Biology subjects

Schreier, D.

Publications and source records attributed to Schreier, D..

3 recordsLinked to original sources

bioRxiv2024

Spike-wave discharges during low-current thalamic deep brain stimulation in mice

BackgroundDeep brain stimulation of central thalamus (CT-DBS) has potential for modulating states of consciousness, but it can also trigger spike-wave discharges (SWDs). ObjectivesTo report the probability of inducing SWDs during CT-DBS in awake mice. MethodsMice were implanted with electrodes to deliver unilateral and bilateral CT-DBS at different frequencies while recording EEG. We titrated stimulation current by gradually increasing it at each frequency until an SWD appeared. Subsequent stimulations to test arousal modulation were performed at the current one step below the current that caused an SWD during titration. ResultsIn 2.21% of the test stimulations (10 out of 12 mice), CT-DBS caused SWDs at currents lower than the titrated current, at currents as low as 20 A. ConclusionOur study found a small but significant probability of inducing SWDs even after titration and at relatively low currents. EEG should be closely monitored for SWDs when performing CT-DBS in both research and clinical settings.

neuroscience↗

bioRxiv2023

The phosphodiesterase 2A regulates lymphatic endothelial development via cGMP-mediated control of Notch signaling

During vascular development endothelial junctions mature and vessel integrity is established to form the endothelial barrier. The molecular mechanisms by which lymphatic vessels induce cell contact inhibition are not understood. Here, we uncover the cGMP-dependent phosphodiesterase 2A (PDE2A) as a selective regulator of lymphatic, but not blood endothelial contact inhibition. Conditional deletion of Pde2a in mouse embryos reveals severe lymphatic dysplasia, while large blood vessel architecture remains unaltered. In the absence of PDE2A, human lymphatic endothelial cells fail to induce mature junctions and cell cycle arrest, while cGMP levels, but not cAMP levels, are increased. Loss of PDE2A-mediated cGMP hydrolysis leads to downregulation of NOTCH signaling. Vice versa, DLL4-induced NOTCH activation restores junctional maturation in PDE2A-deficient lymphatic endothelial cells. Our data demonstrate that PDE2A selectively modulates a crosstalk between cGMP and NOTCH signaling to finetune lymphatic development and suggest that PDE2A may be a druggable target to control lymphatic leakage and regeneration.

developmental biology↗

bioRxiv2020

Defective NETs Clearance contributes to sustained FXII Activation in COVID-19-associated Pulmonary Thrombo-Inflammation

BackgroundCoagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19 disease. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood. MethodsWe performed proteomic analysis and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We further compared coagulation factor XII (FXII) and DNase activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced Factor XIII (FXII) activation using a chromogenic substrate assay. FindingsFXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients. In agreement with this, plasma FXII activation (FXIIa) was increased in samples from COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially due to impaired NET clearance by extracellular DNases as DNase substitution improved NET dissolution and reduced FXII activation in vitro. InterpretationCollectively, our study supports that the NETs/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both, NETs and FXIIa, could provide a strategy to mitigate COVID-19-induced thrombo-inflammation. FundingThis study was supported by the European Union (840189), the Werner Otto Medical Foundation Hamburg (8/95) and the German Research Foundation (FR4239/1-1, A11/SFB877, B08/SFB841 and P06/KFO306).

molecular biology↗