bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetics of human plasma lipidome: Understanding lipid metabolism and its link to diseases beyond traditional lipids
Authors: Tabassum Rubina , Rämö Joel T. , Ripatti Pietari , Koskela Jukka T. , Kurki Mitja , Karjalainen Juha , Hassan Shabbeer , Nunez-Fontarnau Javier , Kiiskinen Tuomo T.J. , Söderlund Sanni , Matikainen Niina , Gerl Mathias J. , Surma Michal A. , Klose Christian , Stitziel Nathan O. , Laivuori Hannele , Havulinna Aki S. , Service Susan K. , Salomaa Veikko , Pirinen Matti , Jauhiainen Matti , Daly Mark J. , Freimer Nelson B. , Palotie Aarno , Taskinen Marja-Riitta , Simons Kai , Ripatti Samuli 
Published: October 2018

AbstractAimGenetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures.Methods and ResultsWe performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical endpoints related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P<5×10−8), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate <0.05). The association patterns of lipid-species-associated loci supplied clues to their probable roles in lipid metabolism e.g. suggestive role of SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92).ConclusionOur study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.
Hereditary Pancreatitis Model by Blastocyst Complementation in Mouse
Authors: Asai Ayumu , Konno Masamitsu , Koseki Jun , Kawamoto Koichi , Arai Takahiro , Satoh Taroh , Eguchi Hidetoshi , Mori Masaki , Doki Yuichiro , Ishii Hideshi 
Published: October 2018

AbstractSummary StatementThe present study is the first report for reproducing human disease by utilizing blastocyst complementation method and would lead to the development of novel therapy for human disease.The application of pluripotent stem cell is expected to contribute to the elucidation of the unknown mechanism of human diseases. However, in vitro induction of cells in several organs, such as the pancreas and liver, remains difficult; therefore, reproduction of those diseases in a model has not been feasible. To reproduce human hereditary pancreatitis (HP), which is most frequently caused by the mutations in thePRSS1gene, we performed the blastocyst complementation (BC) method. In the BC method, mouse embryonic stem (ES) cells harboring CRISPR/CAS9-mediated mutations in thePrss1were injected into the blastocysts of deficientPdx1gene mice, which is a critical transcription factor in the pancreas. The results showed that the blastocysts injected into thePrss1-mutant ES cells induced trypsin activation. This implied that the mouse phenotype mimics that of human HP and that the BC method was useful for the reproduction and study of pancreatic disorders. The present study opens the possibility of investigating uncharacterized human diseases by utilizing the BC method.
A comprehensive genetic characterisation of the mitochondrial Ca2+ uniporter in Drosophila
Authors: Tufi Roberta , Gleeson Thomas P. , Stockum Sophia von , Hewitt Victoria L. , Lee Juliette J. , Terriente-Felix Ana , Sanchez-Martinez Alvaro , Ziviani Elena , Whitworth Alexander J. 
Published: October 2018

AbstractMitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here we report a comprehensive genetic characterisation of the known uniporter components conserved in Drosophila. While loss of MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in surprisingly mild phenotypes. In contrast, loss of the regulatory gatekeeper component MICU1 has a much more severe phenotype, being developmental lethal, consistent with unregulated Ca2+ uptake. Mutants for MICU3 are viable with mild neurological phenotypes. Genetic interaction studies reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that the lethality results from MCU-independent functions. This study helps shed light on the physiological requirements of the mitochondrial Ca2+ uniporter, and provides a suite of tools to interrogate their interplay in homeostasis and disease conditions.
Antagonistic pathogen-mediated selection favours the maintenance of innate immune gene polymorphism in a widespread wild ungulate
Authors: Quéméré Erwan , Hessenauer Pauline , Galan Maxime , Fernandez Marie , Merlet Joël , Chaval Yannick , Morellet Nicolas , Verheyden Hélène , Gilot-Fromont Emmanuelle , Charbonnel Nathalie 
Published: October 2018

