Biology subjects

Thiel, A.

Publications and source records attributed to Thiel, A..

8 recordsLinked to original sources

bioRxiv2025

Perinatal Asphyxia Alters Physiological Responses and Ex Vivo Cardiovascular Function of Preterm Growth-Restricted Lambs

IntroductionFetal growth restriction (FGR) arises from chronic hypoxia and increases the risk of cardiovascular dysfunction following perinatal asphyxia, although the underlying mechanisms are unknown. We investigated whether FGR lambs have altered cardiovascular responses to perinatal asphyxia compared to control lambs, and whether impairments in 1 and {beta}1 adrenergic receptor function underlie these responses. MethodsSingle or twin-bearing ewes underwent sterile fetal surgery at 89 days gestation (dGA; term=148d) to induce FGR (single umbilical artery ligation) or sham surgery (Control). At 126dGA, lambs were delivered via caesarean section, instrumented and randomised to immediate ventilation (ControlVENT n=6; FGRVENT n=6), or asphyxia (ControlASPHYXIA n=12; FGRASPHYXIA n=11) induced by umbilical cord occlusion while withholding resuscitation until diastolic blood pressure (BP) decreased to 10mmHg. Lambs were ventilated for 8 hours before baseline ex vivo cardiac function was assessed via Langendorff perfusion to measure left ventricular developed pressure (LVDP), heart rate (HR) and coronary perfusion pressure (CPP). Ex vivo 1 and {beta}1 adrenergic responses were assessed via phenylephrine (10-5 to 10-2 mmol/L) and dobutamine (10-7 to 10-4) administration, respectively. ResultsFGRASPHYXIA lambs had lower BP during asphyxia (p<0.05 vs ControlASPHYXIA) and took longer to reach a diastolic BP of 10mmHg (14.5 {+/-} 0.8 min vs. 19.2 {+/-} 1.3 min; p=0.005). FGRASPHYXIA lambs had lower BP in the first 5 minutes after return of spontaneous circulation (p<0.05) due to impaired vascular contractility, with reduced Tau, dP/dtmax and dP/dtmin (p<0.03 vs ControlASPHYXIA). Baseline LVDP, HR and CPP were similar between groups, however FGRASPHYXIA lambs had increased LVDP responses to phenylephrine and dobutamine (p<0.05 vs ControlASPHYXIA), without significant changes to HR or CPP. ConclusionFGR lambs have altered physiological responses to perinatal asphyxia due to impaired vascular contractility and dysregulated cardiac 1 and {beta}1 adrenergic receptor function, which may increase susceptibility to cardiovascular dysfunction in the neonatal period.

physiology↗

bioRxiv2025

Regulation of gene expression under high hydrostatic pressure: the versatile role of the master regulator SurR in energy metabolism

In Thermococcus barophilus, a piezophilic hyperthermophilic archaeon, the expression of several gene clusters, including those of energy metabolism, is modulated by hydrostatic pressure. In Thermococcales, SurR, a redox-sensitive transcriptional regulator that responds to sulfur availability, regulates genes involved in energy metabolism. To better understand how high hydrostatic pressure (HHP) influences the expression of energy metabolism genes, several gene deletion mutants including surR partial knockout, were constructed and analyzed under various culture conditions, including different hydrostatic pressures and the presence or absence of sulfur. Phenotypic analysis of the surR mutant revealed that SurR affects both growth and gene expression, independently of sulfur availability. This regulatory behavior differs from that observed in non-piezophilic Thermococcales species such as Pyrococcus furiosus and Thermococcus kodakarensis. These findings suggest that hydrostatic pressure influences the physiological role or functional state of SurR in T. barophilus, highlighting its adaptive versatility in extreme environments. IMPORTANCEThis study provides new insights into the adaptive mechanisms of hyperthermophilic archaea to high hydrostatic pressure, a key factor in deep-sea environments. By demonstrating that SurR regulation differs in T. barophilus compared to non-piezophilic species, it suggests that pressure can modify transcriptional control mechanisms, potentially reshaping energy metabolism strategies in deep-sea archaea. Understanding these regulatory adaptations contributes to our broader knowledge of microbial life under extreme conditions and may have implications for biotechnology, particularly in designing pressure-resistant enzymes or metabolic pathways.

microbiology↗

bioRxiv2024

Aging and viral evolution impair immunity against dominant pan-coronavirus-reactive T cell epitope

Immune evasion by escape mutations subverts immunity against SARS-CoV-2. A role of pan-coronavirus immunity for more durable protection is being discussed but has remained understudied. We here investigated the effects of age, mutations, and homo-/heterologous vaccination regimens on the dominant pan-coronavirus-specific cellular and humoral epitope iCope after SARS-CoV-2 infection and vaccination in detail. In the older, quantitatively, and qualitatively reduced iCope-reactive CD4+ T cell responses with narrow TCR repertoires could not be enhanced by vaccination and were further compromised by emerging spike mutations. In contrast pan-coronavirus-reactive humoral immunity was affected only by mutations and not by age. Our results reveal a distinct deficiency of the dichotomous layer of pan-coronavirus immunity in the older, critical for long-term protection against SARS-CoV-2 variants. One-Sentence SummaryAging and viral evolution impair dominant pan-coronavirus immunity, a hallmark of efficient and broad immune competence against SARS-CoV-2

immunology↗

bioRxiv2024

Rapid oxygen titration following cardiopulmonary resuscitation mitigates cerebral overperfusion and striatal mitochondrial dysfunction in asphyxiated newborn lambs

