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"Hofmann, Heike"
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Human Coronavirus NL63 Employs the Severe Acute Respiratory Syndrome Coronavirus Receptor for Cellular Entry
Coronavirus (CoV) infection of humans is usually not associated with severe disease. However, discovery of the severe acute respiratory syndrome (SARS) CoV revealed that highly pathogenic human CoVs (HCoVs) can evolve. The identification and characterization of new HCoVs is, therefore, an important task. Recently, a HCoV termed NL63 was discovered in patients with respiratory tract illness. Here, cell tropism and receptor usage of HCoV-NL63 were analyzed. The NL63 spike (S) protein mediated infection of different target cells compared with the closely related 229E-S protein but facilitated entry into cells known to be permissive to SARS-CoV-S-driven infection. An analysis of receptor engagement revealed that NL63-S binds angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV, and HCoV-NL63 uses ACE2 as a receptor for infection of target cells. Potent neutralizing activity directed against NL63- but not 229E-S protein was detected in virtually all sera from patients 8 years of age or older, suggesting that HCoV-NL63 infection of humans is common and usually acquired during childhood. Here, we show that SARS-CoV shares its receptor ACE2 with HCoV-NL63. Because the two viruses differ dramatically in their ability to induce disease, analysis of HCoV-NL63 might unravel pathogenicity factors in SARS-CoV. The frequent HCoV-NL63 infection of humans suggests that highly pathogenic variants have ample opportunity to evolve, underlining the need for vaccines against HCoVs.
Journal Article
Fashion and Materiality
Fashion is intimately tied to the material world. With a focus on diverse cultural practices, this book offers new insights into the dynamic relationships between fashion, bodies, and material culture. In a series of original case studies, both historical and contemporary, the collection explores how fashion and clothing affect articulations of body and self, experiences of time and place, and the shaping of social and local/global relationships. With chapters from leading international scholars, Fashion and Materiality takes the reader from the study of clothing and biography, and an early modern \"foreign dress\" collection, to Chinoiserie clothing in 18th-century Europe and fast fashion production in today's China. The book also examines fashion's role in nation building, and entanglements between fashion and migration across clothing donations for Syrian refugees in Germany and the circulation of \"refugee chic\" on international fashion runways. Scrutinizing the dense connections between fashion, clothing, materiality, and humanity, the book shows how the material interacts forcefully with the personal and political.
eBook
Statistical inference for exploratory data analysis and model diagnostics
We propose to furnish visual statistical methods with an inferential framework and protocol, modelled on confirmatory statistical testing. In this framework, plots take on the role of test statistics, and human cognition the role of statistical tests. Statistical significance of 'discoveries' is measured by having the human viewer compare the plot of the real dataset with collections of plots of simulated datasets. A simple but rigorous protocol that provides inferential validity is modelled after the 'lineup' popular from criminal legal procedures. Another protocol modelled after the 'Rorschach' inkblot test, well known from (pop-)psychology, will help analysts acclimatize to random variability before being exposed to the plot of the real data. The proposed protocols will be useful for exploratory data analysis, with reference datasets simulated by using a null assumption that structure is absent. The framework is also useful for model diagnostics in which case reference datasets are simulated from the model in question. This latter point follows up on previous proposals. Adopting the protocols will mean an adjustment in working procedures for data analysts, adding more rigour, and teachers might find that incorporating these protocols into the curriculum improves their students' statistical thinking.
Journal Article
Evidence that Processing of the Severe Fever with Thrombocytopenia Syndrome Virus Gn/Gc Polyprotein Is Critical for Viral Infectivity and Requires an Internal Gc Signal Peptide
The severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging, highly pathogenic bunyavirus against which neither antivirals nor vaccines are available. The SFTSV glycoproteins, Gn and Gc, facilitate viral entry into host cells. Gn and Gc are generated from a precursor protein, Gn/Gc, but it is currently unknown how the precursor is converted into the single proteins and whether this process is required for viral infectivity. Employing a rhabdoviral pseudotyping system, we demonstrate that a predicted signal sequence at the N-terminus of Gc is required for Gn/Gc processing and viral infectivity while potential proprotein convertase cleavage sites in Gc are dispensable. Moreover, we show that expression of Gn or Gc alone is not sufficient for host cell entry while particles bearing both proteins are infectious, and we provide evidence that Gn facilitates Golgi transport and virion incorporation of Gc. Collectively, these results suggest that signal peptidase liberates mature Gc from the Gn/Gc precursor and that this process is essential for viral infectivity and thus constitutes a potential target for antiviral intervention.
