bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control of theAzollasymbiosis sexual reproduction: ferns to shed light on the origin of floral regulation?
Authors: Dijkhuizen Laura W. , Tabatabaei Badraldin Ebrahim Sayed , Brouwer Paul , Rijken Niels , Buijs Valerie A. , Güngör Erbil , Schluepmann Henriette 
Published: September 2020

ABSTRACTAzollaferns and the filamentous cyanobacteriaNostoc azollaeconstitute a model symbiosis that enabled colonization of the water surface with traits highly desirable for development of more sustainable crops: their floating mats capture CO2and fixate N2at high rates phototrophically. Their mode of sexual reproduction is heterosporous. Regulation of the transition from vegetative to spore-forming phases in ferns is largely unknown, yet a pre-requisite forAzolladomestication, and of particular interest since ferns represent the sister lineage of seed plants.Far-red light (FR) induced sporocarp formation inA. filiculoides. Sporocarps obtained, when crossed, verified species attribution of Netherlands strains but not Iran’s Anzali lagoon. FR-responsive transcripts included CMADS1 MIKCC-homologues and miRNA-controlled GAMYB transcription factors in the fern, transporters inN.azollae, and ycf2 in chloroplasts. Loci of conserved miRNA in the fern lineage included miR172, yet FR only induced miR529 and miR535, and reduced miR319 and miR159.Suppression of sexual reproduction in both gametophyte and sporophyte-dominated plant lineages by red light is likely a convergent ecological strategy in open fields as the active control networks in the different lineages differ. MIKCCtranscription factor control of flowering and flower organ specification, however, likely originated from the diploid to haploid phase transition in the homosporous common ancestor of ferns and seed plants.
To rarefy or not to rarefy: Enhancing diversity analysis of microbial communities through next-generation sequencing and rarefying repeatedly
Authors: Cameron Ellen S. , Schmidt Philip J. , Tremblay Benjamin J.-M. , Emelko Monica B. , Müller Kirsten M. 
Published: September 2020

AbstractAmplicon sequencing has revolutionized our ability to study DNA collected from environmental samples by providing a rapid and sensitive technique for microbial community analysis that eliminates the challenges associated with lab cultivation and taxonomic identification through microscopy. In water resources management, it can be especially useful to evaluate ecosystem shifts in response to natural and anthropogenic landscape disturbances to signal potential water quality concerns, such as the detection of toxic cyanobacteria or pathogenic bacteria. Amplicon sequencing data consist of discrete counts of sequence reads, the sum of which is the library size. Groups of samples typically have different library sizes that are not representative of biological variation; library size normalization is required to meaningfully compare diversity between them. Rarefaction is a widely used normalization technique that involves the random subsampling of sequences from the initial sample library to a selected normalized library size. Rarefying is often dismissed as statistically invalid because subsampling effectively discards a portion of the observed sequences. Nonetheless, it remains prevalent in practice. Notably, the superiority of rarefying relative to many other normalization approaches has been argued in diversity analysis. Here, repeated rarefying is proposed as a tool for diversity analyses to normalize library sizes. This enables (i) proportionate representation of all observed sequences and (ii) characterization of the random variation introduced to diversity analyses by rarefying to a smaller library size shared by all samples. While many deterministic data transformations are not tailored to produce equal library sizes, repeatedly rarefying reflects the probabilistic process by which amplicon sequencing data are obtained as a representation of the source microbial community. Specifically, it evaluates which data might have been obtained if a particular sample’s library size had been smaller and allows graphical representation of the effects of this library size normalization process upon diversity analysis results.
Integrative Analysis of Spatial and Single-Cell Transcriptomics Reveals Principles of Tissue Organization and Intercellular Communication in Mouse Olfactory Bulb
Authors: Canozo Francisco Jose Grisanti , Zuo Zhen , Martin James F. , Samee Md. Abul Hassan 
Published: September 2020

