bluuebunny/crossref_metadata_2025_split huggingface dataset:
Convergent mutations in tissue-specific regulatory regions reveal novel cancer drivers
Authors: Sinnott-Armstrong Nasa , Seoane Jose A. , Sallari Richard , Pritchard Jonathan K. , Curtis Christina , Snyder Michael P. 
Published: August 2020

AbstractAlthough much effort has been devoted to identifying coding mutations across cancer types, regulatory mutations remain poorly characterized. Here, we describe a framework to identify non-coding drivers by aggregating mutations in cell-type specific regulatory regions for each gene. Application of this approach to 2,634 patients across 11 human cancer types identified 60 pan-cancer, 22 pan-breast and 192 cancer specific candidate driver genes that were enriched for expression changes. Analysis of high-throughput CRISPR knockout screens revealed large, cancer specific growth effects for these genes, on par with coding mutations and exceeding that for promoter mutations. Amongst the five candidate drivers selected for further analysis, four (IPO9, MED8, PLEKHA6, andOXNAD1)were associated with survival across multiple cancer types. These studies demonstrate the power of our cell-type aware, convergent regulatory framework to define novel tissue specific cancer driver genes, considerably expanding evidence of functional non-coding mutations in cancer.
Time mating guinea pigs by monitoring changes to the vaginal membrane throughout the estrus cycle and with ultrasound confirmation
Authors: Wilson Rebecca L , Lampe Kristin , Matushewski Brad J , Regnault Timothy RH , Jones Helen N 
Published: August 2020

AbstractGuinea pig developmentin uterois more similar to humans than any other rodent species. As such, their importance to reproductive studies is evident, particularly those studies focused on therapeutic interventions to improve human pregnancy outcome. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane. Here, we describe, and provide picture representation, of changes to the guinea pig vaginal membrane throughout the estrus cycle. Utilization of this monitoring enabled a 100% pregnancy success rate on the first mating attempt in a cohort of five guinea pigs. This approach, along with early pregnancy ultrasounds as a secondary method to confirm pregnancy, offers a cost effective and reliable approach to timed-mating in the guinea pig.
DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A
Authors: Leon Kelly E. , Buj Raquel , Lesko Elizabeth , Dahl Erika S. , Chen Chi-Wei , Imamura Yuka , Kossenkov Andrew V. , Hobbs Ryan P. , Aird Katherine M. 
Published: August 2020

AbstractCellular senescence is characterized as a stable cell cycle arrest that can occur as a stress response associated with oncogenic activation, termed oncogene-induced senescence (OIS). Cells undergoing OIS acquire a unique microenvironment termed the senescence-associated secretory phenotype (SASP), which can be both beneficial and detrimental in a context-dependent manner. Additionally, senescent cells are characterized by robust changes in their epigenome. Here, we globally assessed the histone landscape of cells induced to senesce by oncogenic RAS and discovered a novel epigenetic regulatory mechanism of the key SASP regulator IL1A. OIS cells displayed increased di- and tri-methylation of histone H3 lysine 79 (H3K79me2/3), two active histone marks. Depletion of the H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) during OIS resulted in decreased H3K79me2/3 occupancy at theIL1Agene locus, which corresponded to decreased IL1A mRNA and cell surface expression. Decreased expression and secretion of downstream cytokines without a change in senescence markers were also observed upon DOT1L depletion. Overexpression of DOT1L increased H3K79me2/3 occupancy at theIL1Alocus and upregulated the SASP, indicating that DOT1L is both necessary and sufficient for SASP gene expression. Mechanistically, we found that STING, an essential mediator of SASP transcription, is upstream of DOT1L in the epigenetic regulation of the SASP. Together, our studies establish DOT1L as an epigenetic regulator of the SASP whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
Theta and alpha power across fast and slow timescales in cognitive control
Authors: Huycke Pieter , Verbeke Pieter , Boehler C. Nico , Verguts Tom 
Published: August 2020

