bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning of distant state predictions by the orbitofrontal cortex in humans
Authors: Wimmer G. Elliott , Büchel Christian 
Published: October 2018

AbstractRepresentations of our future environment are essential for planning and decision making. Previous research in humans has demonstrated that the hippocampus is a critical region for forming and retrieving associations, while the medial orbitofrontal cortex (OFC) is an important region for representing information about recent states. However, it is not clear how the brain acquires predictive representations during goal-directed learning. Here, we show using fMRI that while participants learned to find rewards in multiple different Y-maze environments, hippocampal activity was highest during initial exposure and then decayed across the remaining repetitions of each maze, consistent with a role in rapid encoding. Importantly, multivariate patterns in the OFC-VPFC came to represent predictive information about upcoming states approximately 30 seconds in the future. Our findings provide a mechanism by which the brain can build models of the world that span long-timescales to make predictions.
Ask1 and Akt act synergistically to promote ROS-dependent regeneration in Drosophila
Authors: Santabárbara-Ruiz Paula , Esteban-Collado José , Pérez Lidia , Viola Giacomo , Milán Marco , Corominas Montserrat , Serras Florenci 
Published: October 2018

AbstractThe mechanism by which apoptotic cells release signals that induce undamaged neighbor cells to proliferate and regenerate missing parts remains elusive. Oxidative stress originated by dying or damaged cells can be propagated to neighboring cells, which then promote regeneration. We investigated the nature of the stress sensing mechanism by which neighboring cells are recruited. We found that Drosophila apoptosis signal-regulating kinase 1 (Ask1) senses reactive oxygen species (ROS) differently in stressed dying cells and unstressed neighboring cells and this differential sensing is pivotal for tissue repair. In undamaged cells, this activity is attenuated, but not abolished, by Akt1 phosphorylation, which thus acts as a survival signal that results in the tolerable levels of p38 and JNK necessary for regeneration. These observations demonstrate that the non-autonomous activation of the ROS-sensing mechanism by Ask1 and Akt1 in neighboring unstressed cells. Collectively, these results provide the basis for understanding the molecular mechanism of communication between dying and living cells that triggers regeneration.Author summaryOne of the early events that occur after tissue damage is oxidative stress production that signals to initiate wound healing and regeneration. Several signaling pathways, such as JNK and p38, respond to oxidative stress and are necessary for regeneration. We decided to explore the mechanism that links the oxidative stress and the activation of these pathways. We used epithelia of Drosophila to genetically direct cell death in specific zones of the tissue as means of experimentally controlled cell damage. We found that the Ask1 protein, which is sensitive to oxidative stress, is a key player in this scenario. Actually it acts as an intracellular sensor that upon damage activates those signaling pathways. However, high activity of Ask1 can be toxic for the cell. This is controlled by Akt, an enzyme dowstream the insulin pathway, with attenuates the activity of Ask1 to tolerable levels. In conclusion, Ask1 and Akt act synergistically to respond to the stress generated after tissue damage and drive regeneration. In other words, we found that the link between oxidative stress and nutrition is key for tissue regeneration.
Bioinspired Design of Lysolytic Triterpenoid-peptide Conjugates that Kill African Trypanosomes
Authors: Leeder W.-Matthias , Giehler Fabian , Joswig Juliane , Göringer H. Ulrich 
Published: October 2018

AbstractHumans have evolved a natural immunity against Trypanosoma brucei infections, which is executed by two serum (lipo)protein complexes known as trypanolytic factors (TLF). Active TLF-ingredient is the primate-specific apolipoprotein L1 (ApoL1). The protein has a pore-forming activity that kills parasites by lysosomal and mitochondrial membrane fenestration. Of the many trypanosome subspecies only two are able to counteract the activity of ApoL1, which illustrates its evolutionary optimized design and trypanocidal potency. Here we ask the question whether a synthetic (syn)TLF can be synthesized using the design principles of the natural TLF-complexes but relying on different chemical building blocks. We demonstrate the stepwise development of triterpenoid-peptide conjugates, in which the triterpenoids act as a cell binding, uptake and lysosomal transport-moduls and the synthetic peptide GALA as a pH-sensitive, pore-forming lysolytic toxin. As designed, the conjugate kills infective-stage African trypanosomes through lysosomal lysis demonstrating proof-of-principle for the bioinspired, forward-design of a synTLF.
INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome
Authors: Ukhanov Kirill , Uytingco Cedric , Green Warren , Zhang Lian , Schurmans Stephane , Martens Jeffrey R. 
Published: October 2018

