bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential screening identifies molecules specifically inhibiting CCR5 transport to the cell surface and HIV infection
Authors: Boncompain Gaelle , Herit Floriane , Tessier Sarah , Lescure Aurianne , Del Nery Elaine , Gestraud Pierre , Staropoli Isabelle , Fukata Yuko , Fukata Masaki , Brelot Anne , Niedergang Florence , Perez Franck 
Published: July 2018

AbstractProteins destined to the cell surface are conveyed through membrane-bound compartments using the secretory pathway. Multiple secretory routes exist in cells, which paves the way to the development of inhibitory molecules able to specifically perturb the transport of a chosen cargo. We used differential high-content screening of chemical libraries to identify molecules reducing the secretion of CCR5, the major co-receptor for HIV-1 entry. Three molecules strongly affected the anterograde transport of CCR5, without inhibiting the transport of the related G protein-coupled receptors CCR1 and CXCR4. These three molecules perturb the transport of endogenous CCR5 and decrease the entry of HIV in human primary target cells. Two molecules were found to share the same mode of action, inhibiting palmitoylation of CCR5. Our results demonstrate that secretory routes can be specifically targeted which allows to envisage novel strategies to provoke the intracellular retention or rerouting of secretory proteins involved in disease development.
Single-cell isoform RNA sequencing (ScISOr-Seq) across thousands of cells reveals isoforms of cerebellar cell types
Authors: Gupta Ishaan , Collier Paul G , Haase Bettina , Mahfouz Ahmed , Joglekar Anoushka , Floyd Taylor , Koopmans Frank , Barres Ben , Smit August B , Sloan Steven , Luo Wenjie , Fedrigo Olivier , Ross M Elizabeth , Tilgner Hagen U 
Published: July 2018

AbstractFull-length isoform sequencing has advanced our knowledge of isoform biology1–11. However, apart from applying full-length isoform sequencing to very few single cells12,13, isoform sequencing has been limited to bulk tissue, cell lines, or sorted cells. Single splicing events have been described for <=200 single cells with great statistical success14,15, but these methods do not describe full-length mRNAs. Single cell short-read 3’ sequencing has allowed identification of many cell sub-types16–23, but full-length isoforms for these cell types have not been profiled. Using our new method of single-cell-isoform-RNA-sequencing (ScISOr-Seq) we determine isoform-expression in thousands of individual cells from a heterogeneous bulk tissue (cerebellum), without specific antibody-fluorescence activated cell sorting. We elucidate isoform usage in high-level cell types such as neurons, astrocytes and microglia and finer sub-types, such as Purkinje cells and Granule cells, including the combination patterns of distant splice sites6–9,24,25, which for individual molecules requires long reads. We produce an enhanced genome annotation revealing cell-type specific expression of known and 16,872 novel (with respect to mouse Gencode version 10) isoforms (see isoformatlas.com).ScISOr-Seq describes isoforms from >1,000 single cells from bulk tissue without cell sorting by leveraging two technologies in three steps: In step one, we employ microfluidics to produce amplified full-length cDNAs barcoded for their cell of origin. This cDNA is split into two pools: one pool for 3’ sequencing to measure gene expression (step 2) and another pool for long-read sequencing and isoform expression (step 3). In step two, short-read 3’-sequencing provides molecular counts for each gene and cell, which allows clustering cells and assigning a cell type using cell-type specific markers. In step three, an aliquot of the same cDNAs (each barcoded for the individual cell of origin) is sequenced using Pacific Biosciences (“PacBio”)1,2,4,5,26 or Oxford Nanopore3. Since these long reads carry the single-cell barcodes identified in step two, one can determine the individual cell from which each long read originates. Since most single cells are assigned to a named cluster, we can also assign the cell’s cluster name (e.g. “Purkinje cell” or “astrocyte”) to the long read in question (Fig 1A) – without losing the cell of origin of each long read.
Extracellular histones, a new class of inhibitory molecules of CNS axonal regeneration
Authors: Siddiq Mustafa M. , Hannila Sari S. , Zorina Yana , Nikulina Elena , Rabinovich Vera , Hou Jianwei , Huq Rumana , Richman Erica L. , Tolentino Rosa E. , Hansen Jens , Velenosi Adam , Kwon Brian K. , Tsirka Stella E. , Maze Ian , Sebra Robert , Iyengar Ravi , Filbin Marie T. 
Published: July 2018

