Global RNA editome landscape discovers reduced RNA editing in glioma: loss of editing of gamma-amino butyric acid receptor alpha subunit 3 (GABRA3) favors glioma migration and invasion
Background Gliomas are the most common and lethal type of intracranial tumors. With the current treatment regime, the median survival of patients with grade IV glioma (glioblastoma/GBM) remains at 14–16 months. RNA editing modifies the function and regulation of transcripts. The development of glial tumors may be caused by altered RNA editing events. Methods In this study, we uncover the global RNA editome landscape of glioma patients from RNA-seq data of control, lower grade glioma (LGG) and GBM samples (n = 1,083). Results A-to-I editing events were found to comprise 80% of the total editing events of which 96% were located in the Alu regions. The total RNA editing events were found to be reduced in glioma compared to control samples. More specifically, we found Gamma-aminobutyric acid type A receptor alpha3 (GABRA3) to be edited (c.1026 A-to-G; pI343M) in 73% (editing ratio 0.8) of control samples compared to LGG (28.96%; 0.47) and GBM (5.2%; 0.53) samples. GABRA3 transcript level was found to be downregulated in glioma compared to control in a grade-specific manner with GBMs having the lowest level of the transcript. Further, GABRA3 transcripts were observed to be higher in edited compared to unedited glioma samples. The transcript and protein levels of exogenously expressed gene were found to be higher for edited compared to unedited GABRA3 in glioma cells. Further, exogenously expressed edited GABRA3 inhibited migration and invasion of glioma cells efficiently but not the unedited GABRA3. Conclusion Collectively, our study discovered a reduction in RNA editing during glioma development. We further demonstrate that elevated RNA editing maintains a high level of GABRA3 RNA and protein in normal glial cells which provides a less migratory environment for the normal functioning of the brain. In contrast, the reduction in GABRA3 protein levels, due to lower stability of unedited RNA, results in the loss of function which confers an aggressive phenotype to GBM tumor.
Patil et al. (2020) Global RNA editome landscape discovers reduced RNA editing in glioma: loss of editing of gamma-amino butyric acid receptor alpha subunit 3 (GABRA3) favors glioma migration and invasion. PeerJ 8:e9755 https://doi.org/10.7717/peerj.9755
Interpreting character variation in turtles: Araripemys barretoi (Pleurodira: Pelomedusoides) from the Araripe Basin, Early Cretaceous of Northeastern Brazil
The Araripe Basin (Northeastern Brazil) has yielded a rich Cretaceous fossil fauna of both vertebrates and invertebrates found mainly in the Crato and Romualdo Formations, of Aptian and Albian ages respectively. Among the vertebrates, the turtles were found to be quite diverse, with several specimens retrieved and five valid species described to this date for the Romualdo Formation. There were also records of turtles from Ipubi and Crato Formations, mainly fragmentary material which precluded proper specific identification; however, Araripemys barretoi is supposed to occur on both Crato and Romualdo Formations. Here we describe thirteen specimens of A. barretoi-including the first description of an almost complete individual, bearing a skull, from the Crato Formation. We report a great amount of morphological variation, interpreted as being essentially of intraspecific nature, including individual, sexual and ontogenetic variation.
