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The insert sequence in SARS-CoV-2 enhances spike protein cleavage by TMPRSS

Abstract (Expand)

Abstract At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China 1 , even more spread than SARS-CoV infection 2 . The entry of SARS-CoV into host cells mainly depends on … the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion 3,4 . The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear 5,6 . Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.

Authors: Tong Meng, Hao Cao, Hao Zhang, Zijian Kang, Da Xu, Haiyi Gong, Jing Wang, Zifu Li, Xingang Cui, Huji Xu, Haifeng Wei, Xiuwu Pan, Rongrong Zhu, Jianru Xiao, Wang Zhou, Liming Cheng, Jianmin Liu

Date Published: 11th Feb 2020

Publication Type: Tech report

Clinical characteristics of 2019 novel coronavirus infection in China

Abstract (Expand)

Background: Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical … characteristics of these cases.

Authors: Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David SC Hui, Bin Du, Lan-juan Li, Guang Zeng, Kowk-Yung Yuen, Ru-chong Chen, Chun-li Tang, Tao Wang, Ping-yan Chen, Jie Xiang, Shi-yue Li, Jin-lin Wang, Zi-jing Liang, Yi-xiang Peng, Li Wei, Yong Liu, Ya-hua Hu, Peng Peng, Jian-ming Wang, Ji-yang Liu, Zhong Chen, Gang Li, Zhi-jian Zheng, Shao-qin Qiu, Jie Luo, Chang-jiang Ye, Shao-yong Zhu, Nan-shan Zhong

Date Published: 9th Feb 2020

Publication Type: Tech report

Emerging coronaviruses: Genome structure, replication, and pathogenesis

Abstract (Expand)

The recent emergence of a novel coronavirus (2019‐nCoV), which is causing an outbreak of unusual viral pneumonia in patients in Wuhan, a central city in China, is another warning of the risk of CoVs … posed to public health. In this minireview, we provide a brief introduction of the general features of CoVs and describe diseases caused by different CoVs in humans and animals. This review will help understand the biology and potential risk of CoVs that exist in richness in wildlife such as bats.

Authors: Yu Chen, Qianyun Liu, Deyin Guo

Date Published: 7th Feb 2020

Publication Type: Journal

Coronavirus infections and immune responses

Abstract (Expand)

Coronaviruses (CoVs) are by far the largest group of known positive-sense RNA viruses having an extensive range of natural hosts. In the past few decades, newly evolved Coronaviruses have posed a global … threat to public health. The immune response is essential to control and eliminate CoV infections, however, maladjusted immune responses may result in immunopathology and impaired pulmonary gas exchange. Gaining a deeper understanding of the interaction between Coronaviruses and the innate immune systems of the hosts may shed light on the development and persistence of inflammation in the lungs and hopefully can reduce the risk of lung inflammation caused by CoVs. In this review, we provide an update on CoV infections and relevant diseases, particularly the host defense against CoV-induced inflammation of lung tissue, as well as the role of the innate immune system in the pathogenesis and clinical treatment.

Authors: Geng Li, Yaohua Fan, Yanni Lai, Tiantian Han, Zonghui Li, Peiwen Zhou, Pan Pan, Wenbiao Wang, Dingwen Hu, Xiaohong Liu, Qiwei Zhang, Jianguo Wu

Date Published: 7th Feb 2020

Publication Type: Journal

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Abstract (Expand)

Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and … radiological characteristics and treatment and clinical outcomes of these patients.

Authors: Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, Zhenshun Cheng, Ting Yu, Jiaan Xia, Yuan Wei, Wenjuan Wu, Xuelei Xie, Wen Yin, Hui Li, Min Liu, Yan Xiao, Hong Gao, Li Guo, Jungang Xie, Guangfa Wang, Rongmeng Jiang, Zhancheng Gao, Qi Jin, Jianwei Wang, Bin Cao

Date Published: 1st Feb 2020

Publication Type: Journal

Nitrogen Preferences during Alcoholic Fermentation of Different Non-Saccharomyces Yeasts of Oenological Interest

Abstract (Expand)