AbstractAxonal regeneration in the mature CNS is limited by extracellular inhibitory factors. Triple knockout mice lacking the major myelin-associated inhibitors do not display spontaneous regeneration after injury, indicating the presence of other inhibitors. Searching for such inhibitors we have detected elevated levels of histone H3 in human cerebrospinal fluid (CSF) 24 hours after spinal cord injury. Following dorsal column lesions in mice and optic nerve crushes in rats, elevated levels of extracellular histone H3 were detected at the injury site. Similar to myelin-associated inhibitors, these extracellular histones induced growth cone collapse and inhibited neurite outgrowth. Histones mediate inhibition through the transcription factor YB-1 and Toll-like receptor 2, and these effects are independent of the Nogo receptor. Histone-mediated inhibition can be reversed by the addition of activated protein C (APC) in vitro, and APC treatment promotes axonal regeneration in the crushed optic nerve in vivo. These findings identify extracellular histones as a new class of nerve regeneration-inhibiting molecules within the injured CNS.One sentence summaryProteins typically associated with chromatin structure play an unexpected role in limiting axonal regeneration after injury.
QTL mapping and identification of corresponding genomic regions for black pod disease resistance to threePhytophthoraspecies inTheobroma cacaoL
Authors: Barreto MA , Rosa JRBF , Holanda ISA , Cardoso-Silva CB , Vildoso CIA , Ahnert D , Souza MM , Corrêa RX , Royaert S , Marelli J , Santos ESL , Luz EDMN , Garcia AAF , Souza AP 
Published: July 2018

AbstractThe cacao tree (Theobroma cacaoL.) is a species of great importance because cacao beans are the raw material used in the production of chocolate. However, the economic success of cacao is largely limited by important diseases such as black pod, which is responsible for losses of up to 30-40% of the global cacao harvest. The discovery of resistance genes could extensively reduce these losses. Therefore, the aims of this study were to construct an integrated multipoint genetic map, align polymorphisms against the available cacao genome, and identify quantitative trait loci (QTLs) associated with resistance to black pod disease in cacao. The genetic map had a total length of 956.41 cM and included 186 simple sequence repeat (SSR) markers distributed among 10 linkage groups. The physical “in silico” map covered more than 200 Mb of the cacao genome. Based on the mixed model predicted means ofPhytophthoraevaluation, a total of 6 QTLs were detected forPhytophthora palmivora(1 QTL),Phytophthora citrophthora(1 QTL), andPhytophthora capsici(4 QTLs). Approximately 1.77% to 3.29% of the phenotypic variation could be explained by the mapped QTLs. Several SSR marker-flanking regions containing mapped QTLs were located in proximity to disease regions. The greatest number of resistance genes was detected in linkage group 6, which provides strong evidence for a QTL. This joint analysis involving multipoint and mixed-model approaches may provide a potentially promising technique for detecting genes resistant to black pod and could be very useful for future studies in cacao breeding.
Uric acid lowering treatment alleviates perivascular carotid collar placement induced neointimal lesions in Uricase knockout mice
Authors: Lu Jie , Sun Ming-Shu , Wu Xin-Jiang , Yuan Xuan , Liu Zhen , Qu Xiao-Jie , Ji Xiao-Peng , Merriman Tony R , Li Chang-Gui 
Published: July 2018

