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Mucosal Immunology Jun 2024Mycobacterium tuberculosis- (Mtb) infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils...
Mycobacterium tuberculosis- (Mtb) infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that IFNγ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb, and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.
PubMed: 38844208
DOI: 10.1016/j.mucimm.2024.05.007 -
Scientific Reports Jun 2024One of the most recent advances in the genome editing field has been the addition of "TALE Base Editors", an innovative platform for cell therapy that relies on the...
One of the most recent advances in the genome editing field has been the addition of "TALE Base Editors", an innovative platform for cell therapy that relies on the deamination of cytidines within double strand DNA, leading to the formation of an uracil (U) intermediate. These molecular tools are fusions of transcription activator-like effector domains (TALE) for specific DNA sequence binding, split-DddA deaminase halves that will, upon catalytic domain reconstitution, initiate the conversion of a cytosine (C) to a thymine (T), and an uracil glycosylase inhibitor (UGI). We developed a high throughput screening strategy capable to probe key editing parameters in a precisely defined genomic context in cellulo, excluding or minimizing biases arising from different microenvironmental and/or epigenetic contexts. Here we aimed to further explore how target composition and TALEB architecture will impact the editing outcomes. We demonstrated how the nature of the linker between TALE array and split DddAtox head allows us to fine tune the editing window, also controlling possible bystander activity. Furthermore, we showed that both the TALEB architecture and spacer length separating the two TALE DNA binding regions impact the target TC editing dependence by the surrounding bases, leading to more restrictive or permissive editing profiles.
Topics: Gene Editing; Humans; Cytosine; Thymine; Transcription Activator-Like Effectors; DNA; HEK293 Cells
PubMed: 38834632
DOI: 10.1038/s41598-024-63203-8 -
Journal of Korean Medical Science Jun 2024Lessons learned from the Household Humidifier Disinfectant Tragedy (HHDT) in Korea, which poisoned thousands of citizens over a period of years, necessitated an... (Review)
Review
BACKGROUND
Lessons learned from the Household Humidifier Disinfectant Tragedy (HHDT) in Korea, which poisoned thousands of citizens over a period of years, necessitated an examination of national poison prevention and surveillance systems. The objectives of this study are to identify essential changes needed in chemical poisoning prevention regulations and surveillance systems for effective poison control by comparing recent trends in international poison control center (PCC) operations, and to delineate the critical elements for establishing a state-of-the-art poison control surveillance system in Korea based on recent advances in PCCs with toxicovigilance.
METHODS
A comprehensive review of Korea's regulatory and surveillance systems for chemical health hazards, with a focus on household products under the HHDT, was conducted. A review of toxicovigilance systems in major countries shows that creating an effective national PCC requires key elements: a centralized database of toxic substances and poisoning cases, mandatory or voluntary reporting of poisoning cases, real-time alerts, collaboration among health organizations, and targeted follow-up of poisoned individuals.
RESULTS
Significant deficiencies in Korea's legislation, toxicological data management, and poisoning surveillance systems, explained the inadequate response of the Korean government to the HHDT for nearly 17 years until the end of 2011. Based on a review of PCC toxicovigilance systems in major countries, a national framework with five core components is recommended for establishing a modern comprehensive Korea PCC system with toxicovigilance capacity. The core components include establishment of a centralized database of toxic substances information and clinical poisoning cases, implementation of mandatory or permissive reporting of poisoning cases, real-time alert mechanisms, collaborative systems among health-related organizations, and clinical follow-up of poisoned sub-groups.
CONCLUSION
A rationale and framework for a state-of-the-art national Korean PCC with toxicovigilance is justified and offered. This proposed system could assist neighboring countries in establishing their own sophisticated, globally integrated PCC networks.
Topics: Humans; Republic of Korea; Disinfectants; Humidifiers; Poisoning; Poison Control Centers
PubMed: 38832480
DOI: 10.3346/jkms.2024.39.e178 -
Journal of Virology Jun 2024Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, is prevalent in natural reservoir pigs and infects mice. This raises concerns...
Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, is prevalent in natural reservoir pigs and infects mice. This raises concerns about host jumping or spillover, but little is known about the cause of occurrence. Here, we revealed that dipeptidyl peptidase 4 (DPP4) is a candidate binding target of PHEV spikes and works as a broad barrier to overcome. Investigations of the host breadth of PHEV confirmed that cells derived from pigs and mice are permissive to virus propagation. Both porcine DPP4 and murine DPP4 have high affinity for the viral spike receptor-binding domain (RBD), independent of their catalytic activity. Loss of DPP4 expression results in limited PHEV infection. Structurally, PHEV spike protein binds to the outer surface of blades IV and V of the DPP4 β-propeller domain, and the DPP4 residues N229 and N321 (relative to human DPP4 numbering) participate in RBD binding via its linked carbohydrate entities. Removal of these -glycosylations profoundly enhanced the RBD-DPP4 interaction and viral invasion, suggesting they act as shielding in PHEV infection. Furthermore, we found that glycosylation, rather than structural differences or surface charges, is more responsible for DPP4 recognition and species barrier formation. Overall, our findings shed light on virus-receptor interactions and highlight that PHEV tolerance to DPP4 orthologs is a putative determinant of its cross-species transmission or host range expansion.IMPORTANCEPHEV is a neurotropic betacoronavirus that is circulating worldwide and has raised veterinary and economic concerns. In addition to being a reservoir species of pigs, PHEV can also infect wild-type mice, suggesting a "host jump" event. Understanding cross-species transmission is crucial for disease prevention and control but remains to be addressed. Herein, we show that the multifunctional receptor DPP4 plays a pivotal role in the host tropism of PHEV and identifies the conserved glycosylation sites in DPP4 responsible for this restriction. These findings highlight that the ability of PHEV to utilize DPP4 orthologs potentially affects its natural host expansion.
PubMed: 38829136
DOI: 10.1128/jvi.00753-24 -
Aging Cell Jun 2024Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along...
Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo-1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.
PubMed: 38825882
DOI: 10.1111/acel.14197 -
BMC Public Health May 2024Mental health problems among adolescents is a global challenge. During the transition to adolescence, physiological, psychological, and social changes occur, leading to...
BACKGROUND
Mental health problems among adolescents is a global challenge. During the transition to adolescence, physiological, psychological, and social changes occur, leading to increased vulnerability. Thus, adolescent boys are less likely to seek help for mental health problems, which makes them an undetected group. The aim of this study was to gain a deeper understanding of adolescent boys' experiences of mental health and school health service.
METHODS
An inductive, qualitative design was chosen using three focus group interviews and three individual interviews. The study included 18 adolescent boys in 7th grade, in a school located in a medium-sized municipality in Norway. The interviews were analysed with qualitative content analysis. The consolidated criteria for reporting qualitative research (COREQ) were followed in this study.
RESULTS
The overall theme "barriers towards seeking help", and three categories- navigating stigma and privacy concerns; perceptions of self-responsibility; and lacking knowledge of mental health problems and help-seeking-described the adolescent boys experiences. The awareness and willingness to seek help were present, but there are barriers preventing the adolescent boys from acting on that willingness.
CONCLUSIONS
Lack of knowledge and a non-permissive culture for mental health problems among adolescents contributes to decreased help-seeking behaviour among adolescent boys. The school health service is the most related health service for adolescents and should focus on being available and strengthening empowerment and mental health literacy through the development and implementation of interventions to promote mental health.
Topics: Humans; Male; Norway; Adolescent; Qualitative Research; Focus Groups; School Health Services; Interviews as Topic; Mental Health Services; Patient Acceptance of Health Care; Social Stigma; Health Knowledge, Attitudes, Practice; Mental Disorders
PubMed: 38822302
DOI: 10.1186/s12889-024-18952-6 -
Nature Communications May 2024Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic...
Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic long-term potentiation or plays a permissive role in determining the impact of synaptic weight increase. We use tactile stimulation and electrical activation of parallel fibers to probe intrinsic and synaptic contributions to receptive field plasticity in awake mice during two-photon calcium imaging of cerebellar Purkinje cells. Repetitive activation of both stimuli induced response potentiation that is impaired in mice with selective deficits in either synaptic or intrinsic plasticity. Spatial analysis of calcium signals demonstrated that intrinsic, but not synaptic plasticity, enhances the spread of dendritic parallel fiber response potentiation. Simultaneous dendrite and axon initial segment recordings confirm these dendritic events affect axonal output. Our findings support the hypothesis that intrinsic plasticity provides an amplification mechanism that exerts a permissive control over the impact of long-term potentiation on neuronal responsiveness.
Topics: Animals; Purkinje Cells; Mice; Neuronal Plasticity; Cerebellum; Long-Term Potentiation; Dendrites; Synapses; Calcium; Male; Axons; Mice, Inbred C57BL; Electric Stimulation; Female
PubMed: 38821918
DOI: 10.1038/s41467-024-48373-3 -
Frontiers in Medicine 2024The open-source software offered by the Observational Health Data Science and Informatics (OHDSI) collective, including the OMOP-CDM, serves as a major backbone for many...