Non-Saccharomyces yeasts have long been considered spoilage microorganisms. Currently, oenological interest in those species is increasing, mostly due to their positive contribution to wine quality. … In this work, the fermentative capacity and nitrogen consumption of several non-Saccharomyces wine yeast (Torulaspora delbrueckii, Lachancea thermotolerans, Starmerella bacillaris, Hanseniaspora uvarum, and Metschnikowia pulcherrima) were analyzed. For this purpose, synthetic must with three different nitrogen compositions was used: a mixture of amino acids and ammonium, only organic or inorganic nitrogen. The fermentation kinetics, nitrogen consumption, and yeast growth were measured over time. Our results showed that the good fermentative strains, T. delbrueckii and L. thermotolerans, had high similarities with Saccharomyces cerevisiae in terms of growth, fermentation profile, and nitrogen assimilation preferences, although L. thermotolerans presented an impaired behavior when only amino acids or ammonia were used, being strain-specific. M. pulcherrima was the non-Saccharomyces strain least affected by the nitrogen composition of the medium. The other two poor fermentative strains, H. uvarum and S. bacillaris, behaved similarly regarding amino acid uptake, which occurred earlier than that of the good fermentative species in the absence of ammonia. The results obtained in single non-Saccharomyces fermentations highlighted the importance of controlling nitrogen requirements of the wine yeasts, mainly in sequential fermentations, in order to manage a proper nitrogen supplementation, when needed.

Authors: Helena Roca-Mesa, Sonia Sendra, Albert Mas, Gemma Beltran, María-Jesús Torija

Date Published: 1st Feb 2020

Publication Type: Journal

GEMtractor: extracting views into genome-scale metabolic models

Abstract (Expand)

SUMMARY: Computational metabolic models typically encode for graphs of species, reactions, and enzymes. Comparing genome-scale models through topological analysis of multipartite graphs is challenging. …. However, in many practical cases it is not necessary to compare the full networks. The GEMtractor is a web-based tool to trim models encoded in SBML. It can be used to extract subnetworks, for example focusing on reaction- and enzyme-centric views into the model. AVAILABILITY AND IMPLEMENTATION: The GEMtractor is licensed under the terms of GPLv3 and developed at github.com/binfalse/GEMtractor - a public version is available at sbi.uni-rostock.de/gemtractor.

Authors: Martin Scharm, Olaf Wolkenhauer, Mahdi Jalili, Ali Salehzadeh-Yazdi

Date Published: 31st Jan 2020

Publication Type: Journal

A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses

Abstract (Expand)

World Health Organization has declared the ongoing outbreak of coronavirus disease 2019 (COVID-19) a Public Health Emergency of International Concern. The virus was named severe acute respiratory … syndrome coronavirus 2 (SARSCoV-2) by the International Committee on Taxonomy of Viruses. Human infection with SARS-CoV-2 leads to a wide range of clinical manifestations ranging from asymptomatic, mild, moderate to severe. The severe cases present with pneumonia, which can progress to acute respiratory distress syndrome. The outbreak provides an opportunity for real-time tracking of an animal coronavirus that has just crossed species barrier to infect humans. The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Here, we review the discovery, zoonotic origin, animal hosts, transmissibility and pathogenicity of SARS-CoV-2 in relation to its interplay with host antiviral defense. A comparison with SARS-CoV, Middle East respiratory syndrome coronavirus, community-acquired human coronaviruses and other pathogenic viruses including human immunodeficiency viruses is made. We summarize current understanding of the induction of a proinflammatory cytokine storm by other highly pathogenic human coronaviruses, their adaptation to humans and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host antiviral defence, including asymptomatic and presymptomatic virus shedding, are also discussed.

Authors: Sin-Yee Fung, Kit-San Yuen, Zi-Wei Ye, Chi-Ping Chan, Dong-Yan Jin

Date Published: 2020

Publication Type: Journal

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

Abstract (Expand)

A mysterious outbreak of atypical pneumonia in late 2019 was traced to a seafood wholesale market in Wuhan of China. Within a few weeks, a novel coronavirus tentatively named as 2019 novel coronavirus … (2019-nCoV) was announced by the World Health Organization. We performed bioinformatics analysis on a virus genome from a patient with 2019-nCoV infection and compared it with other related coronavirus genomes. Overall, the genome of 2019-nCoV has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. The phylogenetic trees of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein also clustered closely with those of the bat, civet and human SARS coronaviruses. However, the external subdomain of Spike’s receptor binding domain of 2019-nCoV shares only 40% amino acid identity with other SARS-related coronaviruses. Remarkably, its orf3b encodes a completely novel short protein. Furthermore, its new orf8 likely encodes a secreted protein with an alpha-helix, following with a beta-sheet(s) containing six strands. Learning from the roles of civet in SARS and camel in MERS, hunting for the animal source of 2019-nCoV and its more ancestral virus would be important for understanding the origin and evolution of this novel lineage B betacoronavirus. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection.