AbstractToll-like Receptors (TLR) play a central role in recognition and host frontline defence against a wide range of pathogens. A number of recent studies have shown that TLR genes (Tlrs) often exhibit a large polymorphism in natural populations. Yet, there is little knowledge on how this polymorphism is maintained and how it influences disease susceptibility in the wild. In a previous work, we showed that someTlrsexhibit similarly high levels of genetic diversity thanMhcand contemporary signatures of balancing selection in roe deer (Capreolus capreolus), an abundant and widespread ungulate in Europe.Here, we tested whether Mhc-DrborTlr(Tlr2, Tlr4andTlr5) diversity is driven bypathogen-mediated selection. Weexamined the relationships between their genotype (heterozygosity status and presence of specific alleles) and infections withToxoplasmaandChlamydia, two intracellular pathogens known to cause reproductive failure in ungulates. We showed thatToxoplasmaandChlamydiaexposures vary significantly across year and landscape structure with few co-infection events detected, and that the two pathogens act antagonistically onTlr2polymorphism. By contrast, we found no evidence of association withMhc-Drband a limited support forTlrheterozygosity advantage. Our study confirmed the importance of looking beyondMhcgenes in wildlife immunogenetic studies. It also emphasized the necessity to consider multiple pathogen challenges and their spatiotemporal variation to improve our understanding of vertebrate defence evolution against pathogens.
The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy
Authors: Klimek Christina , Jahnke Ricarda , Wördehoff Judith , Kathage Barbara , Stadel Daniela , Behrends Christian , Hergovich Alexander , Höhfeld Jörg 
Published: October 2018

Chaperone-assisted selective autophagy (CASA) initiated by the cochaperone Bcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8 and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.AbbreviationsBAG3, BCL2-associated athanogene; CASA, chaperone-assisted selective autophagy; CHIP, carboxy terminus of HSP70 interacting protein; EPS, electrical pulse stimulation; GST, glutathione-S-transferase; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; STK38, serine/threonine protein kinase 38.
Linker histones regulate fine-scale chromatin organization and modulate developmental decisions in Arabidopsis
Authors: Rutowicz Kinga , Lirski Maciej , Mermaz Benoît , Schubert Jasmin , Teano Gianluca , Mestiri Imen , Kroteń Magdalena A. , Fabrice Tohnyui Ndinyanka , Fritz Simon , Grob Stefan , Ringli Christoph , Cherkezyan Lusik , Barneche Fredy , Jerzmanowski Andrzej , Baroux Célia 
Published: October 2018

AbstractChromatin in eukaryotes provides a tunable platform to control gene expression and convey an epigenetic memory throughout cell divisions. H1 linker histones are abundant components with an intrinsic potential in influencing chromatin structure and function. We detail the impact of H1 depletion in Arabidopsis on fine-scale chromatin organization, transcription and development. While required for chromocenter assembly, H1s are dispensable for transposable element (TE) silencing and peripheral positioning of heterochromatin. In euchromatin, H1 regulates nucleosome density, mobility, and regular distribution of nanoscale chromatin domains. While necessary to maintain epigenetic patterns, H1 only moderately affects transcription. Its depletion is associated with failures in transitional fate changes such as lateral root initiation, root hair production, stomata patterning but also flowering and dormancy regulation. Therefore, Arabidopsis H1 variants are chromatin architects mediating nano‐ and microscale levels-of-organization operating downstream of epigenetic and transcriptional establishment processes and contribute to epigenetic reorientations in developmental transitions.
Immediate visualization of recombination events and chromosome segregation defects in fission yeast meiosis
Authors: Li Dmitriy , Rocl Marianne , Yuecel Raif , Lorenz Alexander 
Published: October 2018

AbstractSchizosaccharomyces pombe, also known as fission yeast, is an established model for studying chromosome biological processes. Over the years research employing fission yeast has made important contributions to our knowledge about chromosome segregation during meiosis, as well as meiotic recombination and its regulation. Quantification of meiotic recombination frequency is not a straightforward undertaking, either requiring viable progeny for a genetic plating assay, or relying on laborious Southern blot analysis of recombination intermediates. Neither of these methods lends itself to high-throughput screens to identify novel meiotic factors. Here, we establish visual assays novel toSz. pombefor characterizing chromosome segregation and meiotic recombination phenotypes. Genes expressing red, yellow, and/or cyan fluorophores from spore-autonomous promoters have been integrated into the fission yeast genomes, either close to the centromere of chromosome I to monitor chromosome segregation, or on the arm of chromosome III to form a genetic interval at which recombination frequency can be determined. The visual recombination assay allows straightforward and immediate assessment of the genetic outcome of a single meiosis by epi-fluorescence microscopy without requiring tetrad dissection. We also demonstrate that the recombination frequency analysis can be automatized by utilizing imaging flow cytometry to enable high-throughput screens. These assays have several advantages over traditional methods for analysing meiotic phenotypes.
Local online learning in recurrent networks with random feedback
Authors: Murray James M. 
Published: October 2018

