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Nature Communications Jun 2024Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity...
Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity and the role of APC subpopulations on regulating glucose homeostasis remain unknown. Here, we find that APCs in human visceral adipose tissue contain four subsets. The composition and functionality of APCs are altered in patients with type 2 diabetes (T2D). CD9CD55 APCs are the subset which is significantly increased in T2D patients. Transplantation of these cells from T2D patients into adipose tissue causes glycemic disturbance. Mechanistically, CD9CD55 APCs promote T2D development through producing bioactive proteins to form a detrimental niche, leading to upregulation of adipocyte lipolysis. Depletion of pathogenic APCs by inducing intracellular diphtheria toxin A expression or using a hunter-killer peptide improves obesity-related glycemic disturbance. Collectively, our data provide deeper insights in human APC functionality and highlights APCs as a potential therapeutic target to combat T2D. All mice utilized in this study are male.
Topics: Humans; Animals; Single-Cell Analysis; Diabetes Mellitus, Type 2; Homeostasis; Male; Mice; Stem Cells; Glucose; Obesity; Adipocytes; Intra-Abdominal Fat; Adipose Tissue; Mice, Inbred C57BL; Lipolysis; Female; Middle Aged
PubMed: 38844451
DOI: 10.1038/s41467-024-48914-w -
Frontiers in Genetics 2024Epicardial cells regulate heart growth by secreting numerous growth factors and undergoing lineage specification into other cardiac lineages. However, the lack of...
Epicardial cells regulate heart growth by secreting numerous growth factors and undergoing lineage specification into other cardiac lineages. However, the lack of specific marker genes for epicardial cells has hindered the understanding of this cell type in heart development. Through the analysis of a cardiac single cell mRNA sequencing dataset, we identified a novel epicardial gene named (). Further analysis of the expression patterns of and , a well-known epicardial gene, revealed their preferences in major cardiac cell types. Using lineage-tracing analysis, we analyzed labeled cells at multiple time windows and found that it labels epicardial cells at both embryonic and neonatal stages. Furthermore, we studied the function of epicardial cells using a diphtheria toxin A chain (DTA)-based cell ablation system. We discovered that labeled cells are essential for fetal heart development. Finally, we investigated the function of and labeled cells in neonatal mouse development. We observed that the ; mice displayed a smaller size after tamoxifen treatment, suggesting the potential importance of labeled cells in neonatal mouse development. Additionally, we found that ; mice died at early stages, likely due to defects in the kidney and spleen. In summary, we have identified as a new epicardial cell marker gene and further explored the function of epicardial cells using the and -mediated DTA ablation system.
PubMed: 38831775
DOI: 10.3389/fgene.2024.1385867 -
Iranian Journal of Allergy, Asthma, and... Apr 2024During epithelial to mesenchymal transition, the ability of cancer cells to transform and metastasize is primarily determined by N-cadherin-mediated migration and...
During epithelial to mesenchymal transition, the ability of cancer cells to transform and metastasize is primarily determined by N-cadherin-mediated migration and invasion. This study aimed to evaluate whether the N-cadherin promoter can induce diphtheria toxin expression as a suicide gene in epithelial to mesenchymal transition (EMT)-induced cancer cells and whether this can be used as potential gene therapy. To investigate the expression of diphtheria toxin under the N-cadherin promoter, the promoter was synthesized, and was cloned upstream of diphtheria toxin in a pGL3-Basic vector. The A-549 cells was transfected by electroporation. After induction of EMT by TGF-β and hypoxia treatment, the relative expression of diphtheria toxin, mesenchymal genes such as N-cadherin and Vimentin, and epithelial genes such as E-cadherin and β-catenin were measured by real-time PCR. MTT assay was also performed to measure cytotoxicity. Finally, cell motility was assessed by the Scratch test. After induction of EMT in transfected cells, the expression of mesenchymal markers such as Vimentin and N-cadherin significantly decreased, and the expression of β-catenin increased. In addition, the MTT assay showed promising toxicity results after induction of EMT with TGF-β in transfected cells, but toxicity was less effective in hypoxia. The scratch test results also showed that cell movement was successfully prevented in EMT-transfected cells and thus confirmed EMT occlusion. Our findings indicate that by using structures containing diphtheria toxin downstream of a specific EMT promoter such as the N-cadherin promoter, the introduced toxin can kill specifically and block EMT in cancer cells.