Authors: Jasper Fuk-Woo Chan, Kin-Hang Kok, Zheng Zhu, Hin Chu, Kelvin Kai-Wang To, Shuofeng Yuan, Kwok-Yung Yuen

Date Published: 2020

Publication Type: Journal

Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19

Abstract (Expand)

Coronaviruses (CoVs) are a group of enveloped, single-stranded positive genomic RNA viruses and some of them are known to cause severe respiratory diseases in human, including Severe Acute Respiratory … Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the ongoing coronavirus disease-19 (COVID-19). One key element in viral infection is the process of viral entry into the host cells. In the last two decades, there is increasing understanding on the importance of the endocytic pathway and the autophagy process in viral entry and replication. As a result, the endocytic pathway including endosome and lysosome has become important targets for development of therapeutic strategies in combating diseases caused by CoVs. In this mini-review, we will focus on the importance of the endocytic pathway as well as the autophagy process in viral infection of several pathogenic CoVs inclusive of SARS-CoV, MERS-CoV and the new CoV named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and discuss the development of therapeutic agents by targeting these processes. Such knowledge will provide important clues for control of the ongoing epidemic of SARS-CoV-2 infection and treatment of COVID-19.

Authors: Naidi Yang, Han-Ming Shen

Date Published: 2020

Publication Type: Journal

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human.

Abstract (Expand)

The Hedgehog (Hh) and Wnt/beta-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and … control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Authors: E. Kolbe, S. Aleithe, C. Rennert, L. Spormann, F. Ott, D. Meierhofer, R. Gajowski, C. Stopel, S. Hoehme, M. Kucken, L. Brusch, M. Seifert, W. von Schoenfels, C. Schafmayer, M. Brosch, U. Hofmann, G. Damm, D. Seehofer, J. Hampe, R. Gebhardt, M. Matz-Soja

Date Published: 24th Dec 2019

Publication Type: Journal

Convergent in situ Generation of Both Transketolase Substrates via Transaminase and Aldolase Reactions for Sequential One‐Pot, Three‐Step Cascade Synthesis of Ketoses

Abstract

Not specified

Authors: Marion Lorillière, Christine Guérard‐Hélaine, Thierry Gefflaut, Wolf‐Dieter Fessner, Pere Clapés, Franck Charmantray, Laurence Hecquet

Date Published: 12th Dec 2019

Publication Type: Journal

The therapeutic potential of targeting tryptophan catabolism in cancer.

Abstract (Expand)

Based on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. … Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

Authors: C. A. Opitz, L. F. Somarribas Patterson, S. R. Mohapatra, D. L. Dewi, A. Sadik, M. Platten, S. Trump

Date Published: 11th Dec 2019

Publication Type: Journal

CRISPR/Cas9-mediated ablation of elovl2 in Atlantic salmon (Salmo salar L.) inhibits elongation of polyunsaturated fatty acids and induces Srebp-1 and target genes

Abstract (Expand)

Atlantic salmon can synthesize polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (20:5n-3), arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) via activities of very long … chain fatty acyl elongases (Elovls) and fatty acyl desaturases (Fads), albeit to a limited degree. Understanding molecular mechanisms of PUFA biosynthesis and regulation is a pre-requisite for sustainable use of vegetable oils in aquafeeds as current sources of fish oils are unable to meet increasing demands for omega-3 PUFAs. By generating CRISPR-mediated elovl2 partial knockout (KO), we have shown that elovl2 is crucial for multi-tissue synthesis of 22:6n-3 in vivo and that endogenously synthesized PUFAs are important for transcriptional regulation of lipogenic genes in Atlantic salmon. The elovl2-KOs showed reduced levels of 22:6n-3 and accumulation of 20:5n-3 and docosapentaenoic acid (22:5n-3) in the liver, brain and white muscle, suggesting inhibition of elongation. Additionally, elovl2-KO salmon showed accumulation of 20:4n-6 in brain and white muscle. The impaired synthesis of 22:6n-3 induced hepatic expression of sterol regulatory element binding protein-1 (srebp-1), fatty acid synthase-b, Δ6fad-a, Δ5fad and elovl5. Our study demonstrates key roles of elovl2 at two penultimate steps of PUFA synthesis in vivo and suggests Srebp-1 as a main regulator of endogenous PUFA synthesis in Atlantic salmon.