AbstractIntercellular communication and spatial organization of cells are two critical aspects of a tissue’s function. Understanding these aspects requires integrating data from single-cell RNA-Seq (scRNA-seq) and spatial transcriptomics (ST), the two cutting edge technologies that offer complementary insights into tissue composition, architecture, and function. Integrating these data types is non-trivial since they differ widely in the number of profiled genes and often do not share marker genes for given cell-types. We developed STANN, a neural network model that overcomes these methodological challenges. Given ST and scRNA-seq data of a tissue, STANN models cell-types in the scRNA-seq dataset from the genes that are profiled by both ST and scRNA-seq. The trained STANN model then assigns cell-types to the ST dataset. We apply STANN to assign cell-types in a recent ST dataset (SeqFISH+) of mouse olfactory bulb (MOB). Our analysis of STANN’s assigned cell-types revealed principles of tissue architecture and intercellular communication at unprecedented detail. We find that cell-type compositions are disproportionate in the tissue, yet their relative proportions are spatially consistent within individual morphological layers. Surprisingly, within a morphological layer, there is a high spatial variation in cell-type colocalization patterns and intercellular communication mechanisms. Our analysis suggests that spatially localized gene regulatory networks may account for such variability in intercellular communication mechanisms.
Structural and dynamic characterization of the C-terminal tail of ErbB2: disordered but not random
Authors: Pinet L. , Wang Y.-H. , Deville C. , Lescop E. , Guerlesquin F. , Badache A. , Bontems F. , Morellet N. , Durand D. , Assrir N. , van Heijenoort C. 
Published: September 2020

ABSTRACTErbB2 (or HER2) is a receptor tyrosine kinase overexpressed in some breast cancers, associated with poor prognosis. Treatments targeting the receptor extracellular and kinase domains have greatly improved disease outcome in the last twenty years. In parallel, the structures of these domains have been described, enabling better mechanistic understanding of the receptor function and targeted inhibition. However, ErbB2 disordered C-terminal cytoplasmic tail (CtErbB2) remains very poorly characterized in terms of structure, dynamics and detailed functional mechanism. Yet, it is where signal transduction is triggered, via phosphorylation of tyrosine residues, and carried out, via interaction with adaptor proteins. Here we report the first description of ErbB2 disordered tail at atomic resolution, using NMR and SAXS. We show that although no part of CtErbB2 has any stable secondary or tertiary structure, it has around 20% propensity for a N-terminal helix that is suspected to interact with the kinase domain, and many PPII stretches distributed all along the sequence, forming potential SH3 and WW domains binding sites. Moreover, we identified a long-range transient contact involving CtErbB2 termini. These characteristics suggest new potential mechanisms of auto-regulation and protein-protein interaction.SIGNIFICANCEWe report here the first description of the receptor tyrosine kinase ErbB2 disordered tail (CtErbB2) at atomic resolution, using NMR and SAXS. We show that although CtErbB2 exhibits no stable structure, it does exhibit partial secondary and tertiary structures likely important for its function. These structural elements are consistent with an active role of the C-terminal tail in the regulation of the receptor’s activity, thanks to the presence of preformed structures for intramolecular interactions, as well as long-range contacts modulating accessibility of those sites and proline interaction sites distinct from the main tyrosine sites. Together, those results reinforce the view that disordered tails of receptors are more than random anchors for partners.
PAX8 orchestrates an angiogenic program through interaction with SOX17
Authors: Chaves-Moreira Daniele , Mitchell Marilyn A. , Arruza Cristina , Rawat Priyanka , Sidoli Simone , Nameki Robbin , Reddy Jessica , Corona Rosario I. , Ma Sisi , Winterhoff Boris , Konecny Gottfried E. , Garcia Benjamin A. , Brady Donita C. , Lawrenson Kate , Morin Patrice J. , Drapkin Ronny 
Published: September 2020

