bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical patterns of colony membership and mother-offspring similarity in Antarctic fur seals are reproducible over time
Authors: Tebbe Jonas , Humble Emily , Stoffel Martin A. , Tewes Lisa J. , Müller Caroline , Forcada Jaume , Caspers Barbara , Hoffman Joseph I. 
Published: May 2020

AbstractReplication studies are essential for assessing the validity of previous research findings and for probing their generality. However, it has proven challenging to reproduce the results of ecological and evolutionary studies, partly because of the complexity and lability of many of the phenomena being investigated, but also due to small sample sizes, low statistical power and publication bias. Additionally, replication is often considered too difficult in field settings where many factors are beyond the investigator’s control and where spatial and temporal dependencies may be strong. We investigated the feasibility of reproducing original research findings in the field of chemical ecology by attempting to replicate a previous study by our team on Antarctic fur seals (Arctocephalus gazella). In the original study, skin swabs from 41 mother-offspring pairs from two adjacent breeding colonies on Bird Island, South Georgia, were analysed using gas chromatography-mass spectrometry. Seals from the two colonies differed significantly in their chemical fingerprints, suggesting that colony membership may be chemically encoded, and mothers were also chemically similar to their pups, implying that phenotype matching may be involved in mother-offspring recognition. Here, we generated and analysed comparable chemical data from a non-overlapping sample of 50 mother-offspring pairs from the same two colonies five years later. The original results were corroborated in both hypothesis testing and estimation contexts, withp-values remaining highly significant and effect sizes, standardized between studies by bootstrapping the chemical data over individuals, being of comparable magnitude. We furthermore expanded the geographic coverage of our study to include pups from a total of six colonies around Bird Island. Significant chemical differences were observed in the majority of pairwise comparisons, indicating not only that patterns of colony membership persist over time, but also that chemical signatures are colony-specific in general. Our study systematically confirms and extends our previous findings, while also implying that temporal and spatial heterogeneity need not necessarily negate the reproduction and generalization of ecological research findings.
Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells
Authors: Appelberg Sofia , Gupta Soham , Ambikan Anoop T , Mikaeloff Flora , Végvári Ákos , Akusjärvi Sara Svensson , Benfeitas Rui , Sperk Maike , Ståhlberg Marie , Krishnan Shuba , Singh Kamal , Penninger Josef M. , Mirazimi Ali , Neogi Ujjwal 
Published: May 2020

AbstractHow Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remain largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected HuH7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infectionin vitro. Western blot validation of the downstream effector molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of HIF-1α through the entire time course of the infection, suggesting a crosstalk between the SARS-CoV-2 and the mTOR/HIF-1 signaling. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe COVID-19 patients.
Detecting Early Response to Immune Checkpoint Blockade by Multimodal Molecular Imaging
Authors: Saida Yu , Brender Jeffery R. , Yamamoto Kazutoshi , Mitchell James B. , Krishna Murali C. , Kishimoto Shun 
Published: May 2020

AbstractImmune checkpoint inhibitors have become a standard therapy for several cancers; however, the response is inconsistent and a method for non-invasive assessment has not been established to date. To investigate the capability of multi-modal imaging to evaluate treatment response to immune checkpoint blockade therapy, we employed hyperpolarized13C MRI on tumor bearing mice using [1-13C] pyruvate and [1,4-13C2] fumarate to detect early changes in tumor glycolysis and necrosis, respectively. Following αPD-L1 Ab + αCTLA-4 Ab dual immune checkpoint blockade (ICB) therapy, dynamic contrast enhanced (DCE) MRI was used to determine the treatment effect on intratumor perfusion/permeability. Mice bearing MC38 colon adenocarcinoma and B16.F10 melanoma were used as sensitive and less sensitive models, respectively to immune checkpoint dual blockade of PD-L1 and CTLA-4. Glycolytic flux significantly decreased upon treatment in the less ICB sensitive B16.F10 model but remained essentially unchanged in MC38 tumors. Imaging [1,4-13C] fumarate conversion to [1,4-13C] malate showed a significant increase in necrosis in the treatment group for the ICB sensitive MC38 tumor (p= 0.0003), with essentially no change in ICB sensitive B16.F10 tumors. Histological assessment showed increased necrotic tissue with enhanced lymphocyte infiltration in the MC38 treatment group, suggesting immunogenic tumor cell death. Dynamic contrast enhanced MRI showed significantly increased perfusion/permeability of Gd-DTPA in MC38 treated tumor, while a similar trend but statistically non-significant change was observed in B16.F10 treated tumor. These results provide imaging biomarkers to detect early response to cancer immunotherapy, allowing qualitative assessment of tumors treated with immune checkpoint blockade therapy.
A systematic mutational analysis identifies a 5-residue proline tag that enhances thein vivoimmunogenicity of a non-immunogenic model protein 240 folds
Authors: Rahman Nafsoon , Islam Mohammad Monirul , Kibria Md Golam , Unzai Satoru , Kuroda Yutaka 
Published: May 2020