Authors: Alex K. Datsomor, Nikola Zic, Keshuai Li, Rolf E. Olsen, Yang Jin, Jon Olav Vik, Rolf B. Edvardsen, Fabian Grammes, Anna Wargelius, Per Winge

Date Published: 1st Dec 2019

Publication Type: Not specified

Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice

Abstract (Expand)

Abstract During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain … acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However, a subset of these children remains asymptomatic throughout life. In MCAD-deficient (MCAD-KO) mice, glucose levels are similar to those of wild-type (WT) mice, even during fasting. We investigated if metabolic adaptations in the liver may underlie the robustness of this KO mouse. WT and KO mice were given a high- or low-fat diet and subsequently fasted. We analyzed histology, mitochondrial function, targeted mitochondrial proteomics, and transcriptome in liver tissue. Loss of MCAD led to a decreased capacity to oxidize octanoyl-CoA. This was not compensated for by altered protein levels of the short- and long-chain isoenzymes SCAD and LCAD. In the transcriptome, we identified subtle adaptations in the expression of genes encoding enzymes catalyzing CoA- and NAD(P)(H)-involving reactions and of genes involved in detoxification mechanisms. We discuss how these processes may contribute to robustness in MCAD-KO mice and potentially also in asymptomatic human subjects with a complete loss of MCAD activity.

Authors: Anne-Claire M. F. Martines, Albert Gerding, Sarah Stolle, Marcel A. Vieira-Lara, Justina C. Wolters, Angelika Jurdzinski, Laura Bongiovanni, Alain de Bruin, Pieter van der Vlies, Gerben van der Vries, Vincent W. Bloks, Terry G. J. Derks, Dirk-Jan Reijngoud, Barbara M. Bakker

Date Published: 1st Dec 2019

Publication Type: Journal

Data Management in Computational Systems Biology: Exploring Standards, Tools, Databases, and Packaging Best Practices.

Abstract (Expand)

Computational systems biology involves integrating heterogeneous datasets in order to generate models. These models can assist with understanding and prediction of biological phenomena. Generating … datasets and integrating them into models involves a wide range of scientific expertise. As a result these datasets are often collected by one set of researchers, and exchanged with others researchers for constructing the models. For this process to run smoothly the data and models must be FAIR-findable, accessible, interoperable, and reusable. In order for data and models to be FAIR they must be structured in consistent and predictable ways, and described sufficiently for other researchers to understand them. Furthermore, these data and models must be shared with other researchers, with appropriately controlled sharing permissions, before and after publication. In this chapter we explore the different data and model standards that assist with structuring, describing, and sharing. We also highlight the popular standards and sharing databases within computational systems biology.

Authors: N. J. Stanford, M. Scharm, P. D. Dobson, M. Golebiewski, M. Hucka, V. B. Kothamachu, D. Nickerson, S. Owen, J. Pahle, U. Wittig, D. Waltemath, C. Goble, P. Mendes, J. Snoep

Date Published: 12th Oct 2019

Publication Type: Journal

Genome-scale Model Constrained by Proteomics Reveals Metabolic Changes in Streptomyces coelicolor M1152 Compared to M145

Abstract (Expand)

Streptomyces coelicolor M1152 is a widely used host strain for the heterologous production of novel small molecule natural products, genetically engineered for this purpose through e.g. deletion of … four of its native biosynthetic gene clusters (BGCs) for improved precursor supply. Regardless of its potential, a systems understanding of its tight regulatory network and the effects of the significant genomic changes in M1152 is missing. In this study, we compare M1152 to its ancestor M145, thereby connecting observed phenotypic differences to changes on transcription and translation. Measured protein levels are connected to predicted metabolic fluxes, facilitated by an enzyme-constrained genome-scale model (GEM), that by itself is a consensus result of a community effort. This approach connects observed differences in growth rate and glucose consumption to changes in central carbon metabolism, accompanied by differential expression of important regulons. Results suggest that precursors supply is not limiting secondary metabolism, informing that alternative strategies will be beneficial for further development of S. coelicolor for heterologous production of novel compounds.