AbstractHyperuricemia (HU) is a cause of gout. Clinical studies show a link between HU and cardiovascular disease. However, the role of soluble serum urate on atherosclerosis development remains elusive. We aimed to use a new HU mouse model (Uricase/Uox knockout (KO)) to further investigate the relationship between HU and atherosclerosis. Mouse model of induced carotid atherosclerosis was established in the novel spontaneous HU Uox-KO mouse and their wild type littermates (C57BL/6J background). Mice were implanted with a perivascular collar placement around the right carotid artery in combination with a western-type diet. To investigate urate-lowering treatment (ULT) effects on intima, the mice were gavaged daily from the age of 6 weeks with allopurinol. Human umbilical vein endothelial cells (HUVECs) were co-incubated with soluble urate, with and without probenecid, to study the mechanism of urate-related atherosclerosis. The Uox-KO mice had significantly elevated serum urate levels combined with higher blood urea nitrogen and serum creatinine. Western blot analysis showed enhanced levels of atherosclerosis inflammatory response proteins. However, there were no other risk indicators for the pathogenesis of atherosclerosis, including increased fasting glucose, altered lipid and atherosclerosis characterized cardiovascular and histological manifestations. In contrast, collar placement Uox-KO mice showed severe neointimal changes in histology staining consistent with increases in intimal area and increases in proliferating cell nuclear antigen (PCNA) - and F4/80-positive cells. Allopurinol reduced neointimal areas induced by the perivascular collar in hyperuricemic mice accompanied by decreased expression of PCNA- and F4/80-positive cells (P< 0.05). ULT alleviated atherosclerosis inflammatory response factors and reactive oxygen species intensities in both collar placement Uox-KO mice and urate-stimulated HUVECs. In vitro results using HUVECs showed ROS was induced by urate and ROS induction was abrogated using antioxidants. These data demonstrate that urate per se does not trigger atherosclerosis intima lesions in mice. Urate worsens carotid neointimal lesions induced by the perivascular collar and urate-lowering therapy partially abrogates the effects. The current study warrants the further human based study on the possible benefits of urate-lowering therapy in atherosclerosis patients with HU.Summary statementWe generated a carotid collar placement atherosclerosis model in the novel spontaneous HU Uox-KO mouse and demonstrate that urate plays a contributing rather than a causal role in the carotid neointimal lesions, while urate-lowering treatment may bring additional benefits in this HU mouse model.
Silencing of ANKRD12 circRNA induces molecular and functional changes associated with invasive phenotypes
Authors: Karedath Thasni , Ahmed Ikhlak , Ameri Wafa Al , Al-Dasim Fatima M. , Andrews Simeon S. , Samuel Samson , Al-Azwani Iman K. , Mohamoud Yasmin Ali , Rafii Arash , Malek Joel A. 
Published: July 2018

ABSTRACTCircular RNAs (circRNA) that form through non-canonical backsplicing events of pre-mRNA transcripts are evolutionarily conserved and abundantly expressed across species. However, the functional relevance of circRNAs remains a topic of debate. In this study, we identified and characterized a circular RNA derived from Exon 2 and Exon 8 of the ANKRD12 gene, termed here as circANKRD12. We show that this circRNA is abundantly expressed in breast and ovarian cancers. The circANKRD12 is RNase R resistant and predominantly localized in the cytoplasm in contrast to its source gene mRNA. We confirmed the expression of this circRNA across a variety of cancer cell lines and provide evidence for its functional relevance through downstream regulation of several tumor invasion genes. We show that silencing of circANKRD12 induces a phenotypic change by significantly regulating cell cycle, increasing invasion and migration, altering the metabolism in cancer cells. These results reveal the functional significance of circANKRD12 and provide evidence of a regulatory role for this circRNA in cancer progression.
Structural differences between pri-miRNA paralogs promotes alternative Drosha cleavage and expands target repertoires
Authors: Ros Xavier Bofill-De , Kasprzak Wojciech K. , Bhandari Yuba , Fan Lixin , Cavanaugh Quinn , Jiang Minjie , Dai Lisheng , Yang Acong , Shao Tie-Juan , Shapiro Bruce A. , Wang Yun-Xing , Gu Shuo 
Published: July 2018

AbstractMicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative-miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low grade glioma patient samples indicate that the alternative-miR-9 plays a distinct role in preventing tumor progression. To generalize our model, we provide evidence that distortion of pri-miRNA stems correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.
Translational initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition
Authors: Llácer Jose L. , Hussain Tanweer , Saini Adesh K. , Nanda Jagpreet , Kaur Sukhvir , Gordiyenko Yuliya , Kumar Rakesh , Hinnebusch Alan G. , Lorsch Jon R. , Ramakrishnan V. 
Published: July 2018

