bluuebunny/crossref_metadata_2025_split huggingface dataset:
TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease
Authors: Hegde Ramanath Narayana , Chiki Anass , Petricca Lara , Martufi Paola , Arbez Nicolas , Mouchiroud Laurent , Auwerx Johan , Landles Christian , Bates Gillian P. , Singh-Bains Malvindar K. , Curtis Maurice A , Faull Richard L. M. , Ross Christopher A. , Caricasole Andrea , Lashuel Hilal A 
Published: December 2019

AbstractPhosphorylation of the N-terminal domain of the Huntingtin (HTT) protein (at T3, S13, and S16) has emerged as a key regulator of HTT stability, clearance, localization, aggregation and toxicity. Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that specifically and efficiently phosphorylates both wild-type and mutant full-length or N-terminal fragments of HTTin vitro(S13/S16) and in cell/ neuronal cultures (S13). We show that overexpression of TBK1 in mammalian cells, primary neurons and aCaenorhabditis elegansmodel of Huntington’s Disease (HD) increases mutant HTTex1 phosphorylation, lowers its levels, increases its nuclear localization and significantly reduces its aggregation and cytotoxicity. Our mechanistic studies demonstrate that the TBK1-mediated neuroprotective effects are due to phosphorylation-dependent inhibition of mutant HTTex1 aggregation and an increase in autophagic flux. These findings suggest that upregulation and/or activation of TBK1 represents a viable strategy for the treatment of HD.Graphical abstract
Genomic prediction using low density marker panels in aquaculture: performance across species, traits, and genotyping platforms
Authors: Kriaridou Christina , Tsairidou Smaragda , Houston Ross D. , Robledo Diego 
Published: December 2019

ABSTRACTGenomic selection increases the rate of genetic gain in breeding programmes, which results in significant cumulative improvements in commercially important traits such as disease resistance. Genomic selection currently relies on collecting genome-wide genotype data accross a large number of individuals which requires substantial economic investment. However, global aquaculture production predominantly occurs in small and medium sized enterprises for whom this technology can be prohibitively expensive. For genomic selection to benefit these aquaculture sectors more cost-efficient genotyping is necessary. In this study the utility of low and medium density SNP panels (ranging from 100 to 9000 SNPs) to accurate predict breeding values was tested and compared in four aquaculture datasets with different characteristics (species, genome size, genotyping platform, family number and size, total population size, and target trait). A consistent pattern of genomic prediction accuracy was observed across species, with little or no reduction until SNP density was reduced below 1,000 SNPs. Below this SNP density, heritability estimates and genomic prediction accuracies tended to be lower and more variable (93 % of maximum accuracy achieved with 1,000 SNPs, 89 % with 500 SNPs, and 70% with 100 SNPs). Now that a multitude of studies have highlighted the benefits of genomic over pedigree-based prediction of breeding values in aquaculture species, the results of the current study highlight that these benefits can be achieved at lower SNP densities and at lower cost, raising the possibility of a broader application of genetic improvement in smaller and more fragmented aquaculture settings.
Long-Term In Vivo Biocompatibility of Single-Walled Carbon Nanotubes
Authors: Galassi Thomas V. , Antman-Passig Merav , Yaari Zvi , Jessurun Jose , Schwartz Robert E. , Heller Daniel A. 
Published: December 2019

AbstractOver the past two decades, measurements of carbon nanotube toxicity and biodistribution have yielded a wide range of results. Properties such as nanotube type (single-walled vs. multi-walled), purity, length, aggregation state, and functionalization, as well as route of administration, greatly affect both the biocompatibility and biodistribution of carbon nanotubes. These differences suggest that generalizable conclusions may be elusive and that studies must be material- and application-specific. Here, we assess the short- and long-term biodistribution and biocompatibility of a single-chirality DNA-encapsulated single-walled carbon nanotube complex upon intravenous administration that was previously shown to function as an in-vivo reporter of endolysosomal lipid accumulation. Regarding biodistribution and fate, we found bulk specificity to the liver and >90% signal attenuation by 14 days in mice. Using near-infrared hyperspectral microscopy to measure single nanotubes, we found low-level, long-term persistence in organs such as the heart, liver, lung, kidney, and spleen. Measurements of histology, animal weight, complete blood count, and biomarkers of organ function all suggest short- and long-term biocompatibility. This work suggests that carbon nanotubes can be used as preclinical research tools in-vivo without affecting acute or long-term health.
Dimerization of human drebrin-like protein governs its biological activity
Authors: Ghosh Arindam , Enderlein Jörg , Butkevich Eugenia 
Published: December 2019