Authors: Snorre Sulheim, Tjaša Kumelj, Dino van Dissel, Ali Salehzadeh-Yazdi, Chao Du, Gilles P. van Wezel, Kay Nieselt, Eivind Almaas, Alexander Wentzel, Eduard J Kerkhoven

Date Published: 8th Oct 2019

Publication Type: Unpublished

Developing A Virus-MicroRNA Interactome Using Cystoscope

Abstract (Expand)

It is currently difficult to determine the effect of oncogenic viruses on the global function and regulation of pathways within mammalian cells. A thorough understanding of the molecular pathways and … individual genes altered by oncogenic viruses is needed for the identification of targets that can be utilised for early diagnosis, prevention, and treatment methods. We detail a logical step-by-step guide to uncover viral-protein-miRNA interactions using publically available datasets and the network building program, Cytoscape. This method may be applied to identify specific pathways that are altered in viral infection, and contribute to the oncogenic transformation of cells. To demonstrate this, we constructed a gene regulatory interactome encompassing Human Papillomavirus Type 16 (HPV16) and its control of specific miRNAs. This approach can be broadly applied to understand and map the regulatory functions of other oncogenic viruses, and determine their role in altering the cellular environment in cancer.

Authors: Meredith Hill, Dayna Mason, Tânia Monteiro Marques, Margarida Gama Carvalho, Nham Tran

Date Published: 1st Oct 2019

Publication Type: Not specified

Effects of Agricultural Pesticides in Aquafeeds on Wild Fish Feeding on Leftover Pellets Near Fish Farms

Abstract (Expand)

Screening has revealed that modern-day feeds used in Atlantic salmon aquaculture might contain trace amounts of agricultural pesticides. To reach slaughter size, salmon are produced in open net pens … in the sea. Uneaten feed pellets and undigested feces deposited beneath the net pens represent a source of contamination for marine organisms. To examine the impacts of long-term and continuous dietary exposure to an organophosphorus pesticide found in Atlantic salmon feed, we fed juvenile Atlantic cod (Gadus morhua), an abundant species around North Atlantic fish farms, three concentrations (0.5, 4.2, and 23.2 mg/kg) of chlorpyrifos-methyl (CPM) for 30 days. Endpoints included liver and bile bioaccumulation, liver transcriptomics and metabolomics, as well as plasma cholinesterase activity, cortisol, liver 7-ethoxyresor-ufin-O-deethylase activity, and hypoxia tolerance. The results show that Atlantic cod can accumulate relatively high levels of CPM in liver after continuous exposure, which is then metabolized and excreted via the bile. All three exposure concentrations lead to significant inhibition of plasma cholinesterase activity, the primary target of CPM. Transcriptomics profiling pointed to effects on cholesterol and steroid biosynthesis. Metabolite profiling revealed that CPM induced responses reflecting detoxification by glutathione-S-transferase, inhibition of monoacylglycerol lipase, potential inhibition of carboxylesterase, and increased demand for ATP, followed by secondary inflammatory responses. A gradual hypoxia challenge test showed that all groups of exposed fish were less tolerant to low oxygen saturation than the controls. In conclusion, this study suggests that wild fish continuously feeding on leftover pellets near fish farms over time may be vulnerable to organophosphorus pesticides.

