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Treatment of post-vaccination optic neuritis: implications from the global SARS-CoV-2 vaccination effort
Get PDFPURPOSE: Optic neuritis (ON) is a rare but treatable side effect of vaccination. The global vaccination effort to SARS-CoV-2 offered a unique chance to study post-vaccination ON. METHODS: A one-year, prospective, multi-center follow-up study by the International Consortium for ON (ICON) in specialized neuro-ophthalmological clinical centers. The pre-specified protocol was confirm with the international consensus diagnostic criteria for making a diagnosis of definite ON. The main outcome measures were speed of treatment initiation, best corrected high contrast visual acuity and retinal asymmetry metrics on optical coherence tomography indicating atrophy. RESULTS: Inclusion of 73 individuals from 15 countries with ON following SARS-CoV-2 vaccination. There were notable differences in characteristics of post-vaccination ON meeting diagnostic criteria compared to pre-COVID19 pandemic incidence studies. These included more frequent bilateral presentation 17/69 (25%) and older age at onset. Post-vaccination ON mostly manifested after the first vaccine dose in 58 individuals (84%). The most frequent (78%) presenting symptom was pain which worsened on eye movements. Twenty-two percent had autoantibodies to MOG and none to AQP4. Initial median visual acuity was logMAR 1.0, improving to logMAR 0.0 at one-year follow-up. Early corticosteroid treatment significantly preserved retinal nerve fiber, macular ganglion cell, and inner nuclear layers compared to later or no treatment. CONCLUSION: Functional visual recovery in post-vaccination ON cases is good. Rapid treatment with corticosteroids provides neuroprotection, underscoring the need for timely intervention. Long-term management depends on presence of autoantibodies
Single-cell multi-omics resolved analysis of mitochondrial genome-wide mutational burden, constraint, and mosaicism
Get PDFMitochondria contain their own circular, multi-copy genome, encoding essential components of the mitochondrial respiratory chain vital for cellular metabolism. Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing has allowed analysis of mtDNA variant heteroplasmy, a holistic view of mtDNA mutational landscapes in individual cells has remained limited, prohibiting the investigation of fundamental questions in mitochondrial genetics. Here, we leverage mitochondrial single-cell ATAC-seq (mtscATAC-seq) and mtDNA-hypermutated POLG(D274A) knock-in HEK293 cell lines to introduce two metrics—single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)—to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLG(D274A) cells are characterized by complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a novel framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism in human tissues
Iterative Bleaching Extends Multiplexity (IBEX) Knowledge-Base
No full textThe Iterative Bleaching Extends Multiplexity (IBEX) imaging method is an iterative immunolabeling and chemical bleaching method that enables highly multiplexed imaging of diverse tissues. Development of the IBEX method and related software was led by Dr. Andrea Radtke and Dr. Ziv Yaniv. IBEX and related methods, Ce3D, Ce3D-IBEX, Opal-plex, were originally developed in the laboratory of Dr. Ronald N. Germain, US National Institutes of Health. The IBEX Imaging Community is an international group of scientists committed to sharing knowledge related to multiplexed imaging in a transparent and collaborative manner. This open, global repository is a central resource for reagents, protocols, panels, publications, software, and datasets. In addition to IBEX, we support standard, single cycle multiplexed imaging (Multiplexed 2D imaging), volume imaging of cleared tissues with clearing enhanced 3D (Ce3D), highly multiplexed 3D imaging (Ce3D-IBEX), and extension of the IBEX dye inactivation protocol to the Leica Cell DIVE (Cell DIVE-IBEX). This dataset contains the current state of knowledge with respect to the IBEX microscopy imaging protocol. How to use the Knowledge-Base: Save a copy to your computer. To find a reagent: Open the reagent_resources.csv file found in the data directory. Use a spreadsheet application to filter the columns based on target name, target species, vendor, etc. To view a complete list of fluorescent probes tested by the IBEX imaging community: Open the fluorescent_probes.csv file. This file reports the spectral properties and inactivation conditions of each fluorescent probe. To import publications cited in the Knowledge-Base, import the publications.bib file found in the data directory to your reference manager. To view a local copy of the website: Open the index.md file found in the docs directory using a markdown editor such as the free Visual Studio Code. To view supporting information for a reagent (images, publications, notes): Open a specific target-conjugate-orcid combination under the docs-supporting_material directory structure using a markdown editor. This can also be visualized from the Reagent Resources page and filtered using a catalog number or other unique identifier in your web browser. Join the online IBEX Imaging community and contribute your knowledge. For more details on how to contribute, see these instructions. This research was supported by: The Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases and National Cancer Institute, under grants 1ZIAAI001290-02, 1ZIAAI000545-33, 1ZIAAI000758-24, 1ZIAAI000974-16, 1ZIAAI001034-14. The Wellcome Trust, under grant 224586/Z/21/Z. The National Institute of Allergy and Infectious Diseases, NIH, under grant 1ZIAAI001343-01
