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  • 1
    Online Resource
    Online Resource
    The centrosomal protein 83 (CEP83) regulates human pluripotent stem cell differentiation toward the kidney lineage
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-10-12)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-10-12)
    Abstract: During embryonic development, the mesoderm undergoes patterning into diverse lineages including axial, paraxial, and lateral plate mesoderm (LPM). Within the LPM, the so-called intermediate mesoderm (IM) forms kidney and urogenital tract progenitor cells, while the remaining LPM forms cardiovascular, hematopoietic, mesothelial, and additional progenitor cells. The signals that regulate these early lineage decisions are incompletely understood. Here, we found that the centrosomal protein 83 (CEP83), a centriolar component necessary for primary cilia formation and mutated in pediatric kidney disease, influences the differentiation of human-induced pluripotent stem cells (hiPSCs) toward IM. We induced inactivating deletions of CEP83 in hiPSCs and applied a 7-day in vitro protocol of IM kidney progenitor differentiation, based on timed application of WNT and FGF agonists. We characterized induced mesodermal cell populations using single-cell and bulk transcriptomics and tested their ability to form kidney structures in subsequent organoid culture. While hiPSCs with homozygous CEP83 inactivation were normal regarding morphology and transcriptome, their induced differentiation into IM progenitor cells was perturbed. Mesodermal cells induced after 7 days of monolayer culture of CEP83 -deficient hiPCS exhibited absent or elongated primary cilia, displayed decreased expression of critical IM genes ( PAX8 , EYA1 , HOXB7 ), and an aberrant induction of LPM markers (e.g. FOXF1 , FOXF2 , FENDRR , HAND1 , HAND2 ). Upon subsequent organoid culture, wildtype cells differentiated to form kidney tubules and glomerular-like structures, whereas CEP83 -deficient cells failed to generate kidney cell types, instead upregulating cardiomyocyte, vascular, and more general LPM progenitor markers. Our data suggest that CEP83 regulates the balance of IM and LPM formation from human pluripotent stem cells, identifying a potential link between centriolar or ciliary function and mesodermal lineage induction.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.80165
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
    detail.hit.zdb_id: 2687154-3
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  • 2
    Online Resource
    Online Resource
    Lateral thinking in syndromic congenital cardiovascular disease
    The Company of Biologists ; 2023
    In:  Disease Models & Mechanisms Vol. 16, No. 5 ( 2023-05-01)
    Details
    In: Disease Models & Mechanisms, The Company of Biologists, Vol. 16, No. 5 ( 2023-05-01)
    Abstract: Syndromic birth defects are rare diseases that can present with seemingly pleiotropic comorbidities. Prime examples are rare congenital heart and cardiovascular anomalies that can be accompanied by forelimb defects, kidney disorders and more. Whether such multi-organ defects share a developmental link remains a key question with relevance to the diagnosis, therapeutic intervention and long-term care of affected patients. The heart, endothelial and blood lineages develop together from the lateral plate mesoderm (LPM), which also harbors the progenitor cells for limb connective tissue, kidneys, mesothelia and smooth muscle. This developmental plasticity of the LPM, which founds on multi-lineage progenitor cells and shared transcription factor expression across different descendant lineages, has the potential to explain the seemingly disparate syndromic defects in rare congenital diseases. Combining patient genome-sequencing data with model organism studies has already provided a wealth of insights into complex LPM-associated birth defects, such as heart-hand syndromes. Here, we summarize developmental and known disease-causing mechanisms in early LPM patterning, address how defects in these processes drive multi-organ comorbidities, and outline how several cardiovascular and hematopoietic birth defects with complex comorbidities may be LPM-associated diseases. We also discuss strategies to integrate patient sequencing, data-aggregating resources and model organism studies to mechanistically decode congenital defects, including potentially LPM-associated orphan diseases. Eventually, linking complex congenital phenotypes to a common LPM origin provides a framework to discover developmental mechanisms and to anticipate comorbidities in congenital diseases affecting the cardiovascular system and beyond.
