bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate Epithelial Genes Define Docetaxel-Sensitive Prostate Cancer Molecular Subtype
Authors: Han Hyunho , Choi Kwibok , Moon Young Jun , Heo Ji Eun , Ham Won Sik , Jang Won Sik , Rha Koon Ho , Cho Nam Hoon , Giancotti Filippo G. , Choi Young-Deuk 
Published: August 2020

ABSTRACTBACKGROUND & OBJECTIVESAnalysis of the transcriptomic landscape of prostate adenocarcinoma shows multidimensional gene expression variability. Understanding cancer transcriptome complexity can provide biological insight and therapeutic guidance. To avoid potential confounding factors, such as stromal contamination and stress-related material degradation, we utilized a set of genes expressed by prostate epithelial cells from single-cell transcriptome data of the human prostate gland.MATERIALS & METHODSAnalyzing publicly available bulk and single-cell RNA sequencing data, we defined 1,629 genes expressed by prostate epithelial cells. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival.RESULTSTCGA-PRAD tumors were separated into four subtypes: A (30.0%), B (26.0%), C (14.7%), D (4.2%), and mixed (25.0%). Subtype A was characterized by low frequency of ETS-family fusions and high expression ofKLK3, which encodes prostate-specific antigen (PSA). Subtype B showed the highest expression ofACP3, encoding PAP (prostatic acid phosphatase). Subtypes C and D were commonly associated with advanced T/N stages, high Gleason grades, and p53 or PIK3CA mutations. In silico drug-sensitivity screening suggested that subtype B is likely sensitive to docetaxel and paclitaxel. Serum PSA/PAP ratio was predictive of a radiographic response to docetaxel in metastatic castration-resistant prostate cancer patients.CONCLUSIONWe propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents. Molecular subtypes and biomarkers must be validated in a prospective cohort study.
REAP supplemental fertilizer improves greenhouse crop yield
Authors: Backer Rachel , Solomon Damian 
Published: August 2020

AbstractBackgroundMine tailings contain rare earth elements, including lanthanum and cerium, and plant micronutrients including iron. Previous studies have demonstrated that fertilizers containing rare earth elements and/or micronutrients can influence plant physiology, nutrient uptake and crop yield. However, applying the right dose of these fertilizers is critical since the concentration range associated with benefits is often narrow, and overapplication can lead to crop yield reductions. This study aimed to quantify the effects of a water-soluble fertilizer, REAP, on the yield of greenhouse crops.MethodsIn the first experiment, the effects of three concentrations of REAP (100, 250 or 500 ppm) were compared to a control (0 ppm REAP) on growth of lettuce, tomato and pepper growing in soilless media. In the second experiments, the effects of REAP applied at higher rates (500, 1000 and 2000 ppm) were compared to a control (0 ppm REAP) on the growth of lettuce, peppers, tomato and cantaloupe.ResultsIn the first experiment, there were no significant differences in yield between treatments, REAP appeared to promote root development. In the second experiment, there were significant yield increases for all crops treated with REAP. Gas exchange rates and nutrient concentration of tomato plants receiving REAP were not significantly different from the control. These results demonstrated that nutrient elements in REAP, including lanthanum, cerium, and micronutrients, improved the growth and yield of vegetable crops when applied at rates ranging from 500 to 2000 ppm.
Gene expression profiles of inflammatory breast cancer reveal high heterogeneity across the epithelial-hybrid-mesenchymal spectrum
Authors: Chakraborty Priyanka , George Jason T , Woodward Wendy A , Levine Herbert , Jolly Mohit Kumar 
Published: August 2020

AbstractInflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.
Imbalance of flight-freeze responses and their cellular correlates in theNlgn3-/yrat model of autism
Authors: Anstey Natasha J , Kapgal Vijayakumar , Tiwari Shashank , Watson Thomas C , Toft Anna KH , Dando Owen R , Inkpen Felicity H , Baxter Paul S , Kozić Zrinko , Jackson Adam D , He Xin , Nawaz Mohammad Sarfaraz , Kayenaat Aiman , Bhattacharya Aditi , Wyllie David JA , Chattarji Sumantra , Wood Emma R , Hardt Oliver , Kind Peter C 
Published: August 2020

SummaryMutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. Whilst examining fear in a rat model of ASD/ID lackingNlgn3, we observed that they display a greater propensity to exhibit flight responses in contrast to classic freezing seen in wildtypes during fearful situations. Consequently, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. Inex vivoslices fromNlgn3-/y, rats, dorsal PAG (dPAG) neurons showed intrinsic hyperexcitability. Further analysis of this revealed lower magnitudein vivodPAG stimulation evoked flight behaviour inNlgn3-/y, rats, indicating the functional impact of the increased cellular excitability. This study provides new insight into potential pathophysiologies leading to emotional disorders in individuals with ASD.
A rendezvous of two second messengers: The c-di-AMP receptor protein DarB controls (p)ppGpp synthesis inBacillus subtilis
Authors: Krüger Larissa , Herzberg Christina , Wicke Dennis , Bähre Heike , Heidemann Jana L. , Dickmanns Achim , Schmitt Kerstin , Ficner Ralf , Stülke Jörg 
Published: August 2020

AbstractMany bacteria use cyclic di-AMP as a second messenger to control potassium and osmotic homeostasis. InBacillus subtilis, several c-di-AMP binding proteins and RNA molecules have been identified. Most of these targets play a role in controlling potassium uptake and export. In addition, c-di-AMP binds to two conserved target proteins of unknown function, DarA and DarB, that exclusively consist of the c-di-AMP binding domain. Most likely these proteins transduce their signal by regulatory interactions with other proteins. Here, we have investigated the function of the c-di-AMP-binding protein DarB inB. subtilis, a protein consisting of two CBS (cystathionine-beta synthase) domains. We have used an unbiased search for DarB interaction partners and identified the (p)ppGpp synthetase/hydrolase Rel as a major interaction partner of DarB. (p)ppGpp is another second messenger that is formed upon amino acid starvation and under other stress conditions to stop translation and active metabolism. The interaction between DarB and Rel only takes place if the bacteria grow at very low potassium concentrations and intracellular levels of c-di-AMP are low. Indeed, c-di-AMP inhibits the binding of DarB to Rel. The interaction results in the Rel-dependent accumulation of pppGpp. Our results link potassium and c-di-AMP signaling to the stringent response and thus to the global control of cellular physiology.
Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development
Authors: Joglekar Anoushka , Prjibelski Andrey , Mahfouz Ahmed , Collier Paul , Lin Susan , Schlusche Anna Katharina , Marrocco Jordan , Williams Stephen R. , Haase Bettina , Hayes Ashley , Chew Jennifer G. , Weisenfeld Neil I , Wong Man Ying , Stein Alexander N. , Hardwick Simon , Hunt Toby , Bent Zachary , Fedrigo Olivier , Sloan Steven A. , Risso Davide , Jarvis Erich D. , Flicek Paul , Luo Wenjie , Pitt Geoffrey S. , Frankish Adam , Smit August B. , Ross M. Elizabeth , Tilgner Hagen U. 
Published: August 2020

AbstractAlternative RNA splicing varies across brain regions, but the single-cell resolution of such regional variation is unknown. Here we present the first single-cell investigation of differential isoform expression (DIE) between brain regions, by performing single cell long-read transcriptome sequencing in the mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 (www.isoformAtlas.com). Using isoform tests for brain-region specific DIE, which outperform exon-based tests, we detect hundreds of brain-region specific DIE events traceable to specific cell-types. Many DIE events correspond to functionally distinct protein isoforms, some with just a 6-nucleotide exon variant. In most instances, one cell type is responsible for brain-region specific DIE. Cell types indigenous to only one anatomic structure display distinctive DIE, where for example, the choroid plexus epithelium manifest unique transcription start sites. However, for some genes, multiple cell-types are responsible for DIE in bulk data, indicating that regional identity can, although less frequently, override cell-type specificity. We validated our findings with spatial transcriptomics and long-read sequencing, yielding the first spatially resolved splicing map in the postnatal mouse brain (www.isoformAtlas.com). Our methods are highly generalizable. They provide a robust means of quantifying isoform expression with cell-type and spatial resolution, and reveal how the brain integrates molecular and cellular complexity to serve function.
PP2A-Cdc55 is responsible for mitotic arrest in DNA re-replicating cells inS. cerevisiae
Authors: Khondker Shoily , Ikui Amy E. 
Published: August 2020

AbstractThe cell cycle is an ordered process in which cells replicate their DNA in S-phase and divide them into two identical daughter cells in mitosis. DNA replication takes place only once per cell cycle to preserve genome integrity, which is tightly regulated by Cyclin Dependent Kinase (CDK). Formation of the pre-replicative complex, a platform for origin licensing, is inhibited through CDK-dependent phosphorylation. Failure of this control leads to re-licensing, re-replication and DNA damage. Eukaryotic cells have evolved surveillance mechanisms to maintain genome integrity, termed cell cycle checkpoints. It has been shown that the DNA damage checkpoint is activated upon the induction of DNA re-replication and arrests cell cycle in mitosis inS. cerevisiae. In this study, we show that PP2A-Cdc55 is responsible for the metaphase arrest induced by DNA re-replication, leading to dephosphorylation of APC component, Exclusion of Cdc55 from the nucleus bypassed the mitotic arrest and resulted in enhanced cell lethality in re-replicating cells. The metaphase arrest in re-replication cells was retained in the absence of Mad2, a key component of the spindle assembly checkpoint. Moreover, re-replicating cells showed the same rate of DNA damage induction in the presence or absence of Cdc55. These results indicate that PP2A-Cdc55 maintains metaphase arrest upon DNA re-replication and DNA damage through APC inhibition.
Disproportionate presence of adenosine in mitochondrial and chloroplast DNA ofChlamydomonas reinhardtii
Authors: El-Sayed Waleed M. M. , Gombolay Alli L. , Xu Penghao , Yang Taehwan , Jeon Youngkyu , Balachander Sathya , Newnam Gary , Tao Sijia , Bowen Nicole E. , Schinazi Raymond F. , Kim Baek , Chen Yongsheng , Storici Francesca 
Published: August 2020

SummaryRibonucleoside monophosphates (rNMPs) represent the most common non-standard nucleotides found in the genomic DNA of cells. The distribution of rNMPs in DNA has been studied only in limited genomes, such as yeast nuclear and mitochondrial DNA, as well as human mitochondrial DNA. In this study, we used the ribose-seq protocol and the Ribose-Map bioinformatics toolkit to reveal the distribution of rNMPs incorporated into the whole genome of a photosynthetic unicellular green alga,Chlamydomonas reinhardtii. The study presents the discovery of a disproportionate incorporation of adenosine in the mitochondrial and chloroplast DNA, in contrast to the nuclear DNA, relative to the nucleotide content of theseC. reinhardtiigenomes. Our results demonstrate that the rNMP content in the DNA of the algal organelles reflects an elevated ATP level present in the algal cells. In addition, we reveal specific rNMP biases and patterns in the mitochondrial, chloroplast and nuclear DNA ofC. reinhardtii.
Gene co-expression analysis of humanRNASEH2Areveals functional networks associated with DNA replication, DNA damage response, and cell cycle regulation
Authors: Marsili Stefania , Tichon Ailone , Storici Francesca 
Published: August 2020

AbstractRibonuclease H2 (RNase H2) is a key enzyme for the removal of RNA found in DNA-RNA hybrids, playing a fundamental role in biological processes such as DNA replication, telomere maintenance and DNA damage repair. RNase H2 is a trimer composed of three subunits, being RNASEH2A the catalytic subunit.RNASEH2Aexpression levels have been shown to be upregulated in transformed and cancer cells. In this study we used a bioinformatics approach to identifyRNASEH2Aco-expressed genes in different human tissues to uncover biological processes in whichRNASEH2Ais involved. By implementing this approach, we identified functional networks forRNASEH2Athat are not only involved in the processes of DNA replication and DNA damage response, but also in cell cycle regulation. Additional examination of protein-protein networks for RNASEH2A by the STRING database analysis, revealed a high co-expression correlation betweenRNASEH2Aand the genes of the protein networks identified. Mass spectrometry analysis of RNASEH2A-bound proteins highlighted players functioning in cell cycle regulation. Further bioinformatics investigation showed increased gene expression ofRNASEH2Ain different types of actively cycling cells and tissues, and particularly in several cancers, supporting a biological role for RNASEH2A, but not the other two subunits of RNase H2, in cell proliferation.
Organic nanoelectronics inside us: charge transport and localization in RNA could orchestrate ribosome operation
Authors: Sosorev Andrey , Kharlanov Oleg 
Published: August 2020

AbstractTranslation—protein synthesis at the ribonucleic acid (RNA) based molecular machine, ribosome, — proceeds in a similar manner in all life forms. However, despite several decades of research, the physics underlying this process remains enigmatic. Specifically, during translation, a ribosome undergoes large-scale conformational changes of its distant parts, and these motions are precisely synchronized by an unknown mechanism. In this study, we suggest that such a mechanism could be related to charge (electron hole) transport along and between the RNA molecules, localization of these charges at certain sites and successive relaxation of molecular geometry. Thus, we suppose that RNA-based molecular machines, e.g., ribosome, are electronically controlled, having “wires”, “actuators”, “battery”, and other “circuitry”. Taking transfer RNA as an example, we justify the reasonability of our suggestion using ab initio and atomistic simulations. We anticipate that our findings will qualitatively advance the understanding of the key biological processes and could inspire novel approaches in medicine.
Divergence in alternative polyadenylation contributes to gene regulatory differences between humans and chimpanzees
Authors: Mittleman Briana , Pott Sebastian , Warland Shane , Barr Kenneth , Cuevas Claudia , Gilad Yoav 
Published: August 2020

AbstractComparative functional genomic studies have shown that differences in gene expression between species can often be explained by corresponding inter-species differences in genetic and epigenetic regulatory mechanisms. In the quest to understand gene regulatory evolution in primates, the role of co-transcriptional regulatory mechanisms, such as alternative polyadenylation (APA), have so far received little attention. To begin addressing this gap, we studied APA in lymphoblastoid cell lines from six humans and six chimpanzees, and estimated usage for 44,432 polyadenylation sites (PAS) in 9,518 genes in both species. While APA is largely conserved in humans and chimpanzees, we identified 1,705 genes with significantly different PAS usage (FDR of 0.05) between the two species. We found that genes with divergent APA patterns are enriched among differentially expressed genes, as well as among genes that show differences in protein translation between species. In particular, differences in APA between humans and chimpanzees can explain a subset of observed inter-species protein expression differences that do not display corresponding differences at the transcript level. Finally, we focused on genes that have a dominant PAS, namely a PAS that is used more often than all others. Dominant PAS are highly conserved, and inter-species differences in dominant PAS are particularly enriched for genes that also show expression differences between the species. This study establishes APA as another key mechanism underlying the genetic regulation of transcript and protein expression levels in primates.
The initial gut microbiota and response to antibiotic perturbation influenceClostridioides difficilecolonization in mice
Authors: Tomkovich Sarah , Stough Joshua M.A. , Bishop Lucas , Schloss Patrick D. 
Published: August 2020

AbstractThe gut microbiota has a key role in determining susceptibility toClostridioides difficileinfections (CDIs). However, much of the mechanistic work examining CDIs in mouse models use animals obtained from a single source. We treated mice from 6 sources (2 University of Michigan colonies and 4 commercial vendors) with clindamycin, followed by aC. difficilechallenge and then measuredC. difficilecolonization levels throughout the infection. The microbiota were profiled via 16S rRNA gene sequencing to examine the variation across sources and alterations due to clindamycin treatment andC. difficilechallenge. While all mice were colonized 1-day post-infection, variation emerged from days 3-7 post-infection with animals from some sources colonized withC. difficilefor longer and at higher levels. We identified bacteria that varied in relative abundance across sources and throughout the experiment. Some bacteria were consistently impacted by clindamycin treatment in all sources of mice includingLachnospiraceae, Ruminococcaceae, andEnterobacteriaceae. To identify bacteria that were most important to colonization regardless of the source, we created logistic regression models that successfully classified mice based on whether they clearedC. difficileby 7 days post-infection using community composition data at baseline, post-clindamycin, and 1-day post-infection. With these models, we identified 4 bacteria that were predictive of whetherC. difficilecleared. They varied across sources (Bacteroides), were altered by clindamycin (Porphyromonadaceae), or both (EnterobacteriaceaeandEnterococcus). Allowing for microbiota variation across sources better emulates human inter-individual variation and can help identify bacterial drivers of phenotypic variation in the context of CDIs.ImportanceClostridioides difficileis a leading nosocomial infection. Although perturbation to the gut microbiota is an established risk, there is variation in who becomes asymptomatically colonized, develops an infection, or has adverse infection outcomes. Mouse models ofC. difficileinfection (CDI) are widely used to answer a variety ofC. difficilepathogenesis questions. However, the inter-individual variation between mice from the same breeding facility is less than what is observed in humans. Therefore, we challenged mice from 6 different breeding colonies withC. difficile. We found that the starting microbial community structures andC. difficilepersistence varied by the source of mice. Interestingly, a subset of the bacteria that varied across sources were associated with how longC. difficilewas able to colonize. By increasing the inter-individual diversity of the starting communities, we were able to better model human diversity. This provided a more nuanced perspective ofC. difficilepathogenesis.