Asphyxiated neonates must have oxygenation rapidly restored to limit ongoing hypoxic-ischemic injury. However, the effects of transient hyperoxia after return of spontaneous circulation (ROSC) are poorly understood. We randomly allocated acutely asphyxiated, near-term lambs to cardiopulmonary resuscitation in 100% oxygen ("standard oxygen", n=8) or air (n=7) until 5 minutes after ROSC, or to resuscitation in 100% oxygen immediately weaned to air upon ROSC ("rapid-wean", n=7). From 5 minutes post-ROSC, oxygen was titrated to target preductal oxygen saturation between 90-95%. Cerebral tissue oxygenation was transiently but markedly elevated following ROSC in the standard oxygen group compared to the air and rapid-wean groups. The air group had a delayed rise in cerebral tissue oxygenation from 5 minutes after ROSC coincident with up-titration of oxygen. These alterations in oxygen kinetics corresponded with similar overshoots in cerebral perfusion (pressure and flow), indicating a physiological mechanism. Transient cerebral tissue hyperoxia in the standard oxygen and air groups resulted in significant alterations in mitochondrial respiration and dynamics, relative to the rapid-wean group. Overall, rapid-wean of oxygen following ROSC preserved striatal mitochondrial respiratory function and reduced the expression of genes involved in free radical generation and apoptosis, suggesting a potential therapeutic strategy to limit cerebral reperfusion injury.

physiology↗

bioRxiv2022

3D reconstruction of ultra-high resolution neurotransmitter receptor atlases in human and non-human primate brains

Quantitative maps of neurotransmitter receptor densities are important tools for characterising the molecular organisation of the brain and key for understanding normal and pathologic brain function and behaviour. We describe a novel method for reconstructing 3-dimensional cortical maps for data sets consisting of multiple different types of 2-dimensional post-mortem histological sections, including autoradiographs acquired with different ligands, cell body and myelin stained sections, and which can be applied to data originating from different species. The accuracy of the reconstruction was quantified by calculating the Dice score between the reconstructed volumes versus their reference anatomic volume. The average Dice score was 0.91. We were therefore able to create atlases with multiple accurately reconstructed receptor maps for human and macaque brains as a proof-of-principle. Future application of our pipeline will allow for the creation of the first ever set of ultra-high resolution 3D atlases composed of 20 different maps of neurotransmitter binding sites in 3 complete human brains and in 4 hemispheres of 3 different macaque brains.

neuroscience↗

bioRxiv2022

HDAC7 controls anti-viral and anti-tumor immunity by CD8+ T cells

Class II histone deacetylases (HDAC) orchestrate T cell-dependent immune responses via the epigenetic control of genes and via the post-translational modification of cytoplasmic and nuclear proteins. However, the contribution of single HDAC family members to the differentiation and function of peripheral CD8+ T cells remains elusive. We here demonstrate that HDAC7-deficiency leads to the upregulation of immune checkpoint molecules, decreased calcium influx as well as increased apoptosis of peripheral murine CD8+ T cells, which we could link to a MEF2D-dependent induction of FasL expression ultimately deterring the survival of HDAC7-deficient CD8+ T cells. Likewise, we observed in mouse models of lymphoma, that mice with a T cell specific-deletion of Hdac7 harbor impaired anti-tumor immune responses in syngeneic transfer models of lymphoma and we found that HDAC7 is required for CD8+ T cell-dependent memory recall responses in models of lymphocytic choriomeningitis virus infection. Taken together, we identify HDAC7 as a central regulator of cellular exhaustion and apoptosis of peripheral CD8+ T cells, controlling CD8+ T cell dependent anti-tumor and anti-viral immunity in mice. SignificanceAlthough HDAC7 was identified as an important regulator of thymocyte development and survival, its role in the homeostasis and the functions of adult CD8+ T cells is not fully understood. Here, we identify HDAC7 as a critical regulator of peripheral CD8+ T cells since its deletion impairs anti-tumor and anti-viral immune responses in mouse models of LCMV infection and transfer models of lymphoma. We attribute this phenotype to impaired survival, calcium homeostasis as well as deterred memory function and increased exhaustion of HDAC7-deficient CD8+ T cells. Our findings are of clinical relevance regarding potential immune suppressive side effects of HDAC inhibitors that are currently under clinical trials for the treatment of autoimmune diseases and cancers.

immunology↗

bioRxiv2021

Lower Aβ-PET signal in white matter lesions relates to higher extracellular free water in mixed small vessel disease and Alzheimer's pathology

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (A{beta}-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered A{beta}-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to A{beta}-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in A{beta}-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in A{beta}-PET related more closely to higher cortical A{beta} (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and A{beta}-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

neuroscience↗

bioRxiv2020

Braconidae revisited: Bracon brevicornis genome showcases the potential of linked-read sequencing in identifying a putative complementary sex determiner gene

Bracon brevicornis is an ectoparasitoid of a wide range of larval-stage Lepidopterans, including several pests of important crops, such as the corn borer, Ostrinia nubilalis. It is also one of the earliest documented cases of complementary sex determination in Hymenoptera. Here, we present the linked-read genome of B. brevicornis, complete with an ab initio-derived annotation and protein comparisons with fellow braconids, Fopius arisanus and Diachasma alloem. We demonstrate the potential of linked-read assemblies in exploring regions of heterozygosity and search for structural and homology-derived evidence of the complementary sex determiner gene (csd).

genomics↗