Topics: Humans; A549 Cells; Antigens, CD; beta Catenin; Cadherins; Cell Movement; Diphtheria Toxin; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Genes, Transgenic, Suicide; Promoter Regions, Genetic; Vimentin
PubMed: 38822516
DOI: 10.18502/ijaai.v23i2.15327 -
Scientific Reports May 2024Globally dropout rate for the three dose of penta (DPT) vaccine was highest in the African region. This mainly occurred in the African Region including Ethiopia. Despite...
Globally dropout rate for the three dose of penta (DPT) vaccine was highest in the African region. This mainly occurred in the African Region including Ethiopia. Despite high national incomplete vaccination status, there is lack of study on the determinants of incomplete vaccination in south west region, Ethiopia. Therefore, this study was conducted to identify determinants of incomplete Penta vaccination among children aged 12 to 23 months in Mettu district South-West Ethiopia. A Community based case-control study was conducted from April 24, May 23, 2022 in South-west Ethiopia. Data was collected from 297 participants (99 cases and 198controls) by using simple random sampling techniques. Cases were children age from 9 to 23 months who missed at least one dose from the routine vaccine and controls were completed the entire routine vaccine schedule. Data was entered to Epi-data version 3.1 and exported to SPSS version 23 for statistical analyses. Binary and multivariable logistic regression with a 95% CI and a p-value of < 0.05 was done to declare statistical significance. A total of 95 cases and 197 controls participated in the study. Rural residence [AOR: 3.9; 95% CI; (1.6, 9.4)], wealth indexes [AOR: 3.6; 95% CI; (1.8,7.0)], mothers unimmunized tetanus toxoid [AOR: 4.3; 95% CI; (2.1, 8.6)], postponed schedule [AOR: 4.6; 95% CI; (2.4, 8.8)], un satisfied to service [AOR: 3.7; 95% CI; (1.7,7.6)] and poor perception on benefit of vaccine [AOR:2.7; 95% CI; (1.2, 6.1)] were determinants of incomplete vaccination. Rural Residence, Family wealth index of poor; Mother not received tetanus vaccination; postponed vaccination schedule client satisfaction and caretaker perception on benefit of vaccination were identified determinants of incomplete vaccination.Health information should be given for the community and child caretaker on the benefit of complete vaccination. Community should be encouraged to not post pond vaccine schedule. Pregnant women should be strengthening to receive tetanus toxoid vaccine during pregnancy.
Topics: Humans; Ethiopia; Female; Male; Infant; Vaccination; Case-Control Studies; Diphtheria-Tetanus-Pertussis Vaccine; Adult; Immunization Schedule; Vaccination Coverage
PubMed: 38821964
DOI: 10.1038/s41598-024-62153-5 -
ACS Infectious Diseases Jun 2024is a fungus classified by the World Health Organization as a critically important pathogen, which poses a significant threat to immunocompromised individuals. In this...
is a fungus classified by the World Health Organization as a critically important pathogen, which poses a significant threat to immunocompromised individuals. In this study, we present the chemical synthesis and evaluation of two semisynthetic vaccine candidates targeting the capsular polysaccharide glucuronoxylomannan (GXM) of . These semisynthetic glycoconjugate vaccines contain an identical synthetic decasaccharide (M2 motif) antigen. This antigen is present in serotype A strains, which constitute 95% of the clinical cryptococcosis cases. This synthetic oligosaccharide was conjugated to two proteins (CRM197 and Anthrax 63 kDa PA) and tested for immunogenicity in mice. The conjugates elicited a specific antibody response that bound to the M2 motif but also exhibited additional cross-reactivity toward M1 and M4 GXM motifs. Both glycoconjugates produced antibodies that bound to GXM in ELISA assays and to live fungal cells. Mice immunized with the CRM197 glycoconjugate produced weakly opsonic antibodies and displayed trends toward increased median survival relative to mice given a mock PBS injection (18 vs 15 days, = 0.06). These findings indicate promise, achieving a successful vaccine demands further optimization of the glycoconjugate. This antigen could serve as a component in a multivalent GXM motif vaccine.
