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1.
Systems Research and Behavioral Science ; 2021.
Article in English | Wiley | ID: covidwho-1557806

ABSTRACT

We aim to contribute to improving the management of pandemic crises. Our focus is on federal systems, as these are particularly powerful in dealing with environmental complexity. Through four waves of the pandemic, spanning a year and a half, we studied crisis management based on the case of the Swiss Federation. This research concentrates on three research questions: (1) How is the management of the Covid-19-Crisis organized in Switzerland? (2) How effective is this organization in coping with the dynamics of emergency? (3) What lessons can be learned for the design of a crisis management in the future? We apply the Viable System Model (VSM) as a framework for our study, elaborating a diagnosis and a design for the management of epidemic or pandemic crises. The VSM is a conceptual tool that is particularly strong for analysing federal systems. Hence, substantial insights have surfaced to orientate a future crisis management.

2.
Preprint in English | EuropePMC | ID: ppcovidwho-292398

ABSTRACT

Neuroinvasion by SARS-CoV-2 is now accepted. To investigate whether low testosterone levels observed in men with severe COVID-19 could be of central origin, we retrospectively analyzed blood samples from 60 male intensive-care patients and explored SARS-CoV-2 brain entry using animal and cellular models as well as adult COVID-19 patient and fetal human brains. Most hypotestosteronemic patients displayed hypogonadotropic hypogonadism or abnormal hypothalamic-pituitary-gonadal axis regulation. Neurons producing gonadotropin-releasing hormone (GnRH), the master molecule controlling fertility, expressed angiotensin-converting enzyme 2 and neuropilin-1, two host-cell factors mediating infection, and were infected and dying in all COVID-19 patient brains. Tanycytes - hypothalamic glia that regulate GnRH secretion - were also infected. Additionally, human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, richly expressed both the above host-cell susceptibility factors and formyl peptide receptor 2, a putative vomeronasal receptor that also appeared involved in SARS-CoV-2 pathogenesis in humans and mice. Finally, a fetal human GnRH cell line expressing all these receptors could be infected by a SARS-CoV-2-like pseudovirus. Together, our findings suggest that GnRH neurons, which may be implicated in brain development and aging in addition to reproduction, are particularly vulnerable to SARS-CoV-2 in both adults and fetuses/newborns, with potentially devastating long-term consequences.

3.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500484

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
4.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1483143

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
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