics of HFRS and SFTS which will provide scientific information for differential diagnosis. From 2011 to 2022, a total of 4336 HFRS cases and 737 SFTS cases were reported in Zhejiang Province. Compared to SFTS, there was a higher proportion of males among HFRS cases (72.46% [3142/4336] vs. 50.88% [375/737], p = 0.000). The median age of all 4336 HFRS cases was 49 (39, 59), while the median age of SFTS cases was 66 (57, 74). In addition, the involved counties of HFRS were more than SFTS, but the number of counties affected by SFTS increased from 2011 to 2022. The majority of SFTS cases occurred in summer (from May to July), but besides summer, HFRS cases also showed a peak in winter. Finally, our results showed that the case fatality rate of SFTS was significantly higher than that of HFRS. Although there were some similarities between HFRS and SFTS, our study found several differences between them, such as gender distribution, age distribution, and seasonal distribution, which will provide scientific information for differential diagnosis of HFRS and SFTS. Further studies should be carried out to explore the mechanism of these differences.


Subject(s)
Hemorrhagic Fever with Renal Syndrome , Seasons , Severe Fever with Thrombocytopenia Syndrome , Humans , Hemorrhagic Fever with Renal Syndrome/epidemiology , Hemorrhagic Fever with Renal Syndrome/diagnosis , Male , Middle Aged , Female , Adult , Aged , Severe Fever with Thrombocytopenia Syndrome/epidemiology , Severe Fever with Thrombocytopenia Syndrome/virology , Severe Fever with Thrombocytopenia Syndrome/diagnosis , China/epidemiology , Diagnosis, Differential
12.
Anal Biochem ; 690: 115510, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38513769

ABSTRACT

Phosphorylation is indispensable in comprehending biological processes, while biological experimental methods for identifying phosphorylation sites are tedious and arduous. With the rapid growth of biotechnology, deep learning methods have made significant progress in site prediction tasks. Nevertheless, most existing predictors only consider protein sequence information, that limits the capture of protein spatial information. Building upon the latest advancement in protein structure prediction by AlphaFold2, a novel integrated deep learning architecture PhosAF is developed to predict phosphorylation sites in human proteins by integrating CMA-Net and MFC-Net, which considers sequence and structure information predicted by AlphaFold2. Here, CMA-Net module is composed of multiple convolutional neural network layers and multi-head attention is appended to obtaining the local and long-term dependencies of sequence features. Meanwhile, the MFC-Net module composed of deep neural network layers is used to capture the complex representations of evolutionary and structure features. Furthermore, different features are combined to predict the final phosphorylation sites. In addition, we put forward a new strategy to construct reliable negative samples via protein secondary structures. Experimental results on independent test data and case study indicate that our model PhosAF surpasses the current most advanced methods in phosphorylation site prediction.

13.
Cell Commun Signal ; 22(1): 149, 2024 02 24.
Article in English | MEDLINE | ID: mdl-38402193

ABSTRACT

Apoptosis plays a pivotal role in pathogen elimination and maintaining homeostasis. However, viruses have evolved strategies to evade apoptosis, enabling their persistence within the host. Z-DNA binding protein 1 (ZBP1) is a potent innate immune sensor that detects cytoplasmic nucleic acids and activates the innate immune response to clear pathogens. When apoptosis is inhibited by viral invasion, ZBP1 can be activated to compensate for the effect of apoptosis by triggering an innate immune response. This review examined the mechanisms of apoptosis inhibition and ZBP1 activation during viral invasion. The authors outlined the mechanisms of ZBP1-induced type I interferon, pyroptosis and necroptosis, as well as the crosstalk between ZBP1 and the cGAS-STING signalling pathway. Furthermore, ZBP1 can reverse the suppression of apoptotic signals induced by viruses. Intriguingly, a positive feedback loop exists in the ZBP1 signalling pathway, which intensifies the innate immune response while triggering a cytokine storm, leading to tissue and organ damage. The prudent use of ZBP1, which is a double-edged sword, has significant clinical implications for treating infections and inflammation.


Subject(s)
Apoptosis , Immunity, Innate , Humans , Pyroptosis , Inflammation , Cytoplasm
14.
Arch Virol ; 169(5): 114, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38700535

ABSTRACT

OBJECTIVE: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS: A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS: Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION: EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.