AbstractCiliopathies manifested in part by a dysfunction of several phosphoinositide 5’phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3in knobs. Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation. However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level. These findings implicate phosphoinositide-dependent regulation of active Ca2+extrusion in OSNs whereby controlling the rate of sensory adaptation.Significance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild typeINPP5Eto the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.
Loss ofTP73function contributes to amyotrophic lateral sclerosis pathogenesis
Authors: Downie Jonathan M. , Gibson Summer B. , Tsetsou Spyridoula , Russell Kristi L. , Keefe Matthew D. , Figueroa Karla P. , Bromberg Mark B. , Murtaugh L. Charles , Bonkowsky Joshua L. , Pulst Stefan M. , Jorde Lynn B. 
Published: October 2018

AbstractMuch remains unknown about the genetics and pathophysiology underlying the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We analyzed exome sequences from a cohort of 87 sporadic ALS (SALS) patients and 324 healthy individuals.TP73, a homolog of theTP53tumor suppressor gene, had five rare deleterious protein-coding variants; in a separate collection of >2,900 ALS patients we identified an additional 19 rare deleterious variants inTP73. Anin vitroC2C12 myoblast growth assay confirmed that these variants impair or alterTP73function.In vivomutagenesis of zebrafishtp73using CRISPR led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. Together, these results demonstrate thatTP73is a risk factor for ALS, and identifies a novel dysfunctional cellular process in the pathogenesis of ALS.
Draft genome of the liver fluke Fasciola gigantica
Authors: Tripathi Tripti , Ghosh Arpita , Todur Vivek N , Kalita Parismita , Vijayakumar R , Kalita Jupitara , Shukla Rohit , Chetri Purna B , Shukla Harish , Sonkar Amit , Lyngdoh Denzelle Lee , Singh Radhika , Chikara Surendra K , Tripathi Timir 
Published: October 2018

ABSTRACTFascioliasis is a neglected food-borne disease caused by liver flukes (genus Fasciola) and affects more than 200 million people worldwide. Despite technological advances, little is known about the molecular biology and biochemistry of the fluke. We present the draft genome of Fasciola gigantica for the first time. The assembled draft genome has a size of ~1.04 Gb with an N50 of 129 kb. A total of 20,858 genes were predicted. The de novo repeats identified in the draft genome were 46.85%. In pathway analysis, all the genes of glycolysis, Kreb’s cycle and fatty acid metabolism were found to be present, but the key genes for fatty acid production in fatty acid biosynthesis were missing. This indicates that the fatty acid required for the survival of the fluke may be acquired from the host bile. The genomic information will provide a comprehensive resource to facilitate the development of novel interventions for fascioliasis control.
Sperm gatekeeping: 3D imaging reveals a constricted entrance to zebra finch sperm storage tubules
Authors: Mendonca T. , Cadby A. J. , Hemmings N. 
Published: October 2018

AbstractFemales across many internally fertilising taxa store sperm, often in specialised storage organs in their reproductive tracts. In birds, several hundred sperm storage tubules exist in the utero-vaginal junction of the oviduct and there is growing evidence that sperm storage in these tubules is selective. The mechanisms underlying female sperm storage in birds remain unknown due to our limited ability to make three dimensional, live observations inside the large, muscular avian oviduct. Here, we describe a new application of fluorescence selective plane illumination microscopy to optically section oviduct tissue from zebra finchTaeniopygia guttatafemales label-free, by harnessing tissue autofluorescence. Our data provide the first description of the 3D structure of sperm storage organs in any vertebrate and reveal the presence of gate-like constricted openings that may play a role in sperm selection.Statement of SignificanceFemale birds can store sperm in microscopic tubular structures in their reproductive tract for up to several months, depending on species. Studying these sperm storage tubules has been a major challenge due to the muscular and opaque nature of reproductive tracts in birds. We have developed a new method for imaging live reproductive tract tissue using selective plane illumination microscopy, a fluorescence microscopy technique. From these images, we could extract three-dimensional measurements of sperm storage tubules and found these structures to have a gate-like constriction, providing evidence that females can actively select sperm at storage and ultimately influence the paternity of her offspring. Understanding these reproductive adaptations can help improve captive breeding programs and similar conservation strategies.
Fragmentation of pooled PCR products for highly multiplexed TILLING
Authors: Tramontano Andrea , Jarc Luka , Jankowicz-Cieslak Joanna , Hofinger Bernhard J. , Gajek Katarzyna , Szurman-Zubrzycka Miriam , Szarejko Iwona , Inglebrecht Ivan , Till Bradley J. 
Published: October 2018

AbstractImprovements to massively parallel sequencing have allowed the routine recovery of natural and induced sequence variants. A broad range of biological disciplines have benefited from this, ranging from plant breeding to cancer research. The need for high sequence coverage to accurately recover single nucleotide variants and small insertions and deletions limits the applicability of whole genome approaches. This is especially true in organisms with a large genome size or for applications requiring the screening of thousands of individuals, such as the reverse-genetic technique known as TILLING, where whole genome approaches become cost prohibitive. Using PCR to target and sequence chosen genomic regions provides an attractive alternative as the vast reduction in interrogated bases means that sample size can be dramatically increased through amplicon multiplexing and multidimensional sample pooling while maintaining suitable coverage for recovery of small mutations. Direct sequencing of PCR products is limited, however, due to limitations in read lengths of many next generation sequencers. In the present study we show the optimization and use of ultrasonication for the simultaneous fragmentation of multiplexed PCR amplicons for TILLING highly pooled samples. Thirty-two PCR products were produced from genomic DNA pools representing 265 pooled barley mutant lines. Mutant lines were produced with the chemical mutagen ethyl methanesulfonate. Samples were subjected to 2×300PE illumina sequencing. Evaluation of read coverage and base quality across amplicons suggests this approach is suitable for high-throughput TILLING and other applications employing highly pooled complex sampling schemes. Induced mutations previously identified in a traditional TILLING screen were recovered in this dataset further supporting the efficacy of the approach.
Discovery of the role of a SLOG superfamily biological conflict systems associated protein IodA (YpsA) in oxidative stress protection and cell division inhibition in Gram-positive bacteria
Authors: Brzozowski Robert S. , Graham Gianni , Burroughs A. Maxwell , Huber Mirella , Walker Merryck , Alva Sameeksha S. , Aravind L. , Eswara Prahathees J. 
Published: October 2018

ABSTRACTBacteria adapt to different environments by regulating cell division and several conditions that modulate cell division have been documented. Understanding how bacteria transduce environmental signals to control cell division is critical to comprehend the global network of cell division regulation. In this article we describe a role forBacillus subtilisYpsA, an uncharacterized protein of the SLOG superfamily of nucleotide and ligand-binding proteins, in cell division. We observed that YpsA provides protection against oxidative stress as cells lackingypsAshow increased susceptibility to hydrogen peroxide treatment. We found that increased expression ofypsAleads to cell division inhibition due to defective assembly of FtsZ, the tubulin-like essential protein that marks the sites of cell division. We showed that cell division inhibition by YpsA is linked to glucose availability. We generated YpsA mutants that are no longer able to inhibit cell division. Finally, we show that the role of YpsA is possibly conserved in Firmicutes, as overproduction of YpsA inStaphylococcus aureusalso impairs cell division. Therefore, we proposeypsAto be renamed asiodAforinhibitorofdivision.IMPORTANCEAlthough key players of cell division in bacteria have been largely characterized, the factors that regulate these division proteins are still being discovered and evidence for the presence of yet-to-be discovered factors has been accumulating. How bacteria sense the availability of nutrients and how that information is used to regulate cell division positively or negatively is less well-understood even though some examples exist in the literature. We discovered that a protein of hitherto unknown function belonging to the SLOG superfamily of nucleotide/ligand-binding proteins, YpsA, influences cell division inBacillus subtilisby integrating metabolic status such as the availability of glucose. We showed that YpsA is important for oxidative stress response inB. subtilis. Furthermore, we provide evidence that cell division inhibition function of YpsA is also conserved in another FirmicuteStaphylococcus aureus. This first report on the role of YpsA (IodA) brings us a step closer in understanding the complete tool set that bacteria have at their disposal to regulate cell division precisely to adapt to varying environmental conditions.
ATR and mTOR regulate F-actin to alter nuclear architecture and repair replication stress
Authors: Lamm Noa , Masamsetti V. Pragathi , Read Mark N. , Biro Maté , Cesare Anthony J. 
Published: October 2018