AbstractTheta and alpha frequency neural oscillations are important for learning and cognitive control, but their exact role has remained obscure. In particular, it is unknown whether they operate at similar timescales, and whether they support different cognitive processes. We recorded EEG in 30 healthy human participants while they performed a learning task containing both novel (block-unique) and repeating stimuli. We investigated behavior and electrophysiology at both fast (i.e., within blocks) and slow (i.e., between blocks) time scales. Behaviorally, both response time and accuracy improved (resp. decrease and increase) over both fast and slow timescales. However, on the spectral level, theta power significantly decreased along the slow timescale, whereas alpha power instead significantly increased along the fast timescale. We thus demonstrate that theta and alpha both play a role during learning, but operate at different timescales. This result poses important empirical constraints for theories on learning, cognitive control, and neural oscillations.
Lanthipeptide Synthetases Participate the Biosynthesis of 2-Aminovinyl-Cysteine Motifs in Thioamitides
Authors: Lu Jingxia , Wu Yuan , Li Jiao , Li Yuqing , Zhang Yingying , Bai Zengbing , Zheng Jie , Zhu Jiapeng , Wang Huan 
Published: August 2020

ABSTRACTThioamitides are a group of ribosomally synthesized and post-translational modified peptides with potent antiproliferative and pro-apoptotic activities. Their biosynthesis remains largely unknown, especially for the characteristic C-terminal 2-aminovinyl-Cysteine (AviCys) motifs. Herein, we report the discovery that homologs of class III lanthipeptide synthetases (LanKCts)encodedoutsideputative thioamitide biosynthetic gene clusters (BGCs) fully dehydrate the precursor peptides. Remarkably, LanKCtenzymes bind tightly to cysteine decarboxylases encodedinsidethioamitide BGCs, and the resulting complex complete the macrocyclization of AviCys rings. Furthermore, LanKCtenzymes are present in the genomes of many thioamitide-producing strains and are functional when in complex with cysteine decarboxylases to produce AviCys macrocycles. Thus, our study reveals the participation of lanthipeptide synthetases as a general strategy for dehydration and AviCys formation during thioamitides biosynthesis and thus paves the way for the bioengineering of this class of bioactive natural products.
A dietary sterol trade off determines lifespan responses to dietary restriction inDrosophila melanogaster
Authors: Zanco Brooke , Mirth Christen K. , Sgrò Carla M. , Piper Matthew D.W. 
Published: August 2020

AbstractDiet plays a significant role in maintaining lifelong health. In particular, lowering the dietary protein : carbohydrate ratio can improve lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. UsingDrosophila melanogaster, we show that the role of protein and carbohydrate on lifespan is indirect, acting by altering the partitioning of limiting amounts of dietary sterols between reproduction and lifespan. Shorter lifespans in flies fed on high protein : carbohydrate diets can be rescued by supplementing their food with cholesterol. Not only does this fundamentally alter the way we interpret the mechanisms of lifespan extension by dietary restriction, these data highlight the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study. This brings us closer to understanding the mechanistic basis of dietary restriction.
An Acentriolar Centrosome At TheC. elegansCiliary Base
Authors: Garbrecht Joachim , Laos Triin , Holzer Elisabeth , Dillinger Margarita , Dammermann Alexander 
Published: August 2020