SUMMARYIn eukaryotic translation initiation AUG recognition of the mRNA requires accommodation of Met-tRNAiin a “PIN” state, which is antagonized by the factor eIF1. eIF5 is a GTPase activating protein (GAP) of eIF2 that additionally promotes stringent AUG selection, but the molecular basis of its dual function was unknown. We present a cryo-electron microscopy (cryo-EM) reconstruction of a 48S pre-initiation complex (PIC), at an overall resolution of 3.0 Å, featuring the N-terminal domain (NTD) of eIF5 bound to the 40S subunit at the location vacated by eIF1. eIF5 interacts with and allows a more accommodated orientation of Met-tRNAi. Substitutions of eIF5 residues involved in the eIF5-NTD/tRNAiinteraction influenced initiation at near-cognate UUG codonsin vivo, and the closed/open PIC conformationin vitro, consistent with direct stabilization of the codon:anticodon duplex by the wild-type eIF5-NTD. The present structure reveals the basis for a key role of eIF5 in start-codon selection.
Demultiplexing barcoded Oxford Nanopore reads with deep convolutional neural networks
Authors: Wick Ryan R. , Judd Louise M. , Holt Kathryn E. 
Published: July 2018

AbstractMultiplexing, the simultaneous sequencing of multiple barcoded DNA samples on a single flow cell, has made Oxford Nanopore sequencing cost-effective for small genomes. However, it depends on the ability to sort the resulting sequencing reads by barcode, and current demultiplexing tools fail to classify many reads. Here we present Deepbinner, a tool for Oxford Nanopore demultiplexing that uses a deep neural network to classify reads based on the raw electrical read signal. This ‘signal-space’ approach allows for greater accuracy than existing ‘base-space’ tools (Albacore and Porechop) for which signals must first be converted to DNA base calls, itself a complex problem that can introduce noise into the barcode sequence. To assess Deepbinner and existing tools, we performed multiplex sequencing on 12 amplicons chosen for their distinguishability. This allowed us to establish a ground truth classification for each read based on internal sequence alone. Deepbinner had the lowest rate of unclassified reads (7.8%) and the highest demultiplexing precision (98.5% of classified reads were correctly assigned). It can be used alone (to maximise the number of classified reads) or in conjunction with other demultiplexers (to maximise precision and minimise false positive classifications). We also found cross-sample chimeric reads (0.3%) and evidence of barcode switching (0.3%) in our dataset, which likely arise during library preparation and may be detrimental for quantitative studies that use multiplexing. Deepbinner is open source (GPLv3) and available at https://github.com/rrwick/Deepbinner.
Orienting to Polarized Light at Night—Matching Lunar Skylight to Performance in a Nocturnal Beetle
Authors: Foster James J. , Kirwan John D. , Jundi Basil el , Smolka Jochen , Khaldy Lana , Baird Emily , Byrne Marcus J. , Nilsson Dan-Eric , Johnsen Sönke , Dacke Marie 
Published: July 2018

AbstractFor polarized light to inform behaviour, the typical range of degrees of polarization observable in the animal’s natural environment must be above the threshold for detection and interpretation. Here we present the first investigation of the degree of linear polarization threshold for orientation behaviour in a nocturnal species, with specific reference to the range of degrees of polarization measured in the night sky. An effect of lunar phase on the degree of polarization of skylight was found, with smaller illuminated fractions of the moon’s surface corresponding to lower degrees of polarization in the night sky. We found that South African dung beetleEscarabaeus satyrus(Boheman, 1860) can orient to polarized light for a range of degrees of polarization similar to that observed in diurnal insects, reaching a lower threshold between 0.04 and 0.32, possibly as low as 0.11. For degrees of polarization lower than 0.23, as measured on a crescent moon night, orientation performance was considerably weaker than that observed for completely linearly-polarized stimuli, but was nonetheless stronger than in the absence of polarized light.Summary StatementA degree-of-polarization threshold for orientation behaviour is reported for nocturnal dung beetleEscarabaeus satyrusin the context of measurements showing changes in the degree of polarization of skylight with lunar phase.
Functional characterization of peroxisome biogenic proteins Pex5 and Pex7 of Drosophila
Authors: Di Cara Francesca , Rachubinski Richard A. , Simmonds Andrew J. 
Published: July 2018