Subject(s)
Epstein-Barr Virus Infections , Herpesvirus 4, Human , Stomach Neoplasms , Humans , Stomach Neoplasms/virology , Stomach Neoplasms/pathology , Male , Female , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/mortality , Middle Aged , Herpesvirus 4, Human/genetics , Prognosis , Retrospective Studies , Aged , Adult , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Ki-67 Antigen/metabolism , RNA, Viral/genetics , Gastrectomy
15.
Anal Bioanal Chem ; 416(15): 3569-3584, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38698257

ABSTRACT

Protein adducts are important biological targets for traceability of organophosphorus nerve agents (OPNAs). Currently, the recognized biomarkers that can be used in actual samples in the field of chemical forensics only include Y411 in albumin and the active nonapeptide in butyrylcholinesterase (BChE). To explore stable and reliable protein adducts and increase the accuracy of OPNAs traceability further, we gradually expanded OPNAs-albumin adducts based on single and group adduct collection. Several stable peptides were found via LC-MS/MS analysis in human serum albumin (HSA) exposed to OPNAs in a large exposure range. These adducts were present in HSA samples exposed to OPNAs of each concentration, which provided data support for the reliability and stability of using adducts to trace OPNAs. Meanwhile, the formation mechanism of OPNAs-cysteine adduct was clarified via computer simulations. Then, these active sites found and modified peptides were used as raw materials for progressive expansion of albumin adducts. We constructed an OPNAs-HSA adducts group, in which a specific agent is the exposure source, and three or more active peptides constitute data sets for OPNAs traceability. Compared with single or scattered protein adducts, the OPNAs-HSA adduct group improves OPNAs identification by mutual verification using active peptides or by narrowing the identity range of the exposure source. We also determined the minimum detectable concentration of OPNAs for the adduct group. Two or more peptides can be detected when there is an exposure of 50 times the molar excess of OPNAs in relation to HSA. This improved the accuracy of OPNAs exposure and identity confirmation. A collection of OPNAs-albumin adducts was also examined. The collection was established by collecting, classifying, and integrating the existing albumin adducts according to the species to which each albumin belongs, the types of agents, and protease. This method can serve as a reference for discovering new albumin adducts, characteristic phosphonylated peptides, and potential biomarkers. In addition, to avoid a false negative for OPNAs traceability using albumin adducts, we explored OPNAs-cholinesterase adducts because cholinesterase is more reactive with OPNAs than albumin. Seven active peptides in red blood cell acetylcholinesterase (RBC AChE) and serum BChE can assist in OPNAs exposure and identity confirmation.


Subject(s)
Nerve Agents , Organophosphorus Compounds , Serum Albumin, Human , Tandem Mass Spectrometry , Humans , Nerve Agents/chemistry , Nerve Agents/analysis , Organophosphorus Compounds/chemistry , Tandem Mass Spectrometry/methods , Serum Albumin, Human/chemistry , Chromatography, Liquid/methods , Biomarkers/blood , Peptides/chemistry
16.
Health Qual Life Outcomes ; 22(1): 30, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38561752

ABSTRACT

BACKGROUND: The involvement of quality of life as the UNAIDS fourth 90 target to monitor the global HIV response highlighted the development of patient-reported outcome (PRO) measures to help address the holistic needs of people living with HIV/AIDS (PLWHA) beyond viral suppression. This study developed and tested preliminary measurement properties of a new patient-reported outcome (PROHIV-OLD) measure designed specifically to capture influences of HIV on patients aged 50 and older in China. METHODS: Ninety-three older people living with HIV/AIDS (PLWHA) were interviewed to solicit items and two rounds of patient cognitive interviews were conducted to modify the content and wording of the initial items. A validation study was then conducted to refine the initial instrument and evaluate measurement properties. Patients were recruited between February 2021 and November 2021, and followed six months later after the first investigation. Classical test theory (CTT) and item response theory (IRT) were used to select items using the baseline data. The follow-up data were used to evaluate the measurement properties of the final instrument. RESULTS: A total of 600 patients were recruited at the baseline. Of the 485 patients who completed the follow-up investigation, 483 were included in the validation sample. The final scale of PROHIV-OLD contained 25 items describing five dimensions (physical symptoms, mental status, illness perception, family relationship, and treatment). All the PROHIV-OLD dimensions had satisfactory reliability with Cronbach's alpha coefficient, McDonald's ω, and composite reliability of each dimension being all higher than 0.85. Most dimensions met the test-retest reliability standard except for the physical symptoms dimension (ICC = 0.64). Confirmatory factor analysis supported the structural validity of the final scale, and the model fit index satisfied the criterion. The correlations between dimensions of PROHIV-OLD and MOS-HIV met hypotheses in general. Significant differences on scores of the PROHIV-OLD were found between demographic and clinical subgroups, supporting known-groups validity. CONCLUSIONS: The PROHIV-OLD was found to have good feasibility, reliability and validity for evaluating health outcome of Chinese older PLWHA. Other measurement properties such as responsiveness and interpretability will be further examined.