AbstractSmall proteins are generally non-immunogenic, which can be a major hurdle in developing protein and peptide vaccines or producing antibodies for biopharmaceutical usage. For improving a protein’s immunogenicity, we previously proposed to use short Solubility Controlling Peptide (SCP) tags that oligomerize proteins into soluble aggregates. Here, we systematically analyzed the effect of SCP-tags that do not induce oligomerization on the immunogenicity of a small, non-immunogenic, model protein, Bovine Pancreatic Trypsin Inhibitor (BPTI-19A; 6 kDa). We assessed the effect of the following ten SCP-tags: Six tags made of five consecutive Arg, Lys, His, Asp, Asn, Pro; one made of seven Pro; two tags made of consecutive Arg-lle and Asn-Ile, all attached at the C-terminus of BPTI-19A; and a 5-proline tag attached at the N-terminus. Circular dichroism, fluorescence, dynamic light scattering measurements, and analytical ultra-centrifugation indicated that the addition of the SCP-tags did not change the secondary structure content nor the tertiary structures of the protein nor its monomeric state. On the other hand, the C-terminus 5-proline (C5P) tag unexpectedly increased the immunogenicity (IgG level) of BPTI-19A by up to 240 fold as assessed by ELISA. Additionally, the 5-arginine tag (C5R) increased the titer by up to 73 fold. The titer increase lasted for several weeks, and the effect was cumulative to that of the Freund’s adjuvant, which is commonly used to boost a protein’s immunogenicity. Altogether, SCP-tags that do not oligomerize proteins substantially increased the immunogenicity of a non-immunogenic protein, suggesting that the 5-proline and the 5-arginine SCP-tags may provide a novel tool for facilitating the production of antibodies or improving the effectiveness of protein-based vaccines.
Human and mouse transcriptome profiling identifies cross-species homology in pulmonary and lymph node mononuclear phagocytes
Authors: Leach Sonia M. , Gibbings Sophie L. , Tewari Anita D. , Atif Shaikh M. , Vestal Brian , Danhorn Thomas , Janssen William J. , Wager Tor D. , Jakubzick Claudia V. 
Published: May 2020

SummaryThe mononuclear phagocyte (MP) system consists of macrophages, monocytes, and dendritic cells (DCs). MP subtypes play distinct functional roles in steady state and inflammatory conditions. Though murine MPs are well characterized, their pulmonary and lymph node (LN) human homologs remain poorly understood. To address this gap, we created a gene expression compendium across 15 distinct human and 9 distinct murine MPs from lung, LN, blood, and spleen. Human blood MPs and murine spleen MPs served as validation datasets, as the human-mouse MP homologs are relatively well-defined in these tissues. In-depth RNA sequencing identified corresponding human-mouse MP subtypes and determined marker genes shared and divergent across between species counterparts. Unexpectedly, at the gene expression level, only 13-23% of the top 1000 marker genes (i.e., genes not shared across species-specific MP subtypes) overlapped in corresponding human-mouse MP counterparts, indicating a need for caution when translating mouse studies to human gene targets and functions. Lastly, CD88 was useful in both species to distinguish macrophage and tissue monocytes from DCs. Our cross-species gene expression compendium serves as a resource for future translational studies to investigate beforehand whether pursuing specific MP subtypes, or genes will prove fruitful.
Thermal sensitivity of theSpiroplasma-Drosophila hydeiprotective symbiosis: The best of climes, the worst of climes
Authors: Corbin Chris , Jones Jordan E. , Chrostek Ewa , Fenton Andy , Hurst Gregory D. D. 
Published: May 2020