ABSTRACTPeroxisomes are ubiquitous membrane-enclosed organelles involved in lipid processing and reactive oxygen detoxification. Mutations in human peroxisome biogenesis genes (Peroxin, PEX) cause progressive developmental disabilities and, in severe cases, early death. PEX5 and PEX7 are receptors that recognize different peroxisomal targeting signals called PTS1 and PTS2, respectively, and traffic proteins to the peroxisomal matrix. We characterized mutants of Drosophila melanogaster Pex5 and Pex7 and found that adult animals are affected in lipid processing. Moreover, Pex5 mutants exhibited severe developmental defects in the embryonic nervous system and muscle, similar to what is observed in humans with Pex5 mutations, while Pex7 fly mutants were weakly affected in brain development, suggesting different roles for Pex7 in fly and human. Of note, although no PTS2-containing protein has been identified in Drosophila, Pex7 from Drosophila can function as a bona fide PTS2 receptor because it can rescue targeting of the PTS2-containing protein Thiolase to peroxisomes in PEX7 mutant human fibroblasts.
The expanded universe of prokaryotic Argonaute proteins
Authors: Ryazansky Sergei , Kulbachinskiy Andrey , Aravin Alexei A. 
Published: July 2018

AbstractThe members of the ancient family of Argonaute (Ago) proteins are present in all domains of life. The common feature of Ago proteins is the ability to bind small nucleic acid guides and use them for sequence-specific recognition – and sometimes cleavage – of complementary targets. While eukaryotic Ago (eAgo) proteins are key players in RNA interference and related pathways, the properties and functions of these proteins in archaeal and bacterial species have just started to emerge. We undertook comprehensive exploration of prokaryotic Ago (pAgo) proteins in sequenced genomes and almost tripled the number of previously analyzed genes of this family. In comparison with eAgos, pAgos are highly diverse and have likely spread by horizontal gene transfer. Many pAgos contain divergent variants of the conserved domains involved in interactions with nucleic acids and in target cleavage, while having extra domains that are absent in eAgos, suggesting that they might have unusual specificities in the nucleic acid recognition and processing. Many pAgos, including catalytically inactive variants, are associated with putative nucleases, helicases and DNA binding proteins in the same gene or operon, suggesting that they are involved in DNA processing. The great diversity of pAgos revealed by our analysis opens new ways for exploration of their functions in host cells and their use as potential tools in genome editing.
The role of the chief process officer in organizations
Authors: Kratzer Simon , Lohmann Patrick , Roeglinger Maximilian , Rupprecht Lea , zur Muehlen Michael 
Published: July 2018

PurposeThe design and execution of business processes are important drivers of organizational performance. Organizations design their operations around cross-functional processes adopting business process management (BPM) methods, tools and systems. This often involves assigning BPM accountability to senior executives such as the chief operating officer (COO), chief information officer (CIO), or chief technology officer (CTO). Some organizations appoint a chief process officer (CPO), a phenomenon raising important questions about the skills and responsibilities of this position within the top management team. The purpose of this paper is to conduct an empirical study to explore the skills and responsibilities of CPOs and differences to other executives.Design/methodology/approachThe authors conducted an exploratory content analysis of job resumes from LinkedIn.com to investigate the skills and careers of individuals appointed as COO, CIO, CTO and CPO in organizations from different industries and sizes. The content analysis was complemented with expert interviews of CPOs to obtain rich insights into their perception of the responsibilities of this position.FindingsCPOs possess a unique skill set to serve as change agents. Their skills enable them to serve as integrators and influencers across managerial ranks and corporate functions. COOs, CIOs and CTOs possess more specialized skills related to their corporate function, whereas CPOs are more generalists who facilitate process-oriented strategy and execution, driving cultural change throughout the organization. These findings are consistent across industry and size.Originality/valueThis is the first paper to examine the CPO position in relation to other senior executive positions. Hence, it addresses an important gap in the BPM literature which can help organizations to make informed decisions whether they need a CPO position or have it become a part-time role of one of their existing C-level positions.