Limaverde et al. (2020) Interpreting character variation in turtles: Araripemys barretoi (Pleurodira: Pelomedusoides) from the Araripe Basin, Early Cretaceous of Northeastern Brazil. PeerJ 8:e9840 https://doi.org/10.7717/peerj.9840
Computational perspectives revealed prospective vaccine candidates from five structural proteins of novel SARS corona virus 2019 (SARS-CoV-2)
Background The present pandemic COVID-19 is caused by SARS-CoV-2, a single-stranded positive-sense RNA virus from the Coronaviridae family. Due to a lack of antiviral drugs, vaccines against the virus are urgently required. Methods In this study, validated computational approaches were used to identify peptide-based epitopes from six structural proteins having antigenic properties. The Net-CTL 1.2 tool was used for the prediction of CD8+ T-cell epitopes, while the robust tools Bepi-Pred 2 and LBtope was employed for the identification of linear B-cell epitopes. Docking studies of the identified epitopes were performed using HADDOCK 2.4 and the structures were visualized by Discovery Studio and LigPlot+. Antigenicity, immunogenicity, conservancy, population coverage and allergenicity of the predicted epitopes were determined by the bioinformatics tools like VaxiJen v2.0 server, the Immune Epitope Database tools and AllerTOP v.2.0, AllergenFP 1.0 and ElliPro. Results The predicted T cell and linear B-cell epitopes were considered as prime vaccine targets in case they passed the requisite parameters like antigenicity, immunogenicity, conservancy, non-allergenicity and broad range of population coverage. Among the predicted CD8+ T cell epitopes, potential vaccine targets from surface glycoprotein were; YQPYRVVVL, PYRVVVLSF, GVYFASTEK, QLTPTWRVY, and those from ORF3a protein were LKKRWQLAL, HVTFFIYNK. Similarly, RFLYIIKLI, LTWICLLQF from membrane protein and three epitopes viz; SPRWYFYYL, TWLTYTGAI, KTFPPTEPK from nucleocapsid phosphoprotein were the superior vaccine targets observed in our study. The negative values of HADDOCK and Z scores obtained for the best cluster indicated the potential of the epitopes as suitable vaccine candidates. Analysis of the 3D and 2D interaction diagrams of best cluster produced by HADDOCK 2.4 displayed the binding interaction of leading T cell epitopes within the MHC-1 peptide binding clefts. On the other hand, among linear B cell epitopes the majority of potential vaccine targets were from nucleocapsid protein, viz; 59−HGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLS−105, 227−LNQLE SKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATK−266, 3−DNGPQNQRNAPRITFGGP−20, 29−GERSGARSKQRRPQGL−45. Two other prime vaccine targets, 370−NSASFSTFKCYGVSPTKLNDLCFTNV−395 and 260−AGAAAYYVGYLQPRT−274 were identified in the spike protein. The potential B-cell conformational epitopes were predicted on the basis of a higher protrusion index indicating greater solvent accessibility. These conformational epitopes were of various lengths and belonged to spike, ORF3a, membrane and nucleocapsid proteins. Conclusions Taken together, eleven T cell epitopes, seven B cell linear epitopes and ten B cell conformational epitopes were identified from five structural proteins of SARS-CoV-2 using advanced computational tools. These potential vaccine candidates may provide important timely directives for an effective vaccine against SARS-CoV-2.
Anand et al. (2020) Computational perspectives revealed prospective vaccine candidates from five structural proteins of novel SARS corona virus 2019 (SARS-CoV-2). PeerJ 8:e9855 https://doi.org/10.7717/peerj.9855
Bigfin reef squid demonstrate capacity for conditional discrimination and projected future carbon dioxide levels have no effect on learning capabilities
Anthropogenic carbon dioxide (CO2) emissions are being absorbed by the oceans, a process known as ocean acidification, and risks adversely affecting a variety of behaviours in a range of marine species, including inhibited learning in some fishes. However, the effects of elevated CO2 on learning in advanced invertebrates such as cephalopods are unknown. Any impacts to the learning abilities of cephalopods could have far-reaching consequences for their populations and the communities they inhabit. Cephalopods have some of the most advanced cognitive abilities among invertebrates and are one of the few invertebrate taxa in which conditional discrimination has been demonstrated, though the trait has not been demonstrated in any species of squid. Here, we tested for the first time the capacity for conditional discrimination in a squid species (Sepioteuthis lessoniana). Furthermore, we investigated the effects of projected future CO2 levels (1,084 µatm) on conditional discrimination and learning more generally. A three-task experiment within a two-choice arena was used to test learning and conditional discrimination. Learning was measured by improvements in task completion in repeated trials over time and the number of trials required to pass each task. Squid exhibited significant learning capabilities, with an increase in correct choices over successive trials and a decrease in the number of trials needed to complete the successive tasks. Six of the 12 squid tested successfully passed all three tasks indicating a capacity for conditional discrimination in the species. Elevated CO2 had no effect on learning or on the capacity for conditional discrimination in squid. This study highlights the remarkable cognitive abilities of S. lessoniana, demonstrated by their capacity for conditional discrimination, and suggests that ocean acidification will not compromise learning abilities. However, other behavioural traits in the species have been shown to be altered at comparable elevated CO2 conditions. It is not clear why some ecologically important behaviours are altered by elevated CO2 whereas others are unaffected. Future research should focus on the physiological mechanism responsible for altered behaviours in squid at elevated CO2.