Journal Article
Biomathematical Description of Synthetic Peptide Libraries
Libraries of randomised peptides displayed on phages or viral particles are essential tools in a wide spectrum of applications. However, there is only limited understanding of a library's fundamental dynamics and the influences of encoding schemes and sizes on their quality. Numeric properties of libraries, such as the expected number of different peptides and the library's coverage, have long been in use as measures of a library's quality. Here, we present a graphical framework of these measures together with a library's relative efficiency to help to describe libraries in enough detail for researchers to plan new experiments in a more informed manner. In particular, these values allow us to answer-in a probabilistic fashion-the question of whether a specific library does indeed contain one of the \"best\" possible peptides. The framework is implemented in a web-interface based on two packages, discreteRV and peptider, to the statistical software environment R. We further provide a user-friendly web-interface called PeLiCa (Peptide Library Calculator, http://www.pelica.org), allowing scientists to plan and analyse their peptide libraries.
Journal Article
Letter-Value Plots: Boxplots for Large Data
Boxplots are useful displays that convey rough information about the distribution of a variable. Boxplots were designed to be drawn by hand and work best for small datasets, where detailed estimates of tail behavior beyond the quartiles may not be trustworthy. Larger datasets afford more precise estimates of tail behavior, but boxplots do not take advantage of this precision, instead presenting large numbers of extreme, though not unexpected, observations. Letter-value plots address this problem by including more detailed information about the tails using \"letter values,\" an order statistic defined by Tukey. Boxplots display the first two letter values (the median and quartiles); letter-value plots display further letter values so far as they are reliable estimates of their corresponding quantiles. We illustrate letter-value plots with real data that demonstrate their usefulness for large datasets. All graphics are created using the R package
lvplot
, and code and data are available in the supplementary materials.
Journal Article
TMPRSS2 Isoform 1 Activates Respiratory Viruses and Is Expressed in Viral Target Cells
The cellular protease TMPRSS2 cleaves and activates the influenza virus hemagglutinin (HA) and TMPRSS2 expression is essential for viral spread and pathogenesis in mice. Moreover, severe acute respiratory syndrome coronavirus (SARS-CoV) and other respiratory viruses are activated by TMPRSS2. However, previous studies on viral activation by TMPRSS2 focused on a 492 amino acids comprising form of the protein (isoform 2) while other TMPRSS2 isoforms, generated upon alternative splicing of the tmprss2 mRNA, have not been characterized. Here, we show that the mRNA encoding a TMPRSS2 isoform with an extended N-terminal cytoplasmic domain (isoform 1) is expressed in lung-derived cell lines and tissues. Moreover, we demonstrate that TMPRSS2 isoform 1 colocalizes with HA and cleaves and activates HA. Finally, we show that isoform 1 activates the SARS-CoV spike protein for cathepsin L-independent entry into target cells. Our results indicate that TMPRSS2 isoform 1 is expressed in viral target cells and might contribute to viral activation in the host.
Journal Article
Activation of Sphingomyelinase-Ceramide-Pathway in COVID-19 Purposes Its Inhibition for Therapeutic Strategies
Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs. Here, we report the activation of sphingomyelinase-ceramide pathway in 23 intensive care patients with severe COVID-19. We observed an increase of circulating activity of sphingomyelinase with subsequent derangement of sphingolipids in serum lipoproteins and from red blood cells (RBC). Consistent with increased ceramide levels derived from the inert membrane constituent sphingomyelin, increased activity of acid sphingomyelinase (ASM) accurately distinguished the patient cohort undergoing intensive care from healthy controls. Positive correlational analyses with biomarkers of severe clinical phenotype support the concept of an essential pathophysiological role of ASM in the course of SARS-CoV-2 infection as well as of a promising role for functional inhibition with anti-inflammatory agents in SARS-CoV-2 infection as also proposed in independent observational studies. We conclude that large-sized multicenter, interventional trials are now needed to evaluate the potential benefit of functional inhibition of this sphingomyelinase in critically ill patients with COVID-19.
Journal Article
Variations of Q-Q Plots: The Power of Our Eyes
In statistical modeling, we strive to specify models that resemble data collected in studies or observed from processes. Consequently, distributional specification and parameter estimation are central to parametric models. Graphical procedures, such as the quantile-quantile (Q-Q) plot, are arguably the most widely used method of distributional assessment, though critics find their interpretation to be overly subjective. Formal goodness of fit tests are available and are quite powerful, but only indicate whether there is a lack of fit, not why there is lack of fit. In this article, we explore the use of the lineup protocol to inject rigor into graphical distributional assessment and compare its power to that of formal distributional tests. We find that lineup tests are considerably more powerful than traditional tests of normality. A further investigation into the design of Q-Q plots shows that de-trended Q-Q plots are more powerful than the standard approach as long as the plot preserves distances in x and y to be the same. While we focus on diagnosing nonnormality, our approach is general and can be directly extended to the assessment of other distributions.
Journal Article