Topics: Cryptococcus neoformans; Animals; Fungal Vaccines; Mice; Cryptococcosis; Glycoconjugates; Vaccines, Conjugate; Antibodies, Fungal; Female; Polysaccharides; Mice, Inbred BALB C; Bacterial Proteins; Antigens, Fungal
PubMed: 38819951
DOI: 10.1021/acsinfecdis.4c00094 -
Bioelectronic Medicine May 2024Key to the advancement of the field of bioelectronic medicine is the identification of novel pathways of neural regulation of immune function. Sensory neurons (termed...
BACKGROUND
Key to the advancement of the field of bioelectronic medicine is the identification of novel pathways of neural regulation of immune function. Sensory neurons (termed nociceptors) recognize harmful stimuli and initiate a protective response by eliciting pain and defensive behavior. Nociceptors also interact with immune cells to regulate host defense and inflammatory responses. However, it is still unclear whether nociceptors participate in regulating primary IgG antibody responses to novel antigens.
METHODS
To understand the role of transient receptor potential vanilloid 1 (TRPV1)-expressing neurons in IgG responses, we generated TRPV1-Cre/Rosa-ChannelRhodopsin2 mice for precise optogenetic activation of TRPV1 + neurons and TRPV1-Cre/Lox-diphtheria toxin A mice for targeted ablation of TRPV1-expressing neurons. Antigen-specific antibody responses were longitudinally monitored for 28 days.
RESULTS
Here we show that TRPV1 expressing neurons are required to develop an antigen-specific immune response. We demonstrate that selective optogenetic stimulation of TRPV1 nociceptors during immunization significantly enhances primary IgG antibody responses to novel antigens. Further, mice rendered deficient in TRPV1- expressing nociceptors fail to develop primary IgG antibody responses to keyhole limpet hemocyanin or haptenated antigen.
CONCLUSION
This functional and genetic evidence indicates a critical role for nociceptor TRPV1 in antigen-specific primary antibody responses to novel antigens. These results also support consideration of potential therapeutic manipulation of nociceptor pathways using bioelectronic devices to enhance immune responses to foreign antigens.
PubMed: 38807193
DOI: 10.1186/s42234-024-00145-6 -
Journal of Health Economics Jun 2024Childhood vaccinations are among the most cost-effective health interventions. Yet, in India, where immunisation services are widely available free of charge, a... (Randomized Controlled Trial)
Randomized Controlled Trial
Childhood vaccinations are among the most cost-effective health interventions. Yet, in India, where immunisation services are widely available free of charge, a substantial proportion of children remain unvaccinated. We revisit households 30 months after a randomised experiment of a health information intervention designed to educate mothers on the benefits of child vaccination in Uttar Pradesh, India. We find that the large short-term effects on the uptake of diphtheria-pertussis-tetanus and measles vaccination were sustained at 30 months, suggesting the intervention did not simply bring forward vaccinations. We apply causal forests and find that the intervention increased vaccination uptake, but that there was substantial variation in the magnitude of the estimated effects. We conclude that characterising those who benefited most and conversely those who benefited least provides policy-makers with insights on how the intervention worked, and how the targeting of households could be improved.
Topics: Humans; India; Mothers; Female; Infant; Diphtheria-Tetanus-Pertussis Vaccine; Health Education; Child, Preschool; Adult; Male; Vaccination; Immunization Programs; Measles Vaccine
PubMed: 38805881
DOI: 10.1016/j.jhealeco.2024.102899 -
Cureus Apr 2024Background Mortality audit is important for healthcare workers, but this data is lacking in developing countries. It helps to provide material about the cause of death,...