AbstractDrebrin-like protein (DBNL) is a multidomain F-actin binding protein, which also interacts with other molecules within different intracellular pathways. Here, we present quantitative measurements on size and conformation of human DBNL. Using dual focus fluorescence correlation spectroscopy, we determined the hydrodynamic radius of DBNL monomer. Native gel electrophoresis and dual color fluorescence cross-correlation spectroscopy show that both endogenous and recombinant DBNL exist as dimer under physiological conditions. We demonstrate that C-terminal truncations of DBNL downstream of the coiled-coil domain result in its oligomerization at nanomolar concentration. In contrast, the ADF-H domain alone is a monomer, which displays a concentration-dependent self-assembly. In vivo FLIM-FRET imaging shows that the presence of only actin-binding domains is not sufficient for DBNL to localize properly at actin filament inside the cell. In summary, our work provides a detailed insight on structure-function relationship of human drebrin-like protein.
T-loops Refold after Telomerase Extension and Unfold Again at Late S/G2 for C-strand Fill-in
Authors: Mak Sabrina S.M. , Smiraldo Phillip G. , Chow Tracy T. , Wright Woodring E. , Shay Jerry W. 
Published: December 2019

ABSTRACTTelomeres are the structures that protect the ends of each chromosome and prevent them from being recognized as broken DNA in need of repair. During human fetal development telomere length is ~15 kb and is maintained by the ribonucleoprotein telomerase. In neonates telomerase becomes spliced into inactive forms in most tissues. Afterwards, lagging strand synthesis fails to copy the very end and telomeres become progressively shorter as cells divide. Part of the mechanism for avoiding the DNA damage machinery is by forming a t-loop structure that has no free end. The telomeric 3’ overhang is inserted into the duplex DNA where it displaces the G-rich strand, forming a D-loop. It is unknown whether this D-loop is the size of the overhang, or whether branch migration results in a larger D-loop. Telomere t-loops must unfold for replication and telomerase extension during S phase. It is also unknown whether t-loops remain unfolded after replication until C-strand fill-in at late S/G2, or if they refold after replication and then unfold again for fill-in at late S/G2. We have developed a biochemical t-loop assay to address these issues, and demonstrate that most t-loops persist throughout S phase both before and after their replication.HighlightsT-loops unfold twice during each S-phaseVirtually all telomeres are packaged into t-loopsLarge amounts of t-loops can easily be purified without specialized materials
Cytokines and schizophrenia revisited: a two-sample multi-marker Mendelian randomization approach
Authors: Ren Hongyan , Meng Yajing , Zhang Yamin , Wang Qiang , Deng Wei , Ma Xiaohong , Zhao Liansheng , Li Xiaojing , Wang Yingcheng , Sham Pak , Li Tao 
Published: December 2019

