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Developmental Cell Jul 2023Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries...
Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFP/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic in vivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6.
Topics: Mice; Animals; Astrocytes; Interleukin-6; Glial Fibrillary Acidic Protein; Oligodendroglia; Mice, Transgenic; Brain Injuries
PubMed: 37220747
DOI: 10.1016/j.devcel.2023.04.016 -
The New England Journal of Medicine Sep 2023
PubMed: 37754301
DOI: 10.1056/NEJMc2308776 -
Scientific Reports Nov 2023To investigate the clinical and molecular characteristics and evolution of the Zika virus (ZIKV) in Thailand from March 2020 to March 2023. In all, 751 serum samples...
To investigate the clinical and molecular characteristics and evolution of the Zika virus (ZIKV) in Thailand from March 2020 to March 2023. In all, 751 serum samples from hospitalized patients in Bangkok and the surrounding areas were screened for ZIKV using real-time RT-PCR. Demographic data and clinical variables were evaluated. Phylogenetic and molecular clock analysis determined the genetic relationships among the ZIKV strains, emergence timing, and their molecular characteristics. Among the 90 confirmed ZIKV cases, there were no significant differences in infection prevalence when comparing age groups and sexes. Rash was strongly associated with ZIKV infection. Our ZIKV Thai isolates were categorized into two distinct clades: one was related to strains from Myanmar, Vietnam, Oceania, and various countries in the Americas, and the other was closely related to previously circulating strains in Thailand, one of which shared a close relation to a neurovirulent ZIKV strain from Cambodia. Moreover, ZIKV Thai strains could be further classified into multiple sub-clades, each exhibiting specific mutations suggesting the genetic diversity among the circulating strains of ZIKV in Thailand. Understanding ZIKV epidemiology and genetic diversity is crucial for tracking the virus's evolution and adapting prevention and control strategies.
Topics: Humans; Zika Virus Infection; Zika Virus; Phylogeny; Thailand; Molecular Epidemiology
PubMed: 38030715
DOI: 10.1038/s41598-023-48508-4 -
Redox Biology Dec 2023Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant...
Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability. Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.
Topics: Humans; Ferroptosis; Selenium; Pancreas; Pancreatic Neoplasms; Lipid Peroxidation
PubMed: 38029455
DOI: 10.1016/j.redox.2023.102962 -
Pathologie (Heidelberg, Germany) Mar 2024With the advancements in precision medicine, the demands on pathological diagnostics have increased, requiring standardized, quantitative, and integrated assessments of... (Review)
Review
With the advancements in precision medicine, the demands on pathological diagnostics have increased, requiring standardized, quantitative, and integrated assessments of histomorphological and molecular pathological data. Great hopes are placed in artificial intelligence (AI) methods, which have demonstrated the ability to analyze complex clinical, histological, and molecular data for disease classification, biomarker quantification, and prognosis estimation. This paper provides an overview of the latest developments in pathology AI, discusses the limitations, particularly concerning the black box character of AI, and describes solutions to make decision processes more transparent using methods of so-called explainable AI (XAI).
Topics: Artificial Intelligence; Pathology, Molecular; Hope; Precision Medicine
PubMed: 38315198
DOI: 10.1007/s00292-024-01308-7 -
Progress in Neuro-psychopharmacology &... Dec 2023Alzheimer's disease (AD) is often not recognized or is diagnosed very late, which significantly reduces the effectiveness of available pharmacological treatments....
Alzheimer's disease (AD) is often not recognized or is diagnosed very late, which significantly reduces the effectiveness of available pharmacological treatments. Metabolomic analyzes have great potential for improving existing knowledge about the pathogenesis and etiology of AD and represent a novel approach towards discovering biomarkers that could be used for diagnosis, prognosis, and therapy monitoring. In this study, we applied the untargeted metabolomic approach to investigate the changes in biochemical pathways related to AD pathology. We used gas chromatography and liquid chromatography coupled to mass spectrometry (GC-MS and LC-MS, respectively) to identify metabolites whose levels have changed in subjects with AD diagnosis (N = 40) compared to healthy controls (N = 40) and individuals with mild cognitive impairment (MCI, N = 40). The GC-MS identified significant differences between groups in levels of metabolites belonging to the classes of benzene and substituted derivatives, carboxylic acids and derivatives, fatty acyls, hydroxy acids and derivatives, keto acids and derivatives, and organooxygen compounds. Most of the compounds identified by the LC-MS were various fatty acyls, glycerolipids and glycerophospholipids. All of these compounds were decreased in AD patients and in subjects with MCI compared to healthy controls. The results of the study indicate disturbed metabolism of lipids and amino acids and an imbalance of metabolites involved in energy metabolism in individuals diagnosed with AD, compared to healthy controls and MCI subjects.
