bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Subgenomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections
Authors: Parker Matthew D , Lindsey Benjamin B. , Shah Dhruv R , Hsu Sharon , Keeley Alexander J , Partridge David G , Leary Shay , Cope Alison , State Amy , Johnson Katie , Ali Nasar , Raghei Rasha , Heffer Joe , Smith Nikki , Zhang Peijun , Gallis Marta , Louka Stavroula F , Hornsby Hailey R , Whiteley Max , Foulkes Benjamin H , Christou Stella , Wolverson Paige , Pohare Manoj , Hansford Samantha E , Green Luke R , Evans Cariad , Raza Mohammad , Wang Dennis , Gaudieri Silvana , Mallal Simon ,   The COVID-19 Genomics UK (COG-UK) consortium, de Silva Thushan I. 
Published: March 2021

AbstractSARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome and is a crucial step in the SARS-CoV-2 life cycle. Applying our tool (periscope) to ARTIC Network Oxford Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA expression profiles are significantly increased in B.1.1.7 infections (n=879). This increase is seen over the previous dominant circulating lineage in the UK, B.1.177 (n=943), which is independent of genomic reads, E gene cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median expression. We hypothesise that this is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT>CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern.One Sentence SummaryThe recently emerged and more transmissible SARS-CoV-2 lineage B.1.1.7 shows greater subgenomic RNA expression in clinical infections and enhanced expression of a noncanonical subgenomic RNA near ORF9b.
Uncovered genetic diversity inHemidactylus mabouia(Reptilia: Gekkonidae) from Madeira Island reveals uncertain sources of introduction
Authors: Rato Catarina , Martins Beatriz , Rocha Ricardo , Silva-Rocha Iolanda 
Published: March 2021

AbstractHemidactylus mabouiais one of the most widely distributed species within its genus. It was first reported to Madeira in 2002 and the first individuals were considered to have originated from Cape Verde. Almost 20 years later, we found thatH. mabouiahas substantially expanded its distribution and can now be found >10 km away from Funchal, where it was first reported. Based on a 12S phylogenetic analysis and using 29 individuals from Funchal and Câmara de Lobos we found that Madeira actually harbours two distinct lineages ofH. mabouia: one exclusively South American and another widespread in America and Africa. However, the lack of genetic diversity typical of this species outside its native range and the obtained phylogenetic pattern prevent us to infer possible introduction routes or sources. Our study emphasizes that authorities should remain vigilant regarding the arrival of other non-natives and act to prevent their establishment as soon as they are detected.
Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway
Authors: Li Rong , Zhu Wenqiang , Huang Piaopiao , Yang Yang , Luo Fei , Dai Wen , Shen Li , Pei Wenjing , Huang Xiansheng 
Published: March 2021

ABSTRACTThe antipsychotic drug olanzapine was reported to induce nonalcoholic fatty liver disease (NAFLD), whereas the underlying mechanism remains incompletely understood. This study investigated whether apolipoprotein A5 (apoA5) and sortilin, two interactive factors involved in NAFLD pathogenesis, are implicated in olanzapine-induced NAFLD. In the present study, at week 8, olanzapine treatment successfully induced hepatic steatosis in male C57 BL/6J mice, even when fed a normal chow diet, which was independent of animal body weight gain. Likewise, olanzapine effectively mediated hepatocyte steatosis in human HepG2 cellsin vitro, characterized by substantially elevated intracellular lipid droplets. Increased plasma triglyceride concentration and decreased plasma apoA5 levels were observed in mice treated for 8 weeks with olanzapine. Surprisingly, olanzapine markedly enhanced hepatic apoA5 protein levels in mice, without a significant effect on rodent hepaticApoA5mRNA expression. Ourin vitrostudy showed that olanzapine reduced apoA5 protein levels in the medium and enhanced apoA5 protein expression in hepatocytes, whereas this drug exerted no effect on hepatocyteAPOA5mRNA expression. By transfectingAPOA5siRNA into HepG2 cells, it was demonstrated thatAPOA5knockdown effectively reversed olanzapine-induced hepatocyte steatosis. In addition, olanzapine drastically increased sortilin mRNA and protein levelsin vivoandin vitro. Interestingly,SORT1knockdown reduced intracellular apoA5 protein expression and increased medium apoA5 protein levelsin vitro, without affecting intracellularAPOA5mRNA expression. Furthermore,SORT1knockdown greatly ameliorated hepatocyte steatosisin vitro. This study provides the first evidence that sortilin inhibits the hepatic apoA5 secretion that is attributable to olanzapine-induced NAFLD, which provides new insight into effective strategies against NAFLD for patients with schizophrenia administered olanzapine.
An ancient retroviral RNA element hidden in mammalian genomes and its involvement in coopted retroviral gene regulation
Authors: Kitao Koichi , Nakagawa So , Miyazawa Takayuki 
Published: March 2021