ABSTRACTWorldwide, the number of new ovarian cancer cases approaches 300,000 with more than 180,000 deaths every year. The low survival-rate reflects the limitations of current therapies and highlights the importance of identifying new therapeutic targets. Despite significant recent efforts to identify novel vulnerabilities in ovarian cancer, none have led to effective durable therapies with improvement in overall survival. PAX8, a lineage-transcription factor, whose expression is a major molecular feature of ovarian carcinomas, represents a novel therapeutic target. Herein, we have identified SOX17 as abona fidePAX8-interacting partner and elucidated the impact of this interaction on the development of ovarian cancer. Importantly, we found that PAX8 and SOX17 regulate tumor angiogenesisin vitroandin vivo. The role of PAX8 and SOX17 in the regulation of angiogenesis reveals a novel function for these factors in regulating the tumor microenvironment and highlight this pathway as a viable therapeutic target.
Pro-drug peptide and its metabolites disrupt amyloid fibrils by destabilizing salt bridge interaction and planar beta-sheet topology
Authors: Adupa Vasista , Mandal Bhubaneswar , Reddy K. Anki 
Published: September 2020

AbstractThe most common age-related neurodegenerative disorder, Alzheimer’s disease, is clinically characterized by continuous neuronal loss resulting in loss of memory and dementia with no cure to date. Amyloid-β(Aβ) aggregates and tau protein are believed to be the causative agents of this pathogenesis. In the present study, we have investigated the effect of the Pro-Drug peptide (PDp) and its metabolites (α-aspartyl &β-aspartyl) on the Aβaggregates using atomistic molecular dynamics simulations. One of the key findings in our work is in the presence ofα-aspartyl as a ligand, the salt bridges which hold the N-terminals together are completely disrupted, thus setting the N-terminals free and exposed entirely to the solvent which can make the aggregation of Aβless severe. The efficiency of the ligands, which are responsible for the disruption of Aβ, depends on the alignment and strength of the repulsive interactions. Besides repulsive interactions, we found that there is a need for hydrogen bonding, which acts as a support for the ligand to stay in the vicinity of the aggregate. Moreover, we have noticed that one of the metabolites, namelyβ-aspartyl, formed more hydrogen bonds with the aggregate than the other ligands and had a different mode of action with the chains of Aβdue to its unique flexible kink in the backbone.
HetF protein is a new divisome component in a filamentous and developmental cyanobacterium
Authors: Xing Wei-Yue , Liu Jing , Wang Zi-Qian , Zhang Ju-Yuan , Zeng Xiaoli , Yang Yiling , Zhang Cheng-Cai 
Published: September 2020

AbstractBacterial cell division, with a few exceptions, is driven by FtsZ through a treadmilling mechanism to remodel and constrict the rigid peptidoglycan (PG) layer. Yet, different organisms may differ in the composition of the cell-division complex (divisome). In the filamentous cyanobacteriumAnabaenaPCC 7120,hetFis required for the initiation of the differentiation of heterocysts, cells specialized in N2-fixing cells under combined nitrogen deprivation. In this study, we demonstrate thathetFis expressed in vegetative cells and necessary for cell division in a conditional manner. Under non-permissive conditions, cells of a ΔhetFmutant stop dividing, consistent with increased level of HetF under similar conditions in the wild type. Furthermore, HetF is a membrane protein located at midcell and cell-cell junctions. In the absence of HetF, FtsZ rings are still present in the elongated cells; however, PG remodelling is abolished. This phenotype is similar to that observed with the inhibition of septal PG synthase FtsI. We further reveal that HetF is recruited to or stabilized at the divisome by interacting with FtsI and this interaction is necessary for HetF function in cell division. Our results indicate that HetF is a member of the divisome, and reveal distinct features of the cell-division machinery in cyanobacteria that are of high ecological and environmental importance.Significance StatementCyanobacteria shaped the Earth’s evolutionary history, and are still playing important roles for elementary cycles in different environments. They are consisted of highly diverse species with different cell shape, size and morphology. Although these properties are strongly affected by the process of cytokinesis, the mechanism remains largely unexplored. Using different approaches, we demonstrate that HetF is a new component of the cell division machinery in the filamentous cyanobacteriumAnabaenaPCC 7120. The common and diverged characteristics of cell division in prokaryotes reflect the evolutionary history of different bacteria, as an adaptive measure to proliferate under certain environmental conditions. As a protein for cell differentiation, the recruitment of HetF to the septum illustrates such an adaptive mechanism for cyanobacteria.
Visualizing and isolating iron-reducing microorganisms at single cell level
Authors: Gan Cuifen , Wu Rongrong , Luo Yeshen , Song Jianhua , Luo Dizhou , Li Bei , Yang Yonggang , Xu Meiying 
Published: September 2020

AbstractIron-reducing microorganisms (FeRM) play key roles in many natural and engineering processes. Visualizing and isolating FeRM from multispecies samples are essential to understand the in-situ location and geochemical role of FeRM. Here, we visualized FeRM by a “turn-on” Fe2+-specific fluorescent chemodosimeter (FSFC) with high sensitivity, selectivity and stability. This FSFC could selectively identify and locate active FeRM from either pure culture, co-culture of different bacteria or sediment-containing samples. Fluorescent intensity of the FSFC could be used as an indicator of Fe2+concentration in bacterial cultures. By integrating FSFC with a single cell sorter, we obtained three FSFC-labeled cells from an enriched consortia and all of them were subsequently evidenced to be capable of iron-reduction and two unlabeled cells were evidenced to have no iron-reducing capability, further confirming the feasibility of the FSFC.ImportanceVisualization and isolation of FeRM from samples containing multispecies are commonly needed by researchers from different disciplines, such as environmental microbiology, environmental sciences and geochemistry. However, no available method has been reported. In this study, we provid a solution to visualize FeRM and evaluate their activity even at single cell level. Integrating with single cell sorter, FeRM can also be isolated from samples containing multispecies. This method can be used as a powerful tool to uncover the in-situ or ex-situ role of FeRM and their interactions with ambient microbes or chemicals.
LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population During Temozolomide Therapy in Glioblastoma
Authors: Baisiwala Shivani , Hall Robert H , Saathoff Miranda R , Shireman Jack M , Park Cheol , Warnke Louisa , Hardiman Clare , Wang Jenny Y , Goel Chirag , Budhiraja Shreya , McCortney Kathleen , Horbinski Craig M. , Ahmed Atique U. 
Published: September 2020

ABSTRACTGlioblastoma (GBM) is the most common primary brain malignancy in adults, with a 100% recurrence rate and a 21-month median survival. Our lab and others have shown that GBM contains a subpopulation of glioma stem cells (GSCs) that expand with chemotherapy, and that may contribute to therapeutic resistance and recurrence in GBM. To investigate the mechanism behind this expansion, we applied gene set expression analysis (GSEA) to patient-derived xenograft (PDX) cells in response to temozolomide (TMZ), the most commonly used chemotherapy against GBM. Results showed significant enrichment of cancer stem cell and cell cycle pathways (FDR<0.25). The ligand of numb protein 1 (LNX1), a known regulator of Notch signaling by targeting negative regulator Numb, is strongly upregulated after TMZ therapy (p<0.0001) and is negatively correlated with survival of GBM patients. LNX1 is also upregulated after TMZ therapy in multiple PDX lines with concomitant downregulations in Numb and upregulations in intracellular Notch1 (NICD). Overexpression of LNX1 results in Notch1 signaling activation and increased CSC populations. In contrast, knocking down LNX1 reverses these changes, causing a significant downregulation of NICD, eliminating induction of functional stemness after TMZ therapy, and resulting in more prolonged median survival in a mouse model. Our data indicate that removing LNX1 activity results in a less aggressive and more chemo-sensitive tumor. Based on this, we propose that during anti-GBM chemotherapy, LNX1-regulated Notch1 signaling promotes stemness and contributes to therapeutic resistance.
Radiation induced toxicity in rectal epithelial stem cell contributes to acute radiation injury in rectum
Authors: Tirado Felipe Rodriguez , Bhanja Payel , Castro-Nallar Eduardo , Olea Ximena Diaz , Salamanca Catalina , Saha Subhrajit 
Published: September 2020

AbstractBackgroundRadiation induced rectal epithelial damage is a very common side effect of pelvic radiotherapy and often compromise the life quality and treatment outcome in patients with pelvic malignancies. Unlike small bowel and colon effect of radiation in rectal stem cells has not been explored extensively. Here we demonstrate that Lgr5 positive rectal stem cells are radiosensitive and organoid based transplantation of rectal stem cells mitigates radiation damage in rectumMethodsC57Bl6 male mice (JAX) at 24 h was exposed to pelvic irradiation (PIR) to determine the radiation effect in pelvic epithelium. Effect PIR on Lgr5-positive rectal stem cells (RSCs) was determined in Lgr5-EGFP-Cre-ERT2 mice exposed to PIR. Effect PIR or clinically relevant fractionated PIR on regenerative response of Lgr5-positive RSCs was examined by lineage tracing assay using Lgr5-eGFP-IRES-CreERT2; Rosa26-CAG-tdTomato mice with tamoxifen administration to activate Cre recombinase and thereby marking the ISC and their respective progeny. Ex vivo three-dimensional organoid cultures were developed from Lgr5-EGFP-Cre-ERT2 mice. Organoid growth was determined by quantifying the budding crypt/total crypt ratio. Organoids from Lgr5-EGFP-ires-CreERT2-TdT mice were transplanted in C57Bl6 male mice exposed to PIR. Engraftment and repopulation of Lgr5-positive RSCs were determined after tamoxifen administration to activate Cre recombinase in recipient mice. Statistical analysis was performed using Log-rank (Mantel-Cox) test and paired two-tailttest.ResultExposure to pelvic irradiation significantly damaged rectal epithelium with the loss of Lgr5+ve rectal stem cells. Radio-sensitivity of rectal epithelium was also observed with exposure to clinically relevant fractionated pelvic irradiation. Regenerative capacity of Lgr5+ve rectal stem cells were compromised in response to fractionated pelvic irradiation. Ex-vivo organoid study demonstrated that Lgr5+ve rectal stem cells are sensitive to both single and fractionated radiation. Organoid based transplantation of Lgr5+ve rectal stem cells promote repair and regeneration of rectal epithelium.ConclusionLgr5 positive rectal stem cells are radio-sensitive and contribute to radiation induced rectal epithelial toxicity. Transplantation of Lgr5 positive rectal stem cells mitigates radiation induced rectal injury and promote repair and regeneration process in rectum.
Conserved interactions required for in vitro inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Authors: Shitrit Alina , Zaidman Daniel , Kalid Ori , Bloch Itai , Doron Dvir , Yarnizky Tali , Buch Idit , Segev Idan , Ben-Zeev Efrat , Segev Elad , Kobiler Oren 
Published: September 2020

AbstractThe COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands’ interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screenedin silicoa library of 6,900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were testedin vitroby a protease activity inhibition assay. Two compounds showed activity at the 50μM concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.
Ribosome stalling caused by the Argonaute-microRNA-SGS3 complex regulates the production of secondary siRNAs in plants
Authors: Iwakawa Hiro-oki , Lam Andy Y.W. , Mine Akira , Fujita Tomoya , Kiyokawa Kaori , Yoshikawa Manabu , Takeda Atsushi , Iwasaki Shintaro , Tomari Yukihide 
Published: September 2020

AbstractThe path of ribosomes on mRNAs can be impeded by various obstacles. One such example is halting of ribosome movement by microRNAs, though the exact mechanism and physiological role remain unclear. Here, we find that ribosome stalling caused by the Argonaute-microRNA-SGS3 complex regulates the production of secondary small interfering RNAs (siRNAs) in plants. We show that the double-stranded RNA-binding protein SGS3 directly interacts with the 3′ end of the microRNA in an Argonaute protein, resulting in ribosome stalling. Importantly, microRNA-mediated ribosome stalling positively correlates with efficient production of secondary siRNAs from target mRNAs. Our results illustrate a role for paused ribosomes in regulation of small RNA function that may have broad biological implications across the plant kingdom.