The novel Coronavirus SARS-CoV-2 (CoV) has induced a world-wide pandemic and subsequent non-pharmaceutical interventions (NPI) in order to control the spreading of the virus. NPIs are considered to be critical in order to at least delay the peak number of infected individuals and to prevent the health care system becoming overwhelmed by the number of patients to treat in hospitals or in intensive care units (ICUs). However, there is also increasing concern that the NPIs in place would increase mortality because of other diseases, increase the frequency of suicide and increase the risk of an economic recession with unforeseeable implications. It is therefore instrumental to evaluate the necessity of NPIs and to monitor the progress of containment of the virus spreading.

Background: Early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria initiated the spread of SARS-CoV-2 throughout Austria and Northern Europe. Methods: Between April 21 and 27, a cross-sectional epidemiologic study targeting the full population of Ischgl (n= 1867), of which 79% could be included (n=1473, incl. 214 children), was performed. For each individual, the study involved a SARS-CoV-2 PCR, antibody testing and structured questionnaires. A mathematical model was used to help understand the influence of the determined seroprevalence on virus transmission. Findings: The seroprevalence was 42.4% (95% CI 39.8-44.7). Individuals under 18 showed a significantly lower seroprevalence of 27.1% (95% CI 21.3-33.6) than adults (45%; 95% CI 42.2-47.7; OR of 0.455, 95% CI 0.356-0.682, p<0.001). Of the seropositive individuals, 83.7% had not been diagnosed to have had SARS-CoV-2 infection previously. The clinical course was generally mild. Over the previous two months, two COVID-19-related deaths had been recorded, corresponding to an infection fatality rate (IFR) of 0.25% (95% CI 0.03-0.91). Only 8 (0.5 %) individuals were newly diagnosed to be infected with SARS-CoV-2 during this study. Interpretation: Ischgl was hit early and hard by SARS-CoV-2 leading to a high local seroprevalence of 42.4%, which was lower in individuals below the age of 18 than in adults. Mathematical modeling suggests that a drastic decline of newly infected individuals in Ischgl by the end of April occured due to the dual impact from the non-pharmacological interventions (NPIs) and a significant immunization of the Ischgl population. Funding: Helmholtz Association, European Union's Horizon 2020 research and innovation program, German Research Foundation (DFG), state Tyrol.

Background Sepsis and inflammation can cause intensive care unit-acquired weakness (ICUAW). Increased interleukin-6 (IL-6) plasma levels are a risk factor for ICUAW. IL-6 signalling involves the glycoprotein 130 (gp130) receptor and the JAK/STAT-pathway, but its role in sepsis-induced muscle wasting is uncertain. In a clinical observational study, we found that the IL-6 target gene, SOCS3, was increased in skeletal muscle of ICUAW patients indicative for JAK/STAT-pathway activation. We tested the hypothesis that the IL-6/gp130-pathway mediates ICUAW muscle atrophy. Methods We sequenced RNA (RNAseq) from tibialis anterior (TA) muscle of cecal ligation and puncture-operated (CLP) and sham-operated wildtype (WT) mice. The effects of the IL-6/gp130/JAK2/STAT3-pathway were investigated by analysing the atrophy phenotype, gene expression, and protein contents of C2C12 myotubes. Mice lacking Il6st, encoding gp130, in myocytes (cKO) and WT controls, as well as mice treated with the JAK2 inhibitor AG490 or vehicle were exposed to CLP or sham surgery for 24 or 96 h. Results Analyses of differentially expressed genes in RNAseq (≥2-log2-fold change, P < 0.01) revealed an activation of IL-6-signalling and JAK/STAT-signalling pathways in muscle of septic mice, which occurred after 24 h and lasted at least for 96 h during sepsis. IL-6 treatment of C2C12 myotubes induced STAT3 phosphorylation (three-fold, P < 0.01) and Socs3 mRNA expression (3.1-fold, P < 0.01) and caused myotube atrophy. Knockdown of Il6st diminished IL-6-induced STAT3 phosphorylation (À30.0%; P < 0.01), Socs3 mRNA expression, and myotube atrophy. JAK2 (À 29.0%; P < 0.01) or STAT3 inhibition (À38.7%; P < 0.05) decreased IL-6-induced Socs3 mRNA expression. Treatment with either inhibitor attenuated myotube atrophy in response to IL-6. CLP-operated septic mice showed an increased STAT3 phosphorylation and Socs3 mRNA expression in TA muscle, which was reduced in septic Il6st-cKO mice by 67.8% (P < 0.05) and 85.6% (P < 0.001), respectively. CLP caused a loss of TA muscle weight, which was attenuated in Il6st-cKO mice (WT: À22.3%, P < 0.001, cKO: À13.5%, P < 0.001; WT vs. cKO P < 0.001). While loss of Il6st resulted in a reduction of MuRF1 protein contents, Atrogin-1 remained unchanged between septic WT and cKO mice. mRNA expression of Trim63/MuRF1 and Fbxo32/Atrogin-1 were unaltered between CLP-treated WT and cKO mice. AG490 treatment reduced STAT3 phosphorylation (À22.2%, P < 0.05) and attenuated TA muscle atrophy in septic mice (29.6% relative reduction of muscle weight loss, P < 0.05). The reduction in muscle atrophy was accompanied by a reduction in Fbxo32/Atrogin-1-mRNA (À81.3%, P < 0.05) and Trim63/MuRF1-mRNA expression (À77.6%, P < 0.05) and protein content.