AbstractRetroviruses utilize multiple unique RNA elements to control several aspects of RNA processing, such as splicing, subcellular export, and translation. However, it is mostly unclear whether such functional RNA elements are present in endogenous retroviruses (ERVs), many of which were inserted into the host genomes millions of years ago. Previously, in human ERV-derivedsyncytin-1gene, we found acis-acting RNA element named SPRE that enhances its protein expression. In this study, we found a 17-nt common sequence in SPRE ofsyncytin-1and another ERV-derived gene,syncytin-2, and the sequence is confirmed to be essential for the expression of the proteins. We detected the sequences of SPRE-like elements in 41 ERV families. Though the SPRE-like elements were not found in currently prevailing (i.e.exogenous) viral sequences, more than thousands of copies of the elements were found in several mammalian genomes, suggesting the ancient integration and propagation of the SPRE-harboring retroviruses in mammalian lineages. Indeed, other mammalian ERV-derived genes:mac-syncytin-3of macaque,syncytin-Ten1of tenrec, andsyncytin-Car1of Carnivora contain the SPRE-like elements, and we validated their function for efficient protein expression byin vitroassays. A reporter assay revealed that the enhancement of gene expression by SPRE depended on reporter genes. Moreover, the mutation in SPRE did not affect the gene expression in codon-optimizedsyncytin-2. However, the same mutation in SPRE impaired the gene expression in wild-typesyncytin-2, suggesting that the SPRE dependency of Syncytin-2 expression is due to the negative factors such as inefficient codon frequency or repressive elements within the coding sequence. These results provide new implications that ERVs harbor unique RNA elements involved in the regulation of ERV-derived genes.
Methylation-mediated retuning on the enhancer-to-silencer activity scale of networked regulatory elements guides driver-gene misregulation
Authors: Edrei Y. , levy R. , Marom A. , Radlwimmer B. , Hellman A. 
Published: March 2021

AbstractCancers arise when particular disease-driving genes adopt abnormal functions, but analyses of coding and regulatory sequences leave many of these abnormalities unexplained. We developed a strategy to explore alternations in the regulatory effects of silencers and enhancers in cancer tumors. Applying the method to 177 gene regulatory domains in human glioblastomas, we produced a driver-gene wide dataset of gene-associated, functional regulatory elements. Many genes were controlled by cis-regulatory networks composed of multiple regulatory elements, each of them providing a defined positive or negative input to the overall regulatory output of the network. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints within wide ranges of potential regulatory effects, varying between strong transcriptional enhancing to strong silencing. Extensive analysis of methylation-expression associations reveals the organization of domain-wide cis-regulatory networks, and highlighted key regulatory sites which provide pivotal contributions to the network outputs. Consideration of these effects through mathematical models of gene expression variations signified prime molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Of the observed gene-malfunctioning events, gene misregulation due to epigenetic retuning of networked enhancers and silencers dominated driver-genes mutagenesis, compared with other types of mutation including coding or regulatory sequence alterations. Elucidation of this gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases.
Reduced PTPRD expression differentially alters brain phosphotyrosine phosphoproteomic profiles of 2 and 12 month-old mice
Authors: Uhl George R , Henderson Ian M , Martinez Maria , Stokes Matthew P 
Published: March 2021