    Type of Medium: Online Resource
    ISSN: 1754-8403 , 1754-8411
    URL: Article
    DOI: 10.1242/dmm.049735
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2023
    detail.hit.zdb_id: 2451104-3
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  • 3
    Online Resource
    Online Resource
    Bailout stentectomy of 47 self-expandable intracranial stents
    BMJ ; 2022
    In:  Journal of NeuroInterventional Surgery Vol. 14, No. 2 ( 2022-02), p. 160-163
    Details
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 14, No. 2 ( 2022-02), p. 160-163
    Abstract: Self-expanding stents are increasingly being deployed for stent-assisted coiling or flow diversion of intracranial aneurysms. Complications related to stent misbehavior may arise, however, including lack of expansion, device displacement, or parent vessel thrombosis. We present our experience of various stent removal techniques (stentectomy) with a focus on technical and clinical outcomes. Methods Stentectomy was attempted either with a single device, including the Alligator, Microsnare, or Solitaire, or by combining a Microsnare with a second device. Dual techniques included in this report are the Snare-over-Stentretriever technique we developed using a Microsnare and a Solitaire, and the previously described Loop-and-Snare technique using a Microsnare and a microwire. The technical success and complication rate, as well as the clinical outcome using the mRS were analyzed. Results Forty-seven stentectomies were attempted in 36 patients treated for 37 aneurysms. Forty-two devices (89.3%) were successfully retrieved. Single-device stentectomy was successful in 34% of cases, compared with 74% with dual-device techniques. Of the 20 patients with a thrombosed parent or efferent vessel, 17 were successfully recanalized using stentectomy. All successful stentectomy patients made a clinically uneventful recovery, except one with a minor postoperative stroke (mRS 1 at discharge). Failed stentectomy was associated with major ischemic stroke in two patients and death in one patient. There were no stentectomy-related vessel perforations or dissections. Conclusion While various single devices can be used to safely retrieve dysfunctional intracranial self-expandable stents, dual-device techniques are more than twice as effective, according to our experience.
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    URL: Article
    DOI: 10.1136/neurintsurg-2021-017279
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2506028-4
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  • 4
    Online Resource
    Online Resource
    Molecular Function and Contribution of TBX4 in Development and Disease
    American Thoracic Society ; 2023
    In:  American Journal of Respiratory and Critical Care Medicine Vol. 207, No. 7 ( 2023-04-01), p. 855-864
    Details
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 207, No. 7 ( 2023-04-01), p. 855-864
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    URL: Article
    DOI: 10.1164/rccm.202206-1039TR
    RVK:
    XA 21200
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2023
    detail.hit.zdb_id: 1468352-0
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  • 5
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    Online Resource
    Definitive Hematopoietic Stem Cells Minimally Contribute to Embryonic Hematopoiesis
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3268-3268
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3268-3268
    Abstract: Definitive hematopoietic stem cells (HSCs) emerge in the embryo and sustain major adult hematopoietic lineages. Although their functional potential is detected by transplant, nascent HSC contribution during development is both unknown and difficult to address due to the overlapping emergence of HSC-independent progenitors-cells that lack the multipotency and/or longevity of HSCs but express many of the same markers. Using sorted hematopoietic stem and progenitor cells from zebrafish embryos, we performed single cell RNA sequencing to decipher HSC and HSC-independent progenitor heterogeneity during the time frame of their emergence and initial maturation. After batch correction and dimensional reduction, we identified seven distinct populations that are inferred from RNA velocity analysis to originate from pre-hemogenic endothelium and develop into three main differentiation trajectories. We also determined that HSCs can be distinguished from HSC-independent progenitors based on the temporal regulation and differential activity of the draculin (drl) promoter that was previously shown to mark adult-contributing HSCs. From these studies, we found that the drl promoter is active in HSCs and HSC-independent progenitors at 1-day post-fertilization (dpf) but becomes highly expressed primarily in HSCs by 2 dpf. We applied a drl:cre-ER T2 tamoxifen-inducible Cre-loxP lineage-tracing approach to selectively lineage trace HSCs starting at 2 dpf and track their myeloid and lymphoid contribution