Topics: Humans; Alzheimer Disease; Metabolomics; Metabolome; Mass Spectrometry; Biomarkers
PubMed: 37454721
DOI: 10.1016/j.pnpbp.2023.110830 -
Pathologie (Heidelberg, Germany) Dec 2023Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered... (Review)
Review
Primary vitreoretinal lymphoma (PVRL) represents a subtype of intraocular lymphomas, which are a subgroup of malignant lymphomas of the eye. PVRL is considered a special form of primary diffuse large cell lymphoma (DLBCL) of the CNS (central nervous system) (PCNSL) and arises primary or secondary to PCNSL. According to the cell of origin (COO) classification of DLBCL, PVRL largely belongs to the activated B‑cell (ABC) type of DLBCL. Based on a recently established genetic-biological classification of DLBCL, PCNSL and thus also PVRL belong to a group of DLBCL of the MYD88/CD79B-mutated (MCD) or cluster 5 subtype, which often shows extranodal manifestations and MYD88 and CD79A mutations as well as CDKN2A deletions.PVRL diagnostics is often complicated as it represents a classic masquerade syndrome. Due to the usually limited material with often large numbers of reactive lymphocytes and/or degenerative changes in the cells, the results of diagnostic tests are difficult to interpret. Classic diagnostic tests include cytology on vitreous aspirates, immunocytochemistry, and clonality analysis.New insights into the spectrum of genetic alterations of vitreoretinal lymphomas (VRL) confirm the close relationship to PCNSL and could significantly improve pathological diagnosis. Next-generation sequencing panel-based diagnostics allow VRL diagnosis confirmation with little DNA in almost 100% of patients in cases with insufficient cytological evidence or lack of clonality detection. PVRL, as well as secondary vitreoretinal lymphomas after PCNSL or extracerebral DLBCL, have high mutation frequencies in characteristically mutated genes in PCNSL or MCD/cluster 5 type DLBCL. Supporting diagnostics, mutation detection can also be performed on cell-free DNA from the vitreous supernatant.
Topics: Humans; Retinal Neoplasms; Myeloid Differentiation Factor 88; Pathology, Molecular; Vitreous Body; Eye Neoplasms; Lymphoma, Large B-Cell, Diffuse; Central Nervous System Neoplasms
PubMed: 37947807
DOI: 10.1007/s00292-023-01251-z -
Virchows Archiv : An International... Feb 2024With the explosion in knowledge about the molecular landscape of lymphoid malignancies and the increasing availability of high throughput techniques, molecular... (Review)
Review
With the explosion in knowledge about the molecular landscape of lymphoid malignancies and the increasing availability of high throughput techniques, molecular diagnostics in hematopathology has moved from isolated marker studies to a more comprehensive approach, integrating results of multiple genes analyzed with a variety of techniques on the DNA and RNA level. Although diagnosis of lymphoma still relies on the careful integration of clinical, morphological, phenotypic, and, if necessary molecular features, and only few entities are defined strictly by genetic features, genetic profiling has contributed profoundly to our current understanding of lymphomas and shaped the two current lymphoma classifications, the International Consensus Classification and the fifth edition of the WHO classification of lymphoid malignancies. In this review, the current state of the art of molecular diagnostics in lymphoproliferations is summarized, including clonality analysis, mutational studies, and gene expression profiling, with a focus on practical applications for diagnosis and prognostication. With consideration for differences in accessibility of high throughput techniques and cost limitations, we tried to distinguish between diagnostically relevant and in part disease-defining molecular features and optional, more extensive genetic profiling, which is usually restricted to clinical studies, patients with relapsed or refractory disease or specific therapeutic decisions. Although molecular diagnostics in lymphomas currently is primarily done for diagnosis and subclassification, prognostic stratification and predictive markers will gain importance in the near future.