AbstractBackgroundSchizophrenia is a complex mental disorder with recent evidence suggesting a critical immune component underpinning its pathophysiology. Two-sample Mendelian randomization (MR) provided an opportunity to probe the immune changes in schizophrenia by harnessing the increasing availability of summary-level data from large GWAS consortia.ObjectiveTo map the extensive immune response of schizophrenia in terms of cytokines/chemokines and to explore the effect of cytokines induced by schizophrenia (SCZ-induced cytokines) on the brain structure and functionSources and methodsUsing the summary-level data generated from GWAS of schizophrenia, cytokines in the peripheral blood and imaging-derived phenotypes (IDPs), we performed two rounds of two-sample MR analysis; the identified cytokines from first round of analysis (schizophrenia => cytokines) were modeled for its underlying structure and subsequent clustering analysis further grouped SCZ-induced cytokines based on their genetic similarities. The multi-phenotype summary statistics of each cytokine module were then used as instrumental variables (IVs) for the second round of MR analysis to detect their effect on brain structure and function.ResultsThe first round of MR analysis identified nine cytokines, the highlight of which includes IL18 (OR = 1.292, P = 8.37 × 10−42) and TNFa (OR = 0.721, P = 7.33 × 10−6), to be causally associated with schizophrenia. These SCZ-induced cytokines could be clustered into three modules. The second round of MR analysis (cytokine module => IDPs) indicated that module B (SCGFb-IP10-CTACK-IL6) significantly increased the level of IDPs including IDP_T1_SIENAX_peripheral_grey_normalised_volume (β = 0.0453, P = 4.40×1010), IDP_dMRI_TBSS_MD_Posterior_corona_radiata_R (β= 0.0584, P = 8.89× 10−16) and IDP_dMRI_TBSS_MD_Cingulum_hippocampus_R (β = 0.0563, P = 9.88× 10−15), with module C (IL18-GROa-TNFa) increasing the level of IDP_dMRI_TBSS_L2_Posterior_thalamic_radiation_R (β= 0.0341, P = 2.67× 10−6).ConclusionOur study, for the first time, mapped the causal link from schizophrenia to the comprehensive immune responses, and the findings suggest immune networks play a role in pathophysiology of schizophrenia by mediating the deviations of total gray matter volume and white matter fibers possibly in the mesolimbic system.
Regulating lipid composition rationalizes acyl-tail saturation homeostasis in ectotherms
Authors: Girard M. , Bereau T. 
Published: December 2019

ABSTRACTCell membranes mainly consist of lipid bilayers with an actively regulated composition. The underlying processes are still poorly understood, in particular how the hundreds of components are controlled. Surprisingly, in recent experiments on ectotherms, the cholesterol fraction, along with un- and mono-saturated acyl tail fractions and demixing temperatures, was shown to increase with body temperature. We establish a model based on chemical reaction networks to study regulation of membranes, resulting in multiple semi-grand canonical ensembles. By running computer simulations, we show that higher cholesterol fractions correlate with lower degrees of unsaturation, ultimately controlling the composition of lipid tails. Cholesterol also dictates membrane viscosity and regulation of the latter implies that cholesterol must increase with temperature. Overall, our model proposes a different picture of lipid regulation, where components can be passively, instead of actively, regulated.SIGNIFICANCEIn this article, we propose a regulation model where only some of the components are actively regulated between membranes, while others are naturally balanced by chemical potentials. This model provides a rationale to recently measured puzzling trends in ectotherms, that is, increased plasma membrane cholesterol fraction with temperature. Here, we show that it is directly correlated with with acyl tail saturation and order parameter correlation length. Furthermore, we highlight the relation between cholesterol and membrane viscosity.
GIV/Girdin and Exo70 Constitute the Core of the Mammalian Polarized Exocytic Machinery
Authors: Rohena Cristina , Rajapakse Navin , Lo I-Chung , Novick Peter , Sahoo Debashis , Ghosh Pradipta 
Published: December 2019

SUMMARYPolarized exocytosis is a fundamental process by which membrane and cargo proteins are delivered to the plasma membrane with precise spatial control; it is essential for cell growth, morphogenesis, and migration. Although the need for the octameric exocyst complex is conserved from yeast to humans, what imparts spatial control is known only in yeast, i.e., a polarity scaffold without mammalian homolog, called Bem1p. We demonstrate that polarity scaffold GIV/Girdin fulfills the key criteria and functions of its yeast counterpart Bem1p. Both Bem1p and GIV bind yeast and mammalian Exo70 proteins via similar short-linear interaction motifs, but each preferentially binds its evolutionary counterpart. In cells where this GIV•Exo-70 interaction is selectively disrupted, delivery of the metalloprotease MT1-MMP to podosomes, collagen degradation and haptotaxis through basement membrane matrix were impaired. GIV’s interacting partners reveal other components of polarized exocytosis in mammals. Findings not only expose how GIV “upgrades” the exocytic process in mammals, but also how the ability to regulate exocytosis shapes GIV’s ability to fuel metastasis.GRAPHIC ABSTRACTGraphic Abstract: Schematic comparing the components of polarized exocytosis, i.e., the major polarity scaffold in yeast (Bem1p; left) and humans (Girdin; right) and the various cellular components and signaling mechanisms that are known to converge on them.The eTOC blurbPolarized exocytosis is a precision-controlled process that is enhanced in disease states, e.g., cancer invasion; what imparts polarity was unknown. Authors reveal how the process underwent an evolutionary upgrade from yeast to humans by pinpointing GIV/Girdin as the polarity scaffold which orchestrates the exocytosis of matrix metalloproteases during cell invasion.HIGHLIGHTSGIV (human) and Bem1p (yeast) bind Exo70; are required for exocytosisGIV binds and aids PM localization Exo70 via a conserved short linear motifBinding facilitates MT1-MMP delivery to podosomes, ECM degradation, invasionRegulatory control over polarized exocytosis is upgraded during evolution
Ribosome recycling factor ABCE1 depletion inhibits nonsense-mediated mRNA decay by promoting stop codon readthrough
Authors: Annibaldis Giuditta , Dreos René , Domanski Michal , Carl Sarah , Mühlemann Oliver 
Published: December 2019

