Implications of functional diversity for the pandemic risk of highly pathogenic coronaviruses

The last two decades have seen the zoonotic emergence of three highly pathogenic coronaviruses (CoVs): MERS-, SARS- and SARS-CoV-2. Their epidemic and pandemic spread, respectively, underlines the importance of monitoring emerging CoVs and of developing a deeper understanding of the molecular mechanisms that contribute to their emergence and pathogenicity. CoV are highly diverse in their animal reservoirs, yet how this diversity translates to phenotypical traits that may account for the zoonotic and pandemic potential of these viruses remains elusive. In the first part, several generated clinical Middle East respiratory syndrome coronavirus (MERS-CoV) isolates pertaining to different phylogenetic clades were analyzed for their in-vitro and ex-vivo infection phenotypes. Importantly, the isolate diversity used here reflects phylogenetic lineages sampled before and after the year 2015, when a novel phylogenetic lineage emerged by a recombination event (MERS-CoV lineage 5) and superseded other, hitherto co-circulating viral lineages from circulation, as well as causing large nosocomial outbreaks in Saudi Arabia and South Korea. The present studies demonstrate that MERS-CoV recombinant lineage 5 isolates have increased replicative capacity in the human lung, in correlation with increased interferon resilience and signaling antagonism. These phenotypic differences might explain the dominance of lineage 5 on the Arabian Peninsula and suggests an increased pandemic potential of the currently circulating MERS-CoV lineage 5. The second part comprises a phenotypical comparison of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, focusing on potential differences in their capacity to antagonize the innate immune response. Both viruses share a completely homologous repertoire of open reading frames (ORFs) and pertain to the same phylogenetic clade of SARS-related CoV, yet display differences in their transmission efficiencies and pathogenic traits. The data presented here show that SARS-CoV-2 is more sensitive to the antiviral activity of interferons and that SARS-CoV-2 is less efficient in antagonizing cytokine induction and interferon signaling. SARS-CoV-2 protein 6 expressed in the context of a fully replicating SARS-CoV backbone had reduced functionality in suppressing interferon signaling induction, suggesting that the overall reduced antagonism of SARS-CoV-2 might therefore by a function of reduced antagonistic capacity of protein 6.Drei hochpathogene Coronaviren (CoV) sind in den letzten zwei Jahrzehnten auf den Menschen übergegangen: MERS-, SARS- und SARS-CoV-2. Insbesondere die Ausbreitung des SARS-CoV-2 zeigt auf, wie wichtig die Überwachung neu auftretender CoV ist. Die aktuelle Pandemie demonstriert auch welche Relevanz es für unser Gesundheitswesen hat ein tiefergehendes Verständnis für jene Faktoren zu entwickeln, die das Infektionsrisiko und die Pathogenität solcher Viren beeinflussen. Die Diversität von CoV ist in ihren tierischen Reservoiren groß, doch wie sich diese Vielfalt auf phänotypische Merkmale auswirkt, besonders auf solche, die das zoonotische und pandemische Potenzial dieser Viren beeinflussen könnten, ist nach wie vor unklar. Im ersten Teil der Dissertation wurden in verschiedenen in-vitro- und ex-vivo- Modellen mehrere klinische MERS-CoV-Isolate phänotypisch analysiert. Es konnte gezeigt werden, dass die hierfür isolierten Viren repräsentativ für drei unterschiedliche phylogenetischen Kladen sind, und mit MERS-CoV Linie 5 jene Klade beinhalten, die in oder vor 2014 durch ein Rekombinationsereignis entstanden ist, und nachträglich alle bis dato zirkulierenden Viruslinien verdrängt hat. Die vorliegende Studie zeigt, dass Virusisolate der rekombinanten MERS-CoV-Linie 5 eine erhöhte Replikationskapazität in der menschlichen Lunge haben, die mit einer erhöhten Interferon-Resilienz und einer effektiveren Unterdrückung der Interferon-spezifischen Signaltransduktionskaskade korrelierend. Diese phänotypischen Unterschiede könnten die mögliche Dominanz der Linie 5 auf der Arabischen Halbinsel erklären und implizieren, dass die aktuell zirkulierende MERS-CoV Linie 5 ein erhöhtes zoonotisches und pandemisches Risiko für den Menschen darstellt. Der zweite Teil der Dissertation umfasst einen phänotypischen Vergleich von SARS- und SARS-CoV-2 mit besonderem Fokus auf die virale Interaktion mit der angeborenen Immunität in Wirtszellen. Beide Viren zeigen ein vollständig homologes Repertoire von offenen Leserahmen (open reading frames, ORFs) und gehören der gleichen phylogenetischen Art, den SARS-verwandten CoV an. Die Viren unterscheiden sich jedoch deutlich in ihrer Übertragungseffizienz und in ihrer Pathogenese im Menschen. In dieser Arbeit konnte gezeigt werden, dass SARS-CoV-2 weniger resilient gegenüber der antiviralen Wirkung von Interferon ist. Im Vergleich zu SARS-CoV kann SARS-CoV-2 die Zytokininduktion und Interferon-Signalübertragung weniger effizient unterdrücken. Mittels reverser Genetik konnte gezeigt werden, dass das SARS-CoV-2 Protein 6 im Kontext eines vollständig replizierenden SARS-CoV eine geringere Effizienz als SARS-CoV Protein 6 hat, die Interferon-Signaltransduktionskaskade zu blockieren.