Topics: Humans; Pathology, Molecular; Prognosis; Lymphoma; Gene Expression Profiling; Mutation
PubMed: 37747559
DOI: 10.1007/s00428-023-03644-0 -
Diagnostic Microbiology and Infectious... Jul 2023Carbapenem-resistant Klebsiella pneumoniae (CRKP) is emerging as a worldwide public health concern; however, molecular epidemiological surveillance of clinical CRKP...
PURPOSE
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is emerging as a worldwide public health concern; however, molecular epidemiological surveillance of clinical CRKP bloodstream infection (BSI) in China is limited. We conducted a retrospective observational study to assess risk factors and the molecular epidemiology of CRKP BSI.
METHODS
We reviewed the medical records of enrolled patients to assess risk factors of CRKP BSI. Characteristics of CRKP isolates were analyzed by whole genome sequencing and Kleborate. Evolutionary diversification in CRKP isolates was described through Single Nucleotide Polymorphisms analysis and phylogenetic tree construction.
RESULTS
We found that prior ICU hospitalization and use of carbapenems were independent risk factors for CRKP BSI. The main CRKP sequence type (ST) and capsular serotype were ST11 and KL64, and KPC-2 was the most prevalent enzyme type of carbapenemase-carrying Klebsiella pneumoniae. The most prevalent aerobactin and yersiniabactin of ST11-CRKP were iuc-1 and ybt9 ICEKp3, as for KL64-CRKP. Phylogenomic analysis showed that the antibacterial resistance genes on plasmids were highly consistent, but the genetic background of the chromosomes was still different.
CONCLUSIONS
Our findings are important for hospitals, allowing them to limit dissemination of CRKP and optimize antibiotic administration.
Topics: Humans; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Klebsiella Infections; Klebsiella pneumoniae; Molecular Epidemiology; Multilocus Sequence Typing; Observational Studies as Topic; Phylogeny; Risk Factors; Sepsis
PubMed: 37167651
DOI: 10.1016/j.diagmicrobio.2023.115955 -
JAMA Pediatrics Nov 2023Currently, the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) for short stature cohorts is uncertain. Despite previous studies...
IMPORTANCE
Currently, the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) for short stature cohorts is uncertain. Despite previous studies reporting the widespread use of ES and CMA, a definitive diagnostic yield has not been established.
OBJECTIVE
To investigate the diagnostic yield of ES and CMA in short stature.
DATA SOURCES
A systematic literature search was conducted using relevant keywords in 3 databases (PubMed, Embase, and Web of Science) in February 2023.
STUDY SELECTION
Eligible studies for meta-analysis were those that had at least 10 participants with short stature who were diagnosed using either ES or CMA and the number of diagnosed patients was reported. Of 5222 identified studies, 20 were eventually included in the study.
DATA EXTRACTION AND SYNTHESIS
Two independent investigators extracted relevant information from each study, which was then synthesized using proportional meta-analysis to obtain the overall diagnostic yield of ES and CMA.
MAIN OUTCOMES AND MEASURES
The primary outcome measure was to determine the overall diagnostic yield of ES and CMA. A subgroup meta-analysis was also performed to assess if the diagnostic yield varied depending on whether ES was used as a first-tier or last-resort test. Additionally, a meta-regression was carried out to investigate how the diagnostic yield varied over time.
RESULTS
Twenty studies were included, comprising 1350 patients with short stature who underwent ES and 1070 patients who completed CMA. The overall diagnostic yield of ES among the cohorts and CMA among the cohorts was found to be 27.1% (95% CI, 18.1%-37.2%) and 13.6% (95% CI, 9.2%-18.7%), respectively. No statistically significant difference was observed between the first-tier (27.8%; 95% CI, 15.7%-41.8%) and last-resort groups (25.6%; 95% CI, 13.6%-39.6%) (P = .83) or in the percentage of positively diagnosed patients over time. No statistically significant difference was observed between the first-tier (27.8%; 95% CI, 15.7%-41.8%) and last-resort groups (25.6%; 95% CI, 13.6%-39.6%) (P = .83) or in the percentage of positively diagnosed patients over time.
CONCLUSION AND RELEVANCE
This systematic review and meta-analysis provides high-level evidence supporting the diagnostic efficacy of ES and CMA in patients with short stature. The findings serve as a solid reference for clinicians when making informed decisions about recommending these genetic tests.
Topics: Humans; Exome Sequencing; Pathology, Molecular; Genetic Testing; Microarray Analysis
PubMed: 37695591
DOI: 10.1001/jamapediatrics.2023.3566