Publications

540 Publications visible to you, out of a total of 540

Abstract (Expand)

The circadian clock coordinates plant physiology and development. Mathematical clock models have provided a rigorous framework to understand how the observed rhythms emerge from disparate, molecular processes. However, models of the plant clock have largely been built and tested against RNA timeseries data in arbitrary, relative units. This limits model transferability, refinement from biochemical data and applications in synthetic biology. Here, we incorporate absolute mass units into a detailed, gene circuit model of the clock in Arabidopsis thaliana. We re-interpret the established P2011 model, highlighting a transcriptional activator that overlaps the function of REVEILLE 8/LHY-CCA1-LIKE 5, and refactor dynamic equations for the Evening Complex. The U2020 model incorporates the repressive regulation of PRR genes, a key feature of the most detailed clock model F2014, without greatly increasing model complexity. We tested the experimental error distributions of qRT-PCR data calibrated for units of RNA transcripts/cell and of circadian period estimates, in order to link the models to data more appropriately. U2019 and U2020 models were constrained using these data types, recreating previously-described circadian behaviours with RNA metabolic processes in absolute units. To test their inferred rates, we estimated a distribution of observed, transcriptome-wide transcription rates (Plant Empirical Transcription Rates, PETR) in units of transcripts/cell/hour. The PETR distribution and the equivalent degradation rates indicated that the models’ predicted rates are biologically plausible, with individual exceptions. In addition to updated, explanatory models of the plant clock, this validation process represents an advance in biochemical realism for models of plant gene regulation.

Authors: Uriel Urquiza-Garcia, Andrew J Millar

Date Published: 20th Mar 2021

Publication Type: Tech report

Abstract

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Authors: Jennifer E. Kay, Joshua J. Corrigan, Amanda L. Armijo, Ilana S. Nazari, Ishwar N. Kohale, Dorothea K. Torous, Svetlana L. Avlasevich, Robert G. Croy, Dushan N. Wadduwage, Sebastian E. Carrasco, Stephen D. Dertinger, Forest M. White, John M. Essigmann, Leona D. Samson, Bevin P. Engelward

Date Published: 1st Mar 2021

Publication Type: Journal

Abstract (Expand)

The enzymatic degradation of polyethylene terephthalate (PET) results in a hydrolysate consisting almost exclusively of its two monomers, ethylene glycol and terephthalate. To biologically valorize the PET hydrolysate, microbial upcycling into high-value products is proposed. Fatty acid derivatives hydroxyalkanoyloxy alkanoates (HAAs) represent such valuable target molecules. HAAs exhibit surface-active properties and can be exploited in the catalytical conversion to drop-in biofuels as well as in the polymerization to bio-based poly(amide urethane). This chapter presents the genetic engineering methods of pseudomonads for the metabolization of PET monomers and the biosynthesis of HAAs with detailed protocols concerning product purification.

Authors: Gina Welsing, Birger Wolter, Henric M.T. Hintzen, Till Tiso, Lars M. Blank

Date Published: 2021

Publication Type: Book

Abstract (Expand)

The oxidative Weimberg pathway for the five-step pentose degradation to α-ketoglutarate is a key route for sustainable bioconversion of lignocellulosic biomass to added-value products and biofuels. The oxidative pathway from Caulobacter crescentus has been employed in in-vivo metabolic engineering with intact cells and in in-vitro enzyme cascades. The performance of such engineering approaches is often hampered by systems complexity, caused by non-linear kinetics and allosteric regulatory mechanisms. Here we report an iterative approach to construct and validate a quantitative model for the Weimberg pathway. Two sensitive points in pathway performance have been identified as follows: (1) product inhibition of the dehydrogenases (particularly in the absence of an efficient NAD+ recycling mechanism) and (2) balancing the activities of the dehydratases. The resulting model is utilized to design enzyme cascades for optimized conversion and to analyse pathway performance in C. cresensus cell- free extracts.