during larval development and adulthood. We determined that HSC-independent progenitors primarily contribute to developmental lymphomyelopoiesis with minimal HSC contribution until after 7 dpf. Consistent with this result, we demonstrated that although HSCs robustly regenerated after hematopoietic injury using a novel inducible larval HSC injury model, their depletion had almost no impact on lymphoid and myeloid cell numbers up to 7 dpf. These findings suggest that HSCs are not entirely dormant during development and that there exists an uncoupling of HSC self-renewal and differentiation in development. In conclusion, we determine that it is the HSC-independent progenitors, and not HSCs, that sustain embryonic and early larval lymphomyelopoiesis. Acquiring a greater understanding regarding developmental differences in progenitor and HSC specification and maturation will inform and improve the generation of functional HSCs from renewable pluripotent stem cells. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-147998
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    Online Resource
    Online Resource
    Role of Conventional Dynamic Myelography for Detection of High-Flow Cerebrospinal Fluid Leaks : Optimizing the Technique
    Springer Science and Business Media LLC ; 2021
    In:  Clinical Neuroradiology Vol. 31, No. 3 ( 2021-09), p. 633-641
    Details
    In: Clinical Neuroradiology, Springer Science and Business Media LLC, Vol. 31, No. 3 ( 2021-09), p. 633-641
    Abstract: Spinal imaging is essential to identify and localize cerebrospinal fluid (CSF) leaks in spontaneous intracranial hypotension (SIH) patients when targeted treatment is necessary. Purpose Provide an in-depth presentation of the conventional dynamic myelography (CDM) technique for localizing spinal CSF leaks in SIH patients. Material and Methods Consecutive SIH patients with a CSF leak confirmed on CDM and postmyelography computed tomography (CT) investigated at our institution between 2013 and 2019 were retrospectively analyzed. Intraoperative reports were reviewed to confirm the accuracy of CDM. Results In total, 62 patients (mean age 45 years) were included; 48 with a ventral dural tear, 12 with a meningeal diverticulum, and in 2 patients positive for spinal longitudinal extradural CSF collection the site remained unclear. The leak was identified during the first and the second CDM in 43 and 17 patients, respectively. The use of CDM correctly identified the site of the CSF leak in all but one patient undergoing surgical closure (45/46, 98%). The mean fluoroscopy time was 7.8 min (range 1.8–14.4 min) with a radiation dose for a single examination of 310 mGy (range 28–1237 mGy). Conclusion The CDM procedure has a high accuracy for spinal CSF leak localization including dural tears and spinal nerve diverticula. It is the technique with the highest temporal resolution, is robust to breathing artifacts, allows great flexibility regarding patient positioning, compares favorably to other dynamic examinations with respect to the radiation dose and does not require general anesthesia. For CSF venous fistulas, however, other dynamic examinations, such as digital subtraction myelography, seem more appropriate.
    Type of Medium: Online Resource
    ISSN: 1869-1439 , 1869-1447
    URL: Article
    DOI: 10.1007/s00062-020-00943-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2232347-8
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  • 7
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    Online Resource
    Endovascular Stroke Treatment and Risk of Intracranial Hemorrhage in Anticoagulated Patients
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. 3 ( 2020-03), p. 892-898
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 3 ( 2020-03), p. 892-898
    Abstract: We aimed to determine the safety and mortality after mechanical thrombectomy in patients taking vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). Methods— In a multicenter observational cohort study, we used multiple logistic regression analysis to evaluate associations of symptomatic intracranial hemorrhage (sICH) with VKA or DOAC prescription before thrombectomy as compared with no anticoagulation. The primary outcomes were the rate of sICH and all-cause mortality at 90 days, incorporating sensitivity analysis regarding confirmed therapeutic anticoagulation. Additionally, we performed a systematic review and meta-analysis of literature on this topic. Results— Altogether, 1932 patients were included (VKA, n=222; DOAC, n=98; no anticoagulation, n=1612); median age, 74 years (interquartile range, 62–82); 49.6% women. VKA prescription was associated with increased odds for sICH and mortality (adjusted odds ratio [aOR], 2.55 [95% CI, 1.35–4.84] and 1.64 [95% CI, 1.09–2.47]) as compared with the control group, whereas no association with DOAC intake was observed (aOR, 0.98 [95% CI, 0.29–3.35] and 1.35 [95% CI, 0.72–2.53]). Sensitivity analyses considering only patients within the confirmed therapeutic anticoagulation range did not alter the findings. A study-level meta-analysis incorporating data from 7462 patients (855 VKAs, 318 DOACs, and 6289 controls) from 15 observational cohorts corroborated these observations, yielding an increased rate of sICH in VKA patients (aOR, 1.62 [95% CI, 1.22–2.17] ) but not in DOAC patients (aOR, 1.03 [95% CI, 0.60–1.80]). Conclusions— Patients taking VKA have an increased risk of sICH and mortality after mechanical thrombectomy. The lower risk of sICH associated with DOAC may also be noticeable in the acute setting. Improved selection might be advisable in VKA-treated patients. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03496064. Systematic Review and Meta-Analysis: CRD42019127464.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.026606
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467823-8
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  • 8
    Online Resource
    Online Resource
    Next-generation plasmids for transgenesis in zebrafish and beyond
    The Company of Biologists ; 2023
    In:  Development Vol. 150, No. 8 ( 2023-04-15)
    Details
    In: Development, The Company of Biologists, Vol. 150, No. 8 ( 2023-04-15)
    Abstract: Transgenesis is an essential technique for any genetic model. Tol2-based transgenesis paired with Gateway-compatible vector collections has transformed zebrafish transgenesis with an accessible modular system. Here, we establish several next-generation transgenesis tools for zebrafish and other species to expand and enhance transgenic applications. To facilitate gene regulatory element testing, we generated Gateway middle entry vectors harboring the small mouse beta-globin minimal promoter coupled to several fluorophores, CreERT2 and Gal4. To extend the color spectrum for transgenic applications, we established middle entry vectors encoding the bright, blue-fluorescent protein mCerulean and mApple as an alternative red fluorophore. We present a series of p2A peptide-based 3′ vectors with different fluorophores and subcellular localizations to co-label cells expressing proteins of interest. Finally, we established Tol2 destination vectors carrying the zebrafish exorh promoter driving different fluorophores as a pineal gland-specific transgenesis marker that is active before hatching and through adulthood. exorh-based reporters and transgenesis markers also drive specific pineal gland expression in the eye-less cavefish (Astyanax). Together, our vectors provide versatile reagents for transgenesis applications in zebrafish, cavefish and other models.
    Type of Medium: Online Resource
    ISSN: 0950-1991 , 1477-9129
    URL: Article
    DOI: 10.1242/dev.201531
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2023
    detail.hit.zdb_id: 2007916-3
    SSG: 12
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  • 9
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    Online Resource
    The lateral plate mesoderm
    The Company of Biologists ; 2020
    In:  Development Vol. 147, No. 12 ( 2020-06-15)
    Details
    In: Development, The Company of Biologists, Vol. 147, No. 12 ( 2020-06-15)
    Abstract: The lateral plate mesoderm (LPM) forms the progenitor cells that constitute the heart and cardiovascular system, blood, kidneys, smooth muscle lineage and limb skeleton in the developing vertebrate embryo. Despite this central role in development and evolution, the LPM remains challenging to study and to delineate, owing to its lineage complexity and lack of a concise genetic definition. Here, we outline the processes that govern LPM specification, organization, its cell fates and the inferred evolutionary trajectories of LPM-derived tissues. Finally, we discuss the development of seemingly disparate organ systems that share a common LPM origin.
    Type of Medium: Online Resource
    ISSN: 1477-9129 , 0950-1991
    URL: Article
    DOI: 10.1242/dev.175059
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2020
    detail.hit.zdb_id: 2007916-3
    SSG: 12
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  • 10
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    Heterogeneity and genomic loci of ubiquitous transgenic Cre reporter lines in zebrafish
    Wiley ; 2022
    In:  Developmental Dynamics Vol. 251, No. 10 ( 2022-10), p. 1754-1773
    Details
    In: Developmental Dynamics, Wiley, Vol. 251, No. 10 ( 2022-10), p. 1754-1773
    Abstract: loxP‐based reporters for Cre activity in zebrafish show variable potency ubi:switch and hsp70l:Switch display widespread and reproducible Cre sensitivity Modifying EGFP in ubi:Switch does not alter recombination efficiency Transgene mapping reveals genomic features at Switch reporter integrations
    Type of Medium: Online Resource
    ISSN: 1058-8388 , 1097-0177
    URL: Issue
    URL: Article
    DOI: 10.1002/dvdy.v251.10
    DOI: 10.1002/dvdy.499
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1473797-8
    SSG: 12
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