Permeabilized cardiomyocytes passive force measurement
No full textPassive force measurement in cardiomyocytes isolated from 2 hit mice (2025-05-15
Stress CMR perfusion imaging in the medicare-eligible population: insights from the SPINS study
No full textBACKGROUND: Patients aged =65 years account for a disproportionately large portion of cardiovascular (CV) events and pose a challenge for noninvasive detection of coronary artery disease. OBJECTIVES: This study sought to determine the prognostic value of stress cardiac magnetic resonance (CMR) in a Medicare-eligible group of patients in a multicenter setting in the United States. METHODS: From a multicenter U.S. registry, the study identified patients aged =65 years who were referred for stress CMR for evaluation of myocardial inducible ischemia. The primary outcome was defined as CV death or nonfatal myocardial infarction, whereas the secondary outcome was defined as any primary outcome, hospitalization for unstable angina, hospitalization for congestive heart failure, and unplanned late coronary artery bypass grafting. The associations of CMR findings with CV outcomes adjusted to clinical risk markers and health care cost spending were determined. RESULTS: Among 1,780 patients (aged 73 ± 5.7 years; 46% female), study investigators observed 144 primary events and 323 secondary events, over a median follow-up of 4.8 years. The presence of inducible ischemia and late gadolinium enhancement (LGE) was associated with incrementally higher event rates. Patients with neither inducible ischemia nor LGE experienced a <1% annualized rate of primary outcome. In a multivariable model adjusted for CV risk factors, inducible ischemia and LGE maintained an independent association with primary (HR: 2.80 [95% CI: 1.93-4.05]; P < 0.001; and HR: 1.85 [95% CI: 1.21-2.82]; P = 0.004, respectively) and secondary (HR: 2.46 [95% CI: 1.90-3.19]; P < 0.001; and HR: 1.72 [95% CI: 1.30-2.27]; P < 0.001, respectively) outcomes. Rates of revascularization, as well as downstream costs for patients without CMR-detected inducible ischemia, remained low throughout the follow-up period. CONCLUSIONS: In a multicenter cohort of Medicare-eligible older patients, stress CMR was effective in providing risk stratification. (Stress CMR Perfusion Imaging in the United States [SPINS] study; NCT03192891)
Beyond hemoglobin: critical role of 2,3-bisphosphoglycerate mutase in kidney function and injury
Get PDFAIM: 2,3-bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney. METHODS: A tubular-specific, doxycycline-inducible Bpgm-knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. In vitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress. RESULTS: BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. In vitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules. CONCLUSION: BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury
Deep learning-based whole-brain B(1)(+)-mapping at 7T
Get PDFPURPOSE: This study investigates the feasibility of using complex-valued neural networks (NNs) to estimate quantitative transmit magnetic RF field (B(1)(+)) maps from multi-slice localizer scans with different slice orientations in the human head at 7T, aiming to accelerate subject-specific B(1)(+)-calibration using parallel transmission (pTx). METHODS: Datasets containing channel-wise B(1)(+)-maps and corresponding multi-slice localizers were acquired in axial, sagittal, and coronal orientation in 15 healthy subjects utilizing an eight-channel pTx transceiver head coil. Training included five-fold cross-validation for four network configurations: NN(tra)(cx) used transversal, NN(sag)(cx) sagittal, NN(cor)(cx) coronal data, and NN(all)(cx) was trained on all slice orientations. The resulting maps were compared to B(1)(+)-reference scans using different quality metrics. The proposed network was applied in-vivo at 7T in two unseen test subjects using dynamic kt-point pulses. RESULTS: Predicted B(1)(+)-maps demonstrated a high similarity with measured B(1)(+)-maps across multiple orientations. The estimation matched the reference with a mean relative error in the magnitude of (2.70 ± 2.86)% and mean absolute phase difference of (6.70 ± 1.99)° for transversal, (1.82 ± 0.69)% and (4.25 ± 1.62)° for sagittal (NN(sag)(cx)), as well as (1.33 ± 0.27)% and (2.66 ± 0.60)° for coronal slices (NN(cor)(cx)) considering brain tissue. NN(all)(cx) trained on all orientations enables a robust prediction of B(1)(+)-maps across different orientations. Achieving a homogenous excitation over the whole brain for an in-vivo application displayed the approach's feasibility. CONCLUSION: This study demonstrates the feasibility of utilizing complex-valued NNs to estimate multi-slice B(1)(+)-maps in different slice orientations from localizer scans in the human brain at 7T
Transgenic rat with ubiquitous expression of angiotensin-(1-7)-producing fusion protein: a new tool to study the role of protective arm of the renin-angiotensin system in the pathophysiology of cardio-renal diseases
Get PDFThe aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT(1) and AT(2)) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT(1), AT(2) and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases
Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations
Get PDFThe microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease
Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus
Get PDFThe gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration