bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ovarian Tumor Mitochondria Exhibit Abnormal Phenotypes and Blunted Associations with Biobehavioral Factors
Authors: Bindra Snehal , McGill Marlon A. , Triplett Marina K. , Tyagi Anisha , Thaker Premal H. , Dahmoush Laila , Goodheart Michael J. , Ogden R. Todd , Owusu-Ansah Edward , Karan Kalpita , Cole Steve , Sood Anil K. , Lutgendorf Susan K. , Picard Martin 
Published: February 2021

AbstractTumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and tumor mitochondria remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign and cancerous ovarian tissue in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n=1,435) showed that gene expression of specific mitochondrial proteins in ovarian tumors is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in 51 benign and 128 high-grade epithelial ovarian tumors revealed that compared to benign tissue, tumors exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P<0.001) but similar mitochondrial DNA levels (−3.1%), documenting abnormal mitochondrial phenotypes in tumors. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r=-0.43 to 0.47). In contrast, serous tumors showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in ovarian tumors and warrant further research on the link between biobehavioral factors and mitochondria in cancer.
IL-10 driven memory T cell survival and Tfh differentiation promote HIV persistence
Authors: Ribeiro Susan Pereira , Aid Malika , Dupuy Frank P. , Chan Chi Ngai , Hultquist Judd , Delage Claire , Moysi Eirini , Kulpa Deanna , Li Lianghzu , Xu Xuan , Tamilselvan Banumathi , Tomalka Jeffrey , Nekorchuk Michael , Busman-Sahay Kathleen , Bordi Rebeka , Simoneau Camille , Goulet Jean Philippe , Marconi Vincent , Routy Jean Pierre , Balderas Robert , Micci Luca , Howell Bonnie , Barouch Dan H. , Krogan Nevan , Petrovas Constantinos , Paiardini Mirko , Deeks Steven G , Estes Jacob D. , Gorman Daniel , Hazuda Daria , Sekaly Rafick Pierre 
Published: February 2021

SummaryMechanisms regulating HIV persistence are complex and not well understood. Increased IL-10 levels were positively associated with HIV reservoir in blood and lymph nodes (LN) of treated HIV aviremic individuals. In LNs, B cells, regulatory T cells, follicular T helper cells (Tfh), monocytes and macrophages contributed to the frequencies of IL10+ cells. Cells with HIV DNA in LNs were in close proximity to IL-10+ cells and/or had the active form of STAT3, the transcription downstream of IL-10. Gene signatures and proteins associated to cell survival, Co-inhibitory receptors expression, maintenance of memory T cells, immune metabolism and Tfh frequencies were all modulated by IL-10 and associated with HIV reservoir persistence.In vitro,STAT3 knockout or neutralization of IL-10, reverted all the aforementioned pathways and resulted in 10-fold decay in HIV reservoir. Collectively, these results provide strong evidence for a pivotal role of IL-10 in HIV persistence, and a potential therapeutic strategy for HIV cure.
LSTM-PHV: Prediction of human-virus protein-protein interactions by LSTM with word2vec
Authors: Tsukiyama Sho , Hasan Md Mehedi , Fujii Satoshi , Kurata Hiroyuki 
Published: February 2021

AbstractViral infection involves a large number of protein-protein interactions (PPIs) between human and virus. The PPIs range from the initial binding of viral coat proteins to host membrane receptors to the hijacking of host transcription machinery. However, few interspecies PPIs have been identified, because experimental methods including mass spectrometry are time-consuming and expensive, and molecular dynamic simulation is limited only to the proteins whose 3D structures are solved. Sequence-based machine learning methods are expected to overcome these problems. We have first developed the LSTM model with word2vec to predict PPIs between human and virus, named LSTM-PHV, by using amino acid sequences alone. The LSTM-PHV effectively learnt the training data with a highly imbalanced ratio of positive to negative samples and achieved an AUC of 0.976 with an accuracy of 98.4% using 5-fold cross-validation. By using independent test dataset, we compared the LSTM-PHV with existing state-of-the-art PPI predictors including DeepViral. In predicting PPIs between human and unknown or new virus, the LSTM-PHV presented higher performance than the existing predictors when they were trained by multiple host protein-including datasets. LSTM-PHV learnt multiple host protein sequence contexts more efficiently than the DeepViral. Interestingly, learning of only sequence contexts as words presented remarkably high performances. Use of uniform manifold approximation and projection demonstrated that the LSTM-PHV clearly distinguished the positive PPI samples from the negative ones. We presented the LSTM-PHV online web server that is freely available athttp://kurata35.bio.kyutech.ac.jp/.
Cyclocreatine suppresses prostate tumorigenesis through dual effects on SAM and creatine metabolism
Authors: Patel Rachana , Rodgers Lisa , Ford Catriona A. , Rushworth Linda K , Fleming Janis , Mui Ernest , Zhang Tong , Watson David , Mackay Gillian , Sumpton David , Sansom Owen J. , Leung Hing Y. 
Published: February 2021