Subject(s)
Acquired Immunodeficiency Syndrome , Quality of Life , Humans , Middle Aged , Aged , Quality of Life/psychology , Surveys and Questionnaires , Reproducibility of Results , Patient Reported Outcome Measures , China , Psychometrics/methods
17.
J Appl Microbiol ; 2024 Jan 19.
Article in English | MEDLINE | ID: mdl-38244233

ABSTRACT

AIMS: The intestinal biota, known for its colonization of the human intestine and its modulation of host pathophysiological responses through the immune and endocrine systems, has gained substantial interest in recent years due to its notable correlation with diabetes and stroke. METHODS: In order to examine this association, a comparative study was conducted on the intestinal biota and blood samples obtained from mouse models and type 2 diabetic patients with and without stroke complications. Advanced techniques, such as high-throughput sequencing and enzyme-linked immunosorbent assay were employed to identify the differences in the intestinal biota and blood indices of mouse models and patients. RESULTS: At the phylum level, the dominant gut bacteria identified in patients with diabetes mellitus and stroke were Firmicutes, Bacteroidetes, and Proteobacteria. It was noteworthy that the relative abundance of Bacteroides at the genus level was significantly diminished in the DB-PT group (photothrombotic diabetes mice) as compared to the DB group (diabetesmice). This result was consistent with observations in human samples. Additionally, significant variations were detected in lipid proteins, specifically APOA4, in diabetic patients with and without stroke. CONCLUSIONS: Stroke can diminish the abundance and diversity of intestinal biota, potentially correlating with lipid proteins in patients with diabetes.

18.
Environ Res ; 245: 118011, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38141916

ABSTRACT

Microbes have been confirmed to play key role in biogeochemistry of antimony. However, the impact of indigenous bacteria (from active mines) on the behavior of dissolved antimony remained poorly understood. In current study, the hyper antimony-resistant strain, Achromobacter sp. 25-M, isolated from the world largest antimony deposit, Xikuangshan antimony deposit, was evaluated for its role in dissolved Sb(V) and Sb(III) precipitation and removal. Despite of the high resistance to Sb(III) (up to 50 mM), the facultative alkaliphile, 25-M was not capable of Sb(III) oxidation. Meanwhile 25-M can produce high amount of exopolymeric substance (EPS) with the presence of Sb, which prompted us to investigate the potential role of EPS in the precipitation and removal of Sb. To this end, 2 mM of Sb(III) and Sb(V) were added into the experimental systems with and without 25-M to discern the interaction mechanism between microbe and antimony. After 96 hrs' incubation, 88% [1.73 mM (210 mg/L)] of dissolved Sb(V) and 80% [1.57 mM (190 mg/L)] of dissolved Sb(III) were removed. X-ray diffraction and energy dispersive spectroscopy analysis confirmed the formation of valentinite (Sb2O3) in Sb(III) amended system and a solitary Sb(V) mineral mopungite [NaSb(OH)6] in Sb(V) amended group with microbes. Conversely, no precipitate was detected in abiotic systems. Morphologically valentinite was bowtie and mopungite was pseudo-cubic as indicated by scanning electronic microscopy. EPS was subjected to fourier transform infrared (FT-IR) analysis. FT-IR analysis suggested that -OH and -COO groups were responsible for the complexation and ligand exchange with Sb(III) and Sb(V), respectively. Additionally, the C-H group and N-H group could be involved in π-π interaction and chelation with Sb species. All these interactions between Sb and functional groups in EPS may subsequently favore the formation of valentinite and mopungite. Collectively, current results suggested that EPS play fundamental role in bioprecipitation of Sb, which offered a new strategy in Sb bioremediation.