Authors: Lu Shen, Martha Kohlhaas, Junichi Enoki, Roland Meier, Bernhard Schönenberger, Roland Wohlgemuth, Robert Kourist, Felix Niemeyer, David van Niekerk, Christopher Bräsen, Jochen Niemeyer, Jacky Snoep, Bettina Siebers

Date Published: 1st Dec 2020

Publication Type: Not specified

Abstract

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Authors: Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin, Feixiong Cheng

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract (Expand)

Using standard systems biology methodologies a 14-compartment dynamic model was developed for the Corona virus epidemic. The model predicts that: (i) it will be impossible to limit lockdown intensity such that sufficient herd immunity develops for this epidemic to die down, (ii) the death toll from the SARS-CoV-2 virus decreases very strongly with increasing intensity of the lockdown, but (iii) the duration of the epidemic increases at first with that intensity and then decreases again, such that (iv) it may be best to begin with selecting a lockdown intensity beyond the intensity that leads to the maximum duration, (v) an intermittent lockdown strategy should also work and might be more acceptable socially and economically, (vi) an initially intensive but adaptive lockdown strategy should be most efficient, both in terms of its low number of casualties and shorter duration, (vii) such an adaptive lockdown strategy offers the advantage of being robust to unexpected imports of the virus, e.g. due to international travel, (viii) the eradication strategy may still be superior as it leads to even fewer deaths and a shorter period of economic downturn, but should have the adaptive strategy as backup in case of unexpected infection imports, (ix) earlier detection of infections is the most effective way in which the epidemic can be controlled, whilst waiting for vaccines.

Authors: Hans V. Westerhoff, Alexey N. Kolodkin

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract

Not specified

Authors: Tatjana Walter, Kareen H. Veldmann, Susanne Götker, Tobias Busche, Christian Rückert, Arman Beyraghdar Kashkooli, Jannik Paulus, Katarina Cankar, Volker F. Wendisch

Date Published: 1st Dec 2020

Publication Type: Journal

Abstract (Expand)

The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.

Authors: Roser Marín-Valls, Karel Hernández, Michael Bolte, Teodor Parella, Jesús Joglar, Jordi Bujons, Pere Clapés

Date Published: 18th Nov 2020

Publication Type: Journal

Abstract (Expand)

How the network around ROS protects against oxidative stress and Parkinson's disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased alpha-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for "life-extending interventions": mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.

Authors: A. N Kolodkin, R. P. Sharma, A. M. Colangelo, A. Ignatenko, F. Martorana, D. Jennen, J. J. Briede, N. Brady, M. Barberis, T. D. G. A. Mondeel, M. Papa, V. Kumar, B. Peters, A. Skupin, L. Alberghina, R. Balling, H. V. Westerhoff

Date Published: 26th Oct 2020

Publication Type: Journal

Abstract (Expand)

The use of controlled mixed inocula of Saccharomyces cerevisiae and non-Saccharomyces yeasts is a common practice in winemaking, with Torulaspora delbrueckii, Lachancea thermotolerans and Metschnikowia pulcherrima being the most commonly used non-Saccharomyces species. Although S. cerevisiae is usually the dominant yeast at the end of mixed fermentations, some non-Saccharomyces species are also able to reach the late stages; such species may not grow in culture media, which is a status known as viable but non-culturable (VBNC). Thus, an accurate methodology to properly monitor viable yeast population dynamics during alcoholic fermentation is required to understand microbial interactions and the contribution of each species to the final product. Quantitative PCR (qPCR) has been found to be a good and sensitive method for determining the identity of the cell population, but it cannot distinguish the DNA from living and dead cells, which can overestimate the final population results. To address this shortcoming, viability dyes can be used to avoid the amplification and, therefore, the quantification of DNA from non-viable cells. In this study, we validated the use of PMAxx dye (an optimized version of propidium monoazide (PMA) dye) coupled with qPCR (PMAxx-qPCR), as a tool to monitor the viable population dynamics of the most common yeast species used in wine mixed fermentations (S. cerevisiae, T. delbrueckii, L. thermotolerans and M. pulcherrima), comparing the results with non-dyed qPCR and colony counting on differential medium. Our results showed that the PMAxx-qPCR assay used in this study is a reliable, specific and fast method for quantifying these four yeast species during the alcoholic fermentation process, being able to distinguish between living and dead yeast populations. Moreover, the entry into VBNC status was observed for the first time in L. thermotolerans and S. cerevisiae during alcoholic fermentation. Further studies are needed to unravel which compounds trigger this VBNC state during alcoholic fermentation in these species, which would help to better understand yeast interactions.

Authors: Yurena Navarro, María-Jesús Torija, Albert Mas, Gemma Beltran

Date Published: 1st Oct 2020

Publication Type: Journal

Abstract (Expand)

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

Authors: Ahmed Sadik, Luis F. Somarribas Patterson, Selcen Öztürk, Soumya R. Mohapatra, Verena Panitz, Philipp F. Secker, Pauline Pfänder, Stefanie Loth, Heba Salem, Mirja Tamara Prentzell, Bianca Berdel, Murat Iskar, Erik Faessler, Friederike Reuter, Isabelle Kirst, Verena Kalter, Kathrin I. Foerster, Evelyn Jäger, Carina Ramallo Guevara, Mansour Sobeh, Thomas Hielscher, Gernot Poschet, Annekathrin Reinhardt, Jessica C. Hassel, Marc Zapatka, Udo Hahn, Andreas von Deimling, Carsten Hopf, Rita Schlichting, Beate I. Escher, Jürgen Burhenne, Walter E. Haefeli, Naveed Ishaque, Alexander Böhme, Sascha Schäuble, Kathrin Thedieck, Saskia Trump, Martina Seiffert, Christiane A. Opitz

Date Published: 1st Sep 2020

Publication Type: Journal

Abstract (Expand)

Droplet-based microfluidic systems offer a high potential for miniaturization and automation. Therefore, they are becoming an increasingly important tool in analytical chemistry, biosciences, and medicine. Heterogeneous assays commonly utilize magnetic beads as a solid phase. However, the sensitivity of state of the art microfluidic systems is limited by the high bead concentrations required for efficient extraction across the water–oil interface. Furthermore, current systems suffer from a lack of technical solutions for sequential measurements of multiple samples, limiting their throughput and capacity for automation. Taking advantage of the different wetting properties of hydrophilic and hydrophobic areas in the channels, we improve the extraction efficiency of magnetic beads from aqueous nanoliter-sized droplets by 2 orders of magnitude to the low μg/mL range. Furthermore, the introduction of a switchable magnetic trap enables repetitive capture and release of magnetic particles for sequential analysis of multiple samples, enhancing the throughput. In comparison to conventional ELISA-based sandwich immunoassays on microtiter plates, our microfluidic setup offers a 25–50-fold reduction of sample and reagent consumption with up to 50 technical replicates per sample. The enhanced sensitivity and throughput of this system open avenues for the development of automated detection of biomolecules at the nanoliter scale.

Authors: Lukas Metzler, Ulrike Rehbein, Jan-Niklas Schönberg, Thomas Brandstetter, Kathrin Thedieck, Jürgen Rühe

Date Published: 4th Aug 2020

Publication Type: Journal

Abstract (Expand)

Background: The current COVID-19 pandemic has led to a surge of research activity. While this research provides important insights, the multitude of studies results in an increasing segmentation of information. To ensure comparability across projects and institutions, standard datasets are needed. Here, we introduce the "German Corona Consensus Dataset" (GECCO), a uniform dataset that uses international terminologies and health IT standards to improve interoperability of COVID-19 data. Methods: Based on previous work (e.g., the ISARIC-WHO COVID-19 case report form) and in coordination with experts from university hospitals, professional associations and research initiatives, data elements relevant for COVID-19 research were collected, prioritized and consolidated into a compact core dataset. The dataset was mapped to international terminologies, and the Fast Healthcare Interoperability Resources (FHIR) standard was used to define interoperable, machine-readable data formats. Results: A core dataset consisting of 81 data elements with 281 response options was defined, including information about, for example, demography, anamnesis, symptoms, therapy, medications or laboratory values of COVID-19 patients. Data elements and response options were mapped to SNOMED CT, LOINC, UCUM, ICD-10-GM and ATC, and FHIR profiles for interoperable data exchange were defined. Conclusion: GECCO provides a compact, interoperable dataset that can help to make COVID-19 research data more comparable across studies and institutions. The dataset will be further refined in the future by adding domain-specific extension modules for more specialized use cases.

Authors: Julian Sass, Alexander Bartschke, Moritz Lehne, Andrea Essenwanger, Eugenia Rinaldi, Stefanie Rudolph, Kai Uwe Heitmann, Joerg Janne Vehreschild, Christof von Kalle, Sylvia Thun

Date Published: 29th Jul 2020

Publication Type: Journal

Abstract (Expand)

This paper presents a report on outcomes of the 10th Computational Modeling in Biology Network (COMBINE) meeting that was held in Heidelberg, Germany, in July of 2019. The annual event brings together researchers, biocurators and software engineers to present recent results and discuss future work in the area of standards for systems and synthetic biology. The COMBINE initiative coordinates the development of various community standards and formats for computational models in the life sciences. Over the past 10 years, COMBINE has brought together standard communities that have further developed and harmonized their standards for better interoperability of models and data. COMBINE 2019 was co-located with a stakeholder workshop of the European EU-STANDS4PM initiative that aims at harmonized data and model standardization for in silico models in the field of personalized medicine, as well as with the FAIRDOM PALs meeting to discuss findable, accessible, interoperable and reusable (FAIR) data sharing. This report briefly describes the work discussed in invited and contributed talks as well as during breakout sessions. It also highlights recent advancements in data, model, and annotation standardization efforts. Finally, this report concludes with some challenges and opportunities that this community will face during the next 10 years.

Authors: Dagmar Waltemath, Martin Golebiewski, Michael L Blinov, Padraig Gleeson, Henning Hermjakob, Michael Hucka, Esther Thea Inau, Sarah M Keating, Matthias König, Olga Krebs, Rahuman S Malik-Sheriff, David Nickerson, Ernst Oberortner, Herbert M Sauro, Falk Schreiber, Lucian Smith, Melanie I Stefan, Ulrike Wittig, Chris J Myers

Date Published: 29th Jun 2020

Publication Type: Journal

Abstract (Expand)

This special issue of the Journal of Integrative Bioinformatics presents papers related to the 10th COMBINE meeting together with the annual update of COMBINE standards in systems and synthetic biology.Not specified

Authors: Falk Schreiber, Björn Sommer, Tobias Czauderna, Martin Golebiewski, Thomas E. Gorochowski, Michael Hucka, Sarah M. Keating, Matthias König, Chris Myers, David Nickerson, Dagmar Waltemath

Date Published: 29th Jun 2020

Publication Type: Journal

Abstract (Expand)

The booming demand for environmentally benign industrial processes relies on the ability to quickly find or engineer a biocatalyst suitable to ideal process conditions. Both metagenomic approaches and directed evolution involve the screening of huge libraries of protein variants, which can only be managed reasonably by flexible platforms for (ultra)high-throughput profiling against the desired criteria. Here, we review the most recent additions toward a growing toolbox of versatile assays using fluorescence, absorbance and mass spectrometry readouts. While conventional solution based high-throughput screening in microtiter plate formats is still important, the implementation of novel screening protocols for microfluidic cell or droplet sorting systems supports technological advances for ultra-high-frequency screening that now can dramatically reduce the timescale of engineering projects. We discuss practical issues of scope, scalability, sensitivity and stereoselectivity for the improvement of biotechnologically relevant enzymes from different classes.

Authors: Yuriy V Sheludko, Wolf-Dieter Fessner

Date Published: 29th Jun 2020

Publication Type: Journal

Abstract

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Authors: Tatjana Walter, Nour Al Medani, Arthur Burgardt, Katarina Cankar, Lenny Ferrer, Anastasia Kerbs, Jin-Ho Lee, Melanie Mindt, Joe Max Risse, Volker F. Wendisch

Date Published: 1st Jun 2020

Publication Type: Journal

Abstract

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Authors: Zichen Wang, Amanda B Zheutlin, Yu-Han Kao, Kristin L Ayers, Susan J Gross, Patricia Kovatch, Sharon Nirenberg, Alexander W Charney, Girish N Nadkarni, Paul F O'Reilly, Allan C Just, Carol R Horowitz, Glenn Martin, Andrea D Branch, Benjamin S Glicksberg, Dennis S Charney, David L Reich, William K Oh, Eric E Schadt, Rong Chen, Li Li

Date Published: 4th May 2020

Publication Type: Misc

Abstract (Expand)

The alcohol content in wine has increased due to external factors in recent decades. In recent reports, some non-Saccharomyces yeast species have been confirmed to reduce ethanol during the alcoholic fermentation process. Thus, an efficient screening of non-Saccharomyces yeasts with low ethanol yield is required due to the broad diversity of these yeasts. In this study, we proposed a rapid method for selecting strains with a low ethanol yield from forty-five non-Saccharomyces yeasts belonging to eighteen species. Single fermentations were carried out for this rapid selection. Then, sequential fermentations in synthetic and natural must were conducted with the selected strains to confirm their capacity to reduce ethanol compared with that of Saccharomyces cerevisiae. The results showed that ten non-Saccharomyces strains were able to reduce the ethanol content, namely, Hanseniaspora uvarum (2), Issatchenkia terricola (1), Metschnikowia pulcherrima (2), Lachancea thermotolerans (1), Saccharomycodes ludwigii (1), Torulaspora delbrueckii (2), and Zygosaccharomyces bailii (1). Compared with S. cerevisiae, the ethanol reduction of the selected strains ranged from 0.29 to 1.39% (v/v). Sequential inoculations of M. pulcherrima (Mp51 and Mp FA) and S. cerevisiae reduced the highest concentration of ethanol by 1.17 to 1.39% (v/v) in synthetic or natural must. Second, sequential fermentations with Z. bailii (Zb43) and T. delbrueckii (Td Pt) performed in natural must yielded ethanol reductions of 1.02 and 0.84% (v/v), respectively.

Authors: Xiaolin Zhu, Yurena Navarro, Albert Mas, María-Jesús Torija, Gemma Beltran

Date Published: 1st May 2020

Publication Type: Journal

Abstract (Expand)

Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets.

Authors: Avlant Nilsson, Jurgen R. Haanstra, Martin Engqvist, Albert Gerding, Barbara M. Bakker, Ursula Klingmüller, Bas Teusink, Jens Nielsen

Date Published: 27th Apr 2020

Publication Type: Journal

Abstract (Expand)

Background and aims: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has recently spread worldwide and been declared a pandemic. We aim to describe here the various clinical presentations of this disease by examining eleven cases. Methods: Electronic medical records of 11 patients with COVID-19 were collected and demographics, clinical manifestations, outcomes, key laboratory results, and radiological images are discussed. Results: The clinical course of the eleven cases demonstrated the complexity of the COVID-19 profile with different clinical presentations. Clinical manifestations range from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Laboratory detection of the viral nucleic acid can yield false-negative results, and serological testing of virus specific IgG and IgM antibodies should be used as an alternative for diagnosis. Patients with common allergic diseases did not develop distinct symptoms and severe courses. Cases with a pre-existing condition of chronic obstructive pulmonary disease or complicated with a secondary bacterial pneumonia were more severe. Conclusion: All different clinical characteristics of COVID-19 should be taken into consideration to identify patients that need to be in strict quarantine for the efficient containment of the pandemic.

Authors: Xiang Dong, Yi-yuan Cao, Xiao-xia Lu, Jin-jin Zhang, Hui Du, You-qin Yan, Cezmi A. Akdis, Ya-dong Gao

Date Published: 6th Apr 2020

Publication Type: Journal

Abstract (Expand)

In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.

Authors: B. Coutard, C. Valle, X. de Lamballerie, B. Canard, N.G. Seidah, E. Decroly

Date Published: 1st Apr 2020

Publication Type: Journal

Abstract

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Authors: Michael Letko, Andrea Marzi, Vincent Munster

Date Published: 1st Apr 2020

Publication Type: Journal

Abstract

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Authors: Justin Stebbing, Anne Phelan, Ivan Griffin, Catherine Tucker, Olly Oechsle, Dan Smith, Peter Richardson

Date Published: 1st Apr 2020

Publication Type: Journal

Abstract

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Authors: Shuai Xia, Meiqin Liu, Chao Wang, Wei Xu, Qiaoshuai Lan, Siliang Feng, Feifei Qi, Linlin Bao, Lanying Du, Shuwen Liu, Chuan Qin, Fei Sun, Zhengli Shi, Yun Zhu, Shibo Jiang, Lu Lu