Authors: Pål A. Olsvik, Anett Kristin Larsen, Marc H. G. Berntssen, Anders Goksøyr, Odd André Karlsen, Fekadu Yadetie, Monica Sanden, Torstein Kristensen

Date Published: 26th Sep 2019

Publication Type: Journal

Resistance Exercise Reduces Kynurenine Pathway Metabolites in Breast Cancer Patients Undergoing Radiotherapy

Abstract (Expand)

Purpose: Evidence from preclinical studies and trials in healthy volunteers suggests that exercise may modulate the levels of tryptophan (TRP) metabolites along the kynurenine (KYN) pathway. As KYN and … downstream KYN metabolites are known to promote cancer progression by inhibiting anti-tumor immune responses and by promoting the motility of cancer cells, we investigated if resistance exercise can also control the levels of KYN pathway metabolites in breast cancer patients undergoing radiotherapy (NCT01468766). Patients and Methods: Chemotherapy-naïve breast cancer patients (n = 96) were either randomized to an exercise/intervention group (IG) or a control group (CG). The IG participated in a 12-week supervised progressive resistance exercise program twice a week, whereas the CG received a supervised relaxation program. Serum levels of TRP and KYN as well as urine levels of kynurenic acid (KYNA) and neurotoxic quinolinic acid (QUINA) were assessed before (t0), after radiotherapy, and mid-term of the exercise intervention (t1) and after the exercise intervention (t2). Additionally, 24 healthy women (HIG) participated in the exercise program to investigate potential differences in its effects on KYN metabolites in comparison to the breast cancer patients. Results: At baseline (t0) the breast cancer patients showed a significantly elevated serum KYN/TRP ratio and urine QUINA/KYNA ratio, as well as increased urine QUINA levels in comparison to the healthy women. In response to exercise the healthy women and the breast cancer patients differed significantly in the levels of urine QUINA and the QUINA/KYNA ratio. Most importantly, serum KYN levels and the KYN/TRP ratio were significantly reduced in exercising patients (IG) compared to non-exercising patients (CG) both at t1 and t2. Conclusion: Resistance exercise may represent a potent non-pharmacological avenue to counteract an activation of the KYN pathway in breast cancer patients undergoing radiotherapy.

Authors: Philipp Zimmer, Martina E. Schmidt, Mirja Tamara Prentzell, Bianca Berdel, Joachim Wiskemann, Karl Heinz Kellner, Jürgen Debus, Cornelia Ulrich, Christiane A. Opitz, Karen Steindorf

Date Published: 25th Sep 2019

Publication Type: Not specified

Human Coronavirus: Host-Pathogen Interaction

Abstract (Expand)

Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years, we have witnessed the emergence of two zoonotic, highly pathogenic HCoVs: severe acute … respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Replication of HCoV is regulated by a diversity of host factors and induces drastic alterations in cellular structure and physiology. Activation of critical signaling pathways during HCoV infection modulates the induction of antiviral immune response and contributes to the pathogenesis of HCoV. Recent studies have begun to reveal some fundamental aspects of the intricate HCoV-host interaction in mechanistic detail. In this review, we summarize the current knowledge of host factors co-opted and signaling pathways activated during HCoV infection, with an emphasis on HCoV-infection-induced stress response, autophagy, apoptosis, and innate immunity. The cross talk among these pathways, as well as the modulatory strategies utilized by HCoV, is also discussed.

Authors: To Sing Fung, Ding Xiang Liu

Date Published: 8th Sep 2019

Publication Type: Journal

Excited-state intramolecular proton transfer in a bioactive flavonoid provides fluorescence observables for recognizing its engagement with target proteins.

Abstract (Expand)

A benzothiophene-substituted chromenone with promising activity against Leishmania and Trypanosoma species exhibits peculiar fluorescence properties useful for identifying its complexes with target … proteins in the microorganism proteomes. The emission spectra, anisotropy and time profiles of this flavonoid strongly change when moving from the free to the protein-bound forms. The same two types of emission are observed in organic solvents and their mixtures with water, with the relative band intensities depending on the solvent ability to establish hydrogen bonds with the solute. The regular emission prevails in protic solvents, while in aprotic solvents the anomalously red-shifted emission occurs from a zwitterionic tautomeric form, produced in the excited state by proton transfer within the intramolecularly H-bonded form. This interpretation finds support from an experimental and theoretical investigation of the conformational preferences of this compound in the ground and lowest excited state, with a focus on the relative twisting about the chromenone-benzothiophene interconnecting bond. An analysis of the absorption and emission spectra and of the photophysical properties of the two emitting tautomers highlights the relevance of the local microenvironment, particularly of the intra- and intermolecular hydrogen bonds in which this bioactive compound is involved, in determining both its steady-state and time-resolved fluorescence behaviour.