Spady et al. (2020) Bigfin reef squid demonstrate capacity for conditional discrimination and projected future carbon dioxide levels have no effect on learning capabilities. PeerJ 8:e9865 https://doi.org/10.7717/peerj.9865
The increasing prevalence of CPV-2c in domestic dogs in China
Background Canine parvovirus type 2 (CPV-2), a serious pathogen, leads to high morbidity and mortality in dogs and several wild carnivore species. Although it is a DNA virus, it evolves particularly rapidly, with a genomic substitution rate of approximately 10−4 substitutions/site/year, close to that of some RNA viruses. Tracing the prevalence of CPV-2 in dogs is significant. Methods In this study, an aetiological survey was carried out from 2016 to 2019 in Guangdong Province, China, involving Guangzhou, Shenzhen and Dongguan. Furthermore, to systematically analyse the prevalence of CPV-2 in China, the VP2 gene sequences of all Chinese isolates were downloaded from the NCBI nucleotide database in December 2019, and changes in CPV-2 variants were examined. Results A total of 55.7% (34/61) of samples were CPV-2 positive by PCR detection and virus isolation. In addition to different variants circulating in dogs, coinfection with multiple variants was identified, as was coinfection with other canine enteric pathogens in some cases. Two previously reported amino acid sites, A5G and Q370R of CPV-2c mutants, reported in variants in China were assessed, and several CPV-2 isolates with P13S and K582N mutations were detected in this study. Finally, we speculate on the prevalence of different CPV-2 variants in China. According to the VP2 gene sequence obtained from the NCBI nucleotide database, the proportion of different variants in China has changed, and CPV-2c appears to be growing rapidly. In conclusion, this aetiology survey suggests that CPV-2 continues to be common in China and that the prevalence of CPV-2c is increasing.
Hao et al. (2020) The increasing prevalence of CPV-2c in domestic dogs in China. PeerJ 8:e9869 https://doi.org/10.7717/peerj.9869
The relationship between individual phenotype and the division of labour in naked mole-rats: it’s complicated
Background The naked mole-rat (Heterocephalus glaber) is among the most social mammals on the planet, living in eusocial groups of up to 300 individuals that contain a single reproductive female and up to three reproductive males. A critical aspect of their complex social system is the division of labour that allows non-breeders to form an effective workforce. Age- or weight-based polyethisms are widely cited as explanations for how labour is divided, but evidence in support of these hypotheses has been equivocal. Methods To assess the extent to which individual working behaviour is determined by sex, age, weight and social rank, we studied the behaviours of 103 animals from eight captive colonies. We performed focal sampling and ran mixed-effects models to assess which factors explained variation in working behaviour during six ten-minute observation periods per individual. Results Contrary to widely-held beliefs, we found that working behaviour did not decrease linearly with weight, although polynomial regressions indicated younger and medium-sized individuals worked most frequently, while high-ranking individuals worked for the shortest periods of time. Working behaviour and its relationship with individual characteristics also varied between colonies. Conclusions While age- or size-based polyethisms may have some influence on working behaviour, we argue that other characteristics of the individual and colony are also important. In particular, the interactions of individual, social and environmental factors must be considered in order to understand the emergence and effectiveness of the division of labour that is so critical to many social organisms.