ABSTRACTProstate cancer is highly prevalent, being the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of PTEN and SPRY2 (Sprouty 2) tumour suppressors, we identified enhanced creatine metabolism within the phosphagen system in progressive disease. Altered creatine metabolism was validated inin vitroandin vivoprostate cancer models and in clinical cases. Upregulated creatine levels were due to increased uptake through the SLC6A8 creatine transporter andde novosynthesis, resulting in enhanced cellular basal respiration. Treatment with cyclocreatine (a creatine analogue that potently and specifically blocks the phosphagen system) dramatically reduces creatine and phosphocreatine levels. Blockade of creatine biosynthesis by cyclocreatine leads to cellular accumulation of S-adenosyl methionine (SAM), an intermediary of creatine biosynthesis, and suppresses prostate cancer growthin vitro. Furthermore, cyclocreatine treatment impairs cancer progression in our GEMM and in a xenograft liver metastasis model. Hence, by targeting the phosphagen system, cyclocreatine results in anti-tumourigenic effects from both SAM accumulation and suppressed phosphagen system.
The Epstein-Barr virus ubiquitin deconjugase BPLF1 regulates the activity of Topoisomerase II during virus replication
Authors: Li Jinlin , Nagy Noemi , Liu Jiangnan , Gupta Soham , Frisan Teresa , Hennig Thomas , Cameron Donald P. , Baranello Laura , Masucci Maria G. 
Published: February 2021

AbstractTopoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 selectively inhibited the ubiquitination of TOP2 following treatment with topoisomerase poisons, interacted with TOP2α and TOP2β in co-immunoprecipitation andin vitropull-down, stabilized Etoposide-trapped TOP2 cleavage complexes (TOP2cc) and promoted TOP2 SUMOylation, which halted the DNA-damage response and reduced Etoposide toxicity. Induction of the productive virus cycle promoted the accumulation of TOP2βcc, enhanced TOP2β SUMOylation, and reduced Etoposide toxicity in lymphoblastoid cell lines carrying recombinant EBV encoding the active enzyme. Attenuation of this phenotype upon expression of a catalytic mutant BPLF1-C61A impaired viral DNA synthesis and virus release. These findings highlight a previously unrecognized function of BPLF1 in promoting non-proteolytic pathways for TOP2cc debulking that favor cell survival and virus production.
Integrative network analysis interweaves the missing links in cardiomyopathy diseasome
Authors: Chauhan Pankaj Kumar , Sowdhamini Ramanathan 
Published: February 2021

AbstractCardiomyopathies are progressive disease conditions that give rise to an abnormal heart phenotype and are a leading cause of heart failures in the general population. These are complex diseases that show co-morbidity with other diseases. The molecular interaction network in the localised disease neighbourhood is an important step toward deciphering molecular mechanisms underlying these complex conditions. In this pursuit, we employed network medicine techniques to systematically investigate cardiomyopathy’s genetic interplay with other diseases and uncover the molecular players underlying these associations. We predicted a set of candidate genes in cardiomyopathy by exploring the DIAMOnD algorithm on the human interactome. We next revealed how these candidate genes form association across different diseases and highlighted the predominant association with brain, cancer and metabolic diseases. Through integrative systems analysis of molecular pathways, heart-specific mouse knockout data and disease tissue-specific transcriptomic data, we screened and ascertained prominent candidates that show abnormal heart phenotype, includingNOS3, MMP2andSIRT1. Our computational analysis broadens the understanding of the genetic associations of cardiomyopathies with other diseases and holds great potential in cardiomyopathy research.
Extended numerical analysis of an eyeball injury under direct impact
Authors: Koberda M. , Skorek A. , Kłosowski P. , Żmuda-Trzebiatowski M. , Żerdzicki K. , Lemski P. , Stodolska-Koberda U. 
Published: February 2021