INTRODUCTION
The open-source software offered by the Observational Health Data Science and Informatics (OHDSI) collective, including the OMOP-CDM, serves as a major backbone for many real-world evidence networks and distributed health data analytics platforms. While container technology has significantly simplified deployments from a technical perspective, regulatory compliance can remain a major hurdle for the setup and operation of such platforms. In this paper, we present OHDSI-Compliance, a comprehensive set of document templates designed to streamline the data protection and information security-related documentation and coordination efforts required to establish OHDSI installations.
METHODS
To decide on a set of relevant document templates, we first analyzed the legal requirements and associated guidelines with a focus on the General Data Protection Regulation (GDPR). Moreover, we analyzed the software architecture of a typical OHDSI stack and related its components to the different general types of concepts and documentation identified. Then, we created those documents for a prototypical OHDSI installation, based on the so-called Broadsea package, following relevant guidelines from Germany. Finally, we generalized the documents by introducing placeholders and options at places where individual institution-specific content will be needed.
RESULTS
We present four documents: (1) a record of processing activities, (2) an information security concept, (3) an authorization concept, as well as (4) an operational concept covering the technical details of maintaining the stack. The documents are publicly available under a permissive license.
DISCUSSION
To the best of our knowledge, there are no other publicly available sets of documents designed to simplify the compliance process for OHDSI deployments. While our documents provide a comprehensive starting point, local specifics need to be added, and, due to the heterogeneity of legal requirements in different countries, further adoptions might be necessary.
PubMed: 38818399
DOI: 10.3389/fmed.2024.1378866 -
iGATE analysis improves the interpretability of single-cell immune landscape of influenza infection.JCI Insight May 2024Influenza poses a persistent health burden worldwide. To design equitable vaccines effective across all demographics, it is essential to better understand how host...
Influenza poses a persistent health burden worldwide. To design equitable vaccines effective across all demographics, it is essential to better understand how host factors such as genetic background and aging affect the single-cell immune landscape of influenza infection. Cytometry by time-of-flight (CyTOF) represents a promising technique in this pursuit, but interpreting its large, high-dimensional data remains difficult. We have developed a new analytical approach, in silico gating annotating training elucidating (iGATE), based on probabilistic support vector machine classification. By rapidly and accurately "gating" tens of millions of cells in silico into user-defined types, iGATE enabled us to track 25 canonical immune cell types in mouse lung over the course of influenza infection. Applying iGATE to study effects of host genetic background, we show that the lower survival of C57BL/6 mice compared with BALB/c was associated with a more rapid accumulation of inflammatory cell types and decreased IL-10 expression. Furthermore, we demonstrate that the most prominent effect of aging is a defective T cell response, reducing survival of aged mice. Finally, iGATE reveals that the 25 canonical immune cell types exhibited differential influenza infection susceptibility and replication permissiveness in vivo, but neither property varied with host genotype or aging. The software is available at https://github.com/UmichWenLab/iGATE.
Topics: Animals; Mice; Orthomyxoviridae Infections; Single-Cell Analysis; Mice, Inbred C57BL; Mice, Inbred BALB C; Lung; Influenza, Human; Humans; Disease Models, Animal; Aging; Flow Cytometry; T-Lymphocytes; Computer Simulation
PubMed: 38814732
DOI: 10.1172/jci.insight.172140 -
Mayo Clinic Proceedings. Innovations,... Jun 2024Behavior change is the foundation for effective lifestyle prescriptions, yet such change is individualized, nonlinear and typically requires ongoing support. Health and...
Behavior change is the foundation for effective lifestyle prescriptions, yet such change is individualized, nonlinear and typically requires ongoing support. Health and wellness coaching (HWC) is a behavior change intervention with rapidly accruing evidence of positive impact on health behaviors such as exercise, nutrition and stress management. Furthermore, HWC enhances prevention and mitigates exacerbation of chronic lifestyle diseases, at least in the short-term (up to 6 months post intervention). Although the impact on long-term stability of behavior change remains unclear, it is evident that effective partnering with patients using key communication strategies, autonomy promotion, and flexible permissiveness can empower patients to develop healthy lifestyles. This partnership can be cultivated by clinicians as well as clinical team members including nationally board-certified coaches. Although much research is needed regarding the ongoing maintenance of lifestyle changes beyond 6 months, this article seeks to equip clinicians with current evidence, theoretical insights and practical strategies from a "coach approach" to foster more intrinsic forms of motivation which, in turn, empowers patients to adopt and maintain health-promoting behaviors.
PubMed: 38807973
DOI: 10.1016/j.mayocpiqo.2023.10.002