AbstractA longstanding challenge for computational neuroscience has been the development of biologically plausible learning rules for recurrent neural networks (RNNs) enabling the production and processing of time-dependent signals such as those that might drive movement or facilitate working memory. Classic gradient-based algorithms for training RNNs have been available for decades, but they are inconsistent with known biological features of the brain, such as causality and locality. In this work we derive an approximation to gradient-based learning that comports with these biologically motivated constraints. Specifically, the online learning rule for the synaptic weights involves only local information about the pre- and postsynaptic activities, in addition to a random feedback projection of the RNN output error. In addition to providing mathematical arguments for the effectiveness of the new learning rule, we show through simulations that it can be used to train an RNN to successfully perform a variety of tasks. Finally, to overcome the difficulty of training an RNN over a very large number of timesteps, we propose an augmented circuit architecture that allows the RNN to concatenate short-duration patterns into sequences of longer duration.
Effects of weight and height on hand selection: a low-cost virtual reality paradigm
Authors: James McDermott Eric , Himmelbach Marc 
Published: October 2018

AbstractThe main objective was to evaluate the ability of a virtual reality (VR) system to reliably detect the so-called switch-point of a user; the distinguishing plane between free-choice use of the left and right hand. Independent variables of height and weight were incorporated into the study design and their effects on hand selection were analyzed. The paradigm utilized the Leap Motion Hand Tracker, along with a custom script written in C# and was realized through a Unity3D application. Stimuli appeared in random locations on the computer screen, and required the participant to reach with the hand of their choice to contact them with a virtual hand inside the virtual space. We observed main effects of height and weight on switch-points across the group. We found increased use of the dominant hand as stimuli height increased, as well as a significant increase in overall use of the dominant hand when a 500 gram weighted glove was worn by the non-dominant hand. We validated the average switch-points in VR as compared to real-world setups in previous studies. Our results are in line with previously published real-world data, supporting the use of this paradigm in future VR experiments and applications.
Combined linkage and association mapping of putative QTLs controlling black tea quality and drought tolerance traits
Authors: Koech Robert. K. , Mose Richard , Kamunya Samson M. , Apostolides Zeno 
Published: October 2018

AbstractThe advancements in genotyping have opened new approaches for identification and precise mapping of Quantitative Trait Loci (QTLs) in plants, particularly by combining linkage and association mapping (AM) analysis. In this study, a combination of linkage and the AM approach was used to identify and authenticate putative QTLs associated with black tea quality traits and percent relative water content (%RWC). The population structure analysis clustered two parents and their respective 261 F1 progenies from the two reciprocal crosses into two clusters with 141 tea accessions in cluster one and 122 tea accessions in cluster two. The two clusters were of mixed origin with tea accessions in population TRFK St. 504 clustering together with tea accessions in population TRFK St. 524. A total of 71 putative QTLs linked to black tea quality traits and %RWC were detected in interval mapping (IM) method and were used as cofactors in multiple QTL model (MQM) mapping where 46 putative QTLs were detected. The phenotypic variance for each QTL ranged from 2.8–23.3% in IM and 4.1–23% in MQM mapping. Using Q-model and Q+K-model in AM, a total of 49 DArTseq markers were associated with 16 phenotypic traits. Significant marker-trait association in AM were similar to those obtained in IM, and MQM mapping except for six more putative QTLs detected in AM which are involved in biosynthesis of secondary metabolites, carbon fixation and abiotic stress. The combined linkage and AM approach appears to have great potential to improve the selection of desirable traits in tea breeding.
A short HBV RNA region induces RNR-R2 expression in non-cycling cells and in primary human hepatocytes
Authors: Ricardo-Lax Inna , Broennimann Karin , Adler Julia , Michailidis Eleftherios , de Jong Ype P , Reuven Nina , Shaul Yosef 
Published: October 2018