AbstractThe objective of this study was to develop a numerical model of the eyeball and orbit to simulate a blunt injury to the eyeball leading to its rupture, as well as to conduct a comparative analysis of the results obtained using the finite element method against the clinical material concerning patients who had suffered an eyeball rupture due to a blunt force trauma. Using available sclera biometric and strength data, a numerical model of the eyeball, the orbital contents, and the bony walls were developed from the ground up. Then, eight different blunt force injury scenarios were simulated. The results of numerical analyses made it possible to identify possible locations and configurations of scleral rupture. The obtained results were compared against the clinical picture of patients hospitalized at the Clinic of Ophthalmology in 2010–2016 due to isolated blunt force trauma to the eyeball. It has been demonstrated that the extent of damage observed on the numerical model that indicated a possible location of eyeball rupture did not differ from the clinically observed configurations of the scleral injuries, however this applies to injuries the extend of which did not exceed 2–3 clock-hours on the eyeball. It has been found that the direction of the impact applied determines the location of eyeball rupture. Most often the rupture occurs at the point opposite to the clock-hour of the impact application. The eyeball rupture occurs in the first 7–8 milliseconds after the contact with the striking object, assuming that it strikes at a speed close to the speed of a human fist. It has been established that the injuries most often affected the upper sectors of the eyeball. Men are definitely more likely to sustain such injuries. Eyeball ruptures lead to significant impairment of visual acuity being most often degraded to light perception in front of the eye. Despite immediate specialist treatment, it is possible to achieve, on average, a visual acuity of 0.26 as per the Snellen scale. This study may contribute to a better understanding of injury mechanisms and better treatment planning. It may also contribute to the development of eyeball protection methods for persons exposed to the above-mentioned injuries.
THz irradiation inhibits cell division by affecting actin dynamics
Authors: Yamazaki Shota , Ueno Yuya , Hosoki Ryosuke , Saito Takanori , Idehara Toshitaka , Yamaguchi Yuusuke , Otani Chiko , Ogawa Yuichi , Harata Masahiko , Hoshina Hiromichi 
Published: February 2021

AbstractBiological phenomena induced by terahertz (THz) irradiation are described in recent reports, but underlying mechanisms, structural and dynamical change of specific molecules are still unclear. In this paper, we performed time-lapse morphological analysis of human cells and found that THz irradiation halts cell division at cytokinesis. At the end of cytokinesis, the contractile ring, which consists of filamentous actin (F-actin), needs to disappear; however, it remained for 1 hour under THz irradiation. Induction of the functional structures of F-actin was also observed in interphase cells. Similar phenomena were also observed under chemical treatment (jasplakinolide), indicating that THz irradiation assists actin polymerization. We previously reported that THz irradiation enhances the polymerization of purified actin in vitro; our current work shows that it increases cytoplasmic F-actin in vivo. Thus, we identified one of the key biomechanisms affected by THz waves.
Global genetic heterogeneity in adaptive traits
Authors: Lopez-Arboleda William Andres , Reinert Stephan , Nordborg Magnus , Korte Arthur 
Published: February 2021