Subject(s)
Antimony , Minerals , Antimony/chemistry , Spectroscopy, Fourier Transform Infrared , Oxidation-Reduction , X-Ray Diffraction , Adsorption
19.
BMC Anesthesiol ; 24(1): 105, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38504189

ABSTRACT

OBJECTIVE: Postoperative fasting following thoracoscopic surgery can cause intense thirst and oral discomfort. However, there is currently no research on ultraearly oral hydration (UEOH) in middle-aged or elderly patients after thoracoscopic surgery. The aim of this study was to investigate the effectiveness and safety of UEOH for improving oral discomfort after thoracoscopic surgery. METHODS: This single-center prospective double-blind randomized controlled trial was conducted from April 2022 to November 2023. A total of 64 middle-aged and elderly patients who underwent the first thoracoscopic surgery on the day were enrolled at our institution. Postoperatively, in the Postanesthesia Care Unit (PACU), patients were randomly assigned at a 1:1 ratio to either the UEOH group or the standard care (SC) group. The primary outcome was the patient's thirst score at 6 h after surgery. Secondary outcomes included the incidence of postoperative oral discomfort; pain scores; the occurrence of adverse reactions such as nausea, vomiting, regurgitation and aspiration; anxiety scores on the first postoperative day; the time to first flatus; and recovery satisfaction scores. RESULTS: The demographic and surgical characteristics were similar between the two groups. Patients in the UEOH group had lower thirst scores 6 h after surgery than did those in the SC group(16.1 ± 6.70 vs. 78.4 ± 8.42, P < 0.01). The incidence of postoperative oral discomfort (P < 0.01), anxiety scores on the first postoperative day (P<0.05), and time to first flatus (P<0.05) were better in the UEOH group. Additionally, the incidences of adverse reactions, such as postoperative nausea, vomiting, regurgitation and aspiration, were similar between the two groups (P>0.05). CONCLUSION: For middle-aged and elderly patients undergoing thoracoscopic surgery, the use of a modified UEOH protocol postoperatively can improve thirst and promote gastrointestinal recovery without increasing complications. TRIAL REGISTRATION: This single-center, prospective, RCT has completed the registration of the Chinese Clinical Trial Center at 07/12/2023 with the registration number ChiCTR2300078425.


Subject(s)
Pain, Postoperative , Thirst , Middle Aged , Aged , Humans , Prospective Studies , Flatulence , Postoperative Nausea and Vomiting/epidemiology , Postoperative Nausea and Vomiting/prevention & control , Thoracoscopy , Double-Blind Method
20.
BMC Health Serv Res ; 24(1): 279, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38443959

ABSTRACT

BACKGROUND: Healthcare accessibility and utilization are important social determinants of health. Lack of access to healthcare, including missed or no-show appointments, can have negative health effects and be costly to patients and providers. Various office-based approaches and community partnerships can address patient access barriers. OBJECTIVES: (1) To understand provider perceptions of patient barriers; (2) to describe the policies and practices used to address late or missed appointments, and (3) to evaluate access to patient support services, both in-clinic and with community partners. METHODS: Mailed cross-sectional survey with online response option, sent to all Nebraska primary care clinics (n = 577) conducted April 2020 and January through April 2021. Chi-square tests compared rural-urban differences; logistic regression of clinical factors associated with policies and support services computed odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Response rate was 20.3% (n = 117), with 49 returns in 2020. Perceived patient barriers included finances, higher among rural versus urban clinics (81.6% vs. 56.1%, p =.009), and time (overall 52.3%). Welcoming environment (95.5%), telephone appointment reminders (74.8%) and streamlined admissions (69.4%) were the top three clinic practices to reduce missed appointments. Telehealth was the most commonly available patient support service in rural (79.6%) and urban (81.8%, p =.90) clinics. Number of providers was positively associated with having a patient navigator/care coordinator (OR = 1.20, CI = 1.02-1.40). For each percent increase in the number of privately insured patients, the odds of providing legal aid decreased by 4% (OR = 0.96, CI = 0.92-1.00). Urban clinics were less likely than rural clinics to provide social work services (OR = 0.16, CI = 0.04-0.67) or assist with applications for government aid (OR = 0.22, CI = 0.06-0.90). CONCLUSIONS: Practices to reduce missed appointments included a variety of reminders. Although finances and inability to take time off work were the most frequently reported perceived barriers for patients' access to timely healthcare, most clinics did not directly address them. Rural clinics appeared to have more community partnerships to address underlying social determinants of health, such as transportation and assistance applying for government aid. Taking such a wholistic partnership approach is an area for future study to improve patient access.


Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Cross-Sectional Studies , Pandemics , Ambulatory Care Facilities , Policy , Primary Health Care
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