SUMMARYIn animal cells the functions of the cytoskeleton are coordinated by centriole-based centrosomes via microtubule-nucleating γ-tubulin complexes embedded in the pericentriolar material or PCM [1]. PCM assembly has been best studied in the context of mitosis, where centriolar SPD-2 recruits PLK-1, which in turn phosphorylates key scaffolding components such as SPD-5 and CNN to promote expansion of the PCM polymer [2–4]. To what extent these mechanisms apply to centrosomes in interphase or in differentiated cells remains unclear [5]. Here, we examine a novel type of centrosome found at the ciliary base ofC. eleganssensory neurons, which we show plays important roles in neuronal morphogenesis, cellular trafficking and ciliogenesis. These centrosomes display similar dynamic behavior to canonical, mitotic centrosomes, with a stable PCM scaffold and dynamically localized client proteins. Unusually, however, they are not organized by centrioles, which degenerate early in terminal differentiation [6]. Yet, PCM not only persists but continues to grow with key scaffolding proteins including SPD-5 expressed under control of the RFX transcription factor DAF-19. This assembly occurs in the absence of the mitotic regulators SPD-2, AIR-1 and PLK-1, but requires tethering by PCMD-1, a protein which also plays a role in the initial, interphase recruitment of PCM in early embryos [7]. These results argue for distinct mechanisms for mitotic and non-mitotic PCM assembly, with only the former requiring PLK-1 phosphorylation to drive rapid expansion of the scaffold polymer.ETOC BLURBCentrioles play a critical role in mitotic centrosome assembly. Here, Garbrechtet al.show that pericentriolar material (PCM) persists at the ciliary base ofC. eleganssensory neurons after centriole degeneration, where it contributes to neuronal morphogenesis and cellular trafficking. Remarkably, this PCM displays dynamic properties similar to canonical centrosomes, yet its continued assembly and maintenance is independent of known mitotic regulators, suggesting differential mechanisms for mitotic and non-mitotic centrosome assembly.HIGHLIGHTSPCM persists at the acentriolar ciliary base inC. elegansPCM assembles in a SPD-2, AIR-1 and PLK-1-independent mannerPCMD-1 tethers PCM at the ciliary base in the absence of centriolesPCM is required for neuronal morphogenesis and cilium assembly
Inoculum effect of antimicrobial peptides
Authors: Loffredo M. R. , Savini F. , Bobone S. , Casciaro B. , Franzyk H. , Mangoni M. L. , Stella L. 
Published: August 2020

AbstractThe activity of many antibiotics depends on the initial density of cells used in bacteria growth inhibition assays. This phenomenon, termed the inoculum effect, can have important consequences for the therapeutic efficacy of the drugs, since bacterial loads vary by several orders of magnitude in clinically relevant infections. Antimicrobial peptides are a promising class of molecules to fight drug-resistant bacteria, since they act mainly by perturbing the cell membranes rather than by inhibiting intracellular targets. Here we report the first systematic characterization of the inoculum effect for this class of antibacterial compounds. Thirteen peptides (including all-D enantiomers) and peptidomimetics were analyzed by measuring minimum inhibitory concentration values, covering more than 7 orders of magnitude in inoculated cell density. In all cases, we observed a significant inoculum effect for cell densities above 5 × 104cells/mL, while the active concentrations remained constant (within the micromolar range) for lower densities. In the case of membrane-active peptides, these data can be rationalized by considering a simple model, taking into account peptide-cell association and hypothesizing that a threshold number of cell-bound peptide molecules is required in order to cause a killing effect. The observed effects question the clinical utility of activity and selectivity determinations performed at a fixed, standardized cell density. A routine evaluation of the inoculum dependence of the activity of antimicrobial peptides and peptidomimetics should be considered.Significance statementBacterial drug resistance is a crucial threat to global health and antimicrobials with novel mechanisms of action are severely needed. Antimicrobial peptides are natural molecules that kill bacteria mostly by perturbing their membranes and represent promising compounds to fight resistant microbes. Their activity is normally tested under standardized conditions of bacterial density. However, the bacterial load in clinically relevant infections varies by many orders of magnitude. Here we showed that the minimum peptide concentration needed for bacterial killing can vary by more than 100 times with an increase in the density of cells in the initial inoculum of the assay (inoculum effect) These findings question utility of the presently used activity screening assays and our current understanding of antimicrobial peptides.
Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation
Authors: Orlando Marta , Dvorzhak Anton , Bruentgens Felicitas , Maglione Marta , Rost Benjamin R. , Sigrist Stephan J. , Breustedt Jörg , Schmitz Dietmar 
Published: August 2020

ABSTRACTSynaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of long-term potentiation at large hippocampal mossy fiberboutonsinduced by the adenylyl cyclase activator forskolin. We performed two-photon imaging of the genetically encoded glutamate sensor iGluuthat revealed an increase in the surface area used for glutamate release at potentiated terminals. Moreover, time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between immunofluorescence signals from calcium channels and release sites. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiatedboutons: synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements likely enable long-term increase in synaptic strength.
Effect of cleanup of spiked sludge on corn growth biosorption and leaching of metals
Authors: Barraoui Driss , Blais Jean-François , Labrecque Michel 
Published: August 2020

AbstractA chemical leaching process has been used for the cleanup of two municipal biosolids (MOS and BES) spiked with Cd, Cu, Zn or their mixture prior to agricultural use. Non-cleaned, cleaned and washed biosolids were compared as soil amendments for corn cultivation inside glasshouse. Corn growth, biosorption of metals and leaching of these metals in leachate were measured. Results showed that biosolid amendments tend to produce more aerial biomass. Cleanup and washing of BES biosolid significantly augmented total biomass of roots and stalks, respectively. Regarding biosorption of metals, Cd could not be found neither in corn seeds, nor in stalks, while slight amounts of Cu were detected. Whereas Cd and Cu diminished in the order roots > leaves > stalks, Zn diminished from leaves > roots > stalks. Cleanup and washing of MOS and BES biosolids significantly lowered biosorption of Cd, Cu, Zn, and other metals. Leaching into the outlet water varied with time, but average concentrations were moderately low. There were significant amounts of metal leached from MOS biosolid. The effects of cleanup and washing of both biosolids on biosorption and leaching depended on the initial metallic charge and the biosolid type.
Effects of scent enrichment on behavioural and physiological indicators of stress in zoo primates
Authors: Vaglio Stefano , Kaburu Stefano S. K. , Pearce Richard , Bryant Luke , McAuley Ailie , Lott Alexandria , Sheppard Demi J. , Smith Sarah , Tompkins Beth , Elwell Emily , Fontani Sara , Young Christopher , Marliani Giovanna , Accorsi Pier Attilio 
Published: August 2020

AbstractCaptive breeding is vital for primate conservation, with modern zoos serving a crucial role in breeding populations of threatened species and educating the general public. However, captive populations can experience welfare issues that may also undermine their reproductive success. In order to enhance the well-being of endangered zoo primates, we conducted a study to assess the effects of a new scent enrichment programme on captive red-ruffed lemurs (Varecia rubra), black howler monkeys (Alouatta caraya), siamangs (Symphalangus syndactylus), Lar gibbons (Hylobates lar) and orangutans (Pongo pygmaeus pygmaeus). We combined behavioural observations and faecal endocrinology analyses to evaluate the effects of a series of essential oils (benzoin, lavender, lemongrass) on five captive troops (N = 19) housed at Dudley Zoo & Castle and Twycross Zoo (UK). We recorded observations of natural species-specific and abnormal stress-related behaviours for 480 hr using instantaneous scan sampling. We collected 189 faecal samples and measured the faecal cortisol concentrations using radioimmunoassay. We found a significant effect of the scent enrichment on behaviours, with red-ruffed lemurs and black howler monkeys reducing their social interactions, as well as red-ruffed lemurs and Lar gibbons decreasing their stress-related behaviours, after they were exposed to the series of essential oils. We also found that red-ruffed lemurs displayed a significant increase in faecal glucocorticoids following the exposure to essential oils. Our contradictory findings suggest that the effects of this series of essential oils may change depending on the species-specific social lives and olfactory repertoires of primates. In conclusion, we cannot recommend using these essential oils widely with zoo primates without additional evaluation.
A haplotype-phased genome of wheat stripe rust pathogenPuccinia striiformisf. sp.tritici, race PST-130 from the Western USA
Authors: Vasquez-Gross Hans , Kaur Sukhwinder , Epstein Lynn , Dubcovsky Jorge 
Published: August 2020