Gilbert et al. (2020) The relationship between individual phenotype and the division of labour in naked mole-rats: it’s complicated. PeerJ 8:e9891 https://doi.org/10.7717/peerj.9891
Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies
Background The blockage at the early B lymphoid cell development pathway within the bone marrow is tightly associated with hematopoietic and immune diseases, where the disruption of basal regulatory networks prevents the continuous replenishment of functional B cells. Dynamic computational models may be instrumental for the comprehensive understanding of mechanisms underlying complex differentiation processes and provide novel prediction/intervention platforms to reinvigorate the system. Methods By reconstructing a three-module regulatory network including genetic transcription, intracellular transduction, and microenvironment communication, we have investigated the early B lineage cell fate decisions in normal and pathological settings. The early B cell differentiation network was simulated as a Boolean model and then transformed, using fuzzy logic, to a continuous model. We tested null and overexpression mutants to analyze the emergent behavior of the network. Due to its importance in inflammation, we investigated the effect of NFkB induction at different early B cell differentiation stages. Results While the exhaustive synchronous and asynchronous simulation of the early B cell regulatory network (eBCRN) reproduced the configurations of the hematopoietic progenitors and early B lymphoid precursors of the pathway, its simulation as a continuous model with fuzzy logics suggested a transient IL-7R+ ProB-to-Pre-B subset expressing pre-BCR and a series of dominant B-cell transcriptional factors. This conspicuous differentiating cell population up-regulated CXCR7 and reduced CXCR4 and FoxO1 expression levels. Strikingly, constant but intermediate NFkB signaling at specific B cell differentiation stages allowed stabilization of an aberrant CXCR7+ pre-B like phenotype with apparent affinity to proliferative signals, while under constitutive overactivation of NFkB, such cell phenotype was aberrantly exacerbated from the earliest stage of common lymphoid progenitors. Our mutant models revealed an abnormal delay in the BCR assembly upon NFkB activation, concomitant to sustained Flt3 signaling, down-regulation of Ebf1, Irf4 and Pax5 genes transcription, and reduced Ig recombination, pointing to a potential lineage commitment blockage. Discussion For the first time, an inducible CXCR7hi B cell precursor endowed with the potential capability of shifting central lymphoid niches, is inferred by computational modeling. Its phenotype is compatible with that of leukemia-initiating cells and might be the foundation that bridges inflammation with blockage-related malignancies and a wide range of immunological diseases. Besides the predicted differentiation impairment, inflammation-inducible phenotypes open the possibility of newly formed niches colonized by the reported precursor. Thus, emergent bone marrow ecosystems are predicted following a pro-inflammatory induction, that may lead to hematopoietic instability associated to blockage pathologies.
Enciso et al. (2020) Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies. PeerJ 8:e9902 https://doi.org/10.7717/peerj.9902
Study of marsh wetland landscape pattern evolution on the Zoigê Plateau due to natural/human dual-effects
Zoigê Plateau, China’s largest plateau marsh wetland, has experienced large-scale degradation of the marsh wetland and evolution of the wetland landscape pattern over the past 40 years due to climate warming and human activities. How exactly do the wetland landscape pattern characteristics change? How do climatic change and human activities affect the wetland evolution? These questions are yet to be systematically investigated. In order to investigate changes to the marsh wetland on the Zoigê Plateau, field investigations, spatial and statistical analysis were undertaken. Findings from our study indicate that from 1977–2016, the area of marsh wetland on the Plateau reduced by 56.54%, approximately 66,700 hm2 of marsh wetland has been lost. The centroids of both marsh and marshy meadow migrated and the landscape centroid migration behaviors were also correlated with the distribution and variation of the marsh wetland on different slopes. In addition, the number of marsh landscape patches initially increased before decreasing; the number of marshy meadow landscape patches also recorded an initial increase, followed by a decline before a final increase. As the effects of human activities weakened, the aggregation degrees of both marsh and marshy meadow increased. Overall, the fragmentation degree, diversity and fractal dimension of the marsh wetland all declined. An investigation into the driving factors affecting the Plateau area shows that the increase of annual average temperature was the natural factor while trenching and overgrazing were the main human factors resulting in wetland degradation. Results from this study provide basic data and theoretical foundation for the protection and restoration of marsh wetland in alpine regions.