Authors: D. Vanossi, M. Caselli, G. Pavesi, C. Borsari, P. Linciano, M. P. Costi, G. Ponterini

Date Published: 1st Sep 2019

Publication Type: Journal

Benchmark problems for dynamic modeling of intracellular processes

Abstract

Not specified

Authors: Helge Hass, Carolin Loos, Elba Raimúndez-Álvarez, Jens Timmer, Jan Hasenauer, Clemens Kreutz

Date Published: 1st Sep 2019

Publication Type: Journal

Medicinal Chemistry of Neglected and Tropical Diseases

Abstract

Not specified

Authors: Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay

Date Published: 15th Aug 2019

Publication Type: Book

Identification of evolutionary and kinetic drivers of NAD-dependent signaling.

Abstract (Expand)

Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. … NAD-dependent signaling (e.g., by sirtuins and poly-adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

Authors: M. Bockwoldt, D. Houry, M. Niere, T. I. Gossmann, I. Reinartz, A. Schug, M. Ziegler, I. Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Abstract

Not specified

Authors: Mathias Bockwoldt, Dorothée Houry, Marc Niere, Toni I. Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, Ines Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Abstract (Expand)

Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. …llular events. NAD-dependent signaling (e.g., by sirtuins and poly–adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

Authors: Mathias Bockwoldt, Dorothée Houry, Marc Niere, Toni I. Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, Ines Heiland

Date Published: 6th Aug 2019

Publication Type: Journal

Conceptual and computational framework for logical modelling of biological networks deregulated in diseases.

Abstract (Expand)

Mathematical models can serve as a tool to formalize biological knowledge from diverse sources, to investigate biological questions in a formal way, to test experimental hypotheses, to predict the … effect of perturbations and to identify underlying mechanisms. We present a pipeline of computational tools that performs a series of analyses to explore a logical model's properties. A logical model of initiation of the metastatic process in cancer is used as a transversal example. We start by analysing the structure of the interaction network constructed from the literature or existing databases. Next, we show how to translate this network into a mathematical object, specifically a logical model, and how robustness analyses can be applied to it. We explore the visualization of the stable states, defined as specific attractors of the model, and match them to cellular fates or biological read-outs. With the different tools we present here, we explain how to assign to each solution of the model a probability and how to identify genetic interactions using mutant phenotype probabilities. Finally, we connect the model to relevant experimental data: we present how some data analyses can direct the construction of the network, and how the solutions of a mathematical model can also be compared with experimental data, with a particular focus on high-throughput data in cancer biology. A step-by-step tutorial is provided as a Supplementary Material and all models, tools and scripts are provided on an accompanying website: https://github.com/sysbio-curie/Logical_modelling_pipeline.

Authors: A. Montagud, P. Traynard, L. Martignetti, E. Bonnet, E. Barillot, A. Zinovyev, L. Calzone

Date Published: 19th Jul 2019

Publication Type: Journal

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2019

Abstract (Expand)

This special issue of the Journal of Integrative Bioinformatics presents an overview of COMBINE standards and their latest specifications. The standards cover representation formats for computational … modeling in synthetic and systems biology and include BioPAX, CellML, NeuroML, SBML, SBGN, SBOL and SED-ML. The articles in this issue contain updated specifications of SBGN Process Description Level 1 Version 2, SBML Level 3 Core Version 2 Release 2, SBOL Version 2.3.0, and SBOL Visual Version 2.1.

Authors: Falk Schreiber, Björn Sommer, Gary D. Bader, Padraig Gleeson, Martin Golebiewski, Michael Hucka, Sarah M. Keating, Matthias König, Chris Myers, David Nickerson, Dagmar Waltemath

Date Published: 13th Jul 2019

Publication Type: Journal

Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors.

Abstract (Expand)

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid … parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, in vitro cell-growth-inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.

Authors: G. Landi, P. Linciano, C. Borsari, C. P. Bertolacini, C. B. Moraes, A. Cordeiro-da-Silva, S. Gul, G. Witt, M. Kuzikov, M. P. Costi, C. Pozzi, S. Mangani

Date Published: 12th Jul 2019

Publication Type: Journal

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