AbstractThe outcome of natural enemy attack in insects has commonly been found to be influenced by the presence of protective symbionts in the host. The degree to which protection functions in natural populations, however, will depend on the robustness of the phenotype to variation in the abiotic environment. We studied the impact of a key environmental parameter – temperature – on the efficacy of the protective effect of the symbiontSpiroplasmaon its hostDrosophila hydei, against attack by the parasitoid waspLeptopilina heterotoma. In addition, we investigated the thermal sensitivity of the symbiont’s vertical transmission, which may be a key determinant of the ability of the symbiont to persist. We found that vertical transmission was more robust than previously considered, withSpiroplasmabeing maintained at 25 °C, 18 °C and with 18/15 °C diurnal cycles, with rates of segregational loss only increasing at 15 °C. Protection against wasp attack was ablated before symbiont transmission was lost, with the symbiont failing to rescue the fly host at 18 °C. We conclude that the presence of a protective symbiosis in natural populations cannot be simply inferred from presence of a symbiont whose protective capacity has been tested under narrow controlled conditions. More broadly, we argue that the thermal environment is likely to represent an important determinant of the evolutionary ecology of defensive symbioses in natural environments, potentially driving seasonal, latitudinal and altitudinal variation in symbiont frequency, and modulating the strength of selection for symbiotic protective systems compared to defensive systems encoded in the nuclear genomes.
Optimized photochemistry and enzymology enable efficient analysis of RNA structures and interactions in cells and virus infections
Authors: Zhang Minjie , Li Kongpan , Velema Willem A. , Bai Jianhui , Yu Chengqing , van Damme Ryan , Lee Wilson H. , Corpuz Maia L. , Chen Jian-Fu , Lu Zhipeng 
Published: May 2020

SUMMARYDirect determination of RNA structures and interactions in living cells is critical for understanding their functions. Current crosslinking and proximity-ligation approaches are fundamentally limited due to inefficient RNA crosslinking, purification and high-level photochemical damages. Here we present PARIS2 (psoralen analysis of RNA interactions and structures, second generation), a re-invented method for capturing RNA duplexes in cells with three orders of magnitude improved efficiency. PARIS2 captures ribosome small subunit (SSU) binding sites on mRNAs, reporting translation status on a transcriptome wide scale, and captures spliceosomal snRNP binding sites on various RNA targets. We determine the RNA genome structure of enterovirus D68, a re-emerging viral pathogen associated with severe neurological symptoms, and discover alternative conformations in the internal ribosome entry site (IRES) that controls translation initiation. Together, these results reveal new aspects of RNA photochemistry and enzymology, and enable highly efficient interrogation of the RNA structurome and interactome in cells.
Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection
Authors: Sun Jiya , Ye Fei , Wu Aiping , Yang Ren , Pan Mei , Sheng Jie , Zhu Wenjie , Mao Longfei , Wang Ming , Huang Baoying , Tan Wenjie , Jiang Taijiao 
Published: May 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic COVID-19. It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV and MERS-CoV. Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.
Distinct Inductions of and Responses to Type I and Type III Interferons Promote Infections in Two SARS-CoV-2 Isolates
Authors: Hsin Fu , Chao Tai-Ling , Chan Yun-Rui , Kao Han-Chieh , Liu Wang-Da , Wang Jann-Tay , Pang Yu-Hao , Lin Chih-Hui , Tsai Ya-Min , Lin Jing-Yi , Chang Sui-Yuan , Liu Helene Minyi 
Published: May 2020