SUMMARYNonsense-mediated mRNA decay (NMD) is an essential post-transcriptional surveillance pathway in vertebrates that appears to be mechanistically linked with translation termination. To gain more insight into this connection, we interfered with translation termination by depleting human cells of the ribosome recycling factor ABCE1, which resulted in an upregulation of many but not all endogenous NMD-sensitive mRNAs. Notably, the suppression of NMD on these mRNAs occurs at a step prior to their SMG6-mediated endonucleolytic cleavage. Ribosome profiling revealed that ABCE1 depletion results in ribosome stalling at stop codons and increased ribosome occupancy in 3’ UTRs, indicative of enhanced stop codon readthrough or re-initiation. Using reporter genes, we further demonstrate that the absence of ABCE1 indeed increases the rate of readthrough, which would explain the observed NMD inhibition, since enhanced readthrough has been previously shown to render NMD-sensitive transcripts resistant to NMD by displacing NMD triggering factors like UPF1 and exon junction complexes (EJCs) from the 3’ UTR. Collectively, our results show that improper ribosome disassembly interferes with proper NMD activation.HighlightsABCE1 knockdown suppresses NMD of many NMD-sensitive mRNAsThe observed NMD inhibition occurs at a stage prior to SMG6-mediated cleavage of the mRNAABCE1 depletion enhances ribosome occupancy at stop codons and in the 3’ UTRABCE1 depletion enhances readthrough of the stop codonEnhanced readthrough inhibits NMD, presumably by clearing the 3’ UTR of NMD factors
The regulatory landscape of early maize inflorescence development
Authors: Parvathaneni Rajiv K. , Bertolini Edoardo , Shamimuzzaman Md , Vera Daniel , Lung Pei-Yau , Rice Brian R. , Zhang Jinfeng , Brown Patrick J. , Lipka Alexander E. , Bass Hank W. , Eveland Andrea L. 
Published: December 2019

AbstractBackgroundThe functional genome of agronomically important plant species remains largely unexplored, yet presents a virtually untapped resource for targeted crop improvement. Functional elements of regulatory DNA revealed through profiles of chromatin accessibility can be harnessed for fine-tuning gene expression to optimal phenotypes in specific environments.ResultHere, we investigate the non-coding regulatory space in the maize (Zea mays) genome during early reproductive development of pollen- and grain-bearing inflorescences. Using an assay for differential sensitivity of chromatin to micrococcal nuclease (MNase) digestion, we profile accessible chromatin and nucleosome occupancy in these largely undifferentiated tissues and classify at least 1.6 percent of the genome as accessible, with the majority of MNase hypersensitive sites marking proximal promoters, but also 3’ ends of maize genes. This approach maps regulatory elements to footprint-level resolution. Integration of complementary transcriptome profiles and transcription factor occupancy data are used to annotate regulatory factors, such as combinatorial transcription factor binding motifs and long non-coding RNAs, that potentially contribute to organogenesis, including tissue-specific regulation between male and female inflorescence structures. Finally, genome-wide association studies for inflorescence architecture traits based solely on functional regions delineated by MNase hypersensitivity reveals new SNP-trait associations in known regulators of inflorescence development as well as new candidates.ConclusionsThese analyses provide a comprehensive look into the cis-regulatory landscape during inflorescence differentiation in a major cereal crop, which ultimately shapes architecture and influences yield potential.
Single-crystal diffraction at the high-pressure Indo-Italian beamline Xpress at Elettra, Trieste
Authors: Lotti Paolo , Milani Sula , Merlini Marco , Joseph Boby , Alabarse Frederico , Lausi Andrea 
Published: December 2019