Date Published: 1st Apr 2020

Publication Type: Journal

Abstract (Expand)

During its first two and a half months, the recently emerged 2019 novel coronavirus, SARS-CoV-2, has already infected over one-hundred thousand people worldwide and has taken more than four thousand lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge, we leveraged data about the related coronaviruses that is readily available in public databases and integrated these data into a single computational pipeline. As a result, we provide comprehensive structural genomics and interactomics roadmaps of SARS-CoV-2 and use this information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community.

Authors: Suhas Srinivasan, Hongzhu Cui, Ziyang Gao, Ming Liu, Senbao Lu, Winnie Mkandawire, Oleksandr Narykov, Mo Sun, Dmitry Korkin

Date Published: 1st Apr 2020

Publication Type: Journal

Abstract (Expand)

The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory infection caused by the novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat coronavirus. In this study, conserved domain analysis, homology modeling, and molecular docking were used to compare the biological roles of certain proteins of the novel coronavirus. The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, respectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease. According to the validation analysis of these finds, chloroquine could prevent orf1ab, ORF3a, and ORF10 to attack the heme to form the porphyrin, and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress. Favipiravir could inhibit the envelope protein and ORF7a protein bind to porphyrin, prevent the virus from entering host cells, and catching free porphyrins. Because the novel coronavirus is dependent on porphyrins, it may originate from an ancient virus. Therefore, this research is of high value to contemporary biological experiments, disease prevention, and clinical treatment.

Authors: Liu Wenzhong, Li Hualan

Date Published: 30th Mar 2020

Publication Type: Journal

Abstract

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Authors: Muthiah Vaduganathan, Orly Vardeny, Thomas Michel, John J.V. McMurray, Marc A. Pfeffer, Scott D. Solomon

Date Published: 30th Mar 2020

Publication Type: Journal

Abstract

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Authors: Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, Xiaoping Zhang, Minxia Zhang, Shiji Wu, Jianxin Song, Tao Chen, Meifang Han, Shusheng Li, Xiaoping Luo, Jianping Zhao, Qin Ning

Date Published: 27th Mar 2020

Publication Type: Journal

Abstract (Expand)

The pandemic caused by emerging coronavirus SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. SARS CoV-2 cellular entry depends on binding between the viral Spike protein receptor-binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) target cell receptor. Here, we report on the isolation and characterization of 206 RBD-specific monoclonal antibodies (mAbs) derived from single B cells of eight SARS-CoV-2 infected individuals. These mAbs come from diverse families of antibody heavy and light chains without apparent enrichment for particular families in the repertoire. In samples from one patient selected for further analyses, we found coexistence of germline and germline divergent clones. Both clone types demonstrated impressive binding and neutralizing activity against pseudovirus and live SARS-CoV-2. However, the antibody neutralizing potency is determined by competition with ACE2 receptor for RBD binding. Surprisingly, none of the SARS CoV 2 antibodies nor the infected plasma cross-reacted with RBDs from either SARS CoV or MERS CoV although substantial plasma cross reactivity to the trimeric Spike proteins from SARS-CoV and MERS-CoV was found. These results suggest that antibody response to RBDs is viral species-specific while that cross-recognition target regions outside the RBD. The specificity and neutralizing characteristics of this plasma cross-reactivity requires further investigation. Nevertheless, the diverse and potent neutralizing antibodies identified here are promising candidates for prophylactic and therapeutic SARS-CoV-2 interventions.

Authors: Bin Ju, Qi Zhang, Xiangyang Ge, Ruoke Wang, Jiazhen Yu, Sisi Shan, Bing Zhou, Shuo Song, Xian Tang, Jinfang Yu, Jiwan Ge, Jun Lan, Jing Yuan, Haiyan Wang, Juanjuan Zhao, Shuye Zhang, Youchun Wang, Xuanling Shi, Lei Liu, Xinquan Wang, Zheng Zhang, Linqi Zhang

Date Published: 25th Mar 2020

Publication Type: Tech report

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