ABSTRACT“Replication stress” describes phenomena that alter DNA replication rates 1–3. Multiple architectural challenges within the confined nuclear volume must be navigated during replication to prevent or repair replication stress. Cellular mechanisms potentiating changes in nuclear architecture that facilitate DNA replication remain unclear. Here we show that the ATR, IPMK and mTOR kinases regulate actin polymerisation in human cells to alter nuclear architecture and promote replication fork repair. We demonstrate that replication stress activates mTOR, in an ATR and IPMK-dependent manner, to induce polymerisation of nuclear filamentous actin (F-actin). mTOR and ATR then counteract replication stress-induced nuclear envelope deformation and increase nuclear volume through their regulation of actin dynamics. Additionally, we reveal that FANCD2 labelled replication forks colocalise with actin filaments in late S-phase. mTOR and ATR then regulate the mobility, speed and directionality of stalled replication foci within the three-dimensional nuclear architecture. Importantly, we find nuclear F-actin also acts as a substrate for the directed migration of stalled replication foci to the nuclear periphery. Suppressing mTOR and ATR-dependent actin forces prevents replication fork restart and promotes chromosome segregation errors in primary and cancer cell lines. Together, these data reveal that ATR and mTOR regulate actin dynamics in the replication stress response to alter nuclear architecture and maintain genome stability.
Origins and Evolution of the Global RNA Virome
Authors: Wolf Yuri I. , Kazlauskas Darius , Iranzo Jaime , LucÍa-Sanz Adriana , Kuhn Jens H. , Krupovic Mart , Dolja Valerian V. , Koonin Eugene V. 
Published: October 2018

AbstractViruses with RNA genomes dominate the eukaryotic virome, reaching enormous diversity in animals and plants. The recent advances of metaviromics prompted us to perform a detailed phylogenomic reconstruction of the evolution of the dramatically expanded global RNA virome. The only universal gene among RNA viruses is the RNA-dependent RNA polymerase (RdRp). We developed an iterative computational procedure that alternates the RdRp phylogenetic tree construction with refinement of the underlying multiple sequence alignments. The resulting tree encompasses 4,617 RNA virus RdRps and consists of 5 major branches, 2 of which include positive-sense RNA viruses, 1 is a mix of positive-sense (+) RNA and double-stranded (ds) RNA viruses, and 2 consist of dsRNA and negative-sense (−) RNA viruses, respectively. This tree topology implies that dsRNA viruses evolved from +RNA viruses on at least two independent occasions, whereas -RNA viruses evolved from dsRNA viruses. Reconstruction of RNA virus evolution using the RdRp tree as the scaffold suggests that the last common ancestors of the major branches of +RNA viruses encoded only the RdRp and a single jelly-roll capsid protein. Subsequent evolution involved independent capture of additional genes, particularly, those encoding distinct RNA helicases, enabling replication of larger RNA genomes and facilitating virus genome expression and virus-host interactions. Phylogenomic analysis reveals extensive gene module exchange among diverse viruses and horizontal virus transfer between distantly related hosts. Although the network of evolutionary relationships within the RNA virome is bound to further expand, the present results call for a thorough reevaluation of the RNA virus taxonomy.IMPORTANCEThe majority of the diverse viruses infecting eukaryotes have RNA genomes, including numerous human, animal, and plant pathogens. Recent advances of metagenomics have led to the discovery of many new groups of RNA viruses in a wide range of hosts. These findings enable a far more complete reconstruction of the evolution of RNA viruses than what was attainable previously. This reconstruction reveals the relationships between different Baltimore Classes of viruses and indicates extensive transfer of viruses between distantly related hosts, such as plants and animals. These results call for a major revision of the existing taxonomy of RNA viruses.
Benchmarking the risk assessment in green supply chain using fuzzy approach to FMEA
Authors: Mangla Sachin Kumar , Luthra Sunil , Jakhar Suresh 
Published: October 2018

PurposeThe purpose of this paper is to facilitate green supply chain (GSC) managers and planners to model and access GSC risks and probable failures. This paper proposes to use the fuzzy failure mode and effects analysis (FMEA) approach for assessing the risks associated with GSC for benchmarking the performance in terms of effective GSC management adoption and sustainable production.Design/methodology/approachInitially, different failure modes are defined using FMEA analysis, and in order to decide the risk priority, the risk priority number (RPN) is determined. Such priority numbers are typically acquired from the judgment decisions of experts that could contain the element of vagueness and imperfection due to human biases, and it may lead to inaccuracy in the process of risk assessment in GSC. In this study, fuzzy logic is applied to conventional FMEA to overcome the issues in assigning RPNs. A plastic manufacturer GSC case exemplar of the proposed model is illustrated to present the authenticity of this method of risk assessment.FindingsResults indicate that the failure modes, given as improper green operating procedure, i.e. process, operations, etc. (R6), and green issues while closing the loop of GSC (R14) hold the highest RPN and FRPN scores in classical as well as fuzzy FMEA analysis.Originality/valueThe present research work attempts to propose an evaluation framework for risk assessment in GSC. This paper explores both sustainable developments and risks related to efficient management of GSC initiatives in a plastic industry supply chain context. From a managerial perspective, suggestions are also provided with respect to each failure mode.