A stochastic model for the evolution of the Web

Recently several authors have proposed stochastic models of the growth of the Web graph that give rise to power-law distributions. These models are based on the notion of preferential attachment leading to the "rich get richer" phenomenon. However, these models fail to explain several distributions arising from empirical results, due to the fact that the predicted exponent is not consistent with the data. To address this problem, we extend the evolutionary model of the Web graph by including a non-preferential component, and we view the stochastic process in terms of an urn transfer model. By making this extension, we can now explain a wider variety of empirically discovered power-law distributions provided the exponent is greater than two. These include: the distribution of incoming links, the distribution of outgoing links, the distribution of pages in a Web site and the distribution of visitors to a Web site. A by-product of our results is a formal proof of the convergence of the standard stochastic model (first proposed by Simon)

Declining winter heat loss threatens continuing ocean convection at a Mediterranean dense water formation site

A major change in winter sea surface heat loss between two key Mediterranean dense water formation sites, the North-west Mediterranean (NWMed) and the Aegean Sea, since 1950 is revealed using atmospheric reanalyses. The NWMed heat loss has weakened considerably (from -154 Wm-2 in 1951-1985 to -137 Wm-2 in 1986-2020) primarily because of reduced latent heat flux. This long-term weakening threatens continued dense water formation, and we show by evaluation of historical observations that winter-time ocean convection in the NWMed has declined by 40% from 1969 to 2018. Extension of the heat flux analysis reveals changes at other key dense water formation sites that favour an eastward shift in the locus of Mediterranean convection towards the Aegean Sea (where heat loss has remained unchanged at -172 Wm-2). The contrasting behaviour is due to differing time evolution of sea-air humidity and temperature gradients. These gradients have weakened in the NWMed due to more rapid warming of the air than the sea surface but remain near-constant in the Aegean. The different time evolution reflects the combined effects of global heating and atmospheric circulation changes which tend to offset heating in the Aegean but not the NWMed. The shift in heat loss has potentially significant consequences for dense water formation at these two sites and outflow to the Atlantic. Our observation of differential changes in heat loss has implications for temporal variations in the balance of convection elsewhere e.g., the Labrador-Irminger-Nordic Seas nexus of high latitude Atlantic dense water formation sites

Statistical Properties of Galactic Starlight Polarization

We present a statistical analysis of Galactic interstellar polarization from the largest compilation available of starlight data. The data comprises ~ 9300 stars of which we have selected ~ 5500 for our analysis. We find a nearly linear growth of mean polarization degree with extinction. The amplitude of this correlation shows that interstellar grains are not fully aligned with the Galactic magnetic field, which can be interpreted as the effect of a large random component of the field. In agreement with earlier studies of more limited scope, we estimate the ratio of the uniform to the random plane-of-the-sky components of the magnetic field to be B_u/B_r = 0.8. Moreover, a clear correlation exists between polarization degree and polarization angle what provides evidence that the magnetic field geometry follows Galactic structures on large-scales. The angular power spectrum C_l of the starlight polarization degree for Galactic plane data (|b| < 10 deg) is consistent with a power-law, C_l ~ l^{-1.5} (where l ~ 180 deg/\theta is the multipole order), for all angular scales \theta > 10 arcmin. An investigation of sparse and inhomogeneous sampling of the data shows that the starlight data analyzed traces an underlying polarized continuum that has the same power spectrum slope, C_l ~ l^{-1.5}. Our findings suggest that starlight data can be safely used for the modeling of Galactic polarized continuum emission at other wavelengths.Comment: 31 pages, 11 figures. Minor corrections and some clarifications included. Matches version accepted for publication by the Astrophysical Journa

Neural activity in the human anterior thalamus during natural vision

In natural vision humans and other primates explore environment by active sensing, using saccadic eye movements to relocate the fovea and sample different bits of information multiple times per second. Saccades induce a phase reset of ongoing neuronal oscillations in primary and higher-order visual cortices and in the medial temporal lobe. As a result, neuron ensembles are shifted to a common state at the time visual input propagates through the system (i.e., just after fixation). The extent of the brain’s circuitry that is modulated by saccades is not yet known. Here, we evaluate the possibility that saccadic phase reset impacts the anterior nuclei of the thalamus (ANT). Using recordings in the human thalamus of three surgical patients during natural vision, we found that saccades and visual stimulus onset both modulate neural activity, but with distinct field potential morphologies. Specifically, we found that fixation-locked field potentials had a component that preceded saccade onset. It was followed by an early negativity around 50 ms after fixation onset which is significantly faster than any response to visual stimulus presentation. The timing of these events suggests that the ANT is predictively modulated before the saccadic eye movement. We also found oscillatory phase concentration, peaking at 3–4 Hz, coincident with suppression of Broadband High-frequency Activity (BHA; 80–180 Hz), both locked to fixation onset supporting the idea that neural oscillations in these nuclei are reorganized to a low excitability state right after fixation onset. These findings show that during real-world natural visual exploration neural dynamics in the human ANT is influenced by visual and oculomotor events, which supports the idea that ANT, apart from their contribution to episodic memory, also play a role in natural vision