AbstractThe recent emerging coronavirus, SARS-CoV-2, has been rapidly and widely spread and causing an ongoing viral pneumonia outbreak worldwide. It has been observed that SARS-CoV-2 patients show a rather long and asymptomatic incubation time. We characterized the abilities to induce and to response to IFNβ/IFNλ1 of two or our clinical isolates, SARS-CoV-2/NTU01/TWN/human/2020 and SARS-CoV-2/NTU02/TWN/human/2020, which exhibit only two amino acid differences over the ∼30kb viral genome. We found that both isolates may infect Huh7, A549 and Calu-3 cells, yet the RIG-I-like receptor-dependent antiviral signaling was poorly induced in these cells in the early infections. Unexpectedly, we found that the intracellular vRNA levels of these isolates were sustained upon to type I/III IFN treatments, and this phenotype was more pronounced in the Taiwan/NTU01/2020 isolate. The type I/III IFN responses are antiviral but partially proviral in the case of SARS-CoV-2 infections. Poor induction and response to innate immunity may contribute to destitute neutralization index of the antibody produced, and indeed we found that the patient serum could not efficiently neutralize SARS-CoV-2 virions. With better understandings of the interplay between SARS-CoV-2 and the host antiviral innate immunity, our report may provide new insights for the regimen of therapies for SARS-CoV-2 infected patients.
Mutational spectra of SARS-CoV-2 orf1ab polyprotein and Signature mutations in the United States of America
Authors: Banerjee Shuvam , Seal Sohan , Dey Riju , Mondal Kousik Kr. , Bhattacharjee Pritha 
Published: May 2020

AbstractPandemic COVID-19 outbreak has been caused due to SARS-COV2 pathogen, resulting millions of infection and death worldwide, USA being on top at the present moment. The long, complex orf1ab polyproteins of SARS-COV2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of orf1ab polyprotein from NCBI Virus database from affected patients across various states of USA from December 2019 to 25thApril, 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12) and P5828L and Y5865C (both at nsp 13) were identified in important non-structural proteins, which function either as replicase or helicase. A comparative analysis shows 265T>I, 5828P>L and 5865Y>C are unique to USA and not reported from Europe or Asia; while one, 4715P>L is predominant in both Europe and USA. Mutational changes in amino acids are predicted to alter structure and function of corresponding proteins, thereby it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab.
On spatial molecular arrangements of SARS-CoV2 genomes of Indian patients
Authors: Hassan Sk. Sarif , Moitra Atanu , Rout Ranjeet Kumar , Choudhury Pabitra Pal , Pramanik Prasanta , Jana Siddhartha Sankar 
Published: May 2020

AbstractA pandemic caused by the SARS-CoV2 is being experienced by the whole world since December, 2019. A thorough understanding beyond just sequential similarities among the protein coding genes of SARS-CoV2 is important in order to differentiate or relate to the other known CoVs of the same genus. In this study, we compare three genomes namely MT012098 (India-Kerala), MT050493 (India-Kerala), MT358637 (India-Gujrat) from India with NC_045512 (China-Wuhan) to view the spatial as well as molecular arrangements of nucleotide bases of all the genes embedded in these four genomes. Based on different features extracted for each gene embedded in these genomes, corresponding phylogenetic relationships have been built up. Differences in phylogenetic tree arrangement with individual gene suggest that three genomes of Indian origin have come from three different origins or the evolution of viral genome is very fast process. This study would also help to understand the virulence factors, disease pathogenicity, origin and transmission of the SARS-CoV2.
Release sites are positioned to activate NMDA receptors
Authors: Li Shuo , Raychaudhuri Sumana , Alexander Lee Stephen , Wang Jing , Kusick Grant , Prater Christine , Syed Sarah , Falahati Hanieh , Ramos Raul , Bartol Tomas M. , Hosy Eric , Watanabe Shigeki 
Published: May 2020

AbstractNeurotransmitter is released synchronously and asynchronously following an action potential. The release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release ensures maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are organized to efficiently activate NMDA receptors.
SARS-CoV-2 spike protein predicted to form complexes with host receptor protein orthologues from a broad range of mammals
Authors: Lam SD , Bordin N , Waman VP , Scholes HM , Ashford P , Sen N , van Dorp L , Rauer C , Dawson NL , Pang CSM , Abbasian M , Sillitoe I , Edwards SJL , Fraternali F , Lees JG , Santini JM , Orengo CA 
Published: May 2020

AbstractSARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.