AbstractThe receptor type protein tyrosine phosphatase PTPRD is implicated in maturation of synapses of expressing neurons, vulnerability to addictions, reward from addictive substances, vulnerability to restless leg syndrome and densities of neurofibrillary pathology in Alzheimer’s disease brains by a variety of evidence. However, PTPRD’s physiological substrates and adaptations to differences in levels of PTPRD expression in brains of young and aging animals have not been explored in depth. We report phosphoproteomic studies of brains of young and aged mice with different levels of PTPRD expression, gene ontology studies of genes identified in this way and validation of several candidate PTPRD substrates within vitroassays using recombinant PTPRD phosphatase. PTPRD is well positioned to modulate the extent of phosphorylation of phosphotyrosine phosphoprotein substrates, including those involved in synaptic maturation and adaptation.
Implications of (co)evolution of agriculture and resource foraging for the maintenance of species diversity and community structure
Authors: Picot Aurore , Monnin Thibaud , Loeuille Nicolas 
Published: March 2021

AbstractAgriculture is found in numerous taxa such as humans, ants, beetles, fishes and even bacteria. This type of niche construction has evolved independently from hunting, though many species remain primarily predators. When a consumer has a positive effect on its resource, we can expect an allocative cost of agriculture, as the agricultural care diverts time and energy from other activities. Defending the resource against predators may divert time from its consumption (exploitation cost). The cost may also occur on the foraging of alternative resources, for instance if the consumer spends more time nearby the farmed resource and underexploiting resources elsewhere (opportunity cost). We here investigate transitions from predation to agriculture in a simple three-species model of a farmer that consumes two resources and has a positive effect on one. We study the conditions for the (co)evolution of the investment into agriculture and specialization on the two resources, and its consequences on the ecological dynamics of the community. Eco-evolutionary dynamics generate a feedback between the evolution of agriculture and specialization on the helped resource, that can lead to varying selected intensity of agriculture, from generalist strategies with no agriculture, to specialist farmers, with possible coexistence between these two extreme strategies.
Rhythmic neuronal activities of the rat nucleus of the solitary tract are impaired by short-term high fat diet - implications for daily control of satiety by the brainstem
Authors: Chrobok Lukasz , Klich Jasmin D , Sanetra Anna M , Jeczmien-Lazur Jagoda S , Pradel Kamil , Palus-Chramiec Katarzyna , Kepczynski Mariusz , Piggins Hugh D , Lewandowski Marian H 
Published: March 2021

ABSTRACTTemporal partitioning of daily food intake is crucial for survival and involves the integration of internal circadian states and external influences such as the light-dark cycle and the composition of diet. These intrinsic and extrinsic factors are interdependent with misalignment of circadian rhythms promoting body weight gain, while consumption of a calorie dense diet elevates the risk of obesity and blunts circadian rhythms. Since cardiovascular disease, metabolic disorders, and cancer are comorbid with obesity, understanding the relationships between brain activity and diet is of pivotal importance. Recently, we defined for the first time the circadian properties of the dorsal vagal complex of the brainstem, a structure implicated in the control of food intake and autonomic tone, but if and how 24 h rhythms in this area are influenced by diet remains unresolved. Here we focused on a key structure of this complex, the nucleus of the solitary tract, and using a range of approaches, we interrogated how its neuronal and cellular rhythms are affected by high-fat diet. We report that short term consumption of this diet increases food intake during the day and blunts daily rhythms in gene expression and neuronal discharge in the nucleus of the solitary tract. These alterations in this structure occur without prominent body weight gain, suggesting that high-fat diet acts initially to reduce activity in the nucleus of the solitary tract, thereby disinhibiting mechanisms that suppress daytime feeding.GRAPHICAL ABSTRACT
The Orsay Virus as a model for population-wide viral infection dynamics
Authors: Pirenne Laurence , Jakobs Maximilian A. H. , Jordan David , Franze Kristian , Miska Eric A. 
Published: March 2021

AbstractTo this day, epidemics pose a considerable threat to mankind. Experimental models that simulate the spread of infectious diseases are thus crucial to the inception of effective control policies. Current models have had great success incorporating virulence and host immune response but do rarely take host genetics, behavior and host environment into account. Here, we present a full-scale imaging setup that utilizes the infection of the nematodeC. eleganswith a positive-stranded RNA virus (Orsay Virus) to probe key epidemiological parameters and simulate the spread of infection in a whole population. We demonstrate that our system is able to quantify infection levels and host behavior at a high sampling rate and show that different host genetic backgrounds can influence viral spread, while also highlighting the influence of infection on various host behaviors. Future work will allow the isolation of key behavioral and environmental factors that affect viral spread, potentially enabling novel policies to combat the spread of viral infections.Significance StatementIn the ongoing COVID-19 pandemic, we struggle to find effective control policies that “stop the spread”. While current animal models of virus spread in populations are highly sophisticated, they rarely explore effects of host behavior and its environment. We developed an experimental animal model system that allows us to visualize virus transmission in whole populations ofC. eleganswhile also measuring behaviors. We were able to demonstrate howC. elegansgenetics influences the progression of viral infection in a population and how animals adjust their behavior when infected. In the future, we envision that animal model systems like ours are used to test the effects of viral control policies on viral spread before they are applied in real world scenarios.
MEG Oscillatory and Aperiodic neural dynamics contribute to different cognitive aspects of short-term memory decline through lifespan
Authors: Thuwal Kusum , Banerjee Arpan , Roy Dipanjan 
Published: March 2021

ABSTRACTNeural communication or signal transmission in the brain propagates via distinct oscillatory frequency bands. With aging, the communication mediated by these frequency bands is hindered by noise, which arises from the increased stochastic variability in the baseline neural spiking. This increase in noise measured as 1/f power-law scaling reflects the global background noise and is often linked to impaired cognition in different tasks. In this study, we quantified the 1/f slope and intercept of MEG brain signal as a putative marker of neural noise and examined its effect on cognitive and metacognitive measures. We hypothesize that as neural communication becomes noisier with age, it impacts global information processing, whereas specific periodic features mediate local aspects of cognition. Using recently proposed parametric Fooof model, we first characterised the normative pattern of periodic and aperiodic features (temporal dynamics) across the lifespan, modelled via spectral peaks (Central frequency, power, bandwidth) and 1/f noise activity (slope and intercept) respectively. Secondly, how this Resting-State (RS) baseline shift in temporal dynamics of the signal is associated with various aspects of visual short-term memory (VSTM). Our results suggest that age-associated global change in noisy baseline affects global information processing and crucially impacts the oscillatory features, which relates to more local processing and selective behavioural measures in the VSTM task. Moreover, we suggest that the task-related differences observed across age groups are due to the baseline shift of periodic and aperiodic features.Significant statementAging is accompanied by the decline in cognitive functions and age itself is a major risk factor for Alzheimer’s Disease and other neurological conditions. Our study provides MEG 1/f aperiodic and periodic markers across the healthy adult lifespan and shows that different frequency bands and their spectral features mediate age-related changes across different brain regions, in multiple cognitive and metacognitive domains, which not only provides us with a better understanding of the aging process but would also help in better prevention of cognitive impairments. A clear characterization of the association between baseline MEG temporal dynamics, healthy aging and cognition, is established in this study.
Blockade of SARS-CoV-2 infection in vitro by highly potent PI3K-α/mTOR/BRD4 inhibitor
Authors: Acharya Arpan , Pandey Kabita , Thurman Michellie , Challagundala Kishore B. , Vann Kendra R. , Kutateladze Tatiana G. , Morales Guillermo A , Durden Donald L. , Byrareddy Siddappa N. 
Published: March 2021

AbstractPathogenic viruses like SARS-CoV-2 and HIV hijack the host molecular machinery to establish infection and survival in infected cells. This has led the scientific community to explore the molecular mechanisms by which SARS-CoV-2 infects host cells, establishes productive infection, and causes life-threatening pathophysiology. Very few targeted therapeutics for COVID-19 currently exist, such as remdesivir. Recently, a proteomic approach explored the interactions of 26 of 29 SARS-CoV-2 proteins with cellular targets in human cells and identified 67 interactions as potential targets for drug development. Two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs): BRD2/BRD4 and mTOR, are inhibited by the dual inhibitory small molecule SF2523 at nanomolar potency. SF2523 is the only known mTOR PI3K-α/(BRD2/BRD4) inhibitor with potential to block two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Our results demonstrate that SF2523 effectively blocks SARS-CoV-2 replication in lung bronchial epithelial cellsin vitro, showing an IC50value of 1.5 µM, comparable to IC50value of remdesivir (1.1 µM). Further, we demonstrated that the combination of doses of SF2523 and remdesivir is highly synergistic: it allows for the reduction of doses of SF2523 and remdesivir by 25-fold and 4-fold, respectively, to achieve the same potency observed for a single inhibitor. Because SF2523 inhibits two SARS-CoV-2 driven pathogenesis mechanisms involving BRD2/BRD4 and mTOR signaling, our data suggest that SF2523 alone or in combination with remdesivir could be a novel and efficient therapeutic strategy to block SARS-CoV-2 infection and hence be beneficial in preventing severe COVID-19 disease evolution.One Sentence SummaryEvidence ofin silicodesigned chemotype (SF2523) targeting PI3K-α/mTOR/BRD4 inhibits SARS-CoV-2 infection and is highly synergistic with remdesivir.
Clonal evolution in serially passagedCryptococcus neoformansxdeneoformanshybrids reveals a heterogenous landscape of genomic change
Authors: Michelotti Lucas A. , Sun Sheng , Heitman Joseph , James Timothy Y. 
Published: March 2021

AbstractCryptococcus neoformansxdeneoformanshybrids (also known as serotype AD hybrids) are basidiomycete yeasts that are common in a clinical setting. Like many hybrids, the AD hybrids are largely locked at the F1 stage and are mostly unable to undergo normal meiotic reproduction. However, these F1 hybrids, which display a high (∼10%) sequence divergence are known to genetically diversify through mitotic recombination and aneuploidy, and this diversification may be adaptive. In this study, we evolved a single AD hybrid genotype in six diverse environments by serial passaging and then used genome resequencing of evolved clones to determine evolutionary mechanisms of adaptation. The evolved clones generally increased fitness after passaging, accompanied by an average of 3.3 point mutations, 2.9 loss of heterozygosity (LOH) events, and 0.7 trisomic chromosomes per clone. LOH occurred through nondisjunction of chromosomes, crossing over consistent with break-induced replication, and gene conversion, in that order of prevalence. The breakpoints of these recombination events were significantly associated with regions of the genome with lower sequence divergence between the parents and clustered in subtelomeric regions, notably in regions that had undergone introgression between the two parental species. Parallel evolution was observed, particularly through repeated homozygosity via nondisjunction, yet there was little evidence of environment-specific parallel change for either LOH, aneuploidy, or mutations. These data show that AD hybrids have both a remarkable genomic plasticity and yet are challenged in the ability to recombine through sequence divergence and chromosomal rearrangements, a scenario likely limiting the precision of adaptive evolution to novel environments.