Background SARS-CoV-2 has induced a worldwide pandemic and subsequent non-pharmaceutical interventions (NPIs) to control the spread of the virus. As in many countries, the SARS-CoV-2 pandemic in Germany has led to a consecutive roll-out of different NPIs. As these NPIs have (largely unknown) adverse effects, targeting them precisely and monitoring their effectiveness are essential. We developed a compartmental infection dynamics model with specific features of SARS-CoV-2 that allows daily estimation of a time-varying reproduction number and published this information openly since the beginning of April 2020. Here, we present the transmission dynamics in Germany over time to understand the effect of NPIs and allow adaptive forecasts of the epidemic progression. Methods We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states using our model. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread in different regions of Italy, the model was optimized to fit data from the Robert Koch Institute. Results The time-varying reproduction number (Rt) in Germany decreased to <1 in early April 2020, 2–3 weeks after the implementation of NPIs. Partial release of NPIs both nationally and on federal state level correlated with moderate increases in Rt until August 2020. Implications of state-specific Rt on other states and on national level are characterized. Retrospective evaluation of the model shows excellent agreement with the data and usage of inpatient facilities well within the healthcare limit. While short-term predictions may work for a few weeks, long-term projections are complicated by unpredictable structural changes. Conclusions The estimated fraction of immunized population by August 2020 warns of a renewed outbreak upon release of measures. A low detection rate prolongs the delay reaching a low case incidence number upon release, showing the importance of an effective testing-quarantine strategy. We show that real-time monitoring of transmission dynamics is important to evaluate the extent of the outbreak, short-term projections for the burden on the healthcare system, and their response to policy changes.

Background In early March 2020, a SARS-CoV-2 outbreak in the ski resort Ischgl in Austria initiated the spread of SARS-CoV-2 throughout Austria and Northern Europe. Methods Between April 21st and 27th 2020, a cross-sectional epidemiologic study targeting the full population of Ischgl (n = 1867), of which 79% could be included (n = 1473, incl. 214 children), was performed. For each individual, the study involved a SARS-CoV-2 PCR, antibody testing and structured questionnaires. A mathematical model was used to help understand the influence of the determined seroprevalence on virus transmission. Results The seroprevalence was 42.4% (95% confidence interval (CI) 39.8–44.7). Individuals under 18 showed a significantly lower seroprevalence of 27.1% (95% CI 21.3-33.6) than adults (45%; 95% CI 42.2–47.7; OR of 0.455, 95% CI 0.356–0.682, p < 0.001). Of the seropositive individuals, 83.7% had not been diagnosed to have had SARS-CoV-2 infection previously. The clinical course was generally mild. Over the previous two months, two COVID-19-related deaths had been recorded, corresponding to an infection fatality rate of 0.25% (95% CI 0.03–0.91). Only 8 (0.5 %) individuals were newly diagnosed to be infected with SARS-CoV-2 during this study. Conclusions Ischgl was hit early and hard by SARS-CoV-2 leading to a high local seroprevalence of 42.4%, which was lower in individuals below the age of 18 than in adults. Mathematical modeling suggests that a drastic decline of newly infected individuals in Ischgl by the end of April occurred due to the dual impact from the non-pharmacological interventions and a high immunization of the Ischgl population.

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

Antibody affinity maturation depends on the formation of germinal centers (GCs) in lymph nodes. This process generates a massive number of apoptotic B cells, which are removed by a specialized subset of phagocytes, known as tingible body macrophages (TBMs). Although defects in these cells are associated with pathological conditions, the identity of their precursors and the dynamics of dying GC B cell disposal remained unknown. Here, we demonstrate that TBMs originate from pre-existing lymph node–resident precursors that enter the lymph node follicles in a GC-dependent manner. Intravital imaging shows that TBMs are stationary cells that selectively phagocytose GC B cells via highly dynamic protrusions and accommodate the final stages of B cell apoptosis. Cell-specific depletion and chimeric mouse models revealed that GC B cells drive TBM formation from bone marrow–derived precursors stationed within lymphoid organs prior to the immune challenge. Understanding TBM dynamics and function may explain the emergence of various antibody-mediated autoimmune conditions.

We present a stochastic formalism for signal transduction processes in a bacterial two-component system. Using elementary mass action kinetics, the proposed model takes care of signal transduction in terms of a phosphotransfer mechanism between the cognate partners of a two-component system, viz., the sensor kinase and the response regulator. Based on the difference in functionality of the sensor kinase, the noisy phosphotransfer mechanism has been studied for monofunctional and bifunctional two-component systems using the formalism of the linear noise approximation. Steady-state analysis of both models quantifies different physically realizable quantities, e.g., the variance, the Fano factor (variance/mean), and mutual information. The resultant data reveal that both systems reliably transfer information of extracellular environment under low external stimulus and in a high-kinase-and-phosphatase regime. We extend our analysis further by studying the role of the two-component system in downstream gene regulation.