ABSTRACTMore virulent and aggressive races ofPuccinia striiformisf. sp.tritici(Pst), the pathogen causing wheat stripe rust, have been spreading around the world since 2000 causing large grain yield losses. A better understanding of the genome and genetic diversity of these newPstraces will be useful to develop new strategies to ameliorate production losses. In this study, we generated an improved genome assembly of a very virulent race from the Western USA designated as PST-130. We implemented a haplotype phasing strategy using the diploid-aware assembler, Falcon-Unzip and new long-read technology from PacBio to phase the two genomes of this dikaryotic organism. The combination of these new technologies resulted in an improved PST-130 assembly with only 151 contigs (85.4 Mb, N50 of 1.44 Mb), and a complementary assembly (haplotigs) with 458 contigs (65.9 Mb, N50 of 0.235 Mb, PRJNA650506). This new assembly improved gene predictions resulting in 228 more predicted complete genes than in the initial Illumina assembly (29,178 contigs, N50 of 5 kb). The alignment of the non-repetitive primary and haplotig contigs revealed and average of 5.22 SNP/kb, with 39.1% showing <2 SNP/kb and 15.9% >10 SNP/kb. This large divergent regions may represent introgressions of chromosome segments from more divergentPstraces in regions wherePstcan complete its sexual cycle and where recombination is possible. We hypothesize that some of the divergent regions in PST-130 may be related to the European “Warrior” race PST-DK0911 because this latter genome is more similar to PST-130 (3.18 SNP/kb) than to the older European race PST-104E (3.75 SNP/kb). Phasing of additionalPstgenomes or sequencing individual nuclei will facilitate the tracing of nuclei introduced by the newPstraces into local populations.
Unraveling the molecular basis of host cell receptor usage in SARS-CoV-2 and other human pathogenic β-CoVs
Authors: Pontes Camila , Ruiz-Serra Victoria , Lepore Rosalba , Valencia Alfonso 
Published: August 2020

AbstractThe recent emergence of the novel SARS-CoV-2 in China and its rapid spread in the human population has led to a public health crisis worldwide. Like in SARS-CoV, horseshoe bats currently represent the most likely candidate animal source for SARS-CoV-2. Yet, the specific mechanisms of cross-species transmission and adaptation to the human host remain unknown. Here we show that the unsupervised analysis of conservation patterns across the β-CoV spike protein family, using sequence information alone, can provide rich information on the molecular basis of the specificity of β-CoVs to different host cell receptors. More precisely, our results indicate that host cell receptor usage is encoded in the amino acid sequences of different CoV spike proteins in the form of a set of specificity determining positions (SDPs). Furthermore, by integrating structural data, in silico mutagenesis and coevolution analysis we could elucidate the role of SDPs in mediating ACE2 binding across the Sarbecovirus lineage, either by engaging the receptor through direct intermolecular interactions or by affecting the local environment of the receptor binding motif. Finally, by the analysis of coevolving mutations across a paired MSA we were able to identify key intermolecular contacts occurring at the spike-ACE2 interface. These results show that effective mining of the evolutionary records held in the sequence of the spike protein family can help tracing the molecular mechanisms behind the evolution and host-receptors adaptation of circulating and future novel β-CoVs.SignificanceUnraveling the molecular basis for host cell receptor usage among β-CoVs is crucial to our understanding of cross-species transmission, adaptation and for molecular-guided epidemiological monitoring of potential outbreaks. In the present study, we survey the sequence conservation patterns of the β-CoV spike protein family to identify the evolutionary constraints shaping the functional specificity of the protein across the β-CoV lineage. We show that the unsupervised analysis of statistical patterns in a MSA of the spike protein family can help tracing the amino acid space encoding the specificity of β-CoVs to their cognate host cell receptors. We argue that the results obtained in this work can provide a framework for monitoring the evolution of SARS-CoV-2 specificity to the hACE2 receptor, as the virus continues spreading in the human population and differential virulence starts to arise.