AbstractHepatitis B virus infects non-dividing cells in which dNTPs are scarce. HBV replication requires dNTPs. To cope with this constraint the virus induces the DNA damage response (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR holoenzyme, the key regulator of dNTP levels. Previously we reported that the HBx open reading frame (ORF) triggers this pathway. Unexpectedly however, we report here that the production of HBx protein is not essential. We found that a small region of 125 bases within the HBx transcript is sufficient to induce RNR-R2 expression in growth arrested HepG2 cells and in primary human hepatocytes (PHH). The observed HBx embedded regulatory element is named ERE. We demonstrate that ERE is functional as a positive strand RNA polymerase-II transcript. Remarkably, ERE is sufficient to induce the Chk1-E2F1-RNR-R2 DDR pathway, previously reported to be activated by HBV. Furthermore, we found that ERE activates ATR but not ATM in eliciting this DDR pathway in upregulating RNR-R2. These findings demonstrate the multitasking role of HBV transcripts in mediating virus-host cell interaction, a mechanism that explains how such a small genome effectively serves such a pervasive virus.Author summaryThe hepatitis B virus (HBV) infects the human liver and over 250 million people worldwide are chronically infected with HBV and at risk for cirrhosis and liver cancer. HBV has a very small DNA genome with only four genes, much fewer than other viruses. For propagation the virus consumes dNTPs, the building blocks of DNA, in much higher amounts than the infected cells provide. To cope with this constraint, the virus manipulates the cells to increase the production of dNTPs. We found that the virus activates the cellular response to DNA damage upon which the cells increase the production of dNTPs, but instead of repairing cellular DNA, the virus uses them for production of its own DNA. Usually viruses manipulate host cells with one or more of their unique proteins, however the small HBV genome cannot afford having such a unique gene and protein. Instead, we found that here the virus relies on RNA to manipulate the host cells. Our findings highlight the unprecedented principle of a multitasking viral RNA that is not only designed to be translated into proteins but also harbors an independent role in activating the cellular DNA damage response.
The emergence of multiple retinal cell types through efficient coding of natural movies
Authors: Ocko Samuel A. , Lindsey Jack , Ganguli Surya , Deny Stephane 
Published: October 2018

AbstractOne of the most striking aspects of early visual processing in the retina is the immediate parcellation of visual information into multiple parallel pathways, formed by different retinal ganglion cell types each tiling the entire visual field. Existing theories of efficient coding have been unable to account for the functional advantages of such cell-type diversity in encoding natural scenes. Here we go beyond previous theories to analyze how a simple linear retinal encoding model with different convolutional cell types efficiently encodes naturalistic spatiotemporal movies given a fixed firing rate budget. We find that optimizing the receptive fields and cell densities of two cell types makes them match the properties of the two main cell types in the primate retina, midget and parasol cells, in terms of spatial and temporal sensitivity, cell spacing, and their relative ratio. Moreover, our theory gives a precise account of how the ratio of midget to parasol cells decreases with retinal eccentricity. Also, we train a nonlinear encoding model with a rectifying nonlinearity to efficiently encode naturalistic movies, and again find emergent receptive fields resembling those of midget and parasol cells that are now further subdivided into ON and OFF types. Thus our work provides a theoretical justification, based on the efficient coding of natural movies, for the existence of the four most dominant cell types in the primate retina that together comprise 70% of all ganglion cells.
Parallel patterns of development between independent cases of hybrid seed inviability in Mimulus
Authors: Coughlan Jenn M. , Willis John H. 
Published: October 2018

SummaryRationaleHybrid seed inviability (HSI) is a common reproductive barrier in angiosperms, yet the evolutionary and developmental drivers of HSI remain largely unknown. We test whether conflict between maternal and paternal interests in resource allocation to developing offspring (i.e. parental conflict) are associated with HSI and determine the degree of developmental parallelism between independent incidences of HSI in Mimulus.MethodsWe quantified HSI between M. guttatus and two clades of M. decorus with oppositely asymmetric incompatibilities and surveyed development of hybrid and parental seeds.Key ResultsCrosses between M. guttatus and both clades of M. decorus show parent-of-origin effects on reciprocal F1 seed development, but in opposing directions. Inviable hybrid seeds exhibit paternal excess phenotypes, wherein endosperm is large and chaotic while viable hybrid seeds produce endosperm cells that are smaller and less prolific (i.e. maternal-excess phenotypes).Main ConclusionsWe find strong parent-of-origin effects on development in reciprocal F1s in multiple incidences of HSI in Mimulus. These patterns suggest that parental conflict may be an important force generating HSI in this group, and mismatches between maternal and paternal contributions to developing seeds result in repeatable developmental defects in hybrids.