Spatial and Geographic Information Science
Dong et al. (2020) Study of marsh wetland landscape pattern evolution on the Zoigê Plateau due to natural/human dual-effects. PeerJ 8:e9904 https://doi.org/10.7717/peerj.9904
A glycolysis-related gene pairs signature predicts prognosis in patients with hepatocellular carcinoma
Background Hepatocellular carcinoma (HCC) is one of the most universal malignant liver tumors worldwide. However, there were no systematic studies to establish glycolysis‑related gene pairs (GRGPs) signatures for the patients with HCC. Therefore, the study aimed to establish novel GRGPs signatures to better predict the prognosis of HCC. Methods Based on the data from Gene Expression Omnibus, The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium databases, glycolysis-related mRNAs were used to construct GRGPs. Cox regression was applied to establish a seventeen GRGPs signature in TCGA dataset, which was verified in two validation (European and American, and Asian) datasets. Results Seventeen prognostic GRGPs (HMMR_PFKFB1, CHST1_GYS2, MERTK_GYS2, GPC1_GYS2, LDHA_GOT2, IDUA_GNPDA1, IDUA_ME2, IDUA_G6PD, IDUA_GPC1, MPI_GPC1, SDC2_LDHA, PRPS1_PLOD2, GALK1_IER3, MET_PLOD2, GUSB_IGFBP3, IL13RA1_IGFBP3 and CYB5A_IGFBP3) were identified to be significantly progressive factors for the patients with HCC in the TCGA dataset, which constituted a GRGPs signature. The patients with HCC were classified into low-risk group and high-risk group based on the GRGPs signature. The GRGPs signature was a significantly independent prognostic indicator for the patients with HCC in TCGA (log-rank P = 2.898e−14). Consistent with the TCGA dataset, the patients in low-risk group had a longer OS in two validation datasets (European and American: P = 1.143e−02, and Asian: P = 6.342e−08). Additionally, the GRGPs signature was also validated as a significantly independent prognostic indicator in two validation datasets. Conclusion The seventeen GRGPs and their signature might be molecular biomarkers and therapeutic targets for the patients with HCC.
Zhou et al. (2020) A glycolysis-related gene pairs signature predicts prognosis in patients with hepatocellular carcinoma. PeerJ 8:e9944 https://doi.org/10.7717/peerj.9944
Identification of hub genes and small molecule therapeutic drugs related to breast cancer with comprehensive bioinformatics analysis
Breast cancer is one of the most common malignant tumors among women worldwide and has a high morbidity and mortality. This research aimed to identify hub genes and small molecule drugs for breast cancer by integrated bioinformatics analysis. After downloading multiple gene expression datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, 283 overlapping differentially expressed genes (DEGs) significantly enriched in different cancer-related functions and pathways were obtained using LIMMA, VennDiagram and ClusterProfiler packages of R. We then analyzed the topology of protein–protein interaction (PPI) network with overlapping DEGs and further obtained six hub genes (RRM2, CDC20, CCNB2, BUB1B, CDK1, and CCNA2) from the network via STRING and Cytoscape. Subsequently, we conducted genes expression verification, genetic alterations evaluation, immune infiltration prediction, clinicopathological parameters analysis, identification of transcriptional and post-transcriptional regulatory molecules, and survival analysis for these hub genes. Meanwhile, 29 possible drug candidates (e.g., Cladribine, Gallium nitrate, Alvocidib, 1β-hydroxyalantolactone, Berberine hydrochloride, Nitidine chloride) were identified from the DGIdb database and the GSE85871 dataset. In addition, some transcription factors and miRNAs (e.g., E2F1, PTTG1, TP53, ZBTB16, hsa-miR-130a-3p, hsa-miR-204-5p) targeting hub genes were identified as key regulators in the progression of breast cancer. In conclusion, our study identified six hub genes and 29 potential drug candidates for breast cancer. These findings may advance understanding regarding the diagnosis, prognosis and treatment of breast cancer.
Hao et al. (2020) Identification of hub genes and small molecule therapeutic drugs related to breast cancer with comprehensive bioinformatics analysis. PeerJ 8:e9946 https://doi.org/10.7717/peerj.9946