Background Mortality audit is important for healthcare workers, but this data is lacking in developing countries. It helps to provide material about the cause of death, mortality rate, age, and gender. In a surgical department, such information can help identify key public health challenges that are contributing to morbidity and mortality, and this information can help healthcare workers better tackle those pathologies and focus on their prevention and treatment. Materials and methods A retrospective study was conducted at the Department of ENT - Head and Neck Surgery, Pakistan Institute of Medical Sciences Hospital, Islamabad. Five-year data was collected from the mortality register of the ward from January 2019 to December 2023, including the age, gender, surgical diagnosis, course of hospital stay, and cause of death. The collected data was statistically analyzed and presented in the form of tables and figures. Results A total of 53 deaths in 3890 admissions were found on record, with an overall mortality rate of 1.4%. The median age of participants was 61.5 years, with a preponderance of the male gender (n=34; 64.2%). The most common cause of death was head and neck malignancy (n=39; 73.6%), followed by head and neck abscesses (n=9; 17%). The least common cause of death was diphtheria (n=2; 3.8%). Conclusion Death was more common in old-age patients, with more prevalence in the male population. The most common cause of mortality was head and neck malignancy. The total death count almost remained constant through the years.
PubMed: 38800233
DOI: 10.7759/cureus.58869 -
Vaccines Apr 2024Routine vaccination coverage in Latin America and the Caribbean declined prior to and during the coronavirus pandemic. We assessed the pandemic's impact on national...
BACKGROUND
Routine vaccination coverage in Latin America and the Caribbean declined prior to and during the coronavirus pandemic. We assessed the pandemic's impact on national coverage levels and analyzed whether financial and inequality indicators, immunization policies, and pandemic policies were associated with changes in national and regional coverage levels.
METHODOLOGY
We compared first- and third-dose coverage of diphtheria-pertussis-tetanus-containing vaccine (DTPcv) with predicted coverages using time series forecast modeling for 39 LAC countries and territories. Data were from the PAHO/WHO/UNICEF Joint Reporting Form. A secondary analysis of factors hypothesized to affect coverages during the pandemic was also performed.
RESULTS
In total, 31 of 39 countries and territories (79%) had greater-than-predicted declines in DTPcv1 and DTPcv3 coverage during the pandemic, with 9 and 12 of these, respectively, falling outside the 95% confidence interval. Within-country income inequality (i.e., Gini coefficient) was associated with significant declines in DTPcv1 coverage, and cross-country income inequality was associated with declines in DTPcv1 and DTPcv3 coverages. Observed absolute and relative inequality gaps in DTPcv1 and DTPcv3 coverage between extreme country quintiles of income inequality (i.e., Q1 vs. Q5) were accentuated in 2021, as compared with the 2019 observed and 2021 predicted values. We also observed a trend between school closures and greater-than-predicted declines in DTPcv3 coverage that approached statistical significance ( = 0.06).
CONCLUSION
The pandemic exposed vaccination inequities in LAC and significantly impacted coverage levels in many countries. New strategies are needed to reattain high coverage levels.
PubMed: 38793709
DOI: 10.3390/vaccines12050458 -
Microorganisms Apr 2024(1) Background: We aim to systematically review the current evidence on immunity against tetanus, diphtheria, and pertussis in adult solid organ transplantation (SOT)... (Review)
Review
(1) Background: We aim to systematically review the current evidence on immunity against tetanus, diphtheria, and pertussis in adult solid organ transplantation (SOT) recipients, either through natural infection or vaccination. (2) Methods: This systematic review was conducted per PRISMA guidelines. We assessed the risk of bias using the Cochrane RoB 2 and ROBINS-I and summarized the findings narratively due to the heterogeneity of the studies. (3) Results: Of the 315 screened articles, 11 were included. Tetanus immunity varied between 55% and 86%, diphtheria immunity from 23% to 75%, and pertussis immunity was between 46% and 82%. Post-vaccination immunity showed variation across the studies, with some indicating reductions and others no change, with antibody responses influenced by transplanted organs, gender, age, and immunosuppressive regimens. The single randomized study exhibited a low risk of bias, while of the ten non-randomized studies, six showed moderate and four serious risks of bias, necessitating cautious interpretation of results. (4) Conclusions: SOT recipients exhibit considerable immunity against tetanus and diphtheria at transplantation, but this immunity decreases over time. Although vaccination can enhance this immunity, the response may be suboptimal, and the increased antibody levels may not persist, underscoring the need for tailored vaccination strategies in this vulnerable population.
PubMed: 38792678
DOI: 10.3390/microorganisms12050847