AbstractUnderstanding the genetic architecture of complex traits is a major objective in biology. The standard approach for doing so is genome-wide association studies (GWAS), which aim to identify genetic polymorphisms responsible for variation in traits of interest. In human genetics, consistency across studies is commonly used as an indicator of reliability. However, if traits are involved in adaptation to the local environment, we do not necessarily expect reproducibility. On the contrary, results may depend on where you sample, and sampling across a wide range of environments may decrease the power of GWAS because of increased genetic heterogeneity. In this study, we examine how sampling affects GWAS for a variety of phenotypes in the model plant speciesArabididopsis thaliana. We show that traits like flowering time are indeed influenced by distinct genetic effects in local populations. Furthermore, using gene expression as a molecular phenotype, we show that some genes are globally affected by shared variants, while others are affected by variants specific to subpopulations. Remarkably, the former are essentially allcis-regulated, whereas the latter are predominately affected bytrans-acting variants. Our result illustrate that conclusions about genetic architecture can be incredibly sensitive to sampling and population structure.
Dynamics of the most common pathogenic mtDNA variant m.3243A>G demonstrate frequency-dependency in blood and positive selection in the germline
Authors: Franco Melissa , Pickett Sarah J. , Fleischmann Zoe , Khrapko Mark , Cote-L’Heureux Auden , Aidlen Dylan , Stein David , Markuzon Natasha , Popadin Konstantin , Braverman Maxim , Woods Dori C. , Tilly Jonathan L. , Turnbull Doug M. , Khrapko Konstantin 
Published: February 2021

AbstractThe A-to-G point mutation at position 3243 in the human mitochondrial genome (m.3243A>G) is the most common pathogenic mtDNA variant responsible for disease in humans. It is widely accepted that m.3243A>G levels decrease in blood with age, and an age correction representing ∼2% annual decline is often applied to account for this change in mutation level. Here we report that recent data indicate the dynamics of m.3243A>G are more complex and depend on the mutation level in blood in a bi-phasic way. Consequently, the traditional 2% correction, which is adequate ‘on average’, creates opposite predictive biases at high and low mutation levels. Unbiased age correction is needed to circumvent these drawbacks of the standard model. We propose to eliminate both biases by using an approach where age correction depends on mutation level in a biphasic way to account for the dynamics of m.3243A>G in blood. The utility of this approach was further tested in estimating germline selection of m.3243A>G. The biphasic approach permitted us to uncover patterns consistent with the possibility of positive selection for m.3243A>G. Germline selection of m.3243A>G shows an ‘arching’ profile by which selection is positive at intermediate mutant fractions and declines at high and low mutant fractions. We conclude that use of this biphasic approach will greatly improve the accuracy of modelling changes in mtDNA mutation frequencies in the germline and in somatic cells during aging.
Machine learning for cell classification and neighborhood analysis in glioma tissue
Authors: Solorzano Leslie , Wik Lina , Bontell Thomas Olsson , Wang Yuyu , Klemm Anna H. , Öfverstedt Johan , Jakola Asgeir S. , Östman Arne , Wählby Carolina 
Published: February 2021

AbstractMultiplexed and spatially resolved single-cell analyses that intend to study tissue heterogeneity and cell organization invariably face as a first step the challenge of cell classification. Accuracy and reproducibility are important for the down-stream process of counting cells, quantifying cell-cell interactions, and extracting information on disease-specific localized cell niches. Novel staining techniques make it possible to visualize and quantify large numbers of cell-specific molecular markers in parallel. However, due to variations in sample handling and artefacts from staining and scanning, cells of the same type may present different marker profiles both within and across samples. We address multiplexed immunofluorescence data from tissue microarrays of low grade gliomas and present a methodology using two different machine learning architectures and features insensitive to illumination to perform cell classification. The fully automated cell classification provides a measure of confidence for the decision and requires a comparably small annotated dataset for training, which can be created using freely available tools. Using the proposed method, we reached an accuracy of 83.1% on cell classification without the need for standardization of samples. Using our confidence measure, cells with low-confidence classifications could be excluded, pushing the classification accuracy to 94.5%. Next, we used the cell classification results to search for cell niches with an unsupervised learning approach based on graph neural networks. We show that the approach can re-detect specialized tissue niches in previously published data, and that our proposed cell classification leads to niche definitions that may be relevant for sub-groups of glioma, if applied to larger datasets.
5S-IGS rDNA in wind-pollinated trees (FagusL.) encapsulates 55 million years of reticulate evolution and hybrid origins of modern species
Authors: Cardoni Simone , Piredda Roberta , Denk Thomas , Grimm Guido W. , Papageorgiou Aristotelis C. , Schulze Ernst-Detlef , Scoppola Anna , Shanjani Parvin Salehi , Suyama Yoshihisa , Tomaru Nobuhiro , Worth James R.P. , Simeone Marco Cosimo 
Published: February 2021