In this study the firstin situhigh-pressure single-crystal X-ray diffraction experiments at Xpress, the Indo-Italian beamline of the Elettra synchrotron, Trieste (Italy), are reported. A description of the beamline experimental setup and of the procedures for single-crystal centring, data collection and processing, using diamond anvil cells, are provided. High-pressure experiments on a synthetic crystal of clinoenstatite (MgSiO3), CaCO3polymorphs and a natural sample of leucophoenicite [Mn7Si3O12(OH)2] validated the suitability of the beamline experimental setup to: (i) locate and characterize pressure-induced phase transitions; (ii) solveab initiothe crystal structure of high-pressure polymorphs; (iii) perform fine structural analyses at the atomic scale as a function of pressure; (iv) disclose complex symmetry and structural features undetected using conventional X-ray sources.
Prediction of financial distress in the Spanish banking system
Authors: Paule-Vianez Jessica , Gutiérrez-Fernández Milagros , Coca-Pérez José Luis 
Published: December 2019

Purpose
The purpose of this study is to construct the first short-term financial distress prediction model for the Spanish banking sector.

Design/methodology/approach
The concept of financial distress covers a range of different types of financial problems, in addition to bankruptcy, which is not common in the sector. The methodology used to predict financial problems was artificial neural networks using traditional financial variables according to the capital, assets, management, earnings, liquidity and sensibility system, as well as a series of macroeconomic variables, the impact of which has been proven in a number of studies.

Findings
The results obtained show that artificial neural networks are a highly suitable method for studying financial distress in Spanish credit institutions and for predicting all cases in which an entity has short-term financial problems.

Originality/value
This is the first work that tries to build a model of artificial neural networks to predict the financial distress in the Spanish banking system, grouping under the concept of financial distress, apart from bankruptcy, other financial problems that affect the viability of these entities.
Management, productivity and firm heterogeneity in international trade
Authors: Serrano Javier , Myro Rafael 
Published: December 2019

Purpose
This paper aims to analyse the relevance of management and productivity in the behaviour of firms in international trade.

Design/methodology/approach
Using a survey of Spanish manufacturing firms, the authors use a management quality index to serve as a proxy for the good management practice of the firm.

Findings
The results demonstrate that exporter and multinationals firms are more productive and better managed than domestic firms. Furthermore, in the periods in which switcher firms decide to export or to invest abroad, they are better managed but are not more productive than in the rest of the periods. Finally, results indicate that regardless of its positive relationship with productivity, management also has a direct impact on the firm’s probability of exporting and involving in foreign direct investment.

Originality/value
This paper aims to reconcile the recent international trade literature, which focusses on the role of productivity heterogeneity in international trade, with the international business literature, concentrated on depicting the key management practices that impact internationalization.
The agency cost of ownership and governance adaptations in farm producer organizations
Authors: Grashuis Jasper 
Published: December 2019

Purpose
Many farm producer organizations pursue growth and complexity in response to price volatility, industry consolidation and other external developments. Consequently, as ownership is dispersed and control is delegated, members may face increasing agency cost. In spite of the potential to impact performance and even survival, empirical attention to agency problems in farm producer organizations is limited. The purpose of this paper is to address the gap in the literature with an empirical study.

Design/methodology/approach
With survey responses from 365 farm producer organizations in the USA, the author uses a two-limit tobit model to estimate the relationships of six ownership and governance characteristics (i.e. board size, management size, director independence, manager independence, CEO independence and non-member ownership) to agency cost, which is proxied by the operating expense ratio.

Findings
While controlling for heterogeneity in scale and technology, the author finds positive relationships of board size, management size and CEO independence to agency cost. The novel result illustrates there is a significant cost to the adoption of non-traditional ownership and governance characteristics by farm producer organizations.

Practical implications
The presence of agency cost serves as motivation to farm producer organizations to implement new or adapt old agency mechanisms. One recommendation is to reconsider the payment structure of non-member CEOs. There may not be enough incentive to inspire an upstream bias, which is perhaps possible by linking CEO performance to price, patronage and member-oriented performance measurements.

Originality/value
Agency cost is rarely studied in relation to farm producer organizations. Recent contributions in the empirical literature lacked an explicit connection of ownership and governance characteristics to agency cost.