SummaryStandard models of plant speciation assume strictly dichotomous genealogies in which a species, the ancestor, is replaced by two offspring species. The reality in wind-pollinated trees with long evolutionary histories is more complex: species evolve from other species through isolation when genetic drift exceeds gene flow; lineage mixing can give rise to new species (hybrid taxa such as nothospecies and allopolyploids). The multi-copy, potentially multi-locus 5S rDNA is one of few gene regions conserving signal from dichotomous and reticulate evolutionary processes down to the level of intra-genomic recombination. Therefore, it can provide unique insights into the dynamic speciation processes of lineages that diversified tens of millions of years ago. Here, we provide the first high-throughput sequencing (HTS) of the 5S intergenic spacers (5S-IGS) for a lineage of wind-pollinated subtropical to temperate trees, theFagus crenata – F. sylvaticas.l. lineage, and its distant relativeF. japonica.The observed 4,963 unique 5S-IGS variants reflect a complex history of hybrid origins, lineage sorting, mixing via secondary gene flow, and intra-genomic competition between two or more paralogous-homoeologous 5S rDNA lineages. We show that modern species are genetic mosaics and represent a striking case of ongoing reticulate evolution during the past 55 million years.Significance statementThe evolution of extra-tropical wind-pollinated tree genera involves dynamic speciation processes. High-throughput sequencing of the multi-copy, potentially multi-locus 5S rDNA reveals a complex history of hybrid origins, lineage sorting and mixing, and intra-genomic competition between paralogous-homeologous loci in the core group of Eurasian beech trees (genusFagus) and their distant relative,F. japonica. The modern species are genetic mosaics and represent a striking case of at least 55 million years of ongoing reticulate evolution.
Distribution of methionine sulfoxide reductases in fungi and conservation of the free-methionine-R-sulfoxide reductase in multicellular eukaryotes
Authors: Hage Hayat , Rosso Marie-Noëlle , Tarrago Lionel 
Published: February 2021

AbstractMethionine, either as a free amino acid or included in proteins, can be oxidized into methionine sulfoxide (MetO), which exists as R and S diastereomers. Almost all characterized organisms possess thiol-oxidoreductases named methionine sulfoxide reductase (Msr) enzymes to reduce MetO back to Met. MsrA and MsrB reduce the S and R diastereomers of MetO, respectively, with strict stereospecificity and are found in almost all organisms. Another type of thiol-oxidoreductase, the free-methionine-R-sulfoxide reductase (fRMsr), identified so far in prokaryotes and a few unicellular eukaryotes, reduces the R MetO diastereomer of the free amino acid. Moreover, some bacteria possess molybdenum-containing enzymes that reduce MetO, either in the free or protein-bound forms. All these Msrs play important roles in the protection of organisms against oxidative stress. Fungi are heterotrophic eukaryotes that colonize all niches on Earth and play fundamental functions, in organic matter recycling, as symbionts, or as pathogens of numerous organisms. However, our knowledge on fungal Msrs is still limited. Here, we performed a survey of msr genes in almost 700 genomes across the fungal kingdom. We show that most fungi possess one gene coding for each type of methionine sulfoxide reductase: MsrA, MsrB, and fRMsr. However, several fungi living in anaerobic environments or as obligate intracellular parasites were devoid of msr genes. Sequence inspection and phylogenetic analyses allowed us to identify non-canonical sequences with potentially novel enzymatic properties. Finaly, we identified several ocurences of msr horizontal gene transfer from bacteria to fungi.HighlightsFree and protein-bound methionine can be oxidized into methionine sulfoxide (MetO).Methionine sulfoxide reductases (Msr) reduce MetO in most organisms.Sequence characterization and phylogenomics revealed strong conservation of Msr in fungi.fRMsr is widely conserved in unicellular and multicellular fungi.Some msr genes